About Course
Chapter 63. Treatment of Child and Adolescent Disorders
TREATMENT OF CHILD AND ADOLESCENT DISORDERS: INTRODUCTION
This chapter focuses on the psychopharmacology of psychiatric disorders in children and adolescents. However,
nonpharmacological treatment interventions are also an important component of a child’s psychiatric care. Individual
psychotherapy, group therapy, and family therapy may improve clinical outcome. Working closely with school personnel is
another ingredient in the treatment of a child with a psychiatric disorder. Case management for the child and support for the
family are other facets of treatment for children.
It is important for clinicians to be aware of the evidence base for the use of psychotropic medications for children and
adolescents. In this chapter, data from the literature, with a focus on controlled studies, are presented. On the basis of these
findings, clinical recommendations regarding pharmacotherapy for childhood psychiatric disorders are offered. The appendix
and tables contain specific information about dosages, monitoring, and adverse effects of psychotropics in children.
[Portions of the Attention-Deficit/Hyperactivity Disorder section of this chapter were adapted from Wagner KD: “Management
of Treatment Refractory Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.” Psychopharmacology Bulletin
36:130–142, 2002. Used with permission.]
PSYCHOTROPIC MEDICATION FOR CHILDREN AND ADOLESCENTS
Attention has been focused on the need for controlled studies to assess the safety and efficacy of psychotropic medication for
children and adolescents. Although there has been a substantial increase in the use of psychotropic medications for children
(Safer et al. 1996) and for preschoolers (Zito et al. 2000), there is a significant gap between empirical treatment research
and clinical practice with these agents (Jensen et al. 1999). The pressing need to expand the empirical basis for the
treatment of children has resulted in a substantial increase in National Institute of Mental Health (NIMH)–funded research
for clinical trials in children and adolescents with psychiatric disorders (Vitiello 2001). The U.S. Food and Drug Administration
Modernization Act (FDAMA) of 1997, which provides a 6-month extension of market exclusivity for selected medications for
children, has resulted in a significant increase in the number of industry-sponsored studies of psychotropic medications in
youths. Following this act, the U.S. Food and Drug Administration (FDA) issued “Regulations Requiring Manufacturers to
Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients” (U.S. Food and Drug
Administration 1998), which became effective in April 1999. This rule allows the FDA to require pediatric studies of certain
new and marketed drugs, especially those that are likely to be commonly used for children. The information obtained from
these studies will allow product labeling to include directions for the safe and effective use of these medications in children.
To date, however, there are relatively few FDA-approved psychotropic medications for children and adolescents.
Evaluation
Prior to the initiation of psychotropic medication for children and adolescents, it is essential to conduct a comprehensive
evaluation to ensure the accuracy of the diagnosis. A thorough history and careful attention to the clinical presentation are
central components of the evaluation. The clinician should interview the child and parents separately so that both may have
the opportunity to freely express their concerns. Extended family members, school personnel, and school records are other
potential sources of information.
Clinicians must be skilled at differential diagnosis of childhood disorders, given that there is a significant overlap of
symptoms among these disorders (e.g., bipolar disorder and attention-deficit/hyperactivity disorder [ADHD]). Knowledge of
commonly occurring comorbid disorders is also necessary. Medical conditions, such as seizure disorders and hypothyroidism,
should be considered within the differential diagnosis and adequately assessed.
Disorder-specific rating scales at baseline and during the course of treatment may be useful in assisting with the
measurement of clinical outcome.
Clinical Issues Affecting Response to Pharmacotherapy
Whenever a child fails to respond to initial pharmacotherapy, several clinical issues should be addressed before initiating
alternative or adjunctive medication, as discussed below.
Diagnostic Accuracy
The diagnosis should be reassessed. Often there is symptomatic overlap among disorders that may lead to misdiagnosis. For
example, symptoms of excessive energy and distractibility are common features of both ADHD and bipolar disorder. Similarly,
irritability and sleep disturbance often occur in children with major depression, bipolar disorder, and posttraumatic stress
disorder (PTSD).
Comorbid Disorders
Unrecognized comorbid disorders may adversely affect treatment outcome. As an illustration, children with comorbid
internalizing disorders have been reported to have lower response rates to methylphenidate than children without
comorbidity (Tannock et al. 1995).Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
2 of 58
10/05/2009 16:43
Psychosocial Factors
Child abuse, domestic violence, family conflict, parental psychopathology, and bullying by peers may lead to symptoms that
mimic or exacerbate a preexisting psychiatric disorder. As examples, ostracism by peers may lead to depression in a child, or
a parent with depression who has a negative cognitive style may heighten the pessimistic views of a child with depression.
Medication Compliance
Some children and adolescents are reluctant to take medication because of such reasons as denial of illness, perceived
stigma, and side effects. To increase medication compliance, it is essential that the child or adolescent, as well as the parent,
understand the youth’s disorder, course of illness, and goals of treatment. It is important for parents to participate in
monitoring their child’s medication compliance.
Nonpharmacological Treatment
Psychotherapy may be a component of treatment, either alone or in conjunction with medication. Specific psychotherapies
have been found to be effective in the treatment of some childhood disorders. As examples, cognitive-behavioral therapy
(CBT) (Brent et al. 1997) and interpersonal therapy (Mufson and Sills 2006) have demonstrated efficacy in the treatment of
adolescents with depression. Similarly, CBT is commonly used for the treatment of childhood anxiety disorders (Roblek and
Piacentini 2005). Behavior therapy has led to improvement in symptoms of ADHD for children (Pelham et al. 1998), although
stimulants have demonstrated superiority to behavioral treatment (MTA [Multimodal Treatment of ADHD] Cooperative Group
1999). Adjunctive psychoeducation to medication treatment has shown benefit in the treatment of children with bipolar
disorder (Fristad et al. 2003). Social skills training can be a useful component of treatment in autism spectrum disorders
(Krasny et al. 2003).
Informed Consent
Informed consent is necessary prior to prescribing psychotropic medication to any patient, but it is particularly important in
pediatric psychopharmacology because there are few FDA-approved medications and few controlled studies to address safety
and efficacy in children. There are five recommended components of informed consent for prescribing psychotropic
medications to children and adolescents (Popper 1987). The child’s parent(s) and the child/adolescent should be provided
with the following information:
- The purpose (benefits) of the treatment
- A description of the treatment process
An explanation of the risks of the treatment, including risks that would ordinarily be described by the psychiatrist and risks that would
be relevant to making the decision
- A statement of the alternative treatments, including nontreatment
A statement that there may be unknown risks of these medications (This is particularly essential for children, because there is a
paucity of information on the potential long-term effects of psychotropic medications.)
Evidence Base
It is important for clinicians to be aware of the evidence base for medication treatment of each childhood psychiatric
disorder. Clinical treatment guidelines generally rely on the strength of the available data in determining first-line agents
(Hughes et al. 2007; Kowatch et al. 2005). In most cases, clinicians should select a medication within the group of first-line
agents when initiating medication treatment with a child. Additional factors that will dictate medication choice are prior
medication history, medical history, side-effect profile of the drug, and adolescent and parent preferences.
MAJOR DEPRESSIVE DISORDER
The prevalence of major depression in children and adolescents is estimated to range from 1.8% to 4.6% (Kashani and
Sherman 1988; Kroes et al. 2001). DSM-IV-TR (American Psychiatric Association 2000) criteria are used to establish a
diagnosis of major depression in children and adolescents. The mean length of an episode of major depression in youth
ranges from 8 to 13 months, and relapse rates range from 30% to 70% (Birmaher et al. 2002). There is increasing evidence
for the continuity of depression from youth into adulthood (Dunn and Goodyer 2006).
Recently, a number of double-blind, placebo-controlled multicenter medication studies for treating major depression in
children and adolescents have been reported. In the following subsections, medication groups are discussed in order of
largest to smallest evidence base.
Selective Serotonin Reuptake Inhibitors
Fluoxetine
Fluoxetine is the only selective serotonin reuptake inhibitor (SSRI) medication to have FDA approval for the treatment of
major depression in children and adolescents. There have been three positive medication trials.
In the first study of fluoxetine, 96 child and adolescent outpatients (ages 8–17 years) with major depression were randomly
assigned to fluoxetine (20 mg/day) or placebo for an 8-week trial (Emslie et al. 1997). The fluoxetine group, with 27 youths
(56%) much or very much improved, showed statistically significant greater improvement in Clinical Global Impressions
(CGI) scores than did the placebo group, with 16 youths (33%) much or very much improved. Remission, which was defined
as a Children’s Depression Rating Scale—Revised (CDRS-R; Poznanski et al. 1985) score 28, occurred in 31% of the
fluoxetine group and 23% of the placebo group. Medication side effects leading to discontinuation in the study were manic
symptoms in 3 patients and severe rash in 1 patient.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
3 of 58
10/05/2009 16:43
In a double-blind, placebo-controlled multicenter study of fluoxetine, 219 child and adolescent outpatients (ages 8–17 years)
with major depression were randomly assigned to fluoxetine (20 mg/day) or placebo for an 8-week trial (Emslie et al. 2002).
The fluoxetine group showed statistically significant greater improvement in depression, as assessed by CDRS-R scores, than
did the placebo group. Fifty-two percent of patients treated with fluoxetine were rated as much or very much improved,
compared with 37% of patients treated with placebo. Remission rates were 39% in the fluoxetine group and 20% in the
placebo group. Headache was the only side effect that was reported more frequently in the group treated with fluoxetine than
in the group treated with placebo.
Fluoxetine alone, fluoxetine with CBT, CBT alone, and placebo were compared in a multicenter trial of 439 adolescent
outpatients with a diagnosis of major depression (Treatment for Adolescents with Depression Study [TADS] Team 2004).
Patients were randomly assigned to 12 weeks of fluoxetine (10–40 mg/day), fluoxetine (10–40 mg/day) with CBT, CBT
alone, or placebo. Compared with placebo, the combination of fluoxetine with CBT was significantly superior on CDRS-R
scores. Combination treatment with fluoxetine and CBT was significantly superior to fluoxetine alone and CBT alone.
Fluoxetine monotherapy was superior to CBT. Based on CGI scores of much or very much improved, the response rates were
71% for fluoxetine–CBT combination therapy, 61% for fluoxetine, 43% for CBT, and 35% for placebo. At the end of 12
weeks, only 23% of youths achieved remission (CDRS-R 28). Remission rates were significantly higher in the combination
group (37%) than in the fluoxetine (23%), CBT (16%), and placebo (17%) groups (Kennard et al. 2006).
Citalopram
There have been two controlled trials of citalopram, one with positive and one with negative results in the treatment of
depression in youth.
The efficacy of citalopram was demonstrated in a double-blind, placebo-controlled multicenter trial of 174 outpatient children
and adolescents (ages 7–17 years) with major depression (Wagner et al. 2004b). Patients were randomly assigned to
citalopram (dosage range = 20–40 mg/day; mean daily dose = 23 mg for children, 24 mg for adolescents) or placebo for an
8-week trial. The group treated with citalopram showed statistically significant greater improvement in depression (CDRS-R
scores) than did the placebo group. The response rates (CDRS-R score <28) were 36% for patients receiving citalopram and
24% for patients receiving placebo. The most frequent adverse events were headache, nausea, rhinitis, abdominal pain, and
influenza-like symptoms. The discontinuation rate for adverse events was 5% in both the group being treated with
citalopram and the group receiving placebo.
A European double-blind, placebo-controlled multicenter study (Knorring et al. 2006) of citalopram in 224 adolescents with
major depression failed to show superiority of citalopram to placebo on the primary efficacy measures of Schedule for
Affective Disorders and Schizophrenia for School-Age Children, Present Episode version (Kiddie-SADS-P; Chambers et al.
1985) and the Montgomery-Åsberg Depression Rating Scale (MADRS; Montgomery and Asberg 1979). Interpretation of these
findings is confounded by the allowed use of psychotherapy and other psychotropic medications during the course of the trial.
The most commonly reported adverse events were headache, nausea, and vomiting.
Paroxetine
There have been three double-blind, placebo-controlled trials of paroxetine for treatment of depression in children and
adolescents, all of which have negative findings on the primary outcome measure.
In a study of 275 adolescent outpatients (ages 12–18 years) with major depression, patients were randomly assigned to
paroxetine (dosage range = 20–40 mg/day; mean daily dose = 28 mg), imipramine (dosage range = 200–300 mg; mean daily
dose = 205 mg/day), or placebo for an 8-week trial (Keller et al. 2001). Although there was no statistically significant
difference among the treatment groups on the primary efficacy measure of reduction in the Hamilton Rating Scale for
Depression (Ham-D; Hamilton 1960) total score, there was statistically significant greater global improvement for the group
receiving paroxetine. Sixty-six percent of the group receiving paroxetine was much or very much improved, compared with
52% of the group receiving imipramine and 48% of the group receiving placebo. The most common side effects reported for
paroxetine were headache, nausea, dizziness, dry mouth, and somnolence, which (with the exception of somnolence)
occurred at rates similar to those in the placebo group. The most common side effects reported for imipramine were
dizziness, dry mouth, headache, nausea, and tachycardia.
Two hundred six children and adolescents (ages 7–17 years) with major depression were included in an 8-week double-blind,
placebo-controlled, randomized multicenter study of paroxetine treatment (Emslie et al. 2006). Patients were randomly
assigned to paroxetine (10–50 mg/day) or placebo. There was no statistically significant difference between
paroxetine-treated patients and placebo-treated patients on change from baseline in CDRS-R total score at endpoint. Adverse
events reported for paroxetine with an incidence of >5% and at least twice that of placebo were dizziness, cough, dyspepsia,
and vomiting.
A 12-week international placebo-controlled multicenter trial of paroxetine in 286 adolescents with major depression failed to
show superiority of paroxetine compared with placebo on change from baseline in MADRS or Schedule for Affective Disorders
and Schizophrenia for School-Aged Children—Lifetime version (Kiddie-SADS-L; Kaufman et al. 1997) total scores (Berard et
- 2006).
Sertraline
The efficacy of sertraline was assessed in two identical double-blind, placebo-controlled multicenter studies of 376 outpatient
children and adolescents with major depression (Wagner et al. 2003a). Patients were randomly assigned to sertraline
(dosage range = 50–200 mg per day; mean daily dose = 131 mg) or placebo for a 10-week trial. The group receiving
sertraline showed a statistically significant greater improvement in depression (CDRS-R scores) than did the placebo group.
Response rates (decrease >40% in baseline CDRS-R scores) were 69% in the group treated with sertraline and 59% in thePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
4 of 58
10/05/2009 16:43
group treated with placebo. The most common side effects in the group treated with sertraline were headache, nausea,
insomnia, upper respiratory tract infection, abdominal pain, and diarrhea. In a 24-week open follow-up of 226 of these
patients, continued improvement in depressive symptoms was shown with sertraline treatment. At endpoint, 86% of youths
met response criteria (Rynn et al. 2006).
Sertraline, CBT, and combined CBT plus medication were compared for the treatment of 73 adolescents with depressive
disorders (Melvin et al. 2006). All treatments showed statistically significant improvement on all outcome measures; there
were no significant advantages of combined treatment.
Escitalopram
There has been one controlled study of escitalopram that failed to demonstrate significant improvement on CDRS-R scores at
endpoint between escitalopram and placebo (Wagner et al. 2006a). In this study, 264 children and adolescents were
randomly assigned to escitalopram (10–20 mg/day) or placebo for 8 weeks. In a post hoc analysis of adolescent completers,
escitalopram showed significantly improved CDRS-R scores compared with placebo. Headache and abdominal pain were the
only adverse events reported in more than 10% of the patients in the escitalopram group.
Other Antidepressants
Venlafaxine
Two double-blind, placebo-controlled multicenter studies have evaluated the efficacy of venlafaxine extended-release (XR)
for the treatment of major depression in 165 and 169 child and adolescent outpatients, ages 7–17 years, respectively (Emslie
et al. 2007a, 2007b). Patients were randomly assigned to venlafaxine XR (37.5–225 mg/day) for 8-week trials. Both studies
were negative on the primary outcome measure of change from baseline to endpoint in the CDRS-R scores. A post hoc
analysis of the pooled data showed greater improvement on CDRS-R scores with venlafaxine XR for adolescents than for
children. The most common adverse events were anorexia and abdominal pain (Emslie et al. 2007a). In a 6-month open-label
follow-up study, it was found that most improvement with venlafaxine XR occurred in the first 6 weeks of treatment. At the
end of week 6, mean CDRS-R scores decreased from 60 to 36.3, and to 33.8 at 6 months (Emslie et al. 2007b).
Nefazodone
The efficacy of nefazodone was assessed in a double-blind, placebo-controlled multicenter trial of 195 adolescents (ages
12–17 years) with major depression (Rynn et al. 2002). Adolescents were randomly assigned to nefazodone (dosage range =
300–600 mg/day; mean daily dose = 444 mg) for an 8-week trial. The nefazodone group showed greater improvement than
the placebo group; however, this difference missed statistical significance ( P <0.055), based on the comparison of mean
CDRS-R score from baseline to endpoint between the group being treated with nefazodone and the group receiving placebo.
The most common side effects with nefazodone were headache, abdominal pain, nausea, vomiting, somnolence, and
dizziness, all of which were reported with greater frequency in the nefazodone group than in the group receiving placebo.
In a second double-blind, placebo-controlled multicenter trial of nefazodone in both children and adolescents (ages 7–17
years) with major depression, nefazodone did not differentiate from placebo (U.S. Food and Drug Administration 2004b).
Bupropion
There are no controlled trials of bupropion for the treatment of pediatric depression.
In an 8-week study of bupropion sustained release (SR) (dosage range = 100–400 mg/day; mean daily dose = 362 mg) for
treating 11 adolescents (ages 12–17 years) with major depression, 8 adolescents (79%) showed a 50% reduction in
depression score from baseline (Glod et al. 2000).
Bupropion SR was assessed in an 8-week open study for the treatment of comorbid depression and ADHD in 24 adolescents
(Daviss et al. 2001). Bupropion SR dosages were flexibly titrated up to 4 mg/kg taken twice daily (mean dose = 2.2 mg/kg in
A.M. and 1–7 mg/kg in P.M.). Global improvement was reported for 14 subjects (58%) for both depression and ADHD, 7
subjects (29%) for depression only, and 1 subject (4%) for ADHD only. Common side effects were headache, nausea, rash,
and irritability.
Mirtazapine
There have been two double-blind, placebo-controlled multicenter trials of mirtazapine for the treatment of child and
adolescent outpatients (ages 7–17 years) with major depression. These studies, which included 126 and 133 patients,
respectively, who were randomly assigned to mirtazapine (15–45 mg/day) or placebo for an 8-week trial, failed to
distinguish mirtazapine from placebo on the primary efficacy measure of change from baseline to endpoint in CDRS-R scores
(U.S. Food and Drug Administration 2004b).
Duloxetine
There are no published reports of the use of duloxetine for the treatment of major depression in children and adolescents.
There are two case reports of duloxetine treatment for pediatric chronic pain and comorbid major depressive disorder
(Meighen 2007) and one case report of duloxetine treatment for pediatric depression with pain and dissociative symptoms
(Desarkar et al. 2006) that described improvement in depressive symptoms.
Tricyclic Antidepressants
There have been eight double-blind, placebo-controlled studies of tricyclic antidepressants (TCAs) in children and
adolescents. No significant differences between TCA and placebo were found in any of these studies (Birmaher et al. 1998; B.
Geller et al. 1990, 1992; Keller et al. 2001; Kutcher et al. 1994; Kye et al. 1996; Puig-Antich et al. 1987; Tancer et al. 1992).Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
5 of 58
10/05/2009 16:43
Response rates for TCA-treated patients ranged from 8% to 92% (B. Geller et al. 1990; Kye et al. 1996) and from 17% to
92% for patients treated with placebo (B. Geller et al. 1992; Kye et al. 1996). Several open trials with TCAs have reported a
response rate of 60%–80% (Ambrosini et al. 1994; B. Geller et al. 1986; Preskorn et al. 1982; Puig-Antich et al. 1979).
Monoamine Oxidase Inhibitors
One chart review found a response rate of 74% in 23 adolescents treated with monoamine oxidase inhibitors (MAOIs) who
had been unresponsive to TCAs. Dietary noncompliance was noted for 6 of these adolescents; 1 developed headache and
hypertension, and 1 developed myoclonic jerks (Ryan et al. 1988).
Suicidality and FDA Warning
In a combined analysis of 24 short-term placebo-controlled trials of antidepressant medications in child and adolescent major
depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders, the risk of suicidality (suicidal
thinking and behavior) was 4%, twice the placebo rate (2%). There were no suicides in any of the clinical trials. The FDA
directed manufacturers to add a black box warning to the health professional label of antidepressant medications to describe
the increased risk of suicidal thoughts and behavior in children and adolescents being treated with antidepressant
medications and to emphasize the need for close monitoring of patients on the medications (U.S. Food and Drug
Administration 2004a). Parents and patients should be advised of the black box warning for antidepressant medication.
In a subsequent meta-analysis of 27 trials of pediatric major depression, the rates of suicidal ideation and attempts were 3%
in the youths treated with antidepressants and 2% in the youth who received placebo (Bridge et al. 2007). These
investigators reported that the number needed to treat was 10, whereas the number needed to harm was 112, and therefore
the benefits of antidepressants outweigh the potential risk from suicidal ideation or attempt.
A number of recent studies, in both the United States and Europe, have failed to demonstrate an association between
antidepressant use and youth suicide (Gibbons et al. 2006; Markowitz and Cuellar 2007; Simon et al. 2006; Søndergård et al.
2006). Noteworthy, there was an increase in the suicide rate in youth following the black box warning on antidepressants
(Hamilton et al. 2007). The FDA advisory has been associated with significant decreases in the rates of diagnosis and
treatment in pediatric depression (Libby et al. 2007).
Clinical Recommendations for Major Depressive Disorder
An evidence-based consensus medication algorithm for the treatment of childhood major depression has been recently
updated (Texas Children’s Medication Algorithm Project [TMAP]; Hughes et al. 2007). Based on research evidence and panel
discussion, four stages of medication treatment were identified:
Stage 1: SSRI (fluoxetine, citalopram, sertraline)
Stage 2: Alternate SSRI (fluoxetine, sertraline, citalopram, escitalopram, paroxetine [adolescents only if paroxetine])
Stage 2A (if partial response to SSRI): SSRI + lithium, bupropion, or mirtazapine
Stage 3: Different class of antidepressant medication (venlafaxine, bupropion, mirtazapine, duloxetine)
Stage 4: Reassess, treatment guidance
If a child fails to respond to treatment in one stage, the clinician should move to the next stage of treatment. It was
recommended by the consensus panel that dosage titration should occur in youths who do not have significant improvement
in symptoms by 4–6 weeks of treatment. Additional dose adjustments should be made at 8–10 weeks of treatment before
moving to another stage of treatment.
It was further recommended that antidepressants be continued for 6–12 months after symptom remission. At the time of
discontinuation of an antidepressant, the dose should be tapered slowly (i.e., no more than 25% per week). The typical
tapering and discontinuation period is 2–3 months.
BIPOLAR DISORDER
The prevalence of bipolar disorder in a community sample of adolescents was found to be 1% (Lewinsohn et al. 1995).
Although DSM-IV-TR criteria are used to diagnose bipolar disorder in youths, the clinical features in children may differ from
those in adolescents and adults. Children with bipolar disorder frequently exhibit mixed mania and rapid cycling (B. Geller et
- 2000). One-year recovery rates of 87% and relapse rates of 64% have been reported in children with bipolar disorder (B.
Geller et al. 2004). Despite the severity of bipolar disorder and its significant adverse effects on a child’s social, emotional,
and academic functioning, it has yet to be determined whether pharmacotherapy alters the course of the illness (Birmaher et
- 2006).
Lithium
Lithium is the only medication with FDA approval for the treatment of mania in adolescents.
There is only one small double-blind, placebo-controlled study of lithium treatment for adolescent bipolar disorder and
substance dependence (B. Geller et al. 1998). Twenty-five adolescent outpatients were randomly assigned to either lithium
(mean serum level = 0.97 mEq/L) or placebo for a 6-week trial. There was significantly greater improvement in global
functioning with lithium than with placebo. It was found that onset of bipolar disorder preceded substance dependence by
approximately 6 years. Side effects in the group treated with lithium were polyuria, thirst, nausea, vomiting, and dizziness.
There have been six controlled studies of lithium in the treatment of bipolar disorder in youths. In four of these double-blind
crossover studies, significant improvement was found with lithium, compared with placebo (DeLong and Nieman 1983; Gram
and Rafaelsen 1972; Lena 1979; McKnew et al. 1981). However, small sample size, diagnostic issues, and short treatment
duration limit these findings.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
6 of 58
10/05/2009 16:43
In a 4-week open trial, 100 adolescents with mania received lithium (mean serum level 0.93 mEq/L) (Kafantaris et al. 2003).
Forty-six of these youths also received concomitant antipsychotic medication. The lithium response rate was 55%, based on a
50% reduction in Young Mania Rating Scale (YMRS; Young et al. 1978) scores. The most common side effects were
polydipsia, polyuria, weight gain, gastrointestinal symptoms, headache, and tremor.
Kafantaris et al. (2004) conducted a controlled discontinuation study with 40 adolescents who had responded to lithium in
the open trial. Responders were randomly assigned to continue or discontinue lithium during a 2-week double-blind,
placebo-controlled phase. There was no statistically significant difference on symptom exacerbation rate between the lithium
(52.6%) and placebo (61.9%) groups. The investigators concluded that 4 weeks of lithium monotherapy may be insufficient
for symptom remission in adolescents.
The efficacy of lithium, divalproex, and carbamazepine was compared in a 6-week randomized, open-label trial of 42 children
and adolescents (ages 8–18 years) with bipolar disorder (Kowatch et al. 2000b). There were no significant differences in
response rates (defined as 50% reduction in YMRS from baseline to endpoint) among lithium, divalproex, and
carbamazepine. The lithium response rate was 38%, and the effect size was 1.06.
Lithium treatment for adolescents with bipolar depression was investigated in a 6-week open study of 27 adolescents. The
response rate ( 50% reduction in baseline CDRS-R score) was 48% (Patel et al. 2006).
Anticonvulsants
Divalproex
A 4-week double-blind, placebo-controlled multicenter trial of 150 youths (ages 10–17 years) with bipolar I disorder (mixed
or manic) failed to show a significant difference in scores on the YMRS from baseline to endpoint between divalproex
extended release (ER) and placebo (Abbott Laboratories, accessed 2007). The mean modal dose of divalproex ER was 1,286
- There were no statistically significant differences in adverse-event incidents between the divalproex ER and placebo
groups. Gastrointestinal symptoms were more commonly reported in divalproex ER than in placebo groups.
In a multisite open study of divalproex treatment for youths, 40 children and adolescents (ages 7–19 years) with bipolar
disorder received divalproex for a period of 2–8 weeks (Wagner et al. 2002). Sixty-one percent of the subjects showed >50%
improvement on the YMRS from baseline to endpoint. Twenty-three patients (58%) discontinued the study; of those, 16
patients had a comorbid diagnosis, including ADHD, conduct disorder, or oppositional defiant disorder (ODD). Headache,
nausea, vomiting, diarrhea, and somnolence were the most common side effects.
In the previously mentioned active-comparator study of lithium, divalproex, and carbamazepine, the response rate ( 50%
reduction in baseline YMRS scores) was 53% for divalproex. The effect size for divalproex was 1.63. The most common side
effects of divalproex were nausea and sedation (Kowatch et al. 2000b).
The efficacy of divalproex was compared with that of quetiapine in 50 hospitalized adolescents with bipolar I disorder, manic
or mixed (DelBello et al. 2006). Twenty-five adolescents were randomly assigned to divalproex (serum level 80–120 g/mL)
or quetiapine (400–600 mg/day). There were no significant differences between divalproex and quetiapine across the 28
days of the study. The CGI-BP-I overall response rate (CGI-BP-I overall score 2 at endpoint) was 40%, and the CGI-BP-I
mania response rate was 56% for divalproex, which were significantly lower than the rates for quetiapine. The rate of
remission (YMRS 12) for divalproex was 28%.
Carbamazepine
In a 6-week active-comparator study of lithium, divalproex, and carbamazepine (Kowatch et al. 2000b), carbamazepine had a
response rate (defined as 50% reduction in YMRS from baseline to endpoint) of 38% (vs. 38% for lithium and 53% for
divalproex) and an effect size of 1.00 (vs. 1.6 for lithium and 1.63 for divalproex). The most common side effects of
carbamazepine were sedation, nausea, dizziness, and rash.
Oxcarbazepine
There is one double-blind, placebo-controlled multicenter trial of oxcarbazepine for the treatment of youths with bipolar I
disorder, manic or mixed, that failed to show superiority of oxcarbazepine to placebo. One hundred sixteen youths (ages
7–18 years) were randomly assigned to oxcarbazepine (mean dosage = 1,515 mg/day) or placebo for a 7-week trial (Wagner
et al. 2006b). There was no significant difference in YMRS scores at endpoint between the oxcarbazepine and placebo groups.
The most common side effects in the oxcarbazepine-treated patients were dizziness, nausea, somnolence, diplopia, fatigue,
and rash.
Topiramate
A double-blind, randomized, placebo-controlled multicenter study assessing the efficacy of topiramate treatment in children
and adolescents with acute mania was designed as a 200-patient study but was terminated after randomizing 56 patients
(ages 6–17 years) when adult mania trials failed to show efficacy (DelBello et al. 2005). Patients were titrated to 400
mg/day (mean dosage = 278 mg/day). Over a 4-week period, no significant difference was found between the topiramate
and placebo groups. The most common adverse events in the topiramate group included decreased appetite, nausea,
diarrhea, paresthesias, and somnolence.
Lamotrigine
In a 12-week open-label single-center outpatient study in adolescents diagnosed with bipolar disorder I, depressed or mixed,
23 patients entered, and 13 completed the trial (Swope et al. 2004). The mean dosage of lamotrigine was 241 mg/day. There
was improvement on depression and mania ratings at study endpoint. No subjects discontinued for adverse events related toPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
7 of 58
10/05/2009 16:43
the study drug.
Lamotrigine as monotherapy or adjunctive treatment for 20 adolescents with bipolar depression was assessed in an 8-week
open-label trial (Chang et al. 2006). The mean dosage of lamotrigine was 132 mg/day. Seven adolescents were also taking
other psychotropic medications. The response rate (CGI-I 2) was 84%, and the remission rate (CDRS-R 28 and CGI-S 2)
was 58%. The most common side effects were headache, fatigue, nausea, sweating, and difficulty sleeping. There were no
significant rashes during the trial.
The use of lamotrigine as adjunctive therapy for treatment-refractory bipolar depression in adolescents was assessed in an
open-label study (Kusumakar and Yatham 1997). Twenty-two adolescents whose bipolar depression was refractory to
treatment with a combination of divalproex plus another mood stabilizer and antidepressant were treated with lamotrigine
added to divalproex for 6 weeks. Sixteen of the adolescents (72%) had a positive response by week 6.
Atypical Antipsychotics
Olanzapine
There is one reported double-blind, placebo-controlled multicenter study of olanzapine (2.5–20 mg/day) for the treatment of
adolescent outpatients with bipolar I disorder, mixed or manic (Tohen et al. 2007). Adolescents were randomly assigned to
olanzapine (n = 107) or placebo (n = 54) for 3 weeks. Response rates (defined as 50% decrease in YMRS and a CGI-BP
mania score 3) were significantly greater for the olanzapine group (44.8%) than for the placebo group (18.5%). Remission
rates (defined as YMRS <12 and CGI-BP mania score 3) were significantly greater for the olanzapine (35.2%) than for the
placebo (11.1%) group. Adverse effects in the olanzapine group were hyperprolactinemia, weight gain (mean = 3.7 kg),
somnolence, and sedation.
In an open study, 23 children (ages 5–14 years) with bipolar disorder received olanzapine (2.5 mg/day) for 8 weeks (Frazier
et al. 2001). Using a response definition of 30% or greater improvement on the YMRS, the response rate was 61%. No
significant side effects except weight gain (mean = 5 kg) were reported.
The use of olanzapine in preschoolers is an area of recent interest. An 8-week open-label study of olanzapine and risperidone
in children (ages 4–6 years) with bipolar disorder (manic, mixed, or hypomanic) was conducted by Biederman et al. (2005b).
Fifteen children were treated with olanzapine (mean dosage = 6.3 mg/day). The response rate (CGI-I 2 or YMRS reduction
30%) was 53% for olanzapine. Mean weight increase was 3.2 kg for olanzapine-treated children. The most common side
effects of olanzapine were increased appetite, cold symptoms, headache, and sedation.
Risperidone
There are no data available from controlled trials of risperidone for the treatment of bipolar disorder in youth.
An 8-week open-label study of risperidone (mean dosage = 1.25 mg/day) for 30 youths (ages 6–17 years) with bipolar
disorder (manic, mixed, or hypomanic) was conducted by Biederman et al. (2005c). Twenty-two of 30 youths completed the
study. The response rate (CGI-I in mania score 2 at endpoint) was 70%. Significant side effects included weight increase
(mean 2.1 kg) and a fourfold increase in prolactin levels from baseline.
In the previously mentioned open-label study of preschoolers with bipolar disorder (Biederman et al. 2005b), 16 children
received risperidone (mean dosage = 1.4 mg/day). The response rate (CGI-I 2 or YMRS reduction of 30%) was 69% in the
risperidone group. Weight increase was a mean of 2.2 kg in the risperidone-treated children. The most common side effects
were increased appetite, cold symptoms, headaches, and sedation.
Quetiapine
The efficacy of quetiapine was compared with divalproex in 50 hospitalized adolescents with bipolar I disorder, manic or
mixed (DelBello et al. 2006). Twenty-five adolescents were randomly assigned to quetiapine (400–600 mg/day). There was
no statistically significant difference in YMRS scores across the 28 days of the study between quetiapine and divalproex.
Response rates of 72% (CGI-BP-I overall score 2) and of 84% (CGI-BP-I mania score 2) for quetiapine were significantly
higher than those for divalproex. The rate of remission (YMRS 12) was 60% in the quetiapine group. Improvement occurred
more rapidly in the quetiapine group than in the divalproex group.
Aripiprazole
There are no published controlled studies of aripiprazole treatment for bipolar disorder in children and adolescents.
Three chart reviews reported clinical global improvement in symptoms for youth with bipolar disorder who were treated with
aripiprazole (Barzman et al. 2004; Biederman et al. 2005a; Gibson et al. 2007).
Ziprasidone
There are no data available from controlled trials of ziprasidone for the treatment of bipolar disorder in youth.
In a study of 30 children and adolescents with bipolar disorder given open-label ziprasidone (mean dosage = 56 mg/day) for
a mean treatment duration of 359 days, 70% of patients responded to ziprasidone (CGI-I score of much or very much
improved) (Barnett and Cohen 2004).
The comparative efficacy of atypical antipsychotics was assessed in youths with mania (Biederman 2005). In this study, 21
youths received ziprasidone (mean dosage = 56 mg/day) in an 8-week open-label trial. There were significant reductions in
YMRS scores for all atypical antipsychotics, with no significant difference among them. The CGI 2 response rate was 57% for
ziprasidone. Mean weight gain was 0.6 kg for ziprasidone.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
8 of 58
10/05/2009 16:43
Combination Treatment
Some children may not respond to initial monotherapy treatment or may need combination treatment over the course of the
illness. For example, following acute 6-week treatment with one mood stabilizer, Kowatch et al. (2000a) reported that 20 of
35 youths (58%) required additional psychotropic medication over the next 16 weeks. The response rate to combination
treatment with two mood stabilizers was high (80%) for those youths who did not respond to monotherapy.
The effectiveness of combination lithium and divalproex sodium was assessed in an open trial (Findling et al. 2003a). Ninety
youths (ages 5–17 years) with bipolar I or II disorder were treated for up to 20 weeks with divalproex sodium (mean blood
level = 79.8 g/mL) and lithium (mean blood level = 0.9 mmol/L). The clinical remission rate (defined as contiguous weekly
ratings of YMRS 12.5, CDRS-R 40, Children’s Global Assessment Scale [CGAS] 51, clinical stability, and no mood cycling)
was 42%.
Lithium and adjunctive haloperidol were used to treat five adolescents with psychotic mania (Kafantaris et al. 2001b). In this
trial, haloperidol was discontinued within 1 week of therapeutic lithium levels. All these adolescents had a rapid return to
symptoms, which responded to restarting haloperidol.
In a larger open trial (Kafantaris et al. 2001a), 28 acutely manic adolescents with psychotic features received combination
lithium and antipsychotic medication for 4 weeks. At the end of 4 weeks, only 14 (50%) were clinically stable enough to have
the antipsychotic medication discontinued. On lithium monotherapy, 8 adolescents remained stable over a 4-week period, and
6 adolescents had an exacerbation of symptoms. These investigators concluded that adjunctive antipsychotic medication
needs to be continued for more than 4 weeks for most adolescents with psychotic mania.
The efficacy of combination risperidone and lithium or divalproex sodium was assessed in a 6-month open-label trial
(Pavuluri et al. 2004). Thirty-seven youths (ages 5–18 years) with bipolar I disorder (manic or mixed) received risperidone
(mean dosage = 0.75 mg) plus divalproex sodium (mean serum level = 106 g/mL) or risperidone (mean dosage = 0.70 mg)
plus lithium (mean serum level = 0.9 mEq/L). Response rates ( 50% reduction in baseline YMRS scores) were similar for
both combinations: 80% for divalproex sodium plus risperidone, and 82.4% for lithium plus risperidone. There were no
significant differences between the groups in safety and tolerability.
Risperidone augmentation of lithium nonresponders was assessed in a 1-year open-label study (Pavuluri et al. 2006).
Twenty-one of 38 youths (ages 4–17 years) who failed to respond to lithium monotherapy or relapsed after initial response
were given risperidone (mean dosage = 0.99 mg) for 11 months. Response rates in the lithium plus risperidone group were
85.7%.
In a double-blind, placebo-controlled study of quetiapine, 30 adolescents with bipolar disorder received divalproex (20
mg/kg) and were randomly assigned to adjunctive quetiapine (mean daily dose = 432 mg) or placebo for 6 weeks (DelBello
et al. 2002). Response rates (YMRS reduction from baseline 50%) were significantly higher in the group receiving
divalproex and quetiapine (87%) than in the group receiving divalproex and placebo (53%).
Maintenance Treatment
There is only one reported maintenance study for children and adolescents with bipolar disorder. Sixty youths who had
responded to a combination of lithium and divalproex in a 20-week trial were randomly assigned in a double-blind trial to
either lithium or divalproex for 18 months (Findling et al. 2005). There was no significant difference in the time to relapse
between the groups (median days: divalproex 112, lithium 114).
Clinical Recommendations for Bipolar Disorder
Treatment guidelines were developed by expert consensus and review of the available treatment literature for children and
adolescents (ages 6–17 years) with bipolar I disorder, manic or mixed (Kowatch et al. 2005). Six stages were identified:
Stage 1: Monotherapy with mood stabilizer or atypical antipsychotic (lithium, valproate, carbamazepine, olanzapine, quetiapine,
risperidone)
Stage 2: Switch monotherapy agent (drug class not tried in stage 1)
Stage 3: Switch monotherapy agent (drug class not tried in stage 1 or 2) OR combination treatment (2 agents)
Stage 4: Combination treatment (2 agents) OR combination treatment (3 agents)
Stage 5: Alternative monotherapy (drugs not tried in stages 1, 2, 3)
Stage 6: Electroconvulsive therapy (adolescents) or clozapine
If a child fails to respond to treatment in one stage, the clinician should move to the next stage of treatment. For treatment of
bipolar I disorder, manic or mixed with psychosis, it was recommended that initial treatment be a mood stabilizer plus an
atypical antipsychotic. A minimum of 4–6 weeks at therapeutic blood levels and/or adequate doses for each medication was
recommended. Following sustained remission of at least 12–24 months, medication taper should be considered.
ANXIETY DISORDERS
Obsessive-Compulsive Disorder
OCD has a prevalence rate of 2%–4% in youths (Douglass et al. 1995; Zohar 1999). The DSM-IV-TR criteria for OCD are the
same in children and adults, with the exception that children may not recognize that their obsessions or compulsions are
unreasonable (American Psychiatric Association 2000). The course of OCD in youths is chronic. In a 2- to 7-year follow-up of
54 children and adolescents with OCD, 23 subjects (43%) continued to meet diagnostic criteria for OCD, and only 3 subjects
(6%) achieved complete remission (Leonard et al. 1993).
Serotonin Reuptake InhibitorsPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
9 of 58
10/05/2009 16:43
Four medications have received FDA approval for the treatment of OCD in children and adolescents: clomipramine ( 10 years
old), fluvoxamine ( 7 years old), sertraline ( 6 years old), and fluoxetine ( 7 years old).
Fluvoxamine
The safety and efficacy of fluvoxamine were evaluated in a double-blind, placebo-controlled multicenter study (Riddle et al.
2001). One hundred twenty outpatient children and adolescents (ages 8–17 years) with OCD were randomly assigned to
fluvoxamine (dosage range = 50–200 mg/day; mean daily dose = 165 mg) or placebo for a 10-week trial. Patients who did
not respond after 6 weeks could discontinue the double-blind phase and enter an open-label trial of fluvoxamine. Mean
CY-BOCS scores were significantly different between the group treated with fluvoxamine and the group treated with placebo
at weeks 1, 2, 3, 4, 6, and 10. Response rates (>25% reduction in CY-BOCS scores) were 42% in the group being treated
with placebo. Adverse events occurring at a placebo-adjusted frequency of >10% were insomnia and asthenia.
To assess the safety and effectiveness of fluvoxamine in the long-term treatment of pediatric OCD, 99 patients who
completed the acute double-blind, placebo-controlled fluvoxamine study (Riddle et al. 2001) participated in a 1-year
open-label extension study (Walkup et al. 1998). Fluvoxamine dosages were titrated to 200 mg/day over the first 4 weeks.
Patients experienced a 42% reduction in CY-BOCS scores by the end of long-term treatment. Clinical improvement plateaued
at about 6 months of treatment. The most common side effects were insomnia, asthenia, nausea, hyperkinesias, and
nervousness. There were no clinically significant laboratory or vital sign abnormalities.
Sertraline
In a double-blind, placebo-controlled multicenter study, 187 children and adolescents (ages 6–17 years) with OCD were
randomly assigned to sertraline or placebo (March et al. 1998). Sertraline dosages were titrated to a maximum of 200
mg/day during the first 4 weeks of the trial, and these dosages were maintained for an additional 8 weeks. The mean dosage
of sertraline was 167 mg/day at endpoint. Compared with patients receiving placebo, patients receiving sertraline showed
significantly greater improvement on the CY-BOCS, the NIMH Global Obsessive Compulsive Rating Scale (NIMH GOCS), and
the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) rating scales. Forty-two percent of
patients in the sertraline group and 26% of patients in the placebo group were rated as very much or much improved. Side
effects of insomnia, nausea, agitation, and tremor occurred significantly more often in the group receiving sertraline than in
the group receiving placebo.
To assess the long-term safety and effectiveness of sertraline for pediatric OCD, 137 patients who completed the 12-week
double-blind, placebo-controlled sertraline study (March et al. 1998) were given open-label sertraline (mean dosage = 120
mg/day) in a 52-week extension study. Significant improvement was found on CY-BOCS, NIMH GOCS, and CGI scores. Rates
of response (defined as >25% decrease in CY-BOCS and a CGI-I score of 1 or 2) were 72% for children and 61% for
adolescents (Cook et al. 2001). Full remission (defined as a CY-BOCS score >8) was achieved in 47% of patients, and an
additional 25% achieved partial remission (CY-BOCS score <15 but >8) (Wagner et al. 2003b). The most common side effects
were headache, nausea, diarrhea, somnolence, abdominal pain, hyperkinesias, nervousness, dyspepsia, and vomiting. There
were no clinically significant electrocardiogram (ECG), vital sign, or laboratory abnormalities.
The relative and combined efficacy of sertraline and CBT was assessed in a 12-week trial for 112 children and adolescents
(ages 7–17 years) with OCD (Pediatric OCD Treatment Study [POTS] Team 2004). Patients were randomly assigned to
sertraline, CBT, combined sertraline and CBT, or placebo. Combined treatment was significantly superior to CBT alone and
sertraline alone, which did not differ from each other.
Group cognitive-behavioral therapy (GCBT) was compared with sertraline treatment for OCD in a randomized trial with 40
youths (ages 9–17 years) (Asbahr et al. 2005). Both GCBT and sertraline yielded significant improvement in CY-BOCS scores
after 12 weeks of treatment. After a 9-month follow-up period, GCBT-treated patients had a significantly lower rate of relapse
compared with the sertraline-treated group (5.3% vs. 50%, respectively).
Paroxetine
The efficacy and safety of paroxetine were assessed in a double-blind, placebo-controlled multicenter study of 203 outpatient
children and adolescents (ages 7–17 years) with OCD (D. A. Geller et al. 2004). Patients were randomly assigned to
paroxetine (dosage range = 10–50 mg/day; mean daily dose = 23 mg) or placebo for a 10-week trial. There was a
statistically significant greater reduction in CY-BOCS scores from baseline to endpoint in patients treated with paroxetine
than in patients treated with placebo. Response rates (>25% reduction in CY-BOCS scores) were 64.9% in the
paroxetine-treated patients and 41.2% in the placebo-treated patients. The most common adverse effects in the paroxetine
group were headache, abdominal pain, nausea, respiratory disorder, somnolence, hyperkinesias, and trauma.
The efficacy of paroxetine in 335 outpatients (ages 7–17 years) with OCD was assessed in a 16-week open-label multicenter
study of paroxetine (10–60 mg/day), followed by double-blind randomization of responders to paroxetine or placebo for an
additional 16 weeks (Emslie et al. 2000). The rate of response (defined as >25% reduction in CY-BOCS scores) was 68.7% in
the open-label phase. No significant differences in response rates were found between the group receiving paroxetine and
the group receiving placebo in the randomization phase. However, fewer patients receiving paroxetine relapsed than did
patients receiving placebo (34.7% and 43.9%, respectively).
A post hoc analysis of the study by Emslie et al. (2000) found that the response rates in patients with comorbid ADHD, tic
disorder, or ODD (56%, 53%, and 39%, respectively) were significantly lower than those in patients without comorbid
disorders (75%). Behavioral adverse events, such as insomnia, nervousness, and hyperkinesia, were also significantly more
frequent in patients with psychiatric comorbidity (D. A. Geller et al. 2001a).
FluoxetinePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
10 of 58
10/05/2009 16:43
The safety and efficacy of fluoxetine were assessed in a 13-week double-blind, placebo-controlled multicenter trial (D. A.
Geller et al. 2001b). One hundred three children and adolescents (ages 7–17 years) with OCD were randomly assigned in a
2:1 ratio to either fluoxetine (dosage range = 10–60 mg/day; mean daily dose = 24.6 mg) or placebo. The group treated with
fluoxetine showed a statistically significant reduction in OCD severity compared with the group treated with placebo, as
assessed by CY-BOCS scores. Rates of response (defined as >40% reduction in CY-BOCS score) were 49% in the fluoxetine
group and 25% in the placebo group. There were no significant differences in treatment-emergent adverse events between
the fluoxetine and placebo groups. There were significant differences for change in weight and blood pressure between the
groups, in the direction of mild weight loss and slight decrease in blood pressure for the fluoxetine group.
In post hoc subgroup analyses of the study by D. A. Geller et al. (2001b), no predictive factors in response to fluoxetine
treatment for pediatric OCD were found (D. A. Geller et al. 2001c). There were no statistically significant differences in
treatment effect between children vs. adolescents, females vs. males, patients with vs. without a family history of depression
or OCD, or patients with age at onset <7 years vs. 7 years.
Fluoxetine was compared with placebo in a controlled trial in 43 youths with OCD (Liebowitz et al. 2002). It was found that
after 16 (but not 8) weeks of treatment, the fluoxetine group had significantly lower CY-BOCS scores than the placebo group.
These investigators concluded that fluoxetine’s full effect took longer than 8 weeks to develop.
In a smaller double-blind crossover trial of fixed-dosage fluoxetine (20 mg/day) and placebo, 14 children and adolescents
(ages 8–15 years) with OCD participated in a 20-week trial with crossover at 8 weeks (Riddle et al. 1992). CY-BOCS scores
decreased significantly more after 8 weeks of treatment with fluoxetine than after treatment with placebo (44% and 27%,
respectively). The most frequently reported side effects were insomnia, fatigue, motoric activation, and nausea.
Citalopram
Twenty-three child and adolescent outpatients (ages 9–18 years) with OCD were administered open-label citalopram (dosage
range = 10–40 mg/day; mean daily dose = 37 mg) in a 10-week trial (Thomsen 1997). There was a statistically significant
improvement in CY-BOCS scores from baseline to endpoint. Over 75% of youths showed a moderate to marked improvement
in OCD symptoms. Adverse effects were minimal and transient.
In an 8-week open-label citalopram study of 15 youths (ages 6–17 years) with OCD, 14 patients showed significant
improvement in CY-BOCS scores from baseline to endpoint. Sedation (n = 1) and insomnia (n = 1) were reported in the first
week of treatment (Mukaddes and Abali 2003).
In a long-term, open study of 30 adolescents with OCD, citalopram (dosage range = 20–70 mg/day; mean daily dose = 46.5
- mg) was administered for 1–2 years (Thomsen et al. 2001). There was a significant reduction in CY-BOCS scores from
baseline to assessment at 2 years. No serious adverse events were reported, and the most common side effects were
sedation, sexual dysfunction, and weight gain.
Clomipramine
Clomipramine has been shown to be efficacious in the treatment of pediatric OCD in two double-blind, placebo-controlled
trials. In the first study (Flament et al. 1985), 19 children (ages 10–18 years) with OCD were randomly assigned to
clomipramine (dosage range = 100–200 mg/day; mean daily dose = 141 mg) or placebo for 5 weeks. Significant
improvement in observed and self-reported obsessions and compulsions was found for patients who received clomipramine.
The most common side effects were tremor, dry mouth, dizziness, and constipation. One patient had a grand mal seizure.
In an 8-week double-blind, placebo-controlled multicenter study of 60 children and adolescents (ages 10–17 years) with
OCD, it was found that patients who received clomipramine (up to 200 mg/day) had significantly greater reductions in scores
on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS; Goodman et al. 1991) compared with the placebo group
(37% and 8%, respectively). Forty-seven patients continued in a 1-year open-label extension trial, and effectiveness was
maintained with long-term treatment. The most frequent side effects were dry mouth, somnolence, dizziness, fatigue, tremor,
headache, constipation, and anorexia (DeVeaugh-Geiss et al. 1992).
In a 10-week double-blind crossover trial of clomipramine and desipramine for 48 children and adolescents (ages 7–19
years) with OCD, clomipramine was shown to be significantly superior to desipramine in reducing obsessive-compulsive
symptoms (Leonard et al. 1989). Sixty-four percent of patients who received clomipramine as their first active treatment
showed some signs of relapse during treatment with desipramine.
Leonard et al. (1991) further assessed whether patients who were maintained on long-term clomipramine would relapse
following double-blind desipramine substitution. Twenty-six children and adolescents with OCD who received maintenance
treatment (mean duration = 17.1 months; range = 4–32 months) entered an 8-month double-blind desipramine substitution
trial. Eight of 9 patients (89%) in the desipramine group and 2 of 11 patient (18%) in the clomipramine group relapsed
during the comparison period.
Anxiolytics
Buspirone
In a case report of an 11-year-old girl with treatment-refractory OCD, buspirone (up to 300 mg/day) over a 3-week period
was noted to produce a substantial reduction in obsessive-compulsive symptoms (Alessi and Bos 1991).
Benzodiazepines
A case report of a 14-year-old boy with OCD who received clonazepam (up to 2 mg/day) found a marked decrease in
obsessive-compulsive symptoms over an 11-week period (Ross and Pigott 1993). A 16-year-old boy with OCD who had failedPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
11 of 58
10/05/2009 16:43
to respond to prior trials of clomipramine, fluoxetine, fluvoxamine, and buspirone augmentation showed a 75% improvement
in obsessive-compulsive symptoms when his fluoxetine dosage (60 mg/day) was augmented with clonazepam (4 mg/day)
(Leonard et al. 1994).
Atypical Antipsychotic Augmentation
Adjunctive risperidone ( 2 mg daily) was investigated in an open trial for 17 adolescents with OCD who failed to respond to
two serotonin reuptake inhibitor monotherapy trials. A significant reduction in CY-BOCS scores was reported (Thomsen
2004).
Aripiprazole augmentation of CBT was found to be effective in the case of an adolescent who had a partial response to
combined CBT and sertraline (Storch et al. 2008).
Generalized Anxiety Disorder
The prevalence of generalized anxiety disorder (GAD) in children and adolescents is estimated to range from 2.9% to 7.3%
(J. C. Anderson et al. 1987; Kashani and Orvaschel 1988). Children with GAD have excessive anxiety and worry about several
events or activities (e.g., school performance), have difficulty controlling the worry, and have at least one associated
symptom, such as restlessness, fatigue, concentration difficulties, irritability, muscle tension, and sleep disturbance
(American Psychiatric Association 2000). Most symptoms of childhood overanxious disorder were subsumed within GAD.
Therefore, overanxious disorder was eliminated from DSM-IV (American Psychiatric Association 1994). The course of GAD in
youths tends to be chronic (Keller et al. 1992).
Venlafaxine
The efficacy and safety of venlafaxine XR were evaluated in an 8-week double-blind, placebo-controlled multicenter trial
(Kunz et al. 2002). One hundred fifty-eight children and adolescents (ages 6–17 years) with GAD were randomly assigned to
venlafaxine XR (dosage range = 37.5–225 mg/day) or placebo. There was a statistically significant greater reduction in
anxiety scores in the venlafaxine XR group compared with the placebo group. Forty-nine patients (64%) receiving
venlafaxine were much or very much improved, compared with five patients (6%) receiving placebo. The most common
treatment-related adverse events were hyperkinesia, somnolence, and epistaxis.
Sertraline
Twenty-two children and adolescents (ages 5–17 years) with GAD were randomly assigned to sertraline or placebo in a
9-week double-blind trial (Rynn et al. 2001). The maximum dosage of sertraline was 50 mg/day. Significant differences in
favor of sertraline over placebo were observed on Hamilton Anxiety Scale (Ham-A; Hamilton 1959) scores and on CGI-S and
CGI-I ratings. Side effects found to be more common (but not statistically significant so) with sertraline than with placebo
were dry mouth, drowsiness, leg spasm, and restlessness.
Buspirone
There have been two open studies of buspirone for the treatment of GAD in youths. In an open study of adolescents with
GAD, a significant decrease in anxiety clinical ratings after 6 weeks of treatment with buspirone (mean dosage range =
15–30 mg/day) was reported (Kutcher et al. 1992). Simeon (1993) reported the results of an open trial of buspirone for 13
children with anxiety disorders; 9 of these patients had DSM-III-R (American Psychiatric Association 1987) overanxious
disorder as a primary or secondary diagnosis. Patients received buspirone (maximum dosage = 30 mg/day) over 4 weeks.
Significant improvement in anxiety was found on clinical ratings and parent, teacher, and patient reports. Mild and transient
side effects were reported, including sleep difficulties, tiredness, nausea, stomachaches, and headaches.
Benzodiazepines
A few studies have demonstrated some effectiveness of high-potency benzodiazepines in treating children and adolescents
with GAD. Twelve patients (ages 8–16 years) with a DSM-III-R diagnosis of overanxious disorder or avoidant disorder
received alprazolam (maximum dosage = 0.5–1.5 mg/day) in a 4-week open trial (Simeon and Ferguson 1987). Significant
improvement in anxiety was found on clinical ratings and parent questionnaires. Parental reports indicated a decrease in the
frequency and severity of sleep problems. The most commonly reported adverse effects were initial daytime sleepiness,
agitation, headaches, and nausea. No significant changes in blood pressure, pulse, or respiration were observed.
This open study was followed by a double-blind, placebo-controlled study of alprazolam in the treatment of 30 children (ages
8–16 years) with a DSM-III-R diagnosis of overanxious disorder ( n = 21) or avoidant disorder (n = 9) (Simeon et al. 1992).
Patients were randomly assigned to alprazolam (dosage range = 0.5–3.5 mg/day; mean daily dose = 1.57 mg) or placebo for
a 4-week trial. On the basis of global ratings of improvement, alprazolam was superior to placebo, but this difference was not
statistically significant. Side effects were mild and included dry mouth and fatigue. No rebound or withdrawal symptoms
occurred, and no adverse cognitive effects were noted.
Social Anxiety Disorder
The prevalence of social anxiety disorder (social phobia) is estimated to range from 0.9% to 7% of children and adolescents
(J. C. Anderson et al. 1987; Stein et al. 2001). The diagnostic criteria for social anxiety disorder in children and adolescents
are the same as the diagnostic criteria used in adults (American Psychiatric Association 2000). Social anxiety disorder in
youths is a chronic condition, and it increases the risk of depression (Stein et al. 2001). Social anxiety disorder during
adolescence has been shown to persist into adulthood (Pine et al. 1998).
Selective Serotonin Reuptake InhibitorsPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
12 of 58
10/05/2009 16:43
Paroxetine
The efficacy and safety of paroxetine were evaluated in a 16-week double-blind, placebo-controlled multicenter trial in 322
outpatient children and adolescents (ages 8–17 years) with social anxiety disorder (Wagner et al. 2004a). Paroxetine was
significantly superior to placebo, with rates of response (defined as CGI-I score = 1 or 2) of 77.6% and 38.3%, respectively.
Side effects more common with paroxetine than with placebo were insomnia, decreased appetite, and vomiting.
Sertraline
Fourteen outpatient children and adolescents (ages 10–17 years) with a diagnosis of social anxiety disorder received
sertraline (dosage range = 100–200 mg/day; mean daily dose = 123 mg) in an 8-week open trial (Compton et al. 2001). Five
of the patients (36%) were much or very much improved, and four of the patients (29%) had a partial response by the end of
the 8-week trial. A significant clinical response was noted by week 6. Sertraline was well tolerated, and no patient developed
significant behavioral disinhibition or mania (Compton et al. 2001).
Citalopram
Chavira and Stein (2002) investigated the effectiveness of a combined psychoeducational and pharmacological treatment
program for youths with social anxiety disorder. Twelve children and adolescents (ages 8–17 years) with social anxiety
disorder received citalopram (mean daily dose = 35 mg) and eight 15-minute counseling sessions over a 12-week period. On
the basis of clinical global ratings of change, 41.7% of youths ( n = 5) were very much improved, and 41.7% of youths (n =
5) were much improved.
Nefazodone
A 15-year-old boy with social anxiety who was treated with nefazodone (up to 350 mg/day) over a 5-month period had
resolution of social anxiety symptoms (Mancini et al. 1999).
Buspirone
A 16-year-old boy with social anxiety disorder and a mixed personality disorder with predominantly schizotypal features was
treated with buspirone (up to 20 mg/day). At the end of 12 days of buspirone treatment, he was noted to have a significant
reduction in anxiety, which persisted over a 1-year follow-up period (Zwier and Rao 1994).
Selective Mutism
The prevalence of selective mutism in children is estimated to be less than 1% (Dow et al. 1995). Selective mutism is
characterized by an absence of speech in at least one specific social situation, usually school, despite the child’s ability to
speak in other situations (American Psychiatric Association 2000). Selective mutism has been viewed as a variant of social
anxiety disorder (Black and Uhde 1992).
Selective Serotonin Reuptake Inhibitors
Fluoxetine
Fifteen children and adolescents (ages 6–11 years) with selective mutism were randomly assigned to fluoxetine (dosage
range = 12–27 mg/day; mean daily dose = 21.4 mg) or placebo for a 12-week trial (Black and Uhde 1994). Significant
improvements on ratings of selective mutism were observed in both fluoxetine-treated and placebo-treated subjects. The
group treated with fluoxetine showed significantly more improvement on parent ratings of mutism change and global change
than did the group receiving placebo. However, most patients in the study continued to be very symptomatic at study end.
Side effects were minimal and not significantly different between the groups.
In a 9-week open trial of fluoxetine (dosage range = 10–60 mg/day; mean daily dose = 28.1 mg) in 21 children (ages 5–14
years) with selective mutism, 76% of patients showed improvement, with decreased anxiety and increased speech in public
settings (Dummit et al. 1996).
In case reports of a 4-year-old girl (Wright et al. 1995) and a 12-year-old girl (Black and Uhde 1992) with selective mutism,
fluoxetine treatment resulted in clinically significant improvement of symptoms.
Fluvoxamine
A 6-year-old girl was reported to have resolution of symptoms of selective mutism when treated with fluvoxamine (100
mg/day) (Lafferty and Constantino 1998).
Monoamine Oxidase Inhibitors
Phenelzine
Case studies of five children treated with phenelzine (30–60 mg/day) reported positive response (Golwyn and Sevlie 1999;
Golwyn and Weinstock 1990). Weight gain was the most common side effect.
Separation Anxiety Disorder
The prevalence of separation anxiety in children is estimated to be 3.5% (J. C. Anderson et al. 1987). Children with
separation anxiety disorder have excessive anxiety and worry about separation from home or from a person to whom they
are attached (American Psychiatric Association 2000). School refusal or school phobia may be a symptom of separation
anxiety disorder. A long-term follow-up of children with school phobia found that in adulthood, these individuals lived with
their parents more often, had fewer children, and more psychiatric consultation than did a general population comparisonPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
13 of 58
10/05/2009 16:43
group (Flakierska-Praquin et al. 1997).
Tricyclic Antidepressants
Imipramine
Imipramine has been the most studied medication for the treatment of separation anxiety disorder, and the treatment results
have been mixed. In a 6-week double-blind, placebo-controlled trial, 35 children with school phobia were randomly assigned
to imipramine (dosage range = 100–200 mg/day; mean daily dose = 152 mg) or placebo (Gittelman-Klein and Klein 1971).
All children received concurrent behavioral treatment. Imipramine treatment was significantly superior to placebo in rates of
school return (81% and 47%, respectively). However, in another controlled study of imipramine for separation anxiety
disorder (Klein et al. 1992), no significant superiority was found for imipramine (dosage range = 75–275 mg/day; mean daily
dose = 153 mg), compared with placebo, in reduction of anxiety symptoms. The most frequent imipramine side effect was
irritability or angry outbursts.
Imipramine was compared with alprazolam in an 8-week controlled study in which 24 children and adolescents (ages 7–17
years) with school refusal were randomly assigned to imipramine (dosage range = 150–200 mg/day; mean daily dose =
164.3 mg), alprazolam (dosage range = 1–3 mg/day; mean daily dose = 1.8 mg), or placebo (Bernstein et al. 1990). There
was a significant reduction in anxiety ratings from baseline to endpoint in both groups treated with medication, compared
with the group receiving placebo. Side effects were mild, with abdominal pain, headaches, and drowsiness the most
commonly reported.
The efficacy of imipramine versus placebo in combination with CBT was assessed in the treatment of school refusal in
adolescents (Bernstein et al. 2000). Sixty-three adolescents with school refusal were randomly assigned to either imipramine
(mean daily dose = 182 mg) plus CBT or placebo plus CBT for an 8-week trial. The group treated with imipramine plus CBT
showed a significantly higher rate of school attendance than did the group treated with placebo plus CBT (70% vs. 28%,
respectively). In a 1-year follow-up of 41 of the 63 subjects, no significant differences between the two groups were found in
prevalence of anxiety diagnoses (Bernstein et al. 2001).
Clomipramine
A 12-week double-blind, placebo-controlled trial of clomipramine (dosage range = 40–75 mg/day) in 46 children and
adolescents with school refusal failed to show a significant positive effect (Berney et al. 1981).
Benzodiazepines
Graae et al. (1994) conducted a double-blind crossover trial of 4 weeks of clonazepam therapy (dosage range = 0.5–2.0
mg/day) and 4 weeks of placebo in 15 children (ages 7–13 years) with anxiety disorders, predominantly separation anxiety
disorder. No significant improvement was found relative to baseline for clonazepam or placebo. Two boys discontinued the
study because of significant disinhibition and marked irritability, aggression, and tantrums, and 1 boy was noncompliant with
the protocol. The most common clonazepam side effects were drowsiness, irritability, and oppositional behavior.
In an open-label study, 9 children (ages 8–11 years) with school refusal received chlordiazepoxide (10–30 mg daily) for
5–30 days (D’Amato 1962). Eight of the children (89%) regularly attended school after 2 weeks of treatment. Drowsiness
was the only reported side effect.
Gabapentin
Two adolescents with school refusal who received gabapentin (dosage range = 1,200–2,000 mg/day) were reported to have
a positive response to treatment (Durkin 2002).
Posttraumatic Stress Disorder
The prevalence of PTSD in adolescents is reported to be 6.3% (Giaconia et al. 1995). The criteria for diagnosing PTSD in
youths are the same as those used for adults (American Psychiatric Association 2000). PTSD symptoms in children tend to
vary over time, and although the disorder is chronic, the course is prolonged with greater severity of the stressor (Clarke et
- 1993).
Citalopram
Eight adolescents with PTSD received citalopram in a fixed daily dose of 20 mg in a 12-week open-label study (Seedat et al.
2001). Core PTSD symptoms of reexperiencing, avoidance, and hyperarousal showed statistically significant improvement at
week 12, with a 38% reduction in total score on the Clinician-Administered PTSD Scale—Child and Adolescent Version
(CAPS-CA; Nader et al. 1996). Citalopram was well tolerated, and the most common side effects were increased sweating,
nausea, headache, and tiredness.
In a larger 8-week open trial, Seedat et al. (2002) treated 24 children and adolescents with citalopram (dosage range =
20–40 mg/day; mean daily dose 20 mg). Both the children and adolescents had a significant reduction in CAPS-CA scores at
endpoint. Common side effects of citalopram were drowsiness, headache, nausea, and increased sweating.
Clonidine
Seven preschool children (ages 3–6 years) with a diagnosis of PTSD received open treatment with clonidine at a dosage
range of 0.05–0.15 mg/day (Harmon and Riggs 1996). To decrease sedation, oral clonidine was subsequently converted to a
clonidine patch. The majority of children showed at least moderate improvements in hyperarousal, hypervigilance, insomnia,
nightmares, and mood lability.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
14 of 58
10/05/2009 16:43
Guanfacine
A 7-year-old girl with PTSD received guanfacine 0.5 mg daily, which suppressed PTSD nightmares for the 7-week period of
administration (Horrigan 1996).
Carbamazepine
Twenty-eight children and adolescents (ages 8–17 years) with a diagnosis of PTSD received carbamazepine (dosage range =
300–1,200 mg/day) for an average of 35 days. Twenty-two patients (78%) became asymptomatic, and the remaining six
patients were significantly improved during the course of treatment (Looff et al. 1995).
Propranolol
Eleven children (ages 6–12 years) with a diagnosis of PTSD participated in an off–on–off medication design of 4 weeks of
propranolol treatment (Famularo et al. 1988). Propranolol was initiated at 0.8 mg/kg/day and titrated to a maximum of 2.5
mg/kg/day. A significant improvement in PTSD symptoms was found during the treatment period. Side effects included
sedation and mildly lowered blood pressure and pulse.
Panic Disorder
The prevalence of panic disorder in children and adolescents ranges from 0.6% to 5.0% in the community and from 0.2% to
9.6% in clinical settings (Masi et al. 2001). The diagnostic criteria for panic disorder in children and adolescents are the same
as those for adults (American Psychiatric Association 2000). Panic disorder in youths is a chronic condition, and there is
continuity between pediatric and adult panic disorder (Biederman et al. 1997).
Selective Serotonin Reuptake Inhibitors
In an open-label trial, 12 children and adolescents (ages 7–17 years) with panic disorder were treated with an SSRI for 6–8
weeks (Renaud et al. 1999). Mean daily doses of SSRIs were fluoxetine 34 mg, paroxetine 20 mg, and sertraline 125 mg.
Adjunctive benzodiazepines were used for 8 patients. Seventy-five percent of patients showed much to very much clinical
improvement while receiving treatment with SSRIs. At the end of the trial, 8 patients (67%) no longer fulfilled panic disorder
criteria. No significant side effects were found.
Paroxetine
A chart review was conducted of 18 child and adolescent outpatients (ages 7–16 years) with a diagnosis of panic disorder
who received monotherapy with paroxetine (dosage range = 10–40 mg/day; mean daily dose = 23 mg) (Masi et al. 2001).
The mean paroxetine treatment duration was 11.7 months. Fifteen patients (83%) had a CGI score of much or very much
improved. The most common side effects were nausea, tension–agitation, sedation, insomnia, palpitations, and headache.
Citalopram
Three youths (ages 9, 13, and 16 years) with panic disorder and school phobia were treated with citalopram (up to 20
mg/day) over an 8- to 15-month period. All patients experienced resolution of panic attacks during the course of citalopram
treatment (Lepola et al. 1996).
Tricyclic Antidepressants
An 11-year-old girl with panic disorder and agoraphobia was treated with imipramine (75 mg/day), which resulted in
cessation of panic attacks (Ballenger et al. 1989). A 9 year-old boy with panic disorder and Tourette’s syndrome was treated
with imipramine (25 mg daily). Within 1 week of treatment onset, the boy’s panic episodes ceased, and the cessation was
maintained over a 2-year period (Sverd 1988).
Two cases of children (ages 8 and 13 years) with panic disorder and agoraphobia were reported in which the combination of
imipramine and alprazolam resulted in complete remission of symptoms (see Ballenger et al. 1989).
Benzodiazepines
In a 2-week open trial, four adolescents with panic disorder were treated with clonazepam (0.5 mg twice daily). A significant
reduction in panic attacks (from 3 attacks per week to 0.25 per week) was reported (Kutcher and MacKenzie 1988).
Mixed Anxiety Disorders
Selective Serotonin Reuptake Inhibitors
Fluvoxamine
One hundred twenty-eight outpatient children and adolescents (ages 6–17 years) with GAD, social anxiety disorder, or
separation anxiety disorder (who had received 3 weeks of open treatment with supportive psychoeducational therapy
without improvement) were randomly assigned to fluvoxamine (up to 300 mg) or placebo for an 8-week trial (Research Units
on Pediatric Psychopharmacology Anxiety Study Group 2001). The group treated with fluvoxamine had a significantly greater
reduction in scores on the Pediatric Anxiety Rating Scale (Research Units on Pediatric Psychopharmacology Anxiety Study
Group 2002a) than did the group treated with placebo. On the CGI-I scale, the response rate was 76% in the group treated
with fluvoxamine and 29% in the group receiving placebo. Adverse effects of abdominal discomfort and increased motor
activity were more common in the group treated with fluvoxamine than in the group treated with placebo. Following
completion of the 8-week placebo-controlled study, the 128 patients entered a 6-month open-label treatment phase
(Research Units on Pediatric Psychopharmacology Anxiety Study Group 2002b). Anxiety symptoms remained low in 33 of 35
(94%) subjects who initially responded to fluvoxamine. Of 14 fluvoxamine nonresponders switched to fluoxetine, anxietyPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
15 of 58
10/05/2009 16:43
symptoms significantly improved in 10 (71%) patients. Among 48 placebo nonresponders, 27 (56%) showed significant
improvement in anxiety on fluvoxamine.
Fluoxetine
Seventy-four youths (ages 7–17 years) with GAD, separation anxiety disorder, and/or social phobia were randomly assigned
to fluoxetine (20 mg/day) or to placebo for 12 weeks (Birmaher et al. 2003). Sixty-one percent of fluoxetine-treated patients
and 35% of placebo-treated patients were much or very much improved. Fluoxetine was well tolerated, with mild headache
and gastrointestinal symptoms reported as adverse events.
Fluoxetine’s efficacy in long-term treatment of children with GAD, separation anxiety disorder, and/or social phobia was
assessed in a 1-year open treatment (Clark et al. 2005) following the acute-phase study (Birmaher et al. 2003). Compared
with youths taking no medication, those taking fluoxetine (n = 42) showed significantly superior outcome in anxiety
measures. These investigators concluded that fluoxetine is effective in maintenance treatment of anxiety disorders in youth.
Clinical Recommendations for Anxiety Disorders
SSRIs are the medication treatment of choice for OCD in children and adolescents (Riddle 1998). Clomipramine is also
effective in the treatment of this disorder; however, anticholinergic side effects often make this a less tolerable agent than
SSRIs. A 10- to 12-week trial at adequate dosages is required to determine whether a child with OCD will respond to an SSRI
(Greist et al. 1995). If a child fails to respond to one SSRI, switching to another SSRI is a reasonable strategy. Clomipramine
may be a third treatment option, either as monotherapy or as augmentation of an SSRI. Other possible SSRI augmentation
strategies are clonazepam, antipsychotics, lithium, and buspirone; however, these agents have not received systematic study
in children (American Academy of Child and Adolescent Psychiatry 1998). Some children may require long-term medication
maintenance; however, it is reasonable to attempt medication discontinuation 1 year after symptom resolution. Medication
should be tapered gradually to assess for relapse and to avoid discontinuation symptoms (Grados et al. 1999).
In regard to other childhood anxiety disorders, SSRIs are first-line treatment (Reinblatt and Walkup 2005). Venlafaxine has
also demonstrated efficacy for the treatment of childhood GAD. Other treatment options include buspirone, TCAs, and
benzodiazepines (Bernstein et al. 1996). However, benzodiazepines should be used only on a short-term basis (i.e., weeks)
because of the potential for abuse and dependence in youths (Riddle et al. 1999).
ATTENTION-DEFICIT/HYPERACTIVITY DISORDER
The prevalence of ADHD in children and adolescents is estimated to range from 5% to 12% (Barbaresi et al. 2002; Centers
for Disease Control and Prevention 2005; Rowland et al. 2002), although only about half of children diagnosed with ADHD
receive treatment (Centers for Disease Control and Prevention 2005). In addition to the core behavioral features of
inattention, hyperactivity, and impulsivity, children with ADHD often have significant impairment in social and academic
functioning (Barkley 2005). About 4% of adults in the general population meet criteria for ADHD (Kessler et al. 2006). Of all
of the childhood psychiatric disorders, ADHD has the greatest number of pharmacological treatment studies.
Psychostimulants
The classes of psychostimulants include methylphenidate, dexmethylphenidate, dextroamphetamine, mixed amphetamine
salts, and L-lysine-D-amphetamine (lisdexamfetamine). By the 1980s, there were already hundreds of randomized, controlled
trials showing the efficacy of stimulants for the treatment of ADHD in school-age children (Greenhill et al. 1999). Beginning
in the late 1980s and 1990s, the intensive study of the pharmacokinetics and pharmacodynamics of stimulant medications
was undertaken, pioneered by the group at the University of California at Irvine. Analog classroom settings were used to
examine the hour-by-hour effects of stimulant medications on behavior and cognition and its relationship to serum stimulant
medications. Such studies led to the development of methylphenidate (Swanson et al. 1998, 1999, 2000, 2002, 2003), mixed
salts of amphetamine–dextroamphetamine (Greenhill et al. 2003; McCracken et al. 2003), extended-release methylphenidate
(Swanson et al. 2004; Wigal et al. 2003), dexmethylphenidate hydrochloride (Quinn et al. 2004), and lisdexamfetamine
dimesylate (Findling et al. 2006a).
Subsequently, numerous large-scale clinical trials proved the efficacy of these new agents (Biederman et al. 2002; Greenhill
et al. 2002, 2005; McCracken et al. 2003; Pelham et al. 1999; Wigal et al. 2005a; Wolraich 2000; Wolraich et al. 2001). A
methylphenidate transdermal patch (Findling and Lopez 2005; Pelham et al. 2005) has been recently approved for use in the
treatment of ADHD. In the study of the transdermal patch, 270 children with ADHD were randomly assigned to receive either
a placebo patch or varying dosages of the methylphenidate patch in a double-blind design. At the end of the 5-week study,
72% of those on the active patch were classified as responders compared to 24% on placebo; side effects were similar to oral
methylphenidate (decreased appetite, insomnia, weight loss, tics).
Lisdexamfetamine dimesylate is a “prodrug” in which D-amphetamine is covalently bound to L-lysine (Findling et al. 2006a).
In the bloodstream, the lysine is hydrolyzed to yield the active stimulant. The prodrug appears to have lower potential than
amphetamine for oral or intravenous abuse (Jasinski and Krishman 2006a, 2006b). In the pivotal trials, 290 children (ages
6–12 years) with ADHD were randomly assigned to either placebo ( n = 72) or different dosages of lisdexamfetamine
dimesylate (30, 50, 70 mg/day). All doses of lisdexamfetamine dimesylate were superior to placebo ( P <0.0001) throughout
the 4-week trial at three different time points during the day (10 A.M., 2 P.M., and 6 P.M.). Common side effects of
lisdexamfetamine dimesylate were decreased appetite (39%), irritability (10%), insomnia (19%), nausea/vomiting
(6%–9%), and weight loss (9%). No serious adverse events were reported. The medication was well tolerated in long-term
follow-up, with no significant laboratory or ECG abnormalities reported (Childress et al. 2006).
Initial research with long-acting stimulants was carried out in school-age children, but recent controlled trials of stimulants
have focused on adolescents (T. J. Spencer et al. 2006b; Wilens et al. 2006b) and adults (Biederman et al. 2006a; Weisler etPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
16 of 58
10/05/2009 16:43
- 2006). These studies in older individuals show response rates to stimulants similar to those of children; with adequate
response for most subjects being obtained with 70–100 mg of methylphenidate or 40–60 mg of amphetamine a day.
Preschoolers with ADHD have also been the focus of recent work. In the NIMH Preschool ADHD Treatment Study (PATS), 183
children (ages 3–5 years) underwent an open-label trial of methylphenidate; subsequently 165 of these subjects were
randomized into a double-blind, placebo-controlled crossover trial of methylphenidate lasting 6 weeks (Greenhill et al.
2006b). One hundred forty subjects who completed this second phase went on to enter a long-term maintenance study of
methylphenidate. Parents of subjects in this study were required to complete a 10-week course of parent training before
their child was treated with medication. Of note, only 37 of 279 enrolled parents felt that the behavior training resulted in
significant or satisfactory improvement (Greenhill et al. 2004).
Results from the short-term, open-label run-in and double-blind crossover studies do show that methylphenidate is effective
in preschoolers with ADHD (Wigal et al. 2006). The mean optimal dose of methylphenidate was found to be 0.7 + 0.4
mg/kg/day, which is lower than the mean of 1.0 mg/kg/day found to be optimal in the Multimodal Treatment of ADHD (MTA)
study with school-age children. Eleven percent of subjects discontinued methylphenidate because of adverse events (Wigal et
- 2006). Also relative to the MTA study, the preschool group showed a higher rate of emotional adverse events, including
crabbiness, irritability, and proneness to crying. The conclusion was that the dose of methylphenidate (or any stimulant)
should be titrated more conservatively in preschoolers than in school-age patients, and lower mean doses may be effective. A
pharmacokinetic study done as part of the PATS protocol showed that preschoolers metabolized methylphenidate more slowly
than did school-age children, perhaps explaining these results (McGough et al. 2006).
Longer-term open-label studies of these agents, often lasting up to 2 years (McGough et al. 2005; Wilens et al. 2003b, 2005),
have also been performed, giving the field more data about efficacy and safety after prolonged use. These studies do not
show the presence of any major medical adverse events, with no abnormalities of hematological or chemical measures
(Biederman et al. 2002; Greenhill et al. 2002; McCracken et al. 2003; Wolraich 2000; Wolraich et al. 2001).
Atomoxetine
Atomoxetine is a noradrenergic reuptake inhibitor that has indirect effects on dopamine reuptake in cortex but not in the
striatum (Bymaster et al. 2002). Numerous double-blind, placebo-controlled trials have demonstrated its efficacy in the
treatment of ADHD in children, adolescents, and adults (Michelson et al. 2001, 2002, 2003). Given its pharmacokinetic
half-life of 5 hours, it is generally dosed twice a day. While open trials comparing methylphenidate to atomoxetine showed
the two agents to have similar efficacy (Kratochvil et al. 2002), double-blind, placebo-controlled trials comparing
atomoxetine to amphetamine (Biederman et al. 2006b; Wigal et al. 2005b) and methylphenidate (Michelson 2004) have
shown the stimulants to be more efficacious.
Atomoxetine is effective in treating ADHD in those with comorbid tics and may also reduce tics (Allen et al. 2005). It is also
useful in children with ADHD who have comorbid anxiety, showing effectiveness in treating anxiety and inattention (Sumner
et al. 2005). Atomoxetine is well tolerated in long-term use. In a global multicenter study, 416 children and adolescents who
responded to an initial 12-week open-label period of treatment with atomoxetine were randomly assigned to continued
atomoxetine treatment or placebo for 9 months under double-blind conditions. Atomoxetine was significantly superior to
placebo in preventing relapse (defined as a return to 90% of baseline symptom severity), 22.3% and 37.9%, respectively
(Michelson 2004). Data from 13 atomoxetine studies (6 double-blind, 7 open-label) were pooled for subjects ages 12–18
years with ADHD (Wilens et al. 2006b). Of the 601 atomoxetine-treated subjects in this meta-analysis, 537 (89.4%)
completed 3 months of acute treatment. At the time of publication, a total of 259 subjects (48.4%) were continuing
atomoxetine treatment; 219 of these subjects had completed at least 2 years of treatment. Symptoms remained improved up
to 24 months without dosage escalation. During the 2-year treatment period, 99 (16.5%) subjects discontinued treatment
due to lack of effectiveness, and 31 (5.2%) subjects discontinued treatment due to adverse events. No clinically significant
abnormalities in height, weight, blood pressure, pulse, mean laboratory values, or ECG parameters were found.
Tricyclic Antidepressants
Before the advent of atomoxetine, TCAs were the primary alternative to stimulant treatment of ADHD. There have been 15
double-blind, placebo-controlled studies of TCAs demonstrating the efficacy of desipramine, imipramine, amitriptyline,
nortriptyline, and clomipramine in the treatment of children with ADHD (Daly and Wilens 1998; Popper 2000; Prince et al.
2000). Desipramine is rarely used today because of isolated reports in the 1990s of sudden death at therapeutic dosages
(Popper and Ziminitzky 1995). In general, there has been a decline in the use of TCAs for the treatment of ADHD due to the
need to monitor ECG (see Appendix) and the risk of death in the event of overdose.
Bupropion
Bupropion is an antidepressant with noradrenergic and dopaminergic actions. Simeon et al. (1986) conducted a 14-week
single-blind study consisting of placebo baseline for 4 weeks, bupropion (dosage range = 50–150 mg; mean daily dose = 135
- mg) for 8 weeks, and placebo posttreatment for 2 weeks. Seventeen boys with ADHD and conduct disorder (ages 7–13 years)
participated in the study. Significant improvement in hyperactivity, conduct problems, and global functioning was found.
A double-blind, placebo-controlled four-center study was conducted to assess the efficacy of bupropion in the treatment of
childhood ADHD (Conners et al. 1996). One hundred nine children (ages 6–12 years) with ADHD were randomly assigned to
bupropion (n = 72) or placebo (n = 37) for a 6-week trial. Dosages of bupropion ranged from 3 to 6 mg/kg/day. Significant
treatment effects were found for hyperactivity, impulsivity, conduct problems, and attention. Moderate effect sizes of
bupropion that were somewhat less than those for stimulant treatment of ADHD were found. The most frequent adverse
effects with bupropion were rash, urticaria, nausea, and vomiting. Although no patients experienced a seizure, 6 of 72
children who received bupropion had electroencephalograms (EEGs) that changed from normal at baseline to abnormal onPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
17 of 58
10/05/2009 16:43
the final day of treatment (approximately 4 weeks later) (Conners et al. 1996).
Bupropion was compared with methylphenidate in a small double-blind crossover study (Barrickman et al. 1995). Fifteen
children and adolescents (ages 7–17 years) were randomly assigned to bupropion or methylphenidate for 6 weeks,
underwent washout for 2 weeks, and were crossed over to the other medication. The dosage range of bupropion was 1.4–5.7
mg/kg/day (mean daily dose = 3.3 mg/kg) and the dosage range of methylphenidate was 0.4–1.3 mg/kg/day (mean daily
dose = 0.7 mg/kg). Bupropion and methylphenidate produced significant and similar improvement in ADHD symptoms.
Despite this finding, however, the two medications have never been compared in more rigorous parallel-group designs, and
clinical experience strongly suggests that the effect size for bupropion is not as great as that for stimulants.
Clonidine
A review of the literature from 1980 to 1999 found 39 studies regarding the use of clonidine for symptoms of childhood
ADHD, and 11 of the studies (n = 150) had sufficient data to be included in a meta-analysis (Connor et al. 1999). Of these
150 subjects, 42 received clonidine for ADHD, and the others received clonidine for ADHD comorbid with tic disorders ( n =
67), developmental disorders (n = 15), or conduct disorders (n = 26). The mean daily dose of clonidine was 0.18 mg, and the
average length of treatment was 10.9 weeks. Clonidine showed a moderate effect size of 0.58 on symptoms of ADHD, which
is smaller than the effect size (0.82) reported for stimulant treatment of ADHD (Swanson et al. 1995).
Guanfacine
Two open trials and one controlled trial provide some support for the use of guanfacine in the treatment of youths with
ADHD. In a study by Hunt et al. (1995), 13 children and adolescents with ADHD received guanfacine (mean daily dose = 3.2
- mg) for 1 month. Significant improvements in hyperactivity and inattention were found. In another study by Chappell et al.
(1995b), 10 children and adolescents with comorbid ADHD and Tourette’s syndrome received guanfacine (mean daily dose =
1.5 mg) over a 4- to 20-week period. Four of the 10 children (40%) had moderate to marked improvement in ADHD
symptoms.
In an 8-week double-blind, placebo-controlled trial, 34 children and adolescents (ages 7–14 years) with ADHD and tic
disorder were randomly assigned to guanfacine (dosage range = 1.5–3.0 mg/day) or placebo (Scahill et al. 2001). There was
a 37% improvement in ADHD symptoms for children treated with guanfacine, compared with an 8% improvement in ADHD
symptoms for children receiving placebo. The most common side effects of guanfacine were sedation and dry mouth. There
were no significant changes in pulse or blood pressure with guanfacine.
An extended-release formulation of guanfacine has been recently studied in a double-blind, placebo-controlled Phase III
multicenter trial (Melmed et al. 2006). Children and adolescents ages 6–17 years were randomly assigned to placebo or 2, 3,
or 4 mg/day of guanfacine. All three doses of guanfacine were superior to placebo in reducing symptoms of ADHD. The most
commonly reported side effects were headache, somnolence, and fatigue. No serious adverse events were reported. In
healthy young adults (ages 19–24 years), abrupt discontinuation of 4 mg of extended-release guanfacine did not lead to
increases in blood pressure or ECG abnormalities (Kisicki et al. 2006).
Modafinil
Modafinil, a nonstimulant activator of the cortex approved for the treatment of narcolepsy, was studied to determine its
efficacy in the treatment of ADHD. A 9-week double-blind, placebo-controlled trial randomly assigned 248 subjects to either
placebo or modafinil (dosage range = 170–425 mg once per day) (Biederman et al. 2005d). At study termination, 48% of
subjects on modafinil were rated as much or very much improved compared to 17% of those on placebo (effect size vs.
placebo = 0.69). The most common adverse events reported were insomnia (29%), headache (20%), and decreased appetite
(16%). In a second controlled trial, 200 subjects were randomly assigned to placebo or modafinil (Greenhill et al. 2006a);
52% of those on modafinil were classified as responders versus 18% of subjects on placebo ( P <0.001). A double-blind,
placebo-controlled discontinuation study involving 189 patients with ADHD also demonstrated efficacy of modafinil in ADHD
(Swanson et al. 2006b). While the medication was well tolerated by most subjects in open-label follow-up studies, one case
of suspected Stevens-Johnson syndrome was reported, and the FDA declined to approve the medication for clinical use (U.S.
Food and Drug Administration 2006c). Given the low response rate (~50%) relative to that seen with stimulants
(65%–85%), it is not likely that modafinil would have emerged as a first-line treatment for ADHD. Clinicians face a dilemma
if they choose to use modafinil (Provigil) off label for the treatment of ADHD; this should be attempted only if all other agents
have failed and the patient and family are informed of the reason for the FDA’s failure to approve the medication.
Other Antidepressants
Fenfluramine, a potent serotonergic agonist, was found to be ineffective in the treatment of ADHD (Donnelly et al. 1989).
Thus, findings from open trials suggesting improvement in ADHD symptoms with SSRI treatment (Barrickman et al. 1991;
Gammon and Brown 1993) must be greeted with skepticism. In the Gammon and Brown (1993) study, improvement in mood
and attention was seen when fluoxetine was added to methylphenidate when the clinical response after monotherapy with
the stimulant was deemed insufficient in a sample of 32 children and adolescents with ADHD. However, in a later open-label
study of sertraline or fluoxetine in the treatment of seven children and adolescents with ADHD and major depression, Findling
(1996) found no improvement in ADHD symptoms for any patient treated with SSRIs. More recently, the addition of
fluvoxamine to methylphenidate was not demonstrated to be effective relative to addition of placebo in a sample of children
with ADHD and comorbid anxiety (Abikoff et al. 2005).
In an open trial of venlafaxine, 7 of 16 children and adolescents (44%) showed some improvement in ADHD symptoms of
hyperactivity and impulsivity; however, no improvement was seen in cognitive symptoms (Olvera et al. 1996). The mean
daily dose of venlafaxine was 60 mg. Four patients (25%) were unable to tolerate the medication, with 3 of the patients
discontinuing medication because of worsening hyperactivity. Other side effects included drowsiness, irritability, and nausea.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
18 of 58
10/05/2009 16:43
No effects on blood pressure or heart rate were found. No double-blind, placebo-controlled trials have ever proven the
efficacy of venlafaxine in the treatment of ADHD. Given concerns about antidepressants increasing the risk of suicidal
ideation, anti-depressants without proven efficacy in the treatment of ADHD should not be used in its treatment. They may be
used in conjunction with an established medication treatment for ADHD to treat a comorbid anxiety or depressive disorder.
Clinical Recommendations for Attention-Deficit/Hyperactivity Disorder
Recently, the Texas Children’s Medication Algorithm Project (CMAP) has revised the algorithm for the treatment of ADHD
(Pliszka et al. 2006a). Based on current research and panel discussion, the stages of medication treatment were established
as follows:
Stage 1: Psychostimulant
Stage 2: Alternative psychostimulant
Stage 3: Atomoxetine
Stage 3a: Combination of stimulant and low-dose atomoxetine
Stage 4: Bupropion or TCA
Stage 5: Alternative antidepressant from stage 5
Stage 6: Alpha agonist (guanfacine or clonidine)
Arnold (2000) reviewed studies in which subjects underwent a trial of both amphetamine and methylphenidate. This review
suggested that approximately 41% of subjects with ADHD responded equally to both methylphenidate and amphetamine,
while 44% responded preferentially to one of the classes of stimulants. This suggests the initial response rate to stimulants
may be as high as 85% if both stimulants are tried (in contrast to the finding of 65%–75% response when only one stimulant
is tried). There is at present, however, no method to predict which stimulant will produce the best response in a given
patient. The recent practice parameters of the American Academy of Child and Adolescent Psychiatry (2007) characterize all
FDA-approved agents (stimulants and atomoxetine) as appropriate for initial treatment of ADHD, with antidepressants and
alpha agonists as second line.
DISRUPTIVE BEHAVIOR DISORDERS AND AGGRESSION
Oppositional Defiant Disorder and Conduct Disorder
Oppositional defiant disorder (ODD) is a pattern of negativistic, defiant, angry behavior that is persistent and causes
impairment in the child’s social functioning. Conduct disorder (CD) consists of antisocial and aggressive behavior (lying,
stealing, fighting, fire setting, destruction of property, truancy, running away) (American Psychiatric Association 2000). ODD
and CD are highly comorbid with ADHD, particularly in younger children (Maughan et al. 2004; Pliszka et al. 1999).
Psychostimulants
The efficacy of methylphenidate in treating 84 youths (ages 6–15 years) with CD, with and without ADHD, was assessed in a
5-week double-blind, placebo-controlled trial. Ratings of antisocial behaviors specific to CD were significantly reduced by
methylphenidate treatment (up to 60 mg/day) (Klein et al. 1997). The severity of the ADHD did not affect the response of CD
symptoms to the stimulant studies. Since this study, multiple double-blind, placebo-controlled trials have shown that ODD
responds to stimulant medication, yielding an effect size similar to that for the ADHD symptoms (American Psychiatric
Association 2000; Pelham et al. 2001; T. J. Spencer et al. 2006a).
Atomoxetine
Children and adolescents (ages 8–18 years) with ADHD were treated for approximately 8 weeks with placebo or atomoxetine
under randomized, double-blind conditions. Of the 293 subjects, 39% were diagnosed with comorbid ODD and 61% were not
(Newcorn et al. 2005). Treatment group differences and differences between patients with and without comorbid ODD were
examined post hoc for changes on numerous clinical measures. Youths with ADHD and comorbid ODD showed statistically
significant improvement in ADHD and ODD symptoms as well as in quality-of-life measures on atomoxetine relative to
placebo. Treatment response was similar in youths with and without ODD, although the comorbid group may require higher
doses to achieve response than those with ADHD alone.
In general, a child with ODD or CD should be treated with a stimulant or atomoxetine before proceeding to the use of other
psychotropic agents. The use of more potent agents (mood stabilizers, antipsychotics) is generally reserved for those with
severe aggression, and then only after a behavioral treatment has failed (Pappadopulos et al. 2003; Pliszka et al. 2006a).
Aggressive Behavior
While ODD and CD are syndromes, aggression is a symptom. Although many children and adolescents with CD are aggressive,
a child can meet criteria for CD without being aggressive; aggression may present as a problematic symptom in children with
depression, psychosis or bipolar disorder without the child meeting criteria for CD. Thus, the clinician must be clear whether
ODD/CD or aggression is the target of treatment, as studies have addressed the problems separately. Treatments for ADHD
have been used to target ODD/CD, whereas mood stabilizers and antipsychotics have been used in patients with severe
aggressive outbursts, regardless of diagnosis (Pappadopulos et al. 2006).
Psychostimulants
In a meta-analysis of the literature from 1970 to 2001 that utilized 28 studies to determine the effect size for stimulants on
overt and covert aggression-related behaviors in children with ADHD, it was found that the mean effect size for aggressive
behaviors was similar to that for core behaviors of ADHD (Connor et al. 2002; Pappadopulos et al. 2006).
RisperidonePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
19 of 58
10/05/2009 16:43
A significant body of research has accumulated showing the effectiveness of risperidone in the treatment of aggression,
although most of these studies involve patients with subaverage intelligence (Pappadopulos et al. 2006). One hundred ten
children (ages 5–12 years) with an IQ of 36–84 with a disruptive behavior disorder were enrolled in a clinical trial of
risperidone consisting of a 1-week single-blind, placebo run-in period followed by a 6-week double-blind, placebo-controlled
period (Snyder et al. 2002). Eighty percent of subjects had comorbid ADHD. Risperidone dosages ranged from 0.02 to 0.06
mg/kg/day. The risperidone-treated subjects showed a significant (P <0.001) reduction (47.3%) in mean scores versus
placebo-treated subjects (20.9%) on the Conduct Problem subscale of the Nisonger Child Behavior Rating Form (NCBRF) ( P
<0.001). The effect of risperidone was unaffected by diagnosis, presence/absence of ADHD, psychostimulant use, and IQ
status. Risperidone produced no changes on the cognitive variables, and the most common side effects were somnolence,
headache, appetite increase, and dyspepsia. Somnolence did not predict response of aggressive symptoms. Side effects
related to extrapyramidal symptoms were reported in 7 (13.2%) and 3 (5.3%) of the subjects in the risperidone and placebo
groups, respectively (P = 0.245).
Other double-blind, placebo-controlled trials of risperidone in children and adolescents with disruptive behavior disorders
(and subaverage IQ) have yielded similar results, with no negative trials reported (Aman et al. 2002; Buitelaar et al. 2001;
LeBlanc et al. 2005). Weight gain was a significant side effect in these studies, but there has not been evidence of adverse
neuropsychological effects (Gunther et al. 2006). Addition of stimulant does not appear to increase rates of side effects and
enhances treatment of hyperactivity (Aman et al. 2004). Indeed adding risperidone to a stimulant to control aggression has
become a common practice, although a recent controlled study showed that aggression was equally reduced when either
placebo or risperidone was added to psychostimulant medication (Armenteros et al. 2007). The sample in this study was
small (N = 25), but the study should caution clinicians that aggression can respond to psychosocial events, like the
expectations of a study.
Because of weight gain and increased prolactin associated with risperidone, concern exists regarding its long-term use
(Correll and Carlson 2006). The long-term safety and efficacy of risperidone in disruptive behavior disorders in children with
subaverage IQ were studied in a 48-week open-label extension study of risperidone in 77 children (Turgay et al. 2002).
Subjects received risperidone at daily doses of between 0.02 and 0.06 mg/kg. Adverse events were reported for 76
participants; none were serious, and most were mild/moderate in severity. Somnolence (52%), headache (38%), and weight
gain (36%) were the most common adverse events. The degree of sedation was mild and not associated with cognitive
deterioration. Mean weight gain was 8.5 kg, half of this attributable to normal growth. Asymptomatic peak prolactin levels
were observed within 4 weeks of beginning risperidone treatment and declined over time to within normal range. At study
endpoint, mean prolactin levels were statistically significantly greater than baseline only in male participants but within the
normal range. Twenty participants experienced mild or moderate extrapyramidal symptoms, but these did not cause
withdrawal from the study.
The pooled database of five studies of the long-term use of risperidone ( n = 700) included 700 children ages 5–15 years who
had received risperidone for 11 or 12 months (Dunbar et al. 2004). Subjects also had baseline and 11- or 12-month height
measurements (n = 350); girls 9 years and boys 10 years also had baseline and 11- or 12-month Tanner staging ( n = 222).
Risperidone-treated children had a mean increase in height 1.2 cm greater than the reference population, and they
experienced no delay in progression through Tanner staging. Transient increases in prolactin did not correlate with growth or
sexual maturation. The authors concluded that there was no evidence of statistically or clinically significant growth failure or
delay in pubertal onset or progression in children treated for up to 1 year with risperidone.
A full review of all studies of risperidone in the treatment of childhood aggression was recently published (Pandina et al.
2006). This review pooled adverse-event data from these studies ( n = 688), showing the most common side effects of
risperidone to be somnolence (33%), weight gain (20%), hyperprolactinemia (10.2%), and fatigue (10%). In the pooled
studies, there was an excess mean weight gain (over normal growth) of 6.0 + 7 kg after 35–43 weeks of treatment. Of the
688 patients, 651 were free of dyskinetic movements at baseline, and only 1 patient developed new dyskinetic movements
during the follow-up period (these symptoms resolved even though risperidone was continued). There was no worsening of
dyskinetic movements in those with such preexisting symptoms. Rates of extrapyramidal side effects were low throughout
the long-term follow-up period. It should be noted that the dosages of risperidone used in these studies were quite low (1–2
mg/day); thus, these results may not apply to dosages in the 6 mg/day range.
Quetiapine
Quetiapine has been studied in an open trial with aggressive children with CD (Findling et al. 2006b) The 8-week trial
enrolled 17 children ages 6–12 years. Outcome measures included the Rating of Aggression Against People and/or Property
Scale (RAAPPS), the NCBRF, and the Conners Parent Rating Scale (CPRS-48). Blood sampling for pharmacokinetic analyses
occurred at the end of weeks 2 and 8: the mean dose of quetiapine at week 8 was 4.4 ± 1.1 mg/kg. Significant decreases in
baseline scores of the RAAPPS, and in several subscales of the NCBRF and the CPRS, were found by the end of the study ( P
<0.05). No patients discontinued because of an adverse event or experienced extrapyramidal side effects. These preliminary
data suggest that aggressive children with CD may benefit from quetiapine. The pharmacokinetics of quetiapine supports
twice-daily dosing in children. Nine of the subjects in this study were subsequently enrolled in a 26-week open-label trial;
they were treated with dosages of quetiapine ranging from 75 to 300 mg/day. Aggression remained well controlled, no
subject developed extrapyramidal side effects, and 1 subject had a significant weight gain but remained in the study.
The efficacy and tolerability of quetiapine and divalproex for the treatment of impulsivity and reactive aggression were
studied in 33 subjects with bipolar disorder and disruptive behavior disorders (Barzman et al. 2006). The subjects were
randomly assigned to quetiapine (400–600 mg/day) or divalproex (serum level 80–120 microgram/mL) for 28 days in this
double-blinded study. Repeated-measures analysis of variance (ANOVA) demonstrated statistically significant
within-treatment-group effects for divalproex (baseline = 20.6, endpoint = 13.3, P <0.0001) and quetiapine (baseline = 18.8,Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
20 of 58
10/05/2009 16:43
endpoint = 10.8, P <0.0001) for the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), but there was
no significant difference in the rate of improvement in the PANSS EC scores between the two treatment groups; thus, the two
agents showed similar efficacy for the treatment of impulsivity and reactive aggression in this study. No double-blind,
placebo-controlled trials of quetiapine in the treatment of aggression have been performed.
Other Atypical Antipsychotics
There have only been small open trials and case reports of the use of aripiprazole, olanzapine, and ziprasidone in the
treatment of aggression (Hazaray et al. 2004; Khan et al. 2006; Rugino and Janvier 2005; Staller and Staller 2004; Stephens
et al. 2004; Valicenti-McDermott and Demb 2006). In most of these studies, children had primary psychiatry diagnoses other
than ODD or CD, such as mood disorders or developmental disorders.
Rugino and Janvier (2005) reported on the use of aripiprazole in a mixed sample ( n = 17) of children with bipolar disorder
and developmental disorders. Only 4 of the subjects responded, but coadministration of alpha 2 agonists in a large proportion
of the sample may have confounded the results. A retrospective chart review of 32 children (ages 5–19 years) with
developmental disabilities treated with aripiprazole was conducted (Valicenti-McDermott and Demb 2006). Twenty-four had
diagnoses within the autistic spectrum, and 18 had mental retardation. Other disorders included ADHD/disruptive behavior
disorders (n = 13), mood disorders (n = 7), reactive attachment disorder (n = 2), and sleep disorders ( n = 2). Target
symptoms included aggression, hyperactivity, impulsivity, and self-injurious behaviors. The mean daily aripiprazole starting
dose was 7.1 ± 0.32 mg (0.17 mg/kg/day), and the mean daily maintenance dose was 10.55 ± 6.9 mg (0.27 mg/kg/day).
While improvement in target symptoms was found in 56% of the sample, side effects were reported in 16 (50%), with the
most frequent being sleepiness (n = 6). Mean body mass index (BMI) rose significantly, and weight gain was more
pronounced in children younger than 12 years.
Inpatient children who received intramuscular ziprasidone or olanzapine for emergency treatment of aggression were found
to have similar lengths of stay and number of restraints, but those administered ziprasidone required many more injections
and were more likely to require coadministration of lorazepam (Khan et al. 2006).
The effects of olanzapine on aggressive behavior and tic severity was examined in 10 subjects (ages 7–13 years) with a
primary diagnosis of Tourette’s syndrome and a history of aggressive behavior (Stephens et al. 2004). They were treated in a
2-week single-blind placebo run-in followed by an 8-week treatment-phase trial. The starting dose of olanzapine was
1.25–2.5 mg/day and was titrated at biweekly intervals, as tolerated. The mean dosage at the end of the trial was 14.5
mg/day. Olanzapine produced clinically and statistically significant reductions of aggression and tic severity from baseline to
trial completion, as measured by the Achenbach Child Behavior Checklist (CBCL) and Yale Global Tic Severity Scale (YGTSS).
Weight gain during the treatment period was the most common adverse effect (range = 2–20 lbs; group mean = 12.0 lbs ±
5.71). No other significant adverse effects were observed during the 10-week trial.
Lithium
The efficacy of lithium in the treatment of CD in youths has been demonstrated in three of the four double-blind,
placebo-controlled studies reported to date. Haloperidol, lithium, and placebo were compared in a double-blind, randomized
trial for 61 hospitalized children with aggression (ages 5–12 years) and CD. The optimal dosages of haloperidol ranged from
1 to 6 mg/day; the optimal dosages of lithium ranged from 500 to 2,000 mg/day. Both haloperidol and lithium were found to
be significantly superior to placebo in reducing aggression. However, there were more adverse effects associated with
haloperidol than with lithium, including excessive sedation, acute dystonic reaction, and drooling. Stomachache, headache,
and tremor were more common with lithium than with haloperidol (Campbell et al. 1984).
In a subsequent study, Campbell et al. (1995) conducted a 6-week double-blind, placebo-controlled trial of lithium treatment
for 50 hospitalized children (ages 5–12 years) with aggression and CD. The mean optimal daily dose of lithium was 1,248 mg,
and the mean serum level was 1.12 mEq/L. Lithium was significantly superior to placebo in reducing aggression. The most
common lithium side effects were stomachache, nausea, vomiting, headache, tremor, and urinary frequency.
Eighty-six inpatients (ages 10–17 years) with CD were randomly assigned to lithium (mean daily dose = 1,425 mg; mean
serum level = 1.07 mmol/L) or placebo in a 4-week double-blind trial. Aggression ratings decreased significantly for the
group treated with lithium, compared with the group treated with placebo. More than 50% of patients in the lithium group
experienced nausea, vomiting, and urinary frequency (Malone et al. 2000).
Rifkin et al. (1997) found no significant differences between lithium and placebo in aggression ratings in a 2-week
double-blind study of 33 inpatients with CD. The short duration of treatment may have accounted for the lack of efficacy,
suggesting that a 4- to 6-week trial is necessary to show response. In a clinical series of 17 hospitalized children,
approximately 75% showed reduction of aggression when treated with lithium (Vetro et al. 1985).
Divalproex
Twenty outpatient children and adolescents (ages 10–18 years) with CD or ODD were randomly assigned to divalproex
(dosage range = 750–1,500 mg/day; mean blood level = 82 g/mL) or placebo in a 6-week double-blind, placebo-controlled
crossover study. Of the 15 patients who completed both phases, 12 patients (80%) had a statistically significant superior
response to divalproex. Increased appetite was the only significant side effect (Donovan et al. 2000).
Steiner et al. (2003) randomly assigned 71 adolescents with CD in a residential facility for juvenile offenders to either
therapeutic or low doses of divalproex for 7 weeks; both subjects and outcome raters were blind to treatment status.
Reduction in aggression severity (P = 0.02), improvement in impulse control (P <0.05), and global improvement (P =
0.0008) were greater in the group with therapeutic divalproex levels than in the low-dose condition. Serum level and
“Immature defenses” (as assessed by the Weinberger Adjustment Inventory) predicted response to divalproex, butPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
21 of 58
10/05/2009 16:43
psychiatric comorbidity did not (Saxena et al. 2005).
Saxena et al. (2006) conducted a 12-week open trial of divalproex in 24 children of bipolar parents who had mixed (but
nonbipolar) diagnoses (major depression, cyclothymia, ADHD, and ODD). At the end of the study, 71% of the subjects were
determined to be divalproex responders based on reductions in aggression as assessed by the Overt Aggression Scale.
Clonidine
Seventeen outpatients (ages 5–15 years) with CD or ODD received open treatment with clonidine for 1–18 months.
Aggression decreased significantly in 15 children (88%). The major side effect of clonidine was drowsiness (Kemph et al.
1993).
Despite controversy over its safety (Swanson et al. 1995; see Appendix), clonidine has often been combined with stimulants
to treat comorbid aggression in children with ADHD. In a 2-month randomized comparison of clonidine, methylphenidate, and
clonidine combined with methylphenidate in the treatment of 24 children and adolescents (ages 6–16 years) with ADHD and
CD or ODD, it was found that all three treatment groups showed significant improvement in oppositional and CD symptoms
(Connor et al. 2000). No significant ECG changes were noted.
Children ages 6–14 years with ADHD currently taking methylphenidate were randomly assigned to receive clonidine syrup
0.10–0.20 mg/day (n = 37) or placebo (n = 29) for 6 weeks (Hazell and Stuart 2003). Analysis showed that significantly
more clonidine-treated children than controls were responders on the Conduct subscale (21 of 37 vs. 6 of 29; P <0.01) of the
parent-report Conners Behavior Checklist but not the Hyperactive Index subscale (13 of 37 vs. 5 of 29). Compared with
placebo, clonidine was associated with a greater reduction in systolic blood pressure measured standing and with transient
sedation and dizziness. Clonidine-treated individuals had a greater reduction in a number of unwanted effects associated
with psychostimulant treatment compared with placebo. The findings supported the use of clonidine in combination with
psychostimulant medication to reduce conduct symptoms associated with ADHD.
Beta-Blockers
Propranolol
In an open study of 16 patients (ages 4–24 years) with aggressive outbursts treated with propranolol (mean daily dose =
164 mg), 19 patients (63%) showed a significant reduction in aggressive outbursts. Fatigue was the most common side
effect (Kuperman and Stewart 1987). In a retrospective study of propranolol (dosage range = 50–1,600 mg/day; median
optimal daily dose = 160 mg) for uncontrolled rage outbursts in 30 patients (ages 7–35 years [4 adults]) with organic brain
dysfunction, approximately 75% of patients showed moderate to marked improvement in rage outbursts. The most common
side effects were somnolence, lethargy, and hypotension (Williams et al. 1982). There was a lack of standardized outcome
measures, however, and the wide dosage range is puzzling. Results of this study have never been confirmed by a controlled
trial in children or adolescents.
Nadolol
Nadolol is a beta-blocker that does not cross the blood–brain barrier; thus, any clinical effect would be due to its action on
the peripheral sympathetic nervous system. Its use as an adjunctive pharmacological treatment for aggression and/or
inattention/overactivity was studied in a developmentally delayed child, adolescent, and young adult population (Connor et
- 1997). Twelve subjects (mean age = 13.8 years, range = 9–24 years) completed a 5-month trial of nadolol (mean dosage
= 109 mg/day, range = 30–220 mg/day) with baseline, weekly, and end-of-study assessments of aggression and
inattention/overactivity. Ten subjects (83%) showed clinical improvement while receiving nadolol. Significant improvements
were noted on observer-rated overt categorical aggression, severity of illness, and global impressions of improvement. No
significant effects were found for inattention/overactivity, although blood pressure and pulse were significantly reduced.
Nadolol was well tolerated, with few side effects. While the study suggests usefulness of this agent in treating aggression,
the sample size was small and no controlled trials have been performed. The effectiveness of beta-blockers in the treatment
of aggression must be viewed as unproven; beta-blockers can induce asthma attacks and significant bradycardia so should be
used only as a last resort.
Clinical Recommendations for Disruptive Behavior Disorders and Aggression
The Center for the Advancement of Children’s Mental Health at Columbia University joined with the New York State Office of
Mental Health to develop guidelines for treatment of aggression, which led to the Treatment Recommendations for the Use of
Antipsychotics for Aggressive Youth (TRAAY) (Pappadopulos et al. 2003; Schur et al. 2003). These recommendations call first
for a thorough psychiatric evaluation of the child with severe aggression. Next, a psychosocial intervention should be used
first when the aggression is the primary problem (such as in ODD/CD or intermittent explosive disorder). The clinician should
then treat any primary condition, such as ADHD, psychosis, or mood disorder, that may be causing or contributing to the
aggression. If the aggression does not respond to these steps, then an atypical antipsychotic should be used. Different
atypical antipsychotics should be tried as monotherapy before moving to polypharmacy (e.g., adding a classic mood stabilizer
such as lithium or divalproex to the antipsychotic). Monitoring of weight and laboratory measures of glucose, cholesterol, and
triglycerides is mandatory (Correll and Carlson 2006).
Alpha agonists may be used in more mild aggression or temper outbursts since their effect size on aggression is more modest
(Hazell and Stuart 2003). Beta-blockers should be used only as a last resort. Recently, the Intercontinental Schizophrenia
Outpatient Health Outcomes study compared the response of aggressiveness to clozapine, olanzapine, quetiapine,
risperidone, or haloperidol in a very large sample of adult schizophrenia patients ( n = 3,135) who had 6 months of
monotherapy (Bitter et al. 2005). Olanzapine and risperidone were significantly superior to haloperidol and clozapine for
reducing aggression. Given that typical antipsychotics have higher rates of tardive dyskinesia than atypical antipsychoticsPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
22 of 58
10/05/2009 16:43
(Correll et al. 2004) and now have been shown to be less effective for the treatment of aggression, the use of typical
antipsychotics to treat children with aggression is contraindicated.
TOURETTE’S SYNDROME
The prevalence of Tourette’s syndrome is estimated to be 0.7% in children (Comings et al. 1990). Tourette’s syndrome is
characterized by multiple motor tics and by one or more vocal tics that occur frequently for longer than 1 year (American
Psychiatric Association 2000). The average age at onset of tics is at about age 5 years. Tics tend to increase in severity in the
prepubertal years, but they diminish significantly by age 18 years (Leckman 2002).
-Adrenergic Receptor Agonists
Clonidine
Two of three controlled studies support the efficacy of clonidine treatment for Tourette’s syndrome. In a 12-week
double-blind, placebo-controlled trial, 39 children and adolescents with Tourette’s syndrome were randomly assigned to
clonidine (dosage range = 3.2–5.7 g/kg/day; mean daily dose = 4.4 g/kg) or placebo. The group treated with clonidine had
a statistically significant greater improvement on Tourette’s Syndrome Global Scale (TSGS) scores than did the group
receiving placebo. Clonidine was most effective for motor tics and tics that were noticeable to others. The most common side
effects were sedation, fatigue, dry mouth, dizziness, and irritability (Leckman et al. 1991).
Thirteen children and adolescents (ages 9–16 years) with Tourette’s syndrome were randomly assigned to a 20-week
single-blind, placebo-controlled trial of clonidine (mean daily dose = 5.5 g/kg). Six patients (46%) had a positive response
to clonidine, as determined by TSGS scores. The most common side effects of clonidine were sedation, headache, and
early-morning awakening (Leckman et al. 1985).
Twenty-four children and adolescents with Tourette’s syndrome completed a double-blind crossover study that included two
12-week treatment phases—one phase with clonidine (either 0.0075 mg/kg/day or 0.015 mg/kg/day) and the other phase
with placebo. However, in this study, clonidine did not significantly reduce motor tics, vocalizations, or behaviors. The most
common side effects were sedation, dry mouth, and restlessness. There were no clinically significant changes in blood
pressure or pulse (Goetz et al. 1987).
A retrospective study of 53 children and adolescents (ages 5–18 years) with Tourette’s syndrome was conducted to
determine predictors of response to clonidine treatment. Patients who had a longer duration of vocal tics had a good
behavioral response to clonidine. Of 47 patients who received clonidine for tic control, 57% had a good tic response. The
authors concluded that clonidine is a useful medication for 40%–60% of patients with mild to moderate tics (Lichter and
Jackson 1996).
Clonidine was compared with risperidone in the treatment of children and adolescents with Tourette’s syndrome (Gaffney et
- 2002). Following a single-blind placebo lead-in, 21 subjects (ages 7–17 years) were randomly assigned to 8 weeks of
double-blind treatment with clonidine or risperidone. Research scales evaluated tics and comorbid obsessive-compulsive and
attention-deficit/hyperactivity symptoms. Risperidone (mean dosage = 1.5 ± 0.9 mg/day) and clonidine (mean dosage =
0.175 ± 0.075 mg/day) appeared equally effective in the treatment of tics in an intent-to-treat analysis, as rated by the
YGTSS. Risperidone produced a mean reduction in the YGTSS of 21%; clonidine produced a 26% reduction. There was a
nonsignificant trend for subjects with comorbid obsessive-compulsive symptoms to respond better to risperidone (63%) than
to clonidine (33%). Both treatments caused mild sedation that resolved with time; no clinically significant extrapyramidal
symptoms were observed.
Guanfacine
Scahill et al. (2001) randomly assigned 34 children (mean age 10.4 years) with comorbid ADHD and tic disorders to receive
either placebo or guanfacine for 8 weeks in a double-blind fashion. Tic severity declined by an average of 31% in the
guanfacine group versus 0% in the placebo group. Globally, 9 of 17 subjects were rated as much or very much improved on
the CGI compared with none so rated in the placebo group. One subject withdrew due to sedation; guanfacine was associated
with insignificant decreases in blood pressure. In contrast, in a 4-week double-blind, placebo-controlled study of guanfacine
in 24 children (ages 6–16 years) with Tourette’s syndrome, there was no significant improvement in tic severity for
guanfacine-treated patients compared with placebo-treated patients (Cummings et al. 2002).
Lofexidine
Lofexidine is an 2 agonist used for the treatment of opiate withdrawal in the United Kingdom, similar to the use of clonidine
in the United States. Forty-four medication-free subjects (41 boys and 3 girls; mean age = 10.4 years) with ADHD, combined
type, and a tic disorder participated in an 8-week trial of lofexidine (Niederhofer et al. 2003). Lofexidine was associated with
a mean improvement of 41% in the total score on the teacher-rated ADHD Rating Scale, compared with 7% improvement for
placebo. Eleven of 22 subjects who received lofexidine were blindly rated on the CGI-I as either much improved or very much
improved, compared with none of 22 subjects who received placebo. Tic severity decreased by 27% in the lofexidine group,
compared with 0% in the placebo group. One lofexidine subject withdrew because of sedation at week 4. Lofexidine was
associated with insignificant decreases in blood pressure and pulse. Lofexidine appears to be a safe and effective treatment
for children with tic disorders and ADHD, although it is not clear if it has any advantage over clonidine or guanfacine.
Atypical Antipsychotics
Risperidone
Risperidone is the atypical antipsychotic most studied for the treatment of Tourette’s syndrome and tic disorders. RisperidonePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
23 of 58
10/05/2009 16:43
was compared with pimozide in a 12-week double-blind, placebo-controlled multicenter study of 50 patients (ages 10–65
years) with Tourette’s syndrome. Patients treated with both risperidone (mean daily dose = 3.8 mg) and pimozide (mean
daily dose = 2.9 mg) showed significant improvement on the Tourette’s Syndrome Severity Scale (TSSS; Shapiro et al. 1988).
Fourteen of 26 patients (54%) treated with risperidone and 9 of 24 patients (38%) treated with pimozide had very mild or no
symptoms on the TSSS at endpoint. Fewer patients treated with risperidone than with pimozide reported extrapyramidal side
effects. Side effects common to both treatment groups were depression, fatigue, and somnolence (Bruggeman et al. 2001).
In a double-blind, placebo-controlled trial in 48 adolescent and adult outpatients (ages 14–49 years) with Tourette’s
syndrome, patients were randomly assigned to risperidone (dosage range = 1–6 mg/day; median daily dose = 2.5 mg) or
placebo for an 8-week trial. Risperidone was significantly superior to placebo on the global severity rating of the TSSS.
Adverse effects more common in the group treated with risperidone than in the group treated with placebo were hypokinesia,
tremor, fatigue, and somnolence (Dion et al. 2002).
The efficacy of risperidone was further assessed in an 8-week randomized, double-blind, placebo-controlled trial using the
Total Tic score of the YGTSS as the primary outcome variable (Scahill et al. 2003). Thirty-four medication-free subjects (26
children and 8 adults) ranging in age from 6 to 62 years (mean = 19.7 ± 17.0 years) participated. After 8 weeks of treatment,
the 16 subjects receiving risperidone (mean daily dose = 2.5 ± 0.85) showed a 32% reduction in tic severity from baseline,
compared with a 7% reduction for the 18 subjects receiving placebo (P = 0.004). The 12 children randomly assigned to
risperidone showed a 36% reduction in tic symptoms, compared with an 11% decrease in the 14 children on placebo ( P =
0.004). Two children on risperidone showed acute social phobia, which resolved with dose reduction in 1 subject but resulted
in medication discontinuation in the other. A mean increase in body weight of 2.8 kg was observed in the risperidone group
compared with no change in placebo (P = 0.0001). No extrapyramidal symptoms and no clinically significant alterations in
cardiac conduction times or laboratory measures were observed.
Risperidone was compared to pimozide in the treatment of children and adolescents with tic disorders in a randomized,
double-blind crossover study (Gilbert et al. 2004). Nineteen children (ages 7–17 years) with Tourette’s syndrome or chronic
motor tic disorder were randomly assigned to 4 weeks of treatment with pimozide or risperidone, followed by the alternate
treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the
YGTSS. Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores
(YGTSS: baseline 43.3 ± 17.5, pimozide 34.2 ± 14.2, risperidone 25.2 ± 13.6; P = 0.05). Weight gain during the 4-week
treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse
event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. While
risperidone appeared superior to pimozide for tic suppression, it was associated with greater weight gain.
Most recently, a 6-week open-label study examined the effects of risperidone in the treatment of chronic tic disorder or
Tourette’s disorder in children and adolescents (Kim et al. 2005). The subjects were 15 young children and adolescents
(mean age 10 ± 2.4 years). Seven subjects were diagnosed with Tourette’s disorder and 8 subjects with chronic tic disorder.
Ten of the 15 subjects were administered risperidone for the first time, and 5 of the 15 subjects had been previously treated
with traditional drugs (haloperidol or pimozide). Clinical responses were measured at baseline and after 1, 3, and 6 weeks of
drug treatment by using the Korean version of the YGTSS and the Global Assessment of Functioning Scale. The mean dosage
of risperidone was 0.53 ± 0.13 mg for the first week, 0.90 ± 0.28 mg for the third week, and 1.23 ± 0.37 mg for the sixth
week. Comparison between periods according to the Korean version of the YGTSS showed significant differences ( P <0.01)
between the first week and the third week. After 6 weeks of administration, tic severity scale scores revealed a 36%
reduction in overall tic symptoms; 13 of the 15 subjects showed significant improvement, 1 subject showed no difference in
symptoms, and 1 subject showed worsening of symptoms.
Olanzapine
An open-label trial was performed to explore efficacy and safety of olanzapine for treatment of Tourette’s disorder (Budman
et al. 2001). Ten adult patients (ages 20–44 years) with Tourette’s disorder were treated using an open-label, flexible-dosing
schedule for 8 weeks. Three patients who continued olanzapine were reevaluated after 6 months. Three subjects were
psychotropic medication naive, 5 patients experienced intolerable side effects with conventional antipsychotics, and 2
patients had a past history of successful response to conventional antipsychotics. Tic severity was rated by the YGTSS;
weight, vital signs, and adverse effects were assessed weekly. Two of 10 patients prematurely discontinued olanzapine
owing to excessive sedation. Of 8 patients who completed the 8-week trial, 4 (50%) demonstrated reduction of global tic
severity scores by 20 points, and 6 (75%) demonstrated reductions by 10 points. Sedation, weight gain, increased appetite,
dry mouth, and transient asymptomatic hypoglycemia were the most common side effects. Tic improvements were
maintained in 3 patients reassessed 6 months later. Final olanzapine dosages ranged from 2.5 mg to 20 mg daily (mean =
10.9 mg/day).
The effects of olanzapine on aggressive behavior and tic severity were further examined in children with Tourette’s
syndrome, as described above in the aggression section of this chapter (Stephens et al. 2004). Olanzapine significantly
reduced tics in the 10-week trial.
Ziprasidone
In an 8-week double-blind, placebo-controlled trial, 28 children and adolescents (ages 7–17 years) with Tourette’s syndrome
were randomly assigned to ziprasidone (dosage range = 10–40 mg/day; mean daily dose = 28 mg) or placebo. The group
treated with ziprasidone had a statistically significant reduction in scores on the YGTSS, compared with the group treated
with placebo. The most common adverse event was somnolence. No clinically significant changes in vital signs or ECG
parameters were reported (Sallee et al. 2000).
Nonetheless, concerns continue to be raised about possible cardiovascular effects of ziprasidone. A sudden death occurred inPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
24 of 58
10/05/2009 16:43
a child who participated in a clinical trial of ziprasidone for Tourette’s (Scahill et al. 2005). Despite the fact that a single dose
of ziprasidone did not produce abnormal ECG changes (Sallee et al. 2006), ECG changes were found in the children treated
with ziprasidone for Tourette’s syndrome in a long-term open-label safety study (Blair et al. 2005). In 20 children treated
with ziprasidone, there were statistically significant changes from baseline to peak values in heart rate, pulse rate, and QTc
intervals, but not in QRS complex width. The mean QTc prolongation was 28 ± 26 milliseconds and not related to dose (r =
0.16, P = .07). The peak QTc of three subjects reached or exceeded 450 milliseconds; one subject experienced a
114-millisecond prolongation. These findings, occurring at doses low by current treatment standards, suggest that
electrocardiographic monitoring is warranted when prescribing ziprasidone to children.
Quetiapine
The short-term safety and effectiveness of quetiapine in the treatment of children and adolescents with Tourette’s disorder
were studied in an 8-week open-label trial that included 12 subjects with a mean age of 11.4 ± 2.4 years (Mukaddes and
Abali 2003). Clinical responses, as measured by the Turkish version of the YGTSS, revealed a statistically significant
reduction in tic scores ranging from 30% to 100%. The mean dosage of quetiapine at the end of the study was 72.9 ± 22.5
mg/day. Three subjects complained of sedation in the first week of treatment.
In a retrospective study of clinic patients, 12 patients (ages 8–18 years) with Tourette’s syndrome received quetiapine
therapy at a starting dose of 25 mg/day, which was increased to a mean dosage of 175.0 ± 116.6 mg/day by the eighth week
of the study (Copur et al. 2007). The YGTSS score, which was 21.6 ± 4.0 at baseline, showed significant decreases at 4 and 8
weeks (reducing to 7.5 ± 7.4 and 5.6 ± 8.1, respectively; P <0.003). Routine laboratory parameters and serum prolactin
levels were all normal and did not change throughout treatment. Mild but significant increases in both body weight and BMI
at 4 and 8 weeks compared with baseline were observed. No controlled trials of quetiapine in the treatment of tic disorders
have been performed.
Aripiprazole
Murphy et al. (2005) reported six cases of children and adolescents (age range = 8–19 years, mean age = 12.1 years) who
had comorbid tic disorder and OCD and were treated with aripiprazole (mean dosage = 11.7 mg/day; range = 5–20 mg/day)
for 12 weeks. The subjects experienced a mean reduction of 56% in the severity of their tics as assessed by YGTSS. Similarly,
Yoo et al. (2006) treated 15 children and adolescents with tic disorder with aripiprazole (mean dosage = 10.89 mg/day;
range = 12.5–15 mg/day) and reported a mean reduction of 40% in YGTSS scores; side effects were minimal. Two subjects
experienced nausea, 1 had weight gain, and 1 suffered sedation that responded to dosage reduction.
A case series of 11 consecutive patients with Tourette’s syndrome (age range = 7–50 years; mean age = 7 years) were
treated with aripiprazole; the majority of these had been refractory to other treatments with other antipsychotics (Davies et
- 2006). Ten of the 11 patients who were treated with aripiprazole improved, although to variable degrees. In the majority
of patients, response was sustained with aripiprazole doses ranging from 10 to 20 mg daily. Side effects were mild and
transient.
Typical Antipsychotics: Pimozide and Haloperidol
In a controlled trial comparing pimozide, haloperidol, and placebo in 57 patients (ages 8–65 years) with Tourette’s
syndrome, both active treatments were significantly more effective than placebo, and haloperidol was slightly more effective
than pimozide. No significant differences in side effects were found between haloperidol and pimozide (Shapiro et al. 1989).
Sallee et al. (1997) conducted a 24-week double-blind, placebo-controlled crossover study of haloperidol (mean daily dose =
3.5 mg) and pimozide (mean daily dose = 3.4 mg) in 22 children and adolescents (ages 7–16 years) with Tourette’s
syndrome. Only pimozide was significantly superior to placebo on TSGS scores. There was a threefold higher frequency of
serious side effects (depression, anxiety, and severe dyskinesias) with haloperidol (41%) than with pimozide (14%) in these
youths. Extrapyramidal side effects were reported significantly more often with haloperidol than with pimozide.
In an open clinical trial in 31 patients (ages 10–50 years) with Tourette’s syndrome treated for, on average, 1–2 years, 23
patients (74.2%) receiving pimozide, compared with 14 patients (45.2%) receiving haloperidol, had significant clinical
improvement (Shapiro et al. 1983).
Long-term (6–84 months) treatment with pimozide (0.5–9 mg/day) was reported to produce a good clinical response in 81%
of 65 patients (ages 6–54 years) (Regeur et al. 1986). A 1- to 15-year follow-up of 33 patients (ages 9–50 years) with
Tourette’s syndrome treated with pimozide (2–18 mg/day), haloperidol (2–15 mg/day), or no medications found that
significantly more patients discontinued haloperidol than pimozide because of adverse side effects, especially dyskinesias
and dystonias (Sandor et al. 1990). Thus, pimozide appears superior to haloperidol for treatment of tics.
Other Agents
Metoclopramide
Metoclopramide is a dopamine antagonist used for the treatment of gastroesophageal reflux; it blocks dopamine 2 receptors in
the striatum but not in the cerebral cortex. Acosta and Castellanos (2004) reported that metoclopramide improved tics in 10
patients with tic disorders, with negligible adverse events. Nicolson et al. (2005) randomly assigned 27 children and
adolescents with tic disorders to receive either placebo or metoclopramide in an 8-week double-blind, placebo-controlled
trial. Metoclopramide was started at 5 mg/day and titrated to a maximum dose of 40 mg/day. In the active-drug group, there
was a 39% reduction in tics versus a 13% reduction on placebo ( P = 0.001). No extrapyramidal side effects were reported,
and side effects were not different between metoclopramide and placebo. Further large-scale double-blind,
placebo-controlled trials of this agent are needed.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
25 of 58
10/05/2009 16:43
Nicotine
In a double-blind, placebo-controlled trial, 74 patients (mean age = 11 years) with Tourette’s syndrome who received
haloperidol were randomly assigned to adjunctive transdermal nicotine (7 mg/24 hours) or placebo. Transdermal nicotine
was significantly superior to placebo in reducing symptoms of Tourette’s syndrome (Silver et al. 2001b). A transdermal
nicotine patch (7 mg/24 hours) as adjunctive treatment to antipsychotics was shown to produce significant improvement in
tic severity for 16 children and adolescents with Tourette’s syndrome (Silver et al. 1996).
In a trial of nicotine gum (2 mg) added to haloperidol treatment, 10 youths with Tourette’s syndrome had marked reduction
in tics (Sanberg et al. 1989). In a follow-up study with 10 additional patients, nicotine gum added to haloperidol was shown
to reduce tic frequency during and after 1 hour of gum chewing (McConville et al. 1991). In a controlled study comparing
nicotine gum plus haloperidol, nicotine gum only, and placebo gum in 19 patients with Tourette’s syndrome, the combined
treatment of nicotine gum plus haloperidol showed the greatest reduction in tic frequency and severity (McConville et al.
1992).
Mecamylamine
Mecamylamine is a nicotine receptor antagonist that has been used as an antihypertensive agent and for smoking cessation.
In an 8-week double-blind, placebo-controlled multicenter trial, 61 children and adolescents (ages 8–17 years) with
Tourette’s syndrome were randomly assigned to mecamylamine (dosage range = 2.5–7.5 mg/day) or placebo (Silver et al.
2001a). No significant difference was found on ratings of Tourette’s symptoms between the group treated with
mecamylamine and the group treated with placebo. The most common side effects were weakness, vomiting, muscle
twitching, hypersomnia, and dysphoria.
In one retrospective open-label study of 19 children and adolescents and 5 adults with Tourette’s syndrome treated with
mecamylamine (2.5–6.25 mg/day) for 8–550 days, a significant improvement in severity of illness from baseline was
reported (Macaluso et al. 2000). In another retrospective study that included 9 children with Tourette’s syndrome,
concomitant use of mecamylamine was found to improve symptoms of Tourette’s syndrome (Sanberg et al. 1998). Given that
this agent is rarely used in adults for its indicated purposes, further controlled studies are needed before it is used widely for
tic disorders.
Common Comorbid Conditions
Obsessive-Compulsive Disorder
Tourette’s syndrome is frequently comorbid with OCD (Leckman 2002), necessitating treatment of both conditions. The
Pediatric OCD Treatment Study (POTS) (March et al. 2007) randomly assigned 112 children with OCD (17 of whom had
comorbid tics) to CBT, sertraline, a combination of sertraline and CBT, or placebo. In patients without tics, combination
therapy was superior to CBT alone which in turn was superior to sertraline; all treatments were superior to placebo. In the
small subset of patients with tics, sertraline was not superior to placebo for the treatment of OCD, but combined treatment
was. An earlier study randomly assigned children with OCD and tics to either sulpiride (a typical antipsychotic) or
fluvoxamine for a double-blind treatment period, followed by a single-blind period of combined treatment (George et al.
1993). Fluvoxamine, whether alone or with sulpiride, did not ameliorate tics but was effective for OCD. In contrast, sulpiride
did reduce tics when used as monotherapy.
Attention-Deficit/Hyperactivity Disorder
ADHD is a common comorbid disorder with Tourette’s syndrome. Treatment of both disorders is often necessary in children.
Although prior literature has cautioned against the use of psychostimulants to treat ADHD in Tourette’s syndrome because of
potential exacerbation of tics, recent studies do not support this view. Methylphenidate in low to moderate doses did not
produce a clinically significant increase in motor tics for youths with tic disorders or Tourette’s disorder and ADHD
(Castellanos et al. 1997; Gadow et al. 1995). In a 2-year longitudinal follow-up of 29 children with ADHD and tic disorders
(predominantly Tourette’s syndrome) treated with methylphenidate, there was no evidence that methylphenidate increased
motor or vocal tics (Gadow et al. 1999).
In a 16-week double-blind, placebo-controlled multicenter study, 136 youths with tic disorder and ADHD were randomly
assigned to clonidine (mean daily dose = 0.25 mg), methylphenidate (mean daily dose = 26 mg), combination
methylphenidate plus clonidine (mean daily dose = 0.28 mg), or placebo. Compared with placebo, active treatment groups
showed a significant reduction in tic severity, with combination treatment showing the greatest improvement in tics
(Tourette’s Syndrome Study Group 2002). This is in contrast to an earlier smaller ( N = 37) double-blind, placebo-controlled
trial which found that clonidine did not reduce tic severity in children with Tourette’s syndrome and ADHD (Singer et al.
1995).
Atomoxetine was studied in children and adolescents (ages 7–17 years) who met criteria for ADHD and Tourette’s syndrome
or chronic motor tic disorder (Allen et al. 2005). Patients were randomly assigned to double-blind treatment with placebo ( n
= 72) or atomoxetine (0.5–1.5 mg/kg/day, n = 76) for up to 18 weeks. Atomoxetine treatment was associated with greater
reduction of tic severity at endpoint relative to placebo, approaching significance on the YGTSS total score ( P = 0.063) and
Tic Symptom Self-Report total score (P = 0.095) and achieving significance on the Clinical Global Impressions (CGI)
tic/neurological severity scale score (P = 0.002). Atomoxetine was effective for ADHD symptoms and clearly did not
exacerbate tic symptoms.
In a double-blind, placebo-controlled trial with 37 children with Tourette’s syndrome and ADHD, desipramine, compared with
clonidine, was reported to be more effective for both disorders (Singer et al. 1995). Compared with placebo, desipramine was
found to be significantly more effective for the reduction of both tics and ADHD symptoms in 41 children and adolescents (T.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
26 of 58
10/05/2009 16:43
Spencer et al. 2002). The earlier noted reports of sudden death limit its use. Nortriptyline has also been reported in
retrospective studies to be effective in treating the symptoms of both ADHD and Tourette’s syndrome in children and
adolescents (T. Spencer et al. 1993).
Clinical Recommendations for Tourette’s Syndrome
If a tic is not severe or socially impairing, observation may be in order, as the natural history of tics is to wax and wane; in
general, tics improve over time (Leckman 2002). Often, psychosocial treatment such as habit reversal training is highly
effective at reducing tics (Piacentini and Chang 2006). If conservative treatment fails, use of an alpha agonist would be
desirable, owing to the risk of weight gain and dyslipidemia with atypical antipsychotics. Due to lower efficacy and higher
risk of tardive dyskinesia with typical antipsychotics, the atypical antipsychotics are preferred. Haloperidol and pimozide
should be used only as a last resort when several atypical agents have failed.
In children with comorbid ADHD, a stimulant can be used, but a nonstimulant is indicated if the stimulant exacerbates tics
(Pliszka et al. 2006a). Often stimulants must be combined with alpha agonists or antipsychotics to control both the ADHD and
the tics (Pliszka et al. 2006a; Tourette’s Syndrome Study Group 2002). In children with OCD and comorbid tics, CBT or CBT
combined with a serotonin reuptake inhibitor should be tried first before proceeding with treatment of the tics with alpha
agonists or antipsychotics (March et al. 2007).
SCHIZOPHRENIA
The prevalence of schizophrenia in children younger than 13 years is very rare; however, the prevalence rises in adolescence,
with peak onset from 15 to 30 years (McClellan and Werry 2001). The clinical features of the disorder are similar in youths
and adults, and the same DSM-IV-TR criteria are used to establish a diagnosis (American Psychiatric Association 2000). The
outcome of childhood-onset schizophrenia is reported to be poor (Eggers and Bunk 1997). Typical antipsychotics have been
studied in small randomized, controlled trials of youths with schizophrenia. Recently, the results of large controlled
multicenter trials of atypical antipsychotics in adolescents with schizophrenia have been reported.
Atypical Antipsychotics
Clozapine
There has been one 6-week double-blind, placebo-controlled comparison of clozapine and haloperidol for 21 children and
adolescents (ages 6–18 years) with schizophrenia (Kumra et al. 1996). Clozapine (mean dosage = 176 mg/day; range =
25–525 mg/day) was significantly superior to haloperidol (mean dosage = 16 mg/day; range = 7–27 mg/day) in reducing
positive and negative symptoms of schizophrenia. Clozapine improved interpersonal functioning and enabled patients to live
in a less restrictive setting. Side effects, however, were significant with clozapine. One patient had a seizure, and 3 patients
were given anticonvulsants after they became more irritable and aggressive and experienced epileptiform changes on EEG.
Mild to moderate neutropenia, weight gain, and sinus tachycardia were the other major side effects. One-third of the
clozapine group discontinued use of the medication. One patient was discontinued from the haloperidol treatment group
because of early signs of neuroleptic malignant syndrome.
Clozapine was found to be effective for the treatment of aggressive behavior in children and adolescents with
treatment-refractory schizophrenia (Kranzler et al. 2005). Twenty youths received clozapine (mean daily dose = 476 mg at
week 24) in an open-label study. A significant reduction in the frequency of receiving emergency oral medications and
emergency injectable medications, as well as a decreased use of seclusion, was found on clozapine compared with before
clozapine treatment.
Olanzapine
A positive double-blind, placebo-controlled multicenter study of olanzapine (mean dosage = 11.1 mg/day) for the treatment
of adolescents with schizophrenia was recently reported (Kryzhanovskaya et al. 2006). One hundred adolescents were
randomly assigned to olanzapine (n = 72) or placebo (n = 35) for a 6-week trial. Olanzapine-treated adolescents had
significant improvements on the Brief Psychiatric Rating Scale for Children (BPRS-C; Overall and Pfefferbaum 1984) and
CGI-S compared with the placebo group. There was no significant difference in response rate ( 30% decrease in BPRS-C and
CGI severity 3) between olanzapine (37.5%) and placebo (25.7%) groups. Significantly more olanzapine-treated
adolescents had treatment-emergent high AST/SGOT, ALT/SGPT, and prolactin and low bilirubin and hematocrit during
treatment. There was a significant increase in fasting triglycerides at endpoint in the olanzapine-treated adolescents.
In an 8-week open-label trial of olanzapine (mean dosage = 17.5 mg/day) in the treatment of eight children and adolescents
with schizophrenia, there was a 17% improvement on the BPRS, a 27% improvement on the Scale for the Assessment of
Negative Symptoms, and a 1% improvement on the Scale for the Assessment of Positive Symptoms (Kumra et al. 1998). The
magnitude of the effect size for olanzapine was reported to be greater than that for clozapine. The most common side effects
reported for olanzapine were increased appetite, constipation, nausea, vomiting, headache, somnolence, insomnia, sustained
tachycardia, transient elevation of liver transaminase levels, increased agitation, and difficulty concentrating. Average weight
gain during a 6-week period of olanzapine was 3.4 kg.
In an 8-week open-label prospective trial of olanzapine (mean total daily dose = 12.4 mg/day) in 16 adolescents (age range
= 12–17 years), statistically significant reductions in total PANSS scores and improvement in global functioning were found
(Findling et al. 2003b).
Risperidone
The first positive double-blind, placebo-controlled multicenter trial of risperidone in the treatment of adolescents with
schizophrenia was recently reported (Haas et al. 2007). One hundred sixty patients were randomly assigned to risperidonePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
27 of 58
10/05/2009 16:43
1–3 mg/day (n = 55), risperidone 4–6 mg/day (n = 51), or placebo (n = 54) for a 6-week trial. Both dosage ranges of
risperidone were significantly superior to placebo on the primary efficacy measure, PANSS total change score at endpoint.
The most common adverse events were somnolence (24%), agitation (15%), and headache (13%) in the risperidone 1–3
mg/day group. Extrapyramidal disorder (16%), dizziness (14%), and hypertonia (14%) were the most common adverse
events in the risperidone 4–6 mg/day group. The investigators concluded that the overall risk–benefit ratio favored the lower
dosage range of risperidone.
Aripiprazole
The results of a large double-blind, placebo-controlled multicenter trial of aripiprazole for the treatment of schizophrenia in
adolescents were recently reported (Findling et al. 2007). Three hundred and two patients were randomly assigned to
aripiprazole 10 mg, aripiprazole 30 mg (after 5- or 11-day titration), or placebo over a 6-week period. Both the 10-mg and
30-mg doses of aripiprazole showed statistically significant differences from placebo on the PANSS total score at week 6
(Robb et al. 2007). The most common adverse events associated with aripiprazole were extrapyramidal disorder,
somnolence, and headache.
Quetiapine
No data are available from double-blind, placebo-controlled trials of quetiapine for the treatment of schizophrenia in youth.
There have been two open trials assessing the effectiveness of quetiapine in adolescents with psychotic disorders. J. A. Shaw
et al. (2001) conducted an 8-week open trial of quetiapine (467 mg/day; range 300–800 mg/day) in 15 adolescents with a
diagnosis of psychotic disorder (including 5 with a diagnosis of schizophrenia). Quetiapine significantly reduced psychotic
symptoms in these adolescents. Mean weight gain over the 8-week period was 3.4 kg. There were no changes in prolactin
and cholesterol levels or in ECG or ophthalmic examination findings. The most common adverse effects were somnolence,
agitation, drowsiness, and headache. McConville et al. (2000) assessed the effectiveness of quetiapine in 10 adolescents with
psychotic disorders (7 with schizoaffective disorder, 3 with bipolar disorder). Improvement in both positive and negative
symptoms was observed during the course of the 25-day inpatient trial.
In a long-term study of an adolescent treated with quetiapine, it was reported that continued improvement in positive
symptoms was evident up to 8 months after initiation of treatment, and negative symptoms were still improving at 18
months. After 28 months of treatment, there were no apparent adverse effects (Hayden 2001).
Comparison of Atypical Antipsychotics
In an open-label 12-week trial, risperidone (mean dosage = 1.6 mg/day) was compared with olanzapine (mean dosage = 8.2
mg/day) in the treatment of 25 children with schizophrenia (Mozes et al. 2006). Both groups showed similar significant
improvement in the PANSS total and subscale scores. Eleven (91.7%) of the olanzapine-treated children and 9 (69.2%) of
the risperidone-treated children completed the 12-week study. Both groups showed significant weight increase from baseline
to endpoint (mean 5.8 kg for olanzapine group and mean 4.5 kg for risperidone group).
In an 8-week double-blind study, 50 youths (ages 8–19 years) with psychotic disorders were randomly assigned to
risperidone (mean dosage = 4 mg/day), olanzapine (mean dosage = 12.3 mg/day), or haloperidol (mean dosage = 5
mg/day) (Sikich et al. 2004). Eighty-eight percent of patients treated with olanzapine, 74% treated with risperidone, and
53% treated with haloperidol met response criteria (CGI-I scores of much or very much improved and at least a 20%
reduction in BPRS-C total score). Sedation, extrapyramidal symptoms, and weight gain were the most common side effects.
Clozapine was compared with olanzapine in an 8-week double-blind, randomized trial (P. Shaw et al. 2006). Twenty-five
youths (ages 7–16 years) with schizophrenia who were resistant to treatment with at least two antipsychotics participated in
the trial. Clozapine (mean dosage = 327 mg/day) showed significant improvement in all outcome measures, compared with
olanzapine (mean dosage = 19.1 mg/day), which showed improvement on some outcome measures. Improvement in
negative symptoms was significantly greater for the clozapine group. Clozapine produced more adverse events, including
nocturnal enuresis, tachycardia, and hypertension. Prolactin levels showed significantly greater increases in the olanzapine
group. At 2-year follow-up, 15 patients who were receiving clozapine had continued clinical improvement, although lipid
abnormalities (n = 6) and seizures (n = 1) had occurred.
Typical Antipsychotics
Haloperidol
Haloperidol has been compared with placebo and other typical antipsychotics in controlled trials in youths. In a 10-week
double-blind, placebo-controlled crossover study, the safety and efficacy of haloperidol were assessed in 12 hospitalized
children (ages 5–12 years) with schizophrenia. Haloperidol (optimal dosage range = 0.5–3.5 mg/day) was significantly
superior to placebo in improving overall clinical functioning and reducing ideas of reference, delusions, and hallucinations.
Common side effects were acute dystonic reaction, drowsiness, and dizziness (E. K. Spencer et al. 1992).
Haloperidol was compared with fluphenazine in a 12-week double-blind study of 30 outpatients (ages 6–12 years) with
schizophrenia. Both haloperidol and fluphenazine were very effective in improving symptoms. There was no significant
difference between their overall efficacy; 87% of haloperidol patients and 93% of fluphenazine patients were much or very
much improved. The most common side effects were extrapyramidal symptoms, which occurred more frequently with
fluphenazine than with haloperidol (Engelhardt et al. 1973). In an 8-week double-blind comparison trial of haloperidol and
fluphenazine in 60 children (ages 5–12 years) with schizophrenia, both medications were effective in improving symptoms;
however, haloperidol was more effective than fluphenazine in reducing provocativeness and autism (Faretra et al. 1970).
Haloperidol and loxapine were compared in a 4-week double-blind, placebo-controlled study of 75 adolescent inpatients withPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
28 of 58
10/05/2009 16:43
schizophrenia. Both haloperidol and loxapine were significantly superior to placebo, and there was no significant difference in
efficacy between the two medications. Response rates (based on CGI improvement) were 87.5% for loxapine, 70% for
haloperidol, and 36.4% for placebo. Common side effects were sedation, extrapyramidal symptoms, and somnolence (Pool et
- 1976).
Thiothixene
Thiothixene was compared with thioridazine in a 6-week single-blind study of 21 adolescent inpatients with schizophrenia.
Thiothixene (optimal mean dosage = 16.2 mg/day) and thioridazine (optimal mean dosage = 178 mg/day) were equally
effective in controlling symptoms, although most of the adolescents continued to be quite impaired. Thiothixene was less
sedating than thioridazine (Realmuto et al. 1984). Thiothixene was also compared with trifluoperazine in an 8-week
double-blind study of 16 children (ages 8–15 years) with schizophrenia (Wolpert et al. 1967). The effects of both medications
were similar in terms of decreasing avoidance behavior, reducing stereotypic behavior, and increasing peer socialization. Side
effects were minimal in both groups.
In a single-blind study, thiothixene (10–24 mg/day) was administered to 18 children (ages 5–13 years) with schizophrenia.
All patients experienced global clinical improvement, with significant improvement noted in motor activity, stereotyped
behavior, coordination, sleeping, affect, exploratory behavior, concentration, eating habits, and range of communication.
Common side effects were extrapyramidal symptoms and increased salivation (Waizer et al. 1972).
Trifluoperazine
A study of four children with schizophrenia who received trifluoperazine (4 mg/day) reported that the medication had little
influence in improving classroom behavior for three of the four children (Simpson 1977).
Pimozide
Pimozide (dosage range = 1–2 mg/day) produced improvement in affective contact and social behavior in youths with
schizophrenia in a small open study followed by placebo discontinuation (Pangalila-Ratulangi 1973).
Clinical Recommendations for Schizophrenia
Both typical and atypical antipsychotics have demonstrated some effectiveness in the treatment of schizophrenia in youths,
although the sample sizes have been small in the trials of typical antipsychotics. Given fewer reported extrapyramidal side
effects and tardive dyskinesia with atypical antipsychotics, it would be reasonable to initiate treatment with an atypical
antipsychotic for a child with schizophrenia. Clozapine, however, should not be initiated unless at least two other
antipsychotics have been tried without success. It is important to monitor weight and metabolic parameters for children who
receive atypical antipsychotics.
Antipsychotics should be administered for a period of no less than 4–6 weeks at adequate dosages in order to determine
efficacy. If there is no response or intolerable side effects, then a trial of a different antipsychotic should be initiated
(American Academy of Child and Adolescent Psychiatry 2001).
There are no data to guide maintenance treatment. Because the majority of youths will have a second psychotic episode
within 5–7 years of stabilization, there is a significant risk of relapse with medication withdrawal (Kumra 2000). It is
recommended that first-episode patients receive maintenance pharmacological treatment for 1–2 years after the initial
episode, given the risk of relapse (American Academy of Child and Adolescent Psychiatry 2001). If medication
discontinuation is attempted, the dosage should be gradually reduced over several months.
AUTISTIC DISORDER AND OTHER PERVASIVE DEVELOPMENTAL DISORDERS
The prevalence of autistic disorder and other pervasive developmental disorders is estimated to be up to 18.7 per 10,000
population (Howlin 2000). Core features of these disorders are impairments in communication and social skills and the
restriction of interests and activities (American Psychiatric Association 2000). Associated behavioral features include
hyperactivity, stereotypies, attentional problems, self-injurious behavior, aggression, mood lability, anxiety, obsessions, and
compulsions. The majority of children with autistic disorder will continue to have significant social and communication
impairments throughout adulthood, although some individuals will be able to live independently (Buitelaar and
Willemsen-Swinkels 2000).
Pharmacotherapy is one component of a treatment plan for children with autism. Although there are controlled studies, open
trials, and case reports of a variety of pharmacological agents, no medication has been identified that effectively treats the
core symptoms of autism and other pervasive developmental disorders (Tanguay 2000). Pharmacotherapy is aimed at target
symptoms in order to increase the ability of these children to participate in educational and other psychosocial interventions
(Volkmar et al. 1999).
Atypical Antipsychotics
Risperidone
Risperidone has received FDA approval for the treatment of irritability associated with autistic disorder in children and
adolescents, including symptoms of aggression toward others, deliberate self-injuriousness, temper tantrums, and quickly
changing moods.
Risperidone was chosen as the first drug to be studied by the Research Units on Pediatric Psychopharmacology (RUPP)
network funded by NIMH, which was designed to investigate the safety and efficacy of medications for treating maladaptive
symptoms and behaviors associated with autistic disorders (McDougle et al. 2000b). One hundred one children ranging in age
from 5 to 17 years with autistic disorder participated in an 8-week double-blind, placebo-controlled trial of risperidonePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
29 of 58
10/05/2009 16:43
(dosage range = 0.5–3.5 mg/day; mean = 1.8 mg/day). A significantly greater positive response—defined as a 25% decrease
in the irritability subscale of the Aberrant Behavior Checklist and a rating of much or very much improved on the CGI-I
scale—was found for the risperidone group (69%) compared with the placebo group (12%). Adverse events of increased
appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group.
Mean weight gain was 2.7 kg in the risperidone group and 0.8 kg in the placebo group. An 18-month follow-up showed that
the majority of subjects who responded to risperidone during intermediate-length treatment continued to show improvement
(McDougle et al. 2004).
In an 8-week double-blind, placebo-controlled trial, 79 children (ages 5–12 years) with autism and other pervasive
developmental disorders were randomly assigned to either placebo or risperidone (mean dosage = 1.5 mg/day).
Risperidone-treated patients exhibited a 64% improvement over baseline irritability, compared with a 30.7% improvement in
placebo-treated subjects (Shea et al. 2004).
In a 6-month placebo-controlled study of 40 children (ages 2–9 years) with autism, risperidone (1 mg/day) decreased
aggressiveness, hyperactivity, and irritability and improved social responsiveness and nonverbal communication. Appetite
increase, weight gain, sedation, and transient dyskinesias in the risperidone-treated children were reported (Nagaraj et al.
2006).
The long-term effects of risperidone were assessed in youths (ages 5–17 years) with autism spectrum disorders (Troost et al.
2005). Twenty-four youths received risperidone for 6 months, followed by a double-blind discontinuation to placebo or
continued risperidone. Risperidone was superior to placebo in preventing relapse, with relapse rates of 25% and 75%,
respectively. Weight gain, increased appetite, fatigue, and anxiety were the most common side effects.
Similar rates of relapse were reported after placebo substitution following 4 months of risperidone treatment in 32 children
with autism. The relapse rates were 62.5% in the placebo substitution group and 12.5% in those who continued risperidone
treatment (Research Units on Pediatric Psychopharmacology Autism Network et al. 2005).
Olanzapine
In a 12-week open-label study of olanzapine (mean dosage = 7.8 mg/day) in eight patients (ages 5–42 years) with autistic
disorder or pervasive developmental disorder not otherwise specified, the six patients who completed the trial showed much
or very much global improvement (Potenza et al. 1999). Significant improvements were found in hyperactivity, social
relatedness, affectual responses, sensory responses, language usage, self-injurious behavior, aggression, irritability, anxiety,
and depression. The most significant adverse effects were increased appetite and weight gain in six patients and sedation in
three patients.
In a 3-month open study of olanzapine (dosage range = 1.25–20 mg/day) in 25 subjects (ages 6–16 years) with pervasive
developmental disorder, significant global improvement was reported. The most common side effect was weight gain (mean
= 4.8 kg) (Kemner et al. 2002).
Olanzapine was compared with haloperidol in a 6-week open trial in 12 children (ages 4–11 years) with autistic disorder
(Malone et al. 2001). Both the olanzapine treatment (mean dosage = 7.9 mg/day) and the haloperidol treatment (mean
dosage = 1.4 mg/day) reduced symptoms of social withdrawal and stereotypies and improved speech and object relations.
Quetiapine
The effectiveness of quetiapine (dosage range = 100–350 mg/day) was assessed in a 16-week open-label trial in six children
with autistic disorder (Martin et al. 1999). No significant behavioral improvements were found from baseline to endpoint.
Only two subjects completed the full 16 weeks of treatment; subjects terminated early because of nonresponse and sedation.
One patient had a possible seizure during the fourth week of treatment; other side effects included behavioral activation,
increased appetite, and weight gain.
In a 12-week open-label study of quetiapine of nine adolescents (mean age = 14.6 years) with autistic disorder, only two
patients were much or very much improved at study endpoint (Findling et al. 2004). The most common side effects reported
were sedation and weight gain.
Ziprasidone
The use of ziprasidone (mean daily dose = 59.23) for the treatment of autistic children, adolescents, and young adults was
evaluated in an open-label study of 12 patients (ages 8–20 years) for at least 6 weeks (McDougle et al. 2002). Fifty percent
of patients were responders based on a CGI scale rating of much improved or very much improved. Transient sedation was
the most common side effect.
Clozapine
A case series of three children with autistic disorder treated with clozapine (up to 100 mg/day) for 3 months reported a 40%
improvement in measures of abnormal object relationships, negativism, fidgetiness, and hyperactivity. After 8 months of
clozapine treatment (mean daily dose = 200 mg), two of the children showed a substantial improvement in language and
communication skills (Zuddas et al. 1996).
Typical Antipsychotics
Haloperidol
Haloperidol has been the most widely studied typical antipsychotic for the treatment of autism in children and adolescents. In
double-blind, placebo-controlled studies, haloperidol has been shown to be significantly superior to placebo in reducingPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
30 of 58
10/05/2009 16:43
maladaptive behaviors and facilitating learning on discrimination tasks (Campbell et al. 1982); in increasing retention of
discrimination learning and decreasing maladaptive behaviors in the classroom (L. T. Anderson et al. 1984); in decreasing
occurrence of stereotypies and increasing orienting reactions of children (Cohen et al. 1980); and in decreasing hyperactivity,
temper tantrums, withdrawal, and stereotypies and increasing relatedness (L. T. Anderson et al. 1989). Optimal dosages of
haloperidol in these studies ranged from 0.25 to 4 mg/day. The most common side effects were sedation, increased
irritability, and acute dystonic reactions. Weight gain was modest (0.2 kg) in autistic children who received haloperidol
0.25–3.5 mg/day for a 6-month period (Silva et al. 1993).
Haloperidol was compared with behavioral therapy in a double-blind, placebo-controlled trial in 40 children (ages 2–7 years)
with autistic disorder (Campbell et al. 1978). For children older than 4.5 years, haloperidol was found to be significantly
superior to placebo in reducing the severity of withdrawal behaviors and stereotypies. The combination of behavior therapy
and haloperidol was the most effective in facilitating the acquisition of imitative speech.
The long-term efficacy of haloperidol was assessed in 48 children (ages 2–8 years) with autism who received haloperidol for
6 months (Perry et al. 1989). Haloperidol remained effective throughout the 6-month treatment period, and it was equally
effective whether it was given continuously or on a discontinuous schedule consisting of 5 days on haloperidol and 2 days on
placebo. Children who had symptoms of irritability, angry and labile affect, and uncooperativeness were the best responders
to haloperidol.
Reversible haloperidol-related dyskinesias have been reported in 29% of autistic children (Campbell et al. 1988a). Factors
related to the development of haloperidol-induced dyskinesias in acute studies of autistic children include female gender
(Campbell et al. 1988a) and prenatal and perinatal complications (Armenteros et al. 1995). In a long-term prospective study
of haloperidol treatment for 118 children with autism, withdrawal dyskinesias developed in 40 children (33.9%), with 20
children having more than one dyskinetic episode (Campbell et al. 1997). Female gender, prenatal and perinatal
complications, greater cumulative haloperidol dose, and/or longer exposure to haloperidol increased the risk of withdrawal
dyskinesias.
Pimozide
Pimozide was compared with haloperidol and placebo in a controlled crossover trial that included 34 children with autistic
disorder (Naruse et al. 1982). Pimozide and haloperidol were significantly more effective than placebo in reducing
maladaptive behavior, such as lack of interest, self-centeredness, and aggressiveness. There was no significant difference
between pimozide and haloperidol. An open study of 8 children treated with pimozide (mean dosage = 4.9 mg/day) reported
improved behavioral functioning (Ernst et al. 1992).
Serotonin Reuptake Inhibitors
The only placebo-controlled studies of serotonin reuptake inhibitors are with fluoxetine and fluvoxamine treatment of autistic
disorders.
Fluoxetine
The efficacy of liquid fluoxetine was assessed to treat repetitive behaviors in children and adolescents with autism spectrum
disorders. Forty-five youths were randomly assigned to two 8-week acute phases in a double-blind crossover study.
Low-dose liquid fluoxetine (mean dosage = 9.9 mg/day) was superior to placebo in reducing repetitive behaviors (Hollander
et al. 2005).
In an open study of fluoxetine (dosage range = 20 mg every other day to 80 mg/day) in 23 patients (ages 7–28 years) with
autistic disorder, 15 patients (65%) experienced significant clinical global improvement (Cook et al. 1992). The most
common side effects were restlessness, hyperactivity, agitation, decreased appetite, and insomnia. Case reports and a
retrospective chart review of fluoxetine treatment for youths with autistic disorder reported improvements in irritability,
stereotypies, and inappropriate speech (Fatemi et al. 1998; Ghaziuddin et al. 1991; Todd 1991).
Fluvoxamine
A double-blind, placebo-controlled study of fluvoxamine treatment (mean dosage = 106.9 mg/day) in 34 children and
adolescents with autistic disorder did not find significant clinical improvement with fluvoxamine (McDougle et al. 2000a).
Sertraline
Open-label sertraline (dosage range = 25–50 mg/day) was administered to nine children with autistic disorder (Steingard et
- 1997). Eight of the nine patients showed clinically significant improvement in ability to tolerate changes in their routine or
environment without displaying symptoms of anxiety, irritability, or agitation. Clinical response tended to occur in 2–8
weeks. In two cases, behavioral worsening was observed when the dosage was raised to 75 mg/day.
Citalopram
Seventeen children with autistic spectrum disorders were treated with citalopram for at least 2 months (Couturier and
Nicolson 2002). Ten children (59%) were judged to be much or very much improved on measures of aggression, anxiety, and
stereotypies. Common adverse side effects were insomnia and agitation.
Paroxetine
A child with autistic disorder who received paroxetine (up to 10 mg/day) showed a significant reduction in preoccupations
and temper tantrums within 6 weeks of treatment initiation (Posey et al. 1999). Snead et al. (1994) described a case of an
adolescent with autistic disorder whose symptom of self-injurious behavior resolved within 2 weeks of treatment initiation
with paroxetine (20 mg/day).Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
31 of 58
10/05/2009 16:43
Escitalopram
In a 10-week open-label study, 28 youths (ages 6–17 years) with pervasive developmental disorder received escitalopram.
There was significant improvement in irritability and clinical global functioning. Twenty-five percent of youths responded at
escitalopram daily doses less than 10 mg, and 36% of youths responded at doses greater than or equal to 10 mg (Owley et
- 2005).
Other Antidepressants
Clomipramine
The results of controlled trials with clomipramine in the treatment of autistic disorder have yielded mixed results.
Clomipramine and haloperidol were compared in a placebo-controlled crossover study for 7 weeks with active treatment
(Remington et al. 2001). Thirty-six patients (ages 10–36 years) with autistic disorder were randomly assigned to
clomipramine (mean dosage = 128.4 mg/day; range = 100–150 mg/day), haloperidol (mean dosage = 1.3 mg/day; range =
1–1.5 mg), or placebo. A significant advantage for haloperidol was found on global measures of autistic symptom severity
and on specific measures of irritability and hyperactivity. Clomipramine was comparable to haloperidol only in patients who
were able to complete a full therapeutic trial. However, significantly fewer patients receiving clomipramine versus
haloperidol were able to complete the trial (37.5% vs. 69.7%, respectively) for reasons related to inefficacy, side effects, or
behavioral problems.
Clomipramine was compared with desipramine for the treatment of autistic disorder in a double-blind crossover study with a
sample of 30 patients ranging from 6 to 23 years of age (Gordon et al. 1993). Clomipramine was significantly superior to both
desipramine and placebo on ratings of autistic symptoms, including stereotypies, anger, and compulsive ritualized behaviors.
No differences were found between desipramine and placebo. One patient had a grand mal seizure during the second week of
clomipramine therapy. Clomipramine dosage reduction was necessary in two patients because of QT interval prolongation in
one case and severe tachycardia in the other. Increased irritability, temper outbursts, and aggression occurred in 8 of the 12
subjects receiving desipramine.
Mirtazapine
In an open-label study of mirtazapine (dosage range = 7.5–45 mg/day; mean = 30.3 mg/day) in 26 patients (ages 3–23
years) with pervasive developmental disorders, 9 patients (34.6%) were judged much or very much improved in symptoms
of aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia (Posey et al. 2001). Mirtazapine did
not improve symptoms of social or communication impairment. Common side effects included increased appetite, irritability,
and transient sedation.
Venlafaxine
The effectiveness of venlafaxine was assessed in an open retrospective study of 10 patients (ages 3–21 years) with pervasive
developmental disorders (Hollander et al. 2000). Six of 10 patients who received venlafaxine (mean dosage = 24.4 mg/day;
range = 6.25–50 mg/day) over an average of 5 months were much or very much improved. Improvements were shown in
repetitive behaviors, restricted interests, social deficits, communication and language function, inattention, and
hyperactivity. Side effects of venlafaxine included behavioral activation, nausea, inattention, and polyuria.
Mood Stabilizers
Lamotrigine
Twenty-eight children (ages 3–11 years) with autistic disorder participated in a double-blind, placebo-controlled study of
lamotrigine (mean maintenance dosage = 5 mg/kg/day) for a 12-week study period (Belsito et al. 2001). There were no
significant differences between the lamotrigine and placebo groups on severity of behavioral symptoms. Insomnia and
hyperactivity were the most frequently reported side effects. No children in the study were withdrawn because of rash.
Lithium
Case studies have reported the effectiveness of lithium in improving manic-like symptoms in children with autism
(Kerbeshian et al. 1987; Shafey 1986; Steingard and Biederman 1987).
Anxiolytics
Buspirone
In a 6- to 8-week open trial, 22 children and adolescents with pervasive developmental disorders or autistic disorder were
treated with buspirone (dosage range = 15–45 mg/day) (Buitelaar et al. 1998). Sixteen patients (73%) showed moderate to
marked improvement in anxiety and irritability symptoms. In a 4-week open trial comparing buspirone with fenfluramine or
methylphenidate in children with autistic disorder, two of three children who received buspirone showed improvement in
hyperactivity (Realmuto et al. 1989). One patient who received fenfluramine had a slight decrease in hyperactivity.
Behavioral deterioration was found in one of two patients treated with methylphenidate.
Other Agents
Flumazenil
One of two children who received flumazenil (a benzodiazepine antagonist) showed a mild increase in interpersonal
engagement (Wray et al. 2000). No adverse effects were seen in either child.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
32 of 58
10/05/2009 16:43
Naltrexone
Double-blind, placebo-controlled trials of naltrexone in the treatment of children with autistic disorder have reported modest
improvement of symptoms, including reductions in autistic symptomatology (Scifo et al. 1996); decreased self-injurious
behavior, improved socialization, and increased attentiveness and communication (Leboyer et al. 1992); improved
socialization, decreased withdrawal, increased proximity seeking, increased eye contact, increased attentiveness, and
decreased restlessness and affective lability (Leboyer et al. 1990); decreased irritability (Willemsen-Swinkels et al. 1995);
decreased hyperactivity and irritability (Willemsen-Swinkels et al. 1996); decreased restlessness and hyperactivity (Kolmen
et al. 1995); decreased self-injury (Barrett et al. 1989); decreased hyperactivity (Campbell et al. 1993); and global
improvement as assessed by teacher ratings (Kolmen et al. 1997). Dosage ranges of naltrexone were 0.5–1.5 mg/kg in these
studies. There were no significant changes in cardiovascular parameters of heart rate or systolic blood pressure for children
with autism treated with naltrexone (Herman et al. 1993).
In other controlled trials, naltrexone demonstrated no superiority over placebo in producing beneficial changes in social
behavior (Willemsen-Swinkels et al. 1995), social and stereotypic behavior (Willemsen-Swinkels et al. 1996), social behavior
and activity level (Bouvard et al. 1995), discrimination learning (Campbell et al. 1993), and communication (Feldman et al.
1999).
During 6-month continuation treatment for naltrexone-responsive children with autism, the hyperactivity-reducing effect of
naltrexone was maintained (Willemsen-Swinkels et al. 1999). However, no additional gains in social interaction,
communication, or stereotypic behaviors were observed after the 4-week acute phase. Moreover, parents did not request to
continue treatment with naltrexone for their autistic children. These researchers therefore did not advocate the routine use of
naltrexone for children with autism.
Clonidine
A double-blind, placebo-controlled crossover study with transdermal clonidine (0.005 mg/kg/day or placebo by a weekly
transdermal patch) in nine patients (ages 5–33 years) with autistic disorder was conducted for a total 8-week active period
(Fankhauser et al. 1992). Significant improvement with clonidine, compared with placebo, was found on measures of social
relationship, affectual responses, and sensory responses. In a double-blind, placebo-controlled crossover trial of clonidine in
eight children with autistic disorder, clonidine was found to be modestly effective in reducing irritability and hyperactivity
(Jaselskis et al. 1992).
Methylphenidate
There have been two small double-blind, placebo-controlled crossover studies of methylphenidate for the treatment of
autistic disorder in children ranging in age from 5 to 11 years. In a study that included 10 children, a modest but statistically
significant improvement in hyperactivity was found with methylphenidate treatment, compared with placebo (Quintana et al.
1995). No significant side effects, such as worsening of behavior or of stereotypic movements, were observed. In a study that
included 13 children, 6 patients had a significant decrease in hyperactivity, stereotypies, and inappropriate speech (Handen
et al. 2000). However, there were no changes found on the Child Autism Rating Scale. Significant adverse side effects
occurred in some children and included social withdrawal and irritability, particularly at a methylphenidate dosage of 0.6
mg/kg/day.
Fenfluramine
Fenfluramine, a serotonin agonist, has been studied in autism. It was marketed as an anti-obesity agent but was withdrawn
from the market because of pulmonary hypertension when used in combination with phentermine.
Following the report of significant clinical improvement and an increase in the IQs of three boys who received fenfluramine
(E. Geller et al. 1982), a number of double-blind, placebo-controlled studies were conducted to assess the efficacy and safety
of fenfluramine in the treatment of children with autism. The results of these studies have been mixed, with modest
improvements in autistic symptoms found in a few studies.
Children who received fenfluramine, compared with placebo, were reported to have decreased hyperactivity, decreased
stereotypies, increased eye contact, increased socialization, and increased use of appropriate language (Ritvo et al. 1983);
decreased motor activity, decreased distractibility, and improved mood (August et al. 1984); increased social awareness, eye
contact, and attention to schoolwork (Ritvo et al. 1984); increased IQ, increased communication, and increased socialization
(Ritvo et al. 1986); decreased respiratory stereotypies (Gastaut et al. 1987); reduction in motor activity, anxiety, mood
disturbance, and distractibility (Barthelemy et al. 1989); improved attention span and activity level (Groden et al. 1987);
increased language and awareness of environment in children with IQs above 40 (Stubbs et al. 1986); and decreased activity
level, increased attention, and decreased hyperactivity (August et al. 1985). Open studies with fenfluramine reported
improvement in relatedness, hyperactivity, irritability, and aggressiveness (Campbell et al. 1986) and improved
communication and social awareness (Klykylo et al. 1985).
However, numerous reports of controlled trials failed to show significant superiority of fenfluramine relative to placebo in the
treatment of children with autistic disorder (Beeghly et al. 1987; Beisler et al. 1986; Campbell et al. 1988b; Coggins et al.
1988; Ekman et al. 1989; Ho et al. 1986; Kohler et al. 1987; Leventhal et al. 1993; Ross et al. 1987; Sherman et al. 1989;
Stern et al. 1990; Yarbrough et al. 1987). The average dose of fenfluramine was 1.5 mg/day in these studies.
In a review of the literature, Aman and Kern (1989) concluded that there was no evidence that IQ was increased by
fenfluramine. Fenfluramine may enhance social relatedness, reduce stereotypic behavior, lessen overactivity, and improve
attention span in some children, although the results are inconsistent. In another review, du Verglas et al. (1988) concluded
that fenfluramine may have positive effects in reducing hyperactivity and stereotypic behaviors in 33% of children and notedPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
33 of 58
10/05/2009 16:43
that the best responders were children with the highest baseline IQs.
There had been concern about the untoward effects of fenfluramine in children with autism. Realmuto et al. (1986) described
listlessness, food refusal, and stomach upset in the initial phase of treatment, followed by irritability, agitation, and crying
with continued medication use. Decreased appetite, lethargy, irritability, and behavioral regression were also reported with
fenfluramine use (Piggott et al. 1986). In a 2-year follow-up of autistic children treated with fenfluramine, reasons for
discontinuing the medication included development of tolerance, appetite and weight changes, and the need for other
interventions, particularly other psychotropic medications (Varley and Holm 1990). Significant concern had also been raised
about possible neurotoxicity with the use of fenfluramine in children, based on studies of the neurotoxic effects of
fenfluramine in animals (Schuster et al. 1986).
Famotidine
The efficacy of famotidine, a histamine2 receptor antagonist, was assessed in a randomized, double-blind, placebo-controlled
crossover study in nine children (ages 3–8 years) with a diagnosis of pervasive developmental disorder (Linday et al. 2001).
The maximum daily dose of famotidine was 100 mg (2 mg/kg/day). Four of nine children (44%) randomly assigned to
famotidine showed increased social interaction and affection. Children with marked stereotypy did not respond.
Amantadine
Thirty-nine children and adolescents (ages 5–19 years) with autistic disorder were randomly assigned in a 9-week
double-blind, placebo-controlled trial to amantadine (5 mg/kg/day) or placebo (King et al. 2001). Parent ratings did not
demonstrate a statistically significant change in irritability and hyperactivity, with a mean placebo response rate of 37%
versus 47% for amantadine. However, clinician ratings of improvement in behavioral changes of hyperactivity and
inappropriate speech were significantly higher in the amantadine group than in the placebo group. Overall clinical functioning
was rated higher in the amantadine group than in the placebo group (53% improved vs. 25% improved, respectively). The
most common side effects were insomnia and somnolence.
Amisulpride
Nine children (ages 4–13 years) with autistic disorder participated in a randomized, double-blind crossover trial of
amisulpride (1.5 mg/kg/day) and bromocriptine (0.15–0.20 mg/kg/day) for two consecutive 8-week treatment periods
(Dollfus et al. 1992). Neither amisulpride nor bromocriptine showed a statistically significant effect on global autism scores.
However, the two agents differed in their effects on specific autistic symptoms, with amisulpride having a more positive
effect on behavioral inhibition and withdrawal symptomatology and bromocriptine having a more positive effect on motor
hyperactivity and attention symptoms. The most common side effects were insomnia and anorexia for amisulpride and
bromocriptine, respectively. Amisulpride is not available in the United States or Canada.
Sulpiride
Sulpiride (up to 400 mg/day) was reported to significantly reduce abnormal speech and withdrawal in a teenager with
autistic disorder (Scott and Eames 1988). Sulpiride is not available in the United States or Canada.
Secretin
Following the report of marked improvement in socialization and communication skills in three children with autism who had
received secretin during an upper endoscopy (Horvath et al. 1998), there was a flurry of media reports about the success of
this neuropeptide hormone. It is estimated that approximately 2,500 children have received secretin injections for the
treatment of autism (Kastner 1998). However, randomized, double-blind, placebo-controlled trials of single-dose intravenous
secretin for the treatment of children with autism have produced no evidence that secretin is effective for the treatment of
autism or pervasive developmental disorder in 174 children and adolescents who participated in the studies. There have been
no significant changes in parents’ perceptions of autistic behaviors or language skills (Coniglio et al. 2001), no improvement
in either primary or secondary features of autism (Sandler et al. 1999), and no change in social and communication skills
(Owley et al. 2001).
The efficacy of repeated doses of secretin in the treatment of autism was assessed in a double-blind, placebo-controlled trial
in 64 children (ages 2–7 years) who received two doses of secretin 6 weeks apart (Roberts et al. 2001). No differences
between the secretin and placebo groups were found on measures of language, cognition, or autistic symptomatology.
Similarly, in a controlled study of 12 children with autism, there were no significant differences between secretin and placebo
groups on language or social assessments (Corbett et al. 2001).
Clinical Recommendations for Autistic Disorder and Other Pervasive Developmental Disorders
There is no evidence that pharmacotherapy is effective in treating the core social and communication deficits in autistic
disorder. However, medications have been shown to be useful in treating associated symptoms, such as hyperactivity,
inattention, stereotypies, self-injurious behavior, tantrums, aggression, mood lability, and anxiety. Antipsychotics may
decrease withdrawal, stereotypies, and aggression and may facilitate learning. To date, the most data available support the
use of risperidone for treating irritability, aggression, self-injurious behavior, temper tantrums, and mood lability associated
with autistic disorder in children and adolescents. Serotonin reuptake inhibitors and other antidepressants have been shown
to reduce compulsions, anxiety, and depression in children with autism. In some cases, naltrexone may reduce hyperactivity,
irritability, and self-injurious behavior. Stimulants may increase attention span and reduce hyperactivity. Given concerns
about the potential neurotoxicity and limited effectiveness of fenfluramine, this agent should be used with extreme caution in
children with autism. Secretin is not recommended for use because it has no established efficacy.
There are limited data on the long-term use of pharmacotherapy in children with autism. After receiving anPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
34 of 58
10/05/2009 16:43
intermediate-length (4–6 months) course of treatment with risperidone, children withdrawn from the medication through
placebo substitution had high relapse rates (Research Units on Pediatric Psychopharmacology Autism Network et al. 2005;
Troost et al. 2005). Therefore, clinicians must weigh the risk–benefit ratio of maintenance medication treatment in this
population and carefully monitor children for side effects.
REFERENCES
Abbott Laboratories: Multicenter Controlled Trial of Divalproex ER for Pediatric Bipolar I Disorder. Abbott Park, IL, Abbott
Labs, 2007. Available at: http://www.clinicalstudyresults.org. Accessed May 24, 2007.
Abikoff H, McGough J, Vitiello B et al: Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity
and anxiety disorders. J Am Acad Child Adolesc Psychiatry 44:418–427, 2005 [PubMed]
Acosta MT, Castellanos FX: Use of the “inverse neuroleptic” metoclopramide in Tourette syndrome: an open case series. J
Child Adolesc Psychopharmacol 14:123–128, 2004 [PubMed]
Alessi N, Bos T: Buspirone augmentation of fluoxetine in a depressed child with obsessive-compulsive disorder. Am J
Psychiatry 148:1605–1606, 1991 [PubMed]
Allen AJ, Kurlan RM, Gilbert DL, et al: Atomoxetine treatment in children and adolescents with ADHD and comorbid tic
disorders. Neurology 65:1941–1949, 2005 [PubMed]
Aman MG, Kern RA: Review of fenfluramine in the treatment of the developmental disabilities. J Am Acad Child Adolesc
Psychiatry 28:549–565, 1989 [PubMed]
Aman MG, De Smedt G, Derivan A, et al: Double-blind, placebo-controlled study of risperidone for the treatment of disruptive
behaviors in children with subaverage intelligence. Am J Psychiatry 159:1337–1346, 2002 [Full Text] [PubMed]
Aman MG, Binder C, Turgay A: Risperidone effects in the presence/absence of psychostimulant medicine in children with
ADHD, other disruptive behavior disorders, and subaverage IQ. J Child Adolesc Psychopharmacol 14:243–254, 2004
[PubMed]
Ambrosini PJ, Bianchi MD, Metz C, et al: Evaluating clinical response of open nortriptyline pharmacotherapy in adolescent
major depression. J Child Adolesc Psychopharmacol 4:233–244, 1994
American Academy of Child and Adolescent Psychiatry: Practice parameters for the assessment and treatment of children and
adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 37 (10 suppl):27S–45S, 1998
American Academy of Child and Adolescent Psychiatry: Practice parameters for the assessment and treatment of children and
adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 40 (7 suppl):4S–23S, 2001
American Academy of Child and Adolescent Psychiatry: Practice parameter for the assessment and treatment of children and
adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 46:894–921, 2007
American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al:
Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 27:596–601, 2004
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington,
DC, American Psychiatric Association, 1987
American Psychiatric Association: Diagnostic and Statistical Manual for Mental Disorders, 4th Edition. Washington, DC,
American Psychiatric Association, 1994
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision.
Washington, DC, American Psychiatric Association, 2000
Anderson JC, Williams S, McGee R, et al: DSM-III disorders in preadolescent children. Prevalence in a large sample from the
general population. Arch Gen Psychiatry 44:69–76, 1987 [PubMed]
Anderson LT, Campbell M, Grega DM, et al: Haloperidol in the treatment of infantile autism: effects on learning and behavioral
symptoms. Am J Psychiatry 141:1195–1202, 1984 [PubMed]
Anderson LT, Campbell M, Adams P, et al: The effects of haloperidol on discrimination learning and behavioral symptoms in
autistic children. J Autism Dev Disord 19:227–239, 1989 [PubMed]
Armenteros JL, Adams PB, Campbell M, et al: Haloperidol-related dyskinesias and pre- and perinatal complications in autistic
children. Psychopharmacol Bull 31:363–369, 1995 [PubMed]
Armenteros JL, Lewis JE, Davalos M: Risperidone augmentation for treatment-resistant aggression in
attention-deficit/hyperactivity disorder: a placebo-controlled pilot study. J Am Acad Child Adolesc Psychiatry 46:558–565,
2007 [PubMed]
Arnold LE: Methylphenidate vs amphetamine: comparative review. J Attention Disord 3:200–211, 2000
Asbahr FR, Castillo AR, Montenegro L, et al: Group cognitive-behavioral therapy versus sertraline for the treatment of children
and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 44:1128–1136, 2005 [PubMed]
August GJ, Raz N, Papanicolaou AC, et al: Fenfluramine treatment in infantile autism. Neurochemical, electrophysiological,
and behavioral effects. J Nerv Ment Dis 172:604–612, 1984 [PubMed]
August GJ, Raz N, Baird TD: Effects of fenfluramine on behavioral, cognitive, and affective disturbances in autistic children. J
Autism Dev Disord 15:97–107, 1985 [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
35 of 58
10/05/2009 16:43
Ballenger JC, Carek DJ, Steele JJ, et al: Three cases of panic disorder with agoraphobia in children. Am J Psychiatry
146:922–924, 1989 [PubMed]
Barbaresi WJ, Katusic SK, Colligan RC, et al: How common is attention-deficit/hyperactivity disorder? Incidence in a
population-based birth cohort in Rochester, Minn. Arch Pediatr Adolesc Med 156:217–224, 2002 [PubMed]
Barbey JT, Roose SP: SSRI safety in overdose. J Clin Psychiatry 59 (suppl 15):42–48, 1998
Barkley RA: Attention Deficit Hyperactivity Disorder: A Clinical Handbook, 3rd Edition. New York, Guilford, 2005
Barnett M, Cohen S: Ziprasidone’s metabolic effects in pediatric bipolar disorder. Presented at the 51st annual meeting of
American Academy of Child and Adolescent Psychiatry, Washington, DC, October 19–24, 2004
Barrett RP, Feinstein C, Hole WT: Effects of naloxone and naltrexone on self-injury: a double-blind, placebo controlled
analysis. Am J Ment Retard 93:644–651, 1989 [PubMed]
Barrickman L, Noyes R, Kuperman S, et al: Treatment of ADHD with fluoxetine: a preliminary trial. J Am Acad Child Adolesc
Psychiatry 30:762–767, 1991 [PubMed]
Barrickman LL, Perry PJ, Allen AJ, et al: Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity
disorder. J Am Acad Child Adolesc Psychiatry 34:649–657, 1995 [PubMed]
Barthelemy C, Bruneau N, Jouve J, et al: Urinary dopamine metabolites as indicators of the responsiveness to fenfluramine
treatment in children with autistic behavior. J Autism Dev Disord 19:241–254, 1989 [PubMed]
Barzman DH, DelBello MP, Kowatch RA, et al: The effectiveness and tolerability of aripiprazole for pediatric bipolar disorders:
a retrospective chart review. J Child Adolescent Psychopharmacol 14:593–600, 2004 [PubMed]
Barzman DH, DelBello MP, Adler CM, et al: The efficacy and tolerability of quetiapine versus divalproex for the treatment of
impulsivity and reactive aggression in adolescents with co-occurring bipolar disorder and disruptive behavior disorder(s). J
Child Adolesc Psychopharmacol 16:665–670, 2006 [PubMed]
Beeghly JH, Kuperman S, Perry PJ, et al: Fenfluramine treatment of autism: relationship of treatment response to blood levels
of fenfluramine and norfenfluramine. J Autism Dev Disord 17:541–548, 1987 [PubMed]
Beisler JM, Tsai LY, Stiefel B: The effects of fenfluramine on communication skills in autistic children. J Autism Dev Disord
16:227–233, 1986 [PubMed]
Belsito KM, Law PA, Kirk KS, et al: Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled
trial. J Autism Dev Disord 31:175–181, 2001 [PubMed]
Berard R, Fond R, Carpenter DJ, et al: An international, multicenter, placebo-controlled trial of paroxetine in adolescents with
major depressive disorder. J Child Adolesc Psychopharmacol 16:59–75, 2006 [PubMed]
Berney T, Kolvin I, Bhate SR, et al: School phobia: a therapeutic trial with clomipramine and short-term outcome. Br J
Psychiatry 138:110–118, 1981 [PubMed]
Bernstein GA, Garfinkel BD, Borchardt CM: Comparative studies of pharmacotherapy for school refusal. J Am Acad Child
Adolesc Psychiatry 29:773–781, 1990 [PubMed]
Bernstein GA, Borchardt CM, Perwien AR: Anxiety disorders in children and adolescents: a review of the past 10 years. J Am
Acad Child Adolesc Psychiatry 35:1110–1119, 1996 [PubMed]
Bernstein GA, Borchardt CM, Perwien AR, et al: Imipramine plus cognitive-behavioral therapy in the treatment of school
refusal. J Am Acad Child Adolesc Psychiatry 39:276–283, 2000 [PubMed]
Bernstein GA, Hektner JM, Borchardt CM, et al: Treatment of school refusal: one-year follow-up. J Am Acad Child Adolesc
Psychiatry 40:206–213, 2001 [PubMed]
Biederman J: Comparative efficacy of atypical antipsychotics for pediatric bipolar disorder. Poster presented at the 158th
annual meeting of the American Psychiatric Association, Atlanta, GA, May 21–26, 2005
Biederman J, Faraone SV, Marrs A, et al: Panic disorder and agoraphobia in consecutively referred children and adolescents. J
Am Acad Child Adolesc Psychiatry 36:214–223, 1997 [PubMed]
Biederman J, Lopez FA, Boellner SW, et al: A randomized, double-blind, placebo-controlled, parallel-group study of SLI381
(Adderall XR) in children with attention-deficit/hyperactivity disorder. Pediatrics 110:258–266, 2002 [PubMed]
Biederman J, McDonnell MA, Wozniak J, et al: Aripiprazole in the treatment of pediatric bipolar disorder: a systematic chart
review. CNS Spectr 10:141–148, 2005a
Biederman J, Mick E, Hammerness P, et al: Open-label, 8-week trial of olanzapine and risperidone for the treatment of bipolar
disorder in preschool-age children. Biol Psychiatry 58:589–594, 2005b
Biederman J, Mick E, Wozniak J, et al: An Open-label trial of risperidone in children and adolescents with bipolar disorder. J
Child Adolesc Psychopharmacol 15:311–317, 2005c
Biederman J, Swanson JM, Wigal SB, et al: Efficacy and safety of modafinil film-coated tablets in children and adolescents
with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study.
Pediatrics 116:e777–e784, 2005d
Biederman J, Mick E, Surman C, et al: A randomized, placebo-controlled trial of OROS methylphenidate in adults withPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
36 of 58
10/05/2009 16:43
attention-deficit/hyperactivity disorder. Biol Psychiatry 59:829–835, 2006a
Biederman J, Wigal SB, Spencer TJ, et al: A post hoc subgroup analysis of an 18-day randomized controlled trial comparing
the tolerability and efficacy of mixed amphetamine salts extended release and atomoxetine in school-age girls with
attention-deficit/hyperactivity disorder. Clin Ther 28:280–293, 2006b
Birmaher B, Waterman GS, Ryan ND, et al: Randomized, controlled trial of amitriptyline versus placebo for adolescents with
“treatment resistant” major depression. J Am Acad Child Adolesc Psychiatry 37:527–535, 1998 [PubMed]
Birmaher B, Arbelaez C, Brent D: Course and outcome of child and adolescent major depressive disorder. Child Adolesc
Psychiatry Clin North Am 11:619–637, 2002 [PubMed]
Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc
Psychiatry 42:415–423, 2003 [PubMed]
Birmaher B, Axelson D, Strober M, et al: Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen
Psychiatry 63:175–183, 2006 [PubMed]
Bitter I, Czobor P, Dossenbach M, et al: Effectiveness of clozapine, olanzapine, quetiapine, risperidone, and haloperidol
monotherapy in reducing hostile and aggressive behavior in outpatients treated for schizophrenia: a prospective naturalistic
study (IC-SOHO). Eur Psychiatry 20:403–408, 2005 [PubMed]
Black B, Uhde TW: Elective mutism as a variant of social phobia. J Am Acad Child Adolesc Psychiatry 31:1090–1094, 1992
[PubMed]
Black B, Uhde TW: Treatment of elective mutism with fluoxetine: a double-blind, placebo-controlled study. J Am Acad Child
Adolesc Psychiatry 33:1000–1006, 1994 [PubMed]
Blair J, Scahill L, State M, et al: Electrocardiographic changes in children and adolescents treated with ziprasidone: a
prospective study. J Am Acad Child Adolesc Psychiatry 44:73–79, 2005 [PubMed]
Bouvard MP, Leboyer M, Launay JM, et al: Low-dose naltrexone effects on plasma chemistries and clinical symptoms in
autism: a double-blind, placebo-controlled study. Psychiatry Res 58:191–201, 1995 [PubMed]
Brent DA, Holder D, Kolko D, et al: A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and
supportive therapy. Arch Gen Psychiatry 54:877–885, 1997 [PubMed]
Bridge JA, Iyengar S, Salary CB, et al: Clinical response and risk for reported suicidal ideation and suicide attempts in
pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 297:1683–1696, 2007 [PubMed]
Bruggeman R, van der Linden C, Buitelaar JK, et al: Risperidone versus pimozide in Tourette’s disorder: a comparative
double-blind parallel-group study. J Clin Psychiatry 62:50–56, 2001 [PubMed]
Budman CL, Gayer A, Lesser M, et al: An open-label study of the treatment efficacy of olanzapine for Tourette’s disorder. J
Clin Psychiatry 62:290–294, 2001 [PubMed]
Buitelaar JK, van der Gaag RJ, van der Hoeven J: Buspirone in the management of anxiety and irritability in children with
pervasive developmental disorders: results of an open-label study. J Clin Psychiatry 59:56–59, 1998 [PubMed]
Buitelaar JK, Willemsen-Swinkels SH: Medication treatment in subjects with autistic spectrum disorders. Eur Child Adolesc
Psychiatry 9 (suppl 1):I85–I97, 2000
Buitelaar JK, Van der Gaag RJ, Cohen-Kettenis P, et al: A randomized controlled trial of risperidone in the treatment of
aggression in hospitalized adolescents with subaverage cognitive abilities [comment]. J Clin Psychiatry 62:239–248, 2001
[PubMed]
Bymaster FP, Katner JS, Nelson DL, et al: Atomoxetine increases extracellular levels of norepinephrine and dopamine in
prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.
Neuropsychopharmacology 27:699–711, 2002 [PubMed]
Campbell M, Anderson LT, Meier M, et al: A comparison of haloperidol and behavior therapy and their interaction in autistic
children. J Am Acad Child Psychiatry 17:640–655, 1978 [PubMed]
Campbell M, Anderson LT, Small AM, et al: The effects of haloperidol on learning and behavior in autistic children. J Autism
Dev Disord 12:167–175, 1982 [PubMed]
Campbell M, Small AM, Green WH, et al: Behavioral efficacy of haloperidol and lithium carbonate: a comparison in hospitalized
aggressive children with conduct disorder. Arch Gen Psychiatry 41:650–656, 1984 [PubMed]
Campbell M, Perry R, Polonsky BB, et al: An open study of fenfluramine in hospitalized young autistic children. J Autism Dev
Disord 16:495–506, 1986 [PubMed]
Campbell M, Adams P, Perry R, et al: Tardive and withdrawal dyskinesia in autistic children: a prospective study.
Psychopharmacol Bull 24:251–255, 1988a
Campbell M, Adams P, Small AM, et al: Efficacy and safety of fenfluramine in autistic children. J Am Acad Child Adolesc
Psychiatry 27:434–439, 1988b
Campbell M, Anderson LT, Small AM, et al: Naltrexone in autistic children: behavioral symptoms and attentional learning. J
Am Acad Child Adolesc Psychiatry 32:1283–1291, 1993 [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
37 of 58
10/05/2009 16:43
Campbell M, Adams PB, Small AM, et al: Lithium in hospitalized aggressive children with conduct disorder: a double blind and
placebo controlled study. J Am Acad Child Adolesc Psychiatry 34:445–453, 1995 [PubMed]
Campbell M, Armenteros JL, Malone RP, et al: Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal
study. J Am Acad Child Adolesc Psychiatry 36:835–843, 1997 [PubMed]
Cantwell DP, Swanson J, Connor DF: Case study: adverse response to clonidine. J Am Acad Child Adolesc Psychiatry
36:539–544, 1997 [PubMed]
Castellanos FX, Giedd JN, Elia J, et al: Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of
stimulant and dose. J Am Acad Child Adolesc Psychiatry 36:589–596, 1997 [PubMed]
Centers for Disease Control and Prevention: Mental health in the United States. Prevalence of diagnosis and medication
treatment for attention deficit/hyperactivity disorder—United States 2003. MMWR Morb Mortal Wkly Rep 54:842–847, 2005
Chambers WJ, Puig-Antich J, Hirsch M, et al: The assessment of affective disorders in children and adolescents by
semistructured interview. Test-retest reliability of the schedule for affective disorders and schizophrenia for school-age
children, present episode version. Arch Gen Psychiatry 42:696–702, 1985 [PubMed]
Chang K, Saxena K, Howe M, et al: An open-label study of lamotrigine adjunct or monotherapy for the treatment of
adolescents with bipolar depression. J Am Acad Child Adolesc Psychiatry 45:298–304, 2006 [PubMed]
Chappell PB, Riddle MA, Scahill L, et al: Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and
Tourette’s syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry 34:1140–1146, 1995b
Chavira DA, Stein MB: Combined psychoeducation and treatment with selective serotonin reuptake inhibitors for youth with
generalized social anxiety disorder. J Child Adolesc Psychopharmacol 12:47–54, 2002 [PubMed]
Charach A, Figueroa M, Chen S, et al: Stimulant treatment over 5 years: effects on growth. J Am Acad Child Adolesc Psychiatry
45:415–421, 2006 [PubMed]
Childress AC, Krishman S, McGough JJ, et al: Interim analysis of a long-term, open-label, single-arm study of
lisdexamfetamine (LDX), an amphetamine prodrug, in children with ADHD. Presented at the 53rd Annual Meeting of the
American Academy of Child and Adolescent Psychiatry, San Diego, CA, October 27, 2006
Clark DB, Birmaher B, Axelson D, et al: Fluoxetine for the treatment of childhood anxiety disorder: open-label, long-term
extension to a controlled trial. J Am Acad Child Adolesc Psychiatry 44:1263–1270, 2005 [PubMed]
Clarke GN, Sack WH, Ben R, et al: English language skills in a group of previously traumatized Khmer adolescent refugees. J
Nerv Ment Dis 181:454–456, 1993 [PubMed]
Coggins TE, Morisset C, Krasney L, et al: Brief report: does fenfluramine treatment enhance the cognitive and communicative
functioning of autistic children? J Autism Dev Disord 18:425–434, 1988 [PubMed]
Cohen IL, Campbell M, Posner D, et al: Behavioral effects of haloperidol in young autistic children. An objective analysis using
a within-subjects reversal design. J Am Acad Child Psychiatry 19:665–677, 1980 [PubMed]
Comings DE, Himes JA, Comings BG: An epidemiologic study of Tourette’s syndrome in a single school district. J Clin
Psychiatry 51:463–469, 1990 [PubMed]
Compton SN, Grant PJ, Chrisman AK, et al: Sertraline in children and adolescents with social anxiety disorder. J Am Acad
Adolesc Psychiatry 40:564–571, 2001 [PubMed]
Coniglio SJ, Lewis JD, Lang C, et al: A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin
as treatment for children with autism. J Pediatr 138:649–655, 2001 [PubMed]
Conners CK, Casat CD, Gualtieri CT, et al: Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad
Child Adolesc Psychiatry 35:1314–1321, 1996 [PubMed]
Connor DF, Ozbayrak KR, Benjamin S, et al: A pilot study of nadolol for overt aggression in developmentally delayed
individuals. J Am Acad Child Adolesc Psychiatry 36:826–834, 1997 [PubMed]
Connor DF, Fletcher KE, Swanson JM: A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J
Am Acad Child Adolesc Psychiatry 38:1551–1559, 1999 [PubMed]
Connor DF, Barkley RA, Davis HT: A pilot study of methylphenidate, clonidine, or the combination in ADHD comorbid with
aggressive oppositional defiant disorder or conduct disorder. Clin Pediatr 39:15–25, 2000 [PubMed]
Connor DF, Glatt SJ, Lopez ID, et al: Psychopharmacology and aggression, I: a meta-analysis of stimulant effects on
overt/covert aggression-related behaviors in ADHD. J Am Acad Child Adolesc Psychiatry 41:253–261, 2002 [PubMed]
Cook EH, Rowlett R, Jaselskis C, et al: Fluoxetine treatment of children and adults with autistic disorder and mental
retardation. J Am Acad Child Adolesc Psychiatry 31:739–745, 1992 [PubMed]
Cook EH, Wagner KD, March JS, et al: Long-term sertraline treatment of children and adolescents with obsessive-compulsive
disorder. J Am Acad Child Adolesc Psychiatry 40:1175–1181, 2001 [PubMed]
Copur M, Arpaci B, Demir T, et al: Clinical effectiveness of quetiapine in children and adolescents with Tourette’s syndrome: a
retrospective case-note survey. Clin Drug Investig 27:123–130, 2007 [PubMed]
Corbett B, Khan K, Czapansky-Beilman D, et al: A double-blind, placebo-controlled crossover study investigating the effect ofPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
38 of 58
10/05/2009 16:43
porcine secretin in children with autism. Clin Pediatr 40:327–331, 2001 [PubMed]
Correll CU, Carlson HE: Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J
Am Acad Child Adolesc Psychiatry 45:771–791, 2006 [PubMed]
Correll CU, Leucht S, Kane JM: Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a
systematic review of 1-year studies. Am J Psychiatry 161:414–425, 2004 [Full Text] [PubMed]
Correll CU, Penzer JB, Parikh UH, et al: Recognising and monitoring adverse events of second-generation antipsychotics in
children and adolescents. Child Adolesc Psychiatric Clin N Am 15:177–206, 2006 [PubMed]
Couturier JL, Nicolson R: A retrospective assessment of citalopram in children and adolescents with pervasive developmental
disorders. J Child Adolesc Psychopharmacol 12:243–248, 2002 [PubMed]
Cummings DD, Singer HS, Krieger M, et al: Neuropsychiatric effects of guanfacine in children with mild Tourette syndrome: a
pilot study. Clin Neuropharmacol 25:325–332, 2002 [PubMed]
Daly JM, Wilens T: The use of tricyclic antidepressants in children and adolescents. Pediatr Clin North Am 45:1123–1135,
1998 [PubMed]
D’Amato G: Chlordiazepoxide in management of school phobia. Dis Nerv Syst 23:292–295, 1962 [PubMed]
Davanzo PA, McCracken JT: Mood stabilizers in the treatment of juvenile bipolar disorder: advances and controversies. Child
Adolesc Psychiatr Clin N Am 9:159–182, 2000 [PubMed]
Davies L, Stern JS, Agrawal N, et al: A case series of patients with Tourette’s syndrome in the United Kingdom treated with
aripiprazole. Hum Psychopharmacol. 21:447–453, 2006 [PubMed]
Daviss WB, Bentivoglio P, Racusin R, et al: Bupropion sustained release in adolescents with co morbid
attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry 40:307–314, 2001 [PubMed]
DelBello MP, Kowatch RA: Pharmacological interventions for bipolar youth: developmental considerations. Dev Psychopathol
18:1231–1246, 2006 [PubMed]
DelBello M, Schwiers ML, Rosenberg HL: A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive
treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 41:1216–1223, 2002 [PubMed]
DelBello MP, Findling RL, Kushner S, et al: A pilot controlled trial of topiramate for mania in children and adolescents with
bipolar disorder. J Am Acad Child Adolesc Psychiatry 44:539–547, 2005 [PubMed]
DelBello MP, Kowatch RA, Adler CM, et al: A double-blind randomized pilot study comparing quetiapine and divalproex for
adolescent mania. J Am Acad Child Adolesc Psychiatry, 45:305–313, 2006 [PubMed]
DeLong GR, Nieman GW: Lithium-induced behavior changes in children with symptoms suggesting manic-depressive illness.
Psychopharmacol Bull 19:258–265, 1983 [PubMed]
DeVeaugh-Geiss J, Moroz G, Biederman J, et al: Clomipramine hydrochloride in childhood and adolescent
obsessive-compulsive disorder—a multicenter trial. J Am Acad Child Adolesc Psychiatry 31:45–49, 1992 [PubMed]
Desarkar P, Das A, Sinha VK: Duloxetine for childhood depression with pain and dissociative symptoms. Eur Child Adolesc
Psychiatry 15:496–499, 2006 [PubMed]
Dion Y, Annable L, Sandor P, et al: Risperidone in the treatment of Tourette syndrome: a double blind, placebo controlled trial.
J Clin Psychopharmacol 22:31–39, 2002 [PubMed]
Dollfus S, Petit M, Menard JF, et al: Amisulpride versus bromocriptine in infantile autism: a controlled crossover comparative
study of two drugs with opposite effects on dopaminergic function. J Autism Dev Disord 22:47–60, 1992 [PubMed]
Donnelly M, Rapoport JL, Potter WZ, et al: Fenfluramine and dextroamphetamine treatment of childhood hyperactivity.
Clinical and biochemical findings. Arch Gen Psychiatry 46:205–212, 1989 [PubMed]
Donovan SJ, Stewart JW, Nunes EV, et al: Divalproex treatment for youth with explosive temper and mood lability: a
double-blind, placebo-controlled crossover design. Am J Psychiatry 157:818–820, 2000 [Full Text] [PubMed]
Douglass HM, Moffitt TE, Dar R, et al: Obsessive-compulsive disorder in a birth cohort of 18-year-olds: prevalence and
predictors. J Am Acad Child Adolesc Psychiatry 34:1424–1431, 1995 [PubMed]
Dow SP, Sonies BC, Scheib D, et al: Practical guidelines for the assessment and treatment of selective mutism. J Am Acad
Child Adolesc Psychiatry 34:836–846, 1995 [PubMed]
du Verglas G, Banks SR, Guyer KE: Clinical effects of fenfluramine on children with autism: a review of the research. J Autism
Dev Disord 18:297–308, 1988
Dummit ES III, Klein RG, Tancer NK, et al: Fluoxetine treatment of children with selective mutism: an open trial. J Am Acad
Child Adolesc Psychiatry 35:615–621, 1996 [PubMed]
Dunbar F, Kusumakar V, Daneman D, et al: Growth and sexual maturation during long-term treatment with risperidone. Am J
Psychiatry 161:918–920, 2004 [Full Text] [PubMed]
Dunn V, Goodyer IM: Longitudinal investigation into childhood- and adolescence-onset depression: psychiatric outcome in
early adulthood. Br J Psychiatry 188:216–222, 2006 [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
39 of 58
10/05/2009 16:43
Durkin JP 2nd: Gabapentin in complicated school refusal. J Am Acad Child Adolesc Psychiatry 41:632–633, 2002 [PubMed]
Eggers C, Bunk D: The long-term course of childhood-onset schizophrenia: a 42-year follow-up. Schizophr Bull 23:105–117,
1997 [PubMed]
Ekman G, Miranda-Linne F, Gillberg C, et al: Fenfluramine treatment of twenty children with autism. J Autism Dev Disord
19:511–532, 1989 [PubMed]
Emslie GJ, Rush AJ, Weinberg WA, et al: A double-blind, randomized, placebo-controlled trial of fluoxetine in children and
adolescents with depression. Arch Gen Psychiatry 54:1031–1037, 1997 [PubMed]
Emslie GJ, Wagner KD, Riddle M, et al: Efficacy and safety of paroxetine in juvenile OCD. Poster presented at the 153rd annual
meeting of the American Psychiatric Association, Chicago, IL, May 13–18, 2000
Emslie GJ, Heiligenstein JH, Wagner KD, et al: Fluoxetine for acute treatment of depression in children and adolescents: a
placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 41:1205–1215, 2002 [PubMed]
Emslie GJ, Wagner KD, Kutcher S, et al: Paroxetine treatment in children and adolescents with major depressive disorder: a
randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 45:709–719, 2006
[PubMed]
Emslie GJ, Findling RL, Yeung PP, et al: Venlafaxine ER for the treatment of pediatric subjects with depression: results of two
placebo-controlled trials. J Am Acad Child Adolesc Psychiatry 46:479–488, 2007a
Emslie GJ, Yeung PP, Kunz NR: Long-term, open-label venlafaxine extended-release treatment in children and adolescents
with major depressive disorder. CNS Spectr 12:223–233, 2007b
Engelhardt DM, Polizos P, Waizer J, et al: A double-blind comparison of fluphenazine and haloperidol in outpatient
schizophrenic children. J Autism Child Schizophr 3:128–137, 1973
Ernst M, Magee HJ, Gonzalez NM, et al: Pimozide in autistic children. Psychopharmacol Bull 28:187–191, 1992 [PubMed]
Famularo R, Kinscherff R, Fenton T: Propranolol treatment for childhood posttraumatic stress disorder, acute type: a pilot
study. Am J Dis Child 142:1244–1247, 1988 [PubMed]
Fankhauser MP, Karumanchi VC, German ML et al: A double blind, placebo-controlled study of the efficacy of transdermal
clonidine in autism. J Clin Psychiatry 53:77–82, 1992 [PubMed]
Faretra G, Dooher L, Dowling J: Comparison of haloperidol and fluphenazine in disturbed children. Am J Psychiatry
126:1670–1673, 1970 [PubMed]
Fatemi SH, Realmuto GM, Khan L, et al: Fluoxetine in treatment of adolescent patients with autism: a longitudinal open trial. J
Autism Dev Disord 28:303–307, 1998 [PubMed]
Feldman HM, Kolmen BK, Gonzaga AM, et al: Naltrexone and communication skills in young children with autism. J Am Acad
Child Adolesc Psychiatry 38:587–593, 1999 [PubMed]
Fenichel R: Combining methylphenidate and clonidine: the role of post-marketing surveillance. J Child Adolesc
Psychopharmacol 5:155–156, 1995
Findling RL: Open-label treatment of comorbid depression and attentional disorders with co-administration of serotonin
reuptake inhibitors and psychostimulants in children, adolescents, and adults: a case series. J Child Adolesc Psychopharmacol
6:165–175, 1996 [PubMed]
Findling RL, Lopez FA: Efficacy of transdermal methylphenidate with reference to Concerta in ADHD. Presented at the 25th
annual meeting of the American Academy of Child and Adolescent Psychiatry, Toronto, CA, October 18–23, 2005
Findling RL, McNamara NK, Gracious BL, et al: Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad
Child Adolesc Psychiatry 42:895–901, 2003a
Findling RL, McNamara NK, Youngstrom EA, et al. A prospective, open-label trial of olanzapine in adolescents with
schizophrenia. J Am Acad Child Adolesc Psychiatry 42:170–175, 2003b
Findling RL, McNamara NK, Gracious BL: Quetiapine in nine youths with autistic disorder. J Child Adolesc Psychopharmacol
14:287–294, 2004 [PubMed]
Findling RL, McNamara NK, Youngstrom EA, et al. Double-blind 18-month trial of lithium versus divalproex maintenance
treatment in pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 44:409–417, 2005 [PubMed]
Findling RL, Krishman S, Biederman J: Efficacy and safety of lisdexamfetamine (LDX) in children aged 6 to 12 years with
attention-deficit/hyperactivity disorder (ADHD). Presented at the 53rd Annual Meeting of the American Academy of Child and
Adolescent Psychiatry, San Diego, CA, October 28, 2006a
Findling RL, Reed MD, O’Riordan MA, et al: Effectiveness, safety, and pharmacokinetics of quetiapine in aggressive children
with conduct disorder. J Am Acad Child Adolesc Psychiatry 45:792–800, 2006b
Findling RL, Nyilas M, Auby P, et al: Tolerability of aripiprazole in the treatment of adolescents with schizophrenia. New
research poster presented at the 160th annual meeting of the American Psychiatric Association, San Diego, CA, May 19–24,
2007
Flakierska-Praquin N, Lindstrom M, Gillberg C: School phobia with separation anxiety disorder: a comparative 20- to 29-yearPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
40 of 58
10/05/2009 16:43
follow-up study of 35 school refusers. Compr Psychiatry 38:17–22, 1997 [PubMed]
Flament MF, Rapoport JL, Berg CJ, et al: Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind
controlled study. Arch Gen Psychiatry 42:977–983, 1985 [PubMed]
Frazier JA, Biederman J, Tohen M, et al: A prospective open-label treatment trial of olanzapine monotherapy in children and
adolescents with bipolar disorder. J Child Adolesc Psychopharmacol 11:239–250, 2001 [PubMed]
Fristad MA, Goldberg-Arnold JS, Gavazzi SM, et al: Multifamily psychoeducation groups in the treatment of children with mood
disorders. J Marital Fam Ther 29:491–504, 2003 [PubMed]
Gadow KD, Sverd J, Sprafkin J, et al: Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with
tic disorder. Arch Gen Psychiatry 52:444–455, 1995 [PubMed]
Gadow KD, Sverd J, Sprafkin J, et al: Long-term methylphenidate therapy in children with comorbid attention-deficit
hyperactivity disorder and chronic multiple tic disorder [see comments]. Arch Gen Psychiatry 56:330–336, 1999 [PubMed]
Gaffney GR, Perry PJ, Lund BC, et al: Risperidone versus clonidine in the treatment of children and adolescents with
Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 41:330–336, 2002 [PubMed]
Gammon GD, Brown TE: Fluoxetine and methylphenidate in combination for treatment of attention deficit and comorbid
depressive disorder. J Child Adolesc Psychopharmacol 3:1–10, 1993
Gastaut H, Zifkin B, Rufo M: Compulsive respiratory stereotypies in children with autistic features: polygraphic recording and
treatment with fenfluramine. J Autism Dev Disord 17:391–406, 1987 [PubMed]
Geller B, Cooper TB, Chestnut EC, et al: Preliminary data on the relationship between nortriptyline plasma level and response
in depressed children. Am J Psychiatry 143:1283–1286, 1986 [PubMed]
Geller B, Cooper TB, Graham DL, et al: Double-blind placebo-controlled study of nortriptyline in depressed adolescents using a
“fixed plasma level” design. Psychopharmacol Bull 26:85–90, 1990 [PubMed]
Geller B, Cooper TB, Graham DL, et al: Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in
6- to 12-year-olds with major depressive disorder. J Am Acad Child Adolesc Psychiatry 31:34–44, 1992 [PubMed]
Geller B, Cooper TB, Sun K, et al: Double blind and placebo controlled study of lithium for adolescent bipolar disorders with
secondary substance dependency. J Am Acad Child Adolesc Psychiatry 37:171–178, 1998 [PubMed]
Geller B, Zimerman B, Williams M, et al: Diagnostic characteristics of 93 cases of prepubertal and early adolescent bipolar
disorder phenotype by gender, puberty and comorbid attention deficit hyperactivity disorder. J Child Adolesc
Psychopharmacol 10:157–164, 2000 [PubMed]
Geller B, Tillman MS, Craney JL, et al: Four-year prospective outcome and natural history of mania in children with a
prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry 61:459–467, 2004 [PubMed]
Geller DA, Biederman J, Wagner KD, et al: Comorbid psychiatric illness and response to treatment, relapse rates, and
behavioral adverse event incidence in pediatric OCD. Poster presented at the 41st annual meeting of the New Clinical Drug
Evaluation Unit, Phoenix, AZ, May 28–31, 2001a
Geller DA, Hoog SL, Heiligenstein JH, et al: Fluoxetine treatment for obsessive-compulsive disorder in children and
adolescents: a placebo-controlled clinical trial. J Am Acad Child Adolesc Psychiatry 40:773–779, 2001b
Geller DA, Hoog SL, Heiligenstein JH, et al: Predictive factors in response to fluoxetine treatment for pediatric OCD. Poster
presented at the 48th annual meeting of the American Academy of Child and Adolescent Psychiatry, Honolulu, HI, October
23–28, 2001c
Geller DA, Wagner KD, Emslie G, et al: Paroxetine treatment in children and adolescents with obsessive-compulsive disorder:
a randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 43:1387–1396, 2004
[PubMed]
Geller E, Ritvo ER, Freeman BJ, et al: Preliminary observations on the effect of fenfluramine on blood serotonin and symptoms
in three autistic boys. N Engl J Med 307:165–169, 1982 [PubMed]
Gelperin K: Psychiatric adverse events associated with drug treatment of ADHD: review of postmarketing safety data. U.S.
Food and Drug Administration Pediatric Advisory Committee, March 22, 2006. Available at:
http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4210s_15_Gelperin_Review%20of%20Postmarking%20Safety.ppt.
Accessed December 2008.
George MS, Trimble MR, Robertson MM: Fluvoxamine and sulpiride in comorbid obsessive compulsive disorder and Gilles de la
Tourette’s syndrome. Hum Psychopharmacol 8:327–334, 1993
Ghaziuddin M, Tsai L, Ghaziuddin N, et al: Fluoxetine in autism with depression. J Am Acad Child Adolesc Psychiatry
30:508–509, 1991 [PubMed]
Giaconia RM, Reinherz HZ, Silverman AB, et al: Traumas and posttraumatic stress disorder in a community population of older
adolescents. J Am Acad Child Adolesc Psychiatry 34:1369–1380, 1995
Gibbons RD, Hur K, Bhaumik DK, et al: The relationship between antidepressant prescription rates and rate of early
adolescent suicide. Am J Psychiatry 163:1898–1904, 2006 [Full Text] [PubMed]
Gibson AP, Crismon ML, Mican LM, et al: Effectiveness and tolerability of aripiprazole in child and adolescent inpatients: aPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
41 of 58
10/05/2009 16:43
retrospective evaluation. Int Clin Psychopharmacol 22:101–105, 2007 [PubMed]
Gilbert DL, Batterson JR, Sethuraman G, et al: Tic reduction with risperidone versus pimozide in a randomized, double-blind,
crossover trial. J Am Acad Child Adolesc Psychiatry 43:206–214, 2004 [PubMed]
Gittelman-Klein R, Klein DF: Controlled imipramine treatment of school phobia. Arch Gen Psychiatry 25:204–207, 1971
Gittelman-Klein R, Mannuzza S: Hyperactive boys almost grown up, III: methylphenidate effects on ultimate height. Arch Gen
Psychiatry 45:1131–1134, 1988
Glod CA, Lynch A, Flynn E, et al: Bupropion SR in the treatment of adolescent depression. Poster presented at the 40th Annual
Meeting of the New Clinical Drug Evaluation Unit, Boca Raton, FL, 2000
Goetz CG, Tanner CM, Wilson RS, et al: Clonidine and Gilles de la Tourette’s syndrome: double-blind study using objective
rating methods. Ann Neurol 21:307–310, 1987 [PubMed]
Golwyn DH, Sevlie CP: Phenelzine treatment of selective mutism in four prepubertal children. J Child Adolesc
Psychopharmacol 9:109–113, 1999 [PubMed]
Golwyn DH, Weinstock RC: Phenelzine treatment of elective mutism: a case report. J Clin Psychiatry 51:384–385, 1990
[PubMed]
Goodman WK, Price LH, Rasmusen SA et al: Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). New Haven, CT,
Department of Psychiatry, Yale University School of Medicine, 1991
Gordon CT, State RC, Nelson JE, et al: A double-blind comparison of clomipramine, desipramine, and of autistic disorder. Arch
Gen Psychiatry 50:441–447, 1993 [PubMed]
Graae F, Milner J, Rizzotto L, et al: Clonazepam in childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry
33:372–376, 1994 [PubMed]
Grados M, Scahill L, Riddle MA: Pharmacotherapy in children and adolescents with obsessive-compulsive disorder. Child
Adolesc Clin N Am 8:617–634, 1999 [PubMed]
Gram LF, Rafaelsen OJ: Lithium treatment of psychotic children and adolescents. A controlled clinical trial. Acta Psychiatr
Scand 48:253–260, 1972 [PubMed]
Green WH: Child and Adolescent Clinical Psychopharmacology, 3rd Edition. Philadelphia, PA, Lippincott Williams & Wilkins,
2001
Greenhill LL, Halperin JM, Abikoff H: Stimulant medications. J Am Acad Child Adolesc Psychiatry 38:503–512, 1999 [PubMed]
Greenhill LL, Findling RL, Swanson JM: A double-blind, placebo-controlled study of modified-release methylphenidate in
children with attention-deficit/hyperactivity disorder. Pediatrics 109:e39, 2002
Greenhill LL, Swanson JM, Steinhoff K, et al: A pharmacokinetic/pharmacodynamic study comparing a single morning dose of
Adderall to twice-daily dosing in children with ADHD. J Am Acad Child Adolesc Psychiatry 42:1234–1241, 2003 [PubMed]
Greenhill LL, Vitiello B, Abikoff HB, et al: Outcome results from the NIMH, multi-site, preschool ADHD treatment study (PATS).
Presented at the 51st Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Washington, DC, October
19–24, 2004
Greenhill LL, Ball R, Levine AJ, et al: Extended release dexmethylphenidate in children and adolescents with ADHD. Presented
at the 158th Annual Meeting of the American Psychiatric Association, Atlanta, GA, May 21–25, 2005
Greenhill LL, Biederman J, Boellner SW, et al: A randomized, double-blind, placebo-controlled study of modafinil film-coated
tablets in children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry
45:503–511, 2006a
Greenhill LL, Kollins S, Abikoff H, et al: Efficacy and safety of immediate-release methylphenidate treatment for preschoolers
with ADHD. J Am Acad Child Adolesc Psychiatry 45:1284–1293, 2006b
Gunther T, Herpertz-Dahlmann B, Jolles J, et al: The influence of risperidone on attentional functions in children and
adolescents with attention-deficit/hyperactivity disorder and co-morbid disruptive behavior disorder. J Child Adolesc
Psychopharmacol 16:725–735, 2006 [PubMed]
Greist JH, Jefferson JW, Kobak KA, et al: Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive
disorder. Arch Gen Psychiatry 52:53–60, 1995 [PubMed]
Groden G, Groden J, Dondey M, et al: Effects of fenfluramine on the behavior of autistic individuals. Res Dev Disabil
8:203–211, 1987 [PubMed]
Haas M, Unis AS, Copenhaver M, et al: Efficacy and safety of risperidone in adolescents with schizophrenia. Presented at the
160th Annual Meeting of the American Psychiatric Association, San Diego, CA, May 19–24, 2007
Hamilton BE, Minino AM, Martin JA, et al: Annual summary of vital statistics: 2005. Pediatrics 119:345–360, 2007 [PubMed]
Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol 32:50–55, 1959 [PubMed]
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62, 1960 [PubMed]
Hammerness PG, Vivas FM, Geller DA: Selective serotonin reuptake inhibitors in pediatric psychopharmacology: a review ofPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
42 of 58
10/05/2009 16:43
the evidence. J Pediatr 148:158–165, 2006 [PubMed]
Handen BL, Johnson CR, Lubetsky M: Efficacy of methylphenidate among children with autism and symptoms of
attention-deficit hyperactivity disorder. J Autism Dev Disord 30:245–255, 2000 [PubMed]
Harmon RJ, Riggs PD: Clonidine for posttraumatic stress disorder in preschool children. J Am Acad Child Adolesc Psychiatry
35:1247–1249, 1996 [PubMed]
Hayden F: Long-term remission of schizophrenia in an adolescent treated with quetiapine. J Child Adolesc Psychopharmacol
11:289–293, 2001 [PubMed]
Hazaray E, Ehret J, Posey DJ, et al: Intramuscular ziprasidone for acute agitation in adolescents. J Child Adolesc
Psychopharmacol 14:464–470, 2004 [PubMed]
Hazell PL, Stuart JE: A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and
aggressive children. J Am Acad Child Adolesc Psychiatry 42:886–894, 2003 [PubMed]
Herman BH, Asleson GS, Powell A, et al: Cardiovascular and other physical effects of acute administration of naltrexone in
autistic children. J Child Adolesc Psychopharmacol 3:157–168, 1993
Ho HH, Lockitch G, Eaves L, et al: Blood serotonin concentrations and fenfluramine therapy in autistic children. J Pediatr
108:465–469, 1986 [PubMed]
Hollander E, Kaplan A, Cartwright C, et al: Venlafaxine in children, adolescents, and young adults with autism spectrum
disorders: an open retrospective clinical report. J Child Neurol 15:132–135, 2000 [PubMed]
Hollander E, Phillips A, Chaplin W, et al: A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in
childhood and adolescent autism. Neuropsychopharmacology 30:582–589, 2005 [PubMed]
Horrigan JP: Guanfacine for PTSD nightmares. J Am Acad Child Adolesc Psychiatry 35:975–976, 1996 [PubMed]
Horvath K, Stafanatos G, Sokolski KN, et al: Improved social and language skills after secretin administration in patients with
autistic spectrum disorders. J Assoc Acad Minor Phys 9:9–15, 1998 [PubMed]
Howlin P: Autism and intellectual disability: diagnostic and treatment issues. J R Soc Med 93:351–355, 2000 [PubMed]
Hughes CW, Emslie GJ, Crismon MJ, et al: The Texas Children’s Medication Algorithm Project: Update from Texas Consensus
Conference Panel on Medication Treatment of Childhood Major Depressive Disorder. J Am Acad Child Adolesc Psychiatry
46:667–686, 2007 [PubMed]
Hunt RD, Capper L, O’Connell P: Clonidine in child and adolescent psychiatry. J Child Adolesc Psychopharmacol 1:87–102,
1990
Hunt RD, Amsten AF, Asbell MD: An open trial of guanfacine in the treatment of attention-deficit hyperactivity disorder. J Am
Acad Child Adolesc Psychiatry 34:50–54, 1995 [PubMed]
Jaselskis CA, Cook EH, Fletcher KE, et al: Clonidine treatment of hyperactive and impulsive children with autistic disorder. J
Clin Psychopharmacol 12:322–327, 1992 [PubMed]
Jasinski D, Krishman S: Abuse liability of intravenous lisdexamfetamine (LDX; NRP104). Presented at the 58th Institute on
Psychiatric Services, New York, NY, October 6, 2006a
Jasinski D, Krishman S: A double-blind, randomized, placebo- and active-controlled, 6-period crossover study to evaluate the
likeability, safety, and abuse potential of lisdexamfetamine dimesylate (LDX) in adult stimulant abusers. Presented at the
2006 US Psychiatric and Mental Health Congress, New Orleans, LA, November 17, 2006b
Jensen PS, Bhatara VS, Vitiello B, et al: Psychoactive medication prescribing practices for US children: gaps between research
and clinical practice. J Am Acad Child Adolesc Psychiatry 38:557–565, 1999 [PubMed]
Kaufman J, Birmaher B, Brent D, et al: Schedule for Affective Disorders and Schizophrenia for School Age Children, Present
and Lifetime Versions (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988, 1997
[PubMed]
Kafantaris V, Coletti DJ, Dicker R, et al: Adjunctive antipsychotic treatment of adolescents with bipolar psychosis. J Am Acad
Child Adolesc Psychiatry 40:1448–1456, 2001a
Kafantaris V, Dicker R, Coletti DJ, et al: Adjunctive antipsychotic treatment is necessary for adolescents with psychotic mania.
J Am Acad Child Adolesc Psychopharmacol 11:409–413, 2001b
Kafantaris V, Coletti DJ, Dicker R, et al: Lithium treatment of acute mania in adolescents: a large open trial. J Am Acad Child
Adolesc Psychiatry 42:1038–1045, 2003 [PubMed]
Kafantaris V, Coletti DJ, Dicker R, et al: Lithium treatment of acute mania in adolescents: a placebo-controlled discontinuation
study. J Am Acad Child Adolesc Psychiatry 43:984–993, 2004 [PubMed]
Kappagoda C, Schell DN, Hanson RM, et al: Clonidine overdose in childhood: implications of increased prescribing. J Paediatr
Child Health 34:508–512, 1998 [PubMed]
Kashani JH, Orvaschel H: Anxiety disorders in mid-adolescence: a community sample. Am J Psychiatry 145:960–964, 1988
[PubMed]
Kashani JH, Sherman DD: Childhood depression: epidemiology, etiological models, and treatment implications. IntegrPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
43 of 58
10/05/2009 16:43
Psychiatry 6:1–8, 1988
Kastner T: Secretin and autism. Except Health Care 9:45–46, 1998
Keller MB, Lavori PW, Wunder J, et al: Chronic course of anxiety disorder in children and adolescents. J Am Acad Child
Adolesc Psychiatry 31:595–599, 1992 [PubMed]
Keller MB, Ryan ND, Strober M, et al: Efficacy of paroxetine in the treatment of adolescent major depression: a randomized,
controlled trial. J Am Acad Child Adolesc Psychiatry 40:762–772, 2001 [PubMed]
Kemner C, Willemsen-Swinkels SHN, DeJonge M, et al: Open-label study of olanzapine in children with pervasive
developmental disorder. J Clin Psychopharmacol 22:455–460, 2002 [PubMed]
Kemph JP, DeVane CL, Levin GM, et al: Treatment of aggressive children with clonidine: results of an open pilot study. J Am
Acad Child Adolesc Psychiatry 32:577–581, 1993 [PubMed]
Kennard B, Silva S, Vitiello B, et al: Remission and residual symptoms after short-term treatment in the treatment of
adolescents with depression study (TADS). J Am Acad Child Adolesc Psychiatry 45:1404–1411, 2006 [PubMed]
Kerbeshian J, Burd L, Fisher W: Lithium carbonate in the treatment of two patients with infantile autism and atypical bipolar
symptomatology. J Clin Psychopharmacol 7:401–405, 1987 [PubMed]
Kessler RC, Adler L, Barkley R, et al: The prevalence and correlates of adult ADHD in the United States: results from the
National Comorbidity Survey Replication. Am J Psychiatry 163:716–723, 2006 [Full Text] [PubMed]
Khan SS, Mican LM, Khan SS, et al: A naturalistic evaluation of intramuscular ziprasidone versus intramuscular olanzapine for
the management of acute agitation and aggression in children and adolescents. J Child Adolesc Psychopharmacol
16:671–677, 2006 [PubMed]
Kim BN, Lee CB, Hwang JW, et al: Effectiveness and safety of risperidone for children and adolescents with chronic tic or
Tourette disorders in Korea. J Child Adolesc Psychopharmacol 15:318–324, 2005 [PubMed]
King BH, Wright DM, Handen BL, et al: Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment
of children with autistic disorder. J Am Acad Child Adolesc Psychiatry 40:658–665, 2001 [PubMed]
Kisicki J, Fiske K, Scheckner B, et al: Abrupt cessation of guanfacine extended release in healthy young adults. Presented at
the 53rd Annual Meeting of the American Academy of Child and Adolescent Psychiatry, San Diego, CA, October 24–29, 2006
Klein RG, Koplewicz HS, Kanner A: Imipramine treatment of children with separation anxiety disorder. J Am Acad Child
Adolesc Psychiatry 31:21–28, 1992 [PubMed]
Klein RG, Abikoff H, Klass E, et al: Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit
hyperactivity disorder. Arch Gen Psychiatry 54:1073–1080, 1997 [PubMed]
Klykylo WM, Feldis D, O’Grady D, et al: Clinical effects of fenfluramine in ten autistic subjects. J Autism Dev Disord
15:417–423, 1985 [PubMed]
Knorring A, Olsson GI, Thomsen PH, et al: A randomized, double-blind, placebo-controlled study of citalopram in adolescents
with major depressive disorder. J Clin Psychopharmacol 26:311–315, 2006
Kofoed L, Tadepalli G, Oesterheld JR, et al: Case series: clonidine has no systematic effects on PR or QTc intervals in children.
J Am Acad Child Adolesc Psychiatry 38:1193–1196, 1999 [PubMed]
Kohler JA, Shortland G, Rolles CJ: Effect of fenfluramine on autistic symptoms. Br Med J (Clin Res Ed) 295:885, 1987
[PubMed]
Kolmen BK, Feldman HM, Handen BL, et al: Naltrexone in young autistic children: a double-blind, placebo-controlled crossover
study. J Am Acad Child Adolesc Psychiatry 34:223–231, 1995 [PubMed]
Kolmen BK, Felman HM, Handen BL, et al: Naltrexone in young autistic children: replication study and learning measures. J
Am Acad Child Adolesc Psychiatry 36:1570–1578, 1997 [PubMed]
Kowatch RA, Carmody TJ, Suppes T, et al: Acute and continuation pharmacological treatment of children and adolescents with
bipolar disorders: a summary of two previous studies. Acta Neuropsychiatrica 12:145–149, 2000a
Kowatch RA, Suppes T, Carmody TJ, et al: Effect size of lithium, divalproex sodium, and carbamazepine in children and
adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 39:713–720, 2000b
Kowatch RA, Fristad M, Birmaher B, et al: Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad
Child Adolesc Psychiatry 44:213–235, 2005 [PubMed]
Kramer JR, Loney J, Ponto LB, et al: Predictors of adult height and weight in boys treated with methylphenidate for childhood
behavior problems. J Am Acad Child Adolesc Psychiatry 39:517–524, 2000 [PubMed]
Kranzler H, Roofeh D, Gerbino-Rosen G, et al: Clozapine: its impact on aggressive behavior among children and adolescents
with schizophrenia. J Am Acad Child Adolesc Psychiatry 44:55–63, 2005 [PubMed]
Krasny L, Williams BJ, Provencal S, et al: Social skills interventions for the autism spectrum: essential ingredients and a
model curriculum. Child Adolesc Psychiatric Clin N Am 12:107–122, 2003 [PubMed]
Kratochvil CJ, Heiligenstein JH, Dittmann R, et al: Atomoxetine and methylphenidate treatment in children with ADHD: a
prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry 41:776–784, 2002 [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
44 of 58
10/05/2009 16:43
Kratochvil CJ, Vaughan BS, Harrington MJ, et al: Atomoxetine: a selective noradrenaline reuptake inhibitor for the treatment
of attention-deficit/hyperactivity disorder. Expert Opin Pharmacother 4:1165–1174, 2003 [PubMed]
Kroes M, Kalfe AC, Kessels AG, et al: Child psychiatric diagnoses in a population of Dutch schoolchildren aged 6 to 8 years. J
Am Acad Child Adolesc Psychiatry 40:1401–1409, 2001 [PubMed]
Kryzhanovskaya L, Schultz C, McDougle J, et al: A double-blind, placebo-controlled study of olanzapine in adolescents with
schizophrenia. Presented at the 159th annual meeting of the American Psychiatric Association, Toronto, Canada, May 20–25,
2006
Kumra S: The diagnosis and treatment of children and adolescents with schizophrenia: “My mind is playing tricks on me.”
Child Adolesc Psychiatr Clin N Am 9:183–199, 2000 [PubMed]
Kumra S, Frazier JA, Jacobsen LK, et al: Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison.
Arch Gen Psychiatry 53:1090–1097, 1996 [PubMed]
Kumra S, Jacobsen LK, Lenane M, et al: Childhood-onset schizophrenia: an open-label study of olanzapine in adolescents. J
Am Acad Child Adolesc Psychiatry 37:377–385, 1998 [PubMed]
Kunz NR, Khan A, Nicoloacopoulos E, et al: Venlafaxine extended-release for GAD treatment in children and adolescents.
Poster presented at the 155th annual meeting of the American Psychiatric Association, Philadelphia, PA, May 18–23, 2002
Kuperman S, Stewart MA: Use of propranolol to decrease aggressive outbursts in younger patients. Psychosomatics
28:315–319, 1987 [PubMed]
Kusumakar V, Yatham LN: An open study of lamotrigine in refractory bipolar depression. Psychiatry Res 72:145–148, 1997
[PubMed]
Kutcher SP, MacKenzie S: Successful clonazepam treatment of adolescents with panic disorder. J Clin Psychopharmacol
8:299–301, 1988 [PubMed]
Kutcher SP, Reiter S, Gardner DM, et al: The pharmacotherapy of anxiety disorders in children and adolescents. Psychiatr Clin
North Am 15:41–67, 1992 [PubMed]
Kutcher SP, Boulos C, Ward B, et al: Response to desipramine treatment in adolescent depression: a fixed-dose,
placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 33:686–694, 1994 [PubMed]
Kye CH, Waterman GS, Ryan ND, et al: A randomized, controlled trial of amitriptyline in the acute treatment of adolescent
major depression. J Am Acad Child Adolesc Psychiatry 35:1139–1144, 1996 [PubMed]
Lafferty JE, Constantino JN: Fluvoxamine in selective mutism. J Am Acad Child Adolesc Psychiatry 37:12–13, 1998 [PubMed]
Law SF, Schachar RJ: Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit
hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 38:944–951, 1999 [PubMed]
LeBlanc JC, Binder CE, Armenteros JL, et al: Risperidone reduces aggression in boys with a disruptive behaviour disorder and
below average intelligence quotient: analysis of two placebo-controlled randomized trials. Int Clin Psychopharmacol
20:275–283, 2005 [PubMed]
Leboyer M, Bouvard MP, Lensing P, et al: Opioid excess hypothesis of autism: a double-blind study of naltrexone. Brain
Dysfunction 3:285–298, 1990
Leboyer M, Bouvard MP, Launay JM, et al: Brief report: a double-blind study of naltrexone in infantile autism. J Autism Dev
Disord 22:309–319, 1992 [PubMed]
Leckman JF: Tourette’s syndrome. Lancet 360:1577–1586, 2002 [PubMed]
Leckman JF, Detlor J, Harcherik DF, et al: Short- and long-term treatment of Tourette’s syndrome with clonidine: a clinical
perspective. Neurology 35:343–351, 1985 [PubMed]
Leckman JF, Hardin MT, Riddle MA, et al: Clonidine treatment of Gilles De La Tourette’s syndrome. Arch Gen Psychiatry
48:324–328, 1991 [PubMed]
Lena B: Lithium in child and adolescent psychiatry. Arch Gen Psychiatry 36:854–855, 1979 [PubMed]
Leonard HL, Swedo SE, Rapoport JL, et al: Treatment of obsessive-compulsive disorder with clomipramine and desipramine in
children and adolescents. A double-blind crossover comparison. Arch Gen Psychiatry 46:1088–1092, 1989 [PubMed]
Leonard HL, Swedo SE, Lenane MC, et al: A double-blind desipramine substitution during long-term clomipramine treatment
in children and adolescents with obsessive-compulsive disorder. Arch Gen Psychiatry 48:922–927, 1991 [PubMed]
Leonard HL, Swedo SE, Lanane MC, et al: A 2- to 7-year follow-up study of 54 obsessive-compulsive children and adolescents.
Arch Gen Psychiatry 50:429–439, 1993 [PubMed]
Leonard HL, Topol D, Bukstein O, et al: Clonazepam as an augmenting agent in the treatment of childhood-onset
obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 33:792–794, 1994 [PubMed]
Lepola U, Leinonen E, Koponen H: Citalopram in the treatment of early onset panic disorder and school phobia.
Pharmacopsychiatry 29:30–32, 1996 [PubMed]
Leventhal BL, Cook EH Jr, Morford M, et al: Clinical and neurochemical effects of fenfluramine in children with autism. J
Neuropsychiatry Clin Neurosci 5:307–315, 1993 [Full Text] [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
45 of 58
10/05/2009 16:43
Lewinsohn PM, Klein DN, Seeley JR: Bipolar disorders in a community sample of older adolescents: prevalence,
phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 34:454–463, 1995 [PubMed]
Libby AM, Brent DA, Morrato EH, et al: Decline in treatment of pediatric depression after FDA advisory on risk suicidality with
SSRIs. Am J Psychiatry 164:884–891, 2007 [Full Text] [PubMed]
Liberthson RR: Sudden death from cardiac causes in children and young adults. N Engl J Med 334:1039–1044, 1996 [PubMed]
Lichter DG, Jackson LA: Predictors of clonidine response in Tourette’s syndrome: implications and inferences. J Child Neurol
11:93–97, 1996 [PubMed]
Liebowitz MR, Turner SM, Piacentini J, et al: Fluoxetine in children and adolescents with OCD: a placebo-controlled trial. J Am
Acad Child Adolesc Psychiatry 41:1431–1438, 2002 [PubMed]
Linday LA, Tsiouris JA, Cohen IL, et al: Famotidine treatment of children with autistic spectrum disorders: pilot research using
single subject research design. J Neural Transm 108:593–611, 2001 [PubMed]
Looff D, Grimley P, Kuller F, et al: Carbamazepine for PTSD. J Am Acad Child Adolesc Psychiatry 34:703–704, 1995 [PubMed]
Macaluso E, Frith CD, Driver J: Modulation of human visual cortex by cross-modal spatial attention. Science 289:1206–1208,
2000 [PubMed]
Malone RP, Delaney MA, Luebbert JF, et al: A double-blind placebo-controlled study of lithium in hospitalized aggressive
children and adolescents with conduct disorder. Arch Gen Psychiatry 57:649–654, 2000 [PubMed]
Malone RP, Cater J, Sheikh RM, et al: Olanzapine versus haloperidol in children with autistic disorder: an open pilot study. J
Am Acad Child Adolesc Psychiatry 40:887–894, 2001 [PubMed]
Mancini C, Van Amerigen M, Oakman JM, et al: Serotonergic agents in the treatment of social phobia in children and
adolescents: a case series. Depress Anxiety 10:33–39, 1999 [PubMed]
March JS, Biederman J, Wolkow R, et al: Sertraline in children and adolescents with obsessive-compulsive disorder: a
multicenter randomized controlled trial. JAMA 280:1752–1756, 1998 [PubMed]
March JS, Franklin ME, Leonard H, et al: Tics moderate treatment outcome with sertraline but not cognitive-behavior therapy
in pediatric obsessive-compulsive disorder. Biol Psychiatry 61:344–347, 2007 [PubMed]
Markowitz S, Cuellar A: Antidepressants and youth: healing or harmful? Soc Sci Med 64:2138–2151, 2007 [PubMed]
Martin A, Koenig K, Scahill L, et al: Open-label quetiapine in the treatment of children and adolescents with autistic disorder.
J Child Adolesc Psychopharmacol 9:99–107, 1999 [PubMed]
Masi G, Toni C, Mucci M, et al: Paroxetine in child and adolescent outpatients with panic disorder. J Child Adolesc
Psychopharmacol 11:151–157, 2001 [PubMed]
Maughan B, Rowe R, Messer J, et al: Conduct disorder and oppositional defiant disorder in a national sample: developmental
epidemiology. J Child Psychol Psychiatry 45:609–621, 2004 [PubMed]
McClellan J, Werry J: Practice parameter for the assessment and treatment of children and adolescents with schizophrenia.
American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry 40 (7 suppl):4S–23S, 2001
McClellan J, Kowatch R, Findling RL: Practice parameter for the assessment and treatment of children and adolescents with
bipolar disorder. J Am Acad Child Adolesc Psychiatry 46:107–125, 2007 [PubMed]
McConville BJ, Fogelson MH, Norman AB, et al: Nicotine potentiation of haloperidol in reducing tic frequency in Tourette’s
disorder. Am J Psychiatry 148:793–794, 1991 [PubMed]
McConville BJ, Sanberg PR, Fogelson MH, et al: The effects of nicotine plus haloperidol compared to nicotine only and placebo
nicotine only in reducing tic severity and frequency in Tourette’s disorder. Biol Psychiatry 31:832–840, 1992 [PubMed]
McConville BJ, Arvanitis L, Thyrum P, et al: Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine in
adolescents with selected psychotic disorders. Eur Neuropsychopharmacol 9 (suppl 5):S267, 1999
McCracken JT, Biederman J, Greenhill LL, et al: Analog classroom assessment of a once-daily mixed amphetamine
formulation, SLI381 (Adderall XR), in children with ADHD. J Am Acad Child Adolesc Psychiatry 42:673–683, 2003 [PubMed]
McDougle CJ, Kresch LE, Posey DJ: Repetitive thoughts and behavior in pervasive developmental disorders: treatment with
serotonin reuptake inhibitors. J Autism Dev Disord 30:427–435, 2000a
McDougle CJ, Scahill L, McCracken JT, et al: Research Units on Pediatric Psychopharmacology (RUPP) Autism Network.
Background and rationale for an initial controlled study of risperidone. Child Adolesc Psychiatr Clin N Am 9:201–224, 2000b
McDougle CJ, Kem DL, Posey DJ: Case series: use of ziprasidone for maladaptive symptoms in youths with autism. J Am Acad
Child Adolesc Psychiatry 41:921–927, 2002 [PubMed]
McDougle CJ, Martin A, Aman M, et al: New findings from the RUPP autism network study of risperidone. Presented at the
51st annual meeting of the American Academy of Child and Adolescent Psychiatry, Washington, DC, October 19–24, 2004
McGough JJ, Biederman J, Wigal SB, et al: Long-term tolerability and effectiveness of once-daily mixed amphetamine salts
(Adderall XR) in children with ADHD. J Am Acad Child Adolesc Psychiatry 44:530–538, 2005 [PubMed]
McGough J, McCracken J, Swanson J, et al: Pharmacogenetics of methylphenidate response in preschoolers with ADHD. J AmPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
46 of 58
10/05/2009 16:43
Acad Child Adolesc Psychiatry 45:1314–1322, 2006 [PubMed]
McKnew DH, Cytryn L, Buchsbaum MS, et al: Lithium in children of lithium-responding parents. Psychiatry Res 4:171–180,
1981 [PubMed]
Mei Z, Grummer-Strawn LM, Thompson D, et al: Shifts in percentiles of growth during early childhood: analysis of longitudinal
data from the California Child Health and Development Study. Pediatrics 113:e617–e627, 2004
Meighen KG: Duloxetine treatment of pediatric chronic pain and comorbid major depressive disorder. J Child Adolesc
Psychopharmacol 17:121–127, 2007 [PubMed]
Melmed RD, Patel A, Konow J, et al: Efficacy and safety of guanfacine extended release for ADHD treatment. Presented at the
53rd annual meeting of the American Academy of Child and Adolescent Psychiatry, San Diego, CA, October 24–29, 2006
Melvin GA, Tonge BJ, King NJ, et al: A comparison of cognitive-behavioral therapy, sertraline, and their combination for
adolescent depression. J Am Acad Child Adolescent Psychiatry 45:1151–1161, 2006 [PubMed]
Messenheimer JA: Rash in adult and pediatric patients treated with lamotrigine. Can J Neurol Sci 25:S14–S18, 1998
Michelson D: Active comparator studies in the atomoxetine clinical development program. Presented at the 51st Annual
Meeting of the American Academy of Child and Adolescent Psychiatry, San Francisco, CA, October 19–24, 2004
Michelson D, Faries D, Wernicke J, et al: Atomoxetine in the treatment of children and adolescents with
attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 108:1–9, 2001
Michelson D, Allen AJ, Busner J, et al: Once-daily atomoxetine treatment for children and adolescents with attention deficit
hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 159:1896–1901, 2002 [Full Text] [PubMed]
Michelson D, Adler L, Spencer T, et al: Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol
Psychiatry 53:112–120, 2003 [PubMed]
Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389, 1979
[PubMed]
Mosholder A: Psychiatric adverse events in clinical trials of drugs for attention deficit hyperactivity disorder (ADHD).
Available at: Food and Drug Administration Website, 2006
Mozes T, Ebert T, Michal SE, et al: An open-label randomized comparison of olanzapine versus risperidone in the treatment of
childhood-onset schizophrenia. J Child Adolesc Psychopharmacol 16:393–403, 2006 [PubMed]
Mufson L, Sills R: Interpersonal Psychotherapy for depressed adolescents (IPT-A): an overview. Nord J Psychiatry
60:431–437, 2006 [PubMed]
Mukaddes NM, Abali O: Quetiapine treatment of children and adolescents with Tourette’s Disorder. J Child Adolesc
Psychopharmacol 13:295–299, 2003 [PubMed]
Murphy TK, Bengtson MA, Soto O, et al: Case series on the use of aripiprazole for Tourette syndrome. Int J
Neuropsychopharmacol 8:489–490, 2005 [PubMed]
MTA Cooperative Group: 14 Month randomized clinical trial of treatment strategies for children and attention deficit
hyperactivity disorder. Arch Gen Psychiatry 56:1073–1086, 1999
MTA Cooperative Group: National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in
effectiveness and growth after the end of treatment. Pediatrics 113:762–769, 2004
MTA Cooperative Group: Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child
Adolesc Psychiatry 46:1015–1027, 2007
Nader KO, Kriegler JA, Blake DD, et al: Clinician administered PTSD Scale for Children and Adolescents for (DSM-IV)
(CAPS-CA). Current and Lifetime Diagnostic Version, and Instruction Manual. A National Center for PTSD/UCLA Trauma
Psychiatry Program. Los Angeles, CA, National Center for PTSD and UCLA Trauma Psychiatry Program, 1996
Nagaraj R, Singhi P, Malhi P: Risperidone in children with autism: randomized, place-controlled, double-blind study. J Child
Neurol 21:450–455, 2006 [PubMed]
Naruse H, Nagahata M, Nakane Y, et al: A multi-center double-blind trial of pimozide (Orap), haloperidol and placebo in
children with behavioral disorders, using crossover design. Acta Paedopsychiatr 48:173–184, 1982 [PubMed]
Newcorn JH, Spencer TJ, Biederman J, et al: Atomoxetine treatment in children and adolescents with
attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. J Am Acad Child Adolesc Psychiatry
44:240–248, 2005 [PubMed]
Nicolson R, Craven-Thuss B, Smith J, et al: A randomized, double-blind, placebo-controlled trial of metoclopramide for the
treatment of Tourette’s disorder. J Am Acad Child Adolesc Psychiatry 44:640–646, 2005 [PubMed]
Niederhofer H, Staffen W, Mair A: A placebo-controlled study of lofexidine in the treatment of children with tic disorders and
attention deficit hyperactivity disorder. J Psychopharmacol 17:113–119, 2003 [PubMed]
Olvera RL, Pliszka SR, Luh J, et al: An open trial of venlafaxine in children and adolescents with ADHD. J Child Adolesc
Psychopharmacol 6:241–250, 1996 [PubMed]
Overall J, Pfefferbaum B: A Brief Psychiatric Rating Scale for Children. Innovations 3:264, 1984Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
47 of 58
10/05/2009 16:43
Owley T, McMahon W, Cook EH, et al: Multisite, double-blind, placebo-controlled trial of porcine secretin in autism. J Am Acad
Child Adolesc Psychiatry 40:1293–1299, 2001 [PubMed]
Owley T, Walton L, Salt J, et al: An open-label trial of escitalopram in pervasive developmental disorders. J Am Acad Child
Adolesc Psychiatry 44:343–348, 2005 [PubMed]
Pandina GJ, Aman MG, Findling RL, et al: Risperidone in the management of disruptive behavior disorders. J Child Adolesc
Psychopharmacol 16:379–392, 2006 [PubMed]
Pangalila-Ratulangi EA: Pilot evaluation of Orap (pimozide, R 6238) in child psychiatry. Psychiatr Neurol Neurochir 76:17–27,
1973 [PubMed]
Pappadopulos E, Macintyre Ii JC, Crismon ML, et al: Treatment recommendations for the use of antipsychotics for aggressive
youth (TRAAY), Part II. J Am Acad Child Adolesc Psychiatry 42:145–161, 2003 [PubMed]
Pappadopulos E, Woolston BA, Chait A, et al: Pharmacotherapy of aggression in children and adolescents: efficacy and effect
size. J Am Acad Child Adolesc Psychiatry 15:27–39, 2006 [PubMed]
Patel NC, DelBello MP, Bryan HS, et al: Open-label lithium for the treatment of adolescents with bipolar depression. J Am Acad
Child Adolesc Psychiatry 45:289–297, 2006 [PubMed]
Pavuluri MN, Henry DB, Carbray JA, et al: Open-label prospective trial of risperidone in combination with lithium or divalproex
sodium in pediatric mania. J Affect Disord 82 (suppl 1):S103–S111, 2004
Pavuluri MN, Henry DB, Carbray JA, et al: A one-year open-label trial of risperidone augmentation in lithium nonresponder
youth with preschool-onset bipolar disorder. J Child Adolesc Psychopharmacol 16:336–350, 2006 [PubMed]
Pediatric OCD Treatment Study (POTS) Team: Cognitive-behavior therapy, sertraline, and their combination for children and
adolescents with obsessive-compulsive disorder. JAMA 292:1969–1976, 2004
Pelham WE, Wheeler T, Chronis A: Empirically supported psychosocial treatments for attention deficit hyperactivity disorder.
J Clin Child Psychol 27:190–205, 1998 [PubMed]
Pelham WE, Burrows-MacLean L, Gnagy E, et al: Once-a-day OROS methylphenidate versus tid methylphenidate in natural
settings. Presented at the 46th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Chicago, IL,
October 19–24, 1999
Pelham WE, Gnagy EM, Burrows-MacLean L, et al: Once-a-day Concerta methylphenidate versus three-times-daily
methylphenidate in laboratory and natural settings. Pediatrics 107:e105, 2001
Pelham WE, Burrows-MacLean L, Gnagy EM, et al: Transdermal methylphenidate, behavioral, and combined treatment for
children with ADHD. Exp Clin Psychopharmacol 13:111–126, 2005 [PubMed]
Perry R, Campbell M, Adams P, et al: Long-term efficacy of haloperidol in autistic children: continuous versus discontinuous
drug administration. J Am Acad Child Adolesc Psychiatry 28:87–92, 1989 [PubMed]
Piacentini JC, Chang SW: Behavioral treatments for tic suppression: habit reversal training. Adv Neurol 99:227–233, 2006
[PubMed]
Piggott LR, Gdowski CL, Villanueva D, et al: Side effects of fenfluramine in autistic children. J Am Acad Child Psychiatry
25:287–289, 1986 [PubMed]
Pine DS, Cohen P, Gurley D, et al: The risk for early adulthood anxiety and depressive disorders in adolescent with anxiety
and depressive disorders. Arch Gen Psychiatry 55:56–64, 1998 [PubMed]
Pliszka SR, Carlson CL, Swanson JM: ADHD With Comorbid Disorders: Clinical Assessment and Management. New York,
Guilford, 1999
Pliszka SR, Crismon ML, Hughes CW, et al: The Texas Children’s Medication Algorithm Project: revision of the algorithm for
pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 45:642–657, 2006a
Pliszka SR, Matthews TL, Braslow KJ, et al: Comparative effects of methylphenidate and mixed salts amphetamine on height
and weight in children with attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child Adolesc Psychiatry 45:520–526,
2006b
Pool D, Bloom W, Mielke DH, et al: A controlled evaluation of loxitane in seventy-five adolescent schizophrenic patients. Curr
Ther Res Clin Exp 19:99–104, 1976 [PubMed]
Popper CW: Medical unknowns and ethical consent: prescribing psychotropic medications for children in the face of
uncertainty, in Psychiatric Pharmacosciences of Children and Adolescents. Edited by Popper CW. Washington, DC, American
Psychiatric Press, 1987, pp 127–161
Popper CW: Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder.
Child Adolesc Psychiatr Clin N Am 9:605–646, 2000 [PubMed]
Popper CW, Ziminitzky B: Sudden death putatively related to desipramine treatment in youth: a fifth case and a review of
speculative mechanisms. J Child Adolesc Psychopharmacol 5:283–300, 1995
Posey DJ, Walsh KH, Wilson GA, et al: Risperidone in the treatment of two very young children with autism. J Child Adolesc
Psychopharmacol 9:273–276, 1999 [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
48 of 58
10/05/2009 16:43
Posey DJ, Guenin KD, Kohn AE, et al: A naturalistic open-label study of mirtazapine in autistic and other pervasive
developmental disorders. J Child Adolesc Psychiatry 11:267–277, 2001 [PubMed]
Potenza MN, Holmes JP, Kanes SJ, et al: Olanzapine treatment of children, adolescents, and adults with pervasive
developmental disorders: an open-label pilot study. J Clin Psychopharmacol 19:37–44, 1999 [PubMed]
Poulton A: Growth on stimulant medication: clarifying the confusion: a review. Arch Dis Child 90:801–806, 2005 [PubMed]
Poznanski EO, Freman LN, Mokros HB: Children’s Depression Rating Scale–Revised. Psychopharmacol Bull 21:979–989, 1985
Preskorn SH, Weller EB, Weller RA: Depression in children: relationship between plasma imipramine levels and response. J
Clin Psychiatry 43:450–453, 1982 [PubMed]
Prince JB, Wilens TE, Biederman J, et al: A controlled study of nortriptyline in children and adolescents with attention deficit
hyperactivity disorder. J Child Adolesc Psychopharmacol 10:193–204, 2000 [PubMed]
Puig-Antich J, Perel JM, Lupatkin W, et al: Plasma levels of imipramine (IMI) and desmethylimipramine (DMI) and clinical
response in prepubertal major depressive disorder: a preliminary report. J Am Acad Child Psychiatry 18:616–627, 1979
[PubMed]
Puig-Antich J, Perel JM, Lupatkin W, et al: Imipramine in prepubertal major depressive disorders. Arch Gen Psychiatry
44:81–89, 1987 [PubMed]
Quinn D, Wigal S, Swanson J, et al: Comparative pharmacodynamics and plasma concentrations of d-threo-methylphenidate
hydrochloride after single doses of d-threo-methylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in a
double-blind, placebo-controlled, crossover laboratory school study in children with attention-deficit/hyperactivity disorder. J
Am Acad Child Adolesc Psychiatry 43:1422–1429, 2004 [PubMed]
Quintana H, Birmaher B, Stedge D, et al: Use of methylphenidate in the treatment of children with autistic disorder. J Autism
Dev Disord 25:283–294, 1995 [PubMed]
Rasgon NL: The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence. J Clin
Psychopharmacol 24:322–334, 2004 [PubMed]
Realmuto GM, Erickson WD, Yellin AM, et al: Clinical comparison of thiothixene and thioridazine in schizophrenic adolescents.
Am J Psychiatry 141:440–442, 1984 [PubMed]
Realmuto GM, Jensen J, Klykylo W, et al: Untoward effects of fenfluramine in autistic children. J Clin Psychopharmacol
6:350–355, 1986 [PubMed]
Realmuto GM, August GJ, Garfinkel BD: Clinical effect of buspirone in autistic children. J Clin Psychopharmacol 9:122–125,
1989 [PubMed]
Regeur L, Pakkenberg B, Fog R, et al: Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la
Tourette’s syndrome. J Neurol Neurosurg Psychiatry 49:791–795, 1986 [PubMed]
Reinblatt SP, Walkup JT: Psychopharmacologic treatment of pediatric anxiety disorders. Child Adolesc Psychiatric Clin N Am
14:877–908, 2005 [PubMed]
Remington G, Sloman L, Konstantareas M, et al: Clomipramine versus haloperidol in the treatment of autistic disorder: a
double-blind, placebo-controlled, crossover study. J Clin Psychopharmacol 21:440–444, 2001 [PubMed]
Renaud J, Birmaher B, Wassick SC, et al: Use of selective serotonin reuptake inhibitors for the treatment of childhood panic
disorder: a pilot study. J Child Adolescent Psychopharmacology 9:73–83, 1999 [PubMed]
Research Units on Pediatric Psychopharmacology Anxiety Study Group: Fluvoxamine for the treatment of anxiety disorders in
children and adolescents. N Engl J Med 344:1279–1285, 2001
Research Units on Pediatric Psychopharmacology Anxiety Study Group: The pediatric anxiety rating scale (PARS):
development and psychometric properties. J Am Acad Child Adolesc Psychiatry 41:1061–1069, 2002a
Research Units on Pediatric Psychopharmacology Anxiety Study Group: Treatment of pediatric anxiety disorders: an
open-label extension of the Research Units on Pediatric Psychopharmacology anxiety study. J Am Acad Child Adolesc
Psychiatry 12:175–188, 2002b
Research Units on Pediatric Psychopharmacology Autism Network: Risperidone treatment of autistic disorder: longer-term
benefits and blinded discontinuation after 6 months. Am J Psychiatry 162:1361–1369, 2005
Riddle M: Obsessive-compulsive disorder in children and adolescents. Br J Psychiatry 173 (35 suppl):91–96, 1998
Riddle MA, Scahill L, King RA, et al: Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with
obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 31:1062–1069, 1992 [PubMed]
Riddle MA, Bernstein GA, Cook EH, et al: Anxiolytics, adrenergic agents, and naltrexone. J Am Acad Child Adolesc Psychiatry
38:546–556, 1999 [PubMed]
Riddle MA, Reeve EA, Yaryura-Tobias JA, et al: Fluvoxamine for children and adolescents with obsessive-compulsive disorder:
a randomized, controlled, multicenter trial. J Am Acad Child Adolesc Psychiatry 40:222–229, 2001 [PubMed]
Rifkin A, Karajgi B, Dicker R, et al: Lithium treatment of conduct disorders in adolescents. Am J Psychiatry 154:554–555,
1997 [Full Text] [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
49 of 58
10/05/2009 16:43
Ritvo ER, Freeman BJ, Geller E, et al: Effects of fenfluramine on 14 outpatients with the syndrome of autism. J Am Acad Child
Psychiatry 22:549–558, 1983 [PubMed]
Ritvo ER, Freeman BJ, Yuwiler A, et al: Study of fenfluramine in outpatients with the syndrome of autism. J Pediatr
105:823–828, 1984 [PubMed]
Ritvo ER, Freeman BJ, Yuwiler A, et al: Fenfluramine treatment of autism: UCLA collaborative study of 81 patients at nine
medical centers. Psychopharmacol Bull 22:133–140, 1986 [PubMed]
Robb AS, Auby P, Nyilas M, et al: Efficacy of aripiprazole in the treatment of adolescents with schizophrenia. New research
poster presented at the 160th Annual Meeting of the American Psychiatric Association, San Diego, CA, May 19–24, 2007
Roberts W, Weaver L, Brian J, et al: Repeated doses of porcine secretin in the treatment of autism: a randomized,
placebo-controlled trial. Pediatrics 107:e71, 2001
Roblek T, Piacentini J: Cognitive-behavior therapy for childhood anxiety disorders. Child Adolesc Psychiatric Clin N Am
14:863–876, 2005 [PubMed]
Ross DC, Piggott LR: Clonazepam for OCD. J Am Acad Child Adolesc Psychiatry 32:470–471, 1993 [PubMed]
Ross DL, Klykylo WM, Hitzemann R: Reduction of elevated CSF beta-endorphin by fenfluramine in infantile autism. Pediatr
Neurol 3:83–86, 1987 [PubMed]
Rowland AS, Umbach DM, Stallone L, et al: Prevalence of medication treatment for attention deficit-hyperactivity disorder
among elementary school children in Johnston County, North Carolina. Am J Public Health 92:231–234, 2002 [PubMed]
Rugino TA, Janvier YM: Aripiprazole in children and adolescents: clinical experience. J Child Neurol 20:603–610, 2005
[PubMed]
Ryan ND, Puig-Antich J, Rabinovich H, et al: MAOIs in adolescent major depression unresponsive to tricyclic antidepressants.
J Am Acad Child Adolesc Psychiatry 27:755–758, 1988 [PubMed]
Rynn MA, Siqueland L, Rickels K: Placebo-controlled trial of sertraline in the treatment of children with generalized anxiety
disorder. Am J Psychiatry 158:2008–2014, 2001 [Full Text] [PubMed]
Rynn MA, Findling RL, Emslie GJ, et al: Efficacy and safety of nefazodone in adolescents with MDD. Poster presented at the
155th annual meeting of the American Psychiatric Association, Philadelphia, PA, May 18–23, 2002
Rynn M, Wagner KD, Donnelly C, et al: Long-term sertraline treatment of children and adolescents with major depressive
disorder. J Child Adolescent Psychopharmacol 16:103–113, 2006 [PubMed]
Safer D, Zito JM, Fine EM: Increased methylphenidate usage for attention deficit disorder in the 1990s. Pediatrics
98:1084–1088, 1996 [PubMed]
Sallee FR, Nesbitt L, Jackson C, et al: Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s
disorder. Am J Psychiatry 154:1057–1062, 1997 [Full Text] [PubMed]
Sallee FR, Kurlan R, Goetz CG, et al: Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot
study. J Am Acad Child Adolesc Psychiatry 39:292–299, 2000 [PubMed]
Sallee FR, Miceli JJ, Tensfeldt T, et al: Single-dose pharmacokinetics and safety of ziprasidone in children and adolescents. J
Am Acad Child Adolesc Psychiatry 45:720–728, 2006 [PubMed]
Sanberg PR, McConville BJ, Fogelson HM, et al: Nicotine potentiates the effects of haloperidol in animals and in patients with
Tourette syndrome. Biomed Pharmacother 43:19–23, 1989 [PubMed]
Sanberg PR, Shytle RD, Silver AA: Treatment of Tourette’s syndrome with mecamylamine. Lancet 352:705–706, 1998
[PubMed]
Sandler AD, Sutton KA, DeWeese J, et al: Lack of benefit of a single dose of synthetic human secretin in the treatment of
autism and pervasive developmental disorder. N Engl J Med 341:1801–1806, 1999 [PubMed]
Sandor P, Musisi S, Moldofsky H, et al: Tourette syndrome: a follow-up study. J Clin Psychopharmacol 10:197–199, 1990
[PubMed]
Saxena K, Silverman MA, Chang K, et al: Baseline predictors of response to divalproex in conduct disorder. J Clin Psychiatry
66:1541–1548, 2005 [PubMed]
Saxena K, Howe M, Simeonova D, et al: Divalproex sodium reduces overall aggression in youth at high risk for bipolar
disorder. J Child Adolesc Psychopharmacol 16:252–259, 2006 [PubMed]
Scahill L, Chappell PB, Kim YS, et al: A placebo-controlled study of guanfacine in the treatment of children with tic disorders
and attention deficit hyperactivity disorder. Am J Psychiatry 158:1067–1074, 2001 [Full Text] [PubMed]
Scahill L, Leckman JF, Schultz RT, et al: A placebo-controlled trial of risperidone in Tourette syndrome. Neurology
60:1130–1135, 2003 [PubMed]
Scahill L, Blair J, Leckman JF, et al: Sudden death in a patient with Tourette syndrome during a clinical trial of ziprasidone. J
Psychopharmacol 19:205–206, 2005 [PubMed]
Schur SB, Sikich L, Findling RL, et al: Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY).
Part I: a review. J Am Acad Child Adolesc Psychiatry 42:132–144, 2003 [PubMed]Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
50 of 58
10/05/2009 16:43
Schuster CR, Lewis M, Seiden LS: Fenfluramine: neurotoxicity. Psychopharmacol Bull 22:148–151, 1986 [PubMed]
Scifo R, Cioni M, Nicolosi A, et al: Opioid-immune interactions in autism: behavioural and immunological assessment during a
double-blind treatment with naltrexone. Ann Ist Super Sanita 32:351–359, 1996 [PubMed]
Scott DW, Eames P: Use of sulpiride in a case of atypical autism. J Autism Dev Disord 18:144–146, 1988 [PubMed]
Seedat S, Lockhat R, Kaminer D, et al: An open trial of citalopram in adolescents with post-traumatic stress disorder. Int Clin
Psychopharmacol 16:21–25, 2001 [PubMed]
Seedat S, Stein DJ, Ziervogel C, et al: Comparison of response to a selective serotonin reuptake inhibitor in children,
adolescents, and adults with posttraumatic stress disorder. J Child Adolesc Psychopharmacology 12:37–46, 2002 [PubMed]
Shafey H: Use of lithium and flupenthixol in a patient with pervasive developmental disorder. Am J Psychiatry 143:681, 1986
[PubMed]
Shapiro AK, Shapiro E, Eisenkraft GJ: Treatment of Gilles de la Tourette’s syndrome with clonidine and neuroleptics. Arch Gen
Psychiatry 40:1235–1240, 1983 [PubMed]
Shapiro A, Shapiro E, Young J, et al: Gilles de la Tourette Syndrome, 2nd Edition. New York, Raven, 1988
Shapiro E, Shapiro AK, Fulop G, et al: Controlled study of haloperidol, pimozide, and placebo for the treatment of Gilles de la
Tourette’s syndrome. Arch Gen Psychiatry 46:722–730, 1989 [PubMed]
Shaw JA, Lewis JE, Pascal S, et al: A study of quetiapine: efficacy and tolerability in psychotic adolescents. J Child Adolesc
Psychopharmacol 11:415–424, 2001 [PubMed]
Shaw P, Sporn A, Gogtay N, et al: Childhood-onset schizophrenia: a double-blind, randomized clozapine-olanzapine
comparison. Arch Gen Psychiatry 63:721–730, 2006 [PubMed]
Shea S, Turgay A, Carroll A, et al: Risperidone in the treatment of disruptive behavioral symptoms in children with autistic
and other pervasive developmental disorders. Pediatrics 114:634–641, 2004
Sherman J, Factor DC, Swinson R, et al: The effects of fenfluramine (hydrochloride) on the behaviors of fifteen autistic
children. J Autism Dev Disord 19:533–543, 1989 [PubMed]
Sikich L, Hamer RM, Bashford RA, et al: A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a
double-blind, randomized, 8-week trial. Neuropsychopharmacology 29:133–145, 2004 [PubMed]
Silva RR, Malone RP, Anderson LT, et al: Haloperidol withdrawal and weight changes in autistic children. Psychopharmacol
Bull 29:287–291, 1993 [PubMed]
Silver AA, Shytle RD, Philipp MK, et al: Case study: long-term potentiation of neuroleptics with transdermal nicotine in
Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 35:1631–1636, 1996 [PubMed]
Silver AA, Shytle RD, Philipp MK, et al: Transdermal nicotine and haloperidol in Tourette’s disorder: a double-blind
placebo-controlled study. J Clin Psychiatry 62:707–714, 2001a
Silver AA, Shytle RD, Sheehan KH, et al: Multicenter, double-blind, placebo-controlled study of mecamylamine monotherapy
for Tourette’s disorder. J Am Acad Child Adolesc Psychiatry 40:1103–1110, 2001b
Simeon JG: Use of anxiolytics in children. Encephale 19:71–74, 1993 [PubMed]
Simeon JG, Ferguson HB: Alprazolam effects in children with anxiety disorders. Can J Psychiatry 32:570–574, 1987 [PubMed]
Simeon JG, Ferguson HB, Van-Wyck-Fleet J: Bupropion effects in attention deficit and conduct disorders. Can J Psychiatry
31:581–585, 1986 [PubMed]
Simeon JG, Ferguson HB, Knott V, et al: Clinical, cognitive, and neurophysiological effects of alprazolam in children and
adolescents with overanxious and avoidant disorders. J Am Acad Child Adolesc Psychiatry 31:29–33, 1992 [PubMed]
Simon GE, Savarino J, Operskalski B, et al: Suicide risk during antidepressant treatment. Am J Psychiatry 163:41–47, 2006
[Full Text] [PubMed]
Simpson RL: The effects of an antipsychotic medication on the classroom behavior of four schizophrenic male children. J
Autism Child Schizophr 7:349–358, 1977 [PubMed]
Singer HS, Brown J, Quaskey S, et al: The treatment of attention-deficit hyperactivity disorder in Tourette’s syndrome: a
double blind placebo controlled study with clonidine and desipramine. Pediatrics 95:74–81, 1995 [PubMed]
Snead RW, Boon F, Presberg J: Paroxetine for self-injurious behavior. J Am Acad Child Adolesc Psychiatry 33:909–910, 1994
[PubMed]
Snyder R, Turgay A, Aman M, et al: Effects of risperidone on conduct and disruptive behavior disorders in children with
subaverage IQs. J Am Acad Child Adolesc Psychiatry 41:1026–1036, 2002 [PubMed]
Søndergård L, Kvist K, Andersen PK, et al: Do antidepressants precipitate youth suicide? A nationwide
pharmacoepidemiological study. Eur Child Adolesc Psychiatry 15:232–240, 2006 [PubMed]
Spencer EK, Kafantaris V, Padron-Gayol MV, et al: Haloperidol in schizophrenic children: early findings from a study in
progress. Psychopharmacol Bull 28:183–186, 1992 [PubMed]
Spencer T, Biederman J, Steingard R, et al: Nortriptyline treatment of children with attention deficit hyperactivity disorderPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
51 of 58
10/05/2009 16:43
and tic disorder or Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 32:205–210, 1993 [PubMed]
Spencer T, Biederman J, Coffey B, et al: A double-blind comparison of desipramine and placebo in children and adolescents
with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 59:649–656, 2002
[PubMed]
Spencer TJ, Abikoff HB, Connor DF, et al: Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in
the management of oppositional defiant disorder with or without comorbid attention-deficit/hyperactivity disorder in
school-aged children and adolescents: a 4-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled,
forced-dose-escalation study. Clin Ther 28:402–418, 2006a
Spencer TJ, Wilens TE, Biederman J, et al: Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in
the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind,
placebo-controlled, parallel-group study. Clin Ther 28:266–279, 2006b
Staller JA, Staller JA: Intramuscular ziprasidone in youth: a retrospective chart review. J Child Adolesc Psychopharmacol
14:590–592, 2004 [PubMed]
Stein MB, Fuetsch M, Muller N, et al: Social anxiety disorder and the risk of depression: a prospective community study of
adolescents and young adults. Arch Gen Psychiatry 58:251–256, 2001 [PubMed]
Steiner H, Petersen ML, Saxena K, et al: Divalproex sodium for the treatment of conduct disorder: a randomized controlled
clinical trial. J Clin Psychiatry 64:1183–1191, 2003 [PubMed]
Steingard R, Biederman J: Lithium responsive manic-like symptoms in two individuals with autism and mental retardation. J
Am Acad Child Adolesc Psychiatry 26:932–935, 1987 [PubMed]
Steingard RJ, Zimnitzky B, DeMaso RD, et al: Sertraline treatment of transition-associated anxiety and agitation in children
with autistic disorder. J Child Adolesc Psychopharmacol 7:9–15, 1997 [PubMed]
Stephens RJ, Bassel C, Sandor P, et al: Olanzapine in the treatment of aggression and tics in children with Tourette’s
syndrome—a pilot study. J Child Adolesc Psychopharmacol 14:255–266, 2004 [PubMed]
Stern LM, Walker MK, Sawyer MG, et al: A controlled crossover trial of fenfluramine in autism. J Child Psychol Psychiatry
31:569–585, 1990 [PubMed]
Storch EA, Lehmkuhl H, Geffken GR, et al: Aripiprazole augmentation of incomplete treatment response in an adolescent male
with obsessive-compulsive disorder. Depress Anxiety 25:172–174, 2008 [PubMed]
Stubbs EG, Budden SS, Jackson RH, et al: Effects of fenfluramine on eight outpatients with the syndrome of autism. Dev Med
Child Neurol 28:229–235, 1986 [PubMed]
Sumner CS, Donnelly C, Lopez FA, et al: Atomoxetine treatment for pediatric patients with ADHD and comorbid anxiety.
Presented at the annual meeting of the American Psychiatric Association, Atlanta, GA, May 2005
Sverd J: Imipramine treatment of panic disorder in a boy with Tourette’s syndrome. J Clin Psychiatry 49:31–32, 1988
[PubMed]
Swanson JM, Flockhart D, Udrea D, et al: Clonidine in the treatment of ADHD: questions about safety and efficacy. J Child
Adolesc Psychopharmacol 5:301–304, 1995
Swanson JM, Wigal SB, Udrea D, et al: Evaluation of individual subjects in the analog classroom setting, I: examples of
graphical and statistical procedures for within-subject ranking of responses to different delivery patterns of methylphenidate.
Psychopharmacol Bull 34:825–832, 1998 [PubMed]
Swanson J, Gupta S, Guinta D, et al: Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity
disorder in children. Clin Pharmacol Ther 66:295–305, 1999 [PubMed]
Swanson J, Greenhill L, Pelham W, et al: Initiating Concerta (OROS methylphenidate HCl) qd in children with attention-deficit
hyperactivity disorder. J Clin Res 3:59–76, 2000
Swanson JM, Gupta S, Williams L, et al: Efficacy of a new pattern of delivery of methylphenidate for the treatment of ADHD:
effects on activity level in the classroom and on the playground. J Am Acad Child Adolesc Psychiatry 41:1306–1314, 2002
[PubMed]
Swanson J, Gupta S, Lam A, et al: Development of a new once-a-day formulation of methylphenidate for the treatment of
attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies. Arch Gen Psychiatry 60:204–211,
2003 [PubMed]
Swanson JM, Wigal SB, Wigal T, et al: A comparison of once-daily extended-release methylphenidate formulations in children
with attention-deficit/hyperactivity disorder in the laboratory school (the Comacs Study). Pediatrics 113:e206–e216, 2004
Swanson JM, Greenhill LL, Lopez FA, et al: Modafinil film-coated tablets in children and adolescents with
attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed
by abrupt discontinuation. J Clin Psychiatry 67:137–147, 2006a
Swanson JM, Greenhill LL, Wigal T, et al: Stimulant-related reduction of growth rates in the preschool ADHD treatment study
(PATS). J Am Acad Child Adolesc Psychiatry 45:1304–1313, 2006b
Swope GS, Hoopes SP, Amy LS, et al: An open-label study of lamotrigine in adolescents with bipolar mood disorder. NewPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
52 of 58
10/05/2009 16:43
research poster presented at the 157th annual meeting of the American Psychiatric Association, New York, May 1–6, 2004
Tancer NK, Klein RG, Koplewicz HS, et al: Rate of atypical depression and tricyclic drug response in adolescents. J Am Acad
Child Adolesc Psychiatry 31:576, 1992
Tanguay PE: Pervasive developmental disorders: a 10-year review. J Am Acad Child Adolesc Psychiatry 39:1079–1095, 2000
[PubMed]
Tannock R, Ickowicz A, Schachar R: Differential effects of methylphenidate on working memory in ADHD children with and
without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 34:886–896, 1995 [PubMed]
Thomsen PH: Child and adolescent obsessive-compulsive disorder treated with citalopram: findings from an open trial of 23
cases. J Child Adolesc Psychopharmacol 7:157–166, 1997 [PubMed]
Thomsen PH: Risperidone augmentation in the treatment of severe adolescent OCD in SSRI-refractory cases: a case-series.
Ann Clin Psychiatry 16:201–207, 2004 [PubMed]
Thomsen PH, Ebbesen C, Persson C: Long-term experience with citalopram in the treatment of adolescent OCD. J Am Acad
Child Adolesc Psychiatry 40:895–902, 2001 [PubMed]
Todd RD: Fluoxetine in autism. Am J Psychiatry 148:1089, 1991 [PubMed]
Tohen M, Kryzhanovskaya L, Carlson G, et al: Olanzapine versus placebo in the treatment of adolescents with bipolar mania.
Am J Psychiatry 164:1547–1556, 2007 [Full Text] [PubMed]
Tourette’s Syndrome Study Group: Treatment of ADHD in children with tics: a randomized controlled trial. Neurology
58:527–536, 2002
Treatment for Adolescents with Depression Study (TADS) Team: Fluoxetine, cognitive-behavioral therapy, and their
combination for adolescents with depression. TADS randomized controlled trial. JAMA 292:807–820, 2004
Troost PW, Lahuis BE, Steenhuis MP, et al: Long-term effects of risperidone in children with autism spectrum disorders: a
placebo discontinuation study. J Am Acad Child Adolesc Psychiatry 44:1137–1144, 2005 [PubMed]
Turgay A, Binder C, Snyder R, et al: Long-term safety and efficacy of risperidone for the treatment of disruptive behavior
disorders in children with subaverage IQs. Pediatrics 110:e34, 2002
U.S. Food and Drug Administration: FDA, Final Rule, Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric Patients, 63 Fed. Reg. 66,631 (1998); see also 21 CFR
- 201.23 (1999); 21 CFR §314.55 (1999); 21 CFR §601.27 (1999)
U.S. Food and Drug Administration: FDA News: FDA launches a multi-pronged strategy to strengthen safeguards for children
treated with antidepressant medication. October 15, 2004a. Available at:
http://www.fda.gov/bbs/topics/news/2004/NEW01124.html. Accessed December 2008.
U.S. Food and Drug Administration: Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and Pediatric
Advisory Committee. September 13–14, 2004b. Available at:
http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1.htm. Accessed December 2008.
U.S. Food and Drug Administration: FDA Alert [09/05]: Suicidal thinking in children and adolescents. Available at: Food and
Drug Administration Website, 2005
U.S. Food and Drug Administration: New warning for Strattera. Available at: Food and Drug Administration Website, 2006a
U.S. Food and Drug Administration: Pediatric advisory committee briefing information (March 22, 2006). Available at: Food
and Drug Administration Website, 2006b
U.S. Food and Drug Administration: Psychopharmacological drugs advisory committee briefing information (March 23, 2006).
Available at: Food and Drug Administration Website, 2006c
U.S. Food and Drug Administration: FDA News: FDA Proposes New Warnings About Suicidal Thinking, Behavior in Young
Adults Who Take Antidepressant Medications. May 2, 2007. Available at:
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01624.html. Accessed December 2008.
Valicenti-McDermott MR, Demb H: Clinical effects and adverse reactions of off-label use of aripiprazole in children and
adolescents with developmental disabilities. J Child Adolesc Psychopharmacol 16:549–560, 2006 [PubMed]
Varley CK, Holm VA: A two-year follow-up of autistic children treated with fenfluramine. J Am Acad Child Adolesc Psychiatry
29:137–140, 1990 [PubMed]
Vetro A, Szentistvanyi I, Pallag L, et al: Therapeutic experience with lithium in childhood aggressivity. Neuropsychobiology
14:121–127, 1985 [PubMed]
Villalaba L: Follow-up review of AERS search identifying cases of sudden death occurring with drugs used for the treatment of
attention deficit hyperactivity disorder (ADHD). Available at: Food and Drug Administration Website, 2006
Vitiello B: Psychopharmacology for young children: clinical needs and research opportunities. Pediatrics 108:983–989, 2001
[PubMed]
Volkmar F, Cook EH Jr, Pomeroy J, et al: Practice parameters for the assessment and treatment of children, adolescents, and
adults with autism and other pervasive developmental disorders. American Academy of Child and Adolescent PsychiatryPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
53 of 58
10/05/2009 16:43
Working Group on Quality Issues. J Am Acad Child Adolesc Psychiatry 38 (12 suppl):32S–54S, 1999
Wagner KD, Weller E, Carlson G, et al: An open-label trial of divalproex in children and adolescents with bipolar disorder. J
Am Acad Child Adolesc Psychiatry 41:1224–1230, 2002 [PubMed]
Wagner KD, Ambrosini P, Rynn M, et al: Efficacy of sertraline in the treatment of children and adolescents with major
depressive disorder: two randomized controlled trials. JAMA 290:1033–1041, 2003a
Wagner KD, Cook Eh, Chung H, et al: Remission status after long-term sertraline treatment of pediatric obsessive-compulsive
disorder. J Child Adolesc Psychopharmacol 13 (suppl 1):S53–S60, 2003b
Wagner KD, Berard R, Stein MB, et al. A multicenter, randomized, double-blind, placebo-controlled trial of paroxetine in
children and adolescents with social anxiety disorder. Arch Gen Psychiatry 61:1153–1162, 2004a
Wagner, KD, Robb AS, Findling RL, et al: A randomized, placebo-controlled trial of citalopram for the treatment of major
depression in children and adolescents: Am J Psychiatry 161:1079–1083, 2004b
Wagner KD, Jonas J, Findling RL, et al: A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment
of pediatric depression. J Am Acad Child Adolesc Psychiatry 45:280–288, 2006a
Wagner KD, Kowatch RA, Emslie GJ, et al: A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the
treatment of bipolar disorder in children and adolescents. Am J Psychiatry 163:1179–1186, 2006b
Waizer J, Polizos P, Hoffman SP, et al: A single-blind evaluation of thiothixene with outpatient schizophrenic children. J
Autism Child Schizophr 2:378–386, 1972 [PubMed]
Walkup JT, Reeve E, Yaryura-Tobias J, et al: Fluvoxamine for childhood OCD: long-term treatment. Poster presented at the
45th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Anaheim, CA, October 27–November 1,
1998
Weisler RH, Biederman J, Spencer TJ, et al: Mixed amphetamine salts extended-release in the treatment of adult ADHD: a
randomized, controlled trial. CNS Spectr 11:625–639, 2006 [PubMed]
Weiss G, Hechtman L: Hyperactive Children Grown Up, 2nd Edition. New York, Guilford, 2003
Wigal SB, Sanchez DY, Decroy DY, et al: Selection of the optimal dose ratio for a controlled-delivery formulation of
methylphenidate. J Appl Res 3:46–63, 2003
Wigal S, McGough J, Abikoff HB, et al: Behavioral effects of methylphenidate transdermal system in children with ADHD.
Presented at the 52nd Annual Meeting of the American Academy of Child and Adolescent Psychiatry, Toronto, CA, October
18–23, 2005a
Wigal SB, McGough JJ, McCracken JT, et al: A laboratory school comparison of mixed amphetamine salts extended release
(Adderall XR) and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder. J Atten
Disord 9:275–289, 2005b
Wigal T, Greenhill LL, Chuang S, et al: Safety and tolerability of methylphenidate in preschool children with ADHD. J Am Acad
Child Adolesc Psychiatry 45:1294–1303, 2006 [PubMed]
Wilens TE, Faraone SV, Biederman J, et al: Does stimulant therapy of attention-deficit/hyperactivity disorder beget later
substance abuse? A meta-analytic review of the literature. Pediatrics 111:179–185, 2003a
Wilens T, Pelham W, Stein M, et al: ADHD treatment with once-daily OROS methylphenidate: interim 12-month results from a
long-term open-label study. J Am Acad Child Adolesc Psychiatry 42:424–433, 2003b
Wilens T, McBurnett K, Stein M, et al: ADHD treatment with once daily OROS methylphenidate treatment: final results from a
long term open-label study. J Am Acad Child Adolesc Psychiatry 44:1015–1023, 2005 [PubMed]
Wilens TE, McBurnett K, Bukstein O, et al: Multisite controlled study of OROS methylphenidate in the treatment of adolescents
with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 160:82–90, 2006a
Wilens TE, Newcorn JH, Kratochvil CJ, et al: Long-term atomoxetine treatment in adolescents with
attention-deficit/hyperactivity disorder. J Pediatr 149:112–119, 2006b
Willemsen-Swinkels SH, Buitelaar JK, Weijen FG, et al: Placebo-controlled acute dosage naltrexone study in young autistic
children. Psychiatry Res 58:203–215, 1995 [PubMed]
Willemsen-Swinkels SH, Buitelaar JK, van Engeland H: The effects of chronic naltrexone treatment in young autistic children:
a double-blind placebo controlled crossover study. Biol Psychiatry 39:1023–1031, 1996 [PubMed]
Willemsen-Swinkels SH, Buitelaar JK, van Berckelaer-Onnes IA, et al: Brief report: six months continuation treatment in
naltrexone-responsive children with autism: an open-label case-control design. J Autism Dev Disord 29:167–169, 1999
[PubMed]
Williams DT, Mehl R, Yudofsky S, et al: The effect of propranolol on uncontrolled rage outbursts in children and adolescents
with organic brain dysfunction. J Am Acad Child Psychiatry 21:129–135, 1982 [PubMed]
Wolpert A, Hagamen MB, Merlis S: A comparative study of thiothixene and trifluoperazine in childhood schizophrenia. Curr
Ther Res Clin Exp 9:482–485, 1967 [PubMed]
Wolraich ML: Evaluation of efficacy and safety or OROS methylphenidate HCI (MPH) extended release tablets,Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
54 of 58
10/05/2009 16:43
methylphenidate tid, and placebo in children with ADHD. Pediatr Res 47:36A, 2000
Wolraich ML, Greenhill LL, Pelham W, et al: Randomized, controlled trial of OROS methylphenidate once a day in children with
attention-deficit/hyperactivity disorder. Pediatrics 108:883–892, 2001 [PubMed]
Wray JA, Yoon JH, Vollmer T, et al: Pilot study of the behavioral effects of flumazenil in two children with autism. J Autism
Dev Disord 30:619–620, 2000 [PubMed]
Wright HH, Cuccaro ML, Leonhardt TV, et al: Case study: fluoxetine in the multimodal treatment of a preschool child with
selective mutism. J Am Acad Child Adolesc Psychiatry 34:857–862, 1995 [PubMed]
Yarbrough E, Santat U, Perel I, et al: Effects of fenfluramine on autistic individuals residing in a state developmental center. J
Autism Dev Disord 17:303–314, 1987 [PubMed]
Yoo HK, Kim JY, Kim CY: A pilot study of aripiprazole in children and adolescents with Tourette’s disorder. J Child Adolesc
Psychopharmacol 16:505–506, 2006 [PubMed]
Young RC, Biggs JT, Ziegler VE, et al: A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry
133:429–435, 1978 [PubMed]
Zito JM, Safer DJ, dosReis S, et al: Trends in the prescribing of psychotropic medications in preschoolers. JAMA
283:1025–1030, 2000 [PubMed]
Zohar AH: The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc Psychiatr Clin N Am
8:445–460, 1999 [PubMed]
Zuddas A, Ledda MG, Fratta A, et al: Clinical effects of clozapine on autistic disorder. Am J Psychiatry 153:738, 1996
[PubMed]
Zwier KJ, Rao U: Buspirone use in an adolescent with social phobia and mixed personality. J Am Acad Child Adolesc
Psychiatry 33:1007–1011, 1994 [PubMed]
APPENDIX
Psychotropic Medications Commonly Prescribed for Children and Adolescents
This Appendix describes common classes of psychotropic medications used to treat children and adolescents. Dosages,
common side effects, and monitoring schedules are presented for each medication class.
Antidepressants
Dosage and Monitoring
The starting and target doses of antidepressants for children and adolescents are listed in Table 63–1.
TABLE 63–1. Clinical use of antidepressants in children and adolescents
Typical starting dose (mg)
Medication Child Adolescent Target dose (mg/day)
Citalopram 5–10 10 20–40
Escitalopram 5 10 10–20
Fluoxetine 5–10 10 20–40
Paroxetine 5–10 10 20–40
Sertraline 25 50 100–200
Mirtazapine 15 15 30–45
Venlafaxine 37.5 37.5 150–225
Bupropion 50 bid 50 bid 100–200
Premedication laboratories include complete blood count, blood chemistries, and liver function tests. Blood pressure should
be monitored during dose titration with venlafaxine.
The FDA has issued the following black box warning, which applies to all antidepressants (U.S. Food and Drug Administration
2007):
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and
young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
[Name of Antidepressant] or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical
need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults
beyond age 24 years; there was a reduction in risk with antidepressants compared with placebo in adults ages 65 years and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or
unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the
prescriber.
Side EffectsPrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
55 of 58
10/05/2009 16:43
Common side effects of SSRIs are headache, nausea, abdominal pain, dry mouth, insomnia, and somnolence (Emslie et al.
2002; Keller et al. 2001; Wagner et al. 2003a, 2004b, 2006a). Potential serious adverse events include serotonin syndrome,
extrapyramidal symptoms (tics, myoclonus), amotivational syndrome, and increased bleeding (Hammerness et al. 2006). A
major advantage of SSRIs is their safety in overdose (Barbey and Roose 1998).
Common side effects of mirtazapine are somnolence, increased appetite, weight gain, dizziness, dry mouth, and constipation
(Green 2001).
Common side effects of venlafaxine include anorexia, abdominal pain, insomnia, somnolence, dizziness, dry mouth, increased
sweating and nervousness, and elevated blood pressure with dose increase (Emslie et al. 2007a; Green 2001).
Common side effects of bupropion are headache, nausea, rash, irritability, drowsiness, fatigue, and anorexia (Barrickman et
- 1995; Conners et al. 1996; Daviss et al. 2001). Bupropion is contraindicated in children with seizure disorders, since it
may lower the seizure threshold.
Atomoxetine
Dosage and Monitoring
Atomoxetine can be given in the late afternoon or evening, whereas stimulants generally cannot; atomoxetine may have less
pronounced effects on appetite and sleep than stimulants, though it may produce relatively more nausea or sedation.
Gastrointestinal distress can be minimized by taking the medication after a meal. In children and young adolescents,
atomoxetine is initiated at a dosage of 0.3 mg/kg/day and titrated over 1–3 weeks to a maximum dosage of 1.2–1.8
mg/kg/day (Kratochvil et al. 2003). Adults or adult-sized adolescents should be started on atomoxetine 40 mg daily and
titrated to 80–100 mg/day of atomoxetine over 1–3 weeks, if needed (Kratochvil et al. 2003). Atomoxetine’s labeling
recommends both once-daily and twice-daily dosing, although its elimination half-life of 5 hours (as well as clinical
experience) suggests that twice-daily dosing (early A.M. and early P.M) is more effective and less prone to cause side effects.
Michelson et al. (2002) showed that while atomoxetine was superior to placebo at week 1 of the trial, its greatest effects
were observed at week 6, suggesting that patients should be maintained at the full therapeutic dose for at least several
weeks in order to observe the drug’s full effects.
Side Effects
Side effects of atomoxetine that occurred more often than placebo in clinical trials included gastrointestinal distress,
sedation, and decreased appetite. These can generally be managed by dosage adjustment and often attenuate with time. On
December 17, 2004, the FDA required that a warning be added to atomoxetine due to reports of two patients (an adult and
child) who developed severe liver disease (U.S. Food and Drug Administration 2006a). Both patients recovered. The FDA has
also issued an alert regarding suicidal thinking with atomoxetine in children and adolescents (U.S. Food and Drug
Administration 2005). A black box warning is included in the package insert. In 12 controlled trials involving 1,357 patients
on atomoxetine and 851 on placebo, the average risk of suicidal thinking was 4 per 1,000 in the atomoxetine-treated group
versus none in the placebo group.
Atypical Antipsychotics
Dosage and Monitoring
Typical starting and target dosages of atypical antipsychotics are listed in Table 63–2.
TABLE 63–2. Clinical use of atypical antipsychotics in children and adolescents
Medication Typical starting dose (mg) Target dose (mg/day)
Clozapine 25 twice daily 200–400
Olanzapine 2.5 twice daily 10–20
Quetiapine 50 twice daily 400–600
Risperidone 0.25 twice daily 1–2
Ziprasidone 20 twice daily 80–120
Aripiprazole 2.5–5.0 at bedtime 10–25
Source.DelBello and Kowatch 2006.
Premedication laboratories include complete blood count, blood chemistries, and liver function tests. In addition, the
American Diabetes Association et al. (2004) recommendations should be followed. These include baseline body mass index
(BMI), waist circumference, blood pressure, and fasting glucose and lipid panels. BMI should be followed monthly for 3
months, and then measured quarterly. Blood pressure, fasting glucose, and lipid panels should be followed up at 3 months
and then yearly. Monitoring should also be done for extrapyramidal side effects.
Side Effects
Side effects of atypical antipsychotics include weight gain, dyslipidemia, insulin resistance and diabetes, hyperprolactinemia,
extrapyramidal side effects and akathisia, QTc prolongation, sedation, liver toxicity, neutropenia, and neuroleptic malignant
syndrome. Clozapine has also been associated with seizures, agranulocytosis, and myocarditis (Correll et al. 2006).
ClonidinePrint: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
56 of 58
10/05/2009 16:43
Dosage and Monitoring
Clonidine is initiated at 0.05 mg/day, with dose increases of 0.05 mg every 3 days. Typical dosages for ADHD are in the range
of total 0.15–0.3 mg/day (on a three-times-per-day schedule). Transdermal clonidine delivers doses of 0.1, 0.2, or 0.3
mg/day. During initial treatment, a temporary worsening of motor and phonic tics in Tourette’s syndrome may occur, which
usually resolves within 2–4 weeks. Clonidine should be tapered by 0.05 mg/day upon discontinuation (Hunt et al. 1990).
Given the reports of adverse cardiovascular side effects in children taking clonidine, recommendations have been made
regarding cardiovascular monitoring (Cantwell et al. 1997). Pulse and blood pressure should be measured at baseline, weekly
during titration of dose, and every 4–6 weeks during maintenance treatment. ECGs should be obtained at baseline and after
the maximal dose of clonidine is achieved. Abrupt discontinuation of clonidine is not recommended, because it increases the
risk of adverse cardiovascular side effects, particularly hypertension.
Side Effects
Common side effects of clonidine in children are sedation, depression, irritability, hypotension, sleep disturbance, dry mouth,
and dizziness. Skin irritation and erythema are common with the clonidine patch (Connor et al. 1999; Hunt et al. 1990).
Rebound tachycardia and hypertension may occur if clonidine is abruptly discontinued, particularly after chronic use (Popper
2000).
Safety concerns have been raised about the combination of clonidine and methylphenidate, following the report of four cases
of sudden death in children on this medication combination (Cantwell et al. 1997; Fenichel 1995). Swanson et al. (1995)
described two types of clonidine-related cardiovascular side effects. In one type, fatigue and sedation were associated with a
decrease in pulse and blood pressure and changes in ECG. In the other, tachycardia and tachypnea occurred, which led to
anxiety, fever, and changes in mental status. Adverse cardiovascular side effects, including bradycardia and depressed level
of consciousness, have been reported with clonidine overdose in children (Kappagoda et al. 1998). However, in a
retrospective study of 42 children treated with clonidine alone or clonidine plus stimulants, no systematic effects were found
on ECG parameters of pulse rate or QTc intervals (Kofoed et al. 1999).
Guanfacine
Dosage and Monitoring
Guanfacine is initiated at a daily dose of 0.5 mg, with an upward titration of 0.5 mg every 3 days, based on clinical response
and tolerability, to a maximum daily dose of 4 mg (Hunt et al. 1995).
Pulse and blood pressure should be monitored during guanfacine treatment. Guanfacine should be tapered over a 4-day
period upon discontinuation.
Side Effects
Common side effects of guanfacine in children are sedation, fatigue, headache, dizziness, stomachache, and decreased
appetite (Chappell et al. 1995b; Hunt et al. 1995; Melmed et al. 2006; Scahill et al. 2001). Rebound hypertension,
nervousness, and anxiety may occur if guanfacine is abruptly discontinued (Green 2001).
Mood Stabilizers
Dosage and Monitoring
The starting dose and target doses and therapeutic serum levels of mood stabilizers are listed in Table 63–3.
TABLE 63–3. Clinical use of mood stabilizers in children and adolescents
Medication Typical starting dose
(mg)
Target dose
Therapeutic serum
level
Carbamazepine 7 mg/kg/day Based on response and serum level 8–11 g/L
Lamotrigine 12.5 mg once daily Based on response
NA
Lithium 25 mg/kg/g (2–3 daily
doses)
30 mg/kg/day (2–3 daily doses) 0.8–1.2 mEq/L
Oxcarbazepine 150 mg twice daily 20–29 kg (900 mg/day) 30–39 kg (1,200 mg/day) >39 kg
(1,800 mg/day)
NA
Topiramate 25 mg once daily 100–400 mg/day
NA
Valproic acid, divalproex
sodium
20 mg/kg/day (2 daily
doses)
20 mg/kg/day (2–3 daily doses) 90–120 g/mL
Source.DelBello and Kowatch 2006.
Premedication laboratories in general include complete blood count, liver function tests, and pregnancy test (for females).
For lithium, baseline thyroid function tests, electrolytes, urinalysis, blood urea nitrogen, creatinine, and serum calcium should
also be obtained. Lithium levels, renal function, thyroid function, and urinalysis should be monitored every 3–6 months.
For divalproex, drug serum levels, complete blood count, and liver function tests should be monitored every 3–6 months.
Given concerns about a possible relationship between divalproex and polycystic ovarian syndrome (PCOS) (Rasgon 2004),
female adolescents taking divalproex should be monitored for signs of PCOS, including menstrual abnormalities, weight gain,Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
57 of 58
10/05/2009 16:43
acne, and hirsutism (DelBello and Kowatch 2006; McClellan et al. 2007). Parents and their female adolescents should be
apprised about this possible association prior to initiating medication.
For oxcarbazepine, children should be monitored for hyponatremia.
Side Effects
Common side effects of lithium in children and adolescents include hypothyroidism, nausea, polyuria, polydypsia, acne,
tremor, and weight gain (DelBello and Kowatch 2006).
Common side effects of divalproex in children and adolescents include weight gain, nausea, sedation, and tremor (DelBello
and Kowatch 2006). Concern has been raised about a possible association between divalproex and PCOS (Rasgon 2004).
Other potential side effects of concern are hepatic failure, pancreatitis, thrombocytopenia, behavioral deterioration, and hair
loss (Davanzo and McCracken 2000; Green 2001).
Side effects of topiramate include decreased appetite, weight loss, nausea, diarrhea, paresthesias, somnolence, and
word-finding difficulties (DelBello and Kowatch 2006; DelBello et al. 2005).
Side effects of oxcarbazepine in children include dizziness, nausea, somnolence, diplopia, fatigue, and rash (Wagner et al.
2006b). Hyponatremia is also a side effect of oxcarbazepine.
Common side effects of lamotrigine in children include ataxia, nausea, vomiting, and constipation. Of concern is the incidence
of serious rash, including Stevens-Johnson syndrome, in pediatric patients reported to be 1%. This high incidence of serious
rash may be attributable to the prior use of high doses of lamotrigine with concomitant divalproex (Messenheimer et al.
1998). The current dosing guidelines may reduce this rash incidence in pediatric patients.
Psychostimulants
Dosage and Monitoring
The American Academy of Child and Adolescent Psychiatry (2007) recently revised its parameters for the diagnosis and
treatment of attention-deficit/hyperactivity disorder ADHD). A wide variety of stimulant preparations are available; Table
63–4 describes their use in clinical practice. Each stimulant has a maximum dose suggested by the U.S. Food and Drug
Administration (FDA)–approved package insert, but higher off-label doses are commonly used with careful monitoring. In
terms of safety monitoring, pulse, blood pressure, weight, and height should be obtained at baseline and at least annually. No
laboratory measures or electrocardiogram (ECG) monitoring is required.
TABLE 63–4. Clinical use of psychostimulants in children and adolescents
Medication Dosage form Typical starting dose FDA
max/day
Off-label
max/day
Amphetamine preparations
Adderall 5, 7.5, 10, 12.5, 15, 20, 30
mg
3–5 yr: 2.5 mg qd
6 yr: 5 mg qd–bid
40 mg >50 kg: 60 mg
Dexedrine 5 mg 3–5 yr: 2.5 mg qd
6 yr: 5 mg qd-bid
40 mg >50 kg: 60 mg
DextroStat 5, 10 mg 3–5 yr: 2.5 mg qd
6 yr: 5 mg qd–bid
40 mg >50 kg: 60 mg
Dexedrine
Spansule
5, 10, 15 mg
6 yr: 5–10 mg qd–bid
40 mg >50 kg: 60 mg
Adderall XR 5, 10, 15, 20, 25, 30 mg
6 yr: 10 mg qd
30 mg >50 kg: 60 mg
Vyvanse 30, 50, 70 mg 30 mg qd
70 mg Not determined
Methylphenidate preparations
Focalin 2.5, 5, 10 mg 2.5 mg bid
20 mg 50 mg
Focalin XR 5, 10, 15, 20 mg 5 mg q A.M.
30 mg 50 mg
Methylin 5, 10, 20 mg 5 mg bid
60 mg >50 kg: 100 mg
Metadate ER 10, 20 mg 10 mg q A.M.
60 mg >50 kg: 100 mg
Methylin ER 10, 20 mg 10 mg q A.M.
60 mg >50 kg: 100 mg
Ritalin SR 20 mg 10 mg q A.M.
60 mg >50 kg: 100 mg
Metadate CD 10, 20, 30, 40, 50, 60 mg 20 mg q A.M.
60 mg >50 kg: 100 mg
Ritalin LA 20, 30, 40 mg 20 mg q A.M.
60 mg Not yet known
Concerta 18, 27, 36, 54 mg 18 mg q A.M.
72 mg 108 mg
Daytrana patch 10-, 15-, 20-, 30-mg
patches
Begin with 10-mg patch qd, then titrate up by patch
strength
30 mg Not yet known
Note. qd = once daily; bid = twice daily; q A.M. = every morning.Print: Chapter 63. Treatment of Child and Adolescent Disorders http://www.psychiatryonline.com/popup.aspx?aID=435386&print=yes…
58 of 58
10/05/2009 16:43
Side Effects
Common side effects of psychostimulants are insomnia, diminished appetite, weight loss, irritability, abdominal pain, and
headaches (American Academy of Child and Adolescent Psychiatry 2007). Rebound symptoms of worsening behavior may
occur when the effects of the short-acting psychostimulants dissipate. Switching to sustained-release or longer-acting
psychostimulants may ameliorate rebound symptoms.
There is no evidence that psychostimulants increase substance abuse in youths with ADHD. On the contrary, youths with
ADHD who were treated with psychostimulants were at less risk for developing substance abuse than those youths with
ADHD who did not receive stimulants (Wilens et al. 2003a). Motor tics may develop during treatment with stimulants, but one
study reported no increase in tics for children with or without preexisting tics who received typical clinical doses of
methylphenidate compared with placebo (Law and Schachar 1999).
The FDA and its Pediatric Advisory Committee have reviewed data regarding psychiatric adverse events to stimulant
medication (U.S. Food and Drug Administration 2006b). Data from both controlled trials and post-marketing safety data from
sponsors and the FDA Adverse Events Reporting System (AERS), also referred to as MedWatch, were reviewed. For most of
the agents, these events were slightly more common in the active-drug group relative to placebo in the controlled trials, but
these differences did not reach statistical significance (Mosholder 2006). Postmarketing safety data were also reviewed for
reports of mania/psychotic symptoms, aggression, and suicidality (Gelperin 2006). Rare events of suicidal thoughts,
manic-like activation, or psychosis were reported. At the time, the Pediatric Advisory Committee did not recommend a black
box warning regarding psychiatric adverse events but did suggest clarifying labeling regarding these phenomena. No changes
to the stimulant medication labeling were suggested regarding suicide or suicidal ideation.
There have been rare reports of sudden death in patients taking stimulant medication The FDA has record of 20 cases of
sudden death with amphetamine or dextroamphetamine (14 children, 6 adults), while there were 14 pediatric and 4 adult
cases of sudden death with methylphenidate (Villalaba 2006). It is important to note that the rate of sudden death in the
general pediatric population has been estimated at 1.3–8.5 per 100,000 patient-years (Liberthson 1996). The rate of sudden
death among those with a history of congenital heart disease can be as high as 6% by age 20 years (Liberthson 1996).
Villalaba (2006) estimated the rate of sudden death in treated ADHD children for the exposure period January 1, 1992, to
December 31, 2004, to be 0.2 per 100,000 patient-years for methylphenidate, 0.3 per 100,000 patient-years for
amphetamine, and 0.5 per 100,000 patient-years for atomoxetine (the differences between the agents are not clinically
meaningful). Thus, the rate of sudden death of children on ADHD medications does not appear to exceed the base rate of
sudden death in the general population; therefore, cardiac monitoring of healthy children during treatment with stimulants is
not required. Children with preexisting heart disease (or significant symptoms suggesting the condition) should obtain a
cardiology consultation prior to starting a stimulant.
Poulton (2005) reviewed growth data and concluded that stimulant treatment may be associated with a reduction in
expected height gain, at least in the first 1–3 years of treatment. The National Institute of Mental Health (NIMH) Multimodal
Treatment of ADHD (MTA) study showed reduced growth rates in ADHD patients after 2 years of stimulant treatment
compared with patients who received no medication (MTA Cooperative Group 2004), and these deficits persisted at 36
months (MTA Cooperative Group 2007). The PATS study followed a group of 140 preschoolers who received methylphenidate
for up to a year for ADHD (Swanson et al. 2006b). The subjects had less than expected mean gains in height (–1.38 cm) and
weight (–1.3 kg). Charach et al. (2006) found that higher doses of stimulant correlated with reduced gains in height and
weight and that the effect did not become significant until the dose in methylphenidate equivalents was >2.5 mg/kg/day for
4 years. Pliszka et al. (2006b) did not find that children with ADHD treated with monotherapy with either amphetamine or
methylphenidate showed any failure to achieve expected height; furthermore the two stimulant classes did not have any
differential effect on height, but amphetamine had somewhat greater effects on weight than methylphenidate. The subjects
in this study had drug holidays averaging 31% of time during their treatment course, which may have contributed to the lack
of effect of the stimulant on height.
In assessing for clinically significant growth reduction, it is recommended to use serial plotting of height and weight on
growth charts labeled with lines showing the major percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) (Mei et al.
2004). This should occur one to two times per year, and more frequently if practical. If the patient has a change in height or
weight that crosses 2 percentile lines, this suggests an aberrant growth trajectory. In these cases, a drug holiday should be
considered, if return of symptoms during weekends or summers does not lead to marked impairment of functioning. The
clinician should also consider switching the patient to another ADHD medication. It is important for the clinician to carefully
balance the benefits of medication treatment with the risks of small reductions in height gain, which as of yet have not been
shown to be related to reductions in adult height (Gittelman-Klein and Mannuzza 1988; Kramer et al. 2000; Weiss and
Hechtman 2003).
Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Child & Adolescent Disorders
-
Overview of Child & Adolescent Disorders
-
Developmental Milestones and Their Importance
-
Introduction to Diagnostic Criteria and Tools
-
Quiz on Child & Adolescent Developmental Milestones
-
Factors Influencing Child & Adolescent Disorders
Foundations of Developmental Psychology
Assessment and Diagnosis in Pediatric Populations
Evidence-Based Interventions and Therapies
Integrative Approaches and Multidisciplinary Care
Earn a certificate
Add this certificate to your resume to demonstrate your skills & increase your chances of getting noticed.
Student Ratings & Reviews
