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Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009
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Chapter 61. Treatment of Personality Disorders
WHAT DOES MEDICATION CHANGE IN TREATING PERSONALITY?
Personality disorders are some of the more challenging psychiatric conditions and have traditionally
been viewed by many clinicians as more difficult to treat than numerous Axis I conditions, often
requiring investment in more lengthy treatments that involve a variety of modalities and
approaches. It is also common to attain lesser and more modest degrees of success in treating
personality disorders, with a recognition, however, that even partial modifications in people’s
dysfunctional interpersonal relationships, coping mechanisms, and symptomatology can bring about
notably better adaptations. Psychotherapy continues to be the treatment foundation for all
personality disorders, and psychotherapy studies of personality disorders on the whole find that
patients with these disorders improve with treatment, with large treatment effects—two to four
times greater than the improvement found in the control conditions (Perry and Bond 2000). In
more recent years, the traditional psychodynamic therapy approaches have become enriched with
more eclectic possibilities and structured therapies, such as dialectical-behavioral therapy for
borderline personality disorder (BPD) (Linehan 1993) and various other cognitive psychotherapies
(Tyrer and Davidson 2000). Although medications continue to be an adjunct to the treatment of
personality disorders, and research medication treatment trials in personality disorders continue to
be much fewer than those available in Axis I disorders, medications undoubtedly can play a useful
role in the treatment of personality disorders, at least in some disorders and for some patients.
The main indications for using medications in treating personality disorders are periods of
decompensation, crises, and hospitalizations; the longer-term management of symptom clusters
that are maladaptive and may be responsive to medication; and the reappearance or worsening of
comorbid Axis I conditions. Frameworks have been previously described conceptualizing the
medication treatment of personality disorders (Coccaro 1993; Gabbard 2000; Kapfhammer and
Hippius 1998). Such frameworks must address several interesting questions. Can medication treat
the underlying personality disorder per se or simply some of its symptomatic manifestations? Is
medication effective at targeting Axis II symptom clusters that lie on a dimensional continuum and
are subclinical variants of Axis I conditions? Can medication, in addition, treat unique
symptomatology that may be more temperament related and less Axis I bound? Reflecting on these
questions necessitates a brief overview of the foundations of personality, as well as an overview of
the kinds of changes over time that medication treatment studies of personality disorders examine
and the methodological issues involved.
Overview of Personality
Personality can be broadly conceptualized as an admixture of temperament, which is strongly
determined by genetics, and character, which is mainly environmentally shaped. Evidence from
population twin studies indicates that personality disorders have a heritable component that
presumably is attributable largely to temperament (Coolidge et al. 2001; Torgersen et al. 2000),
with heritability estimates ranging from approximately 0.30 to 0.80, depending on the personality
disorder. Additionally, symptom clusters within a personality disorder may have distinct
heritabilities. For example, there is evidence in BPD that affective and impulsive traits show
independent familial transmission (Silverman et al. 1991).
One of the more widely used temperament models in the mainstream psychiatric literature is
Cloninger’s psychobiological model of personality, which delineates four basic and independentPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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temperaments—novelty seeking, harm avoidance, reward dependence, and persistence—which
contribute about 50% to the formation of personality (Cloninger et al. 1993). It was initially
postulated that there was a single neurochemical axis underlying each temperament: dopamine for
novelty seeking, serotonin for harm avoidance, and norepinephrine for reward dependence.
However, recent genetic studies have not lent support to this simplistic conceptualization but have
rather begun to suggest that each temperament dimension may be more complexly determined by
several neurochemical systems and specific receptor types (Comings et al. 2000). In addition, we
do not yet have behavioral genetic studies confirming the genetic nature of temperament and the
nongenetic nature of character, and thus this traditional dichotomy must not be taken for granted
(Cravchik and Goldman 2000).
Conversely, when character is being reflected on, other aspects of the personality are evoked, those
presumed to be shaped by early parental influences, other environmental effects, trauma, and life
stressors, leading to intrapsychic structure or organization characterized by particular
self-representations, mechanisms for regulating self-cohesion and self-esteem, internalized object
relations, defensive styles, and predominant cognitive schemata. The widely held assumption is
that these constituents of character are not predominantly biologically driven and, therefore, are
not highly amenable to medication treatment. Although the clinical wisdom of this outlook is largely
taken for granted, some caution is called for. The degree to which aspects of character are
biologically determined is a largely unexplored area, notable for the absence of studies rather than
the presence of negative studies. This is due, at least in part, to the complexity of character
concepts, which makes them more difficult to operationalize and study than simple symptoms, as
well as the traditional divergence and absence of collaboration between psychodynamic and
phenomenologically or biologically oriented scientists. On a second note of caution, the assumption
that if something is strongly biologically driven, it will respond better to pharmacotherapy, and if it
is more environmentally determined, it will be more amenable to psychotherapy, is partially a
fallacy. Genetically, high cholesterol can be partly treated with appropriate diet. In strongly
biologically driven disorders such as obsessive-compulsive disorder (OCD), pharmacotherapy and
cognitive-behavioral therapy can have comparable therapeutic efficacy and are accompanied by
similar brain activity changes (for details, see Baxter et al. 1992; Schwartz et al. 1996).
Medication and Personality Disorders
Unfortunately, aspects of character organization, and measures of these, traditionally have been
excluded from pharmacological trials in treating personality disorders; thus, again we are faced
with an absence of studies rather than negative studies. In one small study that partially addressed
this question (Mullen et al. 1999), defense mechanisms as measured by the Defense Style
Questionnaire and personality organization as measured by the Inventory of Personality
Organization were assessed before and after treatment of major depression. Compared with the
nonresponders, the responders showed a significant reduction in the use of primitive defenses.
Personality organization did not change, but this was assessed in only a small subgroup of patients.
It does make sense that treating symptoms such as affective and impulse dysregulation could have
a notable effect on self-perception, self-esteem, and relationships with others and thus could
positively affect character, even if not modifying its core. Indeed, several treatment studies of Axis
I disorders found a decrease in comorbid Axis II disorders after treatment of the target disorder,
and this finding may in part reflect some shift in character structure when gross symptomatology is
stabilized (Baer et al. 1992; Noyes et al. 1991). Furthermore, some evidence indicates that patterns
of relationships between the more “biologically driven” temperament traits and the more
“experience driven” character traits may exist within a given personality disorder. For example, in
BPD, the trait of affective instability has been found to be associated with the defenses of splitting,
projection, acting out, passive aggression, undoing, and autistic fantasy, whereas the trait of
impulsive aggression was positively associated with the defense of acting out and negatively
associated with the defenses of suppression and reaction formation (Koenigsberg et al. 2001).
Another caveat in the biological versus nonbiological conceptualization of personality disorders isPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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that some are typically viewed, with some supporting evidence, as more biologically driven than
others, possibly lying on a continuum with biologically well-characterized Axis I disorders (Siever
et al. 1991). The main biologically driven personality disorders are schizotypal personality disorder,
which can be conceptualized as a schizophrenia spectrum disorder with supporting familial and
biological data; BPD, which can be viewed as a mood spectrum disorder; and avoidant personality
disorder, which may lie on a continuum with social phobia.
Gitlin (1993) described three conceptual frameworks for the pharmacotherapy of personality. The
first is categorical, proposing that the medications treat the disorder itself as a whole. This model
may be more plausible when one is considering the aforementioned more strongly biologically
driven personality disorders. Although it is compelling to speculate that medications may treat
more than the manifest symptoms of personality, as we just described, evidence for this is lacking,
and we hope that it will be addressed by future study designs.
The second framework is dimensional, most supported by the literature to date, and the one
adopted in this chapter. It proposes that pharmacotherapy targets core trait vulnerabilities,
manifested as symptom clusters, that may cut across the various personality disorders or may even
represent Axis I subclinical variants. The major four such dimensions that are consistently cited in
the literature are cognitive–perceptual, impulsivity–aggression, mood instability–lability, and
anxiety–behavioral inhibition (see Siever and Davis 1991; Soloff 1990). The various personality
disorders thus present with various admixtures of these trait symptom clusters (these are
described further in the sections detailing the pharmacological treatment of each disorder).
The third conceptual model speculates that in treating Axis II personality disorders with
medication, efficacy results from the treatment of Axis I disorders that may be masked or distorted
by the prominent personality features. For example, individuals with avoidant personality disorder
may in fact have a very chronic and pervasive generalized type of social phobia that is being
interpreted as personality pathology. This model, in our view, has become less useful in recent
times as both clinicians and researchers have become more educated and adept in diagnosing on
both axes and reflecting on their interactions.
Another important area in critically assessing the medication treatment trials of personality
disorders is an awareness of the significant methodological challenges that face this field (Coccaro
1993; Gitlin 1993). A historical issue relates to the fact that the classification of personality
disorders changed dramatically with the advent of DSM-III-R in 1987 (American Psychiatric
Association 1987); therefore, treatment trials prior to that time can be extrapolated to only
currently defined disorders. Fortunately, at least from a research point of view, DSM-IV (American
Psychiatric Association 1994) did not introduce much change in classifying Axis II disorders.
Pharmacological treatment studies of personality disorders have assessed to varying degrees the
comorbid Axis I or Axis II disorders that may be affecting treatment outcome. Also, personality
disorders, particularly those of Cluster B, can notoriously differ in how they manifest at differing
points in time. For example, BPD patients can be much more or less symptomatic, depending on a
variety of environmental factors. Therefore, the traditional 8- to 12-week trial design that
establishes a very-short-term baseline and then measures short-term change to an arbitrary
endpoint may not be as ideally suited for studying Axis II as it is for Axis I disorders. Trials that use
a more broadly defined baseline, or examine more long-term change across multiple time points,
might be more suited to studying Axis II disorders.
Finally, the choice of instruments used to measure Axis II change is critical. Traditionally, these are
directly borrowed from Axis I studies, such as the Hamilton Rating Scale for Depression and the
Hamilton Anxiety Scale. However, other types of scales measuring less tightly Axis I bound
symptoms and concepts such as mood intensity, mood lability, parasuicidal tendencies, aggressive
outbursts, and subtle cognitive distortions may be better suited to accurately track Axis II
symptomatology. A good example is the Overt Aggression Scale (Coccaro et al. 1991; Yudofsky et
- 1986), which measures and quantifies various types of verbally and physically aggressive
behaviors against the self, objects, and others. It is currently widely used in Axis II treatment trialsPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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and had no good analog prior to its conception, exemplifying the dimensional approach to
personality disorder pathology. Just as important, symptom scales are typically used in Axis II
treatment studies rather than measures of character such as defenses, self-concept, personality
organization, and interpersonal relationships. Character measures have been pervasively absent
from trials to date, and we hope that they will become more prevalent in future studies.
Overview of the Chapter
In this chapter, we review the existing medication trials for the treatment of personality disorders.
The chapter is organized by personality disorder clusters, beginning with Cluster B, which has by
far the largest number of studies, and followed by Clusters A and C, in which the much fewer
existing studies partly overlap with those in Cluster B. We take this pragmatic approach in
presenting the treatment studies because the large majority of them selected subjects by
personality disorder diagnosis as the major inclusion criterion, although in reviewing these studies,
it is always useful to keep in mind the target symptom dimensional approach. Following these
sections, the chapter ends with a section on Axis I comorbidity, in which three pertinent questions
are addressed: 1) How does the presence of Axis II comorbidity affect the likelihood of medication
treatment for Axis I conditions? 2) What is the compliance rate with such treatment? and 3) What
is the likelihood of this treatment being efficacious?
PHARMACOTHERAPY FOR CLUSTER B PERSONALITY DISORDERS
By far the most extensive literature on pharmacological treatment of Cluster B, or any Axis II
disorders for that matter, refers to BPD. The symptom clusters typically targeted in this condition,
although varying from trial to trial and in instruments used, are dysregulated impulsivity and
aggression, affective lability and hyperreactivity, cognitive-perceptual disorganization, anxiety, and
dissociation. Dysregulation of impulses and affective instability are widely viewed as the hallmark
symptoms of BPD. The remaining symptom clusters are examined less systematically in BPD
studies—for example, when there is a focus on psychotic spectrum or trauma spectrum pathology.
Summary of Medication Trials
Conventional Antipsychotics
Cognitive-perceptual symptoms, such as paranoia, perceptual aberrations, and subtle thought
disorder, although not figuring as prominently in the diagnosis of Cluster B as in Cluster A
personality disorders, are definitely present in at least a subgroup of BPD patients, especially under
periods of stress and decompensation. The presence of such target symptoms, more prominent in
the older BPD trials that included schizotypal subgroups of patients, was the impetus for the early
neuroleptic trials. Studies from the late 1970s and early 1980s began to report some efficacy of
low-dose neuroleptics in treating BPD, although these studies were not placebo controlled (Brinkley
et al. 1979; Leone 1982).
Serban and Siegel (1984) reported on a large trial of 52 outpatients with personality disorders (46
completers: 16 with BPD, 14 with schizotypal personality disorder, 16 with both) treated for 12
weeks in a randomized, double-blind design with thiothixene 9.4 mg/day or haloperidol 3 mg/day
(mean dosages). Of the total subjects, 84% showed moderate to marked improvement. The main
symptoms that improved were cognitive disturbance, derealization, ideas of reference, anxiety,
depression, self-esteem, and social functioning, suggesting that medicating target symptoms may
have a wide-reaching effect. Outcome did not vary by borderline or schizotypal diagnosis. In
another study (Montgomery and Montgomery 1982), patients with personality disorders, mostly
borderline, presenting acutely with a suicide attempt and with histories of at least two prior
attempts were treated with a low-dose depot neuroleptic (flupenthixol 20 mg every 4 weeks) or
placebo. The neuroleptic was highly effective in reducing suicide attempts at 4–6 months of
treatment. Shortly after and for the next decade, several placebo-controlled, randomized trials
were published examining conventional antipsychotics in the treatment of BPD and comparing
these agents with other classes of medications such as antidepressants, mood stabilizers, andPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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benzodiazepines.
Goldberg et al. (1986) studied 50 outpatients (17 with BPD, 13 with schizotypal personality
disorder, 20 with both) with a bias toward psychotic presentation: at least one psychotic symptom
was required for inclusion. Subjects were treated for 12 weeks with thiothixene (average dosage =
9 mg/day) or placebo. Thiothixene was significantly better than placebo in treating psychosis
(especially for greater symptom severity at baseline), obsessive-compulsive symptoms, and phobic
anxiety, but not depression. The results suggested narrow efficacy, because total scores for
borderline pathology, schizotypal pathology, and global assessment did not change. When the
results were analyzed by diagnosis, the pure BPD subgroup showed the smallest medication effect,
implying that neuroleptics may have target specificity for psychotic spectrum symptoms.
Another study, however, suggested that low-dose neuroleptics have a more global effect in treating
BPD (Soloff et al. 1986, 1989). Ninety acutely hospitalized inpatients (35 with BPD, 4 with
schizotypal personality disorder, 51 with both) were treated for 5 weeks with haloperidol (average
dosage = 5 mg/day), amitriptyline (average dosage = 150 mg/day), or placebo. Haloperidol was
found to have a broad-spectrum effect in symptom domains, including schizotypal, affective, and
impulsive-behavioral, and was superior to amitriptyline in all areas with the exception of a
comparable weak antidepressant effect. As in the Goldberg et al. (1986) study, more severe
psychotic spectrum symptoms predicted a better response to haloperidol, although overall
improvement was still modest.
However, these results were not replicated by the same investigator group in a subsequent large
study with a very similar design, consisting of 108 consecutively admitted inpatients (42 with BPD,
66 with BPD and schizotypal personality disorder) treated for 5 weeks with haloperidol, the
monoamine oxidase inhibitor (MAOI) phenelzine, or placebo (Soloff et al. 1993). This study failed
to replicate efficacy for haloperidol (average dosage = 4 mg/day), with the exception of some
measures of overt hostile or aggressive behavior. The investigators attributed this discrepancy to
the presence of more severely ill psychotic spectrum patients in the earlier studies and suggested
that in less impaired BPD populations, low-dose neuroleptics had little to contribute and were
poorly tolerated in terms of side effects. The above acute treatment study was extended into a
16-week outpatient continuation trial with 54 continuing participants (Cornelius et al. 1993), which
again yielded essentially negative results. Haloperidol was effective only in treating irritability, and
two-thirds of the subjects dropped out.
Another frequently cited medication trial in BPD is a double-blind, placebo-controlled comparison of
the typical antipsychotic trifluoperazine (average dosage = 8 mg/day), the benzodiazepine
anxiolytic alprazolam (average dosage = 5 mg/day), the anticonvulsant and mood stabilizer
carbamazepine (average dosage = 820 mg/day), and the MAOI tranylcypromine (average dosage =
40 mg/day) (Cowdry and Gardner 1988). This study found very modest effects for neuroleptic
treatment. Trifluoperazine was only associated with a trend toward lessened behavioral dyscontrol,
whereas alprazolam led to paradoxical disinhibition and worsening of severe behavioral dyscontrol.
Psychotic-like symptoms were not assessed. Conventional antipsychotic studies in BPD are
summarized in Table 61–1.
TABLE 61–1. Summary of medication treatment trials with antipsychotics in borderline personality
disorder (BPD)
Study Subjects Antipsychotic(s) Other agent(s) Duration Outcome
Typical
antipsychotics
Montgomery
and
Montgomery
1982
30 BPD Depot flupenthixol Placebo 4–6
months
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Study Subjects Antipsychotic(s) Other agent(s) Duration Outcome
Serban and
Siegel 1984
16 BPD, 14
SPD, 16
both
Thiothixene,
haloperidol
— 12 weeks Improvement on multiple
domains
Goldberg et al.
1986
17 BPD, 13
SPD, 20
both
Thiothixene Placebo 12 weeks Decreased psychosis, anxiety
Soloff et al.
1986, 1989
35 BPD, 4
SPD, 51
both
Haloperidol Amitriptyline,
placebo
5 weeks General improvement
Cowdry and
Gardner 1988
16 BPD Trifluoperazine Alprazolam,
carbamazepine,
tranylcypromine,
placebo
6-week
crossover
Minimal decrease in
behavioral dyscontrol;
psychoticism not measured
Soloff et al.
1993
42 BPD, 66
BPD and
SPD
Haloperidol Phenelzine,
placebo
5 weeks Largely ineffective
Cornelius et al.
1993
Continuation
of above
study
16-week
extension
Atypical
antipsychotics
Frankenburg
and Zanarini
1993
15
refractory
BPD
Clozapine — 2–9
months
33% overall improvement
Schulz et al.
1998
BPD Risperidone Placebo 8 weeks Modest improvement, no
better than placebo
Schulz et al.
1999
11 BPD (7
also SPD)
Olanzapine — 8 weeks General modest to moderate
improvement
Zanarini and
Frankenburg
2001
28 BPD Olanzapine Placebo 6 months Decreased anger, paranoia,
anxiety, interpersonal
sensitivity
Rocca et al.
2002
15 BPD with
marked
aggression
Risperidone — 8 weeks Decreased aggression,
improved global functioning
Villeneuve and
Lemelin 2005
23 BPD Quetiapine — 12 weeks Improved impulsivity, other
measures, and global function
Bellino et al.
2006
14 BPD Quetiapine — 12 weeks Improvement especially for
impulsiveness/aggressiveness
Perrella et al.
2007
29 BPD Quetiapine — 12 weeks Improvement especially in
aggression and low mood
Schulz et al.
2007
314 BPD Olanzapine
2.5–20 mg/day
Placebo 12 weeks No difference in overall
symptom improvement
between groups
Zanarini et al.
2007
451 BPD Low-dose
olanzapine
(2.5mg/day),
Placebo 12 weeks Greater overall improvement
on moderate-dose olanzapine
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Study Subjects Antipsychotic(s) Other agent(s) Duration Outcome
moderate-dose
olanzapine (5–10
mg/day)
groups
Note. SPD = schizotypal personality disorder.
Atypical Antipsychotics
The question of efficacy of atypical antipsychotics in BPD has received growing attention (see Table
61–1), and earlier smaller trials have now been followed by larger studies. An open trial of
clozapine in 15 severely disturbed patients with refractory BPD and pronounced psychotic
symptoms reported an overall 33% improvement during a 2- to 9-month treatment (Frankenburg
and Zanarini 1993). Given the weekly monitoring and the common compliance difficulties of BPD
patients, this antipsychotic is clearly not the optimal choice for the average patient. A case report
noted partial to good response to aripiprazole treatment in 2 out of 3 patients (Mobascher et al.
2006). A small 8-week placebo-controlled risperidone trial in BPD reported similar modest
symptomatic improvement in the two treatment groups (Schulz et al. 1998). An open-label trial of
risperidone in 15 BPD outpatients with prominent histories of aggressive behavior and no current
major Axis I disorders, using a final mean dosage of 3.3 mg/day, reported a marked reduction in
aggression, along with a reduction in depressive symptoms and improved global functioning (Rocca
et al. 2002).
To date, there are three published quetiapine treatment trials in BPD, all open-label. In one
12-week trial in 23 outpatients, at a mean dosage of 250 mg/day, impulsivity significantly
improved, as did most other outcome measures and global functioning (Villeneuve and Lemelin
2005). Another 12-week trial in 14 outpatients employed an average dosage of about 300 mg/day
and reported significant improvement in various symptom domains, particularly
impulsiveness/aggressiveness (Bellino et al. 2006). The third open trial followed 29 outpatients for
12 weeks, at a higher average dosage of 540 mg/day, and reported a highly significant
improvement in a number of BPD features, including aggression and low mood; transient
thrombocytopenia occurred in 2 patients (Perrella et al. 2007). Finally, a case report described a
marked improvement in severe self-mutilation in two BPD patients treated with quetiapine (Hilger
et al. 2003).
An 8-week open trial examined the efficacy of olanzapine (average dosage = 8 mg/day) in 11 BPD
outpatients with comorbid dysthymia, 7 of whom also had schizotypal personality disorder, and
reported moderate significant improvement in all symptom domains (Schulz et al. 1999). In a small
controlled olanzapine trial of 28 women with BPD (Zanarini and Frankenburg 2001), longer duration
of treatment was undertaken for 6 months, a time frame more reflective of clinical reality, at a
mean end dose of 5.3 mg/day. Olanzapine was found to be significantly better than placebo in
decreasing anxiety, paranoia, anger/hostility, and interpersonal sensitivity, but not depression.
More recently, two much larger randomized, controlled multicenter trials have yielded mixed
findings on the efficacy of olanzapine in treating BPD. One 12-week study used flexibly dosed
olanzapine (range 2.5–20 mg/day) versus placebo in 314 outpatient participants with moderate
disorder severity, and although both treatment groups significantly improved during treatment,
there was no difference in overall change between the two groups (P = 0.66), with response rates
of 65% for olanzapine and 54% for placebo group (Schulz et al. 2007). The second 12-week study
of 451 BPD participants was overall similar in design and illness severity but differed in using two
fixed dosages of olanzapine, low (2.5 mg/day) and moderate (5–10 mg/day), versus placebo
(Zanarini et al. 2007). Treatment with the higher olanzapine dose resulted in significantly greater
overall improvement than the lower dose (P = 0.018) and the placebo (P = 0.006), with response
rates of 74%, 60%, and 58%, respectively. Furthermore, both olanzapine-treated groups showed
significantly greater improvement on irritability, suicidality, and family life functioning relative to
placebo. Adverse events more common on olanzapine included somnolence and weight gain (3.2Print: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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kilograms for the higher dose).
Antidepressants
Tricyclic antidepressants (TCAs) have a limited role in treating BPD (Soloff et al. 1986, 1989). The
few MAOI trials that have been conducted have yielded mixed results. Soloff et al. (1993) and
Cornelius et al. (1993) found that phenelzine had only modest efficacy in BPD and was superior to
placebo only against anger and hostility, but not in measures of depression, atypical depression,
psychoticism, impulsivity, or global borderline severity. The investigators speculated that the short
duration of treatment, the use of suboptimal phenelzine dosing (average dosage = 60 mg/day), and
the fact that the atypical depression characteristics known to be responsive to MAOIs were not
highly prominent in the patient samples may have contributed to these studies’ failure to show
efficacy for phenelzine. In contrast, a crossover placebo-controlled study of four classes of
medications in BPD (Cowdry and Gardner 1988) found that the MAOI tranylcypromine was
significantly superior to placebo, according to both clinicians and patients, in global ratings and in
most domains that were measured, including depression, anxiety, anger, rejection sensitivity,
impulsivity, and suicidality. This finding was more in accordance with an earlier report of
phenelzine efficacy in BPD patients, all of whom had concurrent atypical depression (Parsons et al.
1989).
Regardless of efficacy, both TCAs and MAOIs pose serious overdose and dangerous adverse effect
risks that are of particular concern in this unstable, impulsive population. Investigations of newer
antidepressants in treating BPD appear more promising. Preliminary reports in small open trials
first suggested that the selective serotonin reuptake inhibitor (SSRI) fluoxetine at dosages ranging
from 20 to 60 mg/day might be beneficial in treating depression and impulsive aggression in BPD
(Coccaro et al. 1990; Cornelius et al. 1991; Norden 1989). A larger open trial (Markovitz et al.
1991) involved 22 patients with BPD or schizotypal personality disorder treated for 12 weeks with
high-dose fluoxetine (80 mg/day). There was a 74% decline in self-mutilation, as well as an overall
improvement in depressive symptoms, obsessive-compulsive symptoms, anxiety, interpersonal
sensitivity, psychoticism, and paranoia. In a comparable open trial by the same group (Markovitz
1995), 23 BPD patients were treated openly for an initial 12-week period with sertraline 200
mg/day, and about half showed improvement in self-injurious behavior, anxiety, depression, and
suicidality. Of note, half of the responders had previously failed to respond to fluoxetine,
underlining the usefulness of trying more than one SSRI in this population, given the variability of
responses across SSRIs. The trial was continued to a 1-year duration, and dosages in
nonresponders were increased to more than 300 mg/day. By the completion of the study, on
average, depression had decreased by 56% and self-injurious episodes had decreased by 93%. In
another small open trial of sertraline in nine patients with personality disorders, dosages of
100–200 mg/day resulted in a decrease of impulsive aggression over 8 weeks (Kavoussi et al.
1994).
Subsequently, three controlled trials of SSRIs in borderline spectrum patients have been described.
In a small double-blind trial, 17 BPD patients were randomly assigned to high-dose fluoxetine (80
mg/day) or placebo for 14 weeks. A statistically significant improvement was seen in the fluoxetine
group, compared with placebo, on all measures used, including global symptomatology, anxiety,
and depression (Markovitz 1995). A larger study randomly assigned 27 patients with borderline
disorder or traits, at the milder end of the severity spectrum and without current major depression,
to fluoxetine (average dosage = 40 mg/day) or placebo (Salzman et al. 1995). The main finding
after 12 weeks of treatment was a significantly greater decrease in anger and depression with
fluoxetine, despite a pronounced placebo response. Finally, in the largest trial reported (Coccaro
and Kavoussi 1997), the effects of fluoxetine were investigated over a 12-week period in 40
subjects with personality disorder with marked impulsive aggression as the major entry criterion
and without current major depression. About half of the subjects met Cluster B criteria (one-third of
the total had BPD), 40% met Cluster C criteria, and 28% met Cluster A criteria. Compared with
placebo, fluoxetine at dosages of 20–60 mg/day led to a consistent and significant decrease in
aggression and irritability and in global improvement apparent by the second month of treatment,Print: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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and this effect was irrespective of changes in depression or anxiety.
In addition to SSRIs, newer antidepressants have been tried in BPD. In an open trial of the
serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine, 45 subjects were entered and 39
completed a 12-week treatment with an average dosage of 315 mg/day (Markovitz and Wagner
1995). A highly significant overall reduction of 41% occurred on a scale of global symptomatology.
Of the 7 patients who were self-injurious at baseline, only 2 remained self-injurious at the end of
treatment. Although the study was not placebo controlled, this was a fairly large trial, and the
results appear promising. Studies of antidepressant treatment in BPD are summarized in Table
61–2.
TABLE 61–2. Summary of medication treatment trials with antidepressants in borderline
personality disorder (BPD)
Study Subjects Antidepressant(s) Other agent(s) Duration Outcome
Soloff et
- 1986,
1989
35 BPD, 4 SPD, 51
both
Amitriptyline Haloperidol,
placebo
5 weeks Minimally effective
and only for
depression
Soloff et
- 1993
42 BPD, 66 BPD and
SPD
Phenelzine Haloperidol,
placebo
5 weeks Modest efficacy,
better than placebo
Cornelius
et al.
1993
Continuation of above
study
16-week
extension
Only for
hostility/anger
Cowdry
and
Gardner
1988
16 BPD Tranylcypromine Alprazolam,
carbamazepine,
trifluoperazine,
placebo
6-week
crossover
Decreased
depression, anxiety,
anger, rejection
sensitivity,
impulsivity,
suicidality
Markovitz
et al.
1991
22 BPD or SPD Fluoxetine — 12 weeks Marked decline in
self-mutilation,
depression, anxiety,
interpersonal
sensitivity, paranoia
Markovitz
1995
23 BPD Sertraline — 12 weeks Half of subjects
showed improvement
in self-injury, anxiety,
depression,
suicidality
Continuation of above
study
1 year Decline in depression
56%, self-injury 93%
Kavoussi
et al.
1994
9 personality disorder
with impulsive
aggression
Sertraline — 8 weeks Decreased impulsive
aggression
Markovitz
1995
17 BPD Fluoxetine Placebo 14 weeks Global improvement
on all measures
Salzman
et al.
1995
27 BPD or BPD traits Fluoxetine Placebo 12 weeks Decreased anger,
depressionPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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Study Subjects Antidepressant(s) Other agent(s) Duration Outcome
Coccaro
and
Kavoussi
1997
40
impulsive-aggressive
personality disorder
(one-third BPD), no
major depression
Fluoxetine Placebo 12 weeks Marked decrease in
aggression and
irritability irrespective
of changes in
anxiety/depression
Markovitz
and
Wagner
1995
45 BPD Venlafaxine — 12 weeks 40% global
improvement, less
self-injury
Note. SPD = schizotypal personality disorder.
Mood Stabilizers
Mood stabilizers also have emerged as highly promising in treating BPD. The literature on lithium is
unfortunately limited to older studies but looks promising. Most studies examined the effects of
lithium on aggression in mentally retarded or violent inmate populations and reported some
efficacy (reviewed by Wickham and Reed 1987). More directly relevant to BPD, an older study had
first documented the efficacy of lithium in treating mood lability (other symptoms were not
measured) in a 6-week placebo-controlled trial of 21 subjects with “emotionally unstable character
disorder” (Rifkin et al. 1972). Description of the characteristics of this disorder, such as mood
swings, overreactivity, impulsivity, and chronic maladaptive behaviors, clearly overlaps with
current BPD criteria, although these patients may have had a bipolar variant. Finally, a single small
controlled study examined lithium in subjects meeting clear BPD criteria (Links et al. 1990).
Seventeen subjects received 6 weeks each of lithium, the TCA desipramine, and placebo in a
randomized crossover design, and 10 completed at least two medication trials. Neither medication
was better than placebo for depressive symptoms, but lithium resulted in a significant decrease in
anger and suicidality according to clinician, but not patient, perception. A larger study is clearly
warranted but has not been done.
Anticonvulsants are used more widely than lithium in treating BPD. Cowdry and Gardner (1988)
found that carbamazepine led to a dramatic and highly significant decrease in behavioral dyscontrol
but had much more modest effects on mood, and patients subjectively did not feel better while
taking it. This was a 6-week double-blind, placebo-controlled crossover design, comparing
alprazolam (average dosage = 5 mg/day), carbamazepine (average dosage = 820 mg/day),
trifluoperazine (average dosage = 8 mg/day), and tranylcypromine (average dosage = 40 mg/day)
(Cowdry and Gardner 1988). Subjects were 16 female outpatients with BPD, with additional
inclusion criteria of presence of prominent behavioral dyscontrol and absence of current major
depression. However, another carbamazepine study, involving 20 inpatients with BPD without
concurrent depression or concomitant medications, yielded negative results (De La Fuenta and
Lotstra 1994). After 4 weeks of treatment at standard therapeutic drug levels, carbamazepine was
no better than placebo in treating depression, behavioral dyscontrol, or global symptomatology.
More recently, anticonvulsant trials have focused on valproate and, to a lesser extent, on the newer
anticonvulsants. In one open trial, 11 patients with BPD were treated openly with valproate for 8
weeks, attaining blood levels of 50–100 g/mL, and 8 patients completed the trial (Stein et al.
1995). Half of the completers were rated as overall responders, with significant decreases in
depression, anxiety, anger, impulsivity, rejection sensitivity, and irritability. The trial was
summarized as modestly helpful, and larger controlled studies were called for to establish valproate
efficacy in BPD. In another open-label trial, 20 BPD patients were treated for 12 weeks with
extended-release valproate, leading to significant overall improvement and decline in irritability
and aggression (Simeon et al. 2007). In another small but placebo-controlled trial, 16 outpatients
with BPD were treated for 10 weeks with valproate or placebo (Hollander et al. 2001). Global
improvement was significant by two measures in patients treated with valproate, but the smallPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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sample size and dropout rate precluded statistically significant findings. In another controlled
valproate study, efficacy was examined in 30 women with comorbid BPD and bipolar II disorder
over 6 months of treatment (Frankenburg and Zanarini 2002). Valproate at an average dosage of
850 mg/day (with blood levels ranging between 50 and 100 g/mL) was well tolerated and
resulted in significant improvement in interpersonal sensitivity, hostility/anger, and aggression
compared with placebo.
More importantly, there is now a large placebo-controlled multicenter trial of valproate focusing on
the treatment of impulsive aggression in Cluster B personality disorders (Hollander et al. 2003).
Ninety-one outpatients selected for the presence of prominent impulsive aggression and absence of
bipolar I disorder or current major depression were randomly assigned to 12 weeks of treatment
with placebo or valproate, at an average end dosage of 1,400 mg/day with an end mean blood level
of 66 g/mL. About 10% were taking concomitant stable doses of antidepressants, and there was
an approximately equal dropout rate of almost half of the subjects in each group. Valproate was
well tolerated overall, with 17% of the subjects discontinuing for valproate-related adverse events.
The main finding of the study was a significant decrease in impulsive aggression in the last month
of treatment, reflected in significantly greater than placebo declines in overall aggression, including
verbal assault, assault against objects, and assault against others, and in overall irritability. When
the BPD subgroup of the above study was examined separately (Hollander et al. 2005), it was found
that divalproex was indeed superior to placebo in reducing impulsive aggression in this subgroup.
Divalproex-treated patients responded better as a function of higher baseline trait impulsivity
symptoms and state aggression symptoms. These two effects appeared to be independent of one
another, while baseline affective instability did not influence differential treatment response.
With respect to the newer anticonvulsants, there is a report of a small open trial of lamotrigine,
75–300 mg/day, while concomitant psychotropic medications were tapered off, in eight patients
with BPD without concurrent major depression (Pinto and Akiskal 1998). Two subjects were
discontinued secondary to adverse events or noncompliance, and three did not respond. The
remaining three were described as robust responders, with a marked increase in their overall level
of functioning; a cessation of impulsive behaviors such as promiscuity, substance abuse, and
suicidality; and maintenance of response at 1-year follow-up. We can probably expect further trials
of new anticonvulsants in BPD. Medication trials of mood stabilizers in BPD are summarized in
Table 61–3.
TABLE 61–3. Summary of medication treatment trials with mood stabilizers in borderline
personality disorder (BPD)
Study Subjects Mood
stabilizer(s)
Other agent(s) Duration Outcome
Rifkin et al.
1972
21 emotionally
unstable character
disorder
Lithium Placebo 6 weeks Decreased mood
lability
Cowdry and
Gardner 1988
16 BPD Carbamazepine Trifluoperazine,
tranylcypromine,
alprazolam,
placebo
6-week
crossover
Marked decrease in
behavioral
dyscontrol
Links et al.
1990
17 BPD Lithium Desipramine,
placebo
6-week
crossover
Decreased anger
and suicidality
De La Fuenta
and Lotstra
1994
20 BPD without
depression
Carbamazepine Placebo 4 weeks No effect for
depression,
behavioral
dyscontrol, global
symptomsPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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Study Subjects Mood
stabilizer(s)
Other agent(s) Duration Outcome
Stein et al.
1995
11 BPD Valproate — 8 weeks Modest benefit, half
responders, less
depression, anxiety,
anger, impulsivity,
rejection sensitivity
Pinto and
Akiskal 1998
8 BPD without
depression
Lamotrigine — 1 year Two discontinued;
three robust global
responders with
decreased
impulsivity and
suicidality
Frankenburg
and Zanarini
2002
30 BPD Valproate Placebo 6 months Significant
improvement in
hostility, anger,
aggression,
interpersonal
sensitivity
Hollander et
- 2003
91
impulsive-aggressive
Cluster B
Valproate Placebo 12 weeks Significant decrease
in impulsive
aggression
Simeon et al.
2007
20 BPD Valproate
extended
release
— 12 weeks Overall
improvement,
decreased
irritability and
aggression
Other Medications
Another class of medications for which very limited data exist on treating BPD is the opioid
antagonists. A more extensive literature supports the efficacy of naltrexone in treating impulsive
addictive behaviors such as alcoholism and gambling, and therefore naltrexone would be a
consideration in borderline patients with these types of problems. An open trial of naltrexone at
daily dosages of 100–400 mg in 15 women with BPD found that it led to a significant decrease in
dissociative symptoms and flashbacks over a course of treatment of at least 2 weeks (Bohus et al.
1999).
Conclusions and Treatment Guidelines
In conclusion, several open and controlled pharmacological treatment trials of BPD have been
conducted. Interpretation of the findings is somewhat complicated by the diversity of patient
presentations at treatment entry, including inpatient or outpatient status; overall severity of
baseline pathology; presence of comorbid personality disorders; presence or absence of major
depression, including atypical symptoms; emphasis on varying symptomatology, such as
psychoticism or impulsive aggression; and use of a wide range of change measures. In addition,
some of the core features of the disorder, such as identity diffusion, interpersonal vicissitudes, and
primitive defensive structure, were never examined, and thus the assumption that these features
are less medication responsive has not been empirically proven. As mentioned earlier, it is not
unreasonable to assume that stabilization and alleviation of dysregulated affect, cognition, and
impulses could have a beneficial effect on “deeper” aspects of character structure. Furthermore,
concomitant psychotherapy is rarely mentioned as an exclusion criterion in the BPD medication
trials, and clinical knowledge of these populations makes it reasonable to assume that it must havePrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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commonly co-occurred, even if of a general exploratory and supportive nature and not specifically
geared to the structured treatment of the condition. We therefore cannot underestimate the
potential influence of general placebo effects and concomitant therapies in many of these studies,
and medications continue to be viewed as adjuvant features of treating patients with Cluster B
disorders.
Notwithstanding, it is reasonable to conclude that three classes of medications emerge as the most
useful in treating BPD: serotonin reuptake inhibitors, mood stabilizers, and atypical antipsychotics.
Fluoxetine, valproate, and olanzapine are the three best-studied medications to date regarding
efficacy. Comparison trials of these three classes of medications, including combination strategies,
have not been reported and would be of great interest in the future.
Dosing guidelines are also not entirely clear because most trials aim to minimize possible
undertreatment and tend to use relatively high dosages. Therefore, SSRIs may be efficacious at
lower dosages than the 60 or 80 mg/day fluoxetine target dosages that have been studied. There
are also no guidelines for targeted blood levels of valproate in treating BPD, although a recent large
trial reported efficacy at a mean endpoint blood level of 66 g/mL (Hollander et al. 2003). For
olanzapine, it appears that moderate doses are more effective than low doses (Zanarini et al.
2007). In clinical settings, it makes sense to start with lower doses because these are generally
better tolerated and gradually increase the dosage while carefully monitoring response to
increasing dose. Symptoms of the disorder are often chronic and by their nature considerably
fluctuating; thus, the effect of each medication and dose can be more reliably assessed over longer
rather than shorter durations.
With respect to specific target symptoms, certain algorithms can be extrapolated from the existent
trials and have been proposed on the basis of the types of symptoms that are most prevalent in
each patient and the degree of response to the various medication pathways (American Psychiatric
Association 2001; Soloff 1998). These algorithms give useful practical guidance, although they tend
to become quickly outdated with findings of new trials. On the basis of the existent algorithms in
the literature and modifying them according to the results of the latest medication trials, we
propose a medication treatment approach outline for BPD as summarized in Table 61–4.
TABLE 61–4. Psychopharmacological treatment guidelines for borderline personality disorder
If most prominent symptoms are depression, interpersonal sensitivity, and impulsivity and
aggression
- Start with selective serotonin reuptake inhibitor (SSRI) (or related antidepressant).
- If good response, maintain.
If partial response, add mood stabilizer.
If no response, switch to mood stabilizer.
- If significant residual anger, anxiety, dyscontrol, add atypical antipsychotic.
If most prominent symptoms are mood lability, impulsivity and aggression, and family history of
bipolar spectrum
- Start with mood stabilizer (valproate; carbamazepine or lithium as alternatives).
- If good response, maintain.
If partial response, add mood stabilizer.
If no response, switch to mood stabilizer.
- If significant residual anger, anxiety, dyscontrol, add atypical antipsychotic.
If most prominent symptoms are paranoia, psychoticism, hostility, and overwhelming anxiety
- Start with atypical antipsychotic (olanzapine and risperidone most studied).Print: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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- If good response, maintain.
If partial response, add SSRI or mood stabilizer.
If no response and minimal mood symptoms, switch to typical antipsychotic.
Almost all Cluster B personality disorder trials have focused primarily on BPD. Although some of
these trials, as individually mentioned in the overview above, included mixed samples of Cluster B
participants, they did not present separate analyses for non-BPD diagnoses. Therefore, the general
principle to follow in treating these other disorders would be to target symptom clusters with
medications as per the guidelines developed above for BPD. In general, narcissistic and histrionic
personality disorders are not characterized by the severe degree of either mood lability or impulse
dyscontrol encountered in BPD, but in individuals in whom such features are more prominent or
problematic, medication trials can be attempted. With regard to antisocial personality disorder, the
general treatment guideline is that individuals who meet full criteria for the disorder are generally
treatment noncompliant and nonresponsive. Very few pharmacological studies have been done in
patients with antisocial personality disorder (Coccaro 1993), and those closest to showing at least
temporary benefits are some of the earlier lithium studies that reported decreased
impulsive-aggressive behavior in prison inmates (Wickham and Reed 1987). More recently, a report
on four antisocial personality disorder inpatients in a maximum-security facility found decreases in
impulsivity, hostility, aggressiveness, irritability, and rage reactions with quetiapine treatment at
dosages of 600–800 mg/day (Walker et al. 2003). Generally, borderline patients who have some
antisocial traits are more responsive to medication treatment than purely antisocial patients.
Recent studies with the mood stabilizer valproate suggest that subjects with antisocial personality
disorder are less responsive to the pharmacotherapy than are subjects with other Cluster B
personality disorders (Hollander et al. 2003). It also has been found that borderline patients are
significantly more likely than antisocial personality disorder patients to have received adequate
medication trials, including anxiolytics and antidepressants (Zanarini et al. 1988).
PHARMACOTHERAPY FOR CLUSTER A PERSONALITY DISORDERS
Cluster A personality disorders are characterized by cognitive distortions, perceptual distortions,
mild thought disorder, constricted affectivity, and interpersonal mistrust and distance. Schizotypal
personality disorder is the prime example of all these symptom clusters, whereas in paranoid and
schizoid personality disorders, the cognitive-perceptual and thought disorder disturbances are not
prominent. Cluster A symptoms are reminiscent of both the positive and the negative symptoms of
schizophrenia, and dopaminergic dysregulation has been postulated to underlie them (Siever and
Davis 1991). Schizotypal personality disorder is by far the most extensively investigated disorder of
the cluster in terms of biological underpinnings (Siever 1985; Siever et al. 1990), relation to Axis I
as a schizophrenia spectrum disorder (Asarnow et al. 2001; Kendler et al. 1994), and
pharmacological treatment trials. All the treatment trials to date, however, have included subjects
typically with BPD or with mixed personality disorders. They have been presented already in the
Cluster B section, and we summarize them again here with respect to schizotypy findings. We are
not aware of any medication trials examining specifically paranoid or schizoid personality disorder.
Serban and Siegel (1984) treated a sample of patients, one-third of whom had schizotypal
personality disorder and one-third of whom had schizotypal personality disorder and BPD, with
either thiothixene or haloperidol, without placebo, and found marked improvement in psychotic
spectrum symptoms. Goldberg et al. (1986) treated a similar sample with thiothixene or placebo
and found a significant improvement in psychotic symptoms with thiothixene that was more
pronounced in the patients with the schizotypal rather than the borderline diagnosis. Soloff et al.
(1986, 1989), in a sample containing a sizable proportion of combined schizotypal personality
disorder and BPD patients, found significantly better efficacy for haloperidol compared with placebo
for schizotypal symptoms but were not able to replicate this finding in a subsequent haloperidol
trial with similar diagnoses (Soloff et al. 1993). They speculated that their failure to replicate might
have been because the later trial included a less disturbed group of subjects with less prominent
psychotic symptoms.Print: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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With regard to the treatment of schizotypy with atypical antipsychotics, Schulz et al. (1999)
reported improvement in psychotic symptoms in a small group of patients who received olanzapine,
most of whom had schizotypal personality disorder that was comorbid with BPD. There is one
published randomized, placebo-controlled trial of an atypical antipsychotic focusing exclusively on
schizotypal personality disorder, which found risperidone to be significantly more efficacious than
placebo (Koenigsberg et al. 2002). In this 9-week study in 25 schizotypal personality disorder
patients, with low incidence of comorbid depression or BPD, low-dose risperidone was used,
titrated up from 0.25 to 2 mg/day. Active medication resulted in a significantly greater decrease in
negative and positive symptoms compared to placebo, and side effects were generally well
tolerated.
With regard to the effect of antidepressants on schizotypal personality disorder, Markovitz et al.
(1991) conducted an open trial of fluoxetine in patients with BPD and schizotypal personality
disorder (proportions of each unspecified) and reported improvement in psychoticism and paranoia,
among numerous other symptoms. Although the results were not analyzed with respect to
diagnosis, it is notable that no worsening of psychotic spectrum symptoms was found. This finding
is difficult to interpret in that improved paranoia could be consequent to better affective regulation
in subjects with prominent borderline traits. Of note, an older trial reported increased hostility and
paranoia in a subgroup of patients treated with the TCA amitriptyline (Soloff et al. 1986, 1989).
Finally, a large trial of fluoxetine that found significant benefits for impulsive aggression across
Axis II disorders (Coccaro and Kavoussi 1997) included 28% Cluster A subjects, but results did not
focus on psychotic spectrum symptoms and were not presented separately by cluster.
In summary, the limited trials of Cluster A disorders suggest, not surprisingly, that the medications
of choice are conventional antipsychotics. Given the probable need for long-term treatment of the
chronic, stable psychotic spectrum symptoms in these populations, the better safety profile of
atypical antipsychotics with regard to tardive dyskinesia suggests that they should be tried first,
although more data exist in the literature to date examining conventional neuroleptics. Finally, in
subjects with mixed traits and prominent additional affective or impulsive symptoms, SSRIs appear
to cause no worsening of psychosis and may be of some adjuvant benefit.
PHARMACOTHERAPY FOR CLUSTER C PERSONALITY DISORDERS
Anxiety and behavioral inhibition are the main symptoms that characterize individuals with Cluster
C personality disorders, although the focus of the anxiety varies across disorders. It centers on
social interaction in avoidant personality disorder, need for control of uncertainty in
obsessive-compulsive personality disorder, and conflicts surrounding autonomy in dependent
personality disorder. The medication trials in these disorders are very limited to date and are
summarized below. In addition, limited indirect information and insights can be gauged from
studies either of related Axis I disorders or of personality traits or dimensions that are
characteristic of the Cluster C personality disorders.
Avoidant personality disorder has received the most attention in terms of pharmacological
treatment of the Cluster C disorders because it is often viewed as lying on a continuum with Axis I
social phobia. Clinically, it can be difficult to distinguish pervasive, generalized social phobia of
long-standing duration from avoidant personality disorder. The latter tends to be characterized by
deeper interpersonal difficulties, impairments in interpersonal skills, and a very small number of
close relationships, which is often not the case even in very socially phobic individuals (Turner et
- 1986). Numerous studies have convincingly shown the efficacy of MAOIs and SSRIs in social
phobia, including its generalized subtype. Although, unfortunately, these studies did not report on
the presence or change in avoidant personality, they do suggest that these medications may be
worth trying in treating the Axis II variant. Indeed, a few open trials and case reports have
reported promising findings.
Deltito and Perugi (1986) reported the case of a man with pervasive social phobia and avoidant
personality disorder who responded well to phenelzine 45 mg/day, with an overall improvement in
his social adjustment. Subsequently, another four cases were described of individuals with avoidantPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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personality disorder who responded to MAOIs or fluoxetine, showing increased social confidence
and well-being (Deltito and Stam 1989). Liebowitz et al. (1988) also described a sizable proportion
of generalized social phobia patients who also met avoidant personality disorder criteria and
showed substantial overall gain in social and occupational functioning when they were given
phenelzine. However, in all these reports, most, if not all, avoidant subjects had comorbid social
phobia, and the criteria used to differentiate the two conditions and their medication response were
not clearly defined. In a more systematic approach, Reich et al. (1989) openly treated 14 patients
with DSM-III-R social phobia with alprazolam for 8 weeks at a mean daily dosage of 3 mg and
specifically measured treatment response in nine avoidant personality traits based on the
DSM-III-R diagnostic criteria for avoidant personality disorder. Six of the nine avoidant traits
showed significant improvement during treatment, correlating with a change in subjective anxiety
and disability. Further pharmacological studies with precise dissection of social phobia from
avoidant personality would be of great interest.
There is hardly any literature on the pharmacological treatment of obsessive-compulsive
personality disorder. Although Axis I OCD is well known to respond to serotonin reuptake inhibitors,
and the older psychodynamic literature merged the two conditions as obsessional neurosis, recent
studies dispute the notion that the Axis I and II variants are related. The older literature suggested
the presence of definite obsessional traits in as many as two-thirds of patients with OCD, but
structured personality assessments were not used. In more recent standardized evaluations, only a
minority of patients with OCD had DSM-III-R obsessive-compulsive personality disorder, but other
personality disorders such as avoidant or dependent were more common (Thomsen and Mikkelsen
1993). In addition, personality disorders may be more common in the presence of longer OCD
duration, suggesting that they could be secondary to the Axis I disorder, and criteria for personality
disorders may no longer be met after successful treatment of the OCD (Baer et al. 1990, 1992).
However, a recent study presented evidence in favor of a familial spectrum of OCD and
obsessive-compulsive personality disorder (Samuels et al. 2000). Regardless, no medication trials
have examined this personality disorder per se, and SSRI trials in severe obsessive-compulsive
personality disorder would be of some interest.
One report from the early 1990s claimed that major depression in the presence of comorbid
compulsive personality disorder showed better response to serotonin reuptake inhibitors than that
in the absence of comorbid compulsive personality (Ansseau et al. 1991). However, this finding has
not been replicated, and methodological issues have been raised, including the validity of the
distinction between preexisting obsessional personality and depression-related obsessional states
(Pollitt and Tyrer 1992).
We are also not aware of studies examining the pharmacological treatment of dependent
personality disorder. It has been reported in the presence of comorbid Axis I panic disorder, in
particular, that the initial rate of dependent personality traits was to a large extent state related
and waned with the treatment of panic over a 3-year period (Noyes et al. 1991).
Finally, one study examined change in core symptoms of Cluster C disorders, as measured by
personality inventories in the absence of categorical Axis II assessment, in patients treated
pharmacologically for Axis I disorders (Brody et al. 2000). In 37 patients treated with SSRIs for
major depression or OCD, an increase in social dominance and a decrease in social hostility were
found, irrespective of treatment response for Axis I, supporting the notion that serotonin reuptake
inhibitors may be useful to treat avoidant personality traits. Similarly, a decrease in harm
avoidance was found with treatment, which was greater in the Axis I treatment responders, again
supporting the notion that serotonin reuptake inhibitors may be useful in treating
obsessive-compulsive and dependent personality traits. More pharmacological studies using this
dimensional approach to symptom change would be of interest in Cluster C personality disorders.
TREATMENT ISSUES IN THE PRESENCE OF AXIS I COMORBIDITY
This section focuses not on the direct treatment of Axis II disorders but rather on the widely asked
question of whether the presence of Axis II disorders affects the likelihood of, compliance in, orPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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success of treating major Axis I disorders, primarily depression and anxiety. The literature in this
area often shows contradictory results, and lore blends with evidence-based reality. Here we
summarize the major empirical findings against the background of a widely espoused belief, not
necessarily substantiated by fact, that the presence of personality disorders generally impedes the
recognition and successful treatment of Axis I disorders.
A community survey, conducted as part of a 1981 epidemiological study that used DSM-III
(American Psychiatric Association 1980) diagnostic criteria, examined the association between Axis
I and II disorders and the need for and likelihood of treatment (Samuels et al. 1994). Among
subjects with any Axis I disorder, 87% of those with personality disorders were in need of
treatment compared with 46% of those without, a highly significant difference. Furthermore, 18%
of the subjects with personality disorders were actually receiving treatment compared with 6% of
the subjects without. In essence, then, although those with comorbid personality disorders were
proportionately more likely to be receiving some type of psychiatric treatment if in need of it, about
80% of the total individuals with personality disorders who were deemed as needing treatment
were not receiving it.
The literature is most extensive for depressive disorders. Earlier studies from the 1980s reported
that depressed patients with personality disorders were less likely to receive medication treatment
(Black et al. 1988; Charney et al. 1981) or received it for shorter periods (Pfohl et al. 1987) than
did those without personality disorders. However, Downs et al. (1992) found that patients with Axis
II comorbidity were not less likely to receive medications. Based on chart review, they were
actually likely to receive greater numbers of medications, especially if they had BPD, than patients
without personality disorder. In regard to the question of compliance, patients with major
depression who dropped out of controlled medication trials were characterized by a significantly
higher prevalence of “image distorting” defense mechanisms, such as projective identification,
splitting, omnipotence, and idealization/devaluation (Mullen et al. 1999).
Two review studies have examined the impact of Axis II disorders on the efficacy of
pharmacotherapy in depressed patients. A descriptive review study (Mulder 2002) examined more
than 50 relevant trials and concluded that better-designed treatment trials were least supportive of
an adverse effect of personality pathology on depression outcome. A negative impact of personality
on depression treatment was most consistently found for high neuroticism scores, whereas
Cloninger’s personality dimensions bore no consistent relation to depression outcome. Similarly,
when personality disorders were measured by categorical diagnostic instruments, results among
the various studies were quite inconsistent, and the best-designed studies that used structured
diagnostic interviews and randomized, controlled designs showed the least effect. A more recent
meta-analytic review study (Kool et al. 2005) reported similar findings. When all randomized,
controlled trials in adult ambulatory patients with major depression and comorbid personality
disorders were examined according to strict methodological criteria, the difference in depression
remission rates between the groups with and without Axis II disorders was a mere 3%, a
difference neither statistically significant nor clinically pertinent. However, another study reported
that acute response of major depressive disorder to electroconvulsive therapy (ECT) was poorer in
patients with comorbid BPD than in patients with other or no personality disorders, a finding not
accounted for by age, gender, or medication-resistance status (Feske et al. 2004).
Addressing a somewhat different question, a recent 11-year prospective study examined whether
the presence of Axis II comorbidity increases the likelihood of major depression recurrence or
relapse and found that it did (Khan et al. 2007). In a sample of 168 outpatients receiving long-term
treatment with an SSRI, Cluster A, B, and C dimensional personality traits were highly inversely
correlated with duration of stability without mood disorder. Similar findings were reported when
Axis II pathology was examined categorically; patients without personality disorders remained in
remission from depression almost twice as long as did patients with at least one personality
disorder.
Less literature exists examining the relation between the treatment of Axis I bipolar disorder andPrint: Chapter 61. Treatment of Personality Disorders http://www.psychiatryonline.com/popup.aspx?aID=424869&print=yes…
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the presence of Axis II personality disorder. A study of 200 bipolar I and II disorder patients
examining various factors affecting medication compliance found that personality disorder
comorbidity was the factor most strongly associated with poor compliance (Colom et al. 2000).
About one-quarter of the subjects had at least one comorbid Axis II disorder, and of these, 17%
were assessed as having good compliance, 37% medium compliance, and 44% poor compliance.
Fewer studies have examined the relation between Axis II comorbidity and treatment of Axis I
anxiety disorders. A recent report claims to be the first one to examine the amount of psychiatric
treatment received in anxiety disorder patients as a function of comorbid personality disorder
(Phillips et al. 2001). This large study examined several hundred anxious patients with a variety of
Axis I diagnoses: panic disorder, generalized anxiety disorder, social phobia, OCD, posttraumatic
stress disorder, and agoraphobia. Despite minor discrepancies between the two time-point
assessments (1991 and 1996), the findings were fairly consistent: similar percentages of anxious
subjects with and without personality disorders received medication treatment. If medicated, those
with personality disorders, and especially those with BPD, were likely to be receiving a greater
number of medications, specifically heterocyclic antidepressants. Thus, these investigators found
no evidence for medication undertreatment of patients with Axis II comorbidity. They proposed, in
reviewing trends in the pertinent literature, that influential biological studies and medication trials
of Axis II disorders from the late 1980s and the early 1990s may have led toward a more favorable
shift in medicating patients with personality disorders who previously may have been more likely to
be assessed as needing only psychotherapy.
CONCLUSION
In this chapter, we reviewed the pharmacological treatment of personality disorders, providing a
conceptual framework, highlighting methodological limitations, and summarizing treatment trials to
date. Almost all of these trials focused on symptom clusters, such as psychoticism, impulsivity,
hostility/aggression, mood instability, and anxiety/inhibition. Trials were largely limited to BPD,
although from some trials, additional conclusions can be drawn about other personality disorders in
mixed-group study designs or by extrapolation of comparable symptom clusters. It is becoming
increasingly established that medication treatment can play a very important role, albeit adjunctive
to psychotherapy, in the treatment of personality disorders. Even if benefits are more modest than
those encountered with medication treatment of some Axis I conditions, they can still make a
significant contribution to symptom reduction, functional improvement, and overall adaptation.
Continued medication trials of Axis II disorders that also focus on broader dimensions of
personality, including aspects of character, are eagerly awaited.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Personality Disorders
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Understanding Personality Disorders
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Historical Perspectives and Evolution of Diagnosis
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Classification and Diagnostic Criteria
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Introduction to Personality Disorders: Knowledge Check
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The Etiology of Personality Disorders
Understanding Diagnostic Criteria and Classifications
Developing Therapeutic Approaches and Treatment Plans
Advanced Techniques for Managing Complex Cases
Evaluating Treatment Outcomes and Long-term Strategies
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