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Andrew A. Nierenberg, Michael J. Ostacher, Pedro L. Delgado, Gary S. Sachs, Alan J. Gelenberg, Jerrold F. Rosenbaum, Maurizio Fava: Chapter 23.
Antidepressant and Antimanic Medications, in Gabbard’s Treatments of Psychiatric Disorders, 4th Edition. Edited by Glen O. Gabbard. Copyright ©2009
American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585622986.255448. Printed 5/10/2009 from www.psychiatryonline.com
Gabbard’s Treatments of Psychiatric Disorders > Part V. Mood Disorders >
Chapter 23. Antidepressant and Antimanic Medications
Major depressive disorder and bipolar disorder are highly prevalent (Kessler et al. 2003, 2005) and are among the top 10
causes of disability worldwide (Murray and Lopez 1996). These mood disorders tend to be underrecognized and
undertreated (Kessler et al. 2003; Wang et al. 2005), despite substantial evidence that supports the efficacy and
effectiveness of pharmacological and psychotherapeutic interventions. In this chapter we critically review the available
evidence for the efficacy and adverse effects of antidepressant and antimanic medications as well as evidence for the
management of treatment-resistant mood disorders. To the greatest extent possible, only controlled trials of adequate size
will be used to make treatment recommendations.
MECHANISMS OF ACTION
Classification of Antidepressant Drugs and Overview of Their Mechanism of Action
Most effective antidepressants potently increase synaptic levels of norepinephrine (NE) and/or serotonin (5
hydroxytryptamine [5-HT]), and in some cases dopamine (DA). Most accomplish this by inhibiting reuptake of monoamines
(NE, DA, and serotonin) or inhibiting the enzyme monoamine oxidase (MAO). Although increased synaptic monoamine levels
are not temporally correlated with therapeutic response, they are an essential aspect of the mechanism of action of some
medications (Delgado et al. 1993). Selective partial depletion of serotonin or NE and DA causes rapid depression relapse in
depressed patients on antidepressant medications that have been effective.
Depleting serotonin causes a rapid return of depression in depressed patients who have responded to fluoxetine,
fluvoxamine, monoamine oxidase inhibitors (MAOIs), or imipramine, but not in those who have responded to desipramine,
nortriptyline, or bupropion. Depleting NE and DA causes a rapid return of depression in depressed patients who have
improved with desipramine or mazindol, but not with fluoxetine (Delgado et al. 1993). This relapse is qualitatively similar to
the depression prior to treatment and correlates with the time course of monoamine depletion; the patients improve rapidly
as monoamine content returns to baseline levels. These data strongly suggest that the monoamine reuptake–blocking
properties are critical for the therapeutic action of these drugs and that more than one mechanism of action probably exists.
On the other hand, neither serotonin nor NE/DA depletion worsens mood in medication-free euthymic depressed patients.
These findings suggest that the way in which monoamines are involved in the regulation of mood is nonlinear and that they
do not directly modulate mood. Rapidly increasing levels of monoamines does not have an immediate antidepressant effect,
and rapidly lowering monoamines does not lower mood unless patients are being treated with a reuptake inhibitor. Thus,
monoamine reuptake inhibition is only the first step in a process that eventually leads to antidepressant response; important
changes associated with successful antidepressant response take place downstream from (i.e., postsynaptic to) the
monoamine systems (Figure 23–1).
Figure 23–1. Sites of antidepressant action.Print: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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(1) blockade of neurotransmitter reuptake; (2) inhibition of monoamine oxidase (MAO); (3) release of neurotransmitter; (4) blockade or
stimulation of receptors. 5-HT = 5-hydroxytryptamine (serotonin); 5-HIAA = 5-hydroxyindoleacetic acid.
Various secondary effects occur as a consequence of monoamine reuptake inhibition, including presynaptic and postsynaptic
changes in receptor number, G-protein coupling, second-messenger function, and gene transcription, as well as changes in
the critical balance between neurotransmitter systems. Consequently, the mechanism of antidepressant effects is a cascade
of biological effects often triggered by an increase in synaptic levels of monoamines. When the basic mechanisms underlying
antidepressant action are better understood, these drugs will come to be categorized by that mechanism rather than by
chemical structure or side-effect profile.
Most antidepressant drugs are metabolized into pharmacologically active compounds that frequently have effect profiles that
are different from those of the parent compound. For example, clomipramine primarily blocks 5-HT reuptake, whereas its
primary active metabolite, desmethylclomipramine, primarily blocks NE reuptake. Thus, in vivo effects of some
antidepressant drugs include the effects of both the parent compound and the active metabolites. Table 23–1 lists the
available medications with antidepressant properties grouped by the pharmacological effects of the parent compound.
Table 23–1. Categories of antidepressant drugs
NE reuptake inhibitors
Desipramine
Maprotiline
Nortriptyline
Protriptyline
5-HT reuptake inhibitors
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
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Sertraline
Mixed NE/5-HT uptake inhibitors
Amitriptyline
Duloxetine
Doxepin
Imipramine
Trimipramine
Venlafaxine
DA/NE reuptake inhibitor
Bupropion
MAO inhibitors
Irreversible inhibitors of MAO
Isocarboxazid
Phenelzine
Selegeline
Tranylcypromine
Reversible inhibitors of MAO-A (RIMAs)
Brofaromine
Moclobemide
Monoamine-releasing agents
Dextroamphetamine
Methamphetamine
Methylphenidate
Pemoline
Neurotransmitter receptor agonists
5-HT1A partial agonists
Buspirone
Gepirone
Benzodiazepine receptor agonist
Alprazolam
Drugs with mixed actiona
Amoxapine
Clomipramine
Mirtazapine
Nefazodone
Trazodone
Note. NE = norepinephrine; DA = dopamine; MAO = monoamine oxidase; 5-HT = 5-hydroxytryptamine (serotonin).
aMixed action refers to more than two major pharmacological effects possibly related to the mechanism of action.
The following subsections describe the specific pharmacological properties, the evidence for efficacy of each antidepressant
drug group, and the common side effects of each drug. A comparison of drug side effects is presented later.
Neuroprotection Hypotheses and Evidence
Antidepressant and antimanic agents have multiple mechanisms of action. Compelling theoretical frameworks that unify the
actions of these drugs include the neurogenesis and neuroprotective hypotheses. Both hypotheses take neurotransmitters
and receptors as the start of an elegant cascade that ends with gene expression of proteins that increase neurogenesis in
the hippocampus and enhance neuronal arborization and cell growth, as well as protect neurons from stress-induced
apoptosis. Exactly how the antidepressants and antimanic agents have these effects, how hippocampal neurogenesis is
related to the cause or treatment of mood disorders, and how specific genetic haplotypes mediate the stress response that
may provoke the apoptotic process that these medications protect against are subjects of intense research and debate
(Duman 2004; Henn and Volmayr 2004).
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Stress results in decreased gene expression of brain-derived neurotrophic factor (BDNF); administration of antidepressants
results in increased gene expression of BDNF (Duman 2004; Malberg et al. 2000). Exposure to inescapable stress decreases
neurogenesis, and this process is reversed by antidepressants (Malberg and Duman 2003). Thus, stress has detrimental
effects on neuronal survival, and antidepressants can either reverse or prevent stress-induced neuronal degradation.
In humans, converging evidence suggests that the homozygous haplotype for the short arm of the serotonin promotor region
(s/s) imparts increased susceptibility to develop major depressive disorder (MDD) with exposure to common low-threat
events, severe stressful events, or poor parenting (Caspi et al. 2003; Kendler et al. 2005). Furthermore, the s/s haplotype
was found to be associated with reduced gray matter volume in the perigenual cingulate gyrus (area 25) and amygdala as
compared with the l/l haplotype—regions associated with processing of fear and extinction of negative affect—and the short
allele was associated with functional uncoupling of the cingulate-amygdala circuit (Pezawas et al. 2005). The implication is
that individuals with the short allele are less able to stop the experience of fear or anxiety when presented with fearful
stimuli.
As we better understand stress and genetic vulnerability, the apoptosis cascade, and the neuroprotective properties of
antidepressants and antimanic agents, the field will be better able to pinpoint the pathophysiology of mood disorders and to
tailor treatments to patients with the goal of personalized medicine for optimal outcomes with mood disorder treatment.
ANTIDEPRESSANT MEDICATIONS
Monoamine Uptake Inhibitors
Inhibition of monoamine reuptake at presynaptic nerve terminals defines this drug group. It includes the tricyclic
antidepressants (TCAs), the selective serotonin reuptake inhibitors (SSRIs), and the mixed-uptake inhibitors with minimal
receptor-blocking properties (e.g., venlafaxine, duloxetine). Older drugs in this group tend to be pharmacologically
nonselective and often have active metabolites. The newer drugs (e.g., SSRIs, venlafaxine) tend to be more selective for
reuptake blockade and have fewer side effects.
These drugs are metabolized through hepatic microsomal systems, and major differences in absorption, in volume of
distribution, and in excretion exist between individual drugs, causing clinically meaningful differences in plasma levels
following routine dosing. All drugs in this group (and about 90% of all drugs in clinical practice) are metabolized by the
hepatic cytochrome P450 (CYP) 2D6 and 2A (3 and 4) enzymes. The CYP 2D6 enzyme has two subtypes (isoenzymes),
because of a genetic polymorphism. One subtype causes slower metabolism (10% of the population), and the other leads to
relatively faster metabolism. Persons with the slower metabolism subtype (so-called slow metabolizers) develop much
higher plasma concentrations of drugs metabolized by the CYP 2D6 enzyme. Genetic polymorphisms for the CYP 2A enzymes
are not known to exist. Knowing which CYP enzyme is responsible for metabolism of a drug can be important in assessing
the potential influence of drugs that inhibit subsets of these enzymes. This is especially true for the SSRIs, some of which
are potent inhibitors of CYP 2D6.
Selective Serotonin Reuptake Inhibitors
The five drugs in this class are fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram (plus escitalopram). They
have similar side effects and a similar therapeutic spectrum of action, being effective in the treatment of unipolar and bipolar
depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), social anxiety disorder, and panic
disorders.
While these drugs are more similar than different, differences in side-effect profiles include sedation or asthenia versus
activation and gastrointestinal side effects. In general, fluvoxamine and paroxetine are more frequently associated with a
sedation-like “blah” feeling referred to as asthenia and with nausea, whereas fluoxetine and sertraline are more
“activating.” Citalopram is intermediate in most side effects compared with other SSRIs. Escitalopram, the s-stereoisomer of
citalopram, has greater antidepressant potency per milligram compared with citalopram, perhaps because of its more
selective binding to the serotonin transporter. This results in greater efficacy at lower doses and perhaps less side-effect
burden compared with citalopram (Owens et al. 2001). Paroxetine also inhibits the enzyme nitric oxide synthase, which
could possibly lead to a slightly higher rate of sexual dysfunction compared with other SSRIs. The SSRIs are metabolized in
the liver and eliminated renally, with more than 90% of the parent compound inactivated. Fluoxetine and sertraline have
active SSRI metabolites—norfluoxetine and N-desmethylsertraline. SSRIs differ significantly in their elimination half-lives
(see Table 23–2).
Table 23–2. Pharmacokinetics of selective serotonin reuptake inhibitors
Drug Half-life (hours) Protein binding (%) Active metabolites
Citalopram 24–48 80 None
Escitalopram 27–32 56 None
Fluoxetine 48 95 Norfluoxetine
Fluvoxamine 15 77 None
Paroxetine 15 95 None
Sertraline 26 97
N-desmethylsertraline
Fluoxetine, fluvoxamine, and paroxetine have potent inhibitory effects on the hepatic microsomal enzyme system and can
cause clinically significant increases in drugs metabolized by this system. This can be problematic in elderly patients taking
other medications and should be considered as a possible cause of unexplained delirium. All of the SSRIs are potentially
lethal when combined with MAOIs. This combination should be considered an absolute contraindication. Because of its longPrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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half-life and significant accumulation, fluoxetine should be discontinued at least 6 weeks before beginning an MAOI; other
SSRIs should be discontinued at least 2 weeks before initiation of an MAOI. Although the syndrome that occurs with the
combination of an SSRI and an MAOI has been referred to as the serotonin syndrome, it closely resembles the neuroleptic
malignant syndrome and malignant hyperthermia.
Norepinephrine Reuptake Inhibitors
NE reuptake inhibitors are TCAs with secondary-amine side chains. The TCAs include desipramine, nortriptyline,
protriptyline, and maprotiline. Maprotiline is, in essence, a TCA with an ethylene bridge spanning the rings, which is why it is
referred to as a tetracyclic. The drugs in this class vary in side-effect profile, primarily because of differences in
receptor-blocking properties. These drugs are metabolized through hepatic hydroxylation and glucuronidation and are
excreted by the kidneys.
All of these drugs are effective acute treatments for a major depressive episode. The TCAs (with the exception of
clomipramine) are less effective for OCD than are the SSRIs or MAOIs and are less effective for panic disorder than are the
SSRIs, MAOIs, or other TCAs. Therapeutic doses of these drugs vary. The usual therapeutic dosage for desipramine is
150–300 mg/day; for nortriptyline and maprotiline, 75–150 mg/day (maximum 225 mg/day for maprotiline); and for
protriptyline, 20–60 mg/day. For reboxetine, the therapeutic dosage is usually 8–12 mg/day.
Elderly patients may tolerate nortriptyline better than other TCAs due to its lower anticholinergic effects and lower risk of
orthostatic hypotension (Roose and Glassman 1989) in clinically effective doses.
Mixed Norepinephrine/Serotonin Reuptake Inhibitors
The mixed NE/5-HT reuptake inhibitors include the tertiary-amine TCAs (imipramine, amitriptyline, doxepin, and
trimipramine) and the non-TCAs venlafaxine and duloxetine. The TCA members of this family are demethylated in the liver
and converted to secondary-amine active metabolites. The secondary-amine metabolites (e.g., desipramine, nortriptyline)
are potent NE reuptake inhibitors that develop clinically significant plasma levels in clinical practice (see Table 23–1).
All TCAs in this group have established efficacy in the treatment of major depressive episodes in both inpatient and
outpatient populations. Clinical doses are roughly similar for TCAs in this group (therapeutic range: 150–300 mg/day).
Imipramine has established efficacy in panic disorder; amitriptyline and doxepin are effective in chronic pain syndromes.
These TCA compounds have prominent anticholinergic and antihistamine properties that cause sedation, dry mouth,
constipation, and some orthostatic hypotension. Blurred vision, urinary retention, and excessive perspiration (cause
unknown) are also observed. Amitriptyline and doxepin are the most difficult to tolerate.
Venlafaxine has minimal effects on blockade of neurotransmitter receptors. At less than 150 mg/day, it is as potent a
blocker of serotonin reuptake as imipramine but is a weaker blocker of NE reuptake, making it slightly more selective for
serotonin than for NE. Potent NE reuptake inhibition is thought to occur with dosages above 150 mg/day. Venlafaxine
neither inhibits MAO nor significantly binds to serotonin, NE, DA, muscarinic cholinergic, alpha 1-adrenergic, or histamine1
receptors. It is rapidly absorbed after oral administration, with peak plasma levels being achieved in less than 2 hours. The
half-life is extremely short and ranges from 3 to 5 hours, although an active metabolite, O-desmethylvenlafaxine, has a
half-life ranging from 9 to 11 hours. Discontinuation reactions frequently occur when venlafaxine is stopped abruptly, due to
this short elimination half-life (Fava et al. 1997). Clinically therapeutic dosages of venlafaxine range from 150 to 300
mg/day in divided doses. The extended-release form of venlafaxine can be dosed once daily and is associated with a more
favorable side-effect profile.
Because it does not possess receptor antagonist properties, venlafaxine appears to have fewer side effects than TCAs. Most
common are nausea, somnolence, dizziness, dry mouth, headaches, and increased perspiration. Sexual dysfunction has been
spontaneously reported, with up to 12% of patients describing abnormal ejaculation; 6%, impotence; and 2%, anorgasmia.
The true rates of sexual dysfunction are likely to be much higher. Venlafaxine causes dose-related diastolic hypertension in
some patients, making blood pressure monitoring important during treatment. Venlafaxine appears to be as safe as SSRIs in
overdose: in 14 patients who took overdoses of up to 6.75 g, all patients recovered without sequelae, but one (who took
2.75g) had two witnessed tonic-clonic seizures. In postmarketing surveillance, however, there have been deaths reported,
usually in combination with alcohol or other drugs (Wyeth Pharmaceuticals 2006).
Duloxetine
Four out of six randomized clinical trials found duloxetine to be superior to placebo for the acute treatment of MDD (Detke et
- 2002a, 2002b; Goldstein et al. 2002; Nemeroff et al. 2002). Several studies have found that duloxetine is effective for the
pain complaints associated with depression (Brannan et al. 2005). Like venlafaxine, duloxetine is free of antihistaminergic,
antiadrenergic, and antimuscarinic effects. Duloxetine has a longer elimination half-life than venlafaxine (9–19 hours)
(Lantz et al. 2003). Duloxetine is both a substrate and an inhibitor of CYP 2D6.
Adverse events include nausea (especially at treatment initiation), decreased appetite, constipation, diarrhea, increased
sweating, dizziness, insomnia, and sexual dysfunction (Hudson et al. 2005). Duloxetine does not appear to cause blood
pressure increases.
Dopamine/Norepinephrine Reuptake Inhibitors
Only one drug, bupropion, is included in this group (although sertraline has been shown to possess significant potency as a
DA reuptake inhibitor). Clinical studies have demonstrated that bupropion is effective for major depressive episodes.
Bupropion is structurally related to phenylethylamines and unrelated to TCAs, SSRIs, or MAOIs. It is also unique in that it
has no significant potency in binding to any known neurotransmitter receptors. It has no significant effects in blocking
reuptake of serotonin or NE, although its primary metabolite, 306U73 (hydroxybupropion), has significant NEPrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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reuptake–blocking properties. Hydroxybupropion is produced rapidly in humans, with peak plasma levels up to three times
those of bupropion and a half-life of 24 hours.
Bupropion, a very weak DA reuptake blockade inhibitor, has a behavioral profile in laboratory animals and humans of a
central nervous system (CNS) stimulant and indirect DA agonist. Bupropion increases locomotor activity and causes
stereotyped behaviors in laboratory animals. In humans it can cause restlessness, insomnia, anorexia, and psychosis.
Early trials, with doses up to 900 mg, found a high rate of seizures. When subsequent trials with the immediate-release
formulation were conducted with a maximum total daily dosage of 450 mg, efficacy was demonstrated for major depressive
episodes, with an incidence of seizures approximating 0.4%. This incidence is similar to the 0.1% seen with TCAs. The risk
is increased substantially by predisposing factors such as prior history of seizures, head trauma, brain tumor, bulimia
nervosa, or anorexia nervosa and with doses higher than 450 mg/day. The sustained-release formulation of bupropion may
be associated with a lower risk of seizures. The data from clinical trials reveal a risk of seizures of 0.1% in patients treated
with dosages between 100 and 300 mg/day and a rate of 0.4% at the maximum recommended daily dosage of 400 mg. The
immediate- and sustained-release formulations, however, are bioequivalent with regard to rate and extent of absorption
during steady state, the most important parameters in estimating seizure incidence. Sustained-release bupropion is
available in 100-mg, 150-mg, and 200-mg tablets. Because of the longer half-life, it can be dosed twice daily, with the
maximum dose being 200 mg. Bupropion XL formulation allows patients to take bupropion once daily.
Monoamine Oxidase Inhibitors
Following the discovery of MAOIs in the late 1950s, reports of serious side effects and the ensuing availability of TCAs
relegated MAOIs to a treatment of last resort. Serious adverse events, including hypertensive crisis, lethal reactions with
SSRIs, and delirium with meperidine were reported, and less severe reactions with other opiate agonists such as morphine
and partial agonists such as buprenorphine, butorphanol, and pentazocine. Hepatotoxicity appears to be very uncommon
with the currently used MAOIs. Although free of anticholinergic side effects, MAOIs commonly cause insomnia, daytime
somnolence, clinically significant hypotension and orthostatic hypotension, anorgasmia, weight gain, myoclonus, and pedal
edema. The hydrazine MAOIs (phenelzine and isocarboxazid) are associated with pyridoxine (vitamin B 6) deficiency in up to
7% of patients.
MAOIs inhibit the primary enzyme responsible for degradation of monoamines, resulting in increased synaptic levels. Two
forms of MAO exist in the CNS: type A (MAO-A) and type B (MAO-B). MAO-A metabolizes NE, serotonin, DA, and tyramine,
whereas MAO-B metabolizes DA and tyramine but has no effect on NE or serotonin. Selective MAO-B inhibitors such as
L-deprenyl (selegeline), which is used in the treatment of Parkinson’s disease, are being investigated for use in depression.
The earliest MAOIs (phenelzine, tranylcypromine, and isocarboxazid) are all irreversible inhibitors of both MAO-A and
MAO-B. Each molecule of drug permanently inactivates one enzyme molecule. Before enzyme activity can be restored, new
enzyme must be synthesized. The level of MAO activity, therefore, is a balance between MAOI drug level and rate of enzyme
synthesis. It can take up to 2 weeks from the time that an irreversible MAOI drug is discontinued until full MAO activity
returns.
Irreversible MAOIs have been studied extensively with regard to their antidepressant properties, and all are clearly effective
in the treatment of major depressive episodes. They may be more effective than TCAs in the treatment of major depressive
episodes with atypical features (mood reactivity, weight gain or increased appetite, hypersomnia, leaden paralysis,
interpersonal rejection sensitivity) than other antidepressant medications. MAOIs alone appear not to be as effective in the
treatment of patients with a major depressive episode with psychotic features. Because of potential side effects, these drugs
continue to be second- and third-line agents, seldom being used first in treatment-naive patients.
Antidepressant dosages of tranylcypromine and isocarboxazid are 20–60 mg/day, and those of phenelzine are 30–90
mg/day. Clinical studies have shown that antidepressant activity is related to degree of inhibition of plasma MAO, with
patients who show less than 80% inhibition responding less frequently.
A transdermal patch formulation of selegiline has been approved by the U.S. Food and Drug Administration (FDA) for major
depression. The 6-mg patch does not require any dietary restrictions (Amsterdam 2003).
Drugs With Mixed Pharmacological Properties
The drugs in this category (trazodone, nefazodone, amoxapine, clomipramine, and mirtazapine) have multiple
pharmacologically relevant effects, including combinations of monoamine reuptake blockade and direct receptor antagonist
and agonist properties.
Trazodone
Trazodone, a 5-HT2 receptor antagonist with weak serotonin reuptake inhibitor properties, is structurally distinct from TCAs
or other classes of antidepressant drugs. It is metabolized into the compound m-chlorophenylpiperazine (mCPP), which is a
5-HT1A, 5-HT1B, and 5-HT1C agonist as well as a 5-HT2 and 5-HT3 antagonist. Pharmacologically significant plasma levels of
mCPP are found in patients taking therapeutic doses of trazodone, which raises questions about the role of mCPP in this
agent’s therapeutic effects and side effects.
Trazodone has been shown to be more effective than placebo in the treatment of inpatients and outpatients with major
depressive episodes. Some authors have suggested that lower doses are more effective than the maximum total dosages of
400 mg/day for outpatients and 600 mg/day for inpatients.
Side effects include sedation, orthostatic hypotension, dissociative feelings, increased myocardial irritability, and priapism.
Sedation is variable but is often a limiting factor in dosing. Because of its prominent sedating properties, trazodone isPrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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frequently used as a hypnotic in combination with the less sedating SSRIs. Priapism, one of the most serious side effects of
trazodone, is considered a urological emergency, often requiring surgical intervention and sometimes leading to permanent
impotence.
Nefazodone
Nefazodone is chemically related to trazodone and has similar pharmacological properties. It is a 5-HT 2 receptor antagonist
with weak serotonin reuptake inhibitor properties. Unlike trazodone, nefazodone lacks significant alpha 1-adrenergic
antagonist properties, a difference that may account for the lack of orthostatic hypotension, sedation, and priapism with
nefazodone. Nefazodone is also metabolized into mCPP, and plasma levels of mCPP are similar to those obtained with
trazodone.
Nefazodone has been shown to be effective in placebo-controlled trials and has comparable efficacy to that of imipramine
but with fewer side effects. Unlike all other known antidepressants, nefazodone either increases or has no effect on rapid
eye movement (REM) sleep in humans. Nefazodone has been reported to improve memory function and does not potentiate
the depressant effects of alcohol. Clinical doses range from a starting dose of 100 mg twice a day to a maximum total dosage
of 600 mg/day. The lower dosage range of 200–400 mg/day is recommended in elderly patients.
Nefazodone-associated side effects include headache, asthenia, dry mouth, nausea, and constipation. Nefazodone does not
alter cardiac conduction or electrocardiographic indices. It is reported to be less sedating than imipramine and SSRIs and
may cause less sexual dysfunction than the SSRIs. It appears to have no effect on seizure threshold. Nefazodone was found
to be associated with liver failure and death and was removed from the market for branded but not generic formulations.
Amoxapine
Amoxapine is a TCA and NE reuptake inhibitor with potent D 2 and 5-HT2 receptor–blocking properties. Some studies have
examined the use of amoxapine for major depressive episodes with psychotic features, finding it more effective than placebo
and frequently as effective as the combination of other TCAs with an antipsychotic drug. Amoxapine has been reported to
cause extrapyramidal reactions and tardive dyskinesia, consistent with its D 2 antagonist properties. It has a high frequency
of seizures and lethality in overdose.
Clomipramine
Clomipramine is included in this group because it has several pharmacological properties that raise questions about its
mechanism of action. Clomipramine is a tertiary-amine TCA and a potent serotonin reuptake inhibitor with significant D 2
antagonist properties. It is metabolized into a potent secondary-amine NE reuptake inhibitor, norclomipramine.
Clomipramine is a unique TCA as it is effective in OCD. It has also been used successfully in depression refractory to other
TCAs. Clomipramine often causes sedation and anticholinergic-type side effects, making gradual dose escalation important.
Therapeutic dosages are between 150 and 250 mg/day. Like the SSRIs, clomipramine frequently causes anorgasmia, and
like the tertiary-amine TCAs, it can cause difficulty in maintaining an erection.
Mirtazapine
Mirtazapine does not inhibit the reuptake of serotonin, NE, or DA but rather is an alpha 2-adrenergic receptor antagonist and
5-HT2 and 5-HT3 receptor blocker. Its potent antihistaminergic effects at histamine1 receptors result in sedation and
increased appetite for some patients. Mirtazapine has no effects on DA, cholinergic, or alpha 1-adrenergic receptors.
By blocking alpha2- but not alpha1-adrenergic receptors, mirtazapine increases firing rates and release of both NE and 5-HT.
This is because alpha2-adrenergic receptors are localized on both NE and 5-HT neurons. On NE neurons, presynaptic alpha 2
receptors function as autoreceptors, inhibiting NE release. Blocking these receptors increases the firing rate and release of
NE in most brain regions. NE released near the cell bodies of 5-HT neurons activates alpha 1-adrenergic receptors located on
5-HT cell bodies, and because these receptors act in an excitatory fashion, the firing rate of 5-HT neurons is increased. 5-HT
neurons also have alpha2-adrenergic receptors, but in this case the receptors are localized on serotonin terminals and
function to inhibit the release of serotonin. Blocking these alpha 2-adrenergic receptors enhances the amount of 5-HT
released each time the neurons fire.
Mirtazapine is rapidly absorbed after oral dosing and is not affected by the presence of food. It demonstrates a linear
pharmacokinetic profile; half-life ranges between 20 and 40 hours. Steady state is achieved within 3–5 days with daily
dosing. Mirtazapine is 85% protein-bound. Although minor gender and age differences have been noted in plasma
concentrations, these are believed to be clinically insignificant, and no alterations in dose are recommended for age or
gender.
Mirtazapine is extensively metabolized in the liver by the CYP 2D6, 1A2, and 3A4 isoenzymes. The only active metabolite,
demethyl-mirtazapine, is 10-fold less active than the parent compound. Neither mirtazapine nor its metabolites significantly
inhibit CYP isoenzymes, leading to few drug–drug interactions through these mechanisms. Moreover, because multiple CYP
enzymes metabolize mirtazapine, other drugs are less likely to alter its metabolism. The primary side effects of mirtazapine
are sedation, weight gain, and constipation. It is less likely than TCAs or SSRIs to cause sexual side effects, but sexual side
effects have been reported with the drug.
MEDICATIONS FOR BIPOLAR DEPRESSION
Bipolar depression has been remarkably difficult to study, and the efficacy of antidepressants for bipolar depression has yet
to be firmly established for acute and long-term treatment (Altshuler et al. 2003; Ghaemi et al. 2003; Post et al. 2003b;
Nemeroff et al. 2001). Newer agents specific for bipolar depression, however, have gained both evidence for efficacy and
widespread use. This section reviews medications and medication combinations that have efficacy for bipolar depression.Print: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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Lamotrigine
Lamotrigine may be the most significant advance in the treatment of bipolar depression in the past decade (Calabrese et al.
1999, 2000, 2003). Lamotrigine is approved for the maintenance treatment of bipolar disorder. Long-term studies found an
overall reduction in bipolar depressive relapse compared with placebo (Goodwin et al. 2004). In a key study in which
patients who were most recently depressed were first stabilized on lamotrigine and then placed in a placebo-controlled
discontinuation paradigm, the overall relapse rate was about 57% with lamotrigine compared with 46% for lithium and 25%
for placebo, indicating that although lamotrigine is effective compared with placebo, a substantial proportion (43%) of
bipolar patients are not protected by continuation lamotrigine (Calabrese et al. 2003; McElroy et al. 2004). Lamotrigine
inhibits voltage-gated sodium channels and reduces glutamate. It is absorbed within 1–3 hours and has a half-life of 25
hours. Rash can occur in up to 8% of adults, and serious rash requiring hospitalization can be seen in up to 0.5%. Because
of the possibility of Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema, all rashes should be regarded as
potentially serious and monitored closely, and the dose should be increased at the rate suggested in the package insert to
minimize serious rashes.
Olanzapine and Olanzapine/Fluoxetine Combination
Olanzapine and olanzapine combined with fluoxetine were assessed for the treatment of bipolar I depression in a large
seminal study (Tohen et al. 2003c). Although the group that received the combination was added later in the study, and thus
not all patients were eligible to be randomized to all three cells, the proportions who remitted from bipolar depression were
24.5%, 32.8%, and 48.8% for placebo, olanzapine, and the combination, respectively. The proportion of patients who
discontinued during the study was high, with 61.5%, 51.6%, and 36.0%, respectively.
Treatment-emergent mania was no different for the active compared with the placebo condition. Weight gain with
olanzapine and the combination was similar, with an average increase of about 2.7 kg, compared with an average decrease
of 0.5 kg for placebo. Nearly one-fifth of the subjects in the olanzapine and combination groups had gained more than 7% of
their body weight at the end of the 8-week trial, compared with 0.3% in the placebo group.
Quetiapine
In a well-powered study, quetiapine monotherapy at doses of 300 mg and 600 mg for bipolar depression was found to have
a strong antidepressant effect compared with placebo, with 52.9% achieving remission with both doses of quetiapine and
28.4% with placebo (Calabrese et al. 2005a). Effect sizes (difference in the decrease in Montgomery-Asberg Depression
Rating Scale [MADRS] score with active drug compared with placebo divided by the pooled standard deviation) for the entire
group were 0.67 and 0.81 for quetiapine 300 mg and 600 mg, respectively; for those patients with bipolar I depression, the
effect sizes for 300 mg and 600 mg were 1.09 and 0.91, respectively, while for bipolar II, the effect sizes were 0.28 and
0.39—without a statistically significant improvement in MADRS total scores compared with placebo for those with bipolar II
depression. A detailed analysis of specific symptom change showed that core symptoms of depression improved
independently of the sedative effects of quetiapine. Anxiety, quality of sleep, and quality of life all improved more with
quetiapine compared with placebo.
The proportion of patients who discontinued due to adverse events was 16% for the 300-mg and 26.1% for the 600-mg
groups, compared with 8.8% for the placebo group. The most common adverse events were dry mouth, sedation,
somnolence, dizziness, and fatigue. Treatment-emergent mania occurred in less than 4% of patients, a rate no different from
that for placebo. No significant emergence of extrapyramidal symptoms or akathisia occurred with active treatment. Patients
in the 300-mg and 600-mg groups gained 1.0 kg and 1.6 kg, respectively, compared with 0.2 kg for placebo, over the 8
weeks of the study.
MEDICATIONS FOR BIPOLAR MANIA
Lithium
Lithium is most commonly prepared as the carbonate form, although lithium citrate is also available. Most preparations come
in 300- or 450-mg tablets or capsules. Therapeutic total dosages of lithium are quite variable, ranging from 600 mg/day to
as high as 2,100 mg/day. Lithium doses are usually divided (bid or tid) until the therapeutic total daily dose is established,
and then either twice-daily or bedtime dosing is adequate. Given the compliance issues usually involved in the treatment of
patients with bipolar disorder, dosing should be as simple as possible, making one daily dose at bedtime the most desirable,
if tolerated.
Because of potentially serious toxicity, lithium plasma levels are routinely used to establish a therapeutic dose. The usual
trough therapeutic range is between 0.5 and 1.5 mEq/L. In the acute-treatment phase, plasma lithium levels between 0.8
and 1.3 mEq/L are recommended in order to maximize therapeutic effect. Lithium levels above 0.8 mEq/L are associated
with fewer relapses into mania or depression—but greater noncompliance due to side effects—than levels between 0.4 and
0.6 mEq/L (Gelenberg et al. 1989).
Lithium has a narrow therapeutic window, with minimal benefit with blood levels below 0.4 mEq/L and serious toxicity with
levels above 2.0 mEq/L. A doubling of the usual daily dose may result in toxic levels. High lithium levels cause tremor and
gastrointestinal disturbances. More serious toxicity usually involves CNS symptoms (e.g., somnolence, confusion, dysarthria,
pyramidal tract signs, coma) and cardiac toxicity (e.g., hypotension, cardiac arrhythmias). Elderly patients may be more
sensitive to side effects from lithium and have a higher rate of confusion compared with younger patients.
Lithium can cause short-term side effects, including tremor, gastric irritation, nausea, abdominal cramping, diarrhea,
vomiting, increased white blood cell count (up to 15,000 cells/mm3 ), polyuria and polydipsia, dermatitis, extrapyramidal
reactions, fatigue and muscle weakness, and flattening or inversion of T waves and/or flattening of U waves on anPrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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electrocardiogram. Long-term side effects include weight gain, hypothyroidism (5%–30%), diabetes insipidus, decreased
glomerular filtration rate, hyperthyroidism, and hyperparathyroidism.
Lithium may cause fetal heart anomalies, but recent data suggest that the incidence is low, so risks versus benefits must be
weighed (Cohen et al. 1994). Because lithium is excreted in breast milk in significant quantities, breast-feeding should be
approached with caution. Transplacental passage of lithium results in equivalent lithium levels in mother and newborn, and
higher lithium levels (> 0.64 mEq/L) at birth are associated with lower Apgar scores, longer hospital stays, and higher rates
of CNS and neuromuscular complications (Newport et al. 2005). The authors suggest that withholding lithium for 24–48
hours prior to delivery can decrease lithium levels and result in fewer postnatal complications for the newborn.
Anticonvulsants
Carbamazepine
More than 19 studies (most of which were small case series or open trials) have evaluated the effectiveness of
carbamazepine for mania. Only recently has carbamazepine been found to be effective (in extended-release form) for acute
mania in a large, placebo-controlled trial (Weisler et al. 2005). No large-scale trials have compared it with other antimanic
drugs.
Carbamazepine, an anticonvulsant drug structurally related to the TCAs, has variable absorption and metabolism.
Carbamazepine is rapidly absorbed (peak plasma levels within 4–6 hours). Eighty percent of plasma carbamazepine is
protein-bound. The half-life ranges from 13 to 17 hours. Carbamazepine is metabolized by the hepatic CYP 2D6 system.
Carbamazepine induces the CYP enzymes, causing an increase in the rate of its own metabolism over time (as well as that of
other drugs metabolized by the CYP system). Thus, the total dose may need to be raised within 2–4 months of treatment
initiation. Concomitant administration of carbamazepine with oral contraceptives, warfarin, theophylline, doxycycline,
haloperidol, TCAs, or valproic acid leads to decreased plasma levels of these other drugs. Concomitant administration of
drugs that inhibit the CYP system will increase plasma levels of carbamazepine. These drugs include fluoxetine, cimetidine,
erythromycin, isoniazid, calcium channel blockers, and propoxyphene. Concomitant administration of phenobarbital,
phenytoin, and primidone causes a decrease in carbamazepine levels through induction of the CYP enzymes.
Based on its use as an anticonvulsant, dosages of carbamazepine range from 400 mg to 1,200 mg/day, and therapeutic
plasma levels range from 4 to 12 micrograms/mL. The relationship between blood levels and response in mania is not
known.
Carbamazepine frequently causes lethargy, sedation, nausea, tremor, ataxia, and visual disturbances during the
acute-treatment phase. Some patients can develop mild leukopenia or thrombocytopenia during this phase and usually do
not progress. Carbamazepine causes a rare but severe form of aplastic anemia or agranulocytosis—estimated to occur with
an incidence of about 2–5 per 100,000, which is 11 times the incidence in the general population. Although more than 80%
of these reactions occur during the first 3 months of therapy, some cases have been reported as late as 5 years after
initiation of therapy treatment. If the white blood cell count drops below 3,000 cells/mm 3 , the medication should be
discontinued.
Carbamazepine has been associated with fetal anomalies, including a risk of spina bifida (1%), low birth weight, and small
head circumference. It has also been shown to have effects on cardiac conduction, slowing atrioventricular conduction.
Other reported side effects include inappropriate secretion of antidiuretic hormone with concomitant hyponatremia,
decreased thyroid hormone levels without changes in levels of thyroid-stimulating hormone, severe dermatological reactions
such as Stevens-Johnson syndrome, and hepatitis.
Because of the cardiac, hematological, endocrine, and renal side effects associated with carbamazepine, patients should
have had a recent physical examination, complete blood count (CBC) with platelet count, liver function tests, thyroid
function tests, and renal indices before treatment initiation. The CBC and liver function should be monitored every 2–3
weeks during the initial 3–4 months of treatment. All baseline tests should be repeated at a minimum of yearly intervals
thereafter. Any change in the tests listed above should warrant closer evaluation and follow-up. Carbamazepine shares with
the TCAs the risk of hypertensive crisis when coadministered with MAOIs, and so this combination should not be routinely
used. If carbamazepine has a role, it is more likely as an adjunct in patients with rapid cycling and patients with dysphoric
mania or mixed states.
Oxcarbazepine, a keto-analogue of carbamazepine, is purported to have less side effects than carbamazepine, but evidence
of its efficacy in mania is absent.
Valproic Acid
The acute antimanic efficacy of valproic acid has been established by several controlled studies. The largest trial of valproate
maintenance (n = 372) failed to find a difference between valproate, lithium, and placebo for the primary outcome measure
(time to any mood episode) (Bowden et al. 2000). Valproate is not approved by the FDA for the maintenance treatment of
bipolar disorder. Despite this lack of evidence, it has been recommended as first-line prophylactic treatment of bipolar
disorder in multiple treatment guidelines (e.g., American Psychiatric Association 2002; Consensus Group British Association
of Psychopharmacology 2003; Mitchell 2004; Yatham et al. 2005).
Valproic acid (di-n-propylacetic acid) is an anticonvulsant drug chemically unrelated to other psychiatric medications. It is
produced in various preparations, including syrup, sprinkles, capsules, enteric-coated capsules, and tablets. One of the more
commonly used preparations is divalproex sodium (Depakote), a compound of sodium valproate and valproic acid in a 1:1
molar ratio. Absorption is different across the different preparations and is delayed by food. However, becausePrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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anticonvulsant efficacy is not related to peak levels but rather to total daily bioavailable dose, this variability is thought to be
clinically irrelevant. Peak plasma levels are achieved between 2 and 4 hours after ingestion, and the half-life ranges from 6
to 16 hours. More than 90% of plasma valproic acid is protein-bound. The time of dosing is determined by possible side
effects, and if tolerated, once-a-day dosing could be employed. The therapeutic plasma levels used for the treatment of
mania are the same as those used for anticonvulsant therapy (50–100 g/mL), and the total daily dosage required to
achieve these levels ranges from 500 mg to 1,500 mg.
Valproic acid is metabolized by the hepatic CYP 2D6 system but, unlike carbamazepine, does not autoinduce its own
metabolism. Concomitant administration of carbamazepine will decrease plasma levels of valproic acid, and drugs that
inhibit the CYP system (e.g., SSRIs) can cause an increase in valproic acid levels.
Dose-related and common initial side effects include nausea, tremor, and lethargy. Gastric irritation and nausea can be
reduced by dividing the dose or by using enteric-coated preparations. Valproic acid has been associated with potentially fatal
hepatic failure, usually occurring within the first 6 months of treatment and most frequently occurring in children under age
2 years and in persons with preexisting liver disease. Transient dose-related elevations in liver enzymes can occur in up to
44% of patients. Any change in hepatic function should be followed closely, and patients should be warned to report
symptoms of hepatic failure, such as malaise, weakness, lethargy, edema, anorexia, or vomiting. Valproic acid may produce
teratogenic effects, including spina bifida (1%) and other neural tube defects. Other potential side effects include weight
gain, inhibition of platelet aggregation, hair loss, and severe dermatological reactions such as Stevens-Johnson syndrome.
Lamotrigine
Lamotrigine has not demonstrated efficacy for the acute treatment of mania. No single trial found benefit for lamotrigine in
the prevention of manic episodes, but pooled analyses revealed a small effect size for the prevention of mania (Bowden et al.
2003; Calabrese et al. 2003; Goodwin et al. 2004). Lamotrigine is more effective than lithium in preventing depressive
episodes, and lithium is more effective than lamotrigine in preventing manic episodes.
Gabapentin
Gabapentin rose and fell as a popular treatment for mania. Two double-blind studies failed to detect antimanic or
antidepressant effect of gabapentin, and one study found the antimanic response to placebo to be statistically significantly
greater than for the drug (Pande et al. 2000). Current evidence does not support its use in any phase of bipolar disorder.
Others (Topiramate, Zonisamide)
Although case reports and uncontrolled trials suggested efficacy for topiramate in the treatment of bipolar mania, controlled
trials have not demonstrated this effect (Kushner et al. 2006). Topiramate inhibits rapid firing at voltage-dependent sodium
channels, antagonizes kainate binding to the alpha-amino-3-hydroxy-5 methyl-4-isoxazole propionic acid (AMPA) receptor,
and potentiates the effects of GABA at the GABA-A receptor.
Atypical Antipsychotics
Atypical antipsychotics (other than clozapine) have consistently shown robust efficacy for the acute treatment of mania. The
FDA has approved all of the atypical antipsychotics other than clozapine for this indication, but no head-to-head comparisons
have been published. The major features, then, that determine treatment choice among these agents for the treatment of
mania are side-effect profiles. Broadly considered, clozapine, olanzapine, and quetiapine are more likely to be associated
with weight gain and an increase in triglycerides than are aripiprazole, risperidone, and ziprasidone.
Aripiprazole
In a 3-week study of acute mania or mixed states, aripiprazole up to 30 mg resulted in 40% responding compared with 19%
who responded to placebo, with statistically significant separation from placebo by day 4 (Keck et al. 2003a). The group that
took aripiprazole had no increase in weight compared with placebo. A 12-week randomized comparison of aripiprazole and
haloperidol for mania or mixed mania resulted in 49.7% of the aripiprazole and 28.4% of the haloperidol group responding
(Vieta et al. 2005).
Olanzapine
Open reports of the efficacy of olanzapine for mania and refractory rapid cycling are now buttressed by two
placebo-controlled, double-blind studies that showed olanzapine to be more effective than placebo for the treatment of
manic and mixed episodes (Tohen et al. 1999). The antimanic benefit of olanzapine for nonpsychotic and psychotic patients
was similar. Additional long-term studies indicate efficacy for prevention of manic relapse during maintenance treatment
(Tohen et al. 2004, 2005). Compared with valproate and haloperidol, some advantages were observed for olanzapine (Tohen
et al. 2003a, 2003b).
Benefit from olanzapine has been reported at daily dosages ranging from 2.5 to 30.0 mg. Olanzapine has been associated
with substantial weight gain, which limits its utility. Olanzapine has been associated with insulin resistance and metabolic
syndrome in patients with schizophrenia, at a level comparable to that found with clozapine, but less than other atypical
antipsychotics (Henderson et al. 2005).
Quetiapine
Quetiapine is effective in the treatment of acute mania as monotherapy and in combination with lithium or divalproex
sodium in controlled trials of up to 12 weeks’ duration. In two monotherapy studies ( n = 599), 48.1% of quetiapine-treated
subjects were considered responders (as defined by a 50% reduction in Young Mania Rating Scale scores) vs. 31.3% of
those on placebo by day 21 (P < 0.001). By 12 weeks, 66.8% of quetiapine-treated subjects were considered respondersPrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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versus 40.0% on placebo (P < 0.001) (unpublished data on file, AstraZeneca). The mean dosage of quetiapine in these trials
was 581 mg/day. One trial of adjunctive quetiapine added to lithium or sodium divalproex in acute mania found statistically
significant benefit for quetiapine compared with placebo, while another trial failed to find a difference. In the positive
adjunctive treatment trial, 54.3% of quetiapine-treated subjects were considered responders versus 32.6% of the
placebo-treated group at 3 weeks (P = 0.005) (Sachs et al. 2004). Patients with mixed episodes and with rapid cycling were
excluded from these trials.
The most common adverse effects of quetiapine are somnolence, weight gain, dry mouth, and dizziness. Weight gain greater
than 7% of body weight was found in 21% of quetiapine-treated subjects compared with 7% with placebo in the
monotherapy trial. Data regarding the relationship between quetiapine and metabolic syndrome and insulin resistance in
bipolar disorder are not available, but clinicians and patients should monitor weight gain and fasting glucose and lipids as
treatment response is measured.
Risperidone
In a well-powered placebo-controlled study, 1–6 mg/day of risperidone was superior to placebo for the acute treatment of
mania, with extrapyramidal symptoms as an expected adverse effect (Khanna et al. 2005). With regard to remission of
mania, 42% receiving risperidone and 13% receiving placebo achieved remission (Gopal et al. 2005). Risperidone was
superior to placebo and similar to haloperidol for mania or mixed mania when added to lithium or valproate (Sachs et al.
2002). The proportions that was rated as much or very much improved were 30%, 53%, and 50% for placebo, risperidone,
and haloperidol, respectively.
Hyperprolactinemia has been reported more frequently with risperidone than with other atypical antipsychotics. It is
appropriate to monitor women with menstrual irregularity or other clinical signs of increased prolactin.
Ziprasidone
Ziprasidone monotherapy (80 mg and 160 mg/day) was superior to placebo in a 3-week study of patients with manic or
mixed episodes (Keck et al. 2003b). The ziprasidone group had greater decreases in the Mania Rating Scale, with 50%
responding to ziprasidone and 35% responding to placebo. Ziprasidone resulted in greater frequency of side effects that
included somnolence, headache, dizziness, hypertonia, nausea, and akathisia. Neither ziprasidone nor placebo resulted in
weight increase. QTc intervals increased by a mean of 11 msec over baseline, but no increase was greater than 500 msec.
These results have been replicated (Potkin et al. 2005).
ANTIDEPRESSANT OPTIONS FOR TREATMENT-RESISTANT MOOD DISORDERS
The following reviews the evidence for treatment strategies—including augmentation, dose escalation, combination, and
switching treatments—that may be called for in the management of mood disorders that do not adequately benefit from the
first and subsequent treatment steps. Unfortunately, most of these data rely on open, uncontrolled case series.
Augmentation Strategies
Lithium Augmentation
Lithium augmentation is a commonly used strategy to manage treatment-resistant depression (Bauer and Dopfmer 1999;
Nierenberg and Cole 1991). A meta-analysis of nine placebo-controlled studies of lithium augmentation found that the
pooled odds ratio of response during lithium augmentation compared with the response during placebo treatment was 3.31
(95% confidence interval = 1.46–7.53) (Bauer and Dopfmer 1999). Few studies have been reported, however, that assess
the effectiveness of lithium augmentation, especially with regard to augmenting the modern generation of antidepressants,
and even fewer studies generate a cohort of treatment-resistant patients prospectively who are then randomized to receive
lithium plus the antidepressant or alternative augmentations. In a controlled prospective trial, lithium augmentation was
inferior to raising the dose of fluoxetine (Fava et al. 2002). Nierenberg et al. (2003) found that after a prospective trial of
nortriptyline for patients who had up to five treatments that failed, lithium augmentation was no better than placebo.
Although many patients can benefit from lithium augmentation, there is no clear dose–response relationship and no
standardized dosing recommendations for lithium augmentation of antidepressants. For lithium augmentation, it seems
reasonable to begin the lithium at 600 mg/day and expect a 4- to 6-week duration of the lithium trial before assuming lack
of efficacy. The efficacy of this strategy with the SSRIs and other newer antidepressants remains to be established.
In one placebo-discontinuation trial of lithium augmentation, 7 of 15 patients (47%) relapsed with placebo substitution
while none (0 of 14; 0%) relapsed while continuing on lithium over 4 months of follow-up (Bauer et al. 2000).
Thyroid Augmentation
The addition of thyroid hormone to an antidepressant in antidepressant nonresponders has been reported since the late
1960s. The highest success rate for thyroid hormone augmentation was 53% for T 3 compared with 19% for placebo (Joffe et
- 1993). By contrast, no difference was observed between T 3 25 micrograms/day and placebo added to a failed 4-week
trial of imipramine (mean dosage = 206 mg/day; mean imipramine + desipramine blood levels = 200 ng/dL) in 16 unipolar
depressed patients (Gitlin et al. 1987). No drug effect was detected, because all patients improved in the 4 weeks following
the imipramine trial.
A meta-analysis of four placebo-controlled trials of thyroid added to TCAs, however, showed that thyroid augmentation is no
more effective than placebo (Aronson et al. 1996). Case series and anecdotal reports, but not randomized controlled trials,
have been reported for thyroid augmentation of SSRIs (Crowe et al. 1990; Gupta et al. 1991; Joffe 1992).
Adverse effects associated with thyroid augmentation are typically minimal but may include increased anxiety, jitteriness,Print: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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tachycardia, insomnia, and sweating. In addition, thyroid hormones can increase atrial irritability and/or ventricular function
(rate, force, and velocity of contractions) and can potentially lead to high-output failure. Caution should be exercised when
giving thyroid hormone to patients with cardiac insufficiency or to elderly patients. Long-term treatment with high doses of
thyroid hormone has also been associated with an increased risk of osteoporosis.
The evidence for thyroid augmentation of antidepressants for unipolar depressed patients without hypothyroidism suggests
that some patients may benefit from this strategy. Studies to clarify the duration of an adequate acute trial and the utility of
maintenance therapy with this adjunct are needed.
Dopaminergic and Stimulant Augmentation
Dopamine has received less attention than either serotonin or noradrenaline in the pathogenesis and treatment of
depression, although preclinical and clinical evidence indicate that dopamine may have a role in the development of
depression (Kapur and Mann 1992). Furthermore, stimulants and dopaminergic agents may be useful antidepressants either
alone or as adjuncts for some depressed patients.
Dopaminergic Agents
Bromocriptine, piribedil, amantadine, and pramipexole are dopamine agonists used to treat Parkinson’s disease. Studies
have yet to be published on the use of pramipexole as an antidepressant augmentation, although one monotherapy trial
suggested some benefit for pramipexole over placebo (Corrigan et al. 2000).
Stimulants
No controlled trials of stimulants for treatment-resistant depression have been conducted.
Modafinil
Modafinil, a wakefulness-promoting agent approved for the treatment of narcolepsy that is not technically a dopaminergic
agent or a stimulant per se, has been studied as an antidepressant adjunct. Controlled studies found that modafinil was
better than placebo for patients with treatment-resistant depression (DeBattista et al. 2004) and for those with a partial
response to SSRIs who also had persistent fatigue (Fava et al. 2005).
Stimulants and dopaminergic agents may be effective as antidepressant adjuncts, but data from controlled studies are
lacking. Stimulants are best avoided in patients with a history of substance abuse, particularly cocaine. Patients should be
informed that there is an unlikely potential to develop tolerance with the usual antidepressant regimen but that stimulants
are a controlled substance associated with risk of abuse in other populations. The duration of treatment for depressed
patients who respond to dopaminergic and stimulant adjuvants remains to be determined.
Buspirone Augmentation
The only placebo-controlled study in refractory depression comparing buspirone against placebo augmentation did not reveal
any statistically significant difference in response rates between these two treatment groups (51% for buspirone vs. 47%
for placebo) (Landen et al. 1998).
Mirtazapine Augmentation
The use of mirtazapine 15–30 mg once a day at bedtime has been reported to be helpful in an open trial of augmentation of
SSRIs (Price et al. 1998). This finding was followed by a placebo-controlled trial that showed that adding the combination of
mirtazapine and an SSRI was better than adding placebo (Carpenter et al. 2002). Mirtazapine augmentation may also
manage SSRI-induced sexual dysfunction (Farah 1999). The main disadvantages of this strategy are sedation and the
potential for weight gain.
Atypical Antipsychotic Drug Augmentation
There are no published randomized, controlled trials of atypical antipsychotic drug augmentation of antidepressant
treatment in refractory depression, although open trial data suggest that further research be done in this area.
Summary of Augmentation Strategies
Although lithium is the best-studied augmentation strategy, no definitive algorithm based on controlled comparisons has
emerged to guide the clinician in the choice of an augmentation strategy. Selection of a sequence of agents typically reflects
the individual clinician’s preference. Moreover, no data are available on the commonly employed clinical strategy of
combining different augmenting agents in patients with refractory depression. Results from the clinical trials of
augmentation strategies for patients with treatment-resistant unipolar depression are compiled in Table 23–3.
Table 23–3. Clinical trials of augmentation strategies in unipolar depression
Antidepressant Investigators
N
Design Augmenting
agent
Daily dosage of
augmenting agent
Response rate Significantly greater
than seen with
placebo?
Lithium
TCA, mianserin Heninger et al.
1983
15 RCT Lithium 900–1,200 mg 5 of 8 (63%) Yes
TCA Cournoyer et al.
1984
12 RCT Lithium 900 mg ? YesPrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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Antidepressant Investigators
N
Design Augmenting
agent
Daily dosage of
augmenting agent
Response rate Significantly greater
than seen with
placebo?
TCA Kantor et al.
1986
7 RCT Lithium 900 mg 1 of 4 (25%) No
TCA Stein and Bernadt
1993
34 RCT Lithium 250 vs. 750 mg 6 of 34 (18%) vs.
15 of 34 (44%)
Yes, at higher dose
TCA Joffe et al. 1993 50 RCT Lithium 900 mg 9 of 17 (53%) Yes
TCA de Montigny et al.
1983
10 RCT Lithium 900 mg 5 of 5 (100%) Yes
SSRI Fava et al. 1994 41 RCT Lithium 300–600 mg 4 of 14 (29%) —
SSRI, TCA Katona et al.
1995
62 RCT Lithium
400 mg 15 of 29 (52%) Yes
SSRI Baumann et al.
1996
24 RCT Lithium 800 mg 6 of 10 (60%) Yes
TCA Browne et al.
1990
17 RCT Lithium 900–1,200 mg 3 of 7 (43%) No
Thyroid hormone (T3)
Imipramine Gitlin et al. 1987 16 RCT T3
25 g
—a
No
TCA Joffe et al. 1993 50 RCT T3
37.5 g 9 of 17 (53%) Yes
Buspirone
SSRI Landen et al.
1998
119 RCT Buspirone 20–60 mg 29 of 57 (51%) No
Note. TCA = tricyclic antidepressant; RCT = randomized clinical trial; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin
reuptake inhibitor; T3 = triiodothyronine; “—” indicates not applicable; “?” indicates not reported.
aResponse not measured in terms of percentage response/nonresponse, and no drug effect was observed.
Dosage Escalation Strategies
An alternative strategy is to use relatively high doses of antidepressant monotherapy. A double-blind study (Fava et al.
1994) showed that raising the dosage of fluoxetine to 40–60 mg/day was significantly more effective than adding
desipramine 25–50 mg/day or lithium 300–600 mg/day to fluoxetine 20 mg/day among patients who had not responded to
8 weeks of fluoxetine 20 mg/day. Therefore, it would appear that the use of high-dose SSRIs—which are safer than
high-dose TCAs—may serve in managing depressions that are resistant to lower doses.
This approach seems to challenge the assumption of the lack of a dose–response relationship with the SSRIs. However,
although a meta-analysis of the placebo-controlled studies with citalopram demonstrated that the dose–response curves
based on log odds ratios showed a very flat curve across the 20- to 60-mg range, similar to other SSRIs such as fluoxetine
and sertraline, there was evidence for a better response with a higher dosage (60 mg/day) in some subgroups of depressed
patients, such as those with severe depression (Montgomery 1995). Similarly, a 7- to 8-week multicenter randomized,
double-blind, placebo-controlled study involving 600 patients with MDD showed that fluvoxamine (50–150 mg/day) was
therapeutically effective and well tolerated during 6 weeks of therapy, but based on the Hamilton Rating Scale for
Depression (Ham-D) depressed mood item, efficacy was dose-dependent, with the minimum effective dosage being 50
mg/day. Therefore, even though fixed-dose trials do generally suggest the lack of a dose–response relationship with the
SSRIs, it seems plausible that some patients may benefit from a dosage increase.
Combination Strategies
The term combination strategy in resistant depression typically refers to the addition to an antidepressant of a compound
with well-established efficacy as a single agent in the treatment of depression. Neither SSRIs, venlafaxine, duloxetine, nor
clomipramine should ever be combined with MAOIs.
The strategy of combining different classes of antidepressants is a promising one. Results from the clinical trials of
combination strategies of MAOIs and TCAs or SSRIs and TCAs for patients with treatment-resistant unipolar depression are
compiled in Table 23–3. During the coming decade, clinical researchers will need to provide clinicians with controlled data
on the efficacy of these combination strategies to facilitate the development of more accurate algorithms in the treatment of
depressed patients who have undergone failed trials with monotherapy.
Switching Strategies
When patients do not benefit adequately from treatment with one antidepressant, a common clinical strategy is to switch
antidepressants. Results from the clinical studies of switching strategies for patients with treatment-resistant unipolar
depression are compiled in Table 23–4. Switching from a TCA to an SSRI or vice versa does not typically require washout but
rather a taper of the first antidepressant and initiation of the second one. When time is an issue, the new drug may be
started while tapering the first, although the period of overlap increases the possibility of drug interaction side effects.Print: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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Before switching to an MAOI, clinicians should wait at least 1 week after discontinuing either TCAs (with the exception of
protriptyline, which requires 3 weeks of washout) or atypical antidepressants and at least 2 weeks after discontinuing SSRIs
(with the exception of fluoxetine, which requires at least 5 weeks of washout). Clinicians switching patients from an MAOI
to an SSRI, a TCA, or an atypical antidepressant should wait at least 2 weeks before starting the second antidepressant.
When clinicians switch to an antidepressant of the same class, no washout is necessary, except for the change from
phenelzine to tranylcypromine.
Table 23–4. Clinical trials of switching strategies in unipolar depression
Investigators Failed
antidepressant
Switch drug
N
Design Daily dosage Response rate
MAOIs
McGrath et al.
1987
Imipramine or
phenelzine
Imipramine or
phenelzine
101 RCT; cross-over 60–90 mg phenelzine;
200–300 mg
imipramine
17 of 26 (65%)
phenelzine; 4 of 14
(29%) imipramine
Nolen et al. 1988b TCA Tranylcypromine 47 RCT 20–100 mg 13 of 25 (52%)
SSRIs
Nolen et al. 1988a TCA Fluvoxamine or
oxaprotiline
71 Double-blind,
partial cross-over
100–300 mg
fluvoxamine; 100–300
mg oxaprotiline
10% fluvoxamine; 39%
oxaprotiline
Kocsis et al. 1995 Imipramine or
sertraline
Sertraline or
imipramine
62 RCT; cross-over Up to 300 mg
imipramine; up to 200
mg sertraline
15 of 24 (63%)
sertraline; 18 of 38
(47%) imipramine
Other antidepressants
Catterson and
Preskorn 1996
Amitriptyline Mirtazapine 49 RCT; cross-over 15–45 mg 59% of nonresponders
Anticonvulsants and steroid-suppressing agents
Post et al. 1986 Unspecified
antidepressants
Carbamazepine 11 RCT 400–2,000 mg 5 of 11 (45%)
Note. MAOI = monoamine oxidase inhibitor; TCA = tricyclic antidepressant; SSRI = selective serotonin reuptake inhibitor; RCT =
randomized controlled trial.
Switching From SSRIs to TCAs
Even though the switch to TCAs has also been shown to be effective (response rate: 44%–47%) among SSRI nonresponders
in two large randomized and controlled crossover studies (Kocsis et al. 1995; Thase et al. 2002), the popularity of this
strategy has declined because of the improved safety profile of the newer agents.
Switching From TCAs to SSRIs
In a double-blind partial crossover study of 71 patients who had not responded to earlier treatment with TCAs, 10% of
patients treated with the SSRI fluvoxamine responded, in contrast to 39% of patients treated with the selective
norepinephrine reuptake inhibitor (SNRI) oxaprotiline (Nolen et al. 1988a). In an open study, 9 of 11 patients (82%) who
had not responded to desipramine responded to treatment with fluvoxamine. Sixty percent of patients unresponsive to a
prospective imipramine trial went on to respond to a switch to sertraline (Thase et al. 2002).
Switching to Bupropion
The main advantage of switching to bupropion is probably the reduced risk of weight gain and of sexual dysfunction. In fact,
Walker et al. (1993) found improved sexual functioning (and improved depression) upon switching to bupropion among 31
patients who had discontinued fluoxetine because of sexual side effects. An older study (Stern et al. 1983) found
improvement among patients treated with bupropion after nonresponse to TCAs. In that study, 33 outpatients with a history
of nonresponse or nonresponse plus intolerance to TCAs markedly improved after open treatment with the atypical
antidepressant bupropion (Stern et al. 1983).
Switching to Venlafaxine
Nierenberg et al. (1994) found a 30%–33% response among 84 consecutive patients with treatment-resistant depression
who had undergone at least three failed treatment trials. At lower doses, venlafaxine is more of an SSRI than an SNRI and
may work better in TCA nonresponders and MAOI nonresponders than among SSRI nonresponders (de Montigny et al.
1999), but at higher dosages (above 150 mg/day) it appears to be a true dual-uptake inhibitor. A Canadian multicenter
study by de Montigny et al. (1999) observed a 58% response to venlafaxine among 152 treatment-resistant depressed
patients, in further support of the findings by Nierenberg et al. (1994). Further controlled trials are needed.
TREATMENT-RESISTANT BIPOLAR DISORDER
Treatment of bipolar illness involves four primary goals: treatment of mania, treatment of depression, prevention of manic
recurrences, and prevention of depressive recurrences. The concept of treatment resistance is often applied to bipolar illness
when one or more of these goals are not achieved despite adequate treatment with lithium or another appropriatePrint: Chapter 23. Antidepressant and Antimanic Medications http://www.psychiatryonline.com/popup.aspx?aID=255452&print=yes…
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medication. Recurrence rather than sustained remission, even without treatment, is the rule for bipolar disorder. Many
patients diagnosed in adolescence could expect to have 10 or more acute episodes during their lifetimes (Fukuda et al. 1983;
Kraepelin 1921). Patients with bipolar I can spend about one-third, and those with bipolar II about one-half, of their time
with depressive symptoms (Altshuler et al. 2002; Joffe et al. 2004; Post et al. 2003a, 2003b).
Little is known about the treatment of refractory mood episodes in bipolar disorder, due in part to the limited data available
for the treatment of nonrefractory bipolar mood episodes. Given the increase in data regarding the treatment of mania and
the treatment of bipolar depression, it is likely that more studies of treatment-resistant bipolar disorder will be published.
Treatment-Refractory Mania
In case reports and open series, bipolar disorder refractory to antipsychotics, anticonvulsants, and lithium appears to
substantially improve with clozapine. Clozapine was reported to be beneficial for seven of seven patients with mixed
episodes (Suppes et al. 1992). Treatment was continued for 3–5 years, during which time patients made substantial
improvement in psychosocial functioning. In an open follow-up study, 38 subjects with treatment-refractory bipolar I
disorder or schizoaffective disorder, bipolar type, were randomly assigned to treatment as usual ( n = 19) or adjunctive
open-label clozapine (n = 19) and followed for 1 year (Suppes et al. 1999). The clozapine-treated patients showed
improvement on measures of mania, positive and negative symptoms, and overall improvement, but not on depression
scores.
Although it is unlikely that these findings will be replicated in rigorous double-blind studies, these encouraging results may
justify the use of clozapine for treatment-refractory bipolar disorder. Clozapine therapy carries significant risks and
limitations, including the need for weekly monitoring of white blood cell counts; the risk of agranulocytosis, seizures, and
drug interactions; and high cost. It is reasonable to reserve clozapine for patients unresponsive to other therapies.
Treatment-Refractory Bipolar Depression
A small effectiveness study conducted as part of the Systematic Treatment Enhancement Program for Bipolar Disorder
(STEP-BD) randomized patients (n = 66) who had continuing depression in spite of adequate trials of two consecutive
standard antidepressants to open-label treatment with adjunctive lamotrigine, risperidone, or inositol; an equipoise
randomization process allowed subjects to choose to be randomized to any pair of the study treatments (Nierenberg et al.
2006). Although no differences were found in primary pairwise comparisons, a secondary post hoc analysis found that 8
weeks of sustained recovery were seen in 23.8% of the lamotrigine-treated patients, 17.4% of inositol-treated patients, and
4.6% of risperidone-treated patients, suggesting that lamotrigine, added to antimanic treatment, is superior to inositol or
risperidone in this population.
Young et al. (2000) reported that depression that occurs despite ongoing adequate maintenance treatment responded just
as well to the addition of a second mood stabilizer (lithium or valproate) as it did to the addition of paroxetine. The rate of
affective switch was also equivalent for the two treatment groups in this small double-blind study. Some have suggested
that raising lithium levels in patients with breakthrough depression on lithium maintenance treatment enhances
antidepressive efficacy (Jann et al. 1982). The efficacy of increased lithium has not been prospectively studied, however,
and many cases remain refractory to high therapeutic lithium levels. Nemeroff et al. (2001) found, in a secondary analysis,
that subjects with lithium levels below 0.8 mEq/L responded to the addition of paroxetine (compared with imipramine or
placebo); because this was not studied prospectively, it is not clear that raising lithium levels treats breakthrough
depression.
Preliminary small double-blind, placebo-controlled studies suggest that pramipexole might have efficacy for
treatment-resistant bipolar depression (Goldberg et al. 2004; Zarate et al. 2004), but until this is studied in a larger sample,
it is difficult to recommend it.
Treatment-Refractory Rapid Cycling
In a double-blind study, rapid-cycling patients were stabilized on open-label lithium and divalproex sodium and then
randomized in a double-blind fashion to either lithium or divalproex and followed prospectively (Calabrese et al. 2005b).
There were no significant differences between groups in time to dropout or time to additional psychopharmacology.
Data from several studies show that the elimination of antidepressants from the treatment regimen may be the single most
successful intervention for rapid cycling. These data also suggest that antipsychotics may promote cycling. Some patients
improve when they discontinue antipsychotics. Discontinuation of antidepressants can have salutary effects on the cycle rate
of non-rapid-cycling bipolar illness. Reduction of stimulants (including caffeine) and bronchodilators (e.g., albuterol,
theophylline) also appears to be beneficial.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Mood Disorders and Treatment Approaches
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Understanding Mood Disorders
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History and Evolution of Treatment Approaches
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Introduction to Antidepressants
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Quiz on Mood Disorder Classifications
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Introduction to Antimanic Medications
Pharmacology of Antidepressants: Mechanisms and Applications
Exploring Antimanic Medications: Uses and Efficacy
Integrative Approaches: Combining Therapies for Optimal Outcomes
Conclusion and Future Directions in Mood Disorder Pharmacotherapy
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