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Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009

American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.443573. Printed 5/10/2009 from

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Chapter 54. Treatment of Bipolar Disorder

TREATMENT OF BIPOLAR DISORDER: INTRODUCTION

Bipolar disorder is a common, recurrent, often severe psychiatric illness that, without adequate

treatment, is associated with high rates of morbidity and mortality (Goodwin and Jamison 2007). In

the Global Burden of Disease survey, bipolar disorder was the sixth leading cause of disability

worldwide in 1990 and, without improved access to treatment, was projected to remain so well into

this century (Murray and Lopez 1996). Morbidity from bipolar disorder often extends well beyond

manic, hypomanic, mixed, and depressive episodes. Full recovery of functioning can lag many

months behind symptomatic improvement, and repeated episodes can lead to lasting functional

impairment (Judd et al. 2005). Recent naturalistic outcome studies indicate that many patients with

bipolar disorder spend protracted periods of time neither well nor syndromally ill but rather

suffering from chronic subsyndromal, especially depressive, symptoms (Judd et al. 2002, 2003).

Bipolar disorder is also among the most heritable of all medical illnesses (Goodwin and Jamison

2007).

The goals of treatment of bipolar disorder are similar to those of management of many chronic

illnesses: rapid, complete remission of acute episodes; prevention of further episodes; suppression

of subsyndromal symptoms; and optimization of functional outcome and quality of life (Keck et al.

2001). However, the treatment of bipolar disorder is often complicated. Although classified as a

mood disorder, bipolar disorder is also characterized by disturbances of behavior, cognition, and

perception. Thus, successful treatment requires that these multiple symptom domains be

addressed. Treatment is further complicated by the diversity of illness presentation (e.g., pattern,

frequency, and severity of episodes; presence of psychosis, comorbid illnesses, acute or chronic

environmental stressors) and course among individuals. Some medications have particular efficacy

in one phase of illness but not in another, and some may actually increase the likelihood of

precipitating a reciprocal mood episode.

The treatment of bipolar disorder has traditionally been divided into the management of acute

manic, mixed, and depressive episodes and the prevention of further episodes and symptoms

(Hirschfeld et al. 2002). Rush (1999) conceptualized a “strategies and tactics” approach to the

management of major depressive disorder, with principles of pharmacotherapy that are readily

applicable to bipolar disorder (Table 54–1). In this chapter we review strategies (i.e., what

treatments to choose) and tactics (i.e., how to implement these strategies once chosen and what

dose and duration of the chosen medication are to be used) for treating bipolar disorder, drawing

primarily on data from randomized, controlled trials. Where such data are lacking, strategies based

on data from open trials, naturalistic studies, and expert consensus guidelines are included. The

treatment of bipolar disorder in children and adolescents is covered elsewhere in this book (see

Chapter 63 in this volume, “Treatment of Child and Adolescent Disorders,” by Wagner and Pliszka).

TABLE 54–1. Treatment principles for bipolar disorder

Individually tailor guidelines.

Use proven treatments first.

Select best medication that is

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Easiest to use (for the patient).

Easiest to manage (for the physician).

Aim for symptom remission, not just response.

Measure symptomatic outcome.

Remember that no medication is a panacea.

Do not give up.

Recognize that psychosocial restoration follows symptom relief.

Interpersonal, family, educational, and social rhythm–targeted psychotherapies can help.

More chronic illness may respond more slowly.

Source. Adapted from Rush AJ: “Strategies and Tactics in the Management of Maintenance Treatment for

Depressed Patients.” Journal of Clinical Psychiatry 60 (Supplement 14):21–26, 1999.

FORMULATION AND IMPLEMENTATION OF A TREATMENT PLAN

Patients with bipolar disorder enter into treatment at various phases of illness. Regardless of

illness phase, treatment begins with a thorough diagnostic assessment (Hirschfeld et al. 2002). In

addition to the clinical features of bipolar disorder described in DSM-IV-TR (American Psychiatric

Association 2000), patients with bipolar disorder also commonly experience symptoms of anxiety,

impulsivity, recklessness, elevated libido, poor insight, inattention, and sensory hyperacuity during

manic or mixed episodes (Keck et al. 2001).

Bipolar disorder frequently presents with depressive episodes. A family history of bipolar disorder

or early age at onset of depression should raise diagnostic questions about bipolar disorder in an

individual presenting for treatment of depression. Studies suggest that 15%–30% of patients

treated for apparent major depressive disorder in outpatient settings subsequently receive a

diagnosis of bipolar I or II disorder (Manning et al. 1997, 1998). The Mood Disorder Questionnaire

(MDQ) is a 13-item self-report screening instrument for bipolar disorder that has been successfully

tested in psychiatric clinics (Hirschfeld et al. 2000) and in the general population (Hirschfeld 2002).

Bipolar disorder is associated with elevated rates of substance use, anxiety, eating,

attention-deficit/hyperactivity, and impulse-control disorders and migraine (Birmaher et al. 2002;

McElroy et al. 2001). Thus, the presence of these illnesses should be assessed in patients with

bipolar disorder, and conversely, bipolar disorder should be assessed in patients presenting with

these other illnesses. Other elements of a complete psychiatric evaluation are summarized in the

American Psychiatric Association’s (1995) “Practice Guideline for Psychiatric Evaluation of Adults.”

The American Psychiatric Association’s revised “Practice Guideline for the Treatment of Patients

With Bipolar Disorder” (Hirschfeld et al. 2002) lists a number of other important elements in the

treatment of patients with bipolar disorder (Table 54–2). Evaluation of safety of the patient and

others and determination of the appropriate treatment setting are essential because of the risks of

suicide, recklessness, and violence associated with mood episodes (Lopez et al. 2001) (Table

54–3). Establishing and maintaining a treatment alliance are early and ongoing goals to facilitate

patient and family education, treatment adherence, and identification of precipitants and prodromal

symptoms. Monitoring treatment response and providing illness education can be enhanced by

using the Life-Chart Method (Denicoff et al. 2002) or other similar longitudinal self-assessments. In

addition, a number of well-validated rating scales exist for monitoring mood symptoms in patients

with bipolar disorder cross-sectionally. These include the Young Mania Rating Scale (R. C. Young et

1. 1978) for manic symptoms and the Montgomery-Åsberg Depression Rating Scale (Montgomery

and Åsberg 1979) for depressive symptoms, among others. Because bipolar disorder can lead to

disability and varying degrees of functional impairment in all aspects of life, specific

psychotherapeutic and rehabilitation interventions may be needed.

TABLE 54–2. Clinical components of the management of bipolar disorderPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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Perform a diagnostic evaluation.

Evaluate the safety of the patient and others and determine a treatment setting.

Establish and maintain a therapeutic alliance.

Monitor treatment response.

Provide education to the patient and significant others.

Enhance treatment compliance.

Promote awareness of stress and regular patterns of activity and sleep.

Work with the patient to anticipate and address early signs of relapse.

Evaluate and manage functional impairments.

Source. Reprinted from Hirschfeld RMA, Bowden CL, Gitlin MJ, et al.: “Practice Guideline for the Treatment of

Patients With Bipolar Disorder (Revision).” American Journal of Psychiatry 159 (Supplement):1–50, 2002.

Copyright 2002, American Psychiatric Association. Used with permission.

TABLE 54–3. Characteristics to evaluate in an assessment of suicide risk in patients with bipolar

disorder

Presence of suicidal or homicidal ideation, intent, or plans

Access to means for suicide and the lethality of those means

Presence of command hallucinations, other psychotic symptoms, or severe anxiety

Presence of alcohol or substance use

History and seriousness of previous attempts

Family history of or recent exposure to suicide

Source. Adapted from American Psychiatric Association: “Practice Guideline for the Treatment of Patients With

Major Depressive Disorder (Revision).” American Journal of Psychiatry 157 (Supplement):1–45, 2000.

Copyright 2000, American Psychiatric Association; Hirschfeld RMA, Bowden CL, Gitlin MJ, Keck PE, Perlis RH,

Suppes T, Thase ME: “Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision).”

American Journal of Psychiatry 159 (Supplement):1–50, 2002. Copyright 2002, American Psychiatric

Association. Used with permission.

DEFINITIONS: WHAT IS A MOOD STABILIZER?

The treatment of bipolar disorder is among the most challenging of all treatments for psychiatric

illnesses for a variety of reasons, one of which is that some agents effective in the treatment of one

pole can exacerbate or cause a switch into another pole. Goodwin and Jamison (2007) have defined

mood stabilizer as an agent that demonstrates efficacy in the acute treatment of both mania and

depression, as well as in the prevention of both types of mood episodes (ideal definition) or an

agent that is efficacious in two of these three aspects of treatment (strict definition). In this

chapter, we use the term mood stabilizer according to the strict definition. To date, there is no ideal

agent, although data from randomized, controlled trials suggest that lithium and olanzapine

probably come closest.

TREATMENT OF ACUTE BIPOLAR MANIC AND MIXED EPISODES

Manic and mixed episodes are medical emergencies and frequently require treatment in a hospital

to ensure safety of patients and those around them. The primary goal of treatment of manic and

mixed episodes is rapid symptom reduction, followed by full remission of symptoms and restoration

of psychosocial and vocational functioning (Hirschfeld et al. 2002). These are straightforward goals,

but tailoring treatment to specific patients requires consideration of presenting symptoms and their

severity (e.g., presence or absence of psychosis, manic or mixed episode, proximal frequency of

episodes).Print: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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Pharmacotherapy is the cornerstone of treatment of acute manic and mixed episodes and of bipolar

disorder in general. A number of medications have demonstrated efficacy in the treatment of acute

manic and mixed episodes (Table 54–4). Lithium, divalproex, carbamazepine, olanzapine,

risperidone, quetiapine, ziprasidone, aripiprazole, haloperidol, and chlorpromazine have shown

efficacy as monotherapy in the treatment of acute mania in randomized, placebo-controlled trials

(McElroy and Keck 2000; Perlis et al. 2006c). Although these agents typically produce rates of

response (defined as 50% reduction in manic symptoms from baseline to endpoint) of

approximately 50% in short-term (3- to 4-week) trials, relatively few patients (<25%) actually

achieve remission of symptoms within these time intervals while receiving monotherapy with any

of these agents. Thus, use of combination therapy is common in clinical practice to improve

response and remission rates (Suppes et al. 2005). For example, a number of studies comparing

combination treatment with an antipsychotic and lithium or valproate demonstrated superior acute

response rates with combination therapy compared with monotherapy (Scherk et al. 2007).

TABLE 54–4. Evidence-based treatment of acute mania

Treatment Number of positive monotherapy RCTs

Lithium 18

Valproate 9

Carbamazepine 2

Aripiprazole 5

Olanzapine 8

Quetiapine 4

Risperidone 5

Ziprasidone 3

Chlorpromazine 4

Haloperidol 3

ECT 3

Note. ECT = electroconvulsive therapy; RCTs = randomized, controlled trials.

Lithium

Lithium has been a mainstay of treatment for acute mania for more than 50 years, with superior

efficacy compared with placebo (Goodwin et al. 1969; Maggs 1963; Schou et al. 1954; Stokes et al.

1971) and comparable efficacy compared with divalproex (Bowden et al. 1994), carbamazepine

(Lerer et al. 1987; Small et al. 1991), risperidone (Segal et al. 1998), olanzapine (Berk et al. 1999),

quetiapine (Bowden et al. 2005), aripiprazole (Keck et al. 2007), and typical antipsychotics

(Garfinkel et al. 1980; Johnson et al. 1976; Platman 1970; Prien et al. 1972; Shopsin et al. 1975;

Spring et al. 1970; Takahashi et al. 1975). Lithium exerted improvement in psychotic as well as

manic symptoms in these trials. Patients with elated or classic manic symptoms (Bowden 1995)

and relatively few lifetime mood episodes (Swann et al. 1999) appear to have better response rates

to lithium than do patients with mixed episodes, rapid cycling (Dunner and Fieve 1974; McElroy et

1. 1992), and numerous prior mood episodes.

Lithium response for acute mania can be maximized by titrating to plasma concentrations at the

upper end of the therapeutic range (1.0–1.4 mmol/L) as tolerated (Stokes et al. 1976). In

randomized, controlled trials, significant clinical improvement usually was reported within 7–14

days among responders (Keck and McElroy 2001). Preliminary data also suggest that the rate of

lithium titration may affect response. Goldberg et al. (1998) found that the rapidity of antimanic

effect of any mood stabilizer (lithium, valproate, carbamazepine) was proportional to the rate of

titration to therapeutic plasma concentrations. Lithium is generally well tolerated during acutePrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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treatment, and dosages needed to produce acute antimanic effects may be higher than those

needed for maintenance treatment (Bowden 1998). Common side effects associated with acute

treatment with lithium include nausea, vomiting, tremor, somnolence, weight gain, and cognitive

slowing.

Antiepileptics

Divalproex

Divalproex and related formulations of valproic acid had superior efficacy compared with placebo

(Bowden et al. 1994, 2006; Brennan et al. 1984; Emrich et al. 1981; Pope et al. 1991) and

comparable efficacy compared with lithium (Bowden et al. 1994; T. W. Freeman et al. 1992),

haloperidol (McElroy et al. 1996), and olanzapine (Zajecka et al. 2002) in randomized, controlled

acute treatment trials of bipolar manic or mixed episodes. Olanzapine was superior to divalproex in

mean reduction of manic symptoms and in proportion of patients in remission at study completion

in a second head-to-head comparison trial (Tohen et al. 2002a). Muller-Oerlinghausen et al. (2000)

found that the combination of valproate and typical antipsychotics produced significantly lower

mean antipsychotic doses and higher response rates compared with placebo added to typical

antipsychotics in patients with acute mania.

Unlike lithium, valproate has a comparatively wide therapeutic index. Acute antimanic response is

correlated with plasma concentrations between 50 and 125 mg/L, with some evidence of greater

response at the upper end of the therapeutic range (Allen et al. 2006; Zajecka et al. 2002). Some

patients may require plasma concentrations greater than 125 mg/L, but side effects become

progressively more prevalent above this level. Divalproex can be administered at a therapeutic

starting dosage of 20–30 mg/kg/day in inpatients with good tolerability, and some evidence

indicates a more rapid response than with gradual titration from a lower (e.g., 750 mg/day)

starting dose (Hirschfeld et al. 1999; Keck et al. 1993; McElroy et al. 1996; Zajecka et al. 2002).

Divalproex is generally well tolerated during treatment of acute manic or mixed episodes. Common

side effects include somnolence, nausea, vomiting, tremor, weight gain, and cognitive slowing.

Enteric-coated and extended-release formulations (the latter requiring a 20% dosage increase to

yield plasma concentrations equivalent to those with immediate-release formulations) have

improved tolerability compared with valproic acid formulations. Rare serious adverse events

include pancreatitis, thrombocytopenia, significant hepatic transaminase elevation,

hyperammonemic encephalopathy in patients with urea cycle disorders, and hepatic failure.

Carbamazepine and Oxcarbazepine

Until recently, there was a paucity of data from well-designed randomized, controlled trials of

carbamazepine in the treatment of mania. However, an extended-release formulation of

carbamazepine was superior to placebo in two large randomized, placebo-controlled multicenter

trials (Weisler et al. 2004b, 2005). These findings replicated earlier results from a

placebo-controlled crossover trial (Ballenger and Post 1978) and comparison studies against

lithium (Lerer et al. 1987; Small et al. 1991) and chlorpromazine (Grossi et al. 1984; Okuma et al.

1979). In one small comparison study, valproate was more effective than carbamazepine (Vasudev

et al. 2000). Common side effects of carbamazepine include diplopia, blurred vision, ataxia,

somnolence, fatigue, and nausea. Less common side effects include rash, mild leukopenia and

thrombocytopenia, and hyponatremia. Rare serious adverse events include agranulocytosis, aplastic

anemia, thrombocytopenia, hepatic failure, pancreatitis, and exfoliative dermatitis.

Oxcarbazepine, in contrast to carbamazepine, does not induce its own metabolism, has a lower rate

of side effects, and generally has good tolerability (Emrich 1991). Two small randomized, controlled

trials of oxcarbazepine in acute mania found oxcarbazepine to be comparable in efficacy to

haloperidol and lithium (Emrich 1991; Muller and Stoll 1984). However, both trials were

confounded by the use of adjunctive antimanic medications during the trials, and the studies were

too small to detect potential differences in efficacy. In the only large randomized,Print: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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placebo-controlled multicenter trial of oxcarbazepine in acute mania to date, a 7-week study in

children and adolescents, oxcarbazepine was not superior to placebo in reduction of manic

symptoms (Wagner et al. 2006). Thus, the use of oxcarbazepine in acute bipolar mania has not

been substantiated based on evidence from clinical studies but rather is based on putative

similarities in mechanism of action with carbamazepine and improved tolerability.

Antipsychotics

Typical (First-Generation) Antipsychotics

Chlorpromazine (Klein 1967) and haloperidol (McIntyre et al. 2005) were superior to placebo in

randomized, controlled trials. Typical antipsychotics bear the burden of neurological and

neuroendocrinological side effects and may increase the risk of postmanic depressive episodes

(Koukopoulos et al. 1980). Thus, typical antipsychotics are commonly regarded as antimanic but

not mood-stabilizing agents.

Atypical (Second-Generation) Antipsychotics

The atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole all

have demonstrated efficacy in the treatment of acute bipolar mania in at least two randomized,

placebo-controlled trials.

Olanzapine was found to be superior to placebo (Tohen et al. 1999, 2000), superior or equal in

efficacy to divalproex (Tohen et al. 2002a; Zajecka et al. 2002), and comparable to lithium (Berk et

1. 1999; Niufan et al. 2007), risperidone (Perlis et al. 2006a), and haloperidol (Tohen et al. 2003a)

in mean reduction of manic and mixed symptoms in 3- to 4-week monotherapy trials. Adjunctive

treatment with olanzapine was superior to placebo in patients who were inadequately responsive to

lithium or divalproex monotherapy (Tohen et al. 2002b).

In the haloperidol comparison trial, olanzapine was significantly more likely to improve depressive

symptoms during the treatment of manic and mixed episodes (Tohen et al. 2003a). In the two

placebo-controlled trials, the rate of response was faster with an initial starting dosage of 15

mg/day (Tohen et al. 2000) compared with 10 mg/day (Tohen et al. 1999). Baker et al. (2003)

reported significant improvement in agitation in manic patients within 24 hours with the use of

rapid initial dosage escalation (20–40 mg/day) compared with usual titration. The intramuscular

formulation of olanzapine has also been studied in the treatment of manic agitation (Meehan et al.

2001). In this study, an intramuscular olanzapine dose of 10 mg produced significant improvement

compared with placebo and numerically greater improvement compared with intramuscular

lorazepam 2 mg at 2 hours following administration. From these studies, it appears that acute

antimanic response to olanzapine may be more rapid in patients treated with higher initial doses,

with dosage administration in proportion to the degree of psychomotor agitation. In short-term

studies, the most common side effects associated with olanzapine were somnolence, constipation,

dry mouth, increased appetite, weight gain, and orthostatic hypotension.

Risperidone was superior to placebo (Hirschfeld et al. 2004; Khanna et al. 2005) and comparable to

olanzapine (Perlis et al. 2006a), haloperidol (Smulevich et al. 2005), and lithium (Segal et al. 1998)

in mean reduction of manic and mixed symptoms as monotherapy in 3- to 4-week trials.

Risperidone was superior to placebo as adjunctive therapy with lithium or divalproex in one

placebo-controlled trial (Sachs et al. 2002), but not in a second placebo-controlled trial in

combination with lithium, divalproex, or carbamazepine (Yatham et al. 2003). However, because

this latter study included patients receiving carbamazepine, it is possible that risperidone plasma

concentrations may have been significantly reduced in these patients, limiting risperidone’s

efficacy. The rate of extrapyramidal side effects associated with risperidone was low when the drug

was administered at average dosages up to 4 mg/day (Hirschfeld et al. 2004; Sachs et al. 2002;

Yatham et al. 2003) but not when administered at average dosages of 6 mg/day or greater (Khanna

et al. 2005; Segal et al. 1998). In short-term trials, other commonly occurring side effects included

prolactin elevation, akathisia, somnolence, dyspepsia, and nausea.Print: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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Quetiapine was superior to placebo as monotherapy in two 12-week studies in adult patients

(Bowden et al. 2005; McIntyre et al. 2005) and was comparable to lithium in a 4-week study in

adult patients (Li et al. 2008) and to divalproex in adolescents with bipolar mania (DelBello et al.

2006). Similarly, quetiapine was superior to placebo as adjunctive treatment with lithium or

divalproex (DelBello et al. 2002; Sachs et al. 2004; Yatham et al. 2004). In two placebo-controlled

trials, lithium (Bowden et al. 2005) and haloperidol (McIntyre et al. 2005) were included as active

comparators. There were no significant differences in efficacy among patients receiving quetiapine,

lithium, or haloperidol, although the trials were not powered to detect such a difference if one

existed. The mean modal dose of quetiapine associated with antimanic efficacy in most studies was

approximately 600 mg/day (Vieta et al. 2005b). The most common side effects from quetiapine in

monotherapy trials were headache, dry mouth, constipation, weight gain, somnolence, and

dizziness.

Ziprasidone was superior to placebo (mean dose 120–130 mg/day) in two 3-week monotherapy

trials in adult patients (Keck et al. 2003b; Potkin et al. 2005) and comparable to haloperidol in a

12-week trial (Ramey et al. 2003). Ziprasidone was not superior to placebo as adjunctive treatment

with lithium in a study designed to prove superior onset of action by 2 weeks of treatment (Weisler

et al. 2004a). However, ziprasidone was superior to placebo in reduction of manic symptoms at day

4 in this adjunctive trial. Ziprasidone appears to have dose-related antimanic efficacy within the

therapeutic range of 80–160 mg/day. Ziprasidone-related side effects in monotherapy trials

included headache, somnolence, extrapyramidal signs, akathisia, and dizziness. The intramuscular

(IM) formulation of ziprasidone has also been studied in the treatment of manic agitation (Daniel et

1. 2001; Lesem et al. 2001). In these studies, ziprasidone 10–20 mg IM produced significant

improvement compared with ziprasidone 2 mg IM at 0.5–4 hours following administration.

Aripiprazole had significantly greater efficacy in the reduction of manic symptoms compared with

placebo in three 3-week trials (Keck et al. 2003a, 2007; Sachs et al. 2006) and comparable efficacy

with haloperidol (Vieta et al. 2005a) and lithium (Keck et al. 2009) in adequately powered 12-week

comparison trials. Aripiprazole was initiated at 15 or 30 mg/day. Common side effects associated

with aripiprazole in the placebo-controlled trials were headache, nausea, vomiting, constipation,

insomnia, and akathisia.

In the studies of atypical antipsychotics reviewed above, there were no significant differences in

response between patients with or without psychotic features or between patients with manic or

mixed episodes among all agents, with the exception of trials of quetiapine, many of which

excluded mixed patients. Lastly, the prototypical atypical agent clozapine has been reported to

have substantial efficacy in a number of large case series of patients with treatment-refractory

mania (Calabrese et al. 1996; Green et al. 2000) but has not been studied in placebo-controlled

trials in mania.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is an important treatment option for manic patients with severe,

psychotic, or catatonic symptoms. ECT was superior in efficacy to lithium (Small et al. 1988) and

the combination of lithium and haloperidol (Mukherjee et al. 1994) in prospective comparison

studies. In the lithium comparison trial (Small et al. 1988), the presence of depressive symptoms at

baseline was the strongest predictor of ECT response. In addition, ECT in combination with

chlorpromazine was superior to sham ECT and chlorpromazine (Sikdar et al. 1994). Although these

were small studies, their findings are consistent with those of other naturalistic studies of ECT in

the treatment of acute mania (Black et al. 1984; Thomas and Reddy 1982). There is a risk of

neurotoxicity in patients receiving ECT while also receiving lithium; thus, lithium should be

discontinued when ECT is administered (Hirschfeld et al. 2002).

Psychotherapy

Psychotherapeutic interventions in patients with acute mania focus on establishing and maintaining

a therapeutic alliance, improving insight, monitoring treatment response, and providing the initialPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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elements of education about bipolar disorder and its manifestations to patients and their families

(Hirschfeld et al. 2002). As manic symptoms remit, more attention can be paid to further education,

promoting awareness of stressors and sleep hygiene, identifying harbingers of relapse, and

assessing need for rehabilitation services.

Novel Treatments

The new atypical antipsychotics paliperidone, asenapine, and bifeprunox and new antiepileptics

such as zonisamide, levetiracetam, and acamprosate are being studied as potential antimanic

agents. Among these agents, the only randomized, controlled trial reported to date compared

asenapine (mean dosage = 18 mg/day), olanzapine (mean dosage = 16 mg/day), and placebo over

3 weeks (Hirschfeld et al. 2007). Both treatment groups displayed comparable reductions in manic

symptoms, and both were superior to placebo. By contrast, a number of potential antimanic agents

have not demonstrated convincing efficacy in randomized, controlled trials. These include

gabapentin (Frye et al. 2000; Pande et al. 2000), lamotrigine (Anand et al. 1999; Frye et al. 2000),

topiramate (Kushner et al. 2006), and verapamil (Janicak et al. 1998; Walton et al. 1996).

In two short-term pilot trials, the protein kinase C inhibitor tamoxifen was superior to placebo in

reduction of manic symptoms (Yildiz-Yesiloglu 2007; Zarate et al. 2007). The benzodiazepines

lorazepam and clonazepam have been studied in a number of randomized, controlled trials in acute

mania (Chou et al. 1999) but have not been demonstrated to exert specific antimanic effects.

Nevertheless, adjunctive use of benzodiazepines to treat anxiety, insomnia, and agitation in manic

patients is often therapeutic.

Monotherapy Versus Combination Therapy of Acute Bipolar Manic and

Mixed Episodes

The data reviewed above provide evidence of the efficacy of specific agents administered for

adequate treatment trials at therapeutic doses (Table 54–5). Monotherapy with an antimanic agent

represents one of two initial options, primarily for patients with less severe manic symptoms.

However, combination therapy has generally been demonstrated to have greater and more rapid

efficacy than monotherapy (Scherk et al. 2007). Combination therapy may be a particularly useful

option in patients with severe manic symptoms or psychosis.

TABLE 54–5. Criteria for minimum adequate trials of antimanic agents

Medication Definitive (3-week trial) Probable (2-week trial)

Lithium

0.8 mmol/L

0.7 mmol/L

Valproate

75 g/mL

50 g/mL

Carbamazepine

800 mg/day

600 mg/day

Haloperidol

0.2 mg/kg/day

0.1 mg/kg/day

Chlorpromazine

500 mg/day

300 mg/day

Olanzapine

15 mg/day

10 mg/day

Ziprasidone

120 mg/day

80 mg/day

Risperidone

5 mg/day

4 mg/day

Quetiapine

600 mg/day

400 mg/day

Aripiprazole

30 mg/day

15 mg/day

Source. Adapted from Keck PE Jr, McElroy SL: “Definition, Evaluation, and Management of Treatment

Refractory Mania.” Psychopharmacology Bulletin 35:130–148, 2001. Copyright 2001, MedWorks Media. Used

with permission.

To date, mainly combinations of antipsychotics in conjunction with lithium, valproate, and/or

carbamazepine have been studied. The efficacy of combinations of lithium, valproate, or

carbamazepine versus monotherapy with these agents has not been studied in randomized,Print: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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controlled trials, although anecdotal evidence suggests that these combinations may have greater

efficacy than either agent alone (M. P. Freeman and Stoll 1998). Similarly, there are no data to date

to suggest that other than standard therapeutic doses of agents used in combination therapy are

needed.

TREATMENT OF ACUTE BIPOLAR DEPRESSIVE EPISODES

For many patients with bipolar disorder, depressive episodes or chronic waxing and waning

subsyndromal depressive symptoms dominate their course of illness and constitute a major source

of disability (Judd et al. 2002, 2003; Perlis et al. 2006b). In addition, suicide is a substantial risk of

untreated bipolar depression. Thus, the goal of treatment of bipolar depression is full remission of

symptoms (Hirschfeld et al. 2002). This straightforward goal is complicated by the limited efficacy

of many mood stabilizers in bipolar depression (Zornberg and Pope 1993), often requiring the

adjunctive use of unimodal antidepressants with the attendant risk of cycle acceleration or

switching (Table 54–6). Moreover, there are very little data indicating that the addition of

antidepressants to mood stabilizers is more effective than utilization of mood stabilizers alone in

alleviating acute bipolar depressive symptoms (Sachs et al. 2007). To date, only quetiapine and

combination olanzapine–fluoxetine have indications for the treatment of acute bipolar I depression.

TABLE 54–6. Evidence-based treatment of acute bipolar I depression

Treatment Number of positive RCTs

Monotherapy

Quetiapine 2

Lamotrigine 2

Olanzapine 1

Lithium 8

Divalproex 1

Carbamazepine 2

Combination therapy

Olanzapine–fluoxetine 1

Note. RCTs = randomized, controlled trials.

Special Considerations in Bipolar Depression

Antidepressants and the Problem of Switching

The decision to recommend administration or avoidance of antidepressants often means attempting

to walk a therapeutic razor’s edge between alleviating depression and triggering mood switching.

Thus, recent data regarding the protective effect of mood stabilizers against

antidepressant-associated switching and the incidence of switching among antidepressants are

important to weigh in these decisions. Until recently, most treatment guidelines recommended

avoiding antidepressants and relying on mood stabilizers alone in mild to moderate bipolar

depression, and when administering antidepressants for severe or persistent bipolar depression,

they recommended withdrawing them as quickly as possible after remission (Ghaemi et al. 2001;

Sachs et al. 2000). These recommendations were based on reported antidepressant-associated

switch rates, which ranged widely, from 10% to 70% (Thase and Sachs 2000).

Many estimates of the incidence of antidepressant-associated switching were based on naturalistic

studies that did not control for the switch rate associated with the illness itself. The switch rates

reported in recent randomized, controlled acute treatment (i.e., 6–8 weeks) trials of lamotrigine

(Calabrese et al. 1999), quetiapine (Calabrese et al. 2005a; Thase et al. 2006), and olanzapine

monotherapy (Tohen et al. 2003c) and of combinations of paroxetine with lithium (Nemeroff et al.Print: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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2001), lithium with valproate (L. T. Young et al. 2000), and fluoxetine with olanzapine (Tohen et al.

2003c) ranged from 3% to 8%. In addition, Post et al. (2001) reported a switch rate of 14% (8%

hypomania, 6% mania) in a 10-week acute treatment trial comparing bupropion, venlafaxine, and

sertraline in combination with mood stabilizers. The switch rate with venlafaxine was significantly

higher than that with the other agents (Post et al. 2006), a finding consistent with an earlier report

by Vieta et al. (2002), who also found a higher switch rate in patients receiving venlafaxine

compared with paroxetine. Thus, with newer antidepressant medications administered in

conjunction with mood stabilizers, switch rates appear to be low (Peet and Peters 1995), although

switch rates may be slightly higher with dual serotonin and norepinephrine reuptake inhibitors such

as venlafaxine. These data are also consistent with the results of several naturalistic studies that

found that concomitant administration of mood stabilizers with antidepressants cut the risk of

switching by about half (Boerlin et al. 1998; Bottlender et al. 2001). The risk of switching appears

to be greater in patients with bipolar I depression than in those with bipolar II depression

(Altshuler et al. 2006).

Mood Stabilizers as Antidepressants

Most randomized, controlled trials of bipolar depression involved patients with bipolar I disorder.

When bipolar II patients were included, their response usually was not reported separately, except

in the quetiapine trials, in which quetiapine was superior to placebo in reduction of depression

symptoms in both bipolar I and II patients (Calabrese et al. 2005a; Thase et al. 2006). It is not

clear whether patients with bipolar II depression require treatment with a mood stabilizer (Thase

and Sachs 2000), although most recommendations suggest that mood stabilizers also form the

cornerstone of treatment for patients with bipolar II disorder. Treatment with a mood-stabilizing

medication, if a patient is not already receiving one, is usually the first-line treatment for bipolar

depression, because the inherent risk of switching is likely to be less with a mood stabilizer alone

than with an antidepressant alone or with a combination of a mood stabilizer and antidepressant.

Lithium

Eight of nine placebo-controlled trials conducted in the 1960s and 1970s in patients with bipolar I

and II disorders found lithium superior to placebo in acute bipolar depression (reviewed in

Zornberg and Pope 1993). In an analysis of five studies in which it was possible to distinguish

“unequivocal” lithium responders from patients who displayed partial but incomplete improvement

in depression, Zornberg and Pope (1993) found that 36% had an unequivocal response, compared

with 79% who had at least partial benefit. The antidepressant efficacy of lithium also was

examined in two studies of paroxetine added to mood stabilizers for bipolar depression (Nemeroff

et al. 2001; L. T. Young et al. 2000). Nemeroff et al. (2001) found that patients receiving lithium at

plasma concentrations greater than 0.8 mEq/L showed no antidepressant benefit from the addition

of paroxetine or imipramine compared with placebo. In contrast, patients receiving lithium at

concentrations less than or equal to 0.8 mEq/L showed significant antidepressant benefit from the

addition of paroxetine compared with placebo. These data confirm earlier impressions that

maximizing lithium levels in patients already receiving lithium, or titrating to levels greater than

0.8 mEq/L when initiating lithium, is important to ensure an adequate trial of lithium for bipolar

depression. L. T. Young et al. (2000) found that adding an alternative mood stabilizer (lithium or

valproate) to the regimen of patients receiving therapeutic doses of a mood stabilizer but

experiencing breakthrough depressive episodes was as effective as adding the antidepressant

paroxetine. Although this study was too small (N = 27) to detect drug–drug differences in efficacy,

the mood stabilizer–mood stabilizer combination was not as well tolerated as the mood

stabilizer–antidepressant combination, and the only patient who switched did so during this

treatment arm.

Atypical Antipsychotics

Quetiapine

Quetiapine (300 mg and 600 mg/day) was superior to placebo in reduction of depressive symptomsPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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in two large 8-week multicenter trials involving outpatients with bipolar I and II depression

(Calabrese et al. 2005a; Thase et al. 2006). Patients receiving quetiapine also demonstrated

greater improvement in secondary measures of sleep and anxiety compared with patients receiving

placebo. There was no significant difference in efficacy between the two quetiapine dosage groups.

However, the rate of side effects was lower in the 300 mg/day groups compared with the 600

mg/day groups. Switch rates were low (3%–4%) across all treatment groups and were not

significantly different among the quetiapine and placebo groups.

Olanzapine and Olanzapine–Fluoxetine Combination

Olanzapine and the combination of olanzapine and fluoxetine (OFC) were superior to placebo in

reducing depressive symptoms in an 8-week trial of 833 patients with bipolar I depression (Tohen

et al. 2003c). However, the OFC was superior not only to placebo throughout the trial but also to

olanzapine for weeks 4–8. There were no significant differences in switch rates (6%–7%) among

the three groups. Brown et al. (2006) compared OFC with lamotrigine (titrated to 200 mg/day) in a

7-week comparison trial in outpatients with bipolar I depression. Patients receiving OFC displayed

greater reduction in depressive symptoms compared with patients receiving lamotrigine, although

the lamotrigine group may have had a greater response with a longer trial, given the need for

gradual lamotrigine titration. Switch rates were not significantly different between the two groups.

Antiepileptics

Lamotrigine

In an initial large 7-week randomized, placebo-controlled trial, lamotrigine (at 50 mg/day and 200

mg/day) was superior to placebo in patients with bipolar I depression (Calabrese et al. 1999).

Switch rates (3%–8%) were not significantly different among the three groups. A second large

placebo-controlled, parallel-group, flexible-dose trial involving patients with bipolar I and II

depression did not find a significant advantage for lamotrigine over placebo (Bowden 2001).

However, in a post hoc analysis, lamotrigine was superior to placebo in bipolar I patients. Frye et

1. (2000) found lamotrigine superior to placebo in improving depression in a double-blind

crossover trial in patients with treatment-refractory rapid-cycling bipolar I and II disorders.

Lamotrigine was superior to placebo when added to lithium in an 8-week trial in patients with

breakthrough depressive episodes (van der Loos and Nolen 2007). Common side effects of

lamotrigine in these studies included headache, nausea, infection, and xerostomia. The risk of

serious rash from lamotrigine can be reduced by carefully adhering to Physicians’ Desk

Reference–recommended titration schedules, but patients should be warned of the risk of rash and

the need to report it immediately.

Carbamazepine

In two small controlled trials of patients with treatment-refractory bipolar depression, response to

carbamazepine was superior to placebo (Post et al. 1986) and lithium (Small 1990). The results of

these initial intriguing findings have not been followed up by large placebo-controlled,

parallel-group trials.

Divalproex

Two small randomized, placebo-controlled trials of divalproex in the treatment of acute bipolar

depression yielded opposite findings. Sachs and Collins (2001) did not find divalproex to be

superior to placebo in one pilot trial, whereas Davis et al. (2005) found divalproex superior to

placebo in reduction of depressive and anxiety symptoms in a later pilot study. As with

carbamazepine, the results of these initial findings have not been followed up by large

placebo-controlled, parallel-group trials.

Antidepressants

There is a relative dearth of randomized, controlled trials of antidepressants as monotherapy or in

combination with mood stabilizers in bipolar depression (Ghaemi et al. 2001). Thase and SachsPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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(2000, p. 558) emphasized that “not a single antidepressant medication, nor even a particular class

of antidepressant, has been demonstrated to be effective in at least two adequately powered,

placebo-controlled clinical trials.” Thus, with a thin evidence base, current recommendations

regarding the use of antidepressants in conjunction with mood stabilizers for acute bipolar I

depression tend toward the conservative (i.e., avoid antidepressants if possible). However, some

general impressions can be gleaned from the available clinical trials. First, switch rates of newer

antidepressants in short-term trials, in general, appear to be lower than those associated with

tricyclic antidepressants (TCAs) in older studies (Thase and Sachs 2000). Second, among all of the

antidepressants studied, the most substantial evidence for efficacy rests with the monoamine

oxidase inhibitor (MAOI) tranylcypromine (Himmelhoch et al. 1991), but safety concerns often

eliminate this agent from first-line therapy choices (Hirschfeld et al. 2002). Bupropion (Sachs et al.

1994) and selective serotonin reuptake inhibitors (SSRIs) (Nemeroff et al. 2001; L. T. Young et al.

2000) are common first-line agents administered in conjunction with mood stabilizers.

Electroconvulsive Therapy

ECT had significantly greater efficacy than MAOIs, TCAs, or placebo in several randomized,

controlled trials in patients with bipolar depression (reviewed in Zornberg and Pope 1993). ECT

may be particularly indicated for patients with severe, psychotic, or catatonic symptoms.

Psychotherapy

There are very few randomized, controlled trials of any form of psychotherapy for patients with

acute bipolar depression. Cognitive-behavioral and interpersonal therapy have demonstrated

efficacy in the treatment of unipolar major depression, but these modalities have been examined

only in very small preliminary studies in patients with bipolar depression, thus far without

conclusive findings (Cole et al. 2002; Zaretsky et al. 1999).

Novel Treatments

As in the treatment of acute bipolar manic and mixed episodes, there is considerable interest in the

potential efficacy of new atypical antipsychotics and antiepileptic agents in the treatment of acute

bipolar depression. With the exceptions of olanzapine, quetiapine, aripiprazole, lamotrigine, and

gabapentin, these agents have not yet been well studied in randomized, controlled trials in the

depressed phase of the illness. In two placebo-controlled trials, aripiprazole-treated patients did

not display significantly greater improvement in depressive symptoms compared with patients

receiving placebo at the 8-week study endpoint (Thase et al. 2008). Shelton and Stahl (2004)

conducted a small pilot study comparing adjunctive treatment with risperidone, paroxetine, or the

combination added to a mood stabilizer in outpatients with bipolar I or bipolar II depression. There

were no significant differences in efficacy among the three treatment groups, but the study was

limited by its small sample size (N = 30). McIntyre et al. (2002) found comparable efficacy for

topiramate (mean dosage = 176 mg/day) and bupropion sustained-release (mean dosage = 250

mg/day) in an 8-week single-blind comparison trial in 36 patients with bipolar depression receiving

mood stabilizers. No switches occurred in either treatment group.

Among other novel treatment approaches, two preliminary placebo-controlled adjunctive trials

examined the efficacy and safety of the dopamine D2/D3 receptor agonist pramipexole in the

treatment of patients with bipolar I and bipolar II depression (Goldberg et al. 2004; Zarate et al.

2004). In both trials, patients receiving pramipexole added to mood stabilizers had significantly

greater reductions in depressive symptoms and significantly greater response rates compared with

those receiving placebo. Switch rates did not differ significantly from those with placebo.

Stoll et al. (1999) reported significant global improvement in depressive symptoms in patients

receiving omega-3 fatty acids compared with placebo. These findings were not replicated in a

second placebo-controlled trial (Keck et al. 2006b).

Monotherapy Versus Combination Therapy of Acute Bipolar Depressive

EpisodesPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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The “mood stabilizer first” approach has guided most recommendations regarding the acute

treatment of patients with bipolar I depression (Thase and Sachs 2000). This approach is supported

by at least three lines of evidence: 1) randomized, controlled trials have demonstrated the inherent

antidepressant activity of at least some mood stabilizers (lithium, lamotrigine, olanzapine,

quetiapine); 2) mood stabilizer monotherapy appears to carry a lower switch risk as compared with

mood stabilizer–antidepressant combination therapy; 3) protection against switching can be

implemented if the mood stabilizer alone is not adequate and an antidepressant is needed. Lithium,

lamotrigine, quetiapine, and olanzapine are mood stabilizers with demonstrated efficacy as

monotherapy in acute bipolar depression.

Combination therapy with an antidepressant and a mood stabilizer is an important option in two

clinical groups: patients who do not respond adequately to mood stabilizer monotherapy and

patients who have moderate to severe bipolar depression (Hirschfeld et al. 2002). Among

antidepressant options, paroxetine, fluoxetine, venlafaxine, bupropion, and tranylcypromine are the

most well studied in randomized, controlled trials and appear to have a lower switch risk in

comparison with TCAs. Although no randomized, controlled trials of pharmacotherapy of psychotic

bipolar depression have been conducted, mood stabilizer–antidepressant–antipsychotic and

atypical antipsychotic–antidepressant combinations are common clinical approaches (Keck et al.

2004).

MAINTENANCE TREATMENT

Bipolar disorder is a recurrent lifelong illness in more than 90% of the patients who experience a

manic episode (Goodwin and Jamison 2007). Because of the high risk of recurrence and morbidity

associated with mood episodes and interepisode symptoms, maintenance treatment is usually

recommended after a single manic episode (Hirschfeld et al. 2002). The goals of maintenance

treatment include prevention of syndromal relapse and subsyndromal symptoms, optimization of

functioning, and prevention of suicide. As with bipolar depression, there are a limited number of

randomized, controlled trials of maintenance treatment of bipolar disorder on which to base

treatment recommendations (Table 54–7).

TABLE 54–7. Evidence-based maintenance treatment of bipolar disorder

Treatment Number of positive RCTs

Lithium 8

Lamotrigine 2

Olanzapine 3

Aripiprazole 1

Note. RCTs = randomized, controlled trials.

Lithium

Lithium is the most extensively studied medication in the maintenance treatment of bipolar

disorder. Data from randomized, placebo-controlled trials conducted in the 1960s and 1970s

indicated that lithium protected against relapse, with a fourfold lower risk compared with placebo

at 6-month and 1-year follow-up intervals (Keck et al. 2000). Lithium was superior to placebo in

preventing relapse into mania in two randomized, controlled parallel-group trials lasting 18 months

(Bowden et al. 2003; Calabrese et al. 2003).

Lithium may also reduce the risk of suicide in bipolar disorder beyond that predicted by the

successful prevention of mood episode recurrences (Baldessarini et al. 2003). Moreover, this risk

reduction appears to exceed that of treatment by divalproex (Goodwin et al. 2003).

A number of predictors of poor response to lithium maintenance treatment have been identified.

These include rapid cycling, multiple prior mood episodes, negative family history of mood disorder,

co-occurring alcohol or substance use disorder, and episode sequence ofPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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depression–mania–euthymia (Bowden 1995).

The optimal maintenance lithium serum concentration is an important consideration in successful

maintenance treatment. Maintenance lithium serum concentrations usually are lower than those

required to produce acute antimanic efficacy (Bowden 1998). Studies by Gelenberg et al. (1989)

and Keller et al. (1992) found a serum level–response relationship, with levels of 0.4–0.6 mEq/L

being associated with 2.6 times the relapse rate and a significantly greater likelihood of

experiencing subsyndromal symptoms, compared with levels of 0.8 mEq/L or higher. There was

also a serum level–side effect relationship, with patients at higher levels experiencing significantly

higher rates of side effects, often leading to discontinuation. Perlis et al. (2002), in yet another

reanalysis of the Gelenberg et al. (1989) data, reported that an abrupt drop in serum lithium levels,

whether due to random reassignment or to nonadherence, was the most powerful predictor of

relapse. In a comprehensive review of this issue, Baldessarini et al. (2002) concluded that levels of

0.6–0.7 mEq/L appear to provide the best efficacy–tolerability range for most patients. The optimal

lithium level for many patients will be the level that balances relapse prevention and suppression of

subsyndromal symptoms against minimization of bothersome day-to-day side effects.

Antiepileptics

Lamotrigine

Two large 18-month placebo-controlled maintenance trials comparing lamotrigine (200–400

mg/day) with lithium (0.8–1.1 mEq/L) found lamotrigine, but not lithium, superior to placebo in

preventing depressive episodes (Bowden et al. 2003; Calabrese et al. 2003). In contrast, lithium,

but not lamotrigine, was superior to placebo in preventing manic episodes. Taken together, the

results of these two studies suggest that the combination of lithium and lamotrigine might be

especially useful in preventing both manic and depressive episodes, although this remains to be

established in a randomized, controlled trial. Of the nearly 1,200 patients who received lamotrigine

in these trials, 9% had benign rash (morbilliform or exanthematous eruptions), compared with 8%

of the 1,056 patients receiving placebo. When patients who received lamotrigine during the

open-label run-in phase of the studies were included in the analysis, the total incidence of rash was

13%, with two cases of serious rash requiring hospitalization (Calabrese 2002).

Calabrese et al. (2000) conducted a 6-month placebo-controlled relapse prevention study of

lamotrigine (mean dose, 288 mg/day) in 182 patients with rapid-cycling bipolar I and II disorders.

There was no significant difference between the lamotrigine and placebo treatment groups in time

to need for additional medications for recurrent mood symptoms. However, there was a trend in

favor of lamotrigine over placebo specifically in bipolar II patients.

Divalproex

In the only randomized, placebo-controlled maintenance trial of divalproex in bipolar I disorder,

there was no significant difference in the time to development of any mood episode among patients

receiving divalproex, lithium, or placebo (Bowden et al. 2000). A number of unforeseen

methodological limitations in this trial complicated the interpretation of its results. In patients who

received divalproex for treatment of the index manic episode in an open treatment period prior to

randomization, divalproex was superior to placebo in early termination due to any mood episode

(29% vs. 50%) during the subsequent year. This is a clinically relevant observation, since it

supports the efficacy of maintaining patients who respond to divalproex for a manic episode.

Divalproex was also compared with olanzapine in a 47-week blinded maintenance trial (Tohen et al.

2003b) described earlier. Calabrese et al. (2005b) compared divalproex with lithium in a 20-month

study of patients with rapid-cycling bipolar disorder and found comparable relapse rates in both

treatment groups.

There are no data regarding the optimal maintenance valproic acid concentration for bipolar

disorder. Current practice usually consists of titrating to therapeutic serum concentrations (50–125

g/mL) and, as with lithium, balancing relapse and subsyndromal symptom prevention againstPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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minimization of side effects (Hirschfeld et al. 2002). Treatment with valproate appears to pose an

increased risk of polycystic ovarian syndrome (PCOS), although the relationship between PCOS and

weight gain as a possible mechanism is unclear (Hirschfeld et al. 2002).

Carbamazepine

Although a number of studies have examined the efficacy of carbamazepine in the maintenance

treatment of bipolar disorder, most of these studies yielded results that were difficult to interpret

on methodological grounds (Dardennes et al. 1995). Two studies compared carbamazepine with

lithium. In the first study, there were no significant differences in relapse rates after 1 year

between lithium (31%) and carbamazepine (37%) (Denicoff et al. 1997). In the second trial,

lithium was superior to carbamazepine on a number of outcome measures at 2.5 years of treatment

(Greil et al. 1997). There are no data regarding serum level–response relationships for

carbamazepine maintenance therapy. Denicoff et al. (1997) found that patients receiving the

combination of carbamazepine and lithium in the third year of their trial had a better response than

patients receiving either agent alone. Greil et al. (1997) found that patients with atypical symptoms

(e.g., psychosis) responded better to carbamazepine than to lithium (Greil et al. 1998).

Therapeutic Monitoring of Lithium, Valproate, and Carbamazepine

Once lithium treatment is established at therapeutic plasma concentrations, recommendations for

monitoring patients receiving lithium maintenance treatment include creatinine level and thyroid

function test, along with a lithium level at least every 6 months initially (Hirschfeld et al. 2002).

Thyroid function testing should be especially considered in patients with rapid cycling. Similarly, in

patients receiving valproate maintenance treatment, recommendations for ongoing monitoring

include obtaining a valproic acid level, hepatic function tests, and complete blood count (CBC) with

platelet count approximately every 6 months (Hirschfeld et al. 2002). For carbamazepine, CBC and

hepatic function tests are recommended approximately every 3 months (Hirschfeld et al. 2002).

Atypical Antipsychotics

Olanzapine

Olanzapine was comparable to divalproex in a 47-week comparison trial (Tohen et al. 2003b) and

to lithium in a 1-year comparison trial (Tohen et al. 2005). Olanzapine received an indication for

maintenance treatment in bipolar disorder based on superiority over placebo in prevention of manic

and depressive episodes over 48 weeks (Tohen et al. 2006). The combination of olanzapine and

lithium or divalproex was superior to placebo and lithium or divalproex in relapse prevention over

18 months in patients who had initially responded to the active combination acutely (Tohen et al.

2002b) and then were rerandomized (Tohen et al. 2004). This is a very clinically relevant finding,

since it suggests that patients who respond acutely to olanzapine in combination with lithium or

divalproex in the treatment of a manic episode have a lower risk of relapse by staying on such a

combination. However, patients in the combination therapy group had twice the weight gain of

patients in the monotherapy group.

Aripiprazole

Aripiprazole was superior to placebo in preventing manic relapse over a 6-month follow-up period

in patients with bipolar disorder who were initially stabilized on aripiprazole monotherapy for an

acute manic or mixed episode (Keck et al. 2006a). There was no significant difference between

treatment with aripiprazole and placebo in relapse into depressive episodes; however, the overall

low relapse rate into depression of this trial may have been due to the inclusion of patients whose

index episodes were manic or mixed, and not depressed.

Electroconvulsive Therapy

The use of ECT in the maintenance treatment of bipolar disorder has never been studied

systematically in a randomized, controlled trial. However, a number of naturalistic studies suggest

that maintenance ECT may be a useful treatment alternative for patients who are inadequatelyPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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responsive to pharmacotherapy (Schwartz et al. 1995; Vanelle et al. 1994).

Psychotherapy

Most patients with bipolar disorder experience a common cluster of psychological problems

stemming directly from the illness (Table 54–8). A number of specific psychosocial interventions as

adjuncts to mood stabilizer therapy have been shown to improve the long-term outcome of bipolar

disorder (reviewed in Rizvi and Zaretsky 2007). The best-studied interventions include educational,

interpersonal, family, and cognitive-behavioral therapies. Randomized, controlled trials conducted

over 1- to 2-year follow-up periods support the efficacy of cognitive-behavioral therapy (Lam et al.

2005), family-focused and related forms of therapy (Clarkin et al. 1990, 1998; Miklowitz et al.

2003; Rea et al. 2003), interpersonal and social rhythm therapy (Frank et al. 2005), and group

psychoeducation (Colom et al. 2003) in reducing or delaying mood episode recurrence, increasing

treatment adherence, and improving functioning. Family-focused, interpersonal, and social rhythm

therapy were all associated with delaying time to depressive episode relapse compared with brief

treatment (Miklowitz et al. 2007). Only one study, of cognitive-behavioral therapy, found no

significant benefit overall after 1 year, although post hoc analysis suggested that patients with

fewer than 12 lifetime episodes benefited (Scott et al. 2006).

TABLE 54–8. Common psychological issues associated with bipolar disorder

Emotional consequences of manic, mixed, and depressive episodes

Acceptance of and coping with an often chronic mental illness

Effects of stigmatization

Developmental delays or deviations

Fears of recurrence and resulting inhibitions

Interpersonal challenges: marriage, family, pregnancy, child-rearing

Academic and occupational problems

Legal, social, and emotional problems arising from reckless, impulsive, withdrawn, or violent behavior

Source. Adapted from Hirschfeld RMA, Bowden CL, Gitlin MJ, Keck PE, Perlis RH, Suppes T, Thase ME:

“Practice Guideline for the Treatment of Patients With Bipolar Disorder (Revision).” American Journal of

Psychiatry 159 (Supplement):1–50, 2002. Copyright 2002, American Psychiatric Association. Used with

permission.

Novel Treatments

Quetiapine, ziprasidone, risperidone, and paliperidone, as well as new antiepileptics, may be

potential long-term mood-stabilizing agents but have yet to be studied in randomized, controlled

trials. Clozapine was more effective than “treatment as usual” (combinations of mood stabilizers

and typical antipsychotics) in a 1-year study in patients with treatment-refractory bipolar and

schizoaffective disorder (bipolar subtype) (Suppes et al. 1999) and represents an important

treatment option for patients unresponsive to conventional agents.

TREATMENT CONSIDERATIONS

Monotherapy Versus Combination Therapy

Mood Stabilizers

The optimal pharmacological maintenance treatment of bipolar disorder requires titration of any

single mood-stabilizing medication to eradicate subsyndromal symptoms and prevent relapse.

However, outcome assessments from randomized, controlled trials and naturalistic studies indicate

that only a minority of patients with bipolar disorder experience optimal benefit (no relapse or

recurrences, minimal to no subsyndromal symptoms) from monotherapy with any single mood

stabilizer. Combination therapy is therefore frequently necessary and is commonplace in clinicalPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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practice. Unfortunately, very few studies have addressed specific mood stabilizer combinations,

their relative therapeutic advantages, and their tolerability. As described earlier (see “Maintenance

Treatment” section earlier in chapter), the combination of olanzapine with lithium or divalproex

was significantly more likely to prevent relapse compared with lithium or divalproex (with placebo)

in patients initially responsive to the combination (Tohen et al. 2004). In the only other study

reported, Solomon et al. (1997) compared the efficacy of lithium alone versus the combination of

lithium and divalproex for 1 year in 12 patients. The combination significantly reduced the risk of

recurrence of mania or depression but was associated with more side effects. Thus, the clinical

practice of combining mood stabilizers has greatly outstripped the limited data available from

formal studies. Combinations of lithium and divalproex, lithium and carbamazepine, and divalproex

and carbamazepine; triple therapy with all three agents; and lithium and/or divalproex with

atypical antipsychotics, antidepressants, and lamotrigine have all been reported in case series to be

useful maintenance treatment strategies (M. P. Freeman and Stoll 1998).

Mood Stabilizers With Antidepressants

Most recommendations regarding the duration of antidepressant treatment (in conjunction with a

mood stabilizer) in patients with bipolar depression suggest prompt discontinuation of

antidepressants after remission of depression (Ghaemi et al. 2001). Limiting antidepressant

exposure is intended to reduce the risk of switching or cycling. However, discontinuation of

antidepressants during maintenance therapy may also increase the risk of depressive relapse. Two

studies involving different cohorts of bipolar patients treated naturalistically found that termination

of antidepressants was associated with a two- to threefold increased risk of depressive relapse

after 1 year (Altshuler et al. 2001, 2003). In contrast, antidepressant continuation was not

significantly associated with an increased risk of mania. The results of these two studies suggest

that the use of antidepressants in combination with mood stabilizers to prevent recurrence of

bipolar depression may be indicated and necessary for many patients, particularly patients without

a history of or risk factors for rapid cycling (e.g., substance use disorder, thyroid disease). The

optimal duration of antidepressant maintenance treatment and possible predictors of switch versus

depressive relapse require further study.

Rapid Cycling

Rapid cycling, the occurrence of four or more mood episodes within 12 months (Dunner and Fieve

1974), poses a special challenge. Among mood stabilizers, divalproex and atypical antipsychotics

appear to have greater efficacy than lithium in patients with rapid cycling. Lamotrigine is also a

treatment option based on the study by Frye et al. (2000), although its long-term benefit in rapid

cycling may be limited to bipolar II rather than bipolar I disorder (Calabrese et al. 2000). Because

very few randomized, controlled trials are available to inform treatment decisions, most

recommendations are empirical. Combinations of mood stabilizers (e.g., lithium and divalproex,

divalproex and atypical antipsychotics, lithium and lamotrigine) are often recommended (Hirschfeld

et al. 2002).

Co-Occurring Psychiatric Disorders

Among the major psychiatric disorders, bipolar disorder has the highest comorbidity rate (McElroy

et al. 2001). Co-occurring psychiatric disorders can affect treatment recommendations, but to date

very few studies have specifically addressed the acute and long-term treatment of patients with

bipolar disorder and psychiatric comorbidity. In a 6-month placebo-controlled trial in female

patients with bipolar II disorder and borderline personality disorder, divalproex was superior to

placebo in reducing measures of interpersonal sensitivity, anger, hostility, and aggression

(Frankenberg and Zanarini 2002). Lithium was superior to placebo in patients with bipolar

spectrum disorder and co-occurring pathological gambling in a 10-week trial (Hollander et al.

2005). Improvement in gambling severity was correlated with improvement in manic symptoms.

Salloum et al. (2005) conducted a 24-week placebo-controlled trial of adjunctive divalproex in

patients with bipolar I disorder and co-occurring alcohol dependence who were also receiving

lithium and psychosocial treatment. Patients receiving divalproex had significantly fewer days ofPrint: Chapter 54. Treatment of Bipolar Disorder http://www.psychiatryonline.com/popup.aspx?aID=443577&print=yes…

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heavy drinking and showed a trend toward fewer drinks per heavy drinking day compared with

patients receiving placebo. Lastly, Weiss et al. (2007) compared a specifically developed form of

integrated group therapy for patients with bipolar disorder and concurrent substance dependence

with group counseling in patients on mood stabilizers over 20 weeks and found significantly fewer

days of substance use in the integrated therapy group during treatment and at 3-month

posttreatment follow-up.

Mood Stabilizers and Bipolar-Specific Psychotherapy

From the evidence reviewed above regarding the efficacy of several different forms of

psychotherapy specifically developed and operationalized for patients with bipolar disorder, it is

clear that the combination of one of these forms of psychotherapy with maintenance

pharmacotherapy is superior to pharmacotherapy alone in reducing the risk of relapse and

recurrence.

CONCLUSION

There have been substantial advances in the pharmacological treatment of bipolar disorder in the

past decade. A number of medications have demonstrated efficacy in the treatment of acute mania

in placebo-controlled trials, either as monotherapy or as an adjunct to mood stabilizers. In addition,

data are available for the first time indicating that combination therapy with an antipsychotic and a

mood stabilizer is more rapidly effective, with better overall response rates in acute mania, than

either mood stabilizers or antipsychotics alone.

The treatment of bipolar depression remains one of the most understudied aspects of the illness.

The “mood stabilizer first” strategy and combined use of mood stabilizers and antidepressants in

moderate to severe bipolar depression are common approaches.

Most patients with bipolar disorder require treatment with more than one medication during the

course of their illness. The efficacy of combination strategies is only now receiving close scrutiny.

Recent studies suggest that the use of combinations of antidepressants and mood stabilizers as

maintenance treatment for some patients to prevent depressive relapse may be important.

The role and efficacy of different types of psychotherapy at different phases of illness management

in bipolar disorder are now becoming clearly established. These components of treatment are

important in educating patients and families, improving insight and treatment adherence,

enhancing coping skills, and dealing with the sequelae of mood symptoms and episodes—and, it is

hoped, improving functioning and outcome. Treatment advances in bipolar disorder are finally

occurring rapidly. Artfully bringing these treatments to patients with bipolar disorder is both the

challenge and the reward of helping people manage this illness.

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