David J. Muzina, MD

The Art of Psychopharmacology, David S. Janowsky, MD

Hypnotics: How Effective Are They for Insomnia?, Malcolm H. Lader, MD, PhD, LLB

Antidepressants: Brand Name or Generic?, James W. Jefferson, MD

Antipsychotic Combination Strategies in Bipolar Disorder, David J. Muzina, MD and Martha Sajatovic, MD

Optimal management of bipolar disorder (BD) includes the careful selection and regular ingestion of appropriate medication to stabilize mood. Unfortunately, between 40% and 50% of patients with BD in routine clinical settings take breaks or forget to take their medication or even discontinue the drug altogether.

 Treatment nonadherence is associated with mood relapse, hospitalization, and suicide.

Adequate adherence can be defined as the taking of the minimum amount of medication required to achieve acceptable control of symptoms and to prevent relapse to an extent that is mutually agreed on by the patient and the clinician. This definition underscores the need for a collaborative treatment approach that takes into account the nature and severity of the illness, associated comorbidities, the patient’s response to medication (including adverse effects and perceived benefits), and patient preference.

One of the challenges in addressing the issue of nonadherence is that there are a variety of ways to measure adherence, all of which have limitations (

). Various studies have defined a working concept of what constitutes clinically relevant nonadherence, including serum drug levels (for drugs in which serum levels might be typically monitored), categorical stratification (ie, missing a specific percentage of prescribed medication), medication refill frequencies, and combined/composite definitions.

Recognizing that adherence is rarely an all-or-nothing phenomenon, some groups have defined adherence categories within a range. For example, patients who are adherent take 80% or more of the prescribed medication; partially adherent patients take 51% to 79% of a prescribed medication; and those who are nonadherent take 50% or less of a prescribed drug.

 Such categorization allows for comparison of medication prescription filling across various medication classes, 

including medication combination therapies, among groups of individuals in a health care network. Whether any one specific compound or class of compounds (either as monotherapy or in combination) might be generally associated with relatively greater adherence among patients with BD has yet to be determined.

In recent years, the pharmacopeia for BD therapy has expanded substantially to include not only traditional mood-stabilizing compounds (such as lithium and anticonvulsants) but also the atypical antipsychotics. The latter have been associated with antimanic, antidepressant, and mood-stabilizing properties.

Randomized, placebo-controlled trials, which demonstrated the efficacy of atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole), led to their approval for the management of acute bipolar mania with or without psychotic features. The differences in antimanic efficacy among these agents are likely to be small.

There does not appear to be a “class effect” with atypical antipsychotics in the management of acute bipolar depression. The combination of olanzapine and fluoxetine but not olanzapine monotherapy, demonstrated sufficient efficacy to be named the first FDA-approved treatment for patients with acute bipolar depression.

 Quetiapine monotherapy demonstrated efficacy in managing acute bipolar depression; aripiprazole monotherapy did not.

Olanzapine and aripiprazole monotherapies are approved by the FDA for maintenance treatment of patients with BD. In addition, FDA approval of quetiapine in combination with lithium or divalproex as maintenance therapy for patients with BD was recently granted on the basis of controlled data.

Adherence with atypical antipsychotic drugs

Antipsychotics have become an integral component of drug therapy across all phases of BD. More than 90% of acutely manic patients are treated with antipsychotics, and antipsychotics in combination with mood stabilizers are prescribed for 47% to 90% of patients for acute and maintenance treatment.

 Continuation of antipsychotic medications in the outpatient setting is very common: these medications are prescribed for 60% to 89% of affected patients for 6 months or longer.

 Given the expanding role of atypical antipsychotics in the treatment of patients with all phases of BD, exploration of adherence to these medications is critical.

examined claims data for 825 patients with BD who were started on a regimen of antipsychotic monotherapy (risperidone, olanzapine, quetiapine, or typical antipsychotic). A Medicaid database was used during a 3-year period.

 Medication adherence was measured using the medication possession ratio: (MPR = number of days’ supply of medication that was actually received/number of days’ supply of medication that should have been dispensed per prescription). Adherence to antipsychotic therapy was also measured by the total number of days from the start of treatment to any therapy modification.

The overall rate of adherence measured by the MPR was significantly higher among patients treated with an atypical antipsychotic than with a typical antipsychotic (

 There were no significant differences in MPRs among patients treated with 1 of the 3 studied atypical antipsychotics (MPR range, 0.68 to 0.71). There were no significant differences in persistence with antipsychotic therapy between groups during the initial 250 days of therapy; however, after the first 250 days of treatment, patients who started on a regimen of typical antipsychotics were 5.2 times more likely to modify therapy than were patients who started on a regimen of risperidone (

 suggest that typical antipsychotics might be associated with lower adherence and a greater probability that patients would switch therapy than with atypical antipsychotics, not all reports have found treatment adherence differences between typical and atypical antipsychotics in bipolar populations. Sajatovic and colleagues

 found that adherence was highest only with the atypical antipsychotic clozapine. Patients who take this drug need long-term hematological monitoring, which may enhance adherence. A 2006 retrospective claims-based study by Gianfrancesco and colleagues

 evaluated treatment adherence among 15,224 patients with BP who were treated with typical and atypical antipsychotics-risperidone, olanzapine, quetiapine, and ziprasidone. Medication adherence was measured using the MPR as well as treatment duration. Greater adherence intensity was achieved with the majority of the atypical antipsychotics.

Several patient characteristics were positively associated with adherence intensity in this study, including male gender, prior mental health expenditure, switch from another antipsychotic, more frequent physician contact, and greater use of other psychotropics.

 Reduced adherence was observed among older patients and those with bipolar depression, previous use of a higher number of different psychotropic drugs, substance abuse/dependence, more managed forms of health coverage, and longer treatment duration.

 also found significant differences in treatment duration between each of the antipsychotic groups. Quetiapine and risperidone, but not olanzapine and ziprasidone, had significantly longer treatment durations than did the typical antipsychotics (

 < .001). Both quetiapine and risperidone also had significantly longer treatment durations than did olanzapine and ziprasidone.

In short, adherence may be somewhat better with atypical antipsychotics than with typical antipsychotics, although this finding is not consistently noted in the literature. Patient-specific and treatment-related variables also play a key role in adherence outcomes. Atypical antipsychotic therapy coupled with relatively intensive staff involvement, as occurs in clozapine-treated populations, may enhance treatment adherence. Finally, adherence rates as measured by MPRs for lithium and the anticonvulsants valproate, carbamazepine, and lamotrigine (MPR range, 0.76 to 0.81) do not differ markedly from those seen with antipsychotic drugs.

The role of combination therapy in treatment adherence

The choice between monotherapy and combination therapy is dictated largely by clinical impression and individualized treatment planning. In many cases, clinical experience-supported by evidence-based treatment guidelines-suggests that early or initial combinations of mood-stabilizing medications (including atypical antipsychotics) may enhance effectiveness beyond that provided by monotherapy. However, multiple medications or complex treatment regimens may promote nonadherence.

 examined the association between antipsychotic combination therapy and treatment adherence in persons with BD. Using a retrospective claims-based study design among commercially insured individuals with this disorder, the investigators assessed and compared adherence to quetiapine or risperidone monotherapy with these drugs in combination with traditional mood stabilizers and antidepressants. Adherence was measured using MPRs and treatment duration; additional stratification of data was based on predominant bipolar symptoms (manic or mixed, depressed, or unspecified). Treatment episodes from more than 5200 patients with BD were examined.

Among persons with predominantly manic or mixed symptoms, adherence intensity was reduced when an antipsychotic was prescribed with any combination of lithium, an anticonvulsant, and an antidepressant. Adherence to the atypical antipsychotic was better when only 1 other medication was coprescribed; adherence was lowest when all 3 of the other medication types were used. Adherence was lower in those taking risperidone or quetiapine and an anticonvulsant than in those taking lithium and an atypical antipsychotic. The combination of quetiapine with lithium or with lithium and an anticonvulsant was associated with significantly shorter treatment durations than was quetiapine monotherapy. The type of combination therapy for risperidone did not significantly affect treatment duration.

Among individuals with predominant symptoms of depression, any combination of therapy with quetiapine reduced adherence intensity, although the smallest reduction occurred when this drug was combined with an antidepressant. Reduced adherence with risperidone-as reflected by lower MPRs-was observed only with strategies that combined 2 or more other psychotropic medications. Among the predominantly depressed patients with BD, none of the combination strategies with risperidone or quetiapine had a significant effect on adherence.

Other investigators have found evidence that suggests that among some patients with BD, adherence is greater with combination therapies than with monotherapy. Adherence with antipsychotic medications has also been studied in a large cohort of veterans with BD using the Veterans Affairs National Psychosis Registry.

 The study used the MPR to categorize patients as fully adherent, partially adherent, and nonadherent. About 95% of the patients were taking an atypical antipsychotic, and 81.2% were taking a single antipsychotic. Nearly 50% of these patients were either partially adherent (21.2%) or nonadherent (26.9%). The nonadherent patients were significantly more likely to be younger, members of a minority, known substance abusers, or homeless. Interestingly, the mean MPR for individuals who took 2 antipsychotics was higher than MPRs for those taking single antipsychotics (

These findings are strikingly comparable to those from a similar study that examined adherence with lithium and anticonvulsant therapy among patients with BD. Nearly 50% of the study participants were only partially adherent or nonadherent, yet better overall adherence was observed among patients who received 2 mood-stabilizing drugs than among those who were given a single drug.

 Unfortunately, case-registry methodology does not address the question of whether combination therapy actually promotes treatment adherence in bipolar populations, or whether improved adherence with combination therapy is simply due to the fact that clinicians might be more likely to prescribe medication treatments more intensively to adherent individuals.

In contrast to conventional clinical wisdom, which posits that polytherapy promotes nonadherence, recent data on combination therapy in bipolar populations does not support a consistent position that adherence is either generally hurt or helped by combination treatment. As Gianfrancesco and colleagues

 showed, adherence may deteriorate when medication regimens become very large or cumbersome (3 or more drugs). It is possible, however, that appropriately aggressive use of medication combinations that reduce symptoms and enhance quality of life may have beneficial effects on treatment adherence.

Adherence to medications to treat BD is a complex and multifaceted issue that is affected by patient-specific factors as well as by medication choice, drug response, and provider or treatment-setting factors. Atypical antipsychotic drugs are used for both acute and maintenance treatment in patients with BD and nonadherence is common, as is the case with all psychotropics in psychiatric populations.

While recent data suggest that atypical antipsychotics may help promote adherence for some individuals with BD, psychosocial interventions-such as long-term and intensive involvement with mental health clinicians-are important in optimizing adherence outcomes. For example, weight gain or metabolic disturbances associated with atypical antipsychotics may be of such concern that some individuals may refuse to take these medications. Psychoeducation that focuses on goals and expectations of treatment and close monitoring of adverse effects are critical in preventing and minimizing problems in medication therapy that may ultimately lead to treatment nonadherence or discontinuation.

Combination therapies are widely used in clinical settings, yet there has not been extensive research on key outcome domains, such as adherence or quality of life for many commonly used bipolar treatment polytherapies. Polytherapy does not necessarily promote nonadherence. However, combination treatments may exacerbate medication adverse effects and/or create new adverse effects that would not occur with monotherapy.These issues need to be proactively addressed to optimize future symptom response and adherence outcomes.

Finally, given the frequency with which combination therapy is prescribed in clinical settings, there is a critical need for research that comprehensively evaluates outcomes in bipolar populations. As with bipolar mania and bipolar depression monotherapy trials, it is unlikely that atypicals are equivalent and indistinguishable. Differences between the various popular combinations should be explored using rigorous and systematic methods.

Dr Muzina is director of the Center for Mood Disorders Treatment and Research in the department of psychiatry at the Cleveland Clinic in Cleveland. Dr Sajatovic is professor of psychiatry at Case Western Reserve University School of Medicine in Cleveland and director of geropsychiatry at University Hospitals Case Medical Center in Cleveland. Dr Muzina reports that he is on the speakers’ bureau for AstraZeneca, Bristol-Myers Squibb, Pfizer, Sepracor, and Wyeth; and that he is a member of the scientific advisory board for AstraZeneca. Dr Sajatovic reports that she has received research funding from AstraZeneca, GlaxoSmithKline, and the NIMH; and she is a consultant for GlaxoSmithKline, Cognition Group, and AstraZeneca.

Aripiprazole (Abilify)
  Carbamazepine (Carbatrol, Tegretol, others)
  Clozapine (Clozaril)
  Divalproex (Epival, Depakote)
  Fluoxetine (Prozac, Sarafem)
  Lamotrigine (Lamictal)
  Lithium (Eskalith, Lithane, Lithobid)
  Olanzapine (Zyprexa)
  Quetiapine (Seroquel)
  Risperidone (Risperdal)
  Valproate/Valproic acid (Depakote, others)
  Ziprasidone (Geodon)


 Lingam R, Scott J. Treatment non-adherence in affective disorders. 

 Perlick DA, Rosenheck RA, Kaczynski R, Kozma L. Medication non-adherence in bipolar disorder: a patient-centered review of research findings. 

 Scott J, Pope M. Self-reported adherence to treatment with mood stabilizers, plasma levels, and psychiatric hospitalization. 

 Colom F, Vieta E. Treatment adherence in bipolar patients. 

 MÃ¼ller-Oerlinghausen B, MÃ¼ser-Causemann B, Volk J. Suicides and parasuicides in a high-risk patient group on and off lithium long-term medication. 

 Scott J, Pope M. Non-adherence with mood stabilizers: prevalence and predictors. 

 Sajatovic M, Davies M, Hrouda DR. Enhancement of treatment adherence among patients with bipolar disorder. 

 Sajatovic M, Valenstein M, Blow F, et al. Treatment adherence with lithium and anticonvulsant medications among patients with bipolar disorder. 

 Muzina DJ, Kemp DE, Gao K, et al. Atypical antipsychotics in bipolar depression: applying emerging evidence to clinical practice. 

 Muzina DJ, Kemp DE, Gao K, Calabrese JR. Mood stabilizers. In: Tasman A, Kay J, Lieberman J, et al, eds. 

 West Sussex, England: John Wiley & Sons, Ltd; 2008:2202-2222.


 Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebo-controlled trials. 

 Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. 

 Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. 

 Thase ME, Macfadden W, Weisler RH, et al; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). 

 Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. 

 Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). 

 Tohen M, Zhang F, Taylor CC, et al. A meta-analysis of the use of typical antipsychotic agents in bipolar disorder. 

 Keck PE, McElroy SL, Strakowski SM, et al. Factors associated with maintenance antipsychotic treatment of patients with bipolar disorder. 

 Ozerdem A, Tunca Z, Kaya N. The relatively good prognosis of bipolar disorders in a Turkish bipolar clinic. 

 Verdoux H, Gonzales B, Takei N, Bourgeois M. A survey of prescribing practice of antipsychotic maintenance treatment for manic-depressive outpatients. 

 Hassan M, Madhavan SS, Kalsekar ID, et al. Comparing adherence to and persistence with antipsychotic therapy among patients with bipolar disorder. 

 Sajatovic M, Valenstein M, Blow FC, et al. Treatment adherence with antipsychotic medications in bipolar disorder. 

 Gianfrancesco FD, Rajagopalan K, Sajatovic M, Wang RH. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. 

 Kingsbury SJ, Yi D, Simpson GM. Psychopharmacology: rational and irrational polypharmacy. 

 Burton SC. Strategies for improving adherence to second-generation antipsychotics in patients with schizophrenia by increasing ease of use. 

Gianfrancesco FD, Rajagopalan K, Sajatovic M, Wang RH. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. 

 2006;67:222-232.
Perlick DA, Rosenheck RA, Kaczynski R, Kozma L. Medication non-adherence in bipolar disorder: a patient-centered review of research findings. 

Articles

Optimal management of bipolar disorder (BD) includes the careful selection and regular ingestion of appropriate medication to stabilize mood. Unfortunately, between 40% and 50% of patients with BD in routine clinical settings take breaks or forget to take their medication or even discontinue the drug altogether.1-3 Treatment nonadherence is associated with mood relapse, hospitalization, and suicide.4,5

Antipsychotic Combination Strategies in Bipolar Disorder:Strategies to Maximize Treatment Adherence

Some of the most challenging facets of bipolar disorder involve the management of its depressive symptoms. This article will focus on the pharmacologic management of this phase of bipolar disorder, describing the evidence base for controlled studies, emerging treatments, and expert recommendations.

An unmet need exists for acute and maintenance treatments that target depressive symptoms in bipolar disorder. Depression predominates over the course of both bipolar I (BP I) and bipolar II (BP II) disorders, occurring more than 3 times as frequently as manic and hypomanic symptoms combined in BP I,

 and nearly 40 times as frequently as hypomania in BP II.

 Patients repeatedly attribute greater impairment in their work, family life, and psychosocial functioning to depressive symptoms than to mania.

 Even more problematic, the majority of attempted suicides occur in states of depression, in which the rate is 20 times higher than in the general population.

A significant challenge facing clinicians is the misdiagnosis or underdiagnosis of bipolar depression. Perhaps this is because it presents itself less dramatically and is more difficult to recognize. A large French multicentered study of patients experiencing a major depressive episode, as classified by 

, found that when systematic methods for identifying hypomania were employed, the rate of BP II disorder nearly doubled, increasing from 22% to 40% of such patients.

 was used in a primary care clinic, more than one fifth of patients receiving antidepressants for the treatment of depression screened positive for bipolar disorder.

 Before this assessment, bipolar disorder had not been diagnosed in the majority of these patients. It is clear that early discrimination between bipolar disorder and other psychiatric illnesses, particularly major depressive disorder, is essential to minimize misdiagnosis and provide safe and effective care.

Acute and maintenance effects of lamotrigine

A rigorous and methodical evaluation of a pharmacologic treatment for bipolar depression emerged in 1999, when Calabrese and associates

 published the first randomized, parallel group, placebo-controlled trial of lamotrigine in the treatment of patients with BP I depression. Conducted over 7 weeks, the study randomized patients to lamotrigine 50 mg/d (n = 66), lamotrigine 200 mg/d (n = 63), or placebo (n = 66). Significant improvements were seen in patients receiving both dosages of lamotrigine over patients in the placebo group in observed change on the 

On the Montgomery-sberg Depression Rating Scale (MADRS) total score, significant improvement over placebo was evident for only the lamotrigine 200 mg/d group (

 < .05). However, a responder analysis-where response is defined as 50% or greater improvement in MADRS tota score-showed that 54% of the patients receiving lamotrigine 200 mg/d and 48% of the patients receiving lamotrigine 50 mg/d met criteria for response. Response rates for patients treated with both dosages of lamotrigine were significantly greater than the 29% response rate observed for placebo-treated patients (

Not all controlled studies of lamotrigine have demonstrated superior efficacy over placebo.

 Some trial results suggested improvement with lamotrigine in the core symptoms of depression but failed to detach from placebo on the primary outcome measure. Collectively, results demonstrated that lamotrigine was effective in treating bipolar depression, although dosages of 200 mg/d may be needed for maximum benefit.

In terms of safety, lamotrigine has generally been shown to have a sideeffect profile similar to that of placebo. The primary concern is the rare development of a serious rash, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Perhaps even more challenging than the acute relief of depressive symptoms in bipolar disorder is the prevention of depression recurrence. To address this concern, lamotrigine was studied over an 18-month period in recently depressed patients with BP I.

 After completing an open-label phase with lamotrigine for 8 to 16 weeks, 463 patients were randomized to lamotrigine, 50, 200, or 400 mg/d; lithium, 0.8 to 1.1 mEq/L/d; or placebo.

Both lamotrigine and lithium were more effective than placebo at delaying the time to intervention for any mood episode, and lamotrigine (but not lithium) was more effective than placebo at delaying the time to intervention for a depressive episode. In a complementary fashion, lithium (but not lamotrigine) was superior to placebo at delaying the time to intervention for a manic episode. Similar results were observed in another 18-month maintenance study that evaluated recently manic or hypomanic patients.

 Taken together, these studies support the use of lamotrigine for the prophylaxis of depressive episodes in bipolar disorder.

Atypical antipsychotics for acute bipolar depression

In addition to lamotrigine, the atypical antipsychotics olanzapine

 have been evaluated in randomized, placebo-controlled trials for the treatment of bipolar depression. The antidepressant efficacy of olanzapine was studied over the course of 8 weeks in patients with BP I disorder who were experiencing a major depressive episode.

Patients were randomized to olanzapine (n = 370), an olanzapine-fluoxetine combination (n = 86), or placebo (n = 377). The monotherapy group received a mean modal olanzapine dosage of 9.7 mg/d. The combination group received a mean modal olanzapine dosage of 7.4 mg/d and a fluoxetine dosage of 39.3 mg/d.

Beginning at week 1 and continuing throughout the duration of the study, patients receiving olanzapine and the olanzapine-fluoxetine combination demonstrated significantly greater mean improvement over placebo in MADRS total scores. Olanzapine monotherapy was superior to placebo on measures of response (39.0% vs 30.4%; 

However, when fluoxetine was added to olanzapine, the antidepressant efficacy became even more vigorous. The combination of olanzapine and fluoxetine was significantly better on all efficacy measures of depression than either olanzapine monotherapy or placebo, including higher rates of response (56.1%; 

< .001 vs placebo), remission (MADRS < 12; 48.8%; 

< .001 vs placebo), study completion, and times to response and remission.

Treatment with olanzapine was associated with somnolence, weight gain, increased appetite, dry mouth, and asthenia. The side-effect profile of the olanzapine-fluoxetine combination was similar to that seen with olanzapine monotherapy, except for higher rates of nausea and diarrhea. Weight gain, cholesterol levels, and nonfasting glucose levels were higher in patients taking olanzapine or an olanzapine- fluoxetine combination, compared with placebo. No differences were observed among the 3 groups in the rate of treatment-emergent glucose elevations of 200 mg/dL or greater.

To date, quetiapine is the only other atypical antipsychotic studied in the treatment of bipolar depression.

 In an 8-week trial termed the BOLDER (BipOLar DEpRession) I study, patients with BP I and BP II disorder were randomly assigned to receive quetiapine, 600 mg/d (n = 180); quetiapine, 300 mg/d (n = 181); or placebo (n = 181). Patients with BP II disorder were not excluded as in the olanzapine-fluoxetine trial and composed 34% of the study population.

As early as week 1, both dosages of quetiapine resulted in significantly greater mean improvement in MADRS total scores compared with placebo and at all time points in the intent-to-treat group of patients (

 < .001). The mean change in MADRS total score from baseline to last assessment was –16.73 in the 600 mg/d group, –16.39 in the 300 mg/d group, and –10.26 in the placebo group (

 < .001 for both quetiapine dosages vs placebo). The response rate was approximately 58% for patients treated with either dosages of quetiapine, compared with 36.1% for placebo (

 < .001). Remission rates were also significantly higher in patients treated with quetiapine, namely 52.9% for quetiapine at both 600 and 300 mg/d, compared with 28.4% for placebo (

< .001). Adverse effects that occurred at significantly higher rates with the drug than with placebo included dry mouth, sedation, somnolence, dizziness, constipation, headache, and weight gain.

Cross-study comparisons of olanzapine and quetiapine should be interpreted with caution because of methodologic and sample differences. However, some distinct differences have emerged among atypical antipsychotics in their efficacy for treating symptoms of bipolar depression. The magnitude of clinical effect in comparison to placebo can be calculated through measurement of Cohen’s deffect size.

 The effect size for 600 mg/d of quetiapine was 1.09 in patients with BP I depression and 0.91 for a dosage of 300 mg/d. Since both values were 0.8 or greater, they were considered to represent a large treatment effect. Olanzapine, on the other hand, achieved an effect size of 0.32, but this increased to 0.68 when it was combined with fluoxetine.

Other notable differences in medications relate to findings on the MADRS individual item analysis. Patients receiving quetiapine or an olanzapine-fluoxetine combination improved on the core mood items of depression: representing apparent sadness, reporting sadness, inability to feel, and pessimistic thoughts. Olanzapine monotherapy was not more effective than placebo at improving the core mood items of depression. In addition, both dosages of quetiapine were found to reduce suicidal thoughts compared with placebo, whereas both olanzapine groups did not differ from placebo in reducing suicidal thinking.

A replication study of quetiapine in the treatment of bipolar depression (BOLDER II) has recently been completed. 

 The results are yet to be formally published, but a preliminary analysis showed for a second time that quetiapine monotherapy at dosages of both 300 and 600 mg/d was superior to placebo at improving depressive symptoms. In contrast to the BOLDER I study, treatment effect sizes in the replication study were found to decrease in the BP I subgroup of patients. However, significantly greater mean improvement compared to placebo on the MADRS was observed not only in the BP I subgroup but also in patients with BP II disorder.

Challenges in the treatment of bipolar depression

Improving tolerability and treatment effectiveness remain crucial challenges when using pharmacologic agents for the management of bipolar depression. Thirty-four percent of patients receiving olanzapine,

 and 18% of patients receiving lamotrigine7 discontinued treatment because of adverse events, lack of efficacy, or relapse into a mood episode.

In the lamotrigine study, the rate of withdrawals due to adverse events was similar with active drug and placebo. In the olanzapine trial, patients receiving olanzapine monotherapy were most likely to discontinue treatment because of excessive somnolence, and had higher dropout rates because of adverse events than did patients who received an olanzapine- fluoxetine combination or placebo. Analysis of dropouts in patients who received quetiapine also showed higher rates of withdrawal because of sedation and somnolence.

Such data help to answer the question, “When is it best to use lamotrigine or an atypical antipsychotic in the acute treatment of bipolar depression?” In our experience, nonresponders to lamotrigine are typically responders to quetiapine and vice versa. Those who may respond best to quetiapine are typically agitated, restless, anxious, and suicidal patients who benefit from the anxiolytic and sedating properties of quetiapine.

Likewise, nonresponders to quetiapine usually demonstrate symptoms of fatigue, psychomotor retardation, and hypersomnolence; these patients may benefit most from lamotrigine. While these observations are speculative, they could assist the physician in determining which initial agent to prescribe based on the available data linking differences in dropout rates to adverse events.

 and the olanzapine-fluoxetine combination

 the response rates approximated 50%. These figures are similar to the response rate (47%) reported in the recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial

 of unipolar depression. Still, this indicates that available treatments for bipolar depression appear to be effective for only about 50% of patients, leaving significant numbers of individuals with debilitating symptoms, including suicidality.

Even among patients who had achieved recovery from a bipolar mood episode, a recent Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) report determined that when followed prospectively, 144 (22.4%) of 644 patients experienced a depressive recurrence within 1 year.

 A greater percentage of days depressed over the past year, residual depressive symptoms at recovery, and a higher lifetime number of depressive episodes were all indications of recurrence of depressive episodes. Data from the STEP-BD report support the need for alternative therapeutic agents that offer complete recovery from a major depressive episode and can sustain these effects over the maintenance phase.

Other treatment strategies for bipolar depression that have been evaluated in controlled trials are reviewed elsewhere.

 In this article, we have included a summary of agents studied in the depressed phase of bipolar disorder based on the strength of trial methodology .

Not to be overlooked is the use of lithium, a cornerstone in the management of bipolar disorder, with proven antidepressant effects dating back more than 30 years.

 Placebo-controlled studies of lithium, however, have generally enrolled small numbers of patients and are limited by methodologic concerns, such as use of crossover designs. A more recent study of lithium indicates that higher blood levels may be most useful, since no additional antidepressant benefit was achieved by the administration of paroxetine or imipramine when blood levels of lithium were maintained above 0.8 mEq/L.

 With long-term use, another advantage of lithium is its ability to protect patients from suicide.

 have also been studied in placebo-controlled trials of acute bipolar depression, albeit studies involving these drugs have enrolled only limited numbers of patients. Use of a doubleblind, placebo-controlled, off-on-off design found that treatment with carbamazepine achieved response in 63% (15/24) of bipolar patients at an average dosage of 971 mg/d.

 The results of a placebo-controlled trial of divalproex in BPI depression have been published.

 The data from this trial (which consisted of 25 patients) indicated that the rate of improvement over time in depressive symptoms was about twice as high in patients who received divalproex as it was in those who received placebo.

Two unpublished studies have evaluated the antidepressant effects of divalproex in patients with BP I, BP II, or bipolar disorder not otherwise specified. In the first trial, conducted over 8 weeks, patients treated with divalproex showed improvement over placebo at weeks 2 and 5, but not at the study’s end point, as assessed by mean change in 

 In a 6-week trial of divalproex extended release, significant improvement over placebo was demonstrated on the MADRS despite the small sample size of 18 patients.

Taken as a whole, the evidence for divalproex and carbamazepine as monotherapy in the treatment of acute bipolar depression is less substantial than the evidence that exists for lithium, lamotrigine, or the antipsychotics quetiapine and olanzapine. For this reason, expert guidelines often suggest divalproex and carbamazepine as third-

Algorithms for the acute treatment of depressive episodes in bipolar disorder have been developed by the American Psychiatric Association,

 the Texas Implementation of Medication Algorithms Panel,

 and the Canadian Network for Mood and Anxiety Treatments.

 Expert recommendations concur that antidepressants should not be used as monotherapy in BP I depression. It is generally agreed that mood stabilizer treatment should be optimized before beginning a specific antidepressant regimen.

For patients taking lithium, this entails reaching a blood level equal to 0.8 mEq/L, and for patients with a history of severe or recent mania, beginning or continuing an antimanic agent. For patients not taking an antimanic agent or for those without a history of severe or recent mania, lamotrigine would be an appropriate initial choice. Next step treatments include switching to quetiapine or a combination of olanzapinefluoxetine. If patients still remain symptomatic, treatment strategies would incorporate combinations of lithium, lamotrigine, divalproex, carbamazepine, quetiapine, olanzapine, selective serotonin reuptake inhibitors (SSRIs), or bupropion. Electroconvulsive therapy has also shown positive results in treatment of bipolar depression,

Treatment with the SSRI venlafaxine has been associated with higher rates of mania or hypomania,

 as has treatment with tricyclic antidepressants.

 Long-term use of antidepressants in bipolar disorder is an ongoing controversy. Benefits from the addition of an antidepressant may be limited to the first 6 months of treatment,

 with some investigators advocating the withdrawal of antidepressants after resolution of the acute depressive episode.

 Still others argue that antidepressants should not be discontinued if they were used successfully in conjunction with a mood stabilizer during an acute depressive episode. This is based on retrospective data indicating that withdrawal of the antidepressant was associated with significantly higher 1-year relapse rates.

Depressive symptoms are a prominent concern in the care of patients with bipolar disorder. Accurate diagnosis and rapid introduction of treatment in the acute phase are essential to achieving favorable outcomes. There is solid evidence for the use of atypical antipsychotics, lithium, and anticonvulsants in the initial management of bipolar depression. How frequently traditional antidepressants should be prescribed in bipolar disorder and the appropriate duration of their use remains unclear.

For now, the task is to better define optimal treatments that are effective for a majority of patients, that are well tolerated, that do not result in cycling, and are successful at maintaining a lasting response. Given the limitations or partial efficacy of the reviewed monotherapies, future investigation of combined pharmacotherapies for acute bipolar depression seems warranted. Focusing our attention on the depressed phase of bipolar disorder remains the fundamental challenge.

Drs Kemp and Gao are research fellows in the department of psychiatry at Case Western Reserve University and University Hospitals of Cleveland. Dr Kemp has no conflicts of interest to report. Dr Gao reports that he has received honoraria from AstraZeneca.

Dr Muzina is vice chair for research and education in the department of psychiatry at the Cleveland Clinic Foundation. He reports that he has received honoraria, consulting fees, or research support from the following: AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Abbott Laboratories, and Repligen.

Dr Calabrese is a professor of psychiatry, and director of the mood disorders program and the bipolar disorders research center in the department of psychiatry at Case Western Reserve University and University Hospitals of Cleveland. He reports that he receives funding from Abbott Laboratories, AstraZeneca, Merck, GlaxoSmithKline, Janssen, Eli Lilly, and Pfizer. He is on the advisory boards or has consulting agreements with Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb/Otsuka, Eli Lilly, GlaxoSmithKline, Janssen, and Teva.

Amitriptyline (Elavil, Norfranil, others)  
Bupropion (Wellbutrin, Zyban)  
Carbamazepine (Carbatrol, Tegretol, others)  
Citalopram (Celexa)  
Desipramine (Norpramin, others)  
Divalproex (Depacon, Depakene, Depakote)  
Escitalopram (Lexapro)  
Fluoxetine (Prozac, Sarafem)  
Gabapentin (Neurontin)  
Imipramine (Endep, Tofranil, others)  
Lamotrigine (Lamictal)  
Lithium (Eskalith, Lithane, others)  
Moclobemide (Manerix)  
Olanzapine (Zyprexa)  
Paroxetine (Paxil)  
Pramipexole (Mirapex)  
Quetiapine (Seroquel)  
Riluzole (Rilutek)  
Risperidone (Risperdal)  
Sertraline (Zoloft)  
Topiramate (Topamax)  
Tranylcypromine (Parnate)  
Venlafaxine (Effexor)  
Zonisamide (Zonegran)

1. Judd LL, Akiskal HS, Schettler PJ, et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002; 59:530-537.  
2. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the longterm weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.  
3. Calabrese JR, Hirschfeld RM, Frye MA, Reed ML. Impact of depressive symptoms compared with manic symptoms in bipolar disorder: results of a US community-based sample. J Clin Psychiatry. 2004; 65:1499-1504.  
4. Tondo L, Isacsson G, Baldessarini R. Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs. 2003;17:491-511.  
5. Hantouche EG, Akiskal HS, Lancrenon S, et al. Systematic clinical methodology for validating bipolar- II disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord. 1998;50:163-173.  
6. Hirschfeld RM, Cass AR, Holt DC, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18:233-239.  
7. Calabrese JR, Bowden CL, Sachs GS, et al. A doubleblind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 study group. J Clin Psychiatry. 1999;60:79-88.  
8. Calabrese J, Sachs G, Hirschfeld RM, et al. Efficacy and safety of lamotrigine in acute bipolar depression: findings from three completed studies. Poster presented at: 45th Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting. June 6-9, 2005; Boca Raton, Fla.  
9. Gao K, Calabrese JR. Newer treatment studies for bipolar depression. Bipolar Disord. 2005;7(suppl 5): 13-23.  
10. Ketter TA, Wang PW, Chandler RA, et al. Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash. J Clin Psychiatry. 2005;66:642-645.  
11. Calabrese JR, Bowden CL, Sachs G, et al. A placebo- controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003; 64:1013-1024.  
12. Bowden CL, Calabrese JR, Sachs G, et al. A placebo- controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60:392-400.  
13. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1088.  
14. Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162:1351-1360.  
15. Cohen J. Statistical Power Analysis for Behavioral Sciences. Hillsdale, NJ: Erlbaum; 1987.  
16. Thase ME, Macfadden W, McCoy R, et al. Confirmation of the efficacy of quetiapine monotherapy in bipolar depression in a second double-blind, placebocontrolled study: The BOLDER II study. Poster presented at: 159th American Psychiatric Association Annual Meeting. May 20-25, 2006; Toronto.  
17. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006; 163:28-40.  
18. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163:217-224.  
19. Gao K, Gajwani P, Elhaj O, Calabrese JR. Typical and atypical antipsychotics in bipolar depression. J Clin Psychiatry. 2005;66:1376-1385.  
20. Goodwin FK, Murphy DL, Dunner DL, Bunney WE Jr. Lithium response in unipolar versus bipolar depression. Am J Psychiatry. 1972;129:44-47.  
21. Nemeroff CB, Evans DL, Gyulai L, et al. Doubleblind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158:906-912.  
22. Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60(suppl 2):77-84, discussion 111-116.  
23. Post RM, Uhde TW, Roy-Byrne PP, Joffe RT. Antidepressant effects of carbamazepine. Am J Psychiatry. 1986;143:29-34.  
24. Ballenger JC, Post RM. Carbamazepine in manicdepressive illness: a new treatment. Am J Psychiatry. 1980;137:782-790.  
25. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005;85:259-266.  
26. Dunn RT, Gilmer W, Fleck J, et al. Efficacy of divalproex in the treatment of acute bipolar depression: a randomized clinical trial. Poster presented at: 159th American Psychiatric Association Annual Meeting. May 20-25, 2006; Toronto.  
27. Sachs GS, Altshuler LL, Ketter T, et al. Divalproex versus placebo for the treatment of bipolar depression. Poster presented at: American College of Neuropsychopharmacology 40th Meeting. December 9-13, 2001; Waikoloa, Hawaii.  
28. Yatham LN, Kennedy SH, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(suppl 3):5-69.  
29. Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886.  
30. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(suppl 4): 1-50.  
31. Ciapparelli A, Dell’Osso L, Tundo A, et al. Electroconvulsive therapy in medication-nonresponsive patients with mixed mania and bipolar depression. J Clin Psychiatry. 2001;62:552-555.  
32. Vieta E, Martinez-Aran A, Goikolea JM, et al. A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry. 2002; 63:508-512.  
33. Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163:232-239.  
34. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University Press; 1990.  
35. Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry. 1984;41: 1096-1104.  
36. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressants in bipolar disorder: the case for caution. Bipolar Disord. 2003;5:421-433.  
37. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry. 2001;62:612-616.  
38. Frye MA, Ketter TA, Kimbrell TA, et al. A placebocontrolled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20:607-614.  
39. Zornberg GL, Pope HG Jr. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol. 1993;13:397-408.  
40. Himmelhoch JM, Fuchs CZ, Symons BJ. A double-blind study of tranylcypromine treatment of major anergic depression. J Nerv Ment Dis. 1982; 170:628-634.  
41. Bocchetta A, Bernardi F, Burrai C, et al. A doubleblind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives. Acta Psychiatr Scand. 1993;88:434-439.  
42. McIntyre RS, Mancini DA, McCann S, et al. Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord. 2002;4:207-213.  
43. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55:391-393.  
44. Silverstone T. Moclobemide vs. imipramine in bipolar depression: a multicenter double-blind clinical trial. Acta Psychiatr Scand. 2001;104:104-109.  
45. Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment- resistant bipolar depression. Am J Psychiatry. 2004;161:564-566.  
46. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry. 2004;65:1715-1719.  
47. Post RM, Altshuler LL, Leverich GS, et al. Higher switch rate on venlafaxine than bupropion or sertraline in bipolar depression. Br J Psychiatry. In press.  
48. Kupfer DJ, Chengappa KN, Gelenberg AJ, et al. Citalopram as adjunctive therapy in bipolar depression. J Clin Psychiatry. 2001;62:985-990.  
49. Fonseca M, Soares JC, Hatch JP, et al. An open trial of adjunctive escitalopram in bipolar depression. J Clin Psychiatry. 2006;67:81-86.  
50. Osher Y, Bersudsky Y, Belmaker RH. Omega-3 eicosapentaenoic acid in bipolar depression: report of a small open-label study. J Clin Psychiatry. 2005; 66:726-729.  
51. Zarate CA, Jr, Quiroz JA, Singh JB, et al. An openlabel trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57:430-432.  
52. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry. 2005;66:195-198.

A discussion of the pharmacologic management of bipolar depression, including emerging treatments and expert recommendations.

Author | David J. Muzina, MD

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