Of the 2 poles of bipolar disorder, mania is the more dramatic, and indeed the defining, characteristic. Not surprisingly, it has been the major focus of clinical and research attention, while bipolar depression has been relatively neglected. But a growing body of evidence suggests that depression accounts for the greater burden of morbidity and mortality in bipolar disorder and is an underrecognized clinical challenge. Bipolar depression is often misdiagnosed, inappropriately treated in the acute phase, and undertreated in the maintenance phase. Fortunately, increasing interest in bipolar depression has led to an expanding pharmacopoeia, the establishment of international consensus treatment guidelines, and an improved understanding of bipolar disorder as a severe, recurrent illness requiring long-term pharmacotherapy and psychosocial support.

Although manic-depressive illness was classically described in antiquity by Arateus of Cappadocia,^[1] its more modern conceptualization was first described in the 1850s as folie circulaire or folie a` double form^[2] -- apt descriptions of a mental illness causing recurrent oscillations between mania and depression. The pioneer Emil Kraepelin called this syndrome "double attacks," and used the term, "manic-depressive insanity" to describe a broad range of affective disorders that included what we would now call unipolar depression as well as bipolar disorder.^[2] Although the concept of manic-depressive illness involves differing polarities, Kraepelin emphasized the importance of highly recurrent episodes irrespective of mood elevation or depression per se. This Clinical Update uses the term, "bipolar disorder" to refer to the DSM-IV categories of bipolar I disorder (characterized by at least 1 manic episode) and/or bipolar II disorder (characterized by at least 1 hypomanic episode and at least 1 major depressive episode).^[3] Other syndromes that may be considered part of the bipolar spectrum include cyclothymia, hyperthymic temperament, and antidepressant-induced mania and hypomania.^[4]

Epidemiologic studies suggest that the prevalence of bipolar disorder is greater than once believed. Using a self-report screening tool, the Mood Disorders Questionnaire, Hirshfeld and colleagues^[5] found a 3.4% lifetime prevalence of bipolar spectrum disorders (including bipolar I, bipolar II, cyclothymia, and bipolar disorder not otherwise specified) in a US community sample. Unlike unipolar depression, which is more common in women than in men, bipolar disorder has roughly the same gender distribution,^[3] although women appear to have more depressive symptomatology than men^[2] as well as a higher prevalence of rapid cycling, defined as 4 or more episodes per year.^[6] The first mood episode in bipolar disorder tends to occur earlier than in unipolar depression, often during adolescence,^[7] and the episode frequency in bipolar disorder has been reported as double that of unipolar depression.^[8]

In the 1850s, the prognosis of folie circulaire was considered, "desperate, terrible and incurable."^[1] Modern studies of the natural history of bipolar disorder suggest that although the disease is treatable, affective episodes are highly recurrent and subsyndromal mood symptoms are often both common and chronic.^[9] Indeed, the World Health Organization in 1996 ranked bipolar disorder as the sixth most disabling condition worldwide.^[10] The National Institute of Mental Health Collaborative Program on the Psychobiology of Depression, Clinical Studies found overall mood-episode recurrence rates for bipolar disorder of 81% over 7 years.^[11] Among patients on lithium maintenance treatment, recurrence rates were more than 70% during the first 5 years after recovery.^[11] Angst and Presig reported that after the onset of illness, bipolar patients spent about 19% of their lives in mood episodes.^[12] Goldberg and colleagues' naturalistic follow-up study found that only 41% of bipolar patients had a good overall outcome over 4.5 years.^[13] Bipolar patients also have increased rates of suicide and natural causes of death compared with the general population.^[14-16] In bipolar I disorder, rates of completed suicide have been estimated at 10% to 15%.^[3]

The specific impact of depression vs mania in bipolar disorder became the focus of attention in the 1990s. Patients are more likely to seek help when in the depressed rather than the manic or hypomanic state.^[17] Depression -- either alone or in conjunction with manic or hypomanic features -- comprises about three quarters of the time spent with mood symptoms in bipolar I disorder and over 90% of the time spent with mood symptoms in bipolar II disorder.^[18,19] Two recently reported studies suggest that many bipolar II disorder patients experience persistent, subsyndromal depressive symptoms.^[19,20] Patients with repeated depressive episodes or subsyndromal depression are particularly likely to have impaired psychosocial functioning and poor outcomes.^[21] The risk of suicide increases along with the length of depressive episodes^[22] and is more common during depressive or mixed-state episodes than mania.^[22-24] Thus, it appears that the depressive pole of bipolar disorder is responsible for the greater burden of disease.

The first clinical challenge of bipolar depression is simply to make the correct diagnosis. Bipolar disorder is often misdiagnosed as depression in patients who present with depression.^[25,26] Missed diagnoses are also common in part because comorbidity is frequent with bipolar disorder,^[23] and the presence of substance abuse, medical illness, anxiety disorders, and personality disorders may confuse the symptom picture. In addition, eliciting information about past hypomanic or manic symptoms from a currently depressed patient may be extremely difficult. In other cases, the presenting depression is the index episode of bipolar disorder, so there will be no hypomanic or manic history to elicit.^[27] Finally, there may be a tendency to diagnose unipolar depression when the history is ambiguous since bipolar disease is a more stigmatizing condition with a worse prognosis.

Unfortunately, the ramifications of a missed diagnosis can be severe. Patients whose disease is incorrectly assessed as unipolar depression are likely to be prescribed antidepressant monotherapy, which can cause mood destabilization -- that is, the induction of mania or the acceleration of cycling frequency over time, phenomena that have been reported to occur in approximately 25% to 40% of patients with bipolar disorder.^[28] Misdiagnosis may also lead to delayed initiation of a mood stabilizer -- and delaying appropriate treatment may increase the risk of suicide, impair psychosocial functioning, and reduce the likelihood of a response to lithium.^[29,30]

Clinicians can employ several strategies to improve their diagnostic sensitivity for bipolar depression. At a minimum, every patient who presents with a depressive syndrome should be asked about past history of manic or hypomanic symptoms. Obtaining collateral history from family members or close friends may be the key to uncovering a more complete history. Subtle clues that point to underlying bipolar illness in a depressed patient include early onset of illness, presence of psychosis, hyperthymic temperament, and family history of mood disorder.^[27,28] Symptoms reported more commonly in bipolar depression than in unipolar depression include hypersomnia, psychomotor retardation, and mood lability.^[31-33] Finally, when bipolar depression is diagnosed, clinicians should assess the prior frequency of mood episodes, since the presence of rapid cycling or recent mania^[34] affects treatment outcome.

The second clinical challenge of bipolar depression is to select a treatment that will be both efficacious enough for acute treatment and tolerated well enough to encourage patient adherence during long-term maintenance therapy. Unfortunately, data regarding the treatment of bipolar depression are less abundant than data for the treatment of mania, and depressive episodes appear more difficult to treat without causing mood destabilization.^[35] Currently available treatment options include mood stabilizers, as monotherapy or in combination; atypical antipsychotics, as monotherapy or augmentation with mood stabilizers; antidepressants, as augmentation to mood stabilizers; and electroconvulsive therapy (ECT). Psychotherapy alone is not considered sufficient to treat acute bipolar depression.^[36] However, when combined with pharmacotherapy, psychosocial treatments can reduce subsyndromal symptoms and aid in relapse prevention.

Mood Stabilizers

Lithium. Lithium was approved for use in bipolar disorder by the US Food and Drug Administration (FDA) in 1971. It is the most well-studied agent for the treatment of bipolar disorder, although many of the early research trials can be criticized for flawed methodology.^[36]

Evidence supporting the use of lithium for the acute treatment of bipolar depression includes positive results in several randomized, controlled trials.^[37] However, 3 randomized, parallel-design trials comparing lithium with imipramine in the acute treatment of bipolar depression produced conflicting results.^[38] There is no evidence that lithium causes mood destabilization.^[38]

Controlled studies indicate that lithium is effective in preventing depressive and manic relapse in the maintenance treatment of bipolar disorder. For example, Tondo and colleagues studied 360 patients with bipolar I and bipolar II disorder and found that lithium maintenance reduced the duration of mood episodes, percentage of time in mood episodes, and rates of depression, mania, and hospitalization.^[39] Suicidal behaviors and rates of completed suicide have been determined to be significantly lower among bipolar patients receiving long-term lithium treatment compared with untreated subjects.^[40] Overall, the body of evidence suggests that lithium monotherapy is superior to placebo in the acute treatment of bipolar depression and in the maintenance treatment of bipolar disorder, although there is a more pronounced benefit in preventing mania than depression.^[38,41]

Poor adherence with lithium treatment has been noted in several studies,^[42,43] and it may be attributed in some patients to poor tolerability. Lithium has a narrow therapeutic index, and side effects include tremor, hypothyroidism, and renal toxicity. Regular monitoring of thyroid and renal function as well as serum lithium levels is required.

Lamotrigine. In 2003, lamotrigine became the second agent to receive FDA approval for the maintenance treatment of bipolar disorder. It appears to have antidepressant as well as mood-stabilizing properties. Lamotrigine has also been found to be effective in rapid-cycling bipolar disorder,^[44] and there is no evidence that this agent causes mood destabilization.^[45]

In a double-blind, controlled trial of lamotrigine monotherapy for the acute treatment of bipolar I depression, Calabrese and colleagues^[46] found that lamotrigine was superior to placebo at doses of 50 mg and 200 mg per day. Significant improvement in depressive symptoms was seen as early as the third week of treatment in patients treated with lamotrigine at doses less than or equal to 50 mg per day. A second acute illness study by Frye and colleagues,^[47] focusing on treatment-resistant mood disorder patients at the National Institute of Mental Health, also found lamotrigine to be more effective than placebo for depressive symptoms. However, lamotrigine is not FDA-approved for the treatment of acute mood episodes in bipolar disorder.

For maintenance treatment, two 18-month trials studied the effectiveness of lamotrigine compared with lithium and placebo.^[48,49] Both trials found lamotrigine and lithium to be superior to placebo in increasing the time to intervention for mood episode. Lamotrigine was superior to placebo in prolonging time to depressive relapse. In addition, a small open-label trial of lamotrigine as add-on therapy showed efficacy in 72% of patients with bipolar depression.^[50]

Unlike lithium, lamotrigine does not require serum level monitoring. The most significant adverse effect is rash. Calabrese and colleagues^[51] performed a retrospective analysis of rates of lamotrigine-associated rash in 12 multicenter studies. They found that 8.3% of patients receiving lamotrigine in controlled trials reported benign rash, compared with 6.4% of patients on placebo. Serious rash was seen in 0% of lamotrigine-treated patients and 0.1% of patients receiving placebo. In open-label studies, 13.1% of patients receiving lamotrigine reported rash, and 0.1% reported serious rash, including 1 case of mild Stevens-Johnson syndrome.

Serious rashes with lamotrigine are more likely to occur between the second and eighth weeks of treatment and typically involve systemic disturbances, often manifesting with blistering or burn-like lesions on soft mucocutaneous tissues (eg, oral-buccal mucosa, conjunctivae) or the palms and soles. To reduce the risk of rash, gradual titration of lamotrigine is recommended (namely, 25 mg/day for 2 weeks, followed by 50 mg/day for 2 weeks, with further dosage increases to 100 mg/day for 1 week and then a target dose of 200 mg/day). Starting doses should be adjusted downward for children or patients on cytochrome P450 inhibitors such as valproate, and upward for patients on inducing agents such as carbamazepine. The risk for benign rashes also can be minimized by advising patients to avoid exposures to environmental agents that may in themselves cause rashes (eg, new detergents, colognes or perfumes, animals) that could become wrongly attributed to lamotrigine.^[51]

Valproate. This agent was FDA approved to treat acute mania in bipolar disorder in 1995 and is commonly used off-label for maintenance therapy. Only 1 controlled study has thus far examined the usefulness of valproate in bipolar depression. In an 8-week randomized, placebo-controlled trial of valproate in 45 acutely depressed bipolar I and II patients, Sachs and colleagues found no significant difference in rates of recovery or in Hamilton Depression Rating Scale (HDRS) scores at the end of the study. However, patients receiving valproate had significantly lower HDRS scores at the second, fourth, and fifth week.^[52]

Five randomized trials have evaluated valproate in the maintenance treatment of bipolar disorder.^[53-57] An 18-month open-label trial comparing the valpromide formulation with lithium found a slight reduction in the mean number of mood episodes in the valpromide group.^[53] The only placebo-controlled maintenance trial failed to find a significant difference in time to relapse among patients treated with lithium, valproate, and placebo,^[54] but this may be due to methodologic problems.^[57,58]

Valproate is a cytochrome p450 enzyme inhibitor, and its use can lead to several drug-drug interactions, including increasing levels of lamotrigine. The most frequently reported side effects with valproate treatment for acute mania are nausea, vomiting, dizziness, and sedation.^[59,60] Tremor and weight gain are also frequently seen. Serious adverse events include hepatotoxicity, pancreatitis, thrombocytopenia, and teratogenicity. Serum valproate levels, liver function tests, and complete blood counts should be monitored during treatment.

Carbamazepine. Carbamazepine has been used for the maintenance treatment of bipolar disorder since the 1980s, but it has not been well studied in the treatment of bipolar depression. Yatham and colleagues^[38] recently reviewed 3 early placebo-controlled, cross-over studies, which involved a total of 40 patients with bipolar depression.^[61-63] Twenty-seven patients (68%) responded to carbamazepine, and 20 patients (50%) relapsed when placebo was substituted for the anticonvulsant.

Because carbamazepine is a cytochrome p450 enzyme inducer and is highly protein bound, its use can lead to several drug-drug interactions. Common side effects include neurologic symptoms, fatigue, and nausea. Serious adverse events include agranulocytosis, aplastic anemia, hepatic failure, Stevens-Johnson syndrome, and pancreatitis. Serum carbamazepine levels, complete blood counts, platelet counts, and liver function tests should be monitored during treatment.

Antidepressants vs Standard Mood Stabilizers

From the perspective of relative efficacy, it remains uncertain whether some mood stabilizers or combinations of mood stabilizers may possess antidepressant efficacy differing from that associated with standard antidepressants. In the sole randomized, controlled study assessing this question, Young and colleagues^[64] observed similar rates of improvement in depression symptoms among bipolar depressed patients taking either 2 mood stabilizers (lithium plus divalproex) or either 1 of these agents plus the SSRI paroxetine. Overall tolerability was greater with SSRI augmentation than combination mood stabilizers. In addition, patients who had been in a manic phase of illness in the preceding 2 months generally had better outcomes when combination mood stabilizers were used.^[65]

Atypical Antipsychotics

Olanzapine. Olanzapine received FDA approval in 2000 for the treatment of mania, and in 2004 for both maintenance treatment of bipolar disorder and the treatment of bipolar depression when combined with fluoxetine. Along with quetiapine,^[66] olanzapine is the only atypical antipsychotic with established efficacy for bipolar depression based on double-blind, placebo-controlled trials.^[38]

For the acute treatment of bipolar I depression, a randomized, placebo-controlled, 8-week trial evaluated the efficacy of olanzapine and combination olanzapine/fluoxetine.^[67] Patients received either olanzapine 5 to 20 mg/day, placebo, or olanzapine 6 or 12 mg/day combined with fluoxetine 25 or 50 mg/day. The olanzapine groups showed statistically significant reductions in depressive symptoms compared with placebo. Significantly higher response and remission rates were found in the olanzapine/fluoxetine group compared with the olanzapine monotherapy group. Rates of manic switching in the olanzapine groups were low and similar to that in the placebo group. Clinically, the magnitude of the effect size for the olanzapine plus fluoxetine combination was substantial as compared with a more modest effect size with olanzapine alone.

Evidence of olanzapine's usefulness as maintenance treatment includes an open-label 6-month extension phase of the previous trial,^[68] and a randomized, double-blind, 12-month trial that concluded that olanzapine as maintenance treatment is more effective than lithium in preventing manic relapse and similar to lithium in preventing depressive relapse.^[69]

Olanzapine-associated weight gain has been well documented.^[70,71] Olanzapine has also been associated with lipid abnormalities and glucose dysregulation, which may lead to metabolic syndrome and new-onset diabetes. As an atypical antipsychotic, olanzapine is less likely to cause extrapyramidal symptoms (EPS) than typical neuroleptics, although the risk of EPS increases with increasing dose.

Quetiapine. This agent is FDA approved for the treatment of mania, but recent research suggests it may have a role in the depressive phase as well. In an 8-week study of 539 patients, Calabrese and colleagues^[66] demonstrated a superior antidepressant response and large effect size with quetiapine, dosed either at 300 or 600 mg/day, compared with placebo for the treatment of acute bipolar depression. Similarly, a study by Baldassano^[72] showed a low number of patients with treatment-emergent depression when quetiapine was used as either monotherapy or in combination with lithium/divalproex. As with other atypical antipsychotics, the risk of weight gain and associated metabolic disorders are a concern with quetiapine, but in a recent consensus statement,^[73] based on currently available evidence, clozapine and olanzapine were judged to have the greatest effect on weight gain and risk for diabetes and dyslipidemias; risperidone and quetiapine were judged to have intermediate effects; and aripiprazole and ziprasidone were judged to have the least effects, given the more limited available experience with these latter compounds to date.

Other atypical antipsychotics. Clozapine, olanzapine, risperidone, and quetiapine have been FDA approved for the treatment of mania, while others, including ziprasidone and aripiprazole, are anticipating approval. Clozapine, risperidone, ziprasidone, and aripiprazole all have antimanic as well as antipsychotic properties, but none of these agents has been systematically studied in the treatment of bipolar depression.^[74] Some of these agents have been reported to reduce depressive symptoms during episodes of mixed or dysphoric mania either in secondary analyses of controlled trials or in open-label studies, as has been described with risperidone.^[75] McIntyre and Katzman's 2003 review of the role of atypicals in bipolar depression concluded that these agents are important therapeutic options, based primarily on evidence from studies of olanzapine and risperidone.^[74]

The side effect profiles of the atypical antipsychotics vary. Clozapine's usefulness is limited by the possibilities of seizure and agranulocytosis. The latter necessitates frequent monitoring of complete blood counts. Clozapine and olanzapine are the atypicals most likely to cause weight gain, lipid abnormalities, and hyperglycemia,^[73,75-78] while risperidone is more likely to cause hyperprolactinemia.^[79]

Antidepressants and the Risk of Mood Destabilization

The use of antidepressants in bipolar disorder is as controversial as it is common. The major concern is the potential to induce mood destabilization. The risk of antidepressant-induced mania among bipolar disorder patients has been estimated at between 20% and 40%,^[28] and some bipolar patients appear particularly susceptible to mood switching. Patients with a history of substance abuse and/or dependence, and those exposed to multiple antidepressant trials, have been shown to have an elevated risk for developing antidepressant-induced mania.^[80] Patients with a family history of bipolar disorder^[81] or a personal history of prior antidepressant-induced mania or hypomania may also be at increased risk.^[28] Genetic factors related to polymorphic candidate genes in the serotonin system also may contribute to an individual's susceptibility to this adverse outcome.^[82]

Are some antidepressants more or less likely than others to cause mood destabilization? Answers to this question are partly obscured by the remarkably small number of controlled trials using modern antidepressants specifically for bipolar depression, as well as variability across study designs, and the frequent failure to account for baseline characteristics that might inherently predispose some patients to develop manias or hypomanias when exposed to antidepressants, such as past history of this event itself.^[28] Treatment guidelines have suggested that bupropion and SSRIs are safer choices than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).^[36,83] However, a preliminary analysis of a double-blind study of switch rates in bipolar patients treated acutely with mood stabilizers and bupropion, sertraline, or venlafaxine found an overall switch rate of 14%, comparable with rates seen with MAOIs and TCAs.^[84] Calabrese and colleagues^[85] conducted a review of switch rates reported in controlled trials of acute bipolar depression and found that fluoxetine administered with olanzapine, and paroxetine administered with lithium or valproate, had switch rates comparable with the 2% to 6% seen with placebo. Bupropion's switch rate was reported at 11% when given with a mood stabilizer. While there is some evidence that the risk of switching may be reduced by 50% if an antidepressant is added to certain mood stabilizers, such as lithium, rather than given as monotherapy,^[86,87] definitive studies are lacking.^[28]

Novel Pharmacotherapies

A number of innovative somatic treatments have been described specifically for the treatment of bipolar depression, including inositol,^[88] omega-3 fatty acids,^[89] s-adenosyl-methionine,^[90] and calcium channel blockers,^[91] among others. While some of these agents have not been shown to be superior to placebo (eg, omega-3-fatty acids),^[89] or have not yet been examined in controlled studies, one exception is the anti-Parkinsonian drug pramipexole. A pure D2/D3 agonist, pramipexole was initially described as having value comparable with fluoxetine for major depression.^[92] Two recent preliminary, double-blind, randomized, placebo-controlled trials of pramipexole added to mood stabilizers have suggested a marked antidepressant response in about two thirds of treatment-resistant^[93] or bipolar II^[94] bipolar depressed patients, with good overall tolerability.

Electroconvulsive Therapy and Other Forms of Brain Stimulation

ECT is the most effective antidepressant treatment available.^[23] The use of ECT in bipolar depression has been less well studied than in unipolar depression, but short-term response rates appear to be equivalent.^[23,95] Response rates of 50% to 100% in depressed bipolar patients have been reported.^[37] A recent prospective study of the use of ECT in 23 patients with bipolar depression found that after a mean of 7.3 ECT sessions, there was a significant reduction in the patients' symptomatology.^[96] ECT is particularly useful for patients with psychotic depression or for whom pharmacologic treatment is not indicated.

In recent years, novel strategies for delivering more focused brain stimulation that do not rely on seizures have been described for the treatment of depression. Transcranial magnetic stimulation (TMS) creates a magnetic field that generates pulses of electrical activity. A specially designed coil, located in a hand-held device positioned directly above the skull, results in magnetic waves that cause changes in brain activity and can be delivered with intense stimulation and fairly precise control. It has been used mainly in depression, but data are not extensive. Vagal nerve stimulation (VNS) involves the surgical introduction of an electrical stimulator attached to the vagus nerve, delivering stimulation on a frequent schedule (eg, 30 seconds every 5-10 minutes). Taking advantage of the afferent nerve fibers that project to deep brain nuclei, VNS has been developed as a means for providing more targeted stimulation to brain regions thought to play an important role in mood regulation. The procedure is FDA-approved for the treatment of refractory epilepsy and recently became FDA-approved as add-on therapy for treatment-resistant depression (defined as nonresponse to at least 4 adequate standard antidepressant trials). Data with VNS specifically for bipolar depression are not extensive.

Yatham, Calabrese, and Kusumakar^[38] proposed in 2003 that first-line pharmacotherapy for bipolar depression should meet the following 3 criteria:

• Effective in treating acute depressive symptoms,
• Effective in preventing future depressive and/or manic episodes, and
• Without a propensity to induce mood destabilization.

According to these criteria, Yatham and colleagues recommended lithium as the sole first-line agent for bipolar depression. This echoes treatment guidelines published in 2002 by the American Psychiatric Association (APA).^[97] However, evidence from randomized, controlled trials of lamotrigine prompted a revision of the APA guideline, which now includes lamotrigine as a first-line agent for bipolar depression.^[98]

At the December 2003 meeting of the International Consensus Group on Bipolar I Treatment Guidelines, the assembled experts recommended a broader group of medications as first-line options for bipolar depression.^[36] They suggested lithium, lamotrigine, olanzapine, or olanzapine/fluoxetine as first-line treatments for acute and long-term treatment of bipolar I depression.

Depression is generally regarded as virtually an inevitable event in the long-term course of bipolar disorder. In bipolar patients already in treatment, it may arise de novo in those who fail to achieve full remission during treatment with a standard first-line mood stabilizer, or it may arise as a breakthrough episode while taking a mood stabilizer for maintenance treatment. In both cases, the first management strategy is to optimize the original mood stabilizer.^[36] The clinician should consider the likelihood that patients may be nonadherent to a medication, that an adequate dose and duration have been prescribed, and that adequate serum levels of mood stabilizers, where relevant, have been achieved. The clinician should also reassess for substance abuse, medical illness, and other comorbid diagnoses that may affect treatment. If an optimized treatment still fails to achieve an adequate response, most practice guidelines generally advocate next interventions that include either the addition of a second mood stabilizer or atypical antipsychotic, introduction of an antidepressant, or consideration of ECT based on the severity and urgency of a clinical presentation (eg, psychosis with severe suicidal features).

The International Consensus Group on Bipolar I Treatment Guidelines recommended the following treatment strategies for patients who do not respond to first-line pharmacotherapy with lithium, lamotrigine, olanzapine, or olanzapine/fluoxetine:^[36]

• For patients with a recent history of rapid cycling, add lithium, lamotrigine, olanzapine, or valproate.
  
  
• For patients with psychosis, add olanzapine or olanzapine/fluoxetine, or perform ECT.
  
  
• For patients without psychosis or recent history of rapid cycling, add lithium, lamotrigine, olanzapine, or a nontricyclic, non-MAOI antidepressant.

All bipolar patients should be encouraged to continue medication treatment for a minimum of 6 months after remission of an acute depression. Longer-term maintenance treatment is also recommended for bipolar I and bipolar II patients to reduce the risk of relapse.^[36,98] Unfortunately, rates of medication adherence in bipolar disorder are poor.^[99]

One strategy for encouraging medication adherence is to reduce maintenance dosages to minimize side effects. Most patients with bipolar disorder are treated with 2 or more medications during the maintenance phase, with the thought that this strategy may allow for lower doses than if either agent were used singly. However, the only 2 randomized controlled trials of combination vs monotherapy in bipolar maintenance after treatment for an acute manic episode found that combination therapy resulted in increased side effects as well as reduced relapse rates.^[56,57] No published reports have yet described the efficacy of combination maintenance therapies after an index episode of bipolar depression.

For patients treated acutely with a mood stabilizer and an antidepressant, determining when to discontinue the antidepressant may also be problematic. Clinical wisdom suggests that the antidepressant should be discontinued as soon as possible, but 2 studies have shown that early cessation of antidepressants increases the risk of depressive relapse without significantly decreasing the risk of manic or hypomanic switching.^[100,101] Whenever the decision is made to stop an antidepressant, slow tapering is advisable to avoid a discontinuation syndrome, which may trigger or worsen hypomania.^[102]

Medication or ECT alone is inadequate for achieving and maintaining remission for many bipolar patients, and the International Consensus Group recommended that all bipolar I disorder patients should also receive psychosocial treatment.^[36] Psychoeducation, family-based interventions, interpersonal therapy, and cognitive therapy all hold promise for reducing subsyndromal symptoms and/or prolonging time to relapse.

Psychoeducational interventions. This approach is designed to teach patients about bipolar disorder, reduce stigma, encourage medication adherence, and help patients identify prodromal symptoms. Several studies have found that psychoeducational interventions, which may involve fewer than 10 sessions, can increase rates of medication compliance and prolong time to relapse.^[99] For example, Colom and colleagues^[103] performed a randomized trial of 21 sessions of group psychoeducation vs unstructured group meetings for 120 stable bipolar patients that demonstrated that psychoeducation significantly reduced recurrence rates.

Family-based interventions. These attempt to reduce communication problems, blaming, and expressed emotion in families of patients with bipolar disorder. Miklowitz and colleagues' family-focused treatment (FFT) is composed of 21 sessions of psychoeducation and skills training in communication and problem-solving. Two randomized, controlled trials of the treatment found the FFT group had lower relapse rates and less depressive symptomatology than patients treated with psychoeducation and stress management.^[104,105]

Cognitive-behavioral therapy (CBT). CBT is effective in the adjunct treatment of bipolar disorder, including prolonging time to depressive relapse, according to the results of several studies. In a controlled trial specifically for the depressive phase of bipolar disorder, Zaretsky and colleagues^[106] reported testing 20 sessions of CBT in 11 patients with bipolar depression and 11 matched controls with unipolar depression. The authors reported that bipolar subjects had a significant reduction in symptoms, including more than a 50% reduction in HDRS scores. Lam and colleagues^[107] performed a randomized controlled trial of CBT in 103 bipolar I patients prescribed mood stabilizers. They found significantly fewer mood episodes over 1 year of follow-up in the subjects receiving 16 sessions of CBT, compared with those receiving pharmacotherapy alone.

Interpersonal therapy (IPT). IPT has demonstrated benefit in the treatment of unipolar depression; interpersonal and social rhythm therapy (IPSRT) is a form of interpersonal therapy tailored to bipolar patients. In addition to focusing on grief, role conflicts, role transitions, and interpersonal deficiencies, IPSRT includes psychoeducation about bipolar disorder and encourages treatment adherence. There are few data on the efficacy of IPSRT. Frank's preliminary report of a randomized, controlled trial of IPSRT^[108] suggested that bipolar patients receiving the treatment were more often euthymic and less often depressed than patients receiving only clinical management, although there was no difference in time to relapse.

Swartz and Frank's 2001 review^[109] of psychotherapy for bipolar disorder found that adjunctive psychotherapy appears more useful for the depressive than the manic phase of the disorder, and recommended "phase-specific, sequenced" psychotherapies tailored to the state of the patient's illness. Zaretsky's 2003 review^[99] of psychosocial interventions recommends psychoeducation to encourage medication compliance during the early stages of illness, and CBT or IPSRT to resolve residual depressive symptoms.

The final clinical challenge of bipolar depression is to maintain remission in this highly recurrent and sometimes chronic illness. In addition to offering prophylactic medications and psychosocial interventions, clinicians should attend to the therapeutic alliance -- with the patient and, if possible, with the family. Bipolar disorder is associated with poor insight, and a strong alliance with the treating psychiatrist may be a major factor in encouraging adherence to treatment.

Clinicians should also encourage bipolar patients to reduce stress, maintain regular sleep/wake cycles, and be alert for prodromal symptoms that may be harbingers of relapse. A recent review reported that the most common prodromal symptoms of depressive relapse were change in mood and appetite, psychomotor symptoms, and worsening anxiety.^[110]

Bipolar depression has been an underrecognized clinical challenge. It causes significant functional impairment and increased risk of suicide, yet it is commonly underdiagnosed and inadequately treated. Clinicians should consider the diagnosis of bipolar disorder whenever they evaluate patients with depressive symptoms, realizing that a missed diagnosis often means an incorrect treatment and perhaps a worsening of the prognosis. New international consensus guidelines recommend lithium, lamotrigine, olanzapine, or olanzapine/fluoxetine as first-line treatments for bipolar depression, and combination medications or ECT for refractory disease. Antidepressants are commonly -- but controversially -- used in bipolar depression. These agents carry a risk of mood destabilization and should be avoided in patients with a history of rapid cycling. The final, and perhaps most difficult, clinical challenge of bipolar depression is to prevent relapse. Long-term maintenance pharmacotherapy and psychosocial treatment are needed to sustain remission in this highly recurrent and debilitating disorder.

This program was supported by an unrestricted educational grant from GlaxoSmithKline.

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