Caleb Adler, MD

Bipolar disorder is a longitudinal disorder defined by multiple episodes that may occur years apart. As a result, the proper diagnosis requires careful evaluation of both the current symptoms and the patient’s history. The majority of patients with bipolar disorder initially present during an episode of depression, which can be difficult to distinguish from major depressive disorder if there has not been a known manic or mixed episode in the past.

 Not surprisingly, many bipolar patients report a history of diagnostic confusion and delayed treatment.

Mr Smith, a 32-year-old, is referred by a local family practitioner. He complains of a debilitating depression that has lingered for many months. He has not been able to enjoy his usual hobbies and has been feeling increasingly distant from his wife. He observes that his energy has been so low that his work has suffered; he fears that his job may be in jeopardy.

He has been staying home and sleeping more, and he cannot concentrate. Once an avid reader, he now can barely collect himself to watch television or hold a lengthy conversation. With some prodding, Mr Smith admits to a loss of sexual interest in his wife, which has led to marital problems. While he denies being overtly suicidal, Mr Smith concedes that he has been thinking about his death; he fantasizes about being accidentally killed.

His primary care physician diagnosed major depressive disorder last December and began the first of a series of antidepressant medications that eventually included fluoxetine, mirtazapine, and bupropion. Mr Smith tolerated the medications well but reports that none of them improved his mood. By the middle of March, his physician had grown concerned at his lack of progress and suggested that Mr Smith see a psychiatrist as soon as possible for further evaluation; it is now mid-April, and there has been no remission of symptoms.

When asked about his history, Mr Smith reveals that he has had a series of similar episodes, starting in early childhood. While none of the episodes were as debilitating as his current state, many persisted for more than 2 weeks and interfered with his ability to work as well as with family life.

He recounts that for a few weeks in 1998, his mood became quite elevated; the euphoria was accompanied by increased energy and a loss of any need to sleep. He reports that he felt like he was getting a lot of things accomplished but could not focus sufficiently to finish any of the projects he started. Nonetheless, he recalls the immense self-confidence that he had at the time. Ultimately, he was involved in an altercation with the local police and was hospitalized. Mr Smith does not recall what medications he received at the time. Shortly after being discharged, he discontinued the medications. He is embarrassed about the incident and does not like to discuss it. He denies any history of psychiatric symptoms in his first-degree relatives but notes that his grandmother often had “spells” and was hospitalized for a nervous breakdown.

A careful patient history is critical; on closer questioning, Mr Smith revealed what appears to have been a previous manic episode, as well as several potential signs of bipolar depression. He reports numerous episodes of depression that began when he was young and a possible family history of bipolar disorder. Bipolar symptoms in even a second-degree relative increase a person’s risk for the disorder. The atypical symptoms, such as increased sleep, may also suggest bipolar disorder. Other symptoms of bipolar disorder are listed in 

It is far from uncommon for patients such as Mr Smith to receive multiple courses of standard antidepressant medications.

 Unfortunately, there are real risks associated with using these medications for bipolar depression. Standard antidepressants may precipitate manic episodes in a minority of bipolar patients and may be ineffective.

 A delayed diagnosis may prolong depression and further affect the patient’s ability to function effectively at home and at work. Prolonged depression may also increase the risk of self-harm.

Some studies suggest that there may be other, less concrete effects of prolonged depression in bipolar patients as well. Correlations have been observed between the number of past affective episodes and subtle cognitive losses in patients with bipolar disorder.

 More recently, some preliminary neuroimaging studies have suggested a link between mood episodes and evidence of neuropathic changes in several regions of the brain.

An accurate diagnosis is, of course, the first step in making treatment decisions. Treatment choices in psychiatry are rarely straightforward, and bipolar depression is no exception to this general rule. Further complicating the process is the limited number of FDA-approved options. The number of FDA-approved medications for bipolar mania has literally tripled over the past decade while the pharmacopeia available for bipolar depression remains quite limited (

Only 1 medication and 1 medication combination are approved by the FDA to treat depression in patients with bipolar disorder. Quetiapine (both immediate- and extended-release) was approved on the basis of 2 large initial trials and a follow-up trial of the extended-release formulation.

 Olanzapine in combination with fluoxetine was also found to be effective for bipolar depression in 2 large trials and was approved only in this combined formulation.

These medications have not been compared in a head-to-head fashion, but a review by Gao and colleagues

 found higher effect sizes for quetiapine than for the olanzapine/fluoxetine combination, which suggests that the former may be more effective (

). In addition, the large weight gain sometimes observed with olanzapine and other potential adverse effects, including sedation, hyperglycemia, and hypercholesterolemia, can limit the usefulness of the olanzapine/fluoxetine combinations. Despite the FDA approval, some consensus guidelines, such as those of the World Federation of Societies of Biological Psychiatry, do not list the olanzapine/fluoxetine combination as first-line treatment for bipolar depression.

 Quetiapine may also be associated with significant adverse effects, including sedation, weight gain, and metabolic syndrome.

In addition to the 2 FDA-approved pharmacotherapies for bipolar depression, at least 1 other medication-lithium-is usually considered to be a first-line treatment option.

 There is a wealth of clinical experience with lithium, and many practitioners report good clinical outcomes in depressed bipolar patients. Nonetheless, the published data are somewhat mixed. Findings from several small studies of lithium have been positive, but a double-blind study of lithium in bipolar depression did not find it to be significantly more effective than placebo.

 The low mean serum drug concentration of 0.61 mEq/L, however, may have compromised the findings. Some studies suggest that a minimum serum lithium level of 0.8 mEq/L may be necessary for efficacy in depressed bipolar patients.

Lithium carries some advantages over atypical antipsychotics, including its affordability and wide availability. Lithium is also associated with a different collection of potentially significant adverse effects, including GI distress and thyroid and renal pathology. The need to monitor blood lithium levels and to obtain regular laboratory screening tests has probably limited its use by nonpsychiatrist clinicians.

Lamotrigine is often considered to be a first-line intervention for bipolar depression, but it has not been approved for this indication.

 As with lithium, there is anecdotal evidence for its efficacy but limited published study data. While results of a single large, randomized, double-blind, placebo-controlled trial have been positive, 4 smaller clinical trials did not find lamotrigine to be an effective treatment for bipolar depression. Nonetheless, a meta-analysis that included all 5 trials found lamotrigine to be particularly effective in patients with more severe depression. Lamotrigine has also been found to be useful in combination with other medications, particularly lithium.

Lamotrigine is associated with a number of potentially serious adverse effects that include Stevens-Johnson syndrome, a potentially fatal dermatological reaction. As a result, lamotrigine dosing should closely adhere to FDA guidelines for its approved uses.

A comparison of effect sizes suggests that quetiapine may be more effective than the olanzapine/fluoxetine combination, but without more data this suggestion is far from conclusive. While a single study that directly compared lithium with quetiapine suggests the latter to be more effective, these findings may have been driven by the low blood levels of lithium in study patients.

It is not unusual for patients to fail to respond to the first medication prescribed. If symptoms do not improve with the initial agent, a switch to a different first-line therapeutic agent may be beneficial. Alternatively, a combination of first-line medications-typically a combination of quetiapine with lithium or lithium with lamotrigine may work.

 Many patients with bipolar depression do not respond to any of the usual first-line medications, and you may need to consider a second-line agent for which there is less evidence of efficacy.

Divalproex is often prescribed for bipolar depression, and while there are no large studies of this agent, 4 studies found the anticonvulsant to be effective, as did a recent meta-analysis.

 While divalproex is often well tolerated, patients may report fairly significant weight gain and there is a risk of hepatotoxicity. Divalproex is also considered by some clinicians to be contraindicated in young women. The medication may increase the rate of polycystic ovary syndrome, and-given the impulsivity often associated with bipolar disorder-the relatively high teratogenicity of divalproex can pose a potential problem.

Divalproex is often combined with a first-line agent, but caution must be exercised because of possible drug interactions. While divalproex can be combined with lamotrigine, FDA guidelines should be followed closely to avoid inadvertently increasing lamotrigine levels and increasing the risk of lamotrigine-related adverse effects.

There are several third-line interventions that can also be considered. These include carbamazepine and olanzapine. Although a few small studies suggest that carbamazepine may be effective for bipolar depression, the findings from a randomized, double-blind, placebo-controlled study were mixed.

 Olanzapine monotherapy was associated with statistically significant improvement in patients with bipolar depression, but the effect size was quite low (

) and probably not clinically significant.

 Other atypical antipsychotic medications have not been found to be effective for bipolar depression.

Several other medications have shown some limited efficacy for bipolar depression in combination with more typical treatments. Two studies have found that as adjunctive medication, both an isomer of modafinil and modafinil itself (an FDA-approved medication for wakefulness) may improve response.

 Two small studies also found adjunctive levothyroxine to be helpful in treating bipolar patients with treatment-resistant depression.

 Zonisamide-another anticonvulsant-used as adjunctive treatment, improved symptoms of bipolar depression, but the medication was very poorly tolerated, with high dropout rates in all 4 trials.

 Inositol is another possible treatment for bipolar depression, although evidence for its efficacy is limited.

The anticonvulsant gabapentin showed weak antidepressant effects as a monotherapeutic agent, with limited evidence of efficacy when given as an adjunct.

 Although Ï-3 fatty acids are often recommended for both bipolar mania and bipolar depression, only 1 small study of ethyl-eicosapentaenoic acid found evidence of efficacy, while a second study failed to observe clinical effects.

Findings from several small case series and chart reviews, and 2 small studies of patients with bipolar disorder type I and II also suggest that pramipexole-a medication approved for Parkinson disease and restless legs syndrome-may be effective for at least some patients with bipolar depression.

The adjunctive use of standard antidepressants in patients with bipolar depression remains fairly controversial. While there is a strong consensus against treating bipolar patients with standard antidepressants as monotherapy, limited data suggest that standard antidepressants may play an adjunctive role in treating otherwise treatment-resistant symptoms of bipolar depression.

 Antidepressant medications differ a great deal in their propensity to induce mania, and adjunctive mood-stabilizing medications appear to protect against treatment-emergent affective switch. Nonetheless, the large STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) analysis did not observe improvement in patients who received standard antidepressants.

 Other meta-analyses that have purported to observe an effect may be methodologically flawed.

In addition to pharmacological treatments for bipolar depression, nonpharmacological modalities have shown promise in improving symptoms in patients with bipolar depression. Probably the most effective nonpharmacological option is electroconvulsive therapy (ECT), which may improve symptoms in some treatment-resistant patients.

 However, many patients are reluctant to consider ECT because of widespread negative associations with “shock treatment” and fears of memory loss.

Two behaviorally focused forms of psychotherapy-cognitive-behavioral therapy and family-focused therapy-have been found to improve outcomes in patients with bipolar depres-sion. In addition, interpersonal social rhythm therapy may be effective as an adjunct of medication-based interventions.

 Sleep deprivation has long been known to improve symptoms of depression. A few open-label trials suggest that this approach may also be effective in bipolar depression. However, the intervention is not without risk; some patients developed treatment-related manic symptoms, similar to those sometimes observed in bipolar patients treated with standard antidepressants.

 Phototherapy has demonstrated some efficacy but may also induce mania in susceptible individuals.

 In addition, decreased stress and exercise may alleviate some symptoms.

Although, the number of new treatments for bipolar depression has lagged well behind that for bipolar mania, there are some innovative interventions on the horizon. A recent double-blind study looked at the adjunctive use of the N-methyl-d-aspartate antagonist ketamine for bipolar depression. Ketamine infusions were associated with an exceptionally rapid response in a high proportion of the patients.

 Repetitive transcranial magnetic stimulation, currently approved for treatment-resistant unipolar depression, has showed some promise for treatment of bipolar depression. Vagus nerve stimulation is also approved for treatment-resistant unipolar depression and may be effective in bipolar depression as well.

There are no clear-cut correct choices. Treating psychiatric illness typically requires an individualized care plan, and bipolar depression is no exception. The construction of a care plan is further complicated by the lack of FDA-approved medications. Most treatment algorithms agree that first-line treatment consists of monotherapy with a proven agent such as quetiapine; an olanzapine/fluoxetine combination; lithium, dosed to a minimum serum level of 0.8 mEq/L; or possibly lamotrigine.

There are few reliable indicators of clinical efficacy to guide the treatment decisions; thus, each option should be discussed with the patient. The final choice is often driven by which medication is likely to be best tolerated. Only if the patient fails to respond to a first-line medication or a combination of first-line agents (eg, lithium and quetiapine, lithium and lamotrigine, olanzapine/fluoxetine combination) should second- and third-line agents be added (

A review of current treatment algorithms highlights how subjective treatment approaches to bipolar depression remain. Many guidelines differ significantly, even with regard to what agents are considered primary interventions. These discrepancies emphasize the need for both more effective treatments for depressed patients with bipolar disorder and more research on existing pharmacotherapies. A review of older treatment algorithms, even those written just a few years ago, is also educational. Treatment approaches have evolved substantially over just a few years; the bulk of these changes have resulted from new research studies of existing medications. It is clear that we need to increase the pace of research on treatments for bipolar depression; it is equally clear that we are moving in the right direction.

NOTE TO READERS: This article was originally presented as an independent educational activity under the direction of CME LLC and published in the July 2011 issue of 

 (2011;28[7]66-71). The ability to receive CME credits has expired. The article is presented here for your reference. 

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Articles

Bipolar disorder is a longitudinal disorder defined by multiple episodes that may occur years apart. As a result, the proper diagnosis requires careful evaluation of both the current symptoms and the patient’s history.

Caleb Adler, MD

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