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Understanding and Treating Bipolar Depression

by Caleb Adler, MD

ipolar disorder is a longitudinal disor der defined by multiple episodes that may occur years apart. As a result, the proper diagnosis requires careful eval uation of both the current symptoms and the pa tients history. The majority of patients with bi polar disorder initially present during an episode of depression, which can be difficult to distin guish from major depressive disorder if there has not been a known manic or mixed episode in the

past.1 Not surprisingly, many bipolar patients re port a history of diagnostic confusion and de layed treatment.2

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 de-

CREDITS: 1.5 RELEASE DATE: July 20, 2011 EXPIRATION DATE: July 20, 2012 FACULTY Caleb Adler, MD, Assistant Professor, University of Cincinnati College of Medicine, Cincinnati FACULTY DISCLOSURES Dr Adler has received research support from Abbott Laboratories, Bristol-Myers Squibb, Forest Laboratories, Johnson & Johnson, Eli Lilly, Otsuka, Pfizer, Repligen, Shire, and Sunovion; he is on the speakers bureau and a consultant for Merck; and he has received an investigator-initiated research grant from AstraZeneca. Applicable CME LLC staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance. TARGET AUDIENCE This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders. GOAL STATEMENT This activity will provide participants with a better understanding of the psychopharmacological options available for the treatment of bipolar depression, as well as a brief overview of other treatment modalities.

ESTIMATED TIME TO COMPLETE The activity in its entirety should take approximately 90 minutes to complete. LEARNING OBJECTIVES After completing this activity, participants should be able to:  Identify available first and second medication options for patients with bipolar disorder Understand the reasons for switching medications  Recognize other options for treating bipolar depression (eg, electroconvulsive therapy [ECT])  Have a sense of future options for treating bipolar disorder COMPLIANCE STATEMENT This activity is an independent educational activity under the direction of CME LLC. The activity was planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME), the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity. ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and policies of the ACCME through the joint sponsorship of CME LLC and Psychiatric Times. CME LLC is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION CME LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should

claim only the credit commensurate with the extent of their participation in the activity. Physician assistants, nurse practitioners, and nurses may participate in this educational activity and earn a certificate of completion, as AAPA, AANP, and ANCC accept AMA PRA Category 1 Credits through their reciprocity agreements. DISCLAIMER The opinions and recommendations expressed by faculty and other experts whose input is included in this activity are their own and do not necessarily reflect the views of the sponsors or supporter. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the faculty or may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Activity participants are encouraged to refer to primary references or full prescribing information resources. METHOD OF PARTICIPATION Participants are required to read the entire article and to complete the posttest and evaluation to earn a certificate of completion. A passing score of 80% or better earns the participant 1.5 AMA PRA Category 1 Credits. A fee of $15 will be charged. Participants are allowed 2 attempts to successfully complete the activity. SPONSORED BY

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Mr Smith to receive multiple courses of standard antidepressant medications. 2 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 in effective.7 A delayed diagnosis may prolong de pression and further affect the patients ability to function effectively at home and at work. Pro longed 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.8-11 More recently, some pre liminary neuroimaging studies have suggested a link between mood episodes and evidence of neuropathic changes in several regions of the brain.12-15



pressive 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.

pression remains quite limited (Table 2). Only 1 medication and 1 medication combina tion are approved by the FDA to treat depression in patients with bipolar disorder. Quetiapine (both immediate- and extended-release) was ap proved on the basis of 2 large initial trials and a follow-up trial of the extended-release formula tion.16,17 Olanzapine in combination with fluox etine was also found to be effective for bipolar depression in 2 large trials and was approved only in this combined formulation.18 These medications have not been compared in a head-to-head fashion, but a review by Gao and colleagues19 found higher effect sizes for quetia pine than for the olanzapine/fluoxetine combina tion, which suggests that the former may be more effective (Figure 1). In addition, the large weight gain sometimes observed with olanzapine and other potential adverse effects, including seda tion, hyperglycemia, and hypercholesterolemia, can limit the usefulness of the olanzapine/fluox

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 persons risk for the disorder. The atypical symptoms, such as increased sleep, may also suggest bipolar disorder. Other symptoms of bipolar disorder are listed in Table 1.3-6 It is far from uncommon for patients such as

While there is strong consensus against standard antidepressants as monotherapy for bipolar depression, . . . standard antidepressants may play an adjunctive role.
Pharmacotherapeutic treatment options An accurate diagnosis is, of course, the first step in making treatment decisions. Treatment choices in psychiatry are rarely straightforward, and bi polar depression is no exception to this general rule. Further complicating the process is the lim ited number of FDA-approved options. The num ber of FDA-approved medications for bipolar mania has literally tripled over the past decade while the pharmacopeia available for bipolar de
etine combinations. Despite the FDA approval, some consensus guidelines, such as those of the World Federation of Societies of Biological Psy chiatry, do not list the olanzapine/fluoxetine com bination as first-line treatment for bipolar depres sion.20 Quetiapine may also be associated with significant adverse effects, including sedation, weight gain, and metabolic syndrome.21 In addition to the 2 FDA-approved pharmaco therapies for bipolar depression, at least 1 other
(Please see Bipolar Depression, page 68)

Table 1

Clues that unipolar depression may be bipolar depression

Table 2

FDA-approved medications for bipolar disorder

Bipolar mania Bipolar depression Maintenance

Valproic acid Lithium Lamotrigine Carbamazepine Olanzapine Olanzapine + fluoxetine Risperidone Quetiapine Ziprasidone Aripiprazole Asenapine
a b

Yes Yes No Yes Yes No Yes Yes Yes Yes Yes

No No No No No Yes No Yes No No No

No Yes Yes No Yes No Yes (as long-acting injection) Yesa Yesa Yes Nob

Early age at symptom onset Postpartum mood disorders Seasonal mood changes Hypersomnia and/or psychomotor slowing Severe anhedonia Depression with catatonia and/or psychotic features Bipolar family history Pharmacologically induced mania or hypomania History of recurrent but brief depressive episodes Atypical symptoms

Adjunctively with lithium or divalproex. It is generally recommended that in responding patients, asenapine be continued beyond the acute response.



dosing should closely adhere to FDA guidelines for its approved uses. A comparison of effect sizes suggests that que tiapine may be more effective than the olanza pine/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 effec tive, these findings may have been driven by the low blood levels of lithium in study patients.24 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 firstline medicationstypically a combination of 1.2 quetiapine with lithium or lithium with lamotri gine may work.28-30 Many patients with bipolar 1 depression do not respond to any of the usual first-line medications, and you may need to con 0.8 sider a second-line agent for which there is less evidence of efficacy. 0.6 Divalproex is often prescribed for bipolar de pression, and while there are no large studies of 0.4 this agent, 4 studies found the anticonvulsant to be effective, as did a recent meta-analysis.31 0.2 While divalproex is often well tolerated, patients may report fairly significant weight gain and there is a risk of hepatotoxicity. Divalproex is 0 also considered by some clinicians to be contra indicated in young women. The medication may increase the rate of polycystic ovary syndrome, andgiven the impulsivity often associated with bipolar disorderthe relatively high teratogenic ity of divalproex can pose a potential problem.32,33 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 carba mazepine and olanzapine. Although a few small studies suggest that carbamazepine may be ef
Effect size

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Bipolar Depression
Continued from page 67


medicationlithiumis usually considered to be a first-line treatment option.22,23 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 signifi cantly more effective than placebo.24,25 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.26 Lithium carries some advantages over atypical antipsychotics, including its affordability and wide availability. LithiumAir isForce also associated with Navy a different collection of potentially significant Army adverse effects, including Marines GI distress and thyroid and renal pathology. The need to monitor blood lithium levels and to obtain regular laboratory 2005 2006 tests 2007 has 2008 2009 limited its use by screening probably nonpsychiatrist clinicians.27 Lamotrigine is often considered to be a firstline intervention for bipolar depression, but it has not been approved for this indication.22 As with lithium, there is anecdotal evidence for its effi cacy but limited published study data. While re sults of a single large, randomized, double-blind, placebo-controlled trial have been positive, 4 Trigger smaller clinical trials did not find lamotrigine to (perceived loss) be an effective treatment for bipolar depression. Job loss Nonetheless, a recent meta-analysis that included Relationship problem all 5 trials foundFinancial lamotrigine to be particularly stress effective in patients with more severe depression. Lamotrigine has also been found to be useful in combination with other medications, particularly lithium.28 Cognition is associated with a number of Lamotrigine (suicidal belief system)adverse effects that include potentially serious Im a terrible person Stevens-Johnson syndrome, a potentially fatal Im a burden to others dermatological reaction. As a result, lamotrigine
I can never be forgiven I cant take this anymore Things will never get better

fective for bipolar depression, the findings from a randomized, double-blind, placebo-controlled study were mixed.20 Olanzapine monotherapy was associated with statistically significant im provement in patients with bipolar depression, but the effect size was quite low (Figure 1) and probably not clinically significant.19 Other atypi cal antipsychotic medications have not been found to be effective for bipolar depression. Several other medications have shown some limited efficacy for bipolar depression in combi nation 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.34,35 Two small studies also found adjunctive levothyroxine to be helpful in treating bipolar patients with treatment-resistant depression.36,37 Zonisamideanother anticonvul santused as adjunctive treatment, improved symptoms of bipolar depression, but the medica tion was very poorly tolerated, with high dropout rates in all 4 trials.38-41 Inositol is another possible treatment for bipolar depression, although evi dence for its efficacy is limited.42,43 The anticonvulsant gabapentin showed weak antidepressant effects as a monotherapeutic agent, with limited evidence of efficacy when given as an adjunct.44-46 Although -3 fatty acids Olanzapine Olanzapine Quetiapine Quetiapine are often recommended for 300 both bipolar mania + mg 600 mg and bipolar depression, fluoxetine only 1 small study of ethyl-eicosapentaenoic acid found evidence of efficacy, while a second study failed to observe clinical effects.47,48 Findings from several small case series and

Figure 2

Simplified algorithm for bipolar depression

Step 1
Monotherapy with a first-line agent

Step 2

Figure 1
1.2 1 0.8 0.6

Comparison of effect sizes of response in bipolar depression

Shame Guilt Anger Anxiety Depression

Add-on additional agent or change monotherapy Add second-line agent Monotherapeutic or adjunctive lamotrigine

Step 3
Add second-line agent

Effect size

Step 4

Suicidal mode

Add additional agent Add third-line agent Consider a standard antidepressant Continue to combine interventions

Agitation 0 Sleep disturbance Concentration problems Physical pain


Olanzapine Quetiapine + 300 mg fluoxetine

Quetiapine 600 mg

Psychoeducation and psychotherapy

Reproduced with permission from Gao K et al. J Clin Psychiatry. 2005.19 2005 Physicians Postgraduate Press Inc.

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proved for treatment-resistant unipolar depres sion, has showed some promise for treatment of bipolar depression. Vagus nerve stimulation is also approved for treatment-resistant unipolar de pression and may be effective in bipolar depres sion as well.58



chart reviews, and 2 small studies of patients with bipolar disorder type I and II also suggest that pramipexolea medication approved for Parkin son disease and restless legs syndromemay be effective for at least some patients with bipolar depression.49-55 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 an tidepressants as monotherapy, limited data sug gest that standard antidepressants may play an adjunctive role in treating otherwise treatmentresistant symptoms of bipolar depression.20,23 An tidepressant 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 antidepres sants.7,56 Other meta-analyses that have purported to observe an effect may be methodologically flawed.57

Nonpharmacological treatment modalities In addition to pharmacological treatments for bi polar 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 im prove symptoms in some treatment-resistant pa tients.58 However, many patients are reluctant to consider ECT because of widespread negative as sociations with shock treatment and fears of memory loss. Two behaviorally focused forms of psycho therapycognitive-behavioral therapy and fam ily-focused therapyhave been found to im prove outcomes in patients with bipolar depression. In addition, interpersonal social rhythm therapy may be effective as an adjunct of medica tion-based interventions.59 Sleep deprivation has long been known to improve symptoms of de pression. A few open-label trials suggest that this approach may also be effective in bipolar depres sion. However, the intervention is not without risk; some patients developed treatment-related manic symptoms, similar to those sometimes ob served in bipolar patients treated with standard antidepressants.60-62 Phototherapy has demon strated some efficacy but may also induce mania in susceptible individuals.60,62-64 In addition, de creased stress and exercise may alleviate some symptoms.65 A look at the treatment horizon Although, the number of new treatments for bi polar depression has lagged well behind that for bipolar mania, there are some innovative inter ventions on the horizon. A recent double-blind study looked at the adjunctive use of the Nmethyl-d-aspartate antagonist ketamine for bi polar depression. Ketamine infusions were asso ciated with an exceptionally rapid response in a high proportion of the patients.66,67 Repetitive transcranial magnetic stimulation, currently ap

Conclusions There are no clear-cut correct choices. Treating psychiatric illness typically requires an individu alized care plan, and bipolar depression is no ex ception. The construction of a care plan is further complicated by the lack of FDA-approved medi cations. 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 min imum serum level of 0.8 mEq/L; or possibly lamotrigine. There are few reliable indicators of clinical ef ficacy 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 (Figure 2). A review of current treatment algorithms high lights how subjective treatment approaches to bipolar depression remain. Many guidelines dif fer significantly, even with regard to what agents are considered primary interventions. These dis crepancies emphasize the need for both more ef fective 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.
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(Please see Bipolar Depression, page 70)



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1.  What is the one characteristic of bipolar depression that always distinguishes it from unipolar depression? A. Low mood B. A history of a manic or mixed episode C. Poor concentration D. Hypersomnia 2.  What is the risk(s) associated with using standard anti depressant medication to treat bipolar depression? A. Destabilization of disorder B. Rapid cycling C. Precipitation of manic episodes D. All of the above 3.  There are more FDA-approved options for bipolar depression than there are for bipolar mania. A. True B. False 4.  Which of the following are FDA-approved for treatment of bipolar disorder? A. Lithium in combination with fluoxetine and olanzapine B. Lamotrigine and lithium C. Olanzapine in combination with fluoxetine and quetiapine D. All of the above E. None of the above 5.  Some data suggest that treating bipolar depression requires a minimum serum lithium concentration of: A. 0.61 mEq/L B. 0.76 mEq/L C. 0.80 mEq/L D. 0.89 mEq/L 6.  If the first-line interventions for bipolar depression do not reduce symptoms, which of the following may be used? A. Divalproex B. Carbamazepine C. Modafinil D. All of the above E. None of the above 7.  In treating bipolar depression in young women, caution must be used with which of the following agents because it may increase the risk of polycystic ovary syndrome. A. Quetiapine B. Lamotrigine C. Divalproex D. Olanzapine A11001071 8.  Data suggest that standard antidepressants may play a role as monotherapy for bipolar depression. A. True B. False 9.  Which of the following has been found to be efficacious in treating bipolar depression? A. Attachment-based psychotherapy B. Biodynamic psychotherapy C. Cognitive-behavioral therapy D. Guided imagery therapy 10.  Repetitive transcranial magnetic stimulation, currently approved for treatment-resistant unipolar depression has shown some promise as a treatment modality in bipolar depression. A. True B. False