Acute and Maintenance Treatments for Bipolar Depression

Terence A. Ketter, MD

Department of Psychiatry and Behavioral Sciences and the Bipolar Disorders Clinic, Stanford School of Medicine, Stanford, California

Bipolar disorder (BD) is a common, serious, generally lifelong, mental illness with substantial human and economic costs, yet diagnosing and treating BD is often challenging. Patients most often present with depressive symptoms, which can lead to an incorrect diagnosis of unipolar depression.1 Much improvement is needed in the areas of diagnosis and treatment in both the acute and maintenance phases of this illness.

Course of Illness and Misdiagnosis

Studies2,3 have shown that patients with BD are asymptomatic about half of the time; the other half of the time, they experience depression much more often than mood elevation. Because depression is the predominant symptomatic phase in BD, the most common misdiagnosis is unipolar depression, followed by other overlapping and/or commonly comorbid conditions such as anxiety disorders, schizophrenia, cluster B personality disorders, and even alcohol abuse.4 A survey4 showed that, of the roughly 70% of patients who were initially misdiagnosed, 60% received a depression diagnosis. Early age at onset, psychosis, and family history of BD are all probabilistic factors that can aid in making a correct and timely BD diagnosis in patients presenting with depression.5 For more information on diagnosis, see “Improving the Early Recognition and Diagnosis of Bipolar Disorder.”

Lack of Treatment Agents

About a decade ago, antidepressants were the most common initial treatment for BD, followed by mood stabilizers, sedatives, and antipsychotics.6 That clinicians would treat patients who often present with depressive symptoms with antidepressants is understandable. Broadly speaking, antidepressants have fewer somatic side effects than mood stabilizers, which in turn have fewer somatic side effects than antipsychotics. Making tolerability a priority when treating patients is reasonable, especially in non-urgent cases, but the problem is that antidepressant efficacy in acute bipolar depression is commonly very limited.7

While 10 agents are currently FDA-approved for the treatment of acute mania, only 3 drugs are approved for treating acute bipolar depression (AV 1). This situation clearly demonstrates the need for more acute treatment options for bipolar depression.

AV 1. Unmet Need for FDA-Approved Agents for Bipolar Depression (00:30)

For more information, read the product labeling for each drug at the FDA web site
*Approved for use as monotherapy and an adjunctive agent with valproate or lithium
†Approved only for use as an adjunctive agent with valproate or lithium

Furthermore, while 7 agents are approved for maintenance treatment of BD, 5 of the 7 approved treatments are antipsychotics, which commonly have some tolerability challenges. Efficacious and tolerable long-term treatment of BD is another area of unmet need.

Approved Acute Treatments for Bipolar Depression

The first FDA-approved acute bipolar depression treatment, the combination antipsychotic/antidepressant olanzapine/fluoxetine, can yield an almost 50% remission rate, compared with a 25% rate with placebo (P<.001),8 but weight gain is a common side effect. For example, 20% of patients taking the active treatment had at least a 7% weight gain versus less than 1% taking placebo (P < .001).8

The second FDA-approved acute bipolar depression treatment, the antipsychotic quetiapine as monotherapy, also has good efficacy, with a 53% remission rate, compared with a 28% rate for placebo.9 But like the olanzapine/fluoxetine combination, quetiapine has a side effect profile that is challenging for many patients. With quetiapine, for instance, about 30% of patients experienced sedation/somnolence, compared with only 6% of those taking placebo.9 So, while these older FDA-approved bipolar depression treatments are efficacious, they also have the propensity to cause problematic side effects.

The antipsychotic lurasidone, a recently approved acute bipolar depression treatment, has been shown to be efficacious as both monotherapy10 and adjunctive therapy (added to lithium or valproate).11 As monotherapy, lurasidone reduced mean MADRS total scores by 15.4 points, while placebo reduced scores by 10.7 points (effect size = 0.51).10 As adjunctive treatment (added to lithium or valproate), lurasidone reduced mean MADRS total scores by 17.1 points versus a 13.5-point reduction with placebo (effect size = 0.34).11 Although akathisia and nausea can be associated with this agent, these side effects are commonly manageable and may be self-limited (resolving with the passage of time) or resolve with a dosage decrease.

AV 2. Adjusting Acute Treatment for a Patient with Bipolar Depression (02:03)

 

Comparative efficacy studies have been conducted with quetiapine versus lithium and paroxetine in bipolar depression. In an 8-week study,12 quetiapine was superior, with remission rates of 69% (for 300 mg/d; P < .01) and 70% (for 600 mg/d; P < .01), versus 63% for lithium and 56% for placebo. However, in this study, the mean serum lithium level was only 0.61 mEq/L. Had lithium blood levels been higher, the efficacy of lithium may have been better. Regarding adverse events, quetiapine yielded significantly more sedation/somnolence than placebo (P < .0001), while lithium did not.

In another 8-week study of bipolar depression,13 quetiapine was contrasted with paroxetine and placebo. Again, quetiapine 600 mg/d was associated with significantly greater remission rates (67% for both 600 mg/d and compared with placebo [53%; P < .01]), although paroxetine (55%) was not. Unfortunately, with quetiapine, sedation/somnolence remained a problem that fewer patients taking paroxetine or placebo experienced (AV 2).

Unapproved Acute Treatments for Bipolar Depression

While commonly used in patients with acute bipolar depression, antidepressants and lamotrigine are not approved for this indication. As mentioned, although antidepressant somatic tolerability is largely superior to that of other agents, efficacy is lacking in acute bipolar depression.7 Lamotrigine has fair tolerability (aside from rare serious rash), and, while it is efficacious in preventing mood episodes (especially depressive episodes), efficacy in acute bipolar depression has not been sufficiently robust to yield FDA approval for that indication.14

Data are emerging regarding adding stimulants and dopamine agonists to bipolar depression treatment.15 Three phase 3 studies of adjunctive armodafinil have been conducted. The first study was encouraging, demonstrating significant improvement over placebo with generally good somatic tolerability.16 However, 2 subsequent studies did not demonstrate superiority over placebo, so the manufacturer is not pursuing an acute bipolar depression indication.

Another unapproved adjunctive treatment for bipolar depression is the dopamine agonist pramipexole, which has been shown to be efficacious in 2 small placebo-controlled trials.17,18 The side effects were primarily nausea and somnolence but also included hypomania. Because the sample size of each study was less than 25 participants, larger, randomized controlled trials are needed to confirm these encouraging preliminary results.

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Bipolar Maintenance Treatments

The only treatment that is FDA-approved for use in acute mania (as monotherapy or adjunctive therapy), acute bipolar depression (as monotherapy), and relapse prevention (as adjunctive therapy) to date is quetiapine (see AV 1). Research on the use of olanzapine/fluoxetine and lurasidone as maintenance treatments are needed before they can be approved and/or recommended for prevention of bipolar depression.

Lithium and lamotrigine are the 2 agents approved for bipolar disorder maintenance treatment that are not atypical antipsychotics. Lithium was used as an active comparator in an 18-month study of lamotrigine.19 For overall episode prevention, both lamotrigine and lithium led to a longer time to intervention for relapse than placebo (P < .001 for both). For depression prevention specifically, lamotrigine was significantly superior to placebo (P = .009), but lithium was not. For prevention of mania, hypomania, or a mixed episode, both drugs were significantly better than placebo (P < .001 for lithium, P = .034 for lamotrigine), but lithium was superior to lamotrigine (P = .030). Therefore, lamotrigine may be the better agent at preventing bipolar depression, while lithium may be better at preventing mania.

Valproate is not FDA-approved for bipolar maintenance treatment. However, some data suggest that valproate might prevent episodes, especially depressive episodes, better than placebo and at a comparable rate as lithium, with better tolerability than lithium.20 These data have methodological problems, though, so only limited evidence supports the use of valproate in depressive relapse prevention in bipolar disorder patients.

In another comparative efficacy study,21 patients who had been stabilized with open-label quetiapine during acute treatment were randomly assigned to either continue treatment with quetiapine monotherapy or switch to lithium monotherapy or placebo. Both quetiapine and lithium were efficacious in episode prevention over 24 months compared with placebo (P < .0001), although lithium was not quite as effective at preventing depression as quetiapine.

Conclusion

The first step to improving the management of depression in bipolar disorder is to diagnose bipolar depression accurately. Despite a very limited number of approved agents for treating acute bipolar depression and for preventing depressive episodes, progress is being made. While some older FDA-approved treatments for acute bipolar depression are prone to cause problematic adverse events, the newer FDA-approved treatment lurasidone has a more favorable side effect profile. In efforts to avoid tolerability challenges associated with second-generation antipsychotics, some clinicians may resort to unapproved acute bipolar depression treatment strategies such as adding adjunctive antidepressants or novel agents to mood stabilizers. Limited data could be construed to support the use of these generally well-tolerated but very limited efficacy interventions in certain cases, particularly when patients are very sensitive to side effects and are in less urgent need of efficacy. Hopefully, more research with well-designed, adequately powered studies will result in expanded treatment options for not only acute bipolar depression but also for bipolar depression relapse prevention.

Clinical Points

  • Acknowledge that patients with bipolar disorder experience depression more often than mania while symptomatic
  • Recognize that only 3 agents are FDA-approved for the acute treatment of bipolar depression: olanzapine/fluoxetine combination, quetiapine, and lurasidone
  • When treating patients with approved agents, monitor safety and tolerability closely
  • Be aware that several unapproved agents are frequently used and that more approved agents with good efficacy and tolerability are needed

Abbreviations

BD = bipolar disorder

FDA = US Food and Drug Administration

MADRS = Montgomery-Asberg Depression Rating Scale

Drug Names

aripiprazole (Abilify), asenapine (Saphris), carbamazepine (Carbatrol, Equetro, and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), lurasidone (Latuda), olanzapine (Zyprexa and others), olanzapine/fluoxetine combination (Symbyax and others), paroxetine (Paxil, Pexeva, and others), quetiapine (Seroquel and others), risperidone (Risperdal and others), ziprasidone (Geodon and others)

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References

  1. 1. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64(2):161–174. Abstract
  2. 2. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530–537. PubMed
  3. 3. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60(3):261–269. PubMed
  4. 4. Hirschfeld RM, Vornik LA. Recognition and diagnosis of bipolar disorder. J Clin Psychiatry. 2004;65(suppl 15):5–9. Full Text
  5. 5. Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RMA. Diagnostic guidelines for bipolar depression: a probabilistic approach. Bipolar Disord. 2008;10(1, pt 2):144–152. PubMed
  6. 6. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv. 2007;58(1):85–91. PubMed
  7. 7. Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-anaylsis. J Clin Psychiatry. 2011;72(2):156–167. Full Text
  8. 8. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression [correction in Arch Gen Psychiatry. 2004;61(2):176]. Arch Gen Psychiatry. 2003;60(11):1079–1088. PubMed
  9. 9. 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(7):1351–1360. PubMed
  10. 10. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study [published online ahead of print October 30, 2013]. Am J Psychiatry. doi:10.1176/appi.ajp.2013.13070984. PubMed
  11. 11. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study [published online ahead of print October 30, 2013]. Am J Psychiatry. doi:10.1176/appi.ajp.2013.13070985. PubMed
  12. 12. Young AH, McElroy SL, Bauer M, et al . A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71(2):150–162. Full Text
  13. 13. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71(2):163–174. Full Text
  14. 14. Geddes JR, Calbrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4–9. PubMed
  15. 15. Dell’Osso B, Ketter TA, Cremaschi L, et al. Assessing the roles of stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression. Curr Psychiatry Res. 2013;15(8):378. PubMed
  16. 16. Calabrese JR, Frye MA, Yang R, Ketter TA. Use of a novel adjunctive clinical trial design to examine efficacy, safety of and improved generalizability of armodafinil for the treatment of bipolar I depression. In: 10th International Conference on Bipolar Disorder. Miami Beach, FL, June 13–16, 2013. Abstract I-18. Bipolar Disord. 2013;15(suppl 1):59. PubMed
  17. 17. 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(3):564–566. PubMed
  18. 18. Zarate CA Jr, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004;56(1):54–60. PubMed
  19. 19. Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65(3):432–441. Abstract
  20. 20. Cipriani A, Reid K, Young AH, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder [published online ahead of print October 17, 2013]. Cochrane Database Syst Rev. doi:10.1002/14651858. PubMed
  21. 21. Weisler RH, Nolen WA, Neijber A, et al. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (trial 144: a randomized controlled study). J Clin Psychiatry. 2011;72(11):1452–1464. Full Text