Innovation in the Treatment of Bipolar Depression

See Article by Calabrese.

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Innovation in the Treatment of Bipolar Depression

Rif S. El-Mallakh, MD

The treatment of depression in patients with bipolar disorder is fundamental to the management and prognosis of this condition. Despite multiple adequately powered, randomized, placebo-controlled studies that demonstrate that antidepressants added to mood stabilizers are no more effective in bipolar illness than placebo,1-3 and are potentially problematic,4,5 the use of antidepressants in patients with bipolar illness remains controversial.6 The confusion derives, in part, from studies showing that antidepressants added to antipsychotics (in type I patients), or used as monotherapy (in type II patients), are effective acutely.7-9 Continued widespread use of antidepressants in bipolar depression10 is probably emblematic of the lack of effective alternatives in a disorder in which depression is the predominant mood.11-13 This unmet need has become fertile ground for a small flowering of innovation in psychiatry. For example, sub-antipsychotic doses of second-generation antipsychotics are being repurposed for bipolar depression.14,15

In this issue, Calabrese and colleagues16 present data for another novel option for the treatment of bipolar depression. Armodafinil, and modafinil before it, have been shown in randomized, placebo-controlled studies17 to be safe and effective in the acute treatment of bipolar depression when added to a mood stabilizer. The true value of these studies extends beyond the value of yet another option for depressed patients with bipolar illness. While the mechanisms of action of armodafinil and modafinil are not known, they do not alter serotonin. Rather, they appear to augment signals of dopamine and histamine.18,19 As such, they are the only available prohistamine antidepressant agents used in bipolar illness. Thus, Calabrese and colleagues’ article is introducing a new class of antidepressant treatment for bipolar disorder.

Despite the importance of the study, it has clear problems. The effect size was small, and the reason for that is not clear. Armodafinil’s separation from placebo occurred late in the study. It is clear that additional studies are needed to confirm these data and clarify the optimal dose. Furthermore, maintenance studies are required to ensure that the destabilization of the illness that happens with antidepressants does not happen with armodafinil. Ongoing development of these agents, by providing a safe and effective alternative to antidepressants, may ultimately make antidepressant avoidance less controversial in the treatment of bipolar depression.

Author affiliations: Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky.

Potential conflicts of interest: Dr El-Mallakh has received honoraria from AstraZeneca, Otsuka, and Sunovion.

Funding/support: None reported.

REFERENCES

1. Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry. 2001;158(6):906-912. PubMed doi:10.1176/appi.ajp.158.6.906

2. Post RM, Leverich GS, Nolen WA, et al; Stanley Foundation Bipolar Network. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord. 2003;5(6):396-406. PubMed doi:10.1046/j.1399-5618.2003.00065.x

3. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722. PubMed doi:10.1056/NEJMoa064135

4. El-Mallakh RS, Ghaemi SN, Sagduyu K, et al; STEP-BD Investigators. Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients. J Affect Disord. 2008;111(2-3):372-377. PubMed doi:10.1016/j.jad.2008.03.025

5. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry. 2010;71(4):372-380. PubMed doi:10.4088/JCP.08m04909gre

6. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262. PubMed doi:10.1176/appi.ajp.2013.13020185

7. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079-1088 [erratum in Arch Gen Psychiatry. 2004;61:176]. PubMed doi:10.1001/archpsyc.60.11.1079

8. Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18(5):414-417. PubMed doi:10.1097/00004714-199810000-00010

9. Amsterdam JD, Garcia-Espa×±a F, Fawcett J, et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol. 1998;18(6):435-440. PubMed doi:10.1097/00004714-199812000-00003

10. Vieta E, Langosch JM, Figueira ML, et al. Clinical management and burden of bipolar disorder: results from a multinational longitudinal study (WAVE-bd). Int J Neuropsychopharmacol. 2013;16(8):1719-1732. PubMed doi:10.1017/S1461145713000278

11. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry. 2003;64(6):680-690, quiz 738-739. PubMed doi:10.4088/JCP.v64n0610

12. 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 doi:10.1001/archpsyc.60.3.261

13. 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 doi:10.1001/archpsyc.59.6.530

14. Young AH, McElroy SL, Bauer M, et al; EMBOLDEN I (Trial 001) Investigators. 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. PubMed doi:10.4088/JCP.08m04995gre

15. 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. Am J Psychiatry. 2014;171(2):169-177. PubMed doi:10.1176/appi.ajp.2013.13070985

16. Calabrese JR, Frye MA, Yang R, et al. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: a randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054-1061.

17. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249. PubMed doi:10.1176/appi.ajp.2007.06060981

18. Qu WM, Huang ZL, Xu XH, et al. Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci. 2008;28(34):8462-8469. PubMed doi:10.1523/JNEUROSCI.1819-08.2008

19. Ishizuka T, Murotani T, Yamatodani A. Action of modafinil through histaminergic and orexinergic neurons. Vitam Horm. 2012;89:259-278. PubMed doi:10.1016/B978-0-12-394623-2.00014-7