There’s a slight imbalance in our therapeutics for bipolar disorder. While patients spend most of their time in the depressed phase, the FDA-approved treatments for mania outnumber those for depression 4 to 1.
First, here are my biases. In addition to the FDA-approved options, I will consider any treatment with at least one randomized, controlled trial that supports its merits. I tend to favor those with large effect sizes (eg, pramipexole) or low risks (eg, omega-3 fatty acids). I also value treatments with long-term data, even when their short-term benefits are debatable (eg, lamotrigine, psychotherapy). This is, after all, a chronic condition.
The ideal treatment for bipolar depression would lift mood in the short term and prevent new episodes in the years to come. Examples of these mood-lifting stabilizers include lamotrigine, lithium, a few atypical antipsychotics (olanzapine-fluoxetine combination, quetiapine, lurasidone, cariprazine), and possibly valproate.1,2
How to choose among them? Collaborate. Adherence hovers around 50% in bipolar disorder, so it behooves us to ask patients about their hopes and fears in treatment. If fast results are desired, the atypical antipsychotics may be best. More often, patients value tolerability, in which case lamotrigine and lithium might come first. Practitioners often question lamotrigine’s efficacy and lithium’s tolerability, but new research suggests those reputations may be undeserved.3,4
Non-antidepressants for bipolar disorder
Next in line are medicines that can treat acute bipolar depression without destabilizing mood. These are best paired with a mood stabilizer, since they won’t prevent new episodes on their own. I have left antidepressants off this list because their mood-destabilizing potential has not escaped the eye of controlled studies.5 To be fair, all the options on this list probably have some mood-destabilizing potential, as this problem is notoriously difficult to detect in research (and in practice). The non-antidepressants that made the cut are pramipexole, modafinil, armodafinil, thyroid augmentation, omega-3 fatty acids (with more than 60% eicosapentaenoic acid), N-acetylcysteine, L-methylfolate, pioglitazone, and celecoxib.1,6-8
Dr. Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He does not accept honoraria from pharmaceutical companies but receives honoraria from W.W. Norton & Co. for Bipolar, Not So Much, which he coauthored with Jim Phelps, MD.
1. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of NeuroPsychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2017;20:180-195.
2. Durgam S, Earley W, Lipschitz A, et al. An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry. 2016;173:271-281.
3. Parker G, McCraw S. The ‘disconnect’ between initial judgments of lamotrigine vs. its real-world effectiveness in managing bipolar disorder. A tale with wider ramifications. Acta Psychiatr Scand. 2015;132:345-354.
4. Ketter T. Handbook of Diagnosis and Treatment of Bipolar Disorders. Washington, DC: American Psychiatric Publishing; 2009.
5. Viktorin A, Lichtenstein P, Thase ME, et al. The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry. 2014;171:1067-1073.
6. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72:1577-1584.
7. Nierenberg AA, Montana R, Kinrys G, et al. L-methylfolate for bipolar I depressive episodes: an open trial proof-of-concept registry. J Affect Disord. 2017;207:429-433.
8. Aiken CB. Pramipexole in psychiatry: a systematic review of the literature. J Clin Psychiatry. 2007;68:1230-1236.
9. Frye MA, Yatham L, Ketter TA, et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr Scand. 2009;120:10-13.
10. Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 2014;44:225-239.
11. Tseng PT, Chen YW, Tu KY, et al. Light therapy in the treatment of patients with bipolar depression: a meta-analytic study. Eur Neuropsychopharmacol. 2016;26:1037-1047.
12. Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med. 2000;62:633-638.
13. de Sousa RT, van de Bilt MT, Diniz BS, et al. Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study. Neurosci Lett. 2011;494:54-56.
14. Oud M, Mayo-Wilson E, Braidwood R, et al. Psychological interventions for adults with bipolar disorder: systematic review and meta-analysis. Br J Psychiatry. 2016;208:213-222.
15. Harvey AG, Soehner AM, Kaplan KA, et al. Treating insomnia improves mood state, sleep, and functioning in bipolar disorder: a pilot randomized controlled trial. J Consult Clin Psychol. 2015;83:564-577.