Psychopharmacologic Treatment of Bipolar II Depression

Psychiatric TimesVol 40, Issue 3

What is the best evidence-based medication treatment for acute bipolar II depression?



Once you have diagnosed acute bipolar II depression accurately according to the DSM-5 criteria (as we reviewed in detail in a recent Psychiatric Timescolumn1), you are confronted with the problem of what to select for an evidence-based medication treatment. The problem is that you do not have much evidence to rely on.

In a review of 11 US and international evidence-based treatment guideline recommendations for managing bipolar disorders, only 3 of the guidelines offered any specific recommendations for bipolar II disorder.2 The other 8 guidelines all implied—if mentioning bipolar II at all—or stated explicitly, such as in 1 case, that one should more or less use what was recommended for bipolar I depression.

In the other 3 guidelines, there was mention of lamotrigine and lithium having evidence for maintenance (but not acute) treatment. There was also mention of quetiapine, carbamazepine, and several antidepressants as possible treatments.

In a book published in 2019, editor Gordon Parker, MD, MBBS, DSc, PhD, asked 18 experts to comment (in separate chapters) on their preferences for treating bipolar II depression and their rationales.3 There was no consensus, the recommendations varied, and it is fascinating to read through them.

The US Food and Drug administration (FDA) has approved only 2 medications for acute bipolar II depression: quetiapine and lumateperone. Five medications are approved for acute bipolar I depression, including quetiapine, lumateperone, lurasidone, cariprazine, and the olanzapine/fluoxetine combination product.

However, a recent systematic review concluded that quetiapine works better for bipolar I depression than for bipolar II,4 and an editorial evaluating the results of lumateperone as a treatment for bipolar II concluded that efficacy was not well demonstrated.5

In another recent meta-analytic review, antidepressant trials with sertraline and venlafaxine for bipolar II disorder were evaluated and compared with acute treatment with lithium.6 They found no difference in the response rates to the antidepressants compared with lithium (P = .76). Also, all-cause discontinuation rates in the antidepressants versus lithium were not different, which was surprising because clinicians tend to expect more adverse effects and dropouts with lithium.

There were no placebo controls in these studies, so the efficacy of the antidepressants was unclear; however, it is notable that evidence does not support lithium monotherapy in acute bipolar depression. Thus, the same can probably be said for these antidepressants. In practice, many clinicians prescribe antidepressants for bipolar II depression, but the evidence can hardly be considered supportive.

In conclusion, this author generally recommends that bipolar II depression be treated similarly to bipolar I depression, as we have done in consultations through the US Department of Veterans Affairs National Bipolar Disorder Telehealth Program (which has processed over 4000 consultation requests over the past 11 years, mostly due to diagnostic conundrums and treatment resistance).

In other words, we are basically in accord with 8 of the 11 guidelines noted above, given that the more recent reviews cited have not provided a reason to change that stance.

Yet confidence in the effectiveness of the most evidenced bipolar I depression treatments must be considered lower when treating bipolar II depression. In brief summary, our current recommendations are as follows7,8: after considering electroconvulsive therapy for patients who are severely depressed and are in urgent need of treatment, the first-line medication options are quetiapine, lurasidone, cariprazine, lumateperone (all FDA approved), and the combination of lithium and lamotrigine. Olanzapine/fluoxetine is generally not recommended because of the unacceptable long-term adverse effect risks of the olanzapine component.

If these first-line options fail (some of them may be unsuitable for use, given individual patient considerations), you could try an antidepressant if the patient is not a rapid cycler, does not have a depression with mixed (ie, manic) features, or has no history of mania or dysphoria with previous antidepressant use. If any of these predictors of adverse outcomes with antidepressants are present, try more combinations of the top 5 choices next.

Dr Osser is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs National Bipolar Disorder Telehealth Program in Brockton, Massachusetts.


1. Osser DN. Bipolar depression: how to not miss the diagnosis. Psychiatric Times. 2021;38(10):31.

2. Parker GB, Graham RK, Tavella G. Is there consensus across international evidence-based guidelines for the management of bipolar disorder? Acta Psychiatr Scand. 2017;135(6):515-526.

3. Parker G, ed. Bipolar II Disorder: Modelling, Measuring, and Managing, 3rd edition. Cambridge University Press; 2019.

4. Miola A, Tondo L, Baldessarini RJ. Effects of treatment of acute major depressive episodes in bipolar I versus bipolar II disorders with quetiapine. J Clin Psychopharmacol. 2022;42(6):530-535.

5. Ostacher MJ. Slowly working toward more treatments for depression in bipolar II disorder. Am J Psychiatry. 2021;178(12):1075-1076.

6. Park JH, Nuñez NA, Gardea-Resendez M, et al. Short term second-generation antidepressant monotherapy in acute depressive episodes of bipolar II disorder: a systematic review and meta-analysis. Psychopharmacol Bull. 2022;52(2):45-72.

7. Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression. Bipolar Disord. 2020;22(5):472-489.

8. Osser DN. Psychopharmacology algorithms. Accessed January 12, 2023.

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