David N. Osser, MD
Psychiatric TimesVol 40, Issue 4



Let’s start with the treatment of acute mania. Lithium is a good treatment for classic, nonmixed mania, but if there are depression symptoms mixed in (per DSM-5-TR, if 3 or more depressive symptoms are combined with meeting full criteria for mania, it is mania with mixed features), lithium does not work well.1,2 Instead, the first choice for mixed would be a second-generation antipsychotic (SGA). Quetiapine may be favored because it also has evidence for efficacy in treating and preventing bipolar depressions, which is often what happens after mania.3 Cariprazine has efficacy as a treatment for bipolar depression as well as mania including mixed mania,4 so that is another SGA option, but it has not been studied as a maintenance treatment for mania or depression so at this point it is only a guess how it would do for that important function. Despite that consideration, the adverse effect profile (eg, fewer metabolic adverse effects and sedation) may result in it being preferred over quetiapine. It is much more costly, though, as a brand product, and formulary restrictions may make it hard to get.

Other effective SGAs with good efficacy in acute mania are risperidone and olanzapine, but neither has a great track record on managing the depressive symptoms in mixed mania or bipolar depression.3 Other SGAs like aripiprazole, paliperidone, and asenapine have some (but lower) efficacy for mania but none have efficacy for bipolar depression, so they are lower-priority choices.

Though first-generation antipsychotics treat mania effectively, they have a high rate of precipitating depression.3

Valproate, like lithium, is also not very good in mixed mania but you could consider adding it or lithium to the SGA if the initial response is unsatisfactory.2 For classic mania, if lithium is ineffective or not tolerated or refused, the next choice would be to start or add an SGA.3 Once again, quetiapine would be preferred because it has the best evidence of being able to prevent the depressions.

Turning to the management of acute bipolar depression, it seems that the evidence does not support effectiveness of lithium as an acute treatment as a monotherapy, and its effectiveness as a monotherapy for maintenance against future depression is mediocre (risk ratio [RR] vs placebo, 0.79).5 It is more effective at preventing manias (RR vs placebo, 0.54). However, lithium has unique antisuicidal effects and neuroprotective effects not shared by any other bipolar medications,6,7and perhaps because of these qualities is the most likely medication to be maintained as a monotherapy in stabilized patients with bipolar disorder.3 Yet there will be breakthrough bipolar depressions. We have several medication options that have evidence for augmenting the antidepressant effect of lithium: quetiapine, lurasidone, lumateperone, and lamotrigine. Lurasidone and lumateperone are FDA approved as add-on therapies to lithium for acute bipolar depression, and quetiapine has been found to add efficacy on maintenance when combined with lithium.8 The SGAs are preferred because they work more quickly than lamotrigine; improvement typically starts in the first 2 weeks. With lamotrigine addition, because of the slow required titration, the benefits are more likely to become significant in a month.

If the bipolar depression is associated with high levels of anxiety, quetiapine might be the preferred SGA to add to lithium.9

Lamotrigine is not FDA-approved for this indication (acute bipolar depression added to lithium), nor is it approved as an acute monotherapy treatment for bipolar depression, but the placebo-controlled, randomized controlled trial of van der Loos et al in 2009 provided support for the acute effects of lamotrigine added to lithium.10 It might be preferred over the SGA add-ons when considering its generally milder adverse effects.

Dr Osser is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.


1. McIntyre RS, Alda M, Baldessarini RJ, et al. The clinical characterization of the adult patient with bipolar disorder aimed at personalization of management. World Psychiatry. 2022;21(3):364-387.

2. Crapanzano C, Casolaro I, Amendola C, Damiani S. Lithium and valproate in bipolar disorder: from international evidence-based guidelines to clinical predictors. Clin Psychopharmacol Neurosci. 2022;20(3):403-414.

3. 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.

4. McIntyre RS, Masand PS, Earley W, Patel M. Cariprazine for the treatment of bipolar mania with mixed features: a post hoc pooled analysis of 3 trials. J Affect Disord. 2019;257:600-606.

5. Kishi T, Ikuta T, Matsuda Y, et al. Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials. Mol Psychiatry. 2021;26(8):4146-4157.

6. Osser DN. Lithium and suicide: more thoughts on the recent VA study. Psychiatric Times. 2022;39(10):26-29.

7. Osser DN. The neuroprotective effects of lithium. Psychiatric Times. 2020;36(2):21.

8. Kishi T, Sakuma K, Okuya M, et al. Effects of a conventional mood stabilizer alone or in combination with second-generation antipsychotics on recurrence rate and discontinuation rate in bipolar I disorder in the maintenance phase: a systematic review and meta-analysis of randomized, placebo-controlled trials. Bipolar Disord. 2021;23(8):789-800.

9. Crapanzano C, Damiani S, Guiot C. Quetiapine in the anxiety dimension of mood disorders: a systematic review of the literature to support clinical practice. J Clin Psychopharmacol. 2021;41(4):436-449.

10. van der Loos MLM, Mulder PGH, Hartong EGTM, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(2):223-231.