Bipolar Disorder: Practice-Changing Trials from 2019

Psychiatric TimesVol 37, Issue 2
Volume 37
Issue 2

The treatment of bipolar disorder changed in ways big and small in 2019. More in this summary.

Bipolar Trials in 2019

For Part 2 of this 2-part series, see Novel Approaches to Bipolar: What Worked, and What Did Not, in 2019.


The treatment of bipolar disorder changed in ways big and small in 2019. At the regulatory level, cariprazine (Vraylar) joined a select group of atypical antipsychotics with FDA-approval in bipolar depression, and lithium’s FDA-approval was broadened from age 12 and older to age 7 and older. Besides the official decrees, over a dozen randomized controlled trials were released.

Cariprazine in bipolar I depression

Cariprazine (Vraylar) has been studied for bipolar depression since 2009. Most of the results have been positive for the 1.5 mg daily dose but raising the dose to 3 mg daily has not raised the efficacy. There was a new trial in 2019 with results that are consistent with earlier findings.1

Compared with other atypical antipsychotics, cariprazine’s advantage lies in its tolerability profile and its proven efficacy in both mania and depression. The only other atypical with FDA-approval in both poles is quetiapine. However, cariprazine’s positive trials are limited to bipolar I depression (not bipolar II), and its effect size in bipolar I depression is small (0.3), both in this study and in a 2019 meta-analysis.2

Antipsychotic augmentation after mania: 6 months may be enough

When risperidone was used to augment a mood stabilizer in mania, the antipsychotic continued to prevent manic relapses for up to 6 months, but not beyond that. Longer use (1 year) only lead to more weight gain without further mood benefits, according to a post-hoc analysis of a 2016 study that arrived at the same conclusion (the original study lumped patients on risperidone and olanzapine augmentation together).3 This puts a different spin on the maintenance story, as earlier studies stopped the antipsychotic after 2 to 3 months. That design proved that early discontinuation was riskier than ongoing treatment, but it didn’t tell us whether the medication could be safely stopped at a later point. Discontinuation at 6 months is now feasible, but I would taper slowly, lowering the dose every 2 weeks, and make sure to keep the original mood stabilizer in place.

Lithium’s long-lasting benefits in children

In contrast to risperidone, lithium keeps working to prevent episodes after the 6 month-mark. That was the conclusion of this randomized, placebo-controlled trial of children aged 7 to 12 years. The result is not exactly surprising, as these patients had responded to lithium after a manic or mixed episode, and only 40% were taking another mood stabilizer. What’s impressive is that-by chance-there were 3-times as many patients on a back-up mood stabilizer in the placebo group. Despite that unfair advantage, the placebo group was 3-times as likely as the lithium group to have mood and related problems in the 7-month trial (86% vs 35%).4

Separately, lithium performed well in a large uncontrolled study from 2019 that followed youth with bipolar disorder for an average of 10 years. Compared with other mood stabilizers, those on lithium had half as many suicide attempts, better functioning, and less depression and aggression.5

The rebirth of carbamazepine-lithium

Carbamazepine and valproate and have long been used to augment lithium, but the two strategies were never compared head-to-head until this year. The number of study subjects was small but the duration was long, which can be just as informative as a large, short-term trial. Both anticonvulsants performed similarly on measures of mania and depression, but carbamazepine was better tolerated, with lower rates of weight gain, fatigue, and sexual dysfunction.6

The carbamazepine-lithium combination gained popularity in the 1980s after reports of patients who did not respond to either drug alone but recovered when both were used together. The two medications also cancel out some of each other’s adverse effects. Lithium reverses some of the neutropenia with carbamazepine, and the two have opposite effects on water retention, which partially balances out when they are combined.7

Thyroid augmentation is safe for anxiety

Intuition may work for understanding people, but it’s a poor guide for psychopharmacology. Supraphysiologic thyroid does not sound like a good idea for anxious patients, but in this 2019 study it did not worsen anxiety, and anxiety symptoms did not predict its antidepressant effects. The study was a post hoc analysis of a 2014 trial that found that levothyroxine was effective in bipolar depression.8

TMS does not harm, and might even help cognition

Bipolar depression responds to both electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), but ECT is limited by its cognitive effects. A study in 2018 of TMS in bipolar disorder concluded that the treatment did not cause cognitive deficits, and in 2019 a small, sham-controlled study in euthymic bipolar patients found that TMS improved cognitive measures.9


Two medications for dementia-rivastigmine and memantine-underwent trials in bipolar mania.10,11 The results were either not significant, or not clinically significant, so I’ll pass on those interventions until there are more data. Next month I’ll review the 2019 trials of anti-inflammatories (celoxib, aspirin, atorvastatin, and pioglitazone), nutraceuticals (N-Acetylcysteine), and five types of psychotherapy in bipolar disorder. The tension will be high; half of the treatments on that list did not work.

Dr Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. As the Editor in Chief of The Carlat Psychiatry Report, he hosts a weekly podcast with Kellie Newsome on psychiatric practice. He is the coauthor with Jim Phelps, MD, of Bipolar, Not So Much. He does not accept honoraria from pharmaceutical companies.

Editor's note: This article was originally posted on January 9, 2020, and has since been updated.


1. Earley WR, Burgess MV, Khan B, et al. Efficacy and safety of cariprazine in bipolar I depression: a double-blind, placebo-controlled phase 3 study. Bipolar Disord. October 2019; Epub ahead of print.

2. Pinto JV, Saraf G, Vigo D, et al. Cariprazine in the treatment of bipolar disorder: a systematic review and meta-analysis. Bipolar Disord. October 2019; Epub ahead of print.

3. Valdes M, Bertolin S, Qian H, et al. Risperidone adjunctive therapy duration in the maintenance treatment of bipolar I disorder: a post hoc analysis. J Affect Disord. 2019;246:861-866.

4. Findling RL, McNamara NK, Pavuluri M, et al. Lithium for the maintenance treatment of bipolar i disorder: a double-blind, placebo-controlled discontinuation study. J Am Acad Child Adolesc Psychiatry. 2019;58:287-296.

5. Hafeman DM, Rooks B, Merranko J, et al. Lithium versus other mood stabilizing medications in a longitudinal study of bipolar youth. J Am Acad Child Adolesc Psychiatry. July 2019; Epub ahead of print.

6. Missio G, Moreno DH, Demetrio FN, et al. A randomized controlled trial comparing lithium plus valproic acid versus lithium plus carbamazepine in young patients with type 1 bipolar disorder: the LICAVAL study. Trials. 2019;20:608.

7. Aziz R, Aiken C. Harnessing beneficial drug interactions. Carlat Psychiatry Rep. 2018;11:3-7.

8. Pilhatsch M, J Stamm T, Stahl P, et al. Treatment of bipolar depression with supraphysiologic doses of levothyroxine: a randomized, placebo-controlled study of comorbid anxiety symptoms. Int J Bipolar Disord. 2019;7:21.

9. Yang LL, Zhao D, Kong LL, et al. High-frequency repetitive transcranial magnetic stimulation (rTMS) improves neurocognitive function in bipolar disorder. J Affect Disord. 2019;246:851-856.

10. Keshavrzi A, Rezaei H, Haghighi M, Jahangard L. Effect of rivastigmine (acetyl cholinesterase inhibitor) versus placebo on manic episodes in patients with bipolar disorders: results from a double blind, randomized, placebo-controlled clinical trial. Neuropsychobiol. 2019;78:200-208.

11. Omranifard V, Tarrahi MJ, Sharifi S, Karahmadi M. Evaluation of the effect of memantine supplementation in the treatment of acute phase of mania in bipolar disorder of elderly patients: a double-blind randomized controlled trial. Adv Biomed Res. 2018;7:148

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