An Overview of Atypical Antipsychotics for Bipolar Depression

January 3, 2020

For most patients, bipolar is a disorder of depression. It’s here that they spend the majority of their days...

For most patients, bipolar is a disorder of depression. It’s here that they spend the majority of their days, so an atypical antipsychotic that has benefits in depression is usually the best choice.1

The atypical antipsychotics are complex drugs. No two have the same profile, and the line between their receptor profile and clinical effects is a hard one to follow. Only four are FDA-approved in bipolar depression: cariprazine (Vraylar®), lurasidone (Latuda®), olanzapine-fluoxetine combination (Symbyax®), and quetiapine (Seroquel®). The Tableprovides dosage ranges for the four atypical antipsychotics that are FDA-approved for bipolar depression. Most of the other atypical antipsychotics have been tried but failed to show efficacy in bipolar depression, including a few that work in unipolar depression: aripiprazole, ziprasidone, and risperidone.2 Asenapine (Saphris®), brexpiprazole (Rexulti®), and paliperidone (Invega®) are untested.

Cariprazine (Vraylar®)

Cariprazine (no equivalent generic version equivalent in the US) is FDA-approved for both manic and depressive episodes in bipolar disorder. It has favorable rates of weight gain and fatigue, especially in the lower dose range. Adverse effects that get in the way for patients include akathisia and extrapuramidal symptoms. The number needed to treat is higher than for other atypical antipsychotics for bipolar depression (10 versus 2 to 6 for remission and response).3

To minimize akathisia, start with 1.5 mg every other day. Cariprazine’s long half-life (2-5 days) allows this kind of dosing.

Lurasidone (Latuda®)

Lurasidone (no equivalent generic version available in the US) is FDA-approved for bipolar depression in patients as young as 12 years. It has favorable rates of weight gain and fatigue and is the only atypical antipsychotic with evidence to improve cognition in bipolar disorder, based on a small controlled trial in euthymic bipolar I patients.4

No studies have been undertaken in patients with mania, although it does work in unipolar depression with mixed features. It must be taken with a meal of more than 350 kcal. Nausea and akathisia are common causes of discontinuation.

We don’t know the ideal dose of lurasidone because it was dosed flexibly in the bipolar depression trials. An analysis of that data suggests it that higher doses are more effective, with a linear dose-response relationship between 20 and 120 mg.5

Olanzapine-fluoxetine combo (OFC) (Symbyax)

Statistically speaking, OFC may be the most effective therapy for acute bipolar depression, with a number needed to treat (NNT) of 2 compared with 5 to 11 for other FDA-approved atypical antipsychotics.3

Olanzapine does not treat depression on its own so it requires the fluoxetine component to work. This is a potential draw-back because fluoxetine may worsen manic or mixed symptoms. The prescription can be written as a single combo pill, which helps some patients save on their copays, or as the two medications, which is cheaper for patients who pay full price for the medicine.

Weight gain and metabolic adverse effects are also significant risks with this medicine, but they can be ameliorated somewhat with metformin. This anti-diabetic agent has the best preventative effects for weight gain on atypical antipsychotics, and it works better when started earlier (500-1000 mg/d with food).6

Although ost meta-analyses rank OFC at the top of the efficacy list in bipolar depression, the story is different in unipolar depression, where its efficacy usually ranks near the bottom among atypical antipsychotic anugmentation agents.7

Quetiapine (Seroquel)

Quetiapine is FDA-approved for both manic and depressed episodes in bipolar disorder. Moreover, it may improve sleep quality and comorbid anxiety.8,9 Quetiapine has favorable rates of akathisia and extrapyramidal effects.

However, quetiapine’s adverse effects, particularly sedation and hypotension, are a common cause of discontinuation and emergency department visits.10 Weight gain and metabolic effects are significant long-term problems. Furthermore, despite early hopes, patients on quetiapine are at risk for tardive dyskinesia.11

Both the extended release (XR) and instant release (IR) versions of quetiapine are FDA-approved for bipolar depression. For reasons that have more to do with its patent than its pharmacology, only the XR is approved in unipolar depression.

Quetiapine IR can be dosed all-at-night, and this strategy usually results in less daytime fatigue than the XR version. Hypotension, however, is lessened with the smoother peaks of quetiapine XR, particularly in doses higher that 300 mg.12


None of the atypical antipsychotics stands out as the best choice for bipolar depression. Both of the generic options are low on tolerability, but OFC is the most likely to work and quetiapine has additional benefits in sleep and anxiety. Cariprazine and lurasidone are better tolerated overall, unless the problem is akathisia or out-of-pocket expense.


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.


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