What is a good antipsychotic monotherapy for depression?

Antipsychotic Monotherapy for Depression

Quetiapine is the best antipsychotic monotherapy for depression, with FDA approval and robust evidence for efficacy at subantipsychotic doses (300-600 mg/day), demonstrating significant improvement in depressive symptoms compared to placebo. 1, 2

FDA-Approved Options

Quetiapine stands out as the only antipsychotic with both FDA approval and strong evidence for monotherapy in depression:

• FDA-approved for bipolar depression as monotherapy, with efficacy established in two 8-week trials in adults with bipolar I and II disorder 1
• Effective at subantipsychotic doses (300-600 mg/day), producing significant improvements in Montgomery-Asberg Depression Rating Scale (MADRS) scores compared to placebo (effect sizes 0.78-0.80) 3
• Rapid onset of action, with significant improvements observed from week 1 through week 8 of treatment 3
• Antidepressant effects independent of sedation, as changes in depression scores were unrelated to reports of somnolence 3

Alternative Agents with Limited Monotherapy Evidence

While other antipsychotics have FDA approval for depression, they are approved only as adjunctive therapy to antidepressants, not as monotherapy:

• Aripiprazole has FDA approval for adjunctive treatment of major depressive disorder and shows antidepressant effects at subantipsychotic doses, but lacks robust monotherapy data 2, 4
• Brexpiprazole and cariprazine are FDA-approved for adjunctive treatment of treatment-resistant depression but are not indicated as monotherapy 4
• Lurasidone demonstrates efficacy in bipolar depression but is not approved for unipolar depression monotherapy 2, 5

Critical Dosing Principle

All antipsychotics must be used at subantipsychotic doses for depression, as full antipsychotic doses are dysphorogenic and produce depression-like symptoms:

• Quetiapine: 300-600 mg/day (not the 800 mg/day used for schizophrenia) 2, 3
• Full antipsychotic doses worsen mood across all second-generation antipsychotics due to excessive dopamine blockade 2

Safety and Tolerability Profile

Quetiapine monotherapy is generally well-tolerated for depression:

• Most common adverse events include dry mouth, somnolence, sedation, dizziness, and constipation 3
• Withdrawal rates due to adverse events are relatively low 3
• Metabolic monitoring is essential: obtain baseline glucose, lipids, weight, and blood pressure before initiating treatment 6

Clinical Context and Limitations

Important caveats when considering antipsychotic monotherapy for depression:

• Not first-line treatment for unipolar depression: The American College of Physicians guidelines prioritize antidepressants and psychotherapy as initial treatments 7
• Best evidence exists for bipolar depression: Quetiapine's FDA approval and strongest data are in bipolar disorder, not unipolar major depressive disorder 1, 3
• Consider augmentation over monotherapy in treatment-resistant unipolar depression, where aripiprazole, brexpiprazole, and quetiapine extended-release have FDA approval as adjuncts 4
• Weigh benefits against risks: metabolic side effects (weight gain, hyperglycemia, dyslipidemia), akathisia, and tardive dyskinesia must be considered 4

When to Avoid Antipsychotic Monotherapy

Do not use antipsychotic monotherapy in the following scenarios:

• First-line treatment of unipolar depression without psychotic features (use antidepressants or psychotherapy first) 7
• Patients with significant metabolic syndrome, diabetes, or obesity (particularly avoid olanzapine and clozapine) 6
• When adequate trials of antidepressants have not been attempted 4