#357: Overcoming Resistance: Antipsychotics for difficult to treat depression
CLINICAL QUESTION
In patients with treatment-resistant depression, is adding an atypical antipsychotic to current therapy safe and effective?
BOTTOM LINE
About 30% of patients using atypical antipsychotics as adjunctive therapy achieve a response in treatment-resistant depression compared to ~20% on placebo at 6-8 weeks. Somnolence, akathisia, and weight gain are most commonly reported adverse events occurring in 5-20% versus 1-5% for placebo.
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EVIDENCE
- 5 systematic reviews (7-32 Randomized Controlled Trials [RCTs], 2037-8349 patients), from the last 5 years versus placebo in patients with ≥1-2 past antidepressant treatment failures. Adjunctive aripiprazole, brexpiprazole, cariprazine, and quetiapine accounted for 90% of patients (risperidone ~5%).1-5 Results statistically significant unless indicated. After ~6-8 weeks:
- Response (≥50% depression score reduction):1,2
- 24%-37% versus 18%-27% (placebo), Number Needed to Treat (NNT)=10-12.
- Remission:2-5
- 17-31% versus 12-18% (placebo), NNT=10-22.
- Inconsistent/non-significant results for quetiapine and cariprazine.
- Risperidone NNT=6, data at high risk-of-bias.
- 17-31% versus 12-18% (placebo), NNT=10-22.
- Adverse events:
- Discontinuation due to adverse events:2-4
- 3-10% versus 1-3% (placebo), Number Needed to Harm (NNH)=15-58.
- NNH=15 (cariprazine), 16 (quetiapine), 52-57 (aripiprazole), 57-58 (brexpiprazole).
- Inadequate risperidone data.
- 3-10% versus 1-3% (placebo), Number Needed to Harm (NNH)=15-58.
- Akathisia:2,3
- 8-20% versus 2-6% (placebo), NNH=7-20
- NNH=7 (aripiprazole), 9 (cariprazine), 17-20 (brexpiprazole).
- Quetiapine and risperidone similar to placebo.
- 8-20% versus 2-6% (placebo), NNH=7-20
- Somnolence:2,3
- 4-19% versus 1-5% (placebo), NNH=6-32.
- NNH=6 (quetiapine), 23 (cariprazine), 26-32 (brexpiprazole).
- Aripiprazole and risperidone similar to placebo.
- 4-19% versus 1-5% (placebo), NNH=6-32.
- Weight gain (≥7% body weight):2
- 4-8% versus 1-3% (placebo), NNH=19-45.
- NNH=19 (aripiprazole), 34 (quetiapine), 45 (brexpiprazole).
- Cariprazine and risperidone similar to placebo.
- 4-8% versus 1-3% (placebo), NNH=19-45.
- Discontinuation due to adverse events:2-4
- Response (≥50% depression score reduction):1,2
- Limitations: Most RCTs industry-funded; varying definitions of treatment resistance; uncertain long-term benefits/harms (example: weight gain, other metabolic complications); small sample sizes limit risperidone conclusions; inconsistent reporting of olanzapine.
CONTEXT
- Alternative strategies for treatment resistance include cognitive behavioural therapy (response NNT=5, remission NNT=10),6 add-on antidepressants (bupropion similar to aripiprazole for remission),7 or lithium (response NNT=5, remission similar to placebo based on limited data).1,8
- Uncertain dose-response relationship. Lower doses may be as effective while minimizing adverse effects.9,10
- Cost/30 days (currently approved for depression in Canada):11,12
- Brexpiprazole 1-3mg $110.
- Aripiprazole 2-15mg $25-40.
- Quetiapine XR 150-300mg $15-30.
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