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#357: Overcoming Resistance: Antipsychotics for difficult to treat depression


CLINICAL QUESTION
QUESTION CLINIQUE
In patients with treatment-resistant depression, is adding an atypical antipsychotic to current therapy safe and effective?


BOTTOM LINE
RÉSULTAT FINAL
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
DONNÉES PROBANTES
  • 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.
    • 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.
      • 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.
      • 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.
      • 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.
  • 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
CONTEXTE
  • 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.


Greg Sherman January 25, 2024

Confirms clinical expeerience-smaall benefit and expeted side effects

David Reesor April 24, 2024

Good proof of efficacy


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Author(s)
Auteur(s)
  • Bradley LeDrew PharmD candidate
  • Wyatt Baloun PharmD candidate
  • Alex Singer MD CCFP
  • Jamie Falk PharmD

1. Vazquez G, Bahji A, Undurraga J, et al. J Psychopharmacol. 2021;35(8):890-900. Epub 2021 Jul 9.

2. Kishimoto T, Hagi K, Kurokawa S, et al. Psychol Med. 2022;53(9):1-19.

3. Ralovska S, Koychev I, Marinov P, et al. Cochrane Database Syst Rev. 2023;7:CD013866.

4. Luan S, Wan H, Zhang L, et al. Neuropsychiatr Dis Treat. 2018 Feb. 8;14:467-477.

5. Davies P, Ijaz S, Williams CJ, et al. Cochrane Database Syst Rev. 2019;12:CD010557.

6. Ijaz S, Davies P, Williams CJ, et al. Cochrane Database of Syst Rev. 2018;5:CD010558.

7. Mohamed S, Johnson GR, Chen P, et al. JAMA. 2017;318(2):132-145

8. Nunez NA, Boney J, Mehak P, et al. J Affect Dis. 2022;302:385–400

9. Furakawa Y, Hamza T, Cipriani A, et al. Br J Psychiatry. 2022;221(2):440-447.

10. Furakawa Y, Oguro S, Obata S, et al. Psychiatry Clin Neurosci. 2022 Sept. 76(9):416-422. Epub 2022 Jul 12.

11. Price Comparison of Commonly Prescribed Medications in Manitoba 2023. Available at: https://medsconference.files.wordpress.com/2023/05/price-comparison-commonly-rx-drugs-mb-may-9-2023.pdf. Accessed on: Sep 5, 2023.

12. Government of Canada. Drug Product Database. Available at: https://health-products.canada.ca/dpd-bdpp/. Accessed on: Sept 14, 2023.

Authors do not have any conflicts of interest to declare.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.