Tools for Practice Outils pour la pratique

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

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

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.

CFPCLearn Logo

Reading Tools for Practice Article can earn you MainPro+ Credits

La lecture d'articles d'outils de pratique peut vous permettre de gagner des crédits MainPro+

Join Now S’inscrire maintenant

Already a CFPCLearn Member? Log in

Déjà abonné à CMFCApprendre? Ouvrir une session

  • 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.

  • 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

Latest Tools for Practice
Derniers outils pour la pratique

#367 Oral Calcitonin Gene-related Peptide Antagonists: A painfully long name for the acute treatment of migraines

What are the risks and benefits of ubrogepant for the acute treatment of episodic migraines?
Read Lire 0.25 credits available Crédits disponibles

#366 Looking for Closure: Managing simple excisions or wounds efficiently

What are some options for efficiency in wound closure?
Read Lire 0.25 credits available Crédits disponibles

#365 Shrooms for Glooms: Evidence for psilocybin for depression

What are the benefits and harms of psilocybin for treatment-resistant/recurrent depression?
Read Lire 0.25 credits available Crédits disponibles

This content is certified for MainPro+ Credits, log in to access

Ce contenu est certifié pour les crédits MainPro+, Ouvrir une session

  • 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: Accessed on: Sep 5, 2023.

12. Government of Canada. Drug Product Database. Available at: 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.