Tools for Practice

#60 Antipsychotics for depression: An acceptable risk/benefit profile?

Are antipsychotics, either added to standard antidepressants or as monotherapy, effective for the treatment of depression without psychotic features?

Second-generation antipsychotics appear effective in treating depression when given to augment antidepressants.  One antipsychotic (quetiapine) appears effective in treating depression alone but equivalence to antidepressants is uncertain.  The evidence has a high risk of bias and adverse events are common.  

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2010 Cochrane review1 (28 trials, 8487 patients):  
  • Antipsychotic versus antidepressant: Equivalence is uncertain. 
    • Olanzapine (five trials, 779 patients): Two of five olanzapine studies found antidepressants superior (three found no difference). 
    • Quetiapine (one trial, 309 patients): Equivalent but only one trial.   
  • Antipsychotic versus placebo: Only quetiapine (four trials, 2,069 patients) was studied in depression without psychosis: 
    • Response (Number Needed to Treat (NNT)=8) and remission (NNT=17) 
  • Antipsychotic added t(augmenting) antidepressants: 12 trials using aripiprazole, olanzapine, quetiapine, or risperidone: 
    • Response (NNT=7-12) and remission (NNT=7-12). 
  • Adverse events were common, and typical of the antipsychotic studied (example 4 kg weight gain with olanzapine). 
    • More patients stopped due to adverse events in the antipsychotic group: Number Needed to Harm (NNH)=6-13 when used alone and NNH=12-50 when used as augmentation.  
  • Insufficient evidence to determine if one antipsychotic is superior to others. 
Newer systematic reviews found similar.2-5     Context:  
  • Trials in systematic reviews have a high risk of bias including unclear allocation concealment, selective reporting and short trial duration (22 of 28 studies <12 weeks) 
    • Although not assessed, selective publication (not publishing negative studies)6 and sponsorship bias7 are common concerns in the literature.  
  • Canadian8 and American9 depression guidelines include the option of second-generation antipsychotics alone or as augmentation therapy in patients who have failed first-line antidepressants. 
  • Efficacy of second-generation antipsychotics is minimal in some anxiety conditions (like Generalized Anxiety Disorder) but may help others (like Obsessive Compulsive Disorder).10 
updated June 9 2015 by ricky

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  • G. Michael Allan MD CCFP
  • Ricky Turgeon BSc Pharm

1. Komossa K, Depping AM, Gaudchau A, et al. Cochrane Database Syst Rev. 2010 Dec 8; (12):CD008121.

2. Wen XJ, Wang LM, Liu ZL, et al. Braz J Med Biol Res. 2014 Jul; 47(7):605-16.

3. Spielmans GI, Berman MI, Linardatos E, et al. PLoS Med. 2013; 10(3):e1001403.

4. Zhou X, Keitner GI, Qin B, et al. Int J Neuropsychopharmacol. 2015 May 25. pii: pyv060. doi: 10.1093/ijnp/pyv060. [Epub ahead of print]

5. Edwards SJ, Hamilton V, Nherera L, et al. Health Technol Assess. 2013 Nov; 17(54):1-190.

6. Turner EH, Matthews AM, Linardatos E, et al. N Engl J Med. 2008 Jan 17; 358(3):252-60.

7. Heres S, Davis J, Maino K, et al. Am J Psychiatry. 2006; 163:185–194.

8. Kennedy SH, Lam RW, Parikh SV, et al. J Affect Disord. 2009; 117 Suppl 1:S26-43.

9. Gelenberg AJ, Freeman MP, Markowitz, et al. Practice guideline for the treatment of major depressive disorder. Available at: Last accessed June 9, 2015.

10. Lindblad AJ, Freeman L. Tools for Practice. April 15, 2015. Available at: Last accessed June 9, 2015.

Authors do not have any conflicts of interest to declare.