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The purpose of this study was to review the scientific evidence for neurobiological rationale, efficacy, tolerability and cost effectiveness of antipsychotic polypharmacy (APP). A systematic literature search of Medline, Embase, Ovid and the Cochrane Database of Systematic Reviews until April 2012 was carried out. Theories behind APP have only modest pre-clinical and clinical evidence. We found limited statistical evidence supporting modest efficacy of APP in patients with psychotic symptoms refractory to clozapine. APP is associated with increased mortality, metabolic syndrome, decreased cognitive functioning, high dose prescription and non-adherence. It brings up extra costs, lacking evidence for cost-effectiveness. Pre-clinical studies underpinning neurobiological hypotheses in APP are lacking. Evidence supporting efficacy of APP is limited with modest beneficial clinical relevance. APP is associated with several serious adverse effects and increased health costs. In the absence of more convincing pre-clinical support and clinical evidence we advise adherence to existing guidelines and limiting combinations of antipsychotics (in consideration with other pharmacotherapeutic, somatic and psychotherapeutic options) to patients with clozapine-refractory psychosis in well-evaluated individual trials that might need 10 weeks or more.


Marc W H Lochmann van Bennekom, Harm J Gijsman, Frans G Zitman. Antipsychotic polypharmacy in psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost effectiveness. Journal of psychopharmacology (Oxford, England). 2013 Apr;27(4):327-36

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PMID: 23413275

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