Schizophrenia: Are There Any Effective Pharmacologic Combinations?

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Future guidelines on schizophrenia treatment should consider the lack of pharmacologic combination recommendations.
Future guidelines on schizophrenia treatment should consider the lack of pharmacologic combination recommendations.

A systematic review published in JAMA Psychiatry found insufficient evidence to recommend any particular combination of medications for schizophrenia treatment.

A high percentage of patients with schizophrenia show a limited or no response to antipsychotic drugs, necessitating strategies such as switching medications, increasing dosages, and combining treatments.4-6 While adding medications to antipsychotic agents is common practice in these patients, there is currently no approved combination for treatment-resistant schizophrenia. Although multiple trials have investigated combination approaches, most samples have been small and results have been mixed.

Various meta-analyses have explored the efficacy and safety of a range of combination strategies, and this data is more uniform and therefore more comparable. In addition, these analyses can be evaluated for risk of bias. The current review examined such meta-analyses to determine the efficacy of adding a second psychotropic drug to an antipsychotic medication regimen. The level of bias was also assessed for each of the 29 meta-analyses included. There were 42 combined treatment strategies across 381 trials involving a total of 19,833 patients. In each study, combinations of antipsychotic treatment plus another pharmacological agent were compared with controls: placebo or antipsychotic monotherapy.

The results show that 14 treatment combinations outperformed controls (standard mean difference/Hedges g, −1.27 [95% CI, −2.35 to −0.19] to −0.23 [95% CI, −0.44 to −0.02]; P =.05), and none of these included clozapine. Although the methods of the meta-analyses were mostly high quality, the quality of the research they analyzed was low. Further, while treatment recommendations correlated with the effect size in those studies (correlation coefficient, 0.22; 95%CI, 0.35-0.10; P <.001), there was an inverse correlation between effect size and study quality (correlation coefficient, −0.06; 95% CI, 0.01 to−0.12; P =.02), rendering conclusion about these strategies unreliable.

Based on this review, there are “no grounds for recommending any pharmacologic combination treatment for the population with schizophrenia,” the investigators wrote. This lack of evidence should be considered in the development of future guidelines on schizophrenia treatment. “Nevertheless, as noted earlier, we cannot exclude [the possibility] that certain patient subgroups might respond to specific combination treatments, but future trials targeting clinically orbiologically defined subgroups are needed to clarify this possibility.”


  1. Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S. Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence [published online May 17, 2017]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.0624
  2. Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012; 13(5):318-378. doi:10.3109/15622975.2012.696143
  3. Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 suppl):1-56.
  4. National Collaborating Centre for Mental Health. Psychosis and schizophrenia in adults: treatment and management. NICE clinical guideline 178. 2014. Accessed June 1, 2017.
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