Antipsychotic polypharmacy, although often used (~30%) in patients with schizophrenia, is not without concern due to the lack of evidence for its efficacy and safety. Meta-analyses of randomized clinical trials (RCTs) have shown mixed results. Usually RCTs address short term outcomes, as for maintenance management of schizophrenia and long term outcomes high patient numbers would be needed (approximately 1000), which is probably the reason why no such studies have been done. However, as schizophrenia is a lifelong illness, long-term outcomes, including relapse prevention and avoidance of adverse physical morbidity and mortality, is an even more important issue for patients. In the lack of long term RCTs, observational studies using large electronic databases are serving to overcome the gap of information in this field.
This study by Tiihonen et al is a nationwide cohort study from Finland aimed to study the association of specific antipsychotic combinations in the treatment of schizophrenia patients who were re-hospitalized.  Psychiatric rehospitalization was used as a marker for relapse among 62,250 patients during the use of 29 different antipsychotic monotherapy and polypharmacy types between January 1, 1996, and December 31, 2015.  Hazard ratio (HR) was measured for psychiatric rehospitalization during the use of polypharmacy vs during monotherapy within the same individual.  Within-individual analyses, where each patient is used as his or her own control, was used to minimize selection bias.
 
In the cohort, the combination of clozapine plus aripiprazole was associated with the lowest risk of psychiatric rehospitalization.  It was superior to clozapine, the monotherapy associated with the best outcomes (the only monotherapy found in the 10 best treatments), with a difference of 14% (HR, 0.86; 95%CI, 0.79-0.94) in the analysis including all polypharmacy periods, and 18% in the conservatively defined polypharmacy analysis excluding periods shorter than 90 days (HR, 0.82; 95%CI, 0.75-0.89; P < .001).  In first episode patients, these differences between clozapine plus aripiprazole vs clozapine monotherapy were even greater (difference, 22%; HR, 0.78; 95%CI, 0.63-0.96 in the analysis including all polypharmacy periods, and difference, 23%; HR, 0.77; 95%CI, 0.63-0.95 in the conservatively defined polypharmacy analysis).  Overall, any antipsychotic polypharmacy was associated with a 7% to 13% lower risk of psychiatric rehospitalization compared with any monotherapy (ranging from HR, 0.87; 95%CI, 0.85-0.88, to HR, 0.93; 95%CI, 0.91-0.95; P < .001).  
 
This cohort study showed that polypharmacy in the maintenance therapy of schizophrenia was able to outperform monotherapy. Combining clozapine with the partial agonist aripiprazole was associated with the lowest risk of rehospitalization, indicating that using two antipsychotics with different receptor profiles can be beneficial in treating schizophrenia.  The clozapine dose was just slightly lower during polypharmacy than during monotherapy, suggesting that reduction of the dose was not the major explanation for the better outcome.  The different types of receptor profiles may be what accounts for the beneficial effects. The article refers to a meta-analysis in which the addition of aripiprazole (a partial dopamine D2 receptor agonist) to clozapine reduced adverse effects such as weight gain and increased prolactin level, while a combination of 2 dopamine D2 antagonists was associated with greater prolactin elevation but less insomnia. Adherence would also be increased if there is a decrease in adverse events.
The article concludes that since many combinations of polypharmacy are beneficial, “the current treatment guidelines should modify their categorical recommendations discouraging all antipsychotic polypharmacy in the maintenance treatment of schizophrenia.”