This first comprehensive meta-analysis of RCTs investigating antipsychotic cotreatment vs monotherapy in schizophrenia suggests superiority of antipsychotic cotreatment regarding the 2 a priori defined coprimary outcomes of all-cause discontinuation and inefficacy as defined by each study. The relevance of this finding is underscored by the fact that antipsychotic combinations were superior to monotherapy even when using a cutoff score of “much improved” on the CGI and by the relatively low NNT in the efficacy analyses that ranged mostly between 5 and 7. The interpretation of the results for specific psychopathology ratings and adverse effects was limited, however, by the low number of studies and participants with available data.
In 12 of 18 subgroup analyses, antipsychotic combinations were associated with significantly greater efficacy compared with monotherapy. Exceptions were studies with trial durations of <10 weeks and conducted outside of China, as well as those that used combinations after nonresponse to monotherapy rather than right from the start, nonclozapine antipsychotics, and combinations of 2 FGAs or 2 SGAs. However, Chinese studies used mostly designs that were also associated with increased efficacy of antipsychotic combinations. The reverse was true for non-Chinese studies, such as augmentation with a second antipsychotic after nonresponse to monotherapy and use of combinations not including clozapine.
The finding of superior efficacy of antipsychotic cotreatment compared with antipsychotic monotherapy is in contrast to the generally upheld notion that there is no support for combining 2 antipsychotics.17,25,26
However, all the studies discussed widely to date involved antipsychotic augmentation strategies of chronically ill patients refractory to clozapine.30–33
By contrast, positive effects for the antipsychotic polypharmacy were apparent the most in patients with acutely exacerbated schizophrenia and those who had 2 antipsychotics started at the same time, scenarios that have not been investigated except in studies conducted in China. Although, mean chlorpromazine equivalent doses were approximately one-third higher in the antipsychotic combination groups and although the use of therapeutic doses in both the mono- and polytherapy groups was a significant moderator variable, the mono- vs polytherapy chlorpromazine equivalent ratio did not differ between the studies finding superiority for the combination groups compared with those not finding such superiority.
In secondary sensitivity analyses, we confirmed and extended the finding of a relevant effect of study duration from a recent meta-analysis of the 4 well-known clozapine augmentation trials.60
Like in that meta-analysis where superiority of cotreatments was apparent only in the 2 studies lasting ≥10 weeks (n
= 68), we also found antipsychotic cotreatments to be superior in the 6 studies (N
= 9, n
= 394) lasting 10 weeks or longer (NNT = 5, CI = 3–20), but not in the studies lasting <10 weeks. Obviously, this has relevant implications for the design of future studies. However, 4 of 6 studies lasting ≥10 weeks included a combination of clozapine plus either sulpiride (N
= 3) or risperidone (N
= 1). Therefore, it remains to be tested whether combinations that involve antipsychotics other than clozapine are significantly more effective than monotherapy and whether the time course of separation between antipsychotic cotreatment from monotherapy is similar or different if clozapine is not part of the cotreatment. Moreover, in the non-Chinese countries where clozapine is reserved for refractory patients, the 2 moderators of superior efficacy for antipsychotic cotreatment, ie, use of clozapine and simultaneous initiation of antipsychotics in acutely ill patients, present us with a dilemma. Thus, the latter finding needs to be replicated in trials of simultaneous initiation of 2 nonclozapine antipsychotics in acutely ill patients. Nevertheless, in acutely exacerbated patients with confirmed refractory schizophrenia, clozapine could be coinitiated with a second antipsychotic in patients who stopped their prior antipsychotic due to nonadherence or experienced a significant exacerbation despite treatment with a non-clozapine antipsychotic.
Unfortunately, insufficient data were available to evaluate the acute and even less data were available to evaluate the long-term safety of antipsychotic cotreatments. This is an important shortcoming as several cross-sectional and naturalistic studies reported an increased risk for diabetes27
and cardiovascular mortality28,29
associated with antipsychotic polypharmacy. However, it is unclear if these naturalistic findings are related to a direct toxic effect of specific or all antipsychotic combinations or whether it may be related to a cohort effect, in that patients who are selected for antipsychotic combination treatments are both psychiatrically and physically sicker than patients receiving monotherapy. The latter is suggested by a recent study in which the significant association between antipsychotic cotreatment and metabolic syndrome was solely explained by a significant greater prevalence of traditional risk factors compared with patients receiving antipsychotic monotherapy.17
On the other hand, controlled adverse event data in patients cotreated with a second antipsychotic are also required to assess the possibility that certain combinations may be associated with a decreased, rather than increased adverse effect burden because reduced weight gain and metabolic abnormalities have been reported after the addition of aripiprazole to clozapine.61,62
Several limitations need to be considered when interpreting these results. These include the fact that meta-analyses combine results from trials that differ in their methodology, study size and year, use of diagnostic instruments, patient and treatment selection, primary outcome variables, and study conduct. This fact was reflected by the significant heterogeneity of the results, suggesting the effect of relevant moderator and mediator variables. However, we sought to include all available data and were able to confirm the superiority of antipsychotic cotreatments in most of the secondary and sensitivity analyses that sought to disentangle relevant moderator variables, strengthening the primary finding. Importantly, although antipsychotic combination treatments did not separate statistically from monotherapy in all the sensitivity analyses, monotherapy was not superior in any of the analyses, and trends were almost all in the direction of antipsychotic cotreatment. Furthermore, despite extensive clinical utilization of antipsychotic cotreatment, data were restricted to 19 studies worldwide and limited regarding specific combinations, long-term outcomes, and psychopathology and adverse event domains. Moreover, there was a regional effect in that patients from Chinese studies predominated in many of the trials with characteristics that were also associated with superiority of the antipsychotic cotreatment. However, we only included randomized studies and the vast majority of them were double blind. Furthermore, explicit dose information was not available for all studies/treatment arms with data on similar vs reduced dose combination strategies. Besides the fact that the level of accuracy is higher regarding explicit dose information and that meta-regression results of heterogeneous studies have to be interpreted with caution, this partial lack of data could be an additional reason for the seeming disconnect between the fact that “similar dose” combination emerged as a significant moderator of the superior antipsychotic polytherapy efficacy, whereas the chlorpromazine ratio in the mono- vs polytherapy groups did not differ between studies favoring antipsychotic polypharmacy compared with those not finding an advantage of antipsychotic cotreatment. In addition, we cannot exclude a file drawer phenomenon because the funnel plot was significantly skewed toward positive studies. However, a significantly skewed funnel plot does not prove a publication bias because other reasons can lead to marked asymmetry, such as true heterogeneity or differences in the quality of assessments in smaller vs larger studies. In addition, data were insufficient to determine to what degree these results generalize to females, patients treated in the Western world, nonclozapine combinations, and whether antipsychotic cotreatment should be initiated concurrently in acutely exacerbated patients or whether it should be limited to sequential combinations in patients with insufficient response to antipsychotic monotherapy. Moreover, data were insufficient to determine the effect of specific combinations, long-term effects, and cost, further pointing to the need for more studies. Finally, the lack of conclusive adverse effect data make it difficult to weigh potential benefits against risks of antipsychotic polypharmacy because it is possible that certain relevant adverse effects may be additive some or most combinations.
Despite these limitations, this is the largest analysis of RCTs that have investigated the effect of antipsychotic cotreatment vs monotherapy in schizophrenia. Moreover, it is the first study to include all trials available without applying any language restrictions. This allowed the inclusion of previously unrecognized trials that utilized antipsychotic polypharmacy in acutely exacerbated patients and that initiated cotreatment from the beginning of the trial, rather than waiting for nonresponse to antipsychotic monotherapy, especially clozapine. In this sense, the analyzed data extend to some aspects of the general clinical practice where antipsychotic cotreatment strategies seem to be predominantly utilized in patients who have not failed clozapine. On the other hand, most combinations utilized in clinical practice also do not include clozapine, indicating the need to conduct studies with nonclozapine antipsychotic combinations that employ some of the design features that may have mediated the superior efficacy of antipsychotic combinations vs monotherapy in the examined trials. Such studies are necessary to determine whether the superiority of antipsychotic combinations generalizes to a variety of clinical settings and populations.
In summary, these data suggest that, at least, under certain circumstances, antipsychotic cotreatment may be superior to antipsychotic monotherapy regarding all-cause discontinuation and general measures of efficacy. Benefits may be apparent in acutely exacerbated patients in whom cotreatment is initiated at the beginning of treatment and when the cotreatment is administered for 10 weeks or more. Moreover, benefits of antipsychotic cotreatment did not seem to be simply a function of an increase in antipsychotic dose and resultant dopamine blockade in the polytherapy group. However, results were heterogeneous, suggesting the influence of relevant mediator and moderator variables, and there is the possibility of publication bias. Furthermore, the database was too limited to determine the effects of specific combinations, with the exception of the suggested benefits of including clozapine. It is also unclear whether potential benefits in acutely ill patients are restricted to combinations that include clozapine or that include clozapine augmented with an FGA and what the potential short-term and, particularly, long-term risks of antipsychotic combinations are. Thus, the results from this meta-analysis are insufficient to derive conclusive clinical recommendations. Rather, it provides relevant information regarding the need for specific studies and highlights methodological considerations that should guide the design of future controlled trials. Further, large-scale studies are needed, which compare antipsychotic monotherapy to antipsychotic combinations that do not necessarily involve clozapine. Further, studies combining nonclozapine SGAs with each other and with FGAs, utilized most in clinical practice, are required. Such studies should also explore the merits of combining antipsychotics in the acute phase, instead of waiting until nonresponse has occurred, last at least 10 week, and should be conducted in non-Asian countries too. To exclude the possibility of a dose effect in the cotreatment arm, one may need to consider including a “high dose” lead-in phase, high dose monotherapy arm, or both a similar dose plus a reduced dose cotreatment arm. Furthermore, recent data, suggesting that nonresponse at 1–4 weeks is highly predictive of future nonresponse,63,64
should also be taken into account when deciding at what time patients with unsatisfactory response should be randomized to antipsychotic combinations vs continued monotherapy. Until results from such studies are available, the use of antipsychotic cotreatment should most likely be reserved to severely ill patients with a documented lack of response to antipsychotic monotherapy during the acute or chronic illness phase.