An Argument for Antipsychotic Polypharmacy

Antipsychotic polypharmacy in the treatment of people with psychotic disorders is a common practice, with a frequency ranging from 20% to 40% (1, 2). The frequency of the practice represents, in part, the therapeutic limitations associated with the currently available antipsychotic medications. However, there are two major questions concerning the utility of this practice: Is antipsychotic polypharmacy more effective than antipsychotic monotherapy? And is antipsychotic polypharmacy less safe than antipsychotic monotherapy? There is an emerging literature to suggest that antipsychotic polypharmacy may offer some advantages in effectiveness compared with antipsychotic monotherapy. In particular, antipsychotic polypharmacy has been associated with significant reductions in the risk for hospitalizations (3, 4; but see also reference 5). Antipsychotic polypharmacy has also been associated with longer time to all-cause discontinuation (6), a finding that has not always been replicated (3). However, concerns about the safety of the practice have led several schizophrenia treatment guidelines to recommend against the practice (7–9).

The study by Taipale and colleagues in this issue of the Journal addresses the question of the comparative safety of antipsychotic polypharmacy (10). The authors used the Finnish Hospital Discharge register to identify all people with a diagnosis of schizophrenia who had hospitalizations between the years 1972 and 2014 and were alive on January 1, 1996. The Finnish Hospital Discharge, Prescription, and Death registers were then used to identify all hospitalizations, antipsychotic medication prescriptions, and deaths for the study cohort. The hospitalization data were used to define the two primary outcome measures: cardiovascular hospitalizations and nonpsychiatric hospitalizations other than cardiovascular hospitalizations. The two hospitalization measures were used to assess “severe physical morbidity,” with the hypothesis that antipsychotic monotherapy and polypharmacy would be differentially associated with these two outcome measures. The hospitalization data were also used to track psychiatric hospitalizations. The type of hospitalization was defined as the main diagnosis listed by the treating physician for the hospitalization. The prescription data were used to define monotherapy and polypharmacy episodes of antipsychotic treatment; the World Health Organization’s defined daily doses (DDDs) were used to define seven dosing categories. All statistical comparisons were conducted using a within-individual design, which serves to minimize selection bias. The follow-up period for the cohort was from January 1, 1996, to December 31, 2017.

The authors found that antipsychotic monotherapy was used 45.9% of the follow-up time, antipsychotic polypharmacy was used 33.8% of the time, and nonuse of antipsychotic medications occurred 20.3% of the time. The high percentage of antipsychotic polypharmacy during the follow-up time provides further support for the popularity of this treatment approach. In terms of the two primary outcome measures, across all dosing categories, there were no significant differences between antipsychotic monotherapy and polypharmacy for the number of cardiovascular and other nonpsychiatric hospitalizations. However, when the authors looked at the individual dosing categories, they found that for the three highest dosing categories, antipsychotic monotherapy was associated with higher risk of nonpsychiatric hospitalization than the same dosing categories for antipsychotic polypharmacy. The highest dosing category of antipsychotic monotherapy was also associated with greater risk for cardiovascular hospitalization than the highest dosing category of antipsychotic polypharmacy. There was no dosing category for which antipsychotic monotherapy, compared with the corresponding dosing category of antipsychotic polypharmacy, was associated with significantly decreased risk of cardiovascular or nonpsychiatric hospitalization. This pattern of results persisted after sensitivity analyses were conducted in which monotherapy or polypharmacy episodes in which clozapine was one of the agents were excluded, when the first 30 days from treatment or nonuse episodes were excluded, or when treatment episodes during the first year of treatment were excluded. Finally, all dosing categories of antipsychotic monotherapy and polypharmacy were associated with reduced risk of psychiatric hospitalization compared with nonuse of antipsychotic medications. In the comparison of the individual antipsychotic monotherapy and polypharmacy dosing categories, the lower and higher polypharmacy categories were associated with decreased risk of psychiatric hospitalization compared with the corresponding antipsychotic monotherapy dosing categories, a finding that is consistent with previous studies that have found antipsychotic polypharmacy to be associated with decreased risk of psychiatric hospitalization (3, 4).

The study results are part of an emerging body of evidence that calls into question the belief that antipsychotic polypharmacy is less safe than antipsychotic monotherapy. Three recent studies have found that antipsychotic polypharmacy was associated with either a decreased risk of mortality (3) or the absence of an increased risk of mortality compared with antipsychotic monotherapy (11, 12). However, neither the Taipale et al. study nor any of these previous three studies examined the relative occurrence of less medically serious side effects that may not lead to hospitalization or death but are still troublesome to the person treated with these medications (e.g., extrapyramidal symptoms, sedation, and diminished mental acuity). In a systematic review and meta-analysis, Galling et al. (13) did not find marked differences in adverse events, but the relative lack of high-quality studies and comprehensive assessment of adverse events in the reviewed studies limits the conclusions that can be drawn from this review.

One important question that emerges from the study results is, What is the underlying mechanism for the apparent greater safety of high-dose antipsychotic polypharmacy compared with high-dose antipsychotic monotherapy? The authors propose that high-dose polypharmacy may be safer than high-dose monotherapy because the dosages of the individual agents that make up the polypharmacy combination are lower than the dosage of the single high-dose monotherapy agent. The decreased risk of cardiovascular hospitalization for the high-dose olanzapine-quetiapine combination compared with either high-dose olanzapine or quetiapine monotherapy supports the proposal, but the actual dosages of olanzapine and quetiapine used in the combination would need to be provided to confirm the authors’ hypothesis. Furthermore, the validity of this explanation would depend on whether the agents that define the episode of polypharmacy have either distinct adverse event profiles or do not have additive effects for the adverse events that they share in common. An alternative explanation is based on the authors’ observation that long-acting injectable (LAI) preparations were used more frequently in high-dose polypharmacy than in high-dose monotherapy. Since LAIs are associated with lower plasma levels than comparable dosages of the oral formulation of the same agent, the increased use of LAIs may actually lead to comparatively lower dosages in the high-dose polypharmacy dosing category. If so, then the study results would provide another reason for us to increase our use of LAI preparations (5, 14).

The authors also raise the issue of rational polypharmacy. They note that in other fields of medicine, treatment guidelines actually recommend the concurrent use of medications with different mechanisms of action to improve treatment response. The advent of a number of new antipsychotic medications with mechanisms of action that are not limited to full dopamine D₂ receptor antagonism (e.g., aripiprazole, brexpiprazole, cariprazine, lumateperone) increases the opportunities to use combinations of antipsychotic medications with different mechanisms of action. In particular, the authors note the decreased hospitalization risk associated with the combination of clozapine and aripiprazole, which is of interest, since this combination has previously been associated with significantly decreased risk of hospitalization (4). The elucidation of the underlying mechanisms that increase the efficacy and safety of this combination would seem to be of critical importance for the identification of other possible antipsychotic combinations that share the property of increased efficacy and safety and for the development of novel antipsychotic agents. The elucidation of the mechanisms that underlie beneficial antipsychotic combinations may also be helpful in guiding clinicians on which combinations not to use.

Finally, the Taipale et al. study and many of the previously referenced studies that support the efficacy and safety of antipsychotic polypharmacy are observational studies based on the utilization of large databases. As the authors correctly point out, the feasibility of conducting long-term randomized clinical trials to examine the relative efficacy and safety of antipsychotic monotherapy versus antipsychotic polypharmacy is limited. Therefore, we are dependent on observational studies, in which the data utilized were usually not collected to address the questions of interest in these studies.

In summary, the authors found that high-dose antipsychotic polypharmacy was associated with decreased risk of hospitalization for various medical comorbidities compared with high-dose antipsychotic monotherapy and that low-dose and high-dose antipsychotic polypharmacy was associated with decreased risk of psychiatric hospitalization. These data importantly contribute to our reconceptualization of the role of antipsychotic polypharmacy in the treatment of people with schizophrenia.