In this cross-sectional study of adults treated with at least one second-generation antipsychotic at the time of admission to a psychiatric hospital, one in five patients was treated with two or more antipsychotics. A combination of two second-generation antipsychotics was by far the most common polytherapy pattern. Clinical correlates of antipsychotic polytherapy were a diagnosis of schizophrenia and greater BMI. In univariate analyses, patients receiving antipsychotic polytherapy had significantly higher rates of metabolic syndrome and lipid markers of insulin resistance. Within the polytherapy group and taking into account the limited power of these analyses, the prevalence of metabolic syndrome and lipid markers of insulin resistance was not influenced by the drug class (i.e., second-generation/second-generation vs. second-generation/first-generation) or by metabolically high-risk (clozapine and olanzapine) or low-risk (aripiprazole and ziprasidone) SGAs. In multivariate logistic regression analyses, metabolic syndrome and lipid marker-derived insulin resistance were associated with demographic and clinical factors known to increase the risk for metabolic abnormalities, some of which that can be adversely affected by antipsychotic treatment, while antipsychotic polytherapy was not independently correlated with these abnormalities.
Despite differences in settings, populations and definitions, our finding that almost 20% of patients were on two or more antipsychotics is in line with other recent studies in which antipsychotic polypharmacy ranged from 13% to 34% in patients with mixed psychiatric diagnoses (4
). Consistent with previous studies, we found that antipsychotic polytherapy was most prevalent in schizophrenia (6
) and that quetiapine was significantly more likely to be part of antipsychotic polytherapy (7
), most likely due to the little added risk of extrapyramidal symptoms with this agent. In addition, clozapine and ziprasidone were also significantly associated with antipsychotic polytherapy. These practices are supported by the fact that clozapine non-responders are arguably the most appropriate candidates for antipsychotic polytherapy and that ziprasidone has been associated with little weight gain or metabolic burden in chronically treated patients (47
), which makes ziprasidone a rational choice as an augmenting antipsychotic with the aim to not add to the metabolic burden of other antipsychotics. Moreover, first-generation antipsychotics and risperidone were also associated with antipsychotic polypharmacy, likely in an attempt to increase therapeutic efficacy (4
). Consistent with previous findings (49
), olanzapine treatment was not significantly associated with antipsychotic polytherapy, while the number of patients on aripiprazole was insufficient to make conclusive statements. However, the fact that antipsychotic polytherapy consisted of a multitude of different combinations underscores the lack of prevailing data and of mechanistic theories that could guide rational antipsychotic cotreatment. Although in univariate analyses of our sample, patients on more than one antipsychotic were more likely to receive anticholinergic medications, this effect was lost in multiple regression analyses, most likely due to the fact that 95% of patients were on second-generation antipsychotics.
In univariate analyses, we observed the association between antipsychotic polytherapy and poor metabolic status that had previously been suggested (26
). Body mass index and waist circumference values were significantly higher, and HDL-cholesterol levels were more frequently in the abnormally low category in patients on antipsychotic polytherapy. In addition, metabolic syndrome and lipid-marker derived insulin resistance were significantly more common in patients receiving two or more antipsychotics. However, in multivariate logistic regression analyses that were conducted to assess whether this association was independent of other potentially relevant factors, known risk factors for metabolic syndrome (i.e., body mass index, age, bipolar disorder and schizophrenia), and for insulin resistance (i.e., body mass index, sex, and race) emerged as significant contributing factors to poor metabolic health. This finding supports the postulated interaction between underlying risk factors and antipsychotic treatment (50
), rather than an independent effect of antipsychotic polypharmacy on poor metabolic outcome. The same interaction is likely to explain the weak association between first-generation antipsychotic cotreatment and metabolic syndrome, as suggested by the significantly greater waist circumference in the group receiving antipsychotic combinations that included a first-generation drug. Our findings suggest that patients receiving antipsychotic polytherapy represent a subgroup that is more obese and inactive and, thus, is more prone to metabolic risks than patients prescribed antipsychotic monotherapy.
In this context, it is important to note that even in a recent study that reported significant elevations in fasting glucose in the patients randomized to risperidone augmentation of clozapine, no differences between risperidone and placebo augmentation on any of the other metabolically relevant outcome variables were observed after eight weeks of treatment (26
). Changes in body weight, body mass index, waist circumference and total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were similar among the monotherapy and polytherapy groups. This may be explained by a ceiling effect for these changes, at least after prolonged treatment with clozapine, and supports our finding of a lack of an independent association between antipsychotic polypharmacy and metabolic syndrome. Furthermore, in addition to potential differences in patient and other treatment variables between patients on antipsychotic polytherapy and those on monotherapy, the previously reported finding of increased prescriptions for antidiabetic drugs in patients on two or more antipsychotics (29
) is sensitive to a possible measurement bias. This is suggested by a chart review study of 660 inpatients treated with at least one antipsychotic, where less than half of the patients were tested for diabetes, but testing occurred 2.6 times more often in patients on antipsychotic polypharmacy (52
). Nevertheless, our findings do not exclude the possibility that combinations of certain antipsychotic drugs could worsen or improve the risk of increased BMI and abdominal adiposity found to be more prevalent in our polytherapy sample. The potential that individual combinations could improve metabolic risk is suggested by the signal that aripiprazole treatment, which has been reported to be associated with less weight gain and metabolic complications than most other second-generation antipsychotics (53
), was associated with a lower prevalence of insulin resistance in our multiple regression analyses. This is also consistent with data from a recent 6-week, open-label study where aripiprazole augmentation of clozapine treatment at unaltered dose levels was associated with a significant decrease in weight, body mass index, fasting total serum cholesterol and triglycerides, without worsening of psychopathology scores (40
The results of our study need to be interpreted within the limitations of its cross-sectional design, moderate sample size, lack of power to examine individual antipsychotic combinations, lack of sophisticated assessments of insulin resistance, and the potentially confounding presence of multiple diagnoses and comedications. In addition, it is possible that some patients were in the process of antipsychotic cross-titration at the time of admission and would not have been on antipsychotic polypharmacy if followed over a longer period of time (19
). This could have attenuated a potential effect of sustained antipsychotic cotreatment. However, as the assessments were done at the time of admission, the bias of inpatient studies is reduced, which are more likely to capture patients during active treatment changes. Moreover, the rate of antipsychotic polytherapy was not excessive compared to other outpatient studies, suggesting that it is unlikely we included a substantial number of patients who were only on short-term antipsychotic cotreatment. Furthermore, even if some patients were on short-term antipsychotic polytherapy, this would not affect the determination of acute additive metabolic effects of combined antipsychotic treatments.
Our study is the first attempt to examine the relationship between antipsychotic polytherapy and rates of metabolic syndrome as well as of a proxy measure for insulin resistance that is easy to obtain in clinical practice. The results confirm previous reports that patients with schizophrenia are most likely to receive antipsychotic polytherapy (6
). However, in light of findings that patients with schizophrenia are also at particular risk for cardiovascular morbidity and mortality (55
), the combined impact of more than one antipsychotic creates concern in clinical practice. Our data suggest that patients receiving antipsychotic polytherapy have poorer metabolic health, but that treatment with more than one antipsychotic is not a primary factor for this finding. Further research is needed to determine the metabolic effects of specific antipsychotic combinations, duration of treatment and individual dosages used in polytherapy. Moreover, the additive effect of antipsychotic coprescribing on other areas of health, such as cardiac conduction, neuromotor and reproductive system functioning, need to be evaluated. Until such data are available, antipsychotic polytherapy should most likely be reserved for the treatment of patients who cannot be treated with clozapine or have a clozapine-refractory psychotic or mood disorder.