Antipsychotic drugs are the cornerstone in the management of psychotic disorders, but most patients fail to have a “good” response in short-term trials. Alternative strategies are presented here.
FIGURE 1. Pooled antipsychotic polypharmacy rates 
FIGURE 2. Prescribers’ level of justification for antipsychotic polypharmacy (rating 0 - 10) 
TABLE. Summary of recommendations about the use of polypharmacy in psychotic disorders
Antipsychotic drugs are the cornerstone in the management of psychotic disorders, but most patients fail to have a “good” response in short-term trials. Therefore, alternative strategies including dose escalation, switching to another antipsychotic, or co-treatment with polypharmacy are often necessary. At any given time, more than 20% of the patients receive antipsychotic polypharmacy in an attempt to manage suboptimal response to monotherapy (Figure 1).1 Because of the limited evidence supporting the efficacy of this practice, far from being approved, decreasing it is considered a key performance improvement and quality of care target in various states. Nevertheless, to this day this practice is still prevalent in clinical care.
Surveys reveal that most of the patients treated with antipsychotic polypharmacy were in fact inherited from other prescribers, yet most clinicians are reluctant to convert these patients to antipsychotic monotherapy (Figure 2).2 Although switching from polypharmacy to monotherapy is generally safe, data suggest a greater likelihood of dissatisfaction by patients or prescribers with the switch to monotherapy.3
Beyond adding a second antipsychotic, adjunctive treatment with other types of drugs is also common. A recent overview of meta-analyses showed that 42 different compounds had been studied, which shows how extensive this practice is.4 The addition of other compounds to antipsychotics is often studied in the context of managing symptoms such as negative symptoms or cognition, which are known to respond poorly to antipsychotic drugs.
The common use of polypharmacy contrasts with the relatively limited attention that is paid to usual drivers of insufficient treatment response. As with any chronic condition that involves taking drugs on a daily basis, psychotic disorders are associated with high rates of treatment non-adherence. However, this is often challenging for clinicians to recognize and may result in changes in the treatment plan. For example, about one-third of patients deemed to be poor responders and in need of a management strategy change may not have therapeutic antipsychotic serum levels.
Another likely driver of poor response is treatment-resistant schizophrenia (TRS). A diagnosis of TRS and a trial with clozapine are indicated for patients who have had 2 antipsychotic monotherapy trials fail; however, both are often delayed.5 Data show that patients with TRS may undergo more than 5 antipsychotic trials before they receive clozapine, and that it may take a median of 5 years between meeting criteria for TRS and the onset of a clozapine trial. Some clinicians prefer to use polypharmacy over clozapine, and many patients may never have a clozapine trial. The utilization rate of this drug in the US is about 5% of antipsychotic initiations among patients with TRS, which indicates that this drug is largely underutilized.6
The benefits of polypharmacy
To date, no combination strategy has been approved for the management of psychosis. In fact, proving that a combination of 2 drugs in polypharmacy works better than either of those drugs in monotherapy is particularly challenging. The combination needs to be tested independently against each individual drug in monotherapy, to confirm that the combination, and not the augmenting drug only, is superior to the augmented drug-this trial design is rarely done. Instead, most of the data come from studies that only compare the augmented drug to the combination, or directly compare co-treatment to monotherapy without confirming that monotherapy is not efficacious in a particular population.
With these caveats, hundreds of randomized controlled trials have been conducted to test the efficacy of the multiple forms of polypharmacy in various symptom domains of psychoses. These trials are often meta-analyzed as a way of obtaining unique pooled effects, which are often considered more reliable than those obtained from individual studies.
In a recent overview our team looked at the recommendations that resulted from the meta-analyses.4 Out of 42 co-treatment strategies that had been included, 14 combination treatments were found superior to antipsychotic monotherapy. Unfortunately, there was meaningful risk of bias in most of the randomized trials. This risk was even higher for the studies of combinations that showed large benefits compared with monotherapy.
Our team concluded that none of the recommended combinations had a meaningful benefit compared with their monotherapy counterparts. Those that showed benefit, had important risk of bias that did not justify the recommendation of drug combination for any of the symptom domains in schizophrenia. This is particularly disappointing for cognitive or negative symptoms that show limited benefit from antipsychotics monotherapy, yet are very burdensome. Our findings suggest that large high-quality trials are still necessary to address this issue.
Neurobiological research is also looking at the effects of augmenting antipsychotics with other drugs. For example, in a trial of antipsychotics augmented with N-acetylcysteine, researchers have found small improvements in measures of white matter integrity, and decrements in glutamatergic concentration in the anterior cingulate over the course of treatment.7,8
Similarly, when the effects of fatty acids augmentation have been studied, preliminary results showed lower cortical thickness in individuals who received augmentation with placebo rather than fatty acids.9 To our knowledge there have not been neurobiological studies that compared the effects of combining different types of antipsychotics. These findings are deemed to be incipient due to the limitations with sample size and duration of follow up.
The implications of the described neurobiological effects in the pathophysiology of psychotic symptoms is unknown. Furthermore, this type of research is challenged by the simultaneous action of more than one drug intervention at once, which makes it difficult to disentangle the neurobiological effects of each one. There are insufficient data from clinical or biological research that indicate the benefits of polypharmacy compared with antipsychotic monotherapy.
The risks of polypharmacy
In general, the use of antipsychotic polypharmacy has been associated with a greater burden of adverse effects, although some of these effects seem to be specific to the combination of antipsychotics.10 For example, when the effects of transition from various types of antipsychotic combinations to monotherapy were studied, individuals randomized to monotherapy lost weight compared with individuals who continued in polypharmacy.3
Specific drug combinations, particularly those that include aripiprazole may have particular adverse effect profiles. For example, in randomized studies that added aripirazole to clozapine or olanzapine polypharmacy was associated with weight loss.10-12 Similarly, for metabolic status, augmentation with aripiprazole has been found to be beneficial for various parameters, mostly in patients treated with clozapine.10,11 This was also the case for the addition of aripiprazole to haloperidol, which was associated with reductions in prolactinemia.13 Some of the beneficial effects found for polypharmacy including aripiprazole may not apply to other drug combinations, where in fact the adverse effect burden may be greater than with monotherapy.
Notably, most of the randomized studies on antipsychotic polypharmacy have been done using aripiprazole as an augmenting agent, which may have a different adverse effect profile than most other antipsychotics. Non-randomized studies, mostly derived from chart review or claims data, are more consistent in showing associations between polypharmacy and adverse effects across most domains.14 Studies of augmentation with drugs other than antipsychotics have not been systematic in addressing the impact of adverse effects, yet it is very possible that adding other agents may increase the likelihood of adverse effects compared with monotherapy.
Altogether, the adverse effect burden of antipsychotic polypharmacy seems to be specific to the type of combination, with aripiprazole having some possible advantages in selected domains. However, in general findings suggest that most combinations of antipsychotics may have greater adverse effect profile than monotherapy. Most importantly, this practice may result in patients being labelled “poor responders” unnecessarily by preventing the utilization of more effective treatments, such as long-acting injectable or clozapine.
The risk-to-benefit ratio seems to favor the use of antipsychotic monotherapy over polypharmacy in general terms, given the at best inconsistent results that favor combination treatment and the possibility of adverse effects associated with polypharmacy. Most importantly, polypharmacy may divert evidence-based treatments for patients with poor response to antipsychotic monotherapy such as clozapine or long-acting injectable antipsychotics.
The first recommendation for the management of patients with poor treatment response is to construct a clear psychopharmacological history to assure that monotherapy treatment trials reached the maximum recommended dose, and that they were of sufficient duration. This addresses the clinical response to the positive, the negative, and the cognitive domains. Although somewhat controversial, the lack of response (defined as <20% of change in a rating scale) within 2 weeks may be sufficient to recommend a change in the treatment strategy.15 Monitoring the response to a clinical trial using rating scale such as the PANSS-6 for at least 2 weeks is recommended.
Long-acting injectable formulations have substantial advantage over oral formulations because they minimize interruptions to the continuity of treatment. As a next step, consider a diagnosis of TRS. If a diagnosis of TRS is warranted, clozapine is the only approved treatment for these patients.
Clinicians and patients should keep in mind the risk-to-benefit ratio considerations before initiating polypharmacy, especially if they have patients with polypharmacy prescriptions inherited from other providers. Special consideration should be given to the use of long-acting injectables and clozapine for patients with poor response to antipsychotics.
Dr Rubio is Assistant Professor at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell; Feinstein Institute for Biomedical Research, Northwell Health; and Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY. Dr Rubio has received honoraria from Lundbeck.
1. Gallego JA, Bonetti J, Zhang J, et al. Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res. 2012;138:18-28.
2. Correll CU, Shaikh L, Gallego JA, et al. Antipsychotic polypharmacy: a survey study of prescriber attitudes, knowledge and behavior. Schizophr Res. 2011;131:58-62.
3. Essock SM, Schooler NR, Stroup TS, et al. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry. 2011;168:702-708.
4. Correll CU, Rubio JM, Inczedy-Farkas G, et al. Efficacy of 42 pharmacologic co-treatment strategies added to antipsychotic monotherapy in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry. 2017;74:675.
5. 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;13:318-378.
6. Stroup TS, Gerhard T, Crystal S, et al. Geographic and clinical variation in clozapine use in the United States. Psychiatr Serv Wash DC. 2014;65:186-192.
7. Klauser P, Xin L, Fournier M, et al. N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial. Transl Psychiatry. 2018;8:220.
8. McQueen G, Lally J, Collier T, et al. Effects of N-acetylcysteine on brain glutamate levels and resting perfusion in schizophrenia. Psychopharmacol (Berl). 2018;235:3045-3054.
9. Pawelczyk T, Piatkowska-Janko E, Bogorodzki P, et al. Omega-3 fatty acid supplementation may prevent loss of gray matter thickness in the left parieto-occipital cortex in first episode schizophrenia: a secondary outcome analysis of the OFFER randomized controlled study. Schizophr Res. 2018;195:168-175.
10. Fleischhacker WW, Heikkinen ME, Olie JP, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol. 2010;13:1115-1125.
11. Chang JS, Ahn YM, Park HJ, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69:720-731.
12. Henderson DC, Fan X, Copeland PM, et al. Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. J Clin Psychopharmacol. 2009;29;165-169.
13. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007;164:1404-1410.
14. Gallego JA, Nielsen J, De Hert M, et al. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Safe. 2012;11:527-542.
15. Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29,823 patients with schizophrenia. JAMA Psychiatry. 2017;74:686.