Literature Reviewed

Antipsychotic Polypharmacy. Focus (Am Psychiatr Publ) by Foster A, King J. 2020;18(4):375-385.

Original Abstract

Physicians who treat patients with schizophrenia frequently encounter complex clinical situations not fully addressed by published treatment guidelines. Some of these situations lead to antipsychotic polypharmacy, often prescribed when clinical and social obstacles prevent access to clozapine and patients have had suboptimal responses to non-clozapine monotherapy. We offer our perspective on the place of antipsychotic polypharmacy in the current treatment guidelines for patients with schizophrenia. We summarize data on the prevalence of antipsychotic polypharmacy and describe common clinical situations in which this practice is encountered, along with the pharmacological underpinnings of this practice. We briefly review evidence on common risks of antipsychotic polypharmacy and describe the limited evidence for the possible benefits of such practice. Moreover, we take a look at alternative antipsychotic augmentation strategies that address all domains of psychosis.

Read the full paper.

Polypharmacy versus Monotherapy: Commentary and Clinical Takeaways

This clinical synthesis by Foster and King examines, evaluates treatment guideline recommendations, the current literature, and case studies to explore the role of antipsychotic polypharmacy and its appropriateness in managing psychosis.

Polypharmacy Guidelines

The general guideline consensus (summarized in Figure 1 of the paper) is that polypharmacy should be reserved for patients who are treatment-resistant.4 Polypharmacy could be considered for the management of symptoms unaddressed by antipsychotic monotherapy as well (ie, to further improve positive symptoms and improve negative symptoms as well as cognitive impairment).

The prevalence of antipsychotic polypharmacy was identified through a review of available literature that represented a variety of practice settings and demonstrated varying definitions of antipsychotic polypharmacy episodes, ranging from 1 week to 90-plus days.4 While it is difficult to pinpoint an exact prevalence, the trials reviewed by Foster and King showed that between 17% and 57.5% of patients were noted to be on at least two antipsychotics concurrently.4

Antipsychotic Polypharmacy: Safety and Efficacy

As far as safety and efficacy of antipsychotic polypharmacy is concerned, the authors evaluated literature and used case examples to illustrate common situations that would warrant its use. In a meta-analysis by Correll et al, for instance, the authors examined if antipsychotic monotherapy or polypharmacy was more effective in patients with schizophrenia.4,11 The studies analyzed had a variety of outcomes, but ultimately found that the use of combination therapy with antipsychotic polypharmacy was more effective than antipsychotic monotherapy.4,11 The combination therapy was also found to be more effective after 10 weeks of treatment when one antipsychotic was clozapine and when antipsychotic polypharmacy was initiated simultaneously (ie. both antipsychotics at the same time) rather than waiting to add a second antipsychotic due to lack of response.4,11

Essock et al observed the effectiveness of monotherapy versus a combination regimen and found that patients who were randomized to the monotherapy group discontinued treatment (ie. either switched to a different monotherapy agent or returned to antipsychotic polypharmacy) significantly sooner than the who remained on antipsychotic polypharmacy.4,12 The final study by Foster et al compared patients who were initially utilizing antipsychotic polypharmacy – a long-acting injectable or on oral antipsychotic monotherapy – to determine long-term (30 month) outcomes. They found that patients who were switched to monotherapy from antipsychotic polypharmacy “appeared more vulnerable to relapse.”4,13

In the three case examples, the reviewers illustrated situations where antipsychotic polypharmacy may be warranted. 4 All three patients were on antipsychotic monotherapy and their provider saw a need to address additional concerns. With the use of antipsychotic monotherapy, the clinicians were able to address additional psychotic symptoms not addressed properly with monotherapy, to minimize side effects of antipsychotic monotherapy if a patient has a partial response to treatment, and to augment clozapine therapy.

Polypharmacy Treatment Considerations for Psychiatric Disorders

In summary, there is much to be learned about antipsychotic polypharmacy and its utility in the treatment of schizophrenia, bipolar disorder, and other psychotic disorders. While antipsychotic therapy may be warranted, it should be done if monotherapy is not controlling symptoms. Simultaneous initiation could be problematic in determining if antipsychotic polypharmacy was warranted to begin with and also determining which medication made the difference in efficacy.

A prescriber should always ask several questions when considering antipsychotic polypharmacy therapy: What purpose is the additional antipsychotic prescribed serving? If the patient’s schizophrenia is not refractory in nature, would it be reasonable to transition to antipsychotic monotherapy? If their schizophrenia is refractory, what would be a reasonable treatment option for the patient (ie, considerations with lab draws and close monitoring)? Does the patient have regular follow-up with a primary care physician to be proactive regarding metabolic side effects? Answering these questions will best serve the patients and providers by improving psychotic symptoms, reducing the risk of additional side effects, and helping patients tolerate their medications to assist in treatment adherence.

Next Paper in the Literature Review: Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study by Correll CU, Newcomer JW, Silverman B, et al. Am J Psychiatry. 2020.

Prior Paper in the Literature Review: Foster A, King J. Antipsychotic PolypharmacyFocus (Am Psychiatr Publ). 2020.

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Last Updated: Sep 1, 2021