Appropriate Use of Combination Antipsychotics

"When a patient presents...with prescriptions for more than 1 is prudent to discuss the treatment plan with the patient.”
August/September 2014, Vol 2, No 4 - Inside Mental Health

Antipsychotic medications are used in the treatment of patients with various psychiatric conditions, including schizophrenia, bipolar disorder, and in some cases, major depressive disorder. They are categorized into first and second generation.

Medications from each category are listed in Table 1. The first-generation antipsychotics (FGAs), also known as typical antipsychotics, work primarily through the blockade of centrally located dopamine (D2) receptors.1 Second-generation antipsychotics (SGAs), or atypical antipsychotics, exert their mechanism of action through antagonism of both D2 receptors and serotonin 5-HT2A receptors in the central nervous system.1

An antipsychotic from either class can be used alone or in combination with other psychotropic medications, such as mood stabilizers or antidepressants. In some patients, particularly those with schizophrenia, the combination of more than 1 antipsychotic medication may be warranted to help control symptoms; however, this may present additional risks to the patient, which must be taken into account.2

Indications for Combination Antipsychotics
The American Psychiatric Association (APA) practice guidelines for the treatment of patients with schizophrenia briefly discuss potential indications for antipsychotic polypharmacy.2 One indication is if the patient is switched from 1 agent to another using cross-titration. During this process, the dose of the patient’s current antipsychotic is slowly tapered while the new antipsychotic is titrated up to a therapeutic dose.

Psychiatrists may use this approach to help prevent an acute exacerbation while switching medications. Some patients may also be taking multiple long-term antipsychotics because of ineffective response to monotherapy treatment.

The APA specifically notes the use of an antipsychotic to augment clozapine. This may be appropriate for patients who have more resistant schizophrenia, as clozapine is usually reserved for patients who did not respond to at least 2 trials of antipsychotic medications. The Texas Medication Algorithm Project (algorithm for the treatment of patients with schizophrenia developed by the Texas Department of Mental Health and Mental Retardation) also recommends augmentation of clozapine when a patient does not respond to 3 trials of antipsychotic monotherapy.3

Although a limited amount of data supports the use of antipsychotic polypharmacy, much of these data focus on clozapine combinations. Several case reports have shown a benefit with the addition of risperidone.4-6 In 1 randomized controlled trial, investigators evaluated the safety and efficacy of augmenting clozapine with risperidone versus clozapine with placebo in patients with treatment-resistant schizophrenia. Although patients in both groups showed improvement in symptoms during the 12-week period, those in the treatment group who were taking risperidone had a greater reduction in symptoms without a significant difference in adverse events, including parkinsonism, agranulocytosis, weight gain, and seizures.7

In another study, Anil Yagcioglu and colleagues conducted a double-blind study comparing adjunctive risperidone with placebo in patients taking cloza­pine, and found no significant difference in efficacy or safety end points between the 2 groups.8 Although there is conflicting data from randomized trials, augmentation of clozapine remains the most widely studied antipsychotic combination and is a generally accepted treatment option for select patients.2

The APA recognizes that other combinations of antipsychotics may be beneficial to some patients who did not adequately respond to monotherapy.2 These patients should have documentation of a suboptimal response to either medication when used alone before initiating the combination. The Texas Medication Algorithm Project algorithm for schizophrenia lists the combination of 2 antipsychotics (SGA + FGA, or 2 SGAs) as a possible option following the failure of several monotherapy trials and a trial of a combination therapy with clozapine.3 Some antipsychotic combinations that do not include clozapine have been studied, including aripiprazole with risperidone. This combination is of particular interest because risperidone is known to be associated with hyperprolactinemia and aripiprazole has been found to decrease prolactin levels.9 Kane and colleagues compared aripiprazole adjunctive therapy in patients taking either risperidone or quetiapine with placebo and found no significant difference in efficacy end points between the groups.10 However, patients taking risperidone with adjunctive aripiprazole had significantly lower prolactin levels compared with patients in the adjunctive placebo group.

In another study, Chen and colleagues found that the addition of aripiprazole to risperidone in patients with symptomatic hyperprolactinemia effectively reduced serum prolactin to normal levels in the majority of the risperidone patients.9 In 1 meta-analysis, investigators examined studies with various combinations of antipsychotics, including the use of 2 SGAs, 2 FGAs, or 1 of each.11 Combination antipsychotics were found to be more efficacious in producing a clinically significant response than monotherapy, especially when combining an FGA and an SGA, when adding a second antipsychotic to clozapine, and in trials lasting at least 10 weeks. However, this meta-analysis did not have sufficient data to report on adverse event rates.11 Overall, it appears combination antipsychotics may be beneficial for some patients when monotherapy is not effective.

Disadvantages of Combination Antipsychotics
Several arguments exist, however, against the long-term use of combination antipsychotics.12 There are limited clinical studies demonstrating the benefits of this treatment approach. It is reasonable to believe that the addition of a second antipsychotic may increase the risk of adverse events.12 This includes an increased risk for extrapyramidal symptoms (EPS), metabolic disturbances, or other adverse events associated with antipsychotics. Because most antipsychotics are extensively metabolized in the liver and are substrates of cytochrome P450 enzymes, combination therapy could increase the risk of drug interactions.1

The addition of another medication also raises the cost of treatment and may decrease adherence as the drug regimen becomes more complicated.12 Finally, when more than 1 antipsychotic is used, it is more difficult for clinicians to identify which agent is responsible for any changes in symptoms or adverse effects the patient experiences, thus complicating the psychiatrist’s ability to develop the ideal treatment plan for the patient. Overall, due to the lack of available data on combination therapy, it is difficult to effectively weigh the risks and benefits of antipsychotic polypharmacy.

Criteria for Using Combination Antipsychotics
In 2008, The Joint Commission implemented core measures for the care of psychiatric patients known as the Hospital-Based Inpatient Psychiatric Services (HBIPS) measures.13 These standards address various aspects of psychiatric care, including admission criteria, use of physical restraints, seclusion hours, and care plan development and communication. One of the 7 core measures outlines 3 appropriate justifications for discharging patients on multiple antipsychotics (Table 2).

One appropriate justification is documentation that the patient has had at least 3 adequate trials of monotherapy with antipsychotics without a sufficient improvement in symptoms. The second appropriate justification is that there should be a documented plan to describe tapering off the dose of 1 antipsychotic while titrating up the dose of the other. The final justification listed in the HBIPS core measures for the use of combination antipsychotics is the augmentation of clozapine. These criteria align closely with the situations discussed in the APA guidelines for the treatment of patients with schizophrenia and should be used to assess patients seen as outpatients who are on combination antipsychotic therapy. Patients not meeting these criteria may be on inappropriate therapy and could present an opportunity for intervention.

Role for Community Pharmacists
For community pharmacists and other healthcare professionals, it is important to identify patients who may benefit from education or who require an intervention by their care provider. When a patient presents to the pharmacy with prescriptions for more than 1 antipsychotic or with a new prescription for an additional antipsychotic, it is prudent to discuss the treatment plan with the patient.

It may identify patients who are being cross-titrated from 1 antipsychotic to another as well as patients who will continue taking combination therapy. If the patient seems unsure or confused about the plan, a discussion with the prescribing physician or psychiatrist is necessary to clarify whether both antipsychotics are to be dispensed.

If the patient is maintained on a combination of antipsychotics, whether temporarily or long-term, it is impor­tant for community pharmacists to counsel him or her about the potential adverse events of his or her medication. Adverse events vary depending on the antipsychotics prescribed; however, general class adverse effects are a good starting point for counseling. FGAs are known to cause EPS, such as acute dystonia, akathisia, pseudoparkinsonism, and tardive dyskinesia.1 Patients should be aware of how these adverse effects present and should notify their doctor if they occur. These effects are not fatal and patients should be counseled to continue their medication even if they experience EPS until they are seen by their physician. Certain types of EPS, such as dystonia and pseudoparkinsonism, may alleviate with the use of over-the-counter diphenhydramine.3 SGAs as a class tend to have less EPS associated with them than FGAs; however, the risk still exists. SGAs have more metabolic side effects, including increases in weight or cholesterol. Patients’ SGAs are at risk of developing glucose intolerance or diabetes.1 In addition, many antipsychotics have effects on histamine, cholinergic, and alpha-1a adrenergic receptors. They can cause sedation, dry mouth, dizziness, lethargy, or orthostatic hypotension. Patients should always notify their physician or psychiatrist if bothersome or severe adverse events occur. Patients on multiple antipsychotics should also be counseled on the importance of compliance and adherence with their treatment regimen. Lack of adherence can lead to relapses or acute exacerbations of their symptoms, which may lead to self-harm or hospitalization.

Overall, there are many patients who may be managed with multiple antipsychotics. According to APA guidelines and the standard measures listed in the HBIPS criteria, appropriate reasons for combinations include cross-titration of antipsychotics, resistant schizophrenia after failing multiple trials of monotherapy, and augmentation of clozapine. It is important to identify the justification for combination therapy in all patients with antipsychotic polypharmacy. If the treatment is appropriate, patients should be counseled on the risks involved and the importance of adhering to their drug regimen as prescribed.


  1. Ferrando S, Owen J, Levenson J. Psychopharmacology. In: Hales RE, Yudofsky SC, Roberts LW, eds. The American Psychiatric Publishing Textbook of Psychiatry. 6th ed. Arlington, VA: American Psychiatric Publishing; 2014.
  2. Lehman AF, Lieberman JA, Dixon, LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1-56.
  3. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007;68:1751-1762.
  4. Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, et al. Risperidone augmentation of clozapine: a critical review. Eur Arch Psychiatry Clin Neurosci. 2006;256:350-355.
  5. Raskin S, Katz G, Zislin Z, et al. Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand. 2000;101:334-336.
  6. Raju GVL, Kumar R, Khanna S. Clozapine-risperidone combination in treatment-resistant schizophrenia. Aust N Z J Psychiatry. 2001;35:543.
  7. Josiassen RC, Joseph A, Kohegyi E, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005;162:130-136.
  8. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005;66:63-72.
  9. Chen CK, Huang YS, Ree SC, Hsiao CC. Differential add-on effects of aripiprazole in resolving hyperprolactinemia induced by risperidone in comparison to benzamide antipsychotics. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:1495-1499.
  10. Kane JM, Correll CU, Goff DC, et al. A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizo­affective disorder inadequately treated with quetiapine or risperidone monotherapy. J Clin Psychiatry. 2009;70:1348-1357.
  11. Correll CU, Rummel-Kluge C, Corves C, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35:443-457.
  12. Miller AL, Craig CS. Combination antipsychotics: pros, cons, and questions. Schizophr Bull. 2002;28:105-109.
  13. The Joint Commission. Hospital-based inpatient psychiatric services. Updated May 5, 2014. Accessed July 15, 2014.
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