Evidence-Based Reviews

Antipsychotic combinations: Blind step or logical?

Current Psychiatry. 2008 July;7(7):41-53

Though unsupported by evidence, using >1 antipsychotic may make sense for some treatment-resistant patients.

References

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2. Chakos MH, Glick ID, Miller AL, et al. Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial. Psychiatr Serv 2006;57(8):1094-101.

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4. Tapp A, Wood AE, Secrest L, et al. Combination antipsychotic therapy in clinical practice. Psychiatr Serv 2003;54(1):55-9.

5. Paton C, Lelliott P, Harrington M, et al. Patterns of antipsychotic and anticholinergic prescribing for hospital inpatients. J Psychopharmacol 2003;17(2):223-9.

6. Tempier RP, Pawliuk NH. Conventional, atypical, and combination antipsychotic prescriptions: a 2-year comparison. J Clin Psychiatry 2003;64(6):673-9.

7. Jaffe AB, Levine J. Antipsychotic medication coprescribing in a large state hospital system. Pharmacoepidemiol Drug Saf 2003;12(1):41-8.

8. Valuck RJ, Morrato EH, Dodd S, et al. How expensive is antipsychotic polypharmacy? Experience from five US state Medicaid programs. Curr Med Res Opin 2007;23(10):2567-76.

9. Freudenreich O, Henderson DC, Walsh JP, et al. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res 2007;92(1-3):90-4.

10. 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(1):130-6.

11. Honer WG, Thornton AE, Chen EY, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 2006;354(5):472-82.

12. Anil Yağcioğlu 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(1):63-72.

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In a perfect world, every treatment decision would fall under the protective umbrella of evidence-based medicine. The reality is that up to 30% of schizophrenia patients respond poorly to antipsychotic monotherapy,¹ and addressing their chronic debilitating illness requires clinicians to step outside the realm of evidence.

Clinical Point

Adding risperidone to clozapine did not significantly improve schizophrenia’s positive or negative symptoms in short-term controlled trials

This does not have to be a blind step, however. Guided by logic, you can apply knowledge of receptor binding profiles, adverse effects, and kinetic considerations when choosing antipsychotic polypharmacy. This article offers evidence to answer 2 questions:

What clinical evidence and/or pharmacologic rationale support using >1 antipsychotic?
When might it be appropriate to use 2 antipsychotics in patients with treatment-resistant psychosis?

Antipsychotic polypharmacy defined

“Polypharmacy” can carry a negative connotation, but not all forms are bad. In some circumstances, antipsychotic polypharmacy may be necessary to provide optimum benefit and prevent harm to the patient and/or staff.

Short-term polypharmacy often occurs when switching patients from 1 antipsychotic to another. This “crossover phase” is justified to provide a smooth transition between the 2 agents, as abrupt antipsychotic discontinuation may cause a rebound worsening of psychosis. Other short-term antipsychotic polypharmacy strategies may be necessary in inpatient settings, particularly for a patient who is acutely psychotic or aggressive.

The use of a first-generation antipsychotic (FGA) to lead in a second-generation antipsychotic (SGA) is a justifiable treatment strategy. In addition, sedative antipsychotics such as quetiapine often are used during initial treatment of acutely ill patients and subsequently withdrawn.

Box

Other pharmacologic adjuncts proposed for antipsychotics

As our understanding of psychosis’ pathophysiology of improves, more options will come for treatment-resistant cases. Changes in the glutamatergic system, for example, have been implicated in schizophrenia’s pathophysiology.¹⁵

Lamotrigine—a second-generation anticonvulsant with antiglutamatergic activity—has been studied as augmentation to antipsychotics in patients with schizophrenia. Several randomized, controlled trials suggested clinical benefit from adjunctive lamotrigine,^16-18 but 2 recent multicenter, randomized, double-blind trials failed to support that finding.¹⁹

Although not adequately studied, other possible augmentation options may include GABA agonists, COX-2 inhibitors, and selective serotonin reuptake inhibitors.²⁰

Long-term polypharmacy in patients with schizophrenia, which this article addresses, occurs when a clinician elects to use >1 antipsychotic. When a patient improves during cross-titration of 2 antipsychotics, for example, the clinician may decide not to fully complete the switch and continue treatment with both agents.

Clinical Point

Depending on the drugs’ pharmacologic profiles, combining 2 antipsychotics may provide an additive effect or worsen your patient’s symptoms

Experience-based treatment?

Antipsychotic polypharmacy is prevalent (reported in up to 25% of outpatients and 50% of inpatients with schizophrenia),^2-7 costly for patients and insurers,⁸ and likely to be associated with increased risk of adverse effects and drug-drug interactions. Despite what is known, a wide gap exists between the science and clinical practice of combination antipsychotic therapy in schizophrenia (Table 1).

Clinical trials. The efficacy and safety of antipsychotic combinations in schizophrenia (with options including FGA + FGA, FGA + SGA, and SGA + SGA) has not been studied adequately in well-controlled, systematic trials. Four short-term—6 to 26 weeks—randomized, double-blind, controlled studies^9-12 have examined antipsychotic polypharmacy (clozapine + risperidone) in patients with schizophrenia:

In 3 studies,^9,11,12 adding risperidone to clozapine did not significantly improve positive or negative symptoms.
In all 4 studies, clozapine + risperidone was associated with increased sedation, akathisia, hyperprolactinemia, and elevated fasting blood glucose.

These studies do not support a favorable benefit-risk profile for clozapine + risperidone treatment, and this combination’s long-term efficacy and safety has not been examined. Evidence for other antipsychotic combinations (such as olanzapine + risperidone or quetiapine + risperidone) is restricted to open-label, uncontrolled trials and case reports.^13,14 Other options will likely develop for augmenting antipsychotic therapy for treatment-resistant schizophrenia, but none are available and supported by adequate data at this time (Box).^15-20

Clinical Point

Lower dosages of 2 antipsychotics may cause fewer side effects than a high dosage of 1 antipsychotic

Not all combinations make pharmacologic sense, however, such as adding haloperidol to aripiprazole. Haloperidol’s pharmacologic binding profile (potent D2 blockade) may cancel out any benefits with regard to extrapyramidal symptoms and hyperprolactinemia from aripiprazole’s receptor binding profile (D2 agonist/antagonist). In theory, any displacement of antipsychotic medication from D2 receptors because of competing inhibition may increase risk of symptom exacerbation.

Mortality risk? Two independent, longitudinal cohort studies have found antipsychotic polypharmacy to be a statistically significant predictor of reduced survival.^21,22 Although these studies have identified a possible association, additional research is required to determine whether increased mortality in schizophrenia is attributable to the disorder, comorbid medical conditions, antipsychotic medications, or a complex interaction of factors.