Polypharmacy of Schizophrenia

| August 31, 2010 | 0 Comments

by Peter Dussias, MBA; Amir H. Kalali, MD; and Leslie Citrome, MD, MPH

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Funding: There was no funding for the development and writing of this article.

Financial disclosures: Mr. Dussias has no conflicts of interest relevant to the content of this article. Dr. Kalali has served as an advisor to Merck, Novartis, Pfizer, and Vanda Pharmaceuticals. Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Merck, Novartis, Pfizer Inc, Sepracor, and Vanda Pharmaceuticals.

Key words: Schizophrenia, antipsychotics, antidepressants, mood stabilizers, extrapyramidal symptoms

Abstract
In this article, we investigated the current practice for treatment of schizophrenia. According to our data, physicians consider one-product regimens 53 percent of the time. Two-product regimens are considered 29 percent of the time, and regimens of three or more products are considered 18 percent of the time. At the point of the patient visit, antipsychotic medications comprise 97 percent of treatment regimens. Fifty-six percent of treatment regimens involve only antipsychotic medications. Classes used to supplement antipsychotic medications in the treatment of schizophrenia include antidepressants (20%), mood stabilizers (15%), anti-anxiety (7%) drugs, and drugs to treat extrapyramidal symptoms (6%). An expert commentary is also included with the data.

Introduction

To better understand polypharmacy in the management of schizophrenia, we investigated drug classes physicians consider in the selection of treatments to control schizophrenia symptoms.

Methods

We obtained data on product treatment regimens from SDI’s Physician Drug and Diagnosis Audit (PDDA) database from May 2009 to April 2010 for schizophrenic disorders as defined by International Classification of Diseases, Ninth Revision (ICD-9) code 295. PDDA captures data on disease states and associated therapies from 3,200 office-based physicians representing 30 specialties across the United States. PDDA provides a non-longitudinal sample of activities that represent the physician intent of office-based physicians. PDDA does not follow the patient subsequent to drug issuance to ensure adherence.

Results

As seen in Figure 1, physicians consider one-product treatment regimens 53 percent of the time. Two-product regimens are considered 29 percent of the time, and regimens of three or more products are considered 18 percent of the time. According to our data in Figure 2, 56 percent of product regimens are for antipsychotics alone. Twenty percent of treatment regimens are for an antipsychotic supplemented by an antidepressant. Other classes reported to supplement antipsychotics in the management of schizophrenia include mood stabilizers (including lithium or antiepileptics, 15%), anti-anxiety drugs (7%), and drugs to treat extrapyramidal symptoms (6%). Overall, antipsychotic medications comprise 97 percent of treatment regimens.

Expert Commentary—by Leslie Citrome, MD, MPH

Combination medication strategies for the treatment of schizophrenia are commonly used to treat refractory psychotic symptoms, mood instability, aggressivity, negative symptoms, and cognitive impairment. This acknowledges that schizophrenia is a multidimensional disorder with several treatment targets. Additional medications are often prescribed to relieve adverse effects of the primary medications, such as the use of anticholinergic medications for extrapyramidal symptoms, beta-blockers for akathisia, and a variety of potential anorexic agents for antipsychotic-induced body weight gain. It is no surprise then that many patients end up on a complex regimen that is difficult for the clinician to keep track of and even more difficult for the patient to adhere to.

The results presented here from survey data from office-based physicians in the United States provide somewhat lower rates of coprescribing  with other antipsychotics and mood stabilizers than those reported regarding medication utilization within the network of state-operated psychiatric hospitals in New York.[1,2] This may be related to obvious differences in disease severity and/or chronicity between outpatients and inpatients receiving intermediate and long-term care.

Unfortunately, for many of the combination treatments used, the evidence base is lacking. For example, randomized, controlled trials of antipsychotic combinations have not consistently demonstrated a clinically relevant advantage for the combination over monotherapy.[3] Intriguing, however, is the possibility of mitigating some adverse effects of antipsychotics by using combinations.[4]

The use of mood stabilizers, such as lithium or anticonvulsants, added to antipsychotic medication, is also not well supported by the literature. In contrast to the use of combinations of second-generation antipsychotics with mood stabilizers for bipolar disorder, this treatment strategy for schizophrenia has not been approved by regulatory agencies.[5,6] Preliminary data of the usefulness of lithium as an adjunctive agent have been negated by later studies. Similarly, large randomized, controlled trials of adjunctive valproate and adjunctive lamotrigine completed in the wake of early and promising efficacy signals from smaller studies have failed to replicate the initial findings. Also problematic is the lack of well-designed clinical trials of adjunctive mood stabilizers in treatment-refractory schizophrenia or persistent aggressive behavior in schizophrenia, two populations for which there remains a pressing therapeutic need for better treatments. Pragmatically, on an individual patient basis, there may be some advantages to be gained by adding a mood stabilizer to a medication regimen, but these must be weighed against potential adverse effects, and outcomes closely monitored so that discontinuation of the mood stabilizer is prompt should benefits not accrue.

In the future, we can expect medications specifically approved as adjunctive to antipsychotic therapy. Efforts by the pharmaceutical industry and also by partnerships between industry and academia are underway to develop potential treatments for cognitive dysfunction associated with schizophrenia. More information about the Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) program can be found at http://www.turns.ucla.edu/.

In general, the search for efficacious adjunctive treatments has been a slow process, marked by several failures.[7–11] The most promising therapeutic target appears to be glutamate, the main excitatory neurotransmitter in the brain that is present in most neurons. There are several different types of glutamate receptors with differing effects on glutamatergic function.[12]

References
1.    Citrome L, Levine J, Allingham B. Changes in use of valproate and other mood stabilizers for patients with schizophrenia from 1994 to 1998. Psychiatr Serv. 2000;51(5):634-638.
2.    Jaffe AB, Levine J. Antipsychotic medication coprescribing in a large state hospital system. Pharmacoepidemiol Drug Saf. 2003;12(1):41–48.
3.    Correll CU, Rummel-Kluge, Corves C, et al. Antipsychotic combination vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35(2):443–457.
4.    Fleischhacker WW, Heikkinen ME, Olié 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(8):1115–1125.
5.    Citrome L. Adjunctive lithium and anticonvulsants for the treatment of schizophrenia: what is the evidence? Expert Rev Neurother. 2009;9(1):55–71.
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8.    Freudenreich O, Henderson DC, Macklin EA, et al. Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry. 2009;70(12):1674–1680.
9.    Kelly DL, Buchanan RW, Boggs DL, et al. A randomized double-blind trial of atomoxetine for cognitive impairments in 32 people with schizophrenia. J Clin Psychiatry. 2009;70(4):518–525.
10.    Lieberman JA, Papadakis K, Csernansky J, et al. A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology. 2009;34(5):1322–1329.
11.    Piskuliç D, Olver JS, Maruff P, Norman TR. Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5-HT(1A) receptor agonist. Hum Psychopharmacol. 2009;24(6):437–446.
12.    Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9(11):984–997, 979.

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Category: Psychiatry, Schizophrenia, Trend Watch

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