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Antipsychotic Combinations Graylands Hospital DRUG BULLETIN Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email [email protected] Fax (08) 9384 4586 Antipsychotic Combinations Graylands Hospital Drug Bulletin 2008 Vol. 15 No. 3 February ISSN 1323-1251 Antipsychotic combinations Reasons for antipsychotic combinations Despite the development of efficacious medications for the treatment of schizophrenia, many people do There are a number of theoretical benefits and not respond adequately. To address this problem, reasons cited for antipsychotic combination the use of two or more antipsychotics simultaneously prescribing, these include: is a commonly employed treatment strategy. Although the use of combination antipsychotics is Complementary mechanisms of action4 (e.g. common in clinical practice, the risks and benefits adding an antipsychotic with strong dopamine have not been systematically evaluated to date. As a D2 blockade to a weak D2 blocker) result, current Australian treatment algorithms Partial replacement of antipsychotic action for including the Royal Australian and New Zealand drugs with intolerable adverse effects at higher College of Psychiatry Schizophrenia Guidelines and 5 doses (e.g. adding quetiapine to clozapine to the Western Australian Therapeutic Advisory Group minimise metabolic adverse effects) Antipsychotic Guidelines advise against the use of combined antipsychotics, except for short periods of Alternative where clozapine cannot be used6 changeover1,2. Most data on antipsychotic (tolerability issues, patient refusal) combinations are derived from open studies and case Depot antipsychotic ‘cover’ where compliance series. The few randomised controlled trials that with oral medication cannot be assured7 exist are described in this Drug Bulletin. To build on a partial response to monotherapy4 To control symptoms of acute psychosis4 (prn Incidence of antipsychotic antipsychotics) combinations To prevent exacerbation of psychiatric illness 4 when switching antipsychotics Data from a Graylands Hospital drug utilisation review in November 2007 showed that 55% of all inpatients were prescribed two or more Reasons against antipsychotic antipsychotics (excluding pro re nata (prn)). There combinations has been an increasing trend to antipsychotic polypharmacy from 2002, where 37% of patients were receiving two or more regular antipsychotics. This is Absence of evidence from clinical trials to 7 consistent with data from overseas, where support the practice prevalence rates of patients prescribed two or more Additive adverse effects4 (sedation, antipsychotics simultaneously range from 10% to anticholinergic, QTc prolongation) 64%3. Graylands Hospital Drug Bulletin 2008 Vol 15 No.3 - 1 - Decreased compliance with complex treatment Evidence on the use of antipsychotic regimen7 combinations Increased costs7 Increased risk of pharmacokinetic and There are only five randomised controlled trials of pharmacodynamic drug interactions4 currently marketed antipsychotic combinations described in the literature to date. The results from the trials are mixed and are outlined below. Contraindicated antipsychotic combinations Clozapine-risperidone study one 12 Combinations of antipsychotics that significantly Josiassen et al conducted a randomised, double- prolong the QTc interval are contraindicated because blind, placebo-controlled 12-week trial that when used together produce an additive effect that compared a dose of up to 6mg of risperidone (n=20) may increase the risk for ventricular arrhythmias or to placebo (n=20) in 40 patients unresponsive or cardiac arrest8,9. Antipsychotics considered to partially responsive to clozapine. increase QTc interval significantly include: amisulpride, ziprasidone, chlorpromazine, Background characteristics of the two groups were haloperidol, thioridazine*, pimozide* and similar, although the average dose of clozapine was droperidol*9,10. Combinations of these antipsychotics higher in the clozapine-risperidone group (529mg vs should be avoided. 402mg) and the initial Scale for Assessment of Negative Symptoms score lower, however these were not statistically significant. Risks of antipsychotic combinations Response to treatment was defined as a 20% reduction on the Brief Psychiatric Rating Scale In addition to the cardiac risks that may exist with (BPRS). At the end of 12 weeks, BPRS were reduced contraindicated antipsychotic combinations, there significantly in both groups, but the reductions were are also a number of potential drug interactions significantly greater in the clozapine-risperidone involving certain antipsychotic combinations. group (35% vs 10%). Pharmacodynamic interactions are interactions The adverse effect profile for risperidone-clozapine between drugs at the site of action and cause a therapy was similar to placebo-clozapine therapy. change in the pharmacological action. Additive Two patients who received 6mg of risperidone adverse effects are the most common type of experienced akathisia and required a dose reduction. pharmacodynamic interaction between Clozapine levels were not affected by risperidone in antipsychotics. Published reports of severe this study. extrapyramidal side effects, grand mal seizures and prolonged QTc interval have been reported with antipsychotic combinations5. Another concern is the Clozapine-risperidone study two unknown risk of developing tardive dyskinesia when 11 antipsychotics are combined . Other additive Yagcioglu et al13 also conducted a risperidone- adverse effects that should be considered include clozapine study. In this study, 30 patients who had a excessive sedation, increased prolactin levels, partial response to clozapine were randomly assigned postural hypotension, anticholinergic and metabolic to risperidone up to 6mg (n=16) or placebo (n=14). adverse effects4. Baseline characteristics were similar in both groups, Pharmacokinetic drug interactions can also occur for except that the mean number of hospitalisations and certain antipsychotic combinations. Pharmacokinetic mean clozapine dose (516mg vs 414mg) were higher drug interactions involve changes in the absorption, in the risperidone group. distribution, metabolism or excretion of a drug or its metabolites. Most data on antipsychotic drug The primary outcome measure was a 10% reduction in interactions come from case reports and limited the Positive and Negative Syndrome Scale (PANSS). uncontrolled studies, making assessment of the Patients in both groups showed significant clinical significance of the interactions difficult. improvement over a variety of measures at the end However, none of the antipsychotics are potent of the 6-week period, however patients in the inhibitors or inducers of the CYP450 isoenzyme placebo group showed a significantly greater system, so significant pharmacokinetic interactions improvement in the primary outcome measure, the between antipsychotics are unlikely4. positive symptom subscale on the PANSS. *No longer marketed in Australia Graylands Hospital Drug Bulletin 2008 Vol 15 No.3 - 2 - There were no significant differences between the Responses were more pronounced in younger groups in terms of extrapyramidal symptoms, weight experimental patients with lower baseline SAPS. gain, QTc prolongation, vital signs or clozapine levels. Patients in the risperidone group experienced One patient in the experimental group experienced a greater sedation and had significant increases in worsening of pre-existing tardive dyskinesia. There prolactin levels. was also a significant increase in serum prolactin levels in the experimental group, but not the control group. Clozapine-risperidone study three Honer et al14 conducted the largest randomised, Clozapine-chlorpromazine study double-blind antipsychotic combination study to date, where 68 patients with a poor response to A randomised, double-blind flexible-dose 8 week trial clozapine were randomised to receive either 3mg of compared clozapine (n=17), chlorpromazine (n=20) risperidone (n=34) or placebo (n=34) over an 8 week and a combination of the two (n=20) in 57 patients period. was described by Potter et al16. Baseline characteristics were similar in both groups. For the clozapine and placebo and chlorpromazine and placebo groups, the maximum dose of clozapine The primary outcome was reduction in total PANSS or chlorpromazine allowed was 600mg. For the score, which significantly improved in both groups clozapine-chlorpromazine group, the maximum dose but did not differ between the risperidone and allowed of either was 400mg. The mean doses used placebo groups at baseline or at eight weeks. There were not mentioned in the study. Study design were no significant differences between the groups in including baseline characteristics of the patients, Clinical Global Improvement Scale severity or inclusion and exclusion criteria were not described. improvement, which was the secondary outcome Efficacy was measured on the BPRS. Response to measure. treatment in terms of overall BPRS scores was similar in all three treatment groups. There were, however, There were no significant differences in adverse significant improvements on the withdrawal, effects reported between groups. Although, there conceptual disorganisation, unusual thought and was a mildly greater increase in fasting blood glucose hostility items in both the clozapine and clozapine- levels in the risperidone group compared to the chlorpromazine group when compared to the placebo group. chlorpromazine
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