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RESEARCH ARTICLE
Antipsychotic-induced extrapyramidal syndromes in psychiatric practice: a case-control study I. Schillevoort, R.M.C. Herings, G.W.K. Hugenholtz, A. de Boer, W.A. Nolen, R.A.C. Roos and H.G.M. Leufkens
Pharm World Sci (2005) 27: 285–289
ª Springer 2005
I. Schillevoort, R.M.C. Herings, A. de Boer (correspondence, e-mail:
[email protected]), H.G.M. Leufkens: Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands G.W.K. Hugenholtz, W.A. Nolen: HC Ru¨mke Groep, Utrecht, The Netherlands W.A. Nolen: University Medical Centre, Utrecht, The Netherlands R.A.C. Roos: Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands Key words ADRs Antipsychotics Atypical antipsychotics Extrapyramidal syndromes Parkinsonism Schizophrenia Side effect Abstract Background: While several clinical trials showed that atypical antipsychotics have a low risk of extrapyramidal side effects (EPS), this observation is not undisputed. This study compared the risk of EPS between specific subgroups of antipsychotics. Methods: Using the automated dispensing records of a large psychiatric hospital in The Netherlands, we defined cases as first-time users of anticholinergic antiparkinson drugs. Controls were all patients with no recorded use of such medication. Cases and controls were compared with regard to previous use of antipsychotics and relevant co-factors. Results: Out of 1403 patients, we identified 105 cases and 330 controls. Compared to non-users, antipsychotic-users were 10 times more likely to start with anticholinergic antiparkinson medication (adjusted odds ratio: 10.1; 95% CI 4.6–22.3). Depot and non-depot antipsychotics had similar adjusted odds ratios of 10.9 (95% CI 3.7–32.6) and 8.8 (95% CI 3.8–20.4) respectively. Low and high potency antipsychotics gave odds ratios of 3.0 (95% CI 0.9–10.3) versus 10.8 (95% CI 4.7–25.1). Classical and atypical antipsychotics showed comparable odds ratios: 10.0 (95% CI: 4.4–22.5) versus 8.0 (95% CI: 2.6–24.5). Applied doses of classical and atypical antipsychotic drugs were much lower and more equivalent than those used in previous clincial trials. Conclusions: Low potency antipsychotics had a much lower risk of EPS than other antipsychotics. However, we did not corroborate the reduced risk with atypical antipsychotics observed in several clinical trials. This discrepancy may result from the high and non-equivalent doses of classical antipsychotics used in many of these trials.
drugs like haloperidol3. However, their application is limited by the high incidence of cardiovascular and anticholinergic side effects4. In the 1960s clozapine was introduced, which combined unique antipsychotic efficacy with a low risk of extrapyramidal side effects. Starting with risperidone in 1994, several new antipsychotics which tried to mimic this effect have recently been marketed. A number of clinical trials have indeed shown them to be at least as effective as haloperidol, but with considerably less extrapyramidal syndromes5–7. This group of antipsychotics has consequently been classified as atypical. However, their reduced risk of EPS is not undisputed and several other studies observed no difference in risk between atypical and classical antipsychotics8–11. We decided to study whether differences in risk between subgroups of antipsychotics could be observed in daily clinical practice. In a large population of institutionalised and semi-ambulant psychiatric patients in The Netherlands, we compared the risk of starting with anticholinergic antiparkinson medication between classical and atypical, low and high potency and also between depot and non-depot antipsychotics.
Method
Introduction
Setting For this study we used dispensing records from 1992 till 1997 stored in a central computer in a large psychiatric clinic in The Netherlands. The clinic consists of a large group (total 1200 beds) of treatment centers responsible for institutionalised and semi-ambulant psychiatric care in The Netherlands. Three main departments are discerned: adult short stay and medium stay care, long stay care and elderly care, containing all types of psychiatric disorders, most commonly schizophrenia and other psychotic disorders, depressions, bipolar disorders, anxiety disorders and personality disorders. Departments have been automated with respect to dispensing of drugs consecutively since 1992. Therefore, dispensing record histories and thus follow-up may differ in length per department and thus per patient.
Schizophrenia is among the leading contributors to the global burden of disease1. In the Netherlands, the prevalence of schizophrenia is estimated to be 1.5 per 10002. Since the introduction of chlorpromazine in the early 1950s, antipsychotics are the drugs of choice in the treatment of schizophrenia and other psychotic disorders. A drawback in their use is the induction of extrapyramidal syndromes (EPS), including parkinsonism, akathisia, dystonia and tardive dyskinesia. Not all antipsychotics, however, induce EPS to the same extent. Low potency antipsychotics such as chlorpromazine have a lower D2 postsynaptic receptor affinity. These drugs are thought to have a lower risk of extrapyramidal syndromes than high potency
Selection of cases and controls Included as cases in our study were patients who used an anticholinergic antiparkinson drug (benzatropine, biperiden, dexetimide, orphenadrine, procyclidine, trihexyphenidyl) for the first time in their recorded automated dispensing records and who had an automated dispensing record history of at least 180 days preceding that first use. Hence, all included patients were free from use of antiparkinson drugs for at least 180 days. Excluded were patients who used dopaminergic antiparkinson drugs (i.e. levodopa, selegiline, bromocriptine, lisuride, pergolide and amantadine), since these drugs are not specifically
Accepted November 2004
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those factors that either caused a change of the crude odds ratio of at least 10%, had an odds ratio of more than 1.5 or less than 0.67 for starting with antiparkinson medication or were significantly associated with the use of antiparkinson medication19. The resulting multivariate model was also used for all subgroup analyses. Median doses were compared using a Mann–Whitney U test. A Mantel–Haenszel extension of the v2 test for trend is used to test for a dose-response relationship20. The frequency of prior antipsychotic use of patients who started with an atypical antipsychotic and those starting with a clasExposure definition sical one were compared using a v2 test. For all staCases and controls were compared with regard to tistical tests, statistical significance was assumed exposure to antipsychotic drugs within a period of below a two-sided a-level of 0.05. Data was analyzed 180 days before the index date. Antipsychotic expo- using SPSS for Windows, version 7.5.2. sure was defined as a filled prescription for any of the drugs listed in Appendix 1. We divided antipsychotic drugs into classical and atypical. Based on the division Results used by the Dutch Pharmacotherapeutic Guidelines13 From 1992 till 1997, the prescription-database conand the British National Formulary14, clozapine, sul- tained dispensing records of a total of 1403 patients. piride, risperidone, olanzapine and sertindole were Of these, 44.0% (n ¼ 617) had used an anticholinerclassified as atypical; all other antipsychotics were gic antiparkinson drug at some time. Five hundred classified as classical. We further subdivided classical and twelve patients had dispensing record histories of antipsychotics according to potency (low vs. high less than 180 days, leaving 105 patients who met our potency) and duration of action (depot vs. non-de- inclusion criteria. Controls were selected from the 786 pot) (Appendix 1). To assess whether atypical anti- patients who had never used an anticholinergic drug. psychotics were selectively prescribed to patients with This yielded 330 control patients who had a dispensa prior history of antipsychotic use, we compared the ing record history of at least 180 days after random frequency of prior antipsychotic use between patients assignment of the index-date. Patient characteristics are summarized in Table 1. who started with an atypical antipsychotic and those starting with a classical one in a separate analysis, The mean age was comparable for cases and controls according to the method described by Egberts (50 and 52 years respectively, range 20–95 years). et al.15. We also studied the effect of dose and timing Antipsychotics used by the study population are of antipsychotic use. To evaluate dose-response, we summarized in appendix 1. The most often prescribed converted the prescribed daily dose at or closest to antipsychotics were zuclopenthixol and haloperidol, the index-date of each patient into chlorpromazine used by 14.0% (n ¼ 61) and 11.0% (n ¼ 48) respecequivalents, derived from the WHO dose recommen- tively. In the half year preceding the index-date, dations16. Excluded from the dose calculations were 91.4% of the cases and 50.0% of the controls were patients using any injectable formula of antipsychot- exposed to antipsychotics, which yielded a crude and ics. Since meta-analysis showed that classical anti- adjusted odds ratios of 10.7 (95% CI 5.0–23.4) and psychotics have no additional clinical effect at doses 10.1 (95% CI 4.6–22.3), respectively (Table 2). New exceeding 375 mg chlorpromazine equivalents17, use was associated with a substantially higher risk than standardized doses were stratified into
