The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 1985-99 (n = 24,263). The study population comprised all patients using an antidepressant drug at the time the ADR occurred. We calculated ADR-reporting odds ratios (ADR-OR) to estimate the association between SSRI-use and EPS, relative to other antidepressants. We identified 61 patients with EPS. SSRI-use was associated with spontaneous reporting of EPS compared to other antidepressants (adjusted ADR-OR 2.2; 95% confidence interval 1.2-3.9). This risk estimate appeared to be higher in patients concurrently using antipsychotic medication (6.9, 0.7-68.0), although the confidence interval was very wide. In conclusion, SSRI-use seems only to be moderately associated with EPS compared to other antidepressants. However, those concurrently using antipsychotic drugs or presenting with other risk factors may be more susceptible and should be closely monitored.

To study the association between polymorphism of the cytochrome P450 2D6 gene (CYP2D6) and the risk of antipsychotic-induced extrapyramidal syndromes, as measured by the use of antiparkinsonian medication. Data for this case-control study were obtained from a psychiatric hospital where newly admitted patients are routinely screened for several CYP2D6 mutant alleles. Cases were patients prescribed antiparkinsonian medication during oral antipsychotic drug treatment in the period September 1994 to August 2000. They were divided into those using an antipsychotic drug the metabolic elimination of which depends on the activity of the CYP2D6 enzyme ('CYP2D6-dependent') and those using other antipsychotic drugs. We formed a control group of antipsychotic drug users for both case groups using a matching ratio of 3 : 1 (controls : cases). Control patients were matched on whether or not their prescribed antipsychotic drug was CYP2D6-dependent. Odds ratios for patients who were slow metabolizers versus patients who were extensive metabolizers were calculated using conditional logistic regression and were adjusted for age, gender, dose and other potential confounding factors. We identified 77 case patients who were prescribed a CYP2D6-dependent antipsychotic drug and 54 case patients who were prescribed non CYP2D6-dependent antipsychotic drugs. Among the case- and control-patients using a CYP2D6-dependent antipsychotic drug, the poor metabolizers were more than four times more likely to start with antiparkinsonian medication than the extensive metabolizers (odds ratio 4.44; 95% confidence interval 1.11-17.68). An increased risk was not observed for patients using non CYP2D6-dependent antipsychotic drugs (odds ratio 1.20; 95% confidence interval 0.21-6.79). Genetically impaired CYP2D6 activity can increase the risk of antipsychotic-induced extrapyrimidal syndromes. Poor metabolizers should have their antipsychotic drug dosage reduced when the metabolism of the prescribed drug depends on CYP2D6 activity or should receive an antipsychotic drug that is not CYP2D6-dependent.

Plasma nelfinavir concentration ratios (CRs) were calculated for all pregnant (n=27) and nonpregnant (n=48) human immunodeficiency virus type 1-infected women receiving the drug who visited our outpatient clinic. In pregnant women, mean and median nelfinavir CRs were significantly lower (P=.02 and P=.04, respectively), and 51% of the CRs were below the clinically relevant threshold of 0.90, compared with 35% of the CRs in nonpregnant women. After we adjusted for confounders, we found that the mean nelfinavir CR was 34% lower in pregnant women (P=.02). With targeted interventions, subsequent CRs in pregnant women showed a significant increase (median increase, 0.31; P=.01).

OBJECTIVE:To compare the risk of extrapyramidal syndrome (EPS) between risperidone, olanzapine, and haloperidol, taking into account patients' past antipsychotic drug use and past EPS.METHODS: Data were obtained from the PHARMO-database, containing filled prescriptions of 450 000 community-dwelling people in the Netherlands from 1986 through 1999. We defined cohorts of first-time users of haloperidol, risperidone, or olanzapine aged 15 to 54 years. In the first 90 days of treatment, we assessed the occurrence of EPS, defined as first use of any antiparkinsonian agent. We estimated relative risks of EPS for risperidone and olanzapine versus haloperidol using a Cox proportional hazards model. Patients were subdivided according to prior use of antipsychotic and antiparkinsonian drugs. RESULTS:We identified 424 patients starting treatment with haloperidol, 243 with risperidone, and 181 with olanzapine. Prior use of antipsychotic plus antiparkinsonian medication was significantly more frequent among users of risperidone and olanzapine than in those using haloperidol (36.2%, 40.3%, and 4.5%, respectively; p < 0.001). Within most subgroups of comparable treatment history, patients using risperidone and olanzapine showed reduced risks of EPS compared with haloperidol, although some of these findings did not reach statistical significance (RR 0.03-0.22). However, this was not observed for patients using risperidone who had experienced EPS in the past (RR 1.30; 95% CI 0.24 to 7.18). CONCLUSIONS:In general, we observed reduced risks of EPS for risperidone and olanzapine compared with haloperidol within subgroups of patients with a similar treatment history. However, the added value of risperidone in patients who have experienced EPS in the past needs further study.KEY WORDS: atypical antipsychotics, extrapyramidal syndromes, selective prescribing. 2001;35:1517-22. Ann Pharmacother RESEARCH REPORTSSee also page 1659. drugs generally included chronically ill hospitalized schizophrenic patients. In contrast, in clinical practice, users of APDs are much more heterogeneous and include patients who are less severely ill, are treated in an outpatient setting, and receive APDs in doses other than those applied in clinical trials.3 Thus, results from trials need to be confirmed in the everyday clinical setting using observational studies. However, a traditional concern with observational studies regards their potential bias due to the nonrandomized treatment assignment. In the first few years of marketing, new drugs are apt to be prescribed to patients who do not tolerate or who do not respond adequately to older drugs labeled for the same indication.4 Thus, atypical APDs are likely to be selectively prescribed to patients with an overt susceptibility for EPS, that is, those who developed EPS during previous treatment with APDs. When comparing the risk of EPS between atypical and classical APDs in observational studies, such imbalance in prognostic factors needs to be accounted for. In previous observational studies regarding antip...

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.

In particular olanzapine and also risperidone were selectively prescribed to patients formerly treated with other antipsychotics and to those susceptible for EPS. If not recognised or controlled for, observational studies comparing different antipsychotic drugs may produce biased results on efficacy or frequency of side effects for the different types of antipsychotics.

The reduced EPS rates observed when comparing risperidone with high-potency antipsychotics such as haloperidol may not apply to comparisons with low-potency drugs.

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