Phenomenological differences between spontaneous and drug-related extrapyramidal syndromes in patients with schizophrenia-spectrum disorders.

To the Editors: I t is a well-established fact that antipsychotic medication, including the newer atypical drugs, may cause a broad range of extrapyramidal syndromes (EPSs). Furthermore, the EPS observed in schizophrenia patients treated with antipsychotics have been traditionally interpreted as adverse effects of the medication. However, the so-called spontaneous EPSs (ie, neuromotor abnormalities observed in patients never exposed to antipsychotic medication) including dyskinesia, parkinsonism, and akathisia, are increasingly recognized as a prevalent condition in schizophrenia and related disorders. Thus, it is possible that EPS observed in patients treated with antipsychotic drugs represent a mixture of primary and drug-related etiologies, which could have far-reaching implications regarding the phenomenological differentiation between the 2 conditions. To the best of our knowledge, the extent to which spontaneous and drug-related EPSs differ about their symptomatic manifestations has not been previously addressed. This differentiation is important for both research and clinical reasons. For example, spontaneous EPSs are thought to be the manifestation of a neuro-dysfunction intrinsic to the pathogenic of schizophrenia, and they may be erroneously interpreted as an adverse effect of antipsychotic medication, which may lead to changes in treatment that are unnecessary or detrimental to the patients. The goal of this study was to compare the symptomatic manifestations of spontaneous and drug-related EPSs in a relatively broad sample of patients with schizophrenia-spectrum disorders who had never been exposed to antipsychotic drugs. Although spontaneous and drug-related EPSs are thought to be the expression of a dysfunction in the basal ganglia circuitry, the underlying mechanisms are obviously different. We, therefore, hypothesized that the 2 types of syndromes would present with a differentiated clinical manifestations. Data for the present report were derived from our parent study, which was aimed at examining the prevalence, syndromic structure, external correlates, and response to treatment of a broad range of motor behavior abnormalities in drug-naive patients with schizophrenia-spectrum disorders. The 189 patients completing a 4-week trial with antipsychotic medication (haloperidol, 23; risperidone, 93; olanzapine, 57; mixed pattern of antipsychotic drugs, 16) made up the study sample for the present report. The study had a naturalistic pretreatment and posttreatment design and was noncommercially funded. Patients were initially treated based on a monotherapy regimen with antipsychotics, although other medications were allowed if necessary; these included biperiden (n = 34), benzodiazepines (n = 59), antidepressants (n = 33), and mood stabilizers (n = 15). At the start of treatment, patients received a low dose of antipsychotic that was gradually titrated up during the course of the episode. The mean dose of antipsychotic medication in chlorpromazine equivalents was 276.7 (SD, 136.9), with the treatment groups not differing on mean antipsychotics dose. The study was carried out in accordance with the Declaration of Helsinki and was approved by the local institutional review board. All the patients or their legal representatives gave written informed consent to participate. Patients were examined for EPSs including parkinsonism, dyskinesia, and akathisia at the drug-naive state and after 4 weeks of starting antipsychotic treatment. Parkinsonism, dyskinesia, and akathisia were respectively assessed by means of the Simpson-Angus Rating Scale (SARS), the Abnormal Involuntary Movements Scale (AIMS), and the Barnes Akathisia Rating Scale (BARS). The presence of these EPSs was established according to a total score greater than or equal to 4 in the SARS, the Schooler & Kane criteria, and a global severity score greater than or equal to 2 in the BARS. Spontaneous or primary EPSs were defined as present if they met the criteria defined previously at the baseline assessment, before starting antipsychotic medication. Drug-related EPSs were defined as present if a particular syndrome, as defined previously, was absent at baseline and present at 4-week assessment. Thus, for each EPS domain, spontaneous and drug-related syndromes were considered as exclusionary conditions. Extrapyramidal signs were assessed by V.P., M.S.C. , or E.G.J. and the interrater reliability for EPS total scores and syndromes was greater than 0.75. To examine the differential symptomatic manifestations of spontaneous and drug-related conditions, we compared extrapyramidal symptom ratings between the 2 conditions for each EPS domain. For the sake of simplicity and to minimize type I statistical error, the 6 SARS items assessing rigidity were subsumed into a single rigidity rating by averaging the individual scores, and the 7 AIMS items were differentiated into orofacial and limbtruncal dyskinetic ratings by summing up the corresponding items. Given that a normal distribution for EPS ratings could not be assumed, together with the small sample size for some EPS groups, we used nonparametric statistics (Mann-Whitney U test) for group comparison. The mean age of the patients was 29.8 (SD, 10.3) years, and the mean age of onset of the first psychotic symptom was 27.1 (SD, 9.7) years. One hundred twenty-six (66.7%) patients were male and 154 (81.5%) were single. Diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were as follows: schizophrenia (n = 88), schizophreniform disorder (n = 36), schizoaffective disorder (n = 13), brief psychotic disorder (n = 35), delusional disorder (n = 13), and psychotic disorder not otherwise specified (n = 4). At baseline, 57 (30.2%) patients showed at least 1 EPS (parkinsonism, 39, 20.6%; dyskinesia, 23, 12.2%; akathisia, 7, 3.7%), and 12 of them met criteria for more than 1 syndrome. At 4-week assessment, 65 (34.4%) patients showed at least 1 drug-related EPS (parkinsonism, 52, 27.5%; dyskinesia, 13, 6.9%; akathisia, 22, 11.6%), and 22 of them met criteria for more than 1 drug-related syndrome. Table 1 presents the distribution of extrapyramidal ratings for spontaneous and drug-induced syndromes across the 3 EPS domains. During the study period, 18 patients with drug-related parkinsonism, 4 patients with drug-related dyskinesia, and 9 patients with drug-related akathisia were treated with biperiden. Thus, to examine the influence of biperiden treatment on the expressivity of drug-related EPS, these patients were excluded in specific analyses. Because of benzodiazepines may also influence the expression of parkinsonism and akathisia, analyses were repeated excluding those patients treated with benzodiazepines, and the results remained virtually the same (data not shown).