Clozapine in Drug Induced Psychosis in Parkinson's Disease: a Randomised, Placebo Controlled Study with Open Follow Up

689 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029868 on 16 April 2004. Downloaded from PAPER Clozapine in drug induced psychosis in Parkinson’s disease: a randomised, placebo controlled study with open follow up P Pollak, F Tison, O Rascol, A Deste´e, J J Pe´re´, J M Senard, F Durif, I Bourdeix, on behalf of the French Clozapine Parkinson Study Group ............................................................................................................................... J Neurol Neurosurg Psychiatry 2004;75:689–695. doi: 10.1136/jnnp.2003.029868 Objective: To compare the efficacy and safety of clozapine in drug induced psychosis in Parkinson’s disease (PD). Methods: A four week, randomised, double blind, parallel comparison of clozapine and placebo, followed by a 12 week clozapine open period, plus a one month period after drug discontinuation, in 60 See end of article for patients with PD. The primary efficacy outcome was the ‘‘clinical global impression scale’’ (CGI); the authors’ affiliations positive subscore of the ‘‘positive and negative syndrome scale’’ (PANSS) was used as the secondary ....................... efficacy parameter and the ‘‘unified Parkinson’s disease rating scale’’ (UPDRS) and the ‘‘mini mental test Correspondence to: examination’’ (MMSE) as safety outcomes. Dr P Pollak, De´partment de Results: The mean (SD) dosage of clozapine was 35.8 (12.5–50) mg at the end of the double blind period. Neurologie, Centre The mean (SD) scores on the CGI improved by 1.8 (1.5) for the clozapine group compared with 0.6 (1.1) Hospitalier Universitaire de for the placebo group (p = 0.001). The mean (SD) positive subscore of PANSS improved by 5.6 (3.9) for Grenoble, BP 217 X, 38043 Grenoble Cedex 9, the clozapine group (0.8 (2.8) for the placebo group; p , 0.0001). At the end of the open period, 25 France; pierre.pollak@ patients had completely recovered from delusions and hallucinations, and 19 experienced a relapse within ujf-grenoble.fr one month after the clozapine washout period. The UPDRS motor and MMSE mean scores did not change Received 7 October 2003 significantly in either group. Somnolence was more frequent with clozapine than with placebo. Accepted 7 October 2003 Conclusions: Clozapine at a mean dose lower than 50 mg/day improves drug induced psychosis in PD ....................... without significant worsening of motor function, and the effect wears off once the treatment stops. copyright. he occurrence of psychotic symptoms (disturbance of outlined in the first double blind, placebo controlled study.9 perception and thought) induced by dopaminergic drugs Here, we report in detail the results of a large, multicentre marks a new phase in the course of Parkinson’s disease study, including three consecutive, double blind, open and T 12 (PD). To know whether psychosis is induced by drugs or washout periods of clozapine treatment. The first double not is difficult because of confounding factors. However, the blind, placebo controlled period has been briefly reported.10 term drug induced psychosis may be used when other significant psychiatric diseases are excluded in patients with METHODS no history of psychosis. Moreover, because all patients with This prospective, double blind, placebo controlled study was PD received dopaminergic drugs, we have no means of conducted at 13 centres in France between January 1996 and http://jnnp.bmj.com/ distinguishing between the drugs or the disease as the October 1997, in compliance with good clinical research prevalent aetiology. Not only do psychotic symptoms have a practice guidelines and the Helsinki Declaration. The protocol major impact on patients and their caregivers in dramatically was approved by the ethics committee of Grenoble and all limiting treatment possibilities, but they are also a risk factor patients gave their written consent. for nursing home transfer and subsequent increased mortal- ity.3 The prevalence of dopaminomimetic psychosis varies Patient selection from 5% to 20%, depending on the methodology of the study Sixty patients suffering from idiopathic PD according to the and nature of symptoms taken into account.2 A recent ‘‘UK Parkinson’s Disease Society brain bank clinical diag- on September 28, 2021 by guest. Protected community based study found that 16% of patients had nostic’’ criteria and experiencing a drug induced psychosis of hallucinations and delusions, and that age, late disease stage, at least two weeks’ duration were eligible for recruitment. All institutionalisation, cognitive decline, and depression were 4 patients had failed to respond to standard therapeutic significant risk factors. Several approaches have been management; that is, no improvement of psychiatric symp- proposed to manage these symptoms, including attempts to tomatology or an unacceptable worsening in motor symp- withdraw dopaminergic agonists and gradually decrease the toms despite the interruption of all anticholinergic agents levodopa drug ‘‘dose’’ and the use of a ‘‘low potency’’ (including tricyclic antidepressants), in addition to amanta- neuroleptic treatment. However, the neurologist often faces a dine and selegiline, an attempt to withdraw dopaminergic 2 ‘‘motion emotion’’ dilemma, because these approaches can agonists, and a progressive reduction in the doses of 56 lead to unacceptable motor deterioration. Since the early levodopa. 7 study of Scholz and Dichgans, at least 32 open labelled trials The psychotic symptom score had to be > 4 for at least one involving more than 300 patients have suggested the of the items P1 (hallucinations) or P3 (delusions) of the usefulness of the atypical neuroleptic clozapine as a unique positive subscore of the ‘‘positive and negative syndrome possibility of controlling drug induced psychosis, without 8 compromising motor function, in many patients with PD. Abbreviations: CGI, clinical global impression scale; MMSE, mini The efficacy and tolerability of low dose clozapine in the mental test examination; PANSS, positive and negative syndrome scale; treatment of drug induced psychosis in PD has recently been PD, Parkinson’s disease; UPDRS, unified Parkinson’s disease rating scale www.jnnp.com 690 Pollak, Tison, Rascol, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029868 on 16 April 2004. Downloaded from scale’’ (PANSS).11 In addition, patients had to score . 3on discontinuation. Because of the variability of UPDRS evalua- the ‘‘clinical global impression scale’’ (CGI).12 Both of these tions during ‘‘on’’ periods, the Schwab and England’s scales rate the severity of psychotic symptoms from 0 (no activities of daily living scale (UPDRS part VI, with a range symptoms) to 7 (the most severe symptoms). Furthermore, at of scores from 0 to 100, lower scores indicating more severe least 20 had to be scored on Folstein’s ‘‘mini-mental state disability), assessed weekly, was chosen as the criterion to evaluation’’ (MMSE).13 A history of recent changes was detect a possible worsening of parkinsonism: a 20% decrease obtained from the patients. Patients were excluded if they in the UPDRS part VI up to day 14, or a 10% decrease had a history of medical conditions or drug treatment that thereafter entailed the interruption of clozapine dose escala- might put them at special risk or bias the assessment of their tion. Blood samples were taken weekly and physical signs clinical or mental status. Patients likely to require continuous were recorded daily for the first four days in periods II and treatment with drugs that can lower the white blood cell III, and then on a weekly basis. count, and those previously treated with clozapine, were also excluded, as were women of childbearing potential who were Randomisation and blinding not practising a medically approved form of birth control. Randomisation was performed by the biostatistics depart- ment of Sandoz (subsequently Novartis), France using a Overall design and outcome measures validated system that automates the random assignment of Four periods were planned in our study. The first (period I) treatment groups to randomisation numbers. Period II was was a period of screening. After a minimum seven day period double blind. The blinding was maintained when patients of stability with levodopa and dopaminergic agonists at the entered period III and received clozapine open labelled. Blood minimal tolerable dose, eligible patients were randomised to count results were not blinded because of the very low receive clozapine or placebo once daily at bedtime (1/1 number of patients expected to suffer from agranulocytosis.14 randomisation, block size of four). The second period (period II) of four weeks (day 0 to day 28) involved clozapine dose Sample size determination titration according to the following schedule: a starting daily Because of the absence of bibliographical data at the time of dose of 6.25 mg, followed, if necessary, by progressive dose study planning, sample size determination was empirical, increases (maximum of three 12.5 mg steps each week) up to based on practical considerations (feasibility) and previous a maximum daily dose of 50 mg, which could not be reached experience. Sample size was set to 60 evaluable patients (that within less than 10 days. The doses of antiparkinsonian is, randomised patients completing period II). drugs remained unchanged. The dose of clozapine could be reduced if adverse effects occurred by steps of 12.5 mg. The Statistical analysis speed of changes was adapted to adverse effects. Data were

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