Clinical/Scientific Notes Clozapine Replacement by Quetiapine for the Treatment of Drug-Induced Psychosis in Parkinson’s Disease Drug-induced psychosis (DIP) occurs in 5% to 8% of pa- tients with Parkinson’s disease (PD) 1,2 and is probably the most important risk factor for nursing home placement among pa- tients with PD. 3 Although a decrease in anti-PD medication may relieve psychosis, patients may experience reduced motor ability as a result. Atypical antipsychotic (AA) agents, such as clozapine, olanzapine, and risperidone, are increasingly being used for the treatment of DIP in PD. While clozapine is useful in this situation, there have been reports of worsened parkinsonism among patients with PD who have DIP and are receiving risperidone and olanzapine. 4–7 Moreover, a recentarticle has seriously questioned risperi- done’satypicalnature. 8 The frequency of extrapyramidal symptoms (EPS)with risperidone or haloperidol treatment have been noted to be comparable, even among neuroleptic- naive non-PD patients experiencing a primary psychosis in this study. 8 Clozapine is considered the “gold standard” atypical antipsychotic drug for the treatment of DIP in PD at this time because of results from two double-blind, placebo-controlled trials and multiple open-label trials, 2 but the risk of agranulo- cytosis and the cumbersome white blood cell monitoring limit its use.Quetiapine is the newest atypical antipsychotic that shows promise for treating DIP in PD. 9–11 It has the closest pharmacologic resemblance to clozapine among the AA but lacks the risk for agranulocytosis. Like clozapine, quetiapine has a greater affinity for5-HT 2A than dopamine D 2 recep- tors. 12,13 Its effect on parkinsonism and prolactin levels (pre- dictive ofEPS occurrence) has been indistinguishable from placebo in trials of patients with schizophrenia. 14,15 However, cataracts occurred in chronic dog studies. Although no definite causal relationship linking quetiapine to lenticular changes has been established, lens examination by slit lamp or other appro- priate methods is recommended at the initiation of treatment and at 6-month intervals thereafter. 16 Our initial experience in clozapine switch-over to quetiapine among psychiatrically stable patients with PD who have DIP was not encouraging. 9 Only three of eight patients with PD who were on clozapine were successfully switched to quetiapine. We hypothesized that the rapid titration and the shorter overlap period between clozapine and quetiapine might have been con- tributing factors to the high failure rate. Nonetheless, only one patienthad increased tremors. All otherpatients who were unable to tolerate the switch-over did not experience a decline in motor function. 9 We now report ourfindings on clozapine replacement by quetiapine on 15 additional patients using a slower titration schedule with a wider overlap period. Methods Fifteen patients (eight men and seven women) with pre- sumed idiopathic PD, defined by the presence of three of four cardinal features (tremor at rest, rigidity, bradykinesia, gait and balance dysfunction; and a positive initial response to L-dopa) were studied. All patients had a history of DIP (according to Diagnostic and Statistical ManualofMentalDisorders, 4th edition [DSM-IV] criteria) but were psychiatrically stable. All patients were assessed at baseline and reassessed at 4 and 8 weeks after clozapine was totally discontinued using the Brief Psychiatric Rating Scale (BPRS), Mini-Mental Status Exami- nation (MMSE), Unified Parkinson’s Disease Rating Scale (UPDRS parts 1, 2, and 3), Hoehn and Yahr staging (H-Y), and Clinical Global Impressions Scale (CGIS) by the same exam- iner.Starting at baseline visit, the daily clozapine dose was reduced by 6.25 mg per week for 2 weeks, 12.5 mg per week for the next 2 weeks, then 25 mg per week thereafter until the drug was discontinued. Quetiapine was started at the same baseline visit at 12.5 mg per day for1 week and increased weekly by 12.5 mg per day until the patient was no longer on clozapine. If the baseline dose of clozapine was 6.25 mg per day, 1 week of overlap with 12.5 mg quetiapine was given prior to clozapine discontinuation. The titration schedule was strictly adhered to. The duration of the titration period ranged from 1 to 10 weeks depending on the initial clozapine dose. After the titration period, quetiapine adjustment was permitted, such as lowering the drug dose to improve orthostasis or increasing the nighttime dose to improve sleep, as long as the patient remained psychiatrically stable. An open-ended, nonstandardized weekly telephone interview was performed on all patients and their caregivers/ spouses to assess for compliance, recurrence of hallucinations or delusions, and side effects. Anti-PD medications were kept fixed during the cross-over period. Any patient who remained on quetiapine without worsened psychosis or parkinsonism was considered a treatment success. Another follow-up telephone interview was performed after 12 months on all patients (and their caregivers) who successfully switched over to quetiapine to assess the tolerability and continued efficacy of the drug. Paired t test or Wilcoxon signed rank test (if normality test failed because of the small sample) was used to compare the mean MMSE, BPRS,UPDRS,H-Y, and CGIS at4 and 8 weeks with baseline. Results Fifteen psychiatrically stable patients with PD who have a history of DIP on an average 41.6 mg clozapine per day were Received October 6, 1999; revisions received January 13 and March 24,2000.Accepted March 29, 2000. Address correspondence and reprint requests to Hubert H. Fernandez, MD, Memorial Hospital of Rhode Island, Division of Neurology, 111 Brewster St., Pawtucket, RI 02860, U.S.A. Movement Disorders Vol.15,No.3,2000,pp. 579–586 © 2000 Movement Disorder Society 579