SCHIZOPHRENIA RESEARCH ELSEVIER
Schizophrenia Research 30 ( 1998) 105-108
Case Report
A case of treatment-refractory psychosis responsive to sertindole Thomas D. Geracioti
a,c,,, Sharon Parker b Nola B. Lowther a,c, Matthew Wortman a,c Neil M. Richtand
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a Psychiatry Services, Veterans Affairs Medical Center, 3200 Vine St., Cincinnati, OH 45220, USA b Nursing Services, Veterans Affairs Medical Center, 3200 Vine St., Cincinnati, OH 45220, USA c Department o f Psychiatry, University o f Cincinnati College o f Medicine, Cincinnati, 0H45267-0559, USA
Received 26 July 1997; accepted 4 August 1997
Abstract
Sertindole is an antipsychotic with atypical in vitro and ex vivo binding profiles and little propensity to cause extrapyramidal symptoms. However, its potential usefulness in the treatment of psychosis resistant to the 'classical' neuroleptics has not been determined. In the present study we used a double blind, placebo-controlled trial of sertindole and observed dramatic, sustained resolution of formerly-chronic positive and negative psychotic symptoms in a schizophrenic patient. This patient had averaged 2.5 inpatient admissions per year for the 8 years preceding initiation of sertindole therapy, but has had no hospitalizations or psychosis in the 3.5 years since. Improved cognitive function has also been documented. This preliminary, but controlled, experience suggests that sertindole may possess a spectrum of clinical activity distinct from that of the typical antipsychotic agent. © 1998 Elsevier Science B.V. Keywords: Sertindole; Antipsychotics (atypical); Schizophrenia (treatment)
1. Introduction
Sertindole, a phenylindole derivative, has antipsychotic effects with little propensity to cause extrapyramidal symptoms (EPS) in monkeys Casey, 1996) and humans (van K a m m e n et al., 1996). These observations combined with sertindole's 'atypical' in vitro and e x vivo receptor binding profiles (Sanchez et al., 1991; Hyttel et al., 1992) raise the possibility that the drug m a y have a spectrum of clinical activity that differs from that of the standard antipsychotics, whose antipsychotic actions appear to be mediated via blockade * Corresponding author. Tel. +1 513 475 6325; Fax: +1 513 475 6380. 0920-9964/98/$19.00 © 1998 ElsevierScience B.V. All rights reserved. PH S0920-9964(97)00127-8
of the dopamine D 2 receptor. While sertindole too has a high affinity for the D z receptor, it has been estimated to be 100-fold more potent in inhibiting mesolimbic dopaminergic activity than in inhibiting dopaminergic neurotransmission in the nigrostriatal pathway (Skarsfeldt and Perregaard, 1990; Skarsfeldt, 1992). Additionally, sertindole has high affinity for serotonin 5HT2 receptors and ~l-adrenergic receptors (Sanchez et al., 1991 ). Like the prototypic 'atypical' antipsychotic clozapine, sertindole shows a high 5HT2 to D z receptorantogonism ratio (Sanchez et al., 1991). Such a ratio has been proposed to be associated with unique clinical actions and lack of EPS, as have been observed with clozapine (Meltzer et al., 1989). However, unlike clozapine, clinical evidence
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that sertindole has a u n i q u e , or 'atypical', spectrum o f clinical efficacy has been lacking because the effects of sertindole o n treatment-resistant psychotic patients have n o t yet been examined. We n o w report the case of a m a n with 8 years of psychosis refractory to t r e a t m e n t with s t a n d a r d antipsychotics, whose s y m p t o m s responded dramatically to t r e a t m e n t with sertindole. This p a t i e n t had had 20 d o c u m e n t e d psychiatric hospitalizations in the preceding 8 years, including 5 in the 24 m o n t h s prior to t r e a t m e n t with sertindole, b u t has had n o psychotic s y m p t o m s or psychiatric emergency r o o m or day hospital visits in the 3.5 years since.
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Mr. U is a 38-year-old right-handed, left-eyed caucasian male with schizophrenia, undifferentiated type, and an 8-year history of psychosis despite continuous administration of a variety of standard antipsychotic agents. Twenty hospitalizations have been documented in the 8 years between his first psychotic symptoms and the initiation of sertindole therapy more than 3.5 years ago. Most recently, he was again hospitalized with crescendo auditory hallucinations instructing him to harm himself (e.g. 'Pour gasoline on yourself and light yourself on fire') or someone else ('Stab your father with that knife') and with multiple hallucinated voices talking to him or about him. He had a blunted affect and thought blocking. He had difficulty speaking. These symptoms had broken through maintenance dosing with loxitane 200mg/day (his parents, with whom he lives, stated that he had been faithfully taking his medication daily). Even at his best he showed poor ability to care for himsef: he was poorly groomed,
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Fig. 1. Effects of sertindole (given double-blind) on BPRS and PANSS Positive and Negative Syndrome Subscale scores in a treatment-resistant schizophrenic patient. Following months of open-label loxitane 200mg/day, a schizophrenic patient received blinded study medication, first placebo (days - 7 to 0) then sertindole (from day 1). Minimum possible scores on the BPRS and PANSS Positive and Negative Syndrome Subscales are 18, 7, and 7, respectively.
T.D. Geracioti et al. / Schizophrenia Research 30 (1998) 105-108
frequently malodorous, apathetic, unable to drive a car. He attended a day treatment program from 2 to 5 days a week. Mr. U typically experienced partial responses to 'classical' antipsychotics; at various times he took trifluoperazine, mesoridazine, fluphenazine (oral and depot), haloperidol (oral and depot), chlorpromazine, and loxitane. He had also received electroconvulsive therapy. All of these treatments were effective in ameliorating his psychotic symptoms for short periods. His positive symptoms (such as auditory hallucinations) usually resolved temporarily. His negative symptoms (such as apathy and associated lack of personal hygiene) were more resistant to treatment, and Mr. U never received enough benefit from antipsychotic agents to permit him to work as either a paid or volunteer employee, engage in intimate relationships, or live independently. Mr. U was voluntarily enrolled in the Abbott Laboratory-designed and sponsored M93-098 double-blind, placebo-controlled, haldol-referenced multi-site trial of sertindole in schizophrenia after written, informed consent was obtained. For the purpose of this study, he was not considered neuroleptic-refractory (which would have excluded him) on the basis of his history of brief responses to antipsychotics in the past. That the neuroleptics were of some help to Mr. U was also made clear by his clinical deterioration during the 7-day, single-blind placebo lead-in period (Fig. 1). He was randomized to sertindole, the dose of which was increased to 20 mg p.o. every morning over 12 days and maintained. His psychotic symptoms resolved over the next 4-8 weeks, with the minimum possible scores achieved on the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) Positive Syndrome Subscale after 8 weeks of sertindole therapy and the minimum possible PANSS Negative Syndrome Subscale score achieved after 5 weeks (Fig. 1). Mr. U's clinical improvement has thus far persisted for well over 3 years, during which time he has had no psychotic episodes. He has obtained his driver's license, attends his doctor appointments independently, shops alone, participates in a fitness program, and regularly drives his
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parents and sister on errands. His grooming and personal hygiene have greatly improved. Recent neuropsychological test results when compared with those obtained 8 years earlier show 'stabilization of his higher cognitive functioning'. As opposed to the marked variability seen 8 years before, Mr. U's intellectual, language, and motor skills, visuospatial perception, memory, and reasoning functions were consistently in the average range. His full-scale IQ by WAIS, which was 88 eight years ago, is now 95.
3. Discussion The sustainment of the complete resolution of hallucinations and improvement in personal hygiene and social function in our schizophrenic patient, who had had only modest and/or transient positive responses to a variety of neuroleptics, suggests that sertindole may possess a spectrum of therapeutic activity distinct from those of the older antipsychotic agents (except, perhaps, clozapine, which our patient had never been prescribed). The improved cognitive functioning of our patient might also be related to sertindole therapy, by virtue either of the amelioration of negative symptoms (Rossi et al., 1997) or its apparent favourable cognitive side-effect profile (Didriksen, 1995). If this preliminary experience with a single patient is extended and validated, then sertindole may become an important addition to our antipsychotic formulary.
Acknowledgment This work was supported by Abbot Laboratories, Abbot Park, Illinois.
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