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Clozapine and Haloperidol in Moderately Refractory Schizophrenia a 6-Month Randomized and Double-Blind Comparison

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Clozapine and Haloperidol in Moderately Refractory Schizophrenia a 6-Month Randomized and Double-Blind Comparison ORIGINAL ARTICLE Clozapine and Haloperidol in Moderately Refractory Schizophrenia A 6-Month Randomized and Double-blind Comparison John M. Kane, MD; Stephen R. Marder, MD; Nina R. Schooler, PhD; William C. Wirshing, MD; Daniel Umbricht, MD; Robert W. Baker, MD; Donna A. Wirshing, MD; Allan Safferman, MD; Rohan Ganguli, MD; Marjorie McMeniman, PhD; Michael Borenstein, PhD Background: Despite the demonstrated efficacy of cloza- a priori criterion of improvement (57%) compared with pine in severely refractory schizophrenia, questions re- haloperidol-treated subjects (25%). Significantly greater main regarding its efficacy for primary negative symp- improvement was seen in symptoms of psychosis, hostile- toms, comparison with a moderate dose of a first- suspiciousness, anxiety-depression, thought distur- generation antipsychotic, and adverse effects during a bance, and total score measured on the Brief Psychiatric longer-term trial. This study examined its efficacy in par- Rating Scale. No differences were detected in negative tially responsive, community-based patients, compared symptoms using the Brief Psychiatric Rating Scale or the clozapine with moderate-dose haloperidol, and ex- Schedule for Assessment of Negative Symptoms. Sub- tended treatment to 6 months. jects treated with clozapine experienced more excess sali- vation, dizziness, and sweating and less dry mouth and Methods: Randomized, double-blind, 29-week trial com- decreased appetite than those treated with haloperidol. paring clozapine (n=37) with haloperidol (n=34). Sub- jects with schizophrenia who were being treated in com- Conclusions: Compared with a first-generation anti- munity settings at 3 collaborating clinical facilities were psychotic given in a moderate dose, clozapine offers sub- enrolled. stantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are Results: Subjects treated with haloperidol were signifi- seen in a broad range of symptoms but do not extend to cantly more likely to discontinue treatment for lack of ef- negative symptoms. ficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an Arch Gen Psychiatry. 2001;58:965-972 ESPITE ADVANCES in treat- significant reduction in rehospitalization ment of schizophrenia, rather than symptoms.9,10 more than 10% of totally Questions remain about the efficacy disabled individuals in of clozapine for primary negative symp- the United States have toms.11-13 Kane et al5 studied subjects with- this disease, although it affects only 1% of drawn from high-dose haloperidol therapy D 1,2 the population. The introduction of (mean dosage, 60 mg/d) and compared chlorpromazine hydrochloride and other clozapine with high-dose chlorproma- conventional antipsychotic agents revo- zine plus benztropine mesylate (mean lutionized the care of schizophrenia. These maximum dosage, 1200 mg/d).5 They re- medications provide dramatic improve- ported significantly greater improve- ment in psychotic symptoms and reduce ment in the Brief Psychiatric Rating Scale risk for relapse, but recent estimates of pa- (BPRS) anergia factor, which could be at- tients with partial or poor response ex- tributed to reduction in extrapyramidal ad- ceed 40%.3,4 verse effects.14 The time course of cloza- Clozapine was the first medication to pine response also remains in question. produce significantly greater improve- Open and uncontrolled reports sug- ment than conventional antipsychotics in gest that clozapine improves social and carefully selected, treatment-refractory pa- cognitive functioning15 and overall qual- tients.5 Subsequent studies confirmed cloza- ity of life.16 Rosenheck et al17 report that pine’s effectiveness.6-10 Controlled trials that clozapine facilitates psychosocial treat- The affiliations of the authors showed greatest symptom improvement ment participation, enhancing effects on appear in the acknowledgment with clozapine were relatively brief (ie, 6-10 quality of life and long-term symptom out- section at the end of the article. weeks).6-8 Longer randomized trials found come. (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 58, OCT 2001 WWW.ARCHGENPSYCHIATRY.COM 965 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 SUBJECTS AND METHODS evidence that refractoriness was related to medication non- compliance, organic brain disease (eg, epilepsy or brain tu- mor), mental retardation that precluded understanding study We conducted a 6-month, double-blind, prospective, ran- participation or assessment procedures, chronic medical ill- dom-assignment trial comparing clozapine (target dos- ness that made study participation inappropriate, DSM- age, 500 mg/d) with haloperidol (target dosage, 10 mg/d). III-R diagnosis of substance abuse or dependence18 within Identical protocol and procedures were followed at 3 cen- 6 months, current treatment with medication(s) for other ters, including the West Los Angeles Veterans Affairs and medical conditions that may have psychotropic effects or University of California–Los Angeles (UCLA) Medical Cen- agranulocytosis risk or may interfere with drug absorp- ters; Hillside Hospital, North Shore–Long Island Jewish tion or metabolism, total white blood cell count below Health System, Glen Oaks, NY; and the Western Psychi- 3.5ϫ103/µL (3500/mm3), and pregnancy. atric Institute and Clinic and Mayview State Hospital, Pitts- Subject recruitment strategies varied. At Hillside Hos- burgh, Pa. The study was approved by the institutional re- pital, inpatient admissions were reviewed daily, and patient view boards at Long Island Jewish Medical Center, the rosters at Queens Day Treatment Center, Jamaica, NY, a fa- University of Pittsburgh, UCLA, Mayview State Hospital, cility that serves patients with chronic illness, were reviewed and the West Los Angeles Veterans Affairs Medical Cen- quarterly. At the University of Pittsburgh, patient rosters in ter. Seventy-one subjects provided informed consent and the Schizophrenia Treatment and Research Center (outpa- were randomized to treatment. Computer-generated ran- tient clinic and day hospital) were reviewed with primary cli- domization schedules (blocked by site) were provided to nicians quarterly. At Mayview State Hospital, a satellite facil- each site; sealed envelopes with treatment assignment were ity of the University of Pittsburgh, admission service rosters available to clinical personnel if needed to break the blind. were reviewed weekly and continuing care service rosters were reviewed quarterly. Recruitment at UCLA took place in the SUBJECTS Mental Health Clinic and Inpatient Service of the West Los AngelesVeteransAffairsMedicalCenterandtheAftercareClinic Inclusion criteria consisted of DSM-III-R18 diagnosis of schizo- of the UCLA Neuropsychiatric Hospital. Clinicians in each phrenia or schizoaffective disorder by one of the authors us- setting were asked by recruiters to refer refractory individu- ing a diagnostic checklist, 20 to 55 years of age, and living als. If patients met study criteria and provided informed con- in the community or judged clinically treatable in the com- sent, their treatment was transferred to the research clinic. munity despite psychotic symptoms. Partial or poor re- All subjects were competent to give informed con- sponse was defined by documented treatment failure in 2 sent. Competency was assessed by asking the patients to trials of conventional antipsychotics at dosages equivalent describe in their own words the essential elements of the to or greater than chlorpromazine hydrochloride, 600 mg/d, informed consent document. Potential subjects who were for at least 6 weeks (high-dose qualification) and 1 trial of a unable to appreciate risks, benefits, or discomforts of the conventional agent at dosages equivalent to chlorproma- study were considered ineligible. zine hydrochloride, 250 to 500 mg/d, for the same length of Subjects receiving fluphenazine decanoate or halo- time (low-dose qualification). Patients for whom a low- peridol decanoate received oral haloperidol or fluphen- dose trial could not be documented received prospective dose azine for 2 injection intervals before beginning double- reduction for 4 weeks or less if clinical worsening was seen. blind dosage titration. Only patients who met symptom criteria for inclusion after such treatment (a rating of at least moderate on 1 of the fol- TREATMENT IMPLEMENTATION lowing 4 BPRS items19,20: conceptual disorganization, sus- piciousness, hallucinatory behavior, and unusual thought Dosage Titration content) entered the trial. Exclusion criteria consisted of receipt of psycho- Medication was administered under double-blind condi- tropic medication therapy other than antipsychotics (eg, tions. Clozapine therapy was begun at a test dosage of 12.5 antidepressants or mood stabilizers) that could not be dis- mg/d on day 1. Haloperidol therapy was begun at a dosage continued, documented history of intolerance to haloperi- of 5 mg/d. Identical capsules contained haloperidol or cloza- dol at dosages of 4 mg/d or more because of disabling ex- pine in a 1:50 ratio with a range of 200 to 800 mg of cloza- trapyramidal adverse effects, diagnosis of neuroleptic pine or 4 to 16 mg of haloperidol. Dosage was gradually malignant syndrome with recurrence on rechallenge, increased to a target dosage of 500 mg/d for clozapine or The present trial was designed to address several tion of negative symptoms from akinesia. Since cloza-
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