Kane 1988 3y2g6w

Clozapine for the Treatment-Resistant Schizophrenic A Double-blind

Comparison With Chlorpromazine

John Kane, MD; Gilbert Honigfeld, PhD; Jack Singer, MD; Herbert Meltzer, MD; and the Clozaril Collaborative Study Group \s=b\ The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of

scientific interest, but its clinical

development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics. DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 \m=+-\14mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients. (Arch Gen Psychiatry 1988;45:789-796) of antipsychotic drugs in short-term and maintenance treatment of schizophrenia has been well established in numerous double-blind placebo controlled trials over the past 30 years.1-2 However, despite the considerable magnitude of the medication effect in this condition, most controlled trials continue to find a subgroup of 10% to 20% of patients who derive little benefit from typical neuroleptic drug therapy.1 The treatment of this

The efficacy

Accepted for publication March 9, 1988. From the Department of Psychiatry, Hillside Hospital\p=m-\LongIsland Jewish Medical Center, Glen Oaks, NY (Dr Kane); the Department of Psychiatry, State University of New York at Stony Brook (Dr Kane); the Department of Medical Research, the Sandoz Research Institute, East Hanover, NJ (Drs Honigfeld and Singer); the Department of Psychiatry, University of Medicine and Dentistry of New Jersey\p=m-\RobertWood Johnson Medical School, Piscataway (Dr Singer); and the Department of Psychiatry, Case Western Reserve School of Medicine, Cleveland (Dr Meltzer). The of the Clozaril Collaborative Study Group are as follows: Joyce Small, MD, Indianapolis; Richard Borison, MD, Augusta, Ga; Rob Conley, MD, Pittsburgh; Richard Wagner, MD, Providence, RI; Jan Volavka, MD, New York; John Rotrosen, MD, New York; Donald Seidel, MD, San Antonio, Tex; Larry Ereshefsky, PharmD, San Antonio, Tex; Jerome Costa, MD, Norwalk, Calif; John Herrera, PhD, Norwalk, Calif; Samuel Gershon, MD, Detroit; Neil Hartman, MD, Los Angeles; George Simpson, MD, Philadelphia; Richard Abrams, MD, Chicago; Benjamin Graber, MD, Omaha; and Martha Martin, MD, Washington, DC. Read in part before the 140th Annual Meeting of the American Psychiatric Association, Chicago, May 14, 1987. Reprint requests to Department of Psychiatry, Hillside Hospital, Long Island Jewish Medical Center, PO Box 38, Glen Oaks, NY 11004 (Dr Kane).

refractory subgroup remains a major public health prob¬ lem—these individuals require more intensive care and are subject to the persistent disabilities associated with chronic schizophrenia. In addition, the continued presence of psychotic signs and symptoms makes these patients less available to psychosocial and vocational rehabilitation.

It is estimated that about 1 million Americans suffer from schizophrenia. While there are no definitive data available on how many do not respond to neuroleptics, extrapolations from clinical trial data suggest that there may be 100000 to 200000 such patients. Data from maintenance medication trials indicate that

patients initially responsive to antipsychotic relapse during the first year or two of maintenance drug treatment.3 A proportion of these even

among

drugs, 20%

to 30% may

patients contributes to the number in the subgroup of patients refractory to treatment. Since many of these patients remain ill, there is a cumulative increase in the number of people in the treatment-refractory category. See also

865.

The recognition that some patients do not benefit from typical neuroleptics has resulted in research along two fronts: (1) to identify phénoménologie, demographic, and/ or biologic factors that may be associated with poor treatment response and (2) to explore alternative treat¬ ment strategies that might be beneficial to this subgroup. With regard to the former, there are no consistently replicated findings providing clues about why patients are refractory to treatment. There are countless reports of anecdotal or pilot study experiences with a variety of alternative treatments for poor responders. However, no particular strategy has been found to be more than occa¬ sionally useful; with controlled studies, the usual result is that the experimental treatment proves to be no more effective than conventional treatments. Since the introduction of chlorpromazine, numerous other chemical classes and compounds with antipsychotic ac¬ tivity have been used. Despite considerable differences in chemical structures, these agents seem to share an ability to bind to dopamine receptors. When in vitro binding assays are used, antidopaminergic (specifically, dopamine D2 recep¬ tor antagonism) action and therapeutic potency are highly correlated." To a greater or lesser degree these are all "neuroleptics," ie, associated with short-term extrapyram¬ idal side effects (including dystonias) and share the longerterm liability of inducing tardive dyskinesia. Despite nu¬ merous comparative trials, there are no consistent data suggesting that any specific antipsychotic drug or drug class is superior to any other in treating schizophrenia.12 Over the past decade, considerable effort has gone into the development and testing of potential antipsychotic compounds designated atypical. The concept of atypicality, however, is a working concept rather than a well-delineated

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and validated classification. In general, this term has been used to describe drugs that appear to have limited shortterm extrapyramidal effects in animals or human subjects. Most are more selective in their dopamine D2 antagonist

properties (eg, sulpiride or raclopride) and/or more broadly active, with marked antiserotonergic, antinoradrenergic, or other effects as well (eg, clozapine). Clozapine (8-chloro-l l-(4-methyl-l-piperazinyl)-5.H-dibenzo[6,e][l,4]diazepine) belongs to the chemical class of dibenzodiazepines, related chemically to the antipsychotic dibenzoxazepine drug loxapine. However, its pharmaco¬ logie characteristics are different from those of loxapine. Clozapine has serotonin (S2), adrenergic (aj, and histaminergic (HJ blocking activity. It is also a potent muscarinic acetylcholine receptor antagonist.6-7 Its binding to D¡ and D2 receptors is relatively weak and more equivalent than that of most typical neuroleptics.8 The relationship between these characteristics and clozapine's clinical ef¬ fects remains highly speculative, and a full review of this topic is beyond the scope of this report.9 Unlike "typical" neuroleptics, clozapine produces only slight, transient elevations in serum prolactin levels in patients, even when moderate to high doses are given.10·11 Its profile of extrapyramidal side effects appears to be very different from those of typical neuroleptics. In both US and foreign studies, it has been reported that clozapine does not induce dystonia when istered on a shortterm basis, and although akinesia or akathisia develops in some patients, the incidence appears to be low.12 Thirteen cases of "dyskinesia" were reported from a sample of 12 000 patients in Europe, but the nature of these

of agranulocytosis in patients receiving clozapine. Because of this, the use of clozapine was curtailed in many countries, and the drug was withdrawn for a time from clinical research by its US sponsor. For humanitarian reasons, some countries (including the United States) allowed continued use of the drug for carefully selected patients who were resistant to treatment, sensitive to extrapyramidal side effects, or dyskinetic; these patients underwent intensive precautionary monitoring of white blood cell and differential counts. Since the introduction of restrictions in use and intensive hématologie monitoring, cases

is not clear (unpublished results, P. Krupp, MD, and C. Monka, Sandoz Ltd, Basel, Switzerland, 1987). There has been one report of clozapine apparently exacerbating preexisting tardive dyskinesia.13 One case of apparent neuroleptic malignant syndrome has been reported in a

the overall incidence of agranulocytosis has declined, as has the lethal risk for patients in whom this reaction develops. Overall estimates continue to indicate that the risk of agranulocytosis with clozapine exceeds that asso¬ ciated with other antipsychotic drugs. In the United States, this problem developed in ten patients of 894 treated, and all of these patients recovered without any apparent longterm effect. Using the life-table method of calculating risk, data from the US experience indicate a 2% cumulative incidence after 52 weeks of clozapine treatment (95% confidence limits, 0.2% and 4%).19 Based on US and world¬ wide experience, the risk of this adverse effect does not appear to be related to age, sex, or dose. The risk of "benign" neutropenia, however, does not appear to be any higher than with marketed neuroleptics. Given clozapine's apparently greater risk and its promise of benefit for patients unresponsive to neuroleptics, the decision was made to initiate a controlled trial in carefully selected treatment-resistant patients. In considering the benefit-to-risk ratio of a therapeutic trial of clozapine, the time course of the development of agranulocytosis was also considered. The majority of agranulocytosis cases world¬ wide have occurred between the sixth and 18th weeks of clozapine treatment. Previous data also suggest that six weeks would provide a reasonably accurate test of the

Previous controlled clinical trials have been conducted with clozapine. Claghorn et al15 reported a six-center double-blind comparison of clozapine and chlorpromazine in 151 hospitalized schizophrenic patients who had experi¬ enced either extrapyramidal side effects or tardive dyski¬ nesia with at least two different neuroleptics. Clozapine

Study Design

cases

patient receiving clozapine and lithium.14

was

significantly superior to chlorpromazine according to

the major efficacy measures, and it produced fewer side effects. The dosage ratio of chlorpromazine to clozapine in this study was approximately 2:1. Fischer-Cornelssen and Ferner16 conducted a five-center double-blind comparison of clozapine and chlorpromazine in 223 hospitalized schiz¬ ophrenic patients; they found clozapine to be superior in efficacy, particularly among the more severely ill patients. In this study, however, the mean chlorpromazine dose at sjx weeks was only 360 mg compared with 310 mg of clozapine. In a similar two-center European study,16 clozapine was compared with haloperidol in a sample of 79 schizophrenic inpatients. The average dosage of clozapine was 397 mg/d at day 40 compared with a dosage of 7.6 mg/d of haloperidol. Though clozapine was found to be more efficacious, the latter two comparisons could be criticized on the basis of inadequate dosing of the reference drug. The results of these clinical trials suggested that clozapine is an effective antipsychotic drug and also pro¬ vided some suggestions of potential benefit in patients who are more severely ill or refractory to treatment. However, in 1975, granulocytopenia developed in 16 patients in Finland, and agranulocytosis developed in 13 of these patients (eight fatalities resulted from secondary infection).1718 Worldwide experience now reveals over 100

drug's therapeutic potential in individual patients. Expo¬ sure beyond that time was therefore limited in the present study to only those patients who had already shown significant therapeutic benefit from clozapine. METHODS

This study was designed to test the comparative efficacy of clozapine in schizophrenic inpatients who by history and prospec¬ tive study would be considered to be resistant to treatment. Sixteen participating centers contributed data on a total of 319 patients. Patients had to meet DSM-III20 criteria for schizophre¬ nia. The criteria for being classified as refractory to treatment included the following: (1) at least three periods of treatment in the preceding five years with neuroleptic agents (from at least two different chemical classes) at dosages equivalent to or greater than 1000 mg/d of chlorpromazine for a period of six weeks, each without significant symptomatic relief, and (2) no period of good functioning within the preceding five years. Subjects had to meet the following psychopathologic severity criteria: total Brief Psychiatric Rating Scale (BPRS) score of at least 45 (18-item version, in which 1 indicates absent and 7 indicates severe) plus a minimum Clinical Global Impressions (CGI) Scale rating of 4 (moderately ill). In addition, item scores of at least 4 (moderate) were required on two of the following four BPRS items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content. All patients who met both the historical criteria for treatment resistance and the initial severity criteria and gave their informed consent entered a prospective period of treatment with haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of six weeks to confirm the lack of drug responsiveness. Improvement in this context was defined a priori as a 20% decrease in the BPRS total score plus either a post-treatment CGI Scale

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rating of mildly ill (S3) or a post-treatment BPRS score of 35 or less. Any haloperidol responders (ie, those who met the improve¬ ment criteria) were dropped from further study.

Table 1. —Sex, Race, and Diagnosis of Patients Entering the Study (N 319) =

Patients who met the multiple psychiatric symptom criteria were then randomly assigned to a six-week double-blind treatment

clozapine (up to 900 mg/d) or chlorpromazine and benztropine mesylate (up to 1800 mg/d of chlorpromazine hydrochloride and up to 6 mg/d of benztropine mesylate). All medications were coded and istered under double-blind conditions; in addition to coded active antipsychotic medication in blue capsules, patients received either white benztropine tablets (chlorpromazine group) or identical white placebo tablets (clozapine group). The use of prophylactic benztropine mesylate (up to 6 mg/d) for all patients receiving chlorpromazine was designed to enhance the double-blind condition, in light of clozapine's previously estab¬ lished profile of reduced extrapyramidal side effects. In addition, this strategy was thought to minimize the potential for behaviorally manifest adverse effects to confound assessment of the relative clinical efficacy of the two drugs. Before the start of the study, a priori criteria for ing the superiority of clozapine in this patient population were deter¬ mined. These criteria required proof of statistical superiority in all of three predetermined areas: the CGI Scale, changes in BPRS total score, and significant improvement in at least two of the following four BPRS items (or the cluster score derived from summing these four items): conceptual disorganization, halluci¬ natory behavior, suspiciousness, and unusual thought content.

Characteristic

trial with either

Treatment

Patients entering the double-blind phase of the study were treated for six weeks. During the first two weeks, the dosage was titrated upward, if well tolerated, to dosage levels of either

500 mg/d of clozapine or 1000 mg/d of chlorpromazine (plus 6 mg/d of benztropine mesylate for chlorpromazine patients only). Dosing during the final four weeks was flexible, to maximum allowable dosages of 900 mg/d of clozapine and 1800 mg/d of chlorpromazine (plus up to 6 mg/d of benztropine mesylate). The number of patients entering each study period was as follows: No. of Period No. Duration, d Patients Description s 14 319 1 Baseline placebo 2

3 4

Of the

patients

s42

Haloperidol

305

272 Placebo washout <7 Double-blind <42 268 who entered period 4, 126 were randomized to

clozapine, and 142 tropine mesylate.

were

randomized to

Evaluation of

chlorpromazine and

benz¬

Efficacy

Patients were interviewed by physicians or psychologists weekly during the course of double-blind treatment, and their assessments were recorded on the BPRS and on a seven-point CGI Scale (in which 1 indicates no mental illness and 7 indicates severe mental illness). In addition, patients were regularly evaluated in of ward behavior by the nursing staff, using the 30-item Nurses' Observation Scale for Inpatient Evaluation (NOSIE-30).21

Safety Adverse reactions were evaluated by systematic patient query and observation by both medical and nursing personnel. Reactions were graded for severity and evaluated as to attribution to study drug, and the course of the reaction was documented. Regular clinical laboratory tests were performed, as were physical exami¬ nations, an electrocardiogram, and vital sign determinations. Systematic assessments of extrapyramidal symptoms and abnor¬ mal involuntary movements were made weekly using the SimpsonAngus Scale for Extrapyramidal Side Effects22 and the Abnormal Involuntary Movements Scale (AIMS).23 Evaluation of

SUBJECTS Three hundred nineteen inpatients entered this study; their treatment history characteristics are summa¬ rized in Tables 1 and 2. Only 20% of the patients were female, largely due to the high proportion of Veterans istration

demographic and

Sex M F Race White Black

No. (%) of Patients 256 63

(80) (20)

208 (65) 74 (23) 31 (10)

Hispanic

2

Oriental Other

4

Diagnosis (DSM-III schizophrenic subtypes) Undifferentiated Paranoid

Disorganized Residual

Unspecified

Catatonic

160 107 25 11 10 6

(1) (1)

(50) (34) (8) (3) (3) (2)

medical centers among the participating institutions and possibly also because women were less likely to have received 1000-mg

chlorpromazine equivalents of three different neuroleptics. The typical patient was a 35-year-old male chronic undiffer¬ entiated schizophrenic first hospitalized for psychosis at age 20 years, after which seven or eight additional periods of hospitali¬ zation ensued. The median duration of the current hospitalization was

about two years.

RESULTS Over 80% of the patients completed the six-week prospective haloperidol phase of the study. A complete tabulation of patient outcomes after haloperidol treatment is provided in Table 3. Of those patients who completed the full six weeks of haloperidol treatment (dosages up to 60 mg/d and greater; mean [SD], 61 [14] mg/d), 80% were nonresponders. Fewer than 2% were classified as haloperidol responders. In the balance of the patients, haloper¬ idol was terminated early for a variety of reasons, the most prominent of which was intolerance to haloperidol. On average, haloperidol-treated patients showed no change during the course of six weeks of treatment in any areas of the BPRS or NOSIE-30. Twenty-two patients were unable to tolerate the complete halo¬ peridol phase due to adverse effects, but since they met all retrospective criteria for treatment resistance, they were allowed to continue into the double-blind comparison. (Thirteen of these patients received chlorpromazine, and nine received clozapine. Efficacy analyses excluding these patients were also carried out and did not alter the results.) Two hundred sixty-eight patients entered the critical clozapine vs chlorpromazine and benztropine double-blind phase. The diag¬ nostic composition of each treatment subgroup in the double-blind phase was similar to that seen initially: approximately half of the patients in each treatment group were in the "undifferentiated" category and about one third were in the "paranoid" category. From the point of view of psychiatric history, the subgroups did not differ in any significant way in major characteristics of patient history and treatment, including age at first hospitalization for psychosis, number of hospitalizations, duration of illness, duration of current episode, and duration of present hospitalization. Average daily doses of active antipsychotic medication received during double-blind treatment are shown by treatment week in Fig 1. Adequate dose levels of each drug were attained with mean peak dosages exceeding 1200 mg/d of chlorpromazine and 600 mg/d of clozapine. The decrease in average dosage for both treatment groups at week 6 reflects the mandated taper-down at the end of the treatment period for all patients, designed to avoid abrupt discontinuation. Review of dispositions at the end of each patient's double-blind participation indicated high overall completion rates for both clozapine- and chlorpromazine-treated patients (88% and 87%, respectively). Early terminations occurred for the following rea¬ sons: adverse reactions (6%), illness not related to drugs (1%),

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Table 2.—General Characteristics of Patients

Entering the Study (N 319) =

No. of

Patients*

Characteristic

Median

Mean

Age, y_3J8_35_0_35.7 Duration of current

(SD)

Range

(8.87)_20-59

symptoms, wk_307_212.0_314.7 (316.76)_5-1976 Age at first hospitalization, y_294_2(3_20.4 (4.61)_8-40 No. of hospitalizations 245 7.0 1-50 9.2(7.26) Duration of current hospitalization, wk "The number of

patients

Table 3.

304

varies because of

"missing"

or

104.0

0-1976

1400

Patient Classification After Treatment With —

215.9(321.41)

"unknown" data elements.

Haloperidol and Benztropine No. (%) of Patients (n = 305)

Patient Classification

Haloperidol responder

5 (1.6)

Haloperidol nonresponder Terminated early Intolerant of haloperidol Uncooperative

Protocol violated Physical conditions not related to

Other (eg, seizure,

drug

248 (81.3) 52 (17.0) 22 (7.2) 15 (4.9) 4 (1.3) 5 (1.6)

electrocardiographic

changes, withdrew consent)

6 (2.0)

uncooperativeness (2.9%), protocol violations (1%), symptom ex¬ acerbation (1%), and other causes (1%). Rates of early termination for all reasons were comparable for patients in both treatment groups.

3

2

=

Clinical

Efficacy

=

to treat"

analysis24

was

carried out for all

patients who had

6

=

=

=

=

=

=

Analyses of covariance of posttreatment change scores con¬ ducted for week 6 vs baseline (using pretreatment scores as covariates) were performed for all efficacy variables. An "intent

5

4

Week of Study Fig 1.—Mean daily doses of clozapine (solid line) and chlorprom¬ azine (broken line) during double-blind phase of study (period 4). For clozapine, at week 1, 126; week 2, n 126; week 3, 122; week 4, 120; week 5, n 119; and week 6, 116. For 141; week 2, 140; week 3, chlorpromazine, at week 1, 137; week 4, 125. 133; week 5, 128; and week 6, =

=

=

=

a

baseline assessment and at least one assessment following ran¬ domization, with the last observation carried forward, yielding essentially equal numbers of patients in each cell.

Figures 2 and 3 display findings for two of the predetermined critical variables, the two overall indexes of improvement: BPRS total score and the CGI Scale. The improvement in both the BPRS total score and the CGI Scale was approximately three times greater in the clozapine-treated patients. Differences favoring clozapine were statistically significant by the first week of treat¬ ment and continued to be present each week over the entire course of study. Similarly, four "positive" BPRS items determined a priori to be central to the assessment of therapeutic response (conceptual disorganization, hallucinatory behavior, suspiciousness, and unu¬ sual thought content) all demonstrated significant differences favoring clozapine over chlorpromazine and benztropine. These items were combined into a cluster score, which also yielded significant differences favoring clozapine (Fig 4). The mean scores at baseline and end point are presented in Table 4. Clozapine was superior to chlorpromazine in the treatment of negative signs and symptoms as well, as evidenced by statistically significant differ¬ ences on the BPRS items of emotional withdrawal, blunted affect, psychomotor retardation, and disorientation. These items in combination form the BPRS "anergia" factor, displayed in Fig 5. Analysis of variance and analysis of covariance results for all BPRS variables, including the a priori criteria, are shown in Table 5. Therapeutic response was assessed by the nursing staff as well, who rated patients' ward behavior on the NOSIE-30 (Table 5). For all six factors (social competence, social interest, personal neat¬ ness, irritability, manifest psychosis, and retardation), the nursing staff, blind to treatment assignment, judged clozapine effects superior to those of chlorpromazine and benztropine. Weekly

0

2

4 6 5 3 Week of Study Fig 2.—Mean change from baseline in total score on Brief Psychi¬ atric Rating Scale (BPRS) for patients treated with clozapine (solid

line, line,

=

=

changes

1

126) or chlorpromazine and benztropine mesylate (broken 139). P<.001 during each week of study.

the composite score, "total patient assets," are pre¬ Fig 6. Concerning the onset of therapeutic effects, Figs 2 to 6 indicated significant differences favoring clozapine over chlorpromazine as early as the first week. Analysis of variance of the comparative rates of improvement for these treatment groups (analysis of slopes) found that clozapine produced more rapid onset of activity on

sented in

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Table

4.—Comparative Drug Efficacy and Neurologic Ratings Score No. of

(Mean ± SD)

Scale*

Two-Tailed

Analysis of

Baseline End Point Drug Patientsf Covariance, 126 61 ±12 45 ±13 Clozapine -C.001 56±12 139 61 ±11 Chlorpromazine BPRS cluster of four key items 126 19±4 14±5 Clozapine <.001 17±4 139 19±4 Chlorpromazine CGI Scale 126 5.6±0.7 4.4±1.1 Clozapine <.001 139 5.7±0.7 5.3±0.8 Chlorpromazine AIMS total score 8.8±6.8 126 5.1 ±5.4 Clozapine .09 139 6.5±5.4 5.8 ±5.5 Chlorpromazine 126 3.2 ±3.6 1.8±2.1 Clozapine Simpson-Angus Scale for Extrapyramidal Side Effects .03 139 3.3±3.5 2.9±3.2 Chlorpromazine *BPRS indicates Brief Psychiatric Rating Scale: CGI, Clinical Global Impressions; and AIMS, Abnormal Involuntary Movements Scale. tThree patients were excluded from these analyses. One patient did not undergo rating after randomization, and one study site had only two patients, both of whom received chlorpromazine. BPRS total

score

Table 5. —Comparative

Efficacy of Clozapine vs Chlorpromazine and Benztropine

Drug(s) Criterion Variable*

BPRS positive symptoms

Proved

Effectivef

Drug

Proved

Superior/

Conceptual disorganization

Clozapine and chlorpromazine

Mannerisms/posturing Hostility Suspiciousness Hallucinatory behavior

Clozapine Clozapine and chlorpromazine Clozapine and chlorpromazine Clozapine and chlorpromazine

Clozapine/<.001 Clozapine/<.001 Clozapine/<.001 Clozapine/<.001 Clozapine/<.001

Excitement

Clozapine and chlorpromazine Clozapine and chlorpromazine

Clozapine/<.001 Clozapine/<.001

Unusual

thought

Grandiosity

Week of Onset of Superior

Drug

Proved

Drug Activity}:

Faster§

1

Clozapine Clozapine Clozapine

Clozapine

Clozapine

BPRS

negative symptoms Emotional withdrawal Blunted affect

Clozapine Clozapine Clozapine

Disorientation

Clozapine

Uncooperativeness

Motor retardation

general symptoms Somatic concern

Clozapine/<.001 Clozapine/<.001 Clozapine/<.001 Clozapine/<.001 Clozapine/<.05

Clozapine Clozapine Clozapine Clozapine

BPRS

Anxiety Guilt Tension

Depressed mood BPRS total score CGI Scale NOSIE-30 factors Social competence Social interest Personal neatness

Irritability Manifest

psychosis

Motor retardation NOSIE total assets

Clozapine Clozapine and chlorpromazine Clozapine and chlorpromazine Clozapine and chlorpromazine Clozapine and chlorpromazine Clozapine and chlorpromazine Clozapine and chlorpromazine

Clozapine and chlorpromazine Clozapine Clozapine Clozapine and chlorpromazine Clozapine and chlorpromazine

Clozapine/<.01

Clozapine

Clozapine/<.001

Clozapine/<.001 Clozapine/<.001

Clozapine Clozapine

Clozapine/<.001 Clozapine/<.001 Clozapine/<.001 Clozapine/<.01 Clozapine/<.001 Clozapine/<.05 Clozapine/<.001

Clozapine Clozapine Clozapine

Clozapine Clozapine Clozapine and chlorpromazine *BPRS indicates Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; and NOSIE-30; 30-item Nurses' Observation Scale for Inpatient Evaluation. tSignificant pre-post change by within-group f tests. change by between-group analysis of covariance. ^Significantof pre-post ¿Analysis variance of rates of improvement.

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1.4

2

3

4

5

6

Week of Study Fig 3—Mean change from baseline in score on Clinical Global Impressions (CGI) Scale for patients treated with clozapine (solid

line, 126) or chlorpromazine and benztropine mesylate (broken line, .003; weeks 2 through 6, 139). For week 1, P<.001. =

=

=

2

3 Week of

.002; weeks 3 through 6, P<001.

(total BPRS) by treatment group were individually arrayed

for each of the 16 centers. The data were homogeneous: in 14 of 16 centers, greater improvement was found for clozapine-treated

patients. The interpretations allowed by the parametric data are limited by the fact that clinically unimportant changes in rating-scale

statistically significant if a large enough sample of patients is studied. The critical test from a clinical perspective is scores can

be

the extent to which a treatment produces a response; ie, is the patient believed to have

clinically meaningful truly benefited from the medication? This issue underscores the importance of the a

priori

improvement that provide the critical investigation. classified as having "improved" to a clinically

criteria for clinical

outcome measures in this

Patients

were

significant extent or not over the course of double-blind treatment. The a priori criteria for defining a patient as improved included a

reduction greater than 20% from baseline in the BPRS total score plus either a posttreatment CGI Scale score of 3 (mild) or less or a posttreatment BPRS total score of 35 or lower. When these

criteria

were

applied

to all

patients who completed

=

3 Week of

4

Study

Fig 6.—Mean change from baseline in score on total patient assets item from Nurses' Observation Scale for Inpatient Evaluation (NOSIE) for patients treated with clozapine (solid line, 126) or chlorpromazine and benztropine mesylate (broken line, 139). For week 1, .356, weeks 2 through 6, P<.001. =

=

=

in 16 of 27 tests performed; this was never true for chlorpromazine (Table 5). To test for differential effects among centers, mean improvement scores

=

=

2

=

6

=

4

mesylate (broken line, n=139). For week 1, P<.544; week 2,

5

Fig 4.—Mean change from baseline in cluster score on four key items from Brief Psychiatric Rating Scale (BPRS) for patients treated with clozapine (solid line, n 126) or chlorpromazine and .011 ; benztropine mesylate (broken line, 139). For week 1, week 2, .001; weeks 3 through 6, P<.001.

Study

Fig 5.—Mean change from baseline in score on anergia item from Brief Psychiatric Rating Scale (BPRS) for patients treated with clozapine (solid line, 125) or chlorpromazine and benztropine =

4 12 3 Week of Study

0

at least one

week of the double-blind phase of treatment, it was found that only 4% of patients treated with chlorpromazine and benztropine had improved, while 30% of clozapine-treated patients had im¬ proved (P<.001) (Table 6). These results provide the most cogent evidence of clozapine's superiority. Evaluation of

Safety

Comparative incidences of adverse reactions (the number of patients reporting a new or worsened effect one or more times during double-blind treatment) are presented in Table 7 for the more frequent adverse reactions. This table is ordered by descend¬ ing frequency of occurrence for patients receiving clozapine compared with chlorpromazine and benztropine. Extrapyramidal side effects during the chlorpromazine and haloperidol treatment periods were largely masked by the pro¬ phylactic istration of benztropine. Rating-scale evidence of relative extrapyramidal side effects of the three active drug conditions (clozapine, chlorpromazine and benztropine, and halo¬ peridol and benztropine) was provided by weekly assessments using the Simpson-Angus Scale for Extrapyramidal Side Effects. Figure 7 provides mean ratings for these patients throughout the entire course of study, showing a rise in such symptoms (excluding

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Table 6.—No. of Patients Whose Condition

Drug Clozapine Chlorpromazine Total

Improved*

No. (%) of Patients Whose All Others, Condition Improved No. (%) 38 5

43

(30) (4) (16)

Table 7.—Most

Total,

No. (%) 126 (100)

Adverse Reaction

Drowsiness

Tachycardia Constipation

The categorization is based on the last patient. P<.001 by two-tailed Fisher's exact test.

Dizziness

Hypotension Fever (hyperthermia)

salivation) during the haloperidol and benztropine phase followed by a decrease during washout, with little subsequent benefit for patients treated with chlorpromazine and benztropine. However,

Salivation

Hypertension Headache

clozapine-treated patients continued to improve further until the end of the six-week study period. This improvement was statisti¬

Nausea/vomiting Dry mouth

cally significant at weeks 4, 5, and 6. Although the impact of these treatments on tardive dyskinesia

*Based

not a focus of this study, changes in scores on the AIMS were also examined. The clozapine-treated patients had a significantly higher mean baseline score on the AIMS (8.8 vs 6.5). Analyses of

was

clozapine-treated patients to im¬ 09 by two-tailed test). Dry mouth was more prominent in patients receiving chlorprom¬ azine and benztropine (20%), while salivation was more character¬ istic of patients receiving clozapine (13%). In the cardiovascular area, hypotensive reactions occurred in 38% of patients treated with chlorpromazine and benztropine compared with 13% of clozapine-treated patients. However, tachycardia was more prev¬ alent in clozapine-treated patients (17%). In of miscellaneous adverse effects, benign temperature elevations not associated with laboratory test abnormalities were more frequent in clozapine-treated patients (13%). Three cases of hepatic enzyme elevations were judged to be clinically significant in the clozapine group compared with one in the chlorpromazine group. There were no reports of agranulocytosis in this cohort. covariance showed a trend for prove more on this measure (P

Clozapine (n 126), No. (%) of

Chlorpromazine (n 142), No. (%) of

=

(70) 136 (96) 141 (100) 224 (84) 267 (100) evaluation completed for each 88

Frequent Adverse Reactions

on

=

Patients 26 (21) 21 (17) 20 (16) 18 (14) 16 (13)

Patients 18 (13) 16 (11)

(12) 23 (16) 54 (38) 6 (4) 2 (1) 7 (5) 14 (10) 17 (12) 28 (20) 17

16(13) 17 (13) 15 (12) 13 (10) 12 (10) 6 (5)

.098 .218 .380 .735 <.001 .014

<.001 .045 .999 .560 <.001

two-tailed Fisher's exact test.

=

.

(The

cases

that occurred in the United States

were

among "humanitar¬

individuals being treated according to an open-label ian" protocol.) The two treatments did not differ in the proportion of patients who experienced a drop in total white blood cell count below 3.9xl09/L (4.9% for clozapine and 3.3% for chlorpromazine). Thirteen percent of the clozapine-treated patients experienced a drop in neutrophils to below 0.50 of the total white blood cells compared with 20% of the patients receiving chlorpromazine. COMMENT

The results of this 16-center investigation of 319 patients have implications for the understanding of chronic schizo¬

phrenia both methodologically and clinically. From the viewpoint of methodology, this study suggests some valid¬ ity for a set of historical and prospective criteria defining refractoriness to treatment in schizophrenia—the condi¬ tions of fewer than 2% of patients selected improved after six weeks of treatment with haloperidol at daily dosages averaging over 60 mg/d at peak, and the conditions of fewer than 5% of patients treated with chlorpromazine improved with a peak dosage averaging 1200 mg/d. At several of the 16 collaborating sites, many patients who were initially to be refractory to treatment had not in fact received adequate trials of three different neuroleptic drugs in recent years, and some patients did respond to a change in pharmacologie treatment; those patients became ineligible for the trial. Obviously, the clinician treating the

judged

nonresponsive patient must strive for a balanced approach, avoiding both therapeutic nihilism and overzealous utiliza¬ tion of every imaginable pharmacologie or somatic treat¬ ment. Even patients who are apparently hopelessly ill deserve periodic réévaluation of ongoing pharmacotherapy and consideration of shifts to alternative treatments.

èLU ¿O

O)

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ri«

4-

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1-.1.1 4..1.Ì..I -4-

8 2 $<

ß& CO CO CD O

S«co 1 -I-1-1-1-1-1-(-1-1-1-1-1-

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Study Period scores 7.—Mean total Fig (lower scores are better) on SimpsonAngus Scale for Extrapyramidal Side Effects, excluding salivation, for patients treated with clozapine (solid line, 116) or chlorprom¬ =

azine and benztropine mesylate (broken line, 125) during period 2 (haloperidol and benztropine mesylate), period 3 (placebo wash¬ out phase), period 4 (double-blind phase), and period 5 (placebo =

washout

phase).

The response to clozapine demonstrates that this sub¬ group of severely ill schizophrenic patients, previously considered by many to be beyond the reach of conventional therapy, does remain capable of experiencing substantial medication response. This further argues for the impor¬ tance and feasibility of conducting carefully controlled, large-scale treatment trials in this patient population. We believe that this is the first time any specific antipsy¬ chotic drug has been shown to be superior to another in a well-defined group of treatment-resistant patients who are unresponsive to haloperidol and other traditional neurolep¬ tics. In addition, given the use of prophylactic benztropine in the chlorpromazine group, the evident superiority of clozapine cannot be attributed simply to a reduction in or lack of extrapyramidal side effects. Much consideration went into the choice of haloperidol and chlorpromazine in this study design. Both drugs are

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among the most widely used antipsychotic agents, and they represent the high- and low-potency ends of the spectrum. Chlorpromazine was believed to be the best comparison drug for the double-blind phase, because, in

combination with prophylactic antiparkinsonian medica¬ tion, its adverse-effect profile would be more similar to that of clozapine than the adverse-effect profile of haloper¬ idol. Undoubtedly, one or both of these medications might have failed in the past in some patients included in this study, but this in no way diminishes the importance of clozapine's superiority in this design, since the intent was to identify patients who were unresponsive to available compounds. Much deliberation also went into the decision to include prophylactic benztropine along with chlorpromazine and haloperidol. We believed that the potential advantages in enhancing the double-blind character of the study (by reducing the possibility of extrapyramidal side effects) argued for the use of benztropine, given that clozapine is relatively free from extrapyramidal side effects. The superiority of clozapine in this clinical trial is impressive both because of the rigorous manner in which

patients were defined and selected and because the supe¬ riority was consistent across such a full range of items and factors

the BPRS

well as the CGI Scale. These findings were confirmed and extended by the nurses' ratings. This superiority was not confined to a particular aspect or dimension of psychopathologic characteristics (eg, hallucinations, delusions, or suspiciousness) but in¬ volved all the major psychotic signs and symptoms associ¬ on

as

ated with this patient group, including such negative items as blunted affect, emotional withdrawal, apathy, and disorientation. It might be suggested that the antimuscarinic potency of combined chlorpromazine and benztropine pro¬ duced a cognitive dysfunction leading to disorientation or a worsening of some psychotic signs; however, the superi¬ ority of clozapine on the disorientation item resulted from improvement among patients receiving clozapine, not from a worsening among patients treated with chlorpromazine and benztropine. Given these findings, there is an obvious need for further research to explore the mechanisms by which clozapine accomplishes its clinical effects and to identify possible predictors that might help to select, if possible, the subgroup of patients most likely to benefit. Since drug refractoriness probably occurs for various reasons, how¬ ever, even this carefully chosen sample of schizophrenic patients remains heterogeneous. There were no reports of agranulocytosis during this relatively brief study. At present, however, we believe that the apparently increased comparative risk of agranulocy¬ tosis requires that the use of clozapine be limited to selected treatment-resistant patients for whom the potential ben¬ efits are judged to outweigh the risks. At the same time, research is under way that attempts to identify risk factors that might predispose certain individuals to the development of hematopoeitic suppres¬ sion. Careful, regular monitoring of blood cell counts is necessary in patients receiving clozapine, and only those

individuals who demonstrate significant benefits within the first four to six weeks should enter the period during which there is increased risk for the development of

agranulocytosis (between the sixth and 18th weeks of treatment). With prompt drug discontinuation and proper medical treatment, this problem appears to be reversible

within about two weeks, with no physical sequelae. For individuals suffering from treatment-resistant schizophre¬ nia, the availability of clozapine, a potentially helpful

our view, a useful therapeutic advance. If small proportion of these patients can go on to adjust to life in the community, with the associated reduced need for long-term institutionalization, this has signifi¬ cance for public health and health financing.

treatment, is, in even a

This

study was ed by grants from the Sandoz Research Institute,

East Hanover, NJ. Dr Kane is also ed by grant MH41960 from the Public Health Service, and Dr Meltzer is also ed by grants MH41954 and MH 47808 from the Public Health Service. Statistical analyses were performed by John Patin, MS.

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ed From: http://archpsyc.jamanetwork.com/ by a Princeton University on 09/06/2013