Original Articles
`
`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 Clozarii Collaborative Study Group
`
`0 The treatment of schizophrenic patients who fall to re-
`spond to adequate Male or neuroieptlca la a major challenge.
`Clozaplne, an atypical antlpeychotic drug, hea long been of
`ecientitlc Interact. but he clinical development hae been
`delayed becauee of an aeeoclated rlek of egranulocytoele.
`This report deecrlbee a multioenter clinical trial to aeeeee
`ciozapine’a etticacy in the treatment of patienta who are
`refractory to neuroieptica. DSM-m schizophrenic: who had
`tailed to respond to at
`leeet three different neuroleptice
`underwent a proapectlve, single-blind trial of haioperldol
`(mean dosage, 61:14 mold) toralx weeka. Patienta whoae
`condition remained unimproved were then randomly aa-
`aigned,
`In a double-blind manner,
`to ciozaplne (up to
`900 mg/d) or chlorpromazlne (up to 1800 high!) for air: weeks.
`“no hundred sixty-eight patienta were entered in the double-
`bllnd comparieon. When a priorl criteria were used, 30% ot the
`clozapine-treated patients were categorized ae reapendere
`compared with 4% or chlorpromazlne-treated patients. Cloaa-
`pine produced aignltlcantly greater Improvement on the Brie!
`Paychlatric Rating Scale, Clinical Global Impreaeion Scale,
`and Nureea’ Observation Scale tor Inpatient Evaluation; thla
`Improvement included "negative" ea well ea positive symptom
`ereae. Although no caeee at agranutocytoale occurred during
`thie relatively brief study, In our view, the apparently lncreaaed
`comparative riak requiree that the use at clozapine be limited
`to aelected treatment-naiatant patienta.
`(Arch Gen Paychlatry 1980;45:789-796)
`
`he efficacy 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.u 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.‘ The treatment of this
`
`Accepted for publication March 9, 1988.
`From the Department of Psychiatry. Hillside Hospital—Long island
`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 Ruearch, the Sandi): Research Institute, East
`Hanover, NJ (Drs Honigfeld and Singer); the Department of Psychiatry,
`University of Medicine and Dentistry of NewJersey-Robert Wood Johnson
`Medical School, Piscataway (Dr Singer); and the Department of Psychiatry.
`Case Western Reserve School of Medicine. Cleveland (Dr Meltzer). The
`members 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, Rl; Jan Volavka, MD,
`New York; John Rotrosen, MD, New York; Donald Seidel. MD, San Antonio,
`Tex; Larry Ereshefsky. PharmD, San Antonio, 'Dex; Jerome Costa. MD.
`Norwalk, Calif; John Herrera. PhD, Norwalk, Calif; Samuel Gershon, MD,
`Detroit; Neil Harman, MD. Los Angeles; George Simpson, MD, Philadel
`pbia; Richard Abrams, MD. Chicago: Benjamin Graber, MD. Omaha; and
`Martha Martin, MD. Washington. DC.
`Read in part before the 140th Annual Meeting ofthe American Psychiatric
`Association, Chicago, May 14, 1987.
`Reprint requests to Department of Psychiatry, Hillside Hospital, Long
`Island Jewiah 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 200 000 such patients
`Data from maintenance medication trials indicate that
`even among patients initially responsive to antipsychotic
`drugs, 20% to 30% may relapse during the first year or
`two of maintenance drug treatment.3 A proportion of these
`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 p 865.
`
`The recognition that some patients do not. benefit from
`typical neuroleptics has resulted in research along two
`fronts: (1) to identify phenomenologic, 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,” is, associated with short-term extrapyram-
`idal side effects (including dystonias) and share the longer-
`term 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.”
`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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`Ciozapine—Kane et al
`
`789
`
`Exhbil 2046
`Slaybadr v. Sumitomo
`lPR2020—01053
`
`

`

`and validated classification. In general, this term has been
`used to describe drugs that appear to have limited short-
`term 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 (cg, clozapine).
`Clozapine
`(8-chloro-l1-(4-methyl-l-piperazinyl)-5H-di—
`benzo[b,e][l,4]diazepine) belongs to the chemical class of
`dibenzodiazepines, related chemically to the antipsychotic
`dibenzoxazepine drug loxapine. However, its pharmaco-
`logic characteristics are different from those of loxapine.
`Clozapine has serotonin (St), adrenergic (m). and hista-
`minergic (H,) blocking activity. It is also a potent musca—
`rinic acetylcholine receptor antagonist.“ Its binding to D,
`and Da receptors is relatively weak and more equivalent
`than that of most typical neuroleptics.‘ 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.“
`Unlike “typical" neuroleptics, clozapine produces only
`slight, transient elevations in serum prolactin levels in
`patients, even when moderate to high doses are given.'°~”
`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 administered on a short-
`term basis, and although akinesia or akathisia develops in
`some patients, the incidence appears to be low. "
`Thirteen cases of “dyskinesia” were reported from a
`sample of 12 000 patients in Europe, but the nature of these
`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.ls One case of apparent
`neuroleptic malignant syndrome has been reported in a
`patient receiving clozapine and lithium.“
`Previous controlled clinical trials have been conducted
`with clozapine. Claghorn et a!“ 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
`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
`i‘erner‘“ 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
`six weeks was only 360 mg compared with 310 mg of
`clozapine.
`In a similar
`twecenter European study,“
`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 ofinadequate 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
`infect.ion)."-m Worldwide experience now reveals over 100
`
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`cases 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 hematologic monitoring,
`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 long-
`term 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
`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
`Study Design
`
`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-lllm criteria for schimphrc~
`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 doaages equivalent to or greater
`than 1000 mgld of chlorpromazine for a period of six weeks. each
`without significant symptomatic relief. and (2) no [rewind 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 “Silent 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 halopcridol
`(up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a
`periixl 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 CG! Scale
`
`Clozapine—Kane et al
`
`

`

`rating of mildly ill (53) 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.
`Patients who met the multiple psychiatric symptom criteria
`were then randomly assigned to a six-week double-blind treatment
`trial with either clozapine (up to 900 mg/d) or chlorpromazine and
`benztropine mesylate (up to 1800 mg/d of chlorpromazinc hydro-
`chloride and up to 6 mg/d of benztropine mesylate). All medications
`were coded and administered 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 mgr'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 behavior-
`ally 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 supporting 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.
`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
`Patients
`319
`305
`272
`268
`
`Period No.
`1
`2
`3
`4
`
`Description
`Baseline placebo
`Haloperidol
`Placebo washout
`Double-blind
`
`Duration, d
`514
`542
`57
`$42
`
`Of the patients who entered period 4, 126 were randomized to
`clozapine, and 142 were randomized to chlorpromzine and benz-
`tropine meaylate.
`
`Evaluation of Efficacy
`
`Patients were interviewed by physicians or psychologists weekly
`during the course ofdouble-blind treatment, and thelrassessments
`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 terms of
`ward behavior by the nursing staff, using the 30-item Nurses‘
`Observation Scale for Inpatient Evaluation MOSHE-30).“
`Evaluation of 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 Simpson-
`Angus Scale for Extrapyramidal Side Effects” and the Abnormal
`Involuntary Movements Scale (AIMS).‘a
`SUBJECTS
`
`Three hundred nineteen inpatients entered this study; their
`demographic and 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 Administration
`
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`
`
`Table 1.—Sex, Race, and Diagnosis
`of Patients Entering the Study (N = 319)
`
`No. (96)
`of Patient:
`Characteristic
`Sex
`
`
`M
`‘
`256 (80)
`
`
`F
`53 (20)
`Race
`
`
`White
`
`
`Black
`
`
`Hispanic
`Oriental
`
`
`Other
`
`
`Diagnosis (DSM-Iil schizophrenic subtypes)
`160 (50)
`Undifferentiated
`
`
`107 (34)
`Paranoid
`
`
`25 (6)
`Disorganized
`11 (a)
`Residual
`
`
`10 (3)
`Unspecified
`
`6 (2)
`Catalonia
`
`
`
`208 (65)
`74 (23)
`31 (10)
`2 (1)
`4 (1)
`
`medical centers among the participating institutions and possibly
`also because women were less likely to have received 100ng
`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 NOSlE-SO.
`Wenty-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)
`’leo hundred sixty-eight patients entered the critical clozapine
`vs chlorpromazine and bcnztropine 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 “undifferentiaued”
`category and about one third were in the “paranoid" category.
`Horn the point of view of psychiatric history, the subgroups did
`not differ in any signifith 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
`cloupine- 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%),
`
`CIozapine—Kane et al
`
`791
`
`

`

`Table 2——General Characteristics oi Patients Entering the Study (N: 319)
`
`Characteristic
`
`350
`
`Meen(SD)
`35 7 (8.87)
`
`Range
`20-59
`
`
`Patiente'
`
`
`Age,y
`318
`
`Duration oi current
`
`212.0
`314.7 (316.76)
`5-1976
`symptoms. wk
`307
`
`
`20.4 (4.61)
`Age at first hospitalization y
`
`
`
`9.2 (7.25)
`No. oi hospitalizations
`
`
`Duration of current
`
`hospitalization. wk
`
` 215.9 (321.41)
`
`'The number at patients varies because of ‘mlssing" or "unknown" data elements
`
`
`
`Table 3. - Patient Classification After Treatment With
`Haloperldol and Benztroplne
`
`
`
`No. (96) of
`Patient Cleeeltlcetlon
`Patients (n = 305)
`
`Haloperldoi responder
`5 (1.6)
`
`Haloperidol nonresponder
`248 (81.3)
`
`Terminated earty
`52 (17.0)
`
`intolerant ol heioperidol
`22 (7.2)
`
`Unoooperetive
`15 (4.9)
`Protocol violated
`4 (1.3)
`
`Physical conditions not related to drug
`5 (re)
`
`Other (cg. seizure.
`
`electrocardiogram
`
`
`5 (2.0)
`changes. withdrew consent)
`
`
`
`
`
`
`
`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.
`
`Cllnlcel Etticacy
`
`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
`to treat.” analysis“ was carried out for all patients who had 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
`ofstudy. Similarly, four “positive” BPRS items determined a priori
`to be central to the assessment of therapeutic response (conceptual
`disorganization, hallucinatory behavior, suspiciousnese. 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 “anemia" 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 NOSE-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
`
`1400
`
`~
`
`1200
`
`MeanDailyDose.mg
`
`as
`
`§
`
`AO0
`
`/
`
`\\
`
`\
`
`\
`
`Week 01 Study
`Fig 1.—Mean daily doses of clozapine (solid line) and chlorprom-
`azine (broken line) durlng double-blind phase of study (period 4)
`For clozapine. at week 1 . n = 126; week 2. n = 126; week 3. n =122;
`week 4, n=120; week 5. n= 119; and week 6. n=116. For
`chlorpromazlne. at week 1. n =141; week 2. n=140; week 3,
`n= 137; week 4. n: 133: week 5. n=128; and week 6. n= 125.
`
`20
`
`
`.a U!
`
`
`.4 O
`
`
`___J...—
`UI
`
`
`0
`
`
`Total
`
`ScoreonBPRS.MeanChangeFromBaseline
`
`4
`
`5
`
`6
`
`0
`
`1
`
`2
`
`3
`Week of Study
`Fig 2.—Mean change lrom baseline in total score on Brief Psychi-
`atric Rating Scale (BPFIS) (or patients treated with clozapine (solid
`line, n = 126) or chlorpromszine and benztropine mesylate (broken
`line. n - 139). P<.001 during each week at study.
`
`changes on the composite score, “total patient assets.” are pre-
`sented in 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
`
`792
`
`Arch Gen Psychiatry—Vol 45. Sept 1988
`
`Clozaplne—Kene et al
`
`Downloaded From: by .llll Strand on 08/22/2018
`
`

`

`Table 4.—Comparative Drug Efficacy and Neurologic Ratings
`
`score
`No-Talled
`(Mean 1 SD)
`No. of W Analysis of
`Patients?
`Baeellne
`End Point
`Covariance, P
`
`Chiorpromazine
`
`BPRS total score
`
`BPRS cluster oi four key items
`
`AIMS total score
`
`Simpson-Angus Scale for Extrapyramidel Side Eilects
`
`Clozaplne
`Chlorpromazlne
`Clozaplne
`Chlorprornazine
`Clozeplne
`Chlorpromazine
`Clozapine
`Chlorpromazine
`Clozapine
`
`°BPRS indicates Brief Psychiatric Rating Scale: CGl, Clinical Global Impressions; and AIMS, Abnormal involuntary Movements Scale.
`TThree patients were excluded lrom these analyses One patient did not undergo rating alter randomization. and one study site had only two patients. both
`otwhom received chlorpromazlne.
`
`Table 5.--Comparatlve Efficacy oi Clozapine vs Chlorpromazlne and Benztropine
`
`
`
`
`
`
`
`
`Drug“)
`
`Effective?
`
`Clozapine and chlorpromazlne
`Clozapine
`Clozapine and chlorpromazine
`Clozapine and chlororomazlne
`Clozapine and chlorcromazine
`Clozapine and chlorpromazine
`Clozapine and chlorpromezine
`Clozapine
`
`Drug Proved
`Superior/Pt
`
`Onset of Superior
`Drug Activity:
`
`Clozapina/<.001
`Ciozapine/<.001
`Ctozaptnel<.001
`Guanine/«1.001
`Clozapine/<.001
`Clozapinel<.001
`Clozgpine/<.001
`
`1
`1
`1
`2
`2
`3
`t
`
`Drug
`Proved
`Faeter§
`
`Clozapina
`Clozapino
`Clozapine
`
`. .
`.
`Clozapine
`
`
`
`
`
`Clozapine
`Clozapine
`Clozapine
`Clozapine
`
`Clozapino/<.001
`Ctazapine/<.001
`Clozapinel<.oot
`Clozapinal<.001
`
`.
`.
`.
`Clozapinel<.05
`
`2
`1
`3
`2
`6
`
`Clozapina
`Ciozapina
`Ciozapine
`Clozaplna
`
`Criterion
`Variable‘
`BPRS positive symptoms
`Conceptual disorganization
`Manneriamalpoaturing
`Hostility
`Suepiciousness
`Hallucinatory behavior
`Excitement
`Unusual thought
`Grandioslty
`BPRS negative symptoms
`Emotional withdrawal
`Uncooporativoness
`Stunted altect
`Diaorientation
`Motor retardation
`BPRS general symptoms
`Somatic concern
`Anxiety
`Guilt
`Tension
`Depressed mood
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Clozaplne
`Clozaplna and chlorpromazine
`Clozapine and chlorpromazine
`Clozapine and chlorpromazine
`Clozaptne and chtorpromazine
`
`Ciozapinel< .01
`
`Clozapmek.7151”"
`.
`.
`.
`
`6
`
`1
`.
`
`.
`
`.
`
`Ctozaplna
`
`.
`
`.
`
`.
`
`Ciozapine and chlorpromazine
`Clozapine and chlorpromazina
`
`Clozapinel<.001
`Clozaplnal<.001
`
`1
`t
`
`- Clozapine
`.-Clozaplne
`
`I
`
`h H W
`
`‘ ‘
`
`Cloaapine
`Clozaptne
`Clozapéne
`
`2
`1
`2
`2
`2
`2
`
`
`
`
`
`
`
`
`BPRS total score
`CGl Scale
`NOSlE-SO tactors
`Social competence
`Clozepine and chlorprornazine
`Cleaning/(.001
`Social interest
`Clozapine
`Clozaplnel<.001
`Personal neaineas
`Clozapina
`Clozapinol<.001
`Irritability
`Clozapine and chlorprornazine
`Clozapinel< .01
`Manifest psychosis
`Clozapine and ohlorpromazine
`Clozapinel< .001
`Motor retardation
`.
`.
`.
`Genome/(.05
`Clozaplne
`
`
`
`NOSlE total assets
`Clozapine and chlorpromazlne
`Clozapinel<4001
`Clozapine
`
`
`‘BPRS indicates Briet Psychiatric Hating Scale: CGI. Clinical Global impression: and NOSlE-SO; 30-itom Nurses' Observation Scale tor Inpatient Evaluation.
`fSignillcant pre~poat change by withinrgroup ttastei
`t$ignltlcant prevpost change by between-group analysis of covariance.
`§Analysie oi variance at rates at improvement.
`
`Arch Gen Psychiatry—Vol 45. Sept 1988
`
`Downloaded From: h) .llll Strand on 08/22/2018
`
`Ciozaplne—Kane at al
`
`796
`
`

`

`.a I;
`
`rI
`
`s “2
`g 1.0
`g5 0811
`is '
`i
`To 0 0.6
`8 s_
`86
`g 0.2O
`
`0.4
`
`’02
`
`0
`
`l
`
`2
`
`3
`WeekofStudy
`Fig 3,—Mean change from baseline in score on Clinical Global
`impressions (CGI) Scale for patients treated with clozaptne (solid
`line. n = 126) or chlorprornazine and benztropine mesylate (broken
`line,
`n - 139). For week 1, Pecos; weeks 2 through 6,
`P<.001.
`
`
`
`
`l
`i
`i
`I
`
`'
`i
`
`,1.
`
`Li
`
`0:
`
`
`
` .b
`MeanChangeFromBaseline N
`
`
`
`
`
`ClusterScoreonFourKeyitemsFromBPFlS.
`
`WeekofStudy
`Fig 4.—-Mean change from baseline in cluster score on four key
`items lrorn Brief Psychiatric Rating Scale (8988) for patients
`treated with clozapine (solid line, n= 126) or chlorpromazlne and
`benztropine mesylate (broken line, n=139l For week 1. P: .011;
`week 2, P= .001; weeks 3 through 6, P<.001.
`
`4
`
`5
`
`6
`
`FromBaseline
`Score.MeanChange
`BPRSAnergra
`
`.4+_il. |
`
`l
`
`
`
`NOSIETotalPatientAssetsScore,
`
`
`
`
`
`M
`
`
`
`MeanChangeFromBaseline
`
`l
`
`Week of Study
`Fig 5.—Mean change from baseline in score on anergia item lrom
`Brief Psychiatric Plating Scale (BPRS) tor patients treated with
`clozapine (solid line, n w 125) or chlorpromazine and benztropine
`mesylate (broken line, n=139). For week 1, P<.544; week 2,
`P = .002: weeks 3 through 6. P<.001.
`
`Weekol Study
`Fig 6.-—Mean change from baseline in score on total patient assets
`item lrorn Nurses‘ Observation Scale for Inpatient Evaluation
`(NOSIE) for patients treated with clozapine (solid line, n=126) or
`chiorpromazine and benztropine mesylate (broken line. n:: 139).
`For week 1. P = .358. 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 (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
`scores can be statistically significant if a large enough sample of
`patients is studied. The critical test from a clinical perspective is
`the extent to which a treatment produces a clinically meaningful
`response; ie, is the patient believed to have truly benefited from
`the medication? This issue underscores the importance of the a
`priori criteria for clinical improvement that provide the critical
`outcome measures in this investigation.
`Patients were classified as having “improved” to a clinically
`significant exte