The NEW ENGLAND
`
`JOURNAL of MEDICINE
`
`ESTABLISHED IN 1812
`
`SEPTEMBER 22. 2005
`
`VOLJIS? No.12
`
`Effectiveness ofAntipsychotic Drugs in Patients
`with Chronic Schizophrenia
`
`Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H.,joseph P. McEvoy, M.D., Marvin S. Swartz, M.D.,
`Robert A. Rosenheck, M.D.. Diana 0. Perkins. M.D.. M.P.H., Richard S.E. Keefe, Ph.D.,
`Sonia M. Davis. Dr.P.H., Clarence E. Davis, Ph.D.. Barry D. LebOWitz, Ph.D.,joanne Severe, M5,,
`andjohn K. Hsiao. M.D., For the Clinical Antipsychotic Trials oflntervention Eftectiveness (CATlEl Investigators’”
`
`
`ABSTRACT
`
`nc xenou u n
`
`The relative effectiveness ofsccond-generation (atypical) antipsychotic drugs as com-
`pared with that ofolder agents has been incompletely addressed, though newer agents
`are currently used far more commonly. We compared a first-generation antipsychotic,
`perphenazine, with several newer drugs in a double—blind study.
`M er n cos
`
`A total of 1493 patients with schizophrenia were recruited at 57 US. sites and random-
`ly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per
`day). quetiapine (200 to 800 mg per day). or risperidone (1.5 to 6.0 mg per day] for up
`to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the
`Food and Drug Administration. The primary aim was to delineate differences in the
`overall efl‘ectiveness of these five treatments.
`RESULTS
`
`Overall, 74 percent of patients discontinued the study medication before 18 months
`(1061 OFthe 1432 patients who received at least one dose): 64 percent of those assigned
`to olanzapine, 75 percent of those assigned to perphenazine. 82 percent of those as-
`signed to quetiapine, 74 percent of those assigned to risperidone. and 79 percent of
`those assigned to ziprasidone. The time to the discontinuation oftreatment For any
`cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001)
`or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone
`(P=0.028) group. The times to discontinuation because ofintolerable side effects were
`similar among the groups, but the rates differed (P=0.04); olanzapine was associated
`with more discontinuation for weight gain or metabolic effects, and perphenazine
`was associated with more discontinuation For extrapyramidal effects.
`eon ct u s IO us
`
`The majority ofpatients in each group discontinued their assigned treatment owing to
`inefficacy or intolerable side effects or for other reasons. Olanzapine was the most ef-
`fective in terms ofthe rates ofdiscontinuation, and the efficacy ofthe conventional anti-
`psychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and
`ziprasidone. Olanzapine was associated with greater weight gain and increases in mea-
`sures ofglucose and lipid metabolism.
`
`From the Department ofPsychiatry. College
`of Physicians and Surgeons. Columbia Uni-
`versity. New York State Psychiatric Institute,
`New York (j.A.L.); the Department ofPsy»
`(hiatry, School of Medicine [T,S.S.. D.O.P.).
`and the Department ofBiostatistics, School
`of Public Health (S.M.D.. CE.D.). Universi-
`tyofNorth Carolina at Chapel Hill. Chapel
`Hill. Quintiles. Research Triangle Park. NC.
`(S.M.D.). the Depanment ofBiological Psy-
`ehiatry. John Umstead Hospkal. Butner.
`N.C. 0,P.M.); the Department ofPsychia-
`try and Behavioral Sciences. Duke Univer-
`sity Medical Center, Durham. NC. 0PM”
`M.S.S.. R.S.EI(.): the Department of Psy-
`chiatry. Yale University School of Medicine.
`New Haven. Conn. (RAIL); and the Div'r
`sion ofServices and Intervention Research.
`National Institute of Mental Health. Na-
`tional Institutes of Health, Bethesda. Md.
`(BD.LJ.S.,].K.H.). Address reprint requests
`to Dr. Lieberman at the Department of
`Psychiatry. College of Physicrans and Sur-
`geons. Columbia University. NewYork State
`Psychiatric Institute. 1051 Riverside On,
`New York. NY 10032. or at jlieberman®
`columbiaedu.
`
`*The CATlE investigators are listed in the
`Appendix.
`
`N Enzl] Med 2005;353:120923.
`Copyright 0 2005 Massachuwm Medical Soriny
`
`N ENCLJ men 353:1: www.~e;u.oac
`
`SEPTEMBER 22. 2005
`
`1209
`
`The New England Joumal of Medicine
`Downloaded from nejm,org on September [4. 2018. For personal use only. No other uses Without permission
`Copyright "O 2005 Massachusetts Medical Society. All rights reserved
`
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`Slayback v. Sumitomo
`|PR2020—01053
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`IPR2020-01053
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`

`

`Till NEW ENGLAND IOURNAL ufMEDlClNE
`
`NTI PSYCHOTIC DRUGS HAVE BECOM E
`
`A thecornerstone oftreatment forschizo-
`
`phrenia. The first-generation “conven-
`tional" antipsychotic drugs are high-affinity an-
`tagonists ofdopamine D2 receptors that are most
`effective against psychotic symptoms but have high
`rates ofneurologic side effects, such as extrapyrami-
`dal signs and tardive dyskinesia.1 The introduction
`of second-generation, or “atypical,” antipsychotic
`drugs promised enhanced efficacy and safety.z The
`atypical agents differ phannacologically from previ-
`ous antipsychotic agents in their lower affinity for
`dopamine D2 receptors and greater affinities for
`other neuroreceptors, including those for serotonin
`(S-hydroxytryptaminem. 2A. 20 3. 6, and 7) and nor-
`epinephrine (0:1 and all).l
`Although studies indicated that the atypical
`drugs are similar to the conventional drugs in reduc-
`ing psychotic symptoms and produce few neuro-
`logic effects, the evidence oftheir superior efficacy
`has been neither consistent nor robust,3‘8 with the
`exception of clozapine, which repeatedly has been
`elfective in patients whose condition is refractory to
`treatrnentwith other types ofagents but has severe
`side effects that limit its use."‘11 The newer agents
`appear more efficacious than conventional drugs
`in reducing negative symptoms (e.g., lack of emo-
`tion, interest, and expression] , possiblyowing to the
`absence ofextrapyramidal symptomsnorother sec-
`ondary causes ofnegative symptoms (e.g., depres-
`sion) rather than to direct therapeutic effects.13
`The results ofstudies of the efiects oftreatment on
`
`cognitive impairment and mood symptoms have
`been inconclusive. 14‘ 15 The ability ofatypical agents
`to prevent relapse and their effects on social and
`vocational functioning, quality of life, long-term
`outcome. and the caregivers‘ burden have been in-
`completely exploredfi-lz‘w
`The safety advantages ofthe atypical drugs have
`been questioned because oftheir propensity to in-
`duce weight gain” and alter glucose and lipid me-
`tabolists‘ 1‘9 Nevertheless, these medications are
`widely used and have a 90 percent market share in
`the United States,20‘21 resulting in burgeoning
`costs. In the wake of this trend, questions have
`been raised about the clinical advantages and cost
`effectiveness of the atypical drugs. We report the
`primary outcomes ofa double-blind, active-co ntrol
`clinical trial sponsored by the National Institute of
`Mental Health (NIMH) that was designed to com-
`pare the effectiveness ofatypical and conventional
`antipsychotic drugsfi-23
`
`METHODS
`
`sruov snrmc AND DESIGN
`
`The Clinical Antipsychotic Trials of Intervention
`Effectiveness (CATIE) study was initiated by the
`NIMH to compare the effectiveness ofantipsychotic
`drugs. Its rationale. design, and methods have been
`described previously.24'18 The protocol was made
`available to the public for comment, and a commit-
`tee ofscientific experts, health care administrators,
`and consumer advocates critiqued the studyunder
`the auspices ofthe NIMH. The study was conduct-
`ed between Ianuary 2001 and December 2004 at 57
`clinical sites in the United States (16 university clin-
`ics, 10 state mental health agencies, 7 Veterans Af-
`fairs medical centers, 6 private nonprofit agencies,
`4 private-practice sites, and 14 mixed-system sites).
`Patients were initially randomly assigned to receive
`olanzapine, perphenazine, quetiapine, or risperi-
`done under double-blind conditions and followed
`
`for up to 18 months or until treatmentwas discon-
`tinued for any reason {phase 1). (Ziprasidone was
`approved for use by the Food and Drug Adminis-
`tration [FDA] after the study began and was added
`to the study in January 2002 in the form ofan iden-
`tical-appearing capsule containing 40 mg.) Patients
`whose assigned treatment was discontinued could
`receive other treatments in phases 2 and 3.14 The
`present report is limited to phase 1 results.
`
`PARTICIPANTS
`
`Eligible patients were 18 to 65 years ofage; had re-
`ceived a diagnosis ofschizophrenia, as determined
`on the basis ofthe Structured Clinical Interview of
`
`the Diagnosiitand Statistical Manual ofMental Disorders,
`fourth edition; and were able to take oral antipsy-
`chotic medication, as determined by the study doc-
`tor. Patients were excluded if they had received a
`diagnosis ofschizoai‘fective disorder, mental retar-
`dation, or other cognitive disorders; had a history
`of serious adverse reactions to the proposed treat-
`ments; had had only one schizophrenic episode;
`had a history oftreatment resistance. defined by the
`persistence of severe symptoms despite adequate
`trials of one of the proposed treatments or prior
`treatmentwith clozapine; were pregnant or breast-
`feeding; or had a serious and unstable medical
`condition.
`
`The study was approved by the institutional re-
`view board at each site, and written informed con-
`sent was obtained from the patients or their legal
`guardians.
`
`1210
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`Copyright '0 2005 :Vlassachusetts Medical Society. All rights reserved
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`

`

`EFFECTIVENESS 0f ANTIPSYCHOTKC DRUGS IN CHRONIC SCHIZOPHRENIA
`
`munvmnons
`
`Identical-appearing capsules contained olanzap-
`ine (Zyprexa, Eli Lilly) (7.5 mg), quetiapine (Sero-
`quel, Asn'aZeneca) (200 mg), risperidone (Risper-
`dalJanssen Pharmaceutica) (1.5 mg), perphenazine
`(’l‘rilafon, Schering-Plough, at the time ofthe study)
`(8 mg), or (after January 2002) Ziprasidone (Geo-
`don, Pfizer) (40 mg). The packaging was done by
`Quintiles. The dose of medications was flexible,
`ranging from one to four capsules daily, and was
`based on the study doctor’s judgment. Overlap in
`the administration ofthe antipsychotic agents that
`patients received before study entry was pemiitted
`for the first four weeks after randomization to allow
`
`a gradual transition to study medication. Concom-
`itant medications were permitted throughout the
`trial, except for additional antipsychotic agents.
`Patients had monthly visits with study doctors.
`Because of product labeling. quetiapine and
`Ziprasidone are given twice daily and olanzapine,
`perphenazine, and risperidone once daily. To pro-
`tect blinding, half the patients randomly assigned
`to perphenazine. olanzapine, and risperidone were
`assigned to twice-daily dosing and half to once-
`daily dosing. To minimize initial side effects, pa-
`tients assigned to quetiapine began treatment by
`receiving one 100-mg capsule on days 1 and 2, one
`twice daily on day 3, and one for the first dose of
`day 4. All patients assigned to twice-daily closing
`received five identical-appearing capsules to begin
`treatment. Patients with current tardive dyskine-
`sia could enroll, but the randomization scheme
`prevented their assignment to treatment with per-
`phenazine.
`
`OBjEC'I'WES AND ourcouss
`
`We hypothesized that there would be significant
`differences in the overall effectiveness of olanza-
`
`pine, perphenazine. quetiapine, rispcridone, and
`Ziprasidone in treating schizophrenia that reflected
`variations in efficacy and tolerability. The primary
`outcome measure was the discontinuation oftreat-
`
`ment forany cause. a discrete outcome selected be-
`cause stopping or changingmedication isafrequent
`occurrence and major problem in the neatment of
`schizophrenia. In addition, this measure integrates
`patients’ and clinicians‘ judgments ofefiicacy, safe-
`ty, and tolerability into a global measure of effec-
`tiveness that reflects their evaluation oftherapeutic
`benefits in relation to undesirable effects. The key
`secondary outcomes were the specific reasons for
`the discontinuation oftreatment (e.g., inefficacy or
`
`intolerability owing to side effects such as weight
`gain, extrapyramidal signs, or sedation as judged
`by the study doctor). Additional secondary ePficacy
`outcomes included scores on the Positive and Neg-
`ative Syndrome Scale (PANSS) and the Clinical
`Global Impressions (CGl) Scale. PANSS scores can
`range from 30 to 210, with higher scores indicat-
`ing more severe psychopathology. Scores for the
`CG] Scale can range from 1 to 7, with higher scores
`indicating greater severity ofillness. Secondary safe-
`ty and tolerability outcomes, which were evaluated
`atmonths 1, 3, 6, 9, 12, 15, and 18, included the in-
`cidence of serious adverse events, the incidence of
`adverse events during treatment, the incidence of
`neurologic side efi'ects, and changes in weight, elec-
`trocardiographic findings, and laboratory analytes.
`
`snrrs‘rrcau. runners
`
`Randomized patients who received at least one
`dose ofstudy medication made up the intention-to-
`treat population. Two hundred thirty-one patients
`with tardive dyskinesia were excluded from random
`assigntn ent to perphenazine. Ziprasidone was add-
`ed to the trial after approximately 40 percent of
`the patients had been enrolled. Consequently, com-
`parisons involving the perphenazine group were
`limited to patients without tardive dyskinesia, and
`comparisons involving the ziprasidone group were
`limited to the cohort of patients who underwent
`randomization after Ziprasidone was added (the
`Ziprasidone cohort). In general. the trial had a sta-
`tistical power of 85 percent to identify an absolute
`difference of12 percent in the rates ofdiscontinu-
`ation between two atypical agents; however, it had
`a statistical power of 76 percent for comparisons
`involving perphenazine and ofS8 percent for com-
`parisons involving Ziprasidone.
`We used Kaplan—Meier survival curves to esti-
`mate the time to the discontinuation of treatment.
`
`Treatment groups were compared with use ofCox
`proportional-hazards regression models” strati-
`fied according to site, with adjustment forwhether
`the patient had had an exacerbation ofschizophre-
`nia in the preceding diree months and tardive dys-
`kinesia status (for models excluding perphena-
`zine). Sites with 15 or fewer patients were grouped
`according to the sites’ health care systems.
`The overall difierence among the olanzapine,
`quetiapine, rispcridone, and perphenazine groups
`was evaluated with the use of a test with 3 degrees
`offreedom (df) . Ifthe diFference was significant at
`a P value of less than 0.05, the three atypical-drug
`
`N INCL] MED 353:12 wwwmqmonc
`
`srrremesn 22, 2005
`
`1211
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`
`

`

`TII! NEW ENGLAND IOURNAL ufMEDlClNE
`
`groups were compared with each other by means
`ofstep-down or closed testing, with a P value of
`less than 0.05 considered to indicate statistical sig-
`nificance. Each group was then compared with the
`perphenazine group by means of a Hochberg ad-
`justment for multiple comparisons.30 The smallest
`resulting P value was compared with a value of 0.017
`(0.05 + 3) . The ziprasidone group was directly com-
`pared with the other three atypical-drug groups and
`the perphenazine group within the ziprasidone co-
`hort by means of a Hochberg adjustment for four
`pairwise comparisons. The smallest resulting Pval-
`ue was compared with a value of 0.013 (0.05 + 4).
`Successful treatment time was defined as the
`
`number ofmonths oftreatment during phase 1 in
`which patients had a CGI Scale score of at last 3
`(mildly ill) or a score of 4 (moderately ill) with an
`improvement of at least two points from baseline.
`Treatment groups were compared with use of pro-
`portional-hazards regression.
`A sensitivity analysis of the Cox model for the
`discontinuation oftreatment forany cause evaluat-
`ed the el'fects ofpotentially important baseline co-
`variates and their interaction with the treatment
`group.
`The PANSS total scores and CGI Scale scores
`
`over time were compared among the groups with
`the use ofa mixed model including the same fixed
`covariates as for the time to discontinuation, plus
`baseline value, time, the interaction between treat-
`ment and time, and the interaction between base-
`line value and time. Time was classified into months
`
`(1, 3. 6, 9, 12, 15, and 18). The results ofassess-
`merits made at the end ofphase 1 were assigned to
`the next interval. The correlation of the repeated
`measures within each patient was modeled with
`the use of a random subject intercept and an un-
`structured covariance matrix.
`
`The studywas funded by the NIMH. The pharma-
`ceutical companies whose drugs were included in
`the study donated drug supplies, and each provid-
`ed advice on the dose of its own drug; they were
`otherwise not involved in the design of the study,
`analyses, or interpretation of results. The manu-
`script was written solely by the listed authors.
`
`RESULTS
`
`CHARACTERISTICS AND DISPOSITION
`OF PATIENTS
`
`Table 1 shows the baseline demographic and clini-
`cal characteristics of the patients. Figure 1 depicts
`the enrollment, randomization, and follow-up of
`
`study patients; 1493 patients were enrolled in the
`study and randomlyassigned to treatment. All data
`fi'om one site (33 patients) were excluded before
`analysis, owing to concern about the integrity ofdata
`from that site before the end ofthe study and before
`unblinding. The mean modal doses were 20. 1 mg
`per day for olanzapine, 20.8 mg per day for per-
`phenazine, 543.4 mg perdayfor quetiapine, 3.9 mg
`per day for risperidone, and 112.8 mg per day for
`ziprasidone (Table 2). Seventy-four percent of pa-
`tients in the intention-to-treat analysis (1061 of
`1432) discontinued their assigned treatment in
`phase 1 before 18 months (median, 6).
`
`DISCONTINUATION or TREATMENT
`
`The time to the discontinuation of treatment for
`
`any cause was longer in the olanzapine group than
`in the quetiapine group (hazard ratio, 0.63;P<0.001) ,
`the risperidone group (hazard ratio, 0.75; P=0.002),
`or the perphenazine group (hazard ratio, 0.78;
`P:0.021) (Table 2). However, the difference be-
`tween the olanzapine group and the perphenazine
`group was not significant after adjustment for mul-
`tiple comparisons (required P value, $0.017). With-
`in the cohort of 889 patients who underwent ran-
`domization after ziprasidone was added to the trial,
`those receiving olanzapine had a longer interval be-
`fore discontinuing treatment for any cause than
`did those in the ziprasidone group (hazard ratio,
`0.76; P=0.028). However, this difference was not
`significant after adjustment for multiple compari-
`sons (required P value, $0.013).
`The time to the discontinuation oftreatment for
`
`lack ofefficacy was longer in the olanzapine group
`than in the perphenazine group (hazard ratio, 0.47;
`P<0.001), the quetiapinegroup (hazard ratio, 0.41;
`P<0.001), the risperidone group (hazard ratio,
`0.45; P<0.001), or the ziprasidone group (hazard
`ratio, 0.59; P:0.026), but the diflference between
`the olanzapine and ziprasidone groups was not sig-
`nificant after adjustment for multiple comparisons
`(required Pvalue, $0.013) (Table 2). There were no
`significant differences between groups in time un-
`til discontinuation owing to intolerable side effects
`(P:0.054). The time until discontinuation owing
`to the patient’s decision (i.e., the patient indepen-
`dently chose to stop treatment) was similar to that
`for discontinuation for any cause (Table 2).
`The duration of successfiil treatment was sig-
`nificantly longer in the olanzapine group than in
`the quetiapine group (hazard ratio, 0.53; P<0.001),
`the risperidone group (hazard ratio, 0.69; P=0.002),
`or the perphenazine group (hazard ratio, 0.73;
`
`1212
`
`N ENGLJME0353112 WWW.NE}M.ORG SEPTEMBER 22, 2005
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`The New England Joumal of Medicine
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`Copyright .0 2005 Massachusetts Medical Society. All rights reserved
`
`

`

`EFFECTIVENESS Of ANTIPSYCHOTIC DRUGS IN CHRONIC SCHIZOPHRENIA
`
`Table 1. Baseline Demogaphic and Clinical Characteristics of Randomized Patients?
`
`
`
`Characteristic
`Demographic characteristics
`Age —yr
`Se! — no. (96)
`Male
`Female
`Race — no. (96):;
`White
`Black
`Other
`Spanish. Hispanic, or Latino ethnicity — no. (96)
`Education—yr
`Marital status — no. (96)
`Married
`Previously marriedfi
`Never married
`Unemployed —_ no. (96”
`Exacerbation in previous 3 mo— no. (96)
`PAN SS total score)
`Clinidan-rated CGI severity score“
`Psychiatric history
`Age at 151: treatment for any behavioral
`or emotional problem — yr
`Years since lst antipsychotic medication
`prescribed
`SCID diagnosis in past 5 yr — no. (96)
`Depression
`Alcohol dependence or alcohol abuse
`Drug dependence or drug abuse
`Obsessive—compulsive disorder
`Other anxiety disorder
`Baseline antlpsyd'lotlc medicatlons — no. (%)TT
`Olanzapine alone
`Quetiapine alone
`Risperidone alone
`Any combination lncludingolanzapine.quetia-
`pine, or risperidone
`All others
`None
`Baseline medical diagnoses — no. (96)
`Diabetes (type 1 or 2)
`Hyperlipidemla
`Hypertension
`
`86 (26)
`74 (22)
`86 (26)
`10 (3)
`44 (13)
`
`78 (23)
`24 (7)
`57 (17)
`31 (9)
`
`52 (15)
`94 (28)
`
`36 (11)
`56 (17)
`68 (20)
`
`84 (25)
`81 (24)
`95 (28)
`22 (7)
`46 (14)
`
`69 (20)
`17 (5)
`59 (18)
`32 (10)
`
`58 (17)
`102 (30)
`
`40 (12)
`44 (13)
`67 (20)
`
`104 (30)
`92 (27)
`110 (32)
`21 (6)
`52 (15)
`
`76 (22)
`22 (6)
`63 (18)
`33 (10)
`
`60 (18)
`87 (25)
`
`32(9)
`42 (12)
`63 (18)
`
`Olanzapine
`(Ns336)
`
`Quetiapine
`(N-337)
`
`Risperidone
`(N-341)
`
`Perphenazine
`(N-261)'i‘
`
`Ziprasidone
`(N-185)
`
`Total
`(N-1460)
`
`40.81108
`
`40.91112
`
`40.61113
`
`40.0111.1
`
`40.11110
`
`40.61111
`
`244 (73)
`92 (27)
`
`196 (58)
`119 (35)
`21 (6)
`42 (12)
`12212.2
`
`36 (11)
`105 (31)
`195 (58)
`281 (85)
`90 (27)
`76.11182
`4.0110
`
`255 (76)
`82 (24)
`
`213 (63)
`114 (34)
`10 (3)
`48 (14)
`12112.4
`
`34 (10)
`90 (27)
`213 (63)
`274 (84)
`89 (26)
`75.71169
`3310.9
`
`253 (74)
`88 (26)
`
`204 (60)
`122 (36)
`15 (4)
`38 (11)
`12.0122
`
`37 (11)
`101 (30)
`203 (60)
`288 (85)
`95 (28)
`76.41166
`4.0109
`
`199 (76)
`62 (24)
`
`152 (58)
`93 (36)
`16 (6)
`24 (9)
`12112.1
`
`43 (16)
`68 (26)
`150 (57)
`219 (85)
`68 (26)
`74. 3118.1
`3.9110
`
`129 (70)
`56 (30)
`
`109 (60)
`65 (36)
`9 (5)
`18 (10)
`12012.5
`
`17(9)
`61 (33)
`107 (58)
`155 (85)
`60 (32)
`75.41186
`3.9109
`
`1080 (74)
`380 (26)
`
`874 (60)
`513 (35)
`71 (5)
`170 (12)
`12.1123
`
`167 (11)
`425 (29)
`868 (59)
`1217 (85)
`402 (28)
`75.71176
`4.0109
`
`24.1190
`
`23618.1
`
`23.7193
`
`24.5186
`
`24.1197
`
`24.0189
`
`14.51110
`
`14.61103
`
`14.81107
`
`13.81110
`
`14.01105
`
`14.41107
`
`71 (27)
`74 (28)
`74 (28)
`12 (5)
`29 (11)
`
`58 (22)
`15 (6)
`64 (25)
`21 (8)
`
`30 (11)
`73 (28)
`
`29 (11)
`36 (14)
`6o (23)
`
`6O (32)
`37 (20)
`57 (31)
`8 (4)
`28 (15)
`
`41 (22)
`l7 (9)
`32 (17)
`8 (4)
`
`29 (16)
`58 (31)
`
`17(9)
`26 (14)
`31 (17)
`
`405 (28)
`358 (25)
`422 (29)
`73 (5)
`199 (14)
`
`322 (22)
`9S (7)
`275 (19)
`95 (7)
`
`229 (16)
`414 (28)
`
`154 (11)
`204 (14)
`289 (20)
`
`* Plus-minus values are means 15D. Becauseof'rounding. percentages may not sum to 100. SCID denotes Structured Clinical Interview for DSM-IV.
`1‘ Patients with tardive dyskinesia were excluded From the perphenazine group.
`1 Race was selfimported. "Other" includes American Indian or Alaska Native [less than 1 percentofpatients), Asian (2 percent). Native Hawaiian
`or other Pacific Islander (less than 1 percent], and two or more races (2 percent). Percentages are based on the number of patients with data
`available: 336 in the olanzapine group, 337 in the quetiapine group, 341 in the risperidone group, 261 in the perphenazine group, and 183 in
`the ziprasidone group.
`S This category includes patients who were widowed, divorced, or separated.
`1 Percentages are based on the number ofpatients with data available: 330 in the olanzapine group, 328 in the quetiapine group. 336 in the ris-
`peridone group, 259 in the perphenazine group, and 182 in the ziprasidone group.
`I Scores on the Positive and Negative Syndrome Scale (PANSS) for schizophrenia can range from 30 to 210, with higher scoresindicating
`more severe psychopathology.
`** The CGI severity score can range from 1 to 7. with higher scores indicating greater severity ofillness.
`ff Percentages for baseline medications are based on the number ofpatients with data on concomitant medications: 333 in the olanzapi ne
`group, 333 in the quetiapine group, 340in the risperidone group, 259 in the perphenazine group, and 184 in the ziprasidone group.
`
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`Copyright '0 2005 Massachusetts Medical Society. All rights reserved
`
`

`

`ThrNEW ENGLAND IOURNAL ufMEDlClNE
`
`1894 Screened
`
`401 Excluded
`124 Did not meet study criteria
`10‘) Declined
`33 Decided against changing
`antipsychotic agent
`135 Had other reasons
`
`All 33 patients from one site
`excluded before analysis
`because ofcoricem about
`integrity ofthe data
`
`1493 Underwent randomization
`
`38 (2196) Completed
`phase 1
`145 (79%) Discontinued
`ziprasidone
`44 For laclr ofefiicacy
`28 Owrng to intoler-
`ability
`63 Owing to patients
`deasron
`10 For other reasons
`
`183 Included in analysis
`
`
`
`185 Assigned to
`ziprasidone
`Z Did not take drug
`
`336 Assigned to
`olanzaplne
`6 Did not take drug
`
`261 Assigned to
`perphenazine
`4 Did not take drug
`
`337 Assigned to
`quetiapine
`3 Did not take drug
`
`120 (36%) Completed
`phase 1
`210 (64%) Discontinued
`olanzapine
`48 For lack ofefficacy
`62 meg to intoler-
`ability
`7! Owing to patient's
`deasion
`22 For other reasons
`
`65 (2596) Completed
`phase 1
`192 (75%) Discontinued
`perphenazine
`GS For lack ofeflicacy
`40 meg to intoler-
`ability
`77 Owing to patient's
`deasron
`10 For other reasons
`
`60 (18%) Completed
`phase 1
`269 (82%) Discontinued
`quetiapine
`92 For Iaclr ofefficacy
`49 Owing to intoler-
`ability
`109 Owing topatient's
`decision
`19 For other reasons
`
`330lnduded in analysis
`
`257Ir1clud
`
`analysis
`
`329 Included in anal
`
`341 Assigned to
`nspendone
`8 Did not take drug
`
`88 (2696) Completed
`phase 1
`245 (74%) Discontinued
`risperidone
`91 For lack deflicacy
`34 Owing to intoler-
`ability
`101 Owing to patient's
`decision
`19 For other reasons
`
`333 included in analysis
`
`
`
`Figure l. Enrollment and Outcome.
`Patients with tardive dyskinesia were not assigned to perphenazine. Ziprasidone was added to the study alter approximately 40 percent
`ofpatients had been enrolled.
`
`P=0.013) and was significantly longerin the risperi-
`done group than in the quetiapine group (hazard
`ratio. 0.77; P=0.021).
`
`ADJUSTMENT Of OUTCOMES FOR COVARIATES
`
`An exploratory analysis identified the following
`predictors of an earlier time to discontinuation:
`higher baseline PANSS score (P=0.001), younger
`age (P<0.001). longer duration since the first use
`ofantipsychotic medication (P=0.057), and the an-
`tipsychotic drug taken before study entry (P=0.001).
`Baseline antipsychotic agents were grouped into six
`categories (Table 1). Patients receiving olanzapinc
`or risperidone before enrollment stayed in phase 1
`
`ofthe trial longer than those taking no antipsychot-
`ic agents, drose taking combination treatments, or
`those receiving a single antipsychotic agent exclud-
`ing olanzapine, quetiapine, or risperidone; pair-
`wise hazard ratios ranged from 0.68 (P<0.001) to
`0.80 (P<0.02). No interactions with treatmentgroup
`were significant at a P value of less than 0.10. After
`adjustment for these predictors of discontinuation,
`the results of treatment-group comparisons were
`similar to the primary results.
`
`EFFICACY MEASURES
`
`Total PANSS scores improved over time in all groups
`(Fig. 2). The mixed model revealed significantvari—
`
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`
`The New England Joumal of Medicine
`Dovmloaded from nejm.org on September [4. 2018. For personal use only. No other uses withoul pennission
`Copyright C) 2005 Massachusetts Medical Society. All rights reserved
`
`

`

`EFFECTIVENESS Of ANTIPSYCHOTIC DRUGS IN CHRONIC SCHIZOPIIRENIA
`
`ation in treatment eiiects over time (P:0.002). Im-
`provement was initially greatest in the olanzapine
`group. but its advantage diminished over time. The
`pattern of change in the scores for the CG] Scale
`was similar to that for the PANSS scores (P:0.004
`for the interaction between treatment and time).
`
`“wens: events
`
`The rates ofadverse events and side efiecm are list-
`
`ed in Table 3. Fewer patients in the olanzapine group
`than in the other four groups were hospitalized for
`an exacerbation ofschizophrenia (11 percentvs. 15
`to 20 percent. P<0.001). After adjustment for the
`different durations of treatment, the olanzapine
`group had a risk ratio for hospitalization of0.17 per
`person-year of treatment, as compared with risk
`ratios of0.30 to 0.44 in the other groups.
`The rates of treatment discontinuation due to
`intolerable side effects differed between treatments
`
`(P=0.04). Risperidone had the lowest rate (10 per-
`cent), and olanzapine had the highest rate (18 per-
`cent). Moreover, more patients discontinued olan-
`zapine owing to weight gain or metabolic efirects
`(9 percent vs. 1 percent to 4 percent with the other
`four drugs, P<0.001) and more patients discontin-
`ued perphenazine owing to extrapyramidal efiects
`[8 percent vs. 2 percent to 4 percent, P=0.002) .
`Patients in the olanzapineand quetiapine groups
`had lower rates of insomnia (16 and 18 percent. re-
`spectively) than did patients in the other groups (24
`percentin the risperidone group, 25 percentin the
`perphenazine group, and 30 percent in the ziprasi-
`done group). Quetiapine was associated with a high-
`er rate ofanticholinergic effects than were the other
`drugs (31 percent vs. 20 to 25 percent, P<0.001).
`
`Neurologic Side Efl‘ects
`There were no significant differences among the
`groups in the incidence of extrapyramidal side ef-
`fects, akathisia, or movement disorders as reflected
`by rating-scale measures ofseverity.
`
`Weight Gain and Metabolic Changes
`Patients in the olanzapine group gained more
`weight than patients in any other group, with an av-
`erage weightgain of2 lb (0.9 kg) per month. A larger
`proportion ofpatients in the olanzapine group than
`in the other groups gained 7 percent or moreoftheir
`baseline body weight (30 percentvs. 7 to 16 percent,
`P<0.001).
`
`olanzapine had effects consistent with the po-
`tential development ofthe metabolic syndrome and
`
`was associated with greater increases in glycosylat-
`ed hemoglobin, total cholesterol, and triglycerides
`after randomization than the other study drugs,
`even after adjustment for the duration of treat-
`ment. Ziprasidone was the only study drug associ-
`ated with improvement in each of these metabolic
`variables. Only risperidone was associated with a
`substantial increase in prolactin levels.
`
`Other Potential Adverse Events
`
`There were no substantially different effects of the
`medications on the corrected QT interval on elec-
`trocardiography, and torsades de pointes did not
`develop in any patients. There were no significant
`differences among the groups in the incidence of
`new cataracts. There were no significant differences
`among the grouPs in the rates ofsuicide attempts
`or suicidal ideation reported as serious adverse
`events.
`
`coueom rum MEDICATIONS
`
`There were few substantial differences among the
`groups in the rates or types of medications added
`during the study. Patients in the olanzapine and ris-
`peridone groups were the least likely to have anxio-
`lytic agents added (9 and 10 percent, respectively,
`vs. 14 to 15 percent). Fewer patients receiving que-
`tiapine were prescribed anticholinergic drugs (3 per-
`cent vs. 8 to 10 percent).
`
`DISCUSSION
`
`All second-generation antipsychotic drugs were in-
`cluded in phase 1 of this study except aripiprazole
`(which was approved by the FDA in November
`2002) and clozapine, which was included in phase 2
`For patients who discontinued phase 1 oftreatment
`owing to lack of efficacy of the assigned drug. Al-
`though haloperidol is the first-generation agent
`most commonly used for comparison, we chose to
`use perphenazine because of its lower potency and
`moderate side-effect profile.31
`Only a minority ofpatients in each group took
`their assigned drug forthe duration ofphase 1 (rates
`ofdiscontinuation ranged from 64 to 82 percent).
`This outcome indicates that antipsychotic drugs,
`though effective, have substantial limitations in
`their effectiveness in patients with chronic schizo-
`phrenia. Although the rates ofdiscontinuation may
`have been increased by the fact that patients were
`participating in a blinded, controlled trial, the rates
`are generally consistent with those previously ob-
`
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