JOURNAL of MEDICINE
`
`Th NEW ENGLAND
`
`ESTABLISHED IN 1812
`
`SEPTEMBER 22, 2005
`
`VOL.353 NO.12
`
`Effectiveness ofAntipsychotic Drugsin 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 O. 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, M.S.,
`and John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators*
`
`
`ABSTRACT
`
`BACKGROUND
`
`Therelative effectiveness ofsecond-generation (atypical) antipsychotic drugs as com-
`paredwiththat ofolder agents has been incompletely addressed, though newer agents
`are currently used far more commonly. We compareda first-generationantipsychotic,
`perphenazine,with several newerdrugsin a double-blind study.
`METHODS
`
`A total of1493 patients with schizophrenia were recruited at 57 U.S.sites and random-
`ly assignedto receive olanzapine (7.5 to 30 mgper day), perphenazine(8 to 32 mg per
`day), quetiapine (200 to 800 mgperday), or risperidone (1.5 to 6.0 mg perday) for up
`to 18 months. Ziprasidone (40 to 160 mgper day) wasincludedafter its approval by the
`Food and Drug Administration. The primary aim wasto delineate differences in the
`overall effectiveness of thesefive treatments.
`RESULTS
`
`Overall, 74 percentof patients discontinued the study medication before 18 months
`(1061 ofthe 1432patients whoreceived at least one dose): 64 percent ofthose assigned
`to olanzapine, 75 percentof those assigned to perphenazine, 82 percentof 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 longerin the olanzapine groupthanin the quetiapine (P<0.001)
`orrisperidone (P=0.002) group, but notin the perphenazine (P=0.021) or ziprasidone
`(P=0.028) group. Thetimesto discontinuation becauseofintolerable side effects were
`similar amongthe groups,butthe rates differed (P=0.04); olanzapine wasassociated
`with more discontinuation for weight gain or metabolic effects, and perphenazine
`wasassociated with more discontinuation for extrapyramidaleffects.
`CONCLUSIONS
`
`The majority ofpatients in each group discontinuedtheir assigned treatment owing to
`inefficacy or intolerable side effects or for other reasons. Olanzapine wasthe mostef-
`fective in termsoftherates ofdiscontinuation, andthe efficacy ofthe conventional anti-
`psychotic agent perphenazine appearedsimilar to that ofquetiapine,risperidone, and
`ziprasidone. Olanzapine wasassociated withgreater weight gain and increases in mea-
`sures ofglucose and lipid metabolism.
`
`From the Departmentof Psychiatry, College
`of Physicians and Surgeons, Columbia Uni-
`versity, New York State Psychiatric Institute,
`New York (J.A.L.); the Department of Psy-
`chiatry, School of Medicine (T-S.S., D.O.P.),
`and the DepartmentofBiostatistics, School
`of Public Health (S.M.D., C.E.D.), Universi-
`ty of North Carolina at ChapelHill, Chapel
`Hill; Quintiles, Research Triangle Park, N.C.
`(S.M.D.); the Department of Biological Psy-
`chiatry, John Umstead Hospital, Butner,
`N.C. (J.P.M.); the Department of Psychia-
`try and Behavioral Sciences, Duke Univer-
`sity Medical Center, Durham, N.C. {J.P.M.,
`M.S.S., R.S.E.K.); the Department of Psy-
`chiatry, Yale University School of Medicine,
`New Haven, Conn. (R.A.R.); and the Divi-
`sion of Services and Intervention Research,
`Nationa! Institute of Menta! Health, Na-
`tional Institutes of Health, Bethesda, Md.
`(B.D.L.,J.S.,J.K.H.). Address reprint requests
`to Dr. Lieberman at the Department of
`Psychiatry, College of Physicians and Sur-
`geons, Columbia University, New York State
`Psychiatric Institute, 1051 Riverside Dr.,
`New York, NY 10032, or at jlieberman@
`columbia.edu.
`
`*The CATIE investigators arelisted in the
`Appendix.
`
`N Engl J Med 2005;353:1209-23.
`Copyright © 2005 Massachuserts Medica! Society
`
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`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`NTIPSYCHOTIC DRUGS HAVE BECOME
`
`A thecornerstoneoftreatmentforschizo-
`
`phrenia. The first-generation “conven-
`tional” antipsychotic drugs are high-affinity an-
`tagonists ofdopamine D2 receptorsthat are most
`effective against psychotic symptomsbuthave high
`rates ofneurologic side effects, such as extrapyrami-
`dal signs and tardive dyskinesia. The introduction
`of second-generation, or“atypical,” antipsychotic
`drugs promised enhanced efficacy and safety.? The
`atypical agents differ pharmacologically from previ-
`ous antipsychotic agents in their loweraffinity for
`dopamine D2 receptors and greater affinities for
`other neuroreceptors, including thosefor serotonin
`(5-hydroxytryptamine,,, 24, 2c, 3, 6 and 7) and nor-
`epinephrine (a, and a).
`Although studies indicated that the atypical
`drugsare similarto the conventional drugs in reduc-
`ing psychotic symptoms and produce few neuro-
`logic effects, the evidence oftheir superiorefficacy
`has been neither consistent nor robust,3-* with the
`exception of clozapine, which repeatedly has been
`effective in patients whose conditionis refractory to
`treatmentwith other types ofagents but has severe
`side effects that limit its use.~1+ The neweragents
`appear more efficacious than conventional drugs
`in reducing negative symptoms(e.g., lack of emo-
`tion,interest, and expression), possibly owingto the
`absenceofextrapyramidal symptoms??orothersec-
`ondary causesofnegative symptoms(e.g., depres-
`sion) rather than to direct therapeutic effects.13
`The results ofstudiesoftheeffects oftreatment on
`cognitive impairment and mood symptoms have
`beeninconclusive.14.15 The ability ofatypical agents
`to preventrelapse and their effects on social and
`vocational functioning, quality oflife, long-term
`outcome,andthe caregivers’ burden have beenin-
`completely explored.*.12,16
`The safety advantages ofthe atypical drugs have
`been questioned becauseoftheir propensity to in-
`duce weight gain’? andalter glucose andlipid me-
`tabolism.45:19 Nevertheless, these medications are
`widely used and have a 90 percent market share in
`the United States,?°.21 resulting in burgeoning
`costs. In the wake of this trend, questions have
`been raised aboutthe clinical advantages and cost
`effectiveness of the atypical drugs. We report the
`primary outcomes ofa double-blind, active-control
`clinical trial sponsored bythe National Institute of
`Mental Health (NIMH)that was designed to com-
`pare the effectiveness ofatypical and conventional
`antipsychotic drugs.?2:23
`
`METHODS
`
`STUDY SETTING AND DESIGN
`
`The Clinical Antipsychotic Trials of Intervention
`Effectiveness (CATIE) study wasinitiated by the
`NIMH to comparetheeffectivenessofantipsychotic
`drugs. Its rationale, design, and methods have been
`described previously.2+-28 The protocol was made
`available to the public for comment, and a commit-
`tee ofscientific experts, health care administrators,
`and consumeradvocatescritiqued the study under
`the auspices ofthe NIMH. The study was conduct-
`ed between January 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-practicesites, and 14 mixed-systemsites).
`Patients wereinitially randomly assigned to receive
`olanzapine, perphenazine, quetiapine, or risperi-
`done underdouble-blind conditions and followed
`for up to 18 monthsor until treatment wasdiscon-
`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
`whoseassigned treatment wasdiscontinued could
`receive other treatments in phases 2 and 3.74 The
`presentreport is limited to phase 1 results.
`
`PARTICIPANTS
`
`Eligible patients were 18 to 65 years ofage; had re-
`ceived a diagnosis ofschizophrenia, as determined
`on thebasis ofthe Structured ClinicalInterview of
`the Diagnosticand Statistical Manual ofMentalDisorders,
`fourth edition; and were able to take oral antipsy-
`chotic medication, as determinedbythe study doc-
`tor. Patients were excludedif they had received a
`diagnosis ofschizoaffective disorder, mentalretar-
`dation, or other cognitive disorders; had a history
`ofseriousadverse reactions to the proposed treat-
`ments; had had only one schizophrenic episode;
`hada history oftreatmentresistance,defined by the
`persistence of severe symptomsdespite adequate
`trials of one of the proposed treatments or prior
`treatment with clozapine; were pregnantorbreast-
`feeding; or had a serious and unstable medical
`condition.
`The study was approved bythe institutionalre-
`view board at each site, and written informed con-
`sent was obtained from the patients or their legal
`guardians.
`
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`Copyright © 2005 Massachusetts Medical Society. All rights reserved.
`
`

`

`EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS IN CHRONIC SCHIZOPHRENIA
`
`INTERVENTIONS
`
`Identical-appearing capsules contained olanzap-
`ine (Zyprexa,Eli Lilly) (7.5 mg), quetiapine (Sero-
`quel, AstraZeneca) (200 mg), risperidone (Risper-
`dal, Janssen Pharmaceutica) (1.5 mg), perphenazine
`(Trilafon, 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 oneto 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 permitted
`for the first four weeksafter randomizationto 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, halfthe patients randomlyassigned
`to perphenazine, olanzapine, and risperidone were
`assigned to twice-daily dosing and half to once-
`daily dosing. To minimizeinitial side effects, pa-
`tients assigned to quetiapine began treatmentby
`receiving one 100-mgcapsule on days 1 and 2, one
`twice daily on day 3, and one forthefirst dose of
`day 4. All patients assigned to twice-daily dosing
`received five identical-appearing capsules to begin
`treatment. Patients with current tardive dyskine-
`sia could enroll, but the randomization scheme
`preventedtheir assignmentto treatmentwith per-
`phenazine.
`
`OBJECTIVES AND OUTCOMES
`Wehypothesized that there would be significant
`differences in the overall effectiveness of olanza-
`pine, perphenazine, quetiapine, risperidone, and
`ziprasidonein treating schizophrenia thatreflected
`variationsin efficacy and tolerability. The primary
`outcome measure was the discontinuationoftreat-
`mentforanycause, a discrete outcomeselected be-
`cause stopping or changing medicationis a frequent
`occurrence and major problemin the treatment of
`schizophrenia. In addition, this measureintegrates
`patients’ and clinicians’ judgments ofefficacy,safe-
`ty, and tolerability into a global measure ofeffec-
`tiveness thatreflects their evaluation oftherapeutic
`benefits in relation to undesirableeffects. 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 efficacy
`outcomes included scores onthe Positive and Neg-
`ative Syndrome Scale (PANSS) and the Clinical
`Global Impressions (CGI) Scale. PANSS scores can
`range from 30 to 210, with higher scores indicat-
`ing more severe psychopathology. Scores for the
`CGI Scale can range from 1 to 7, with higherscores
`indicating greaterseverity ofillness. Secondary safe-
`ty and tolerability outcomes, which were evaluated
`at months1, 3, 6, 9, 12, 15, and 18, includedthe in-
`cidence of serious adverse events, the incidence of
`adverse events during treatment, the incidence of
`neurologic side effects, and changesin weight,elec-
`trocardiographic findings, and laboratory analytes.
`
`STATISTICAL ANALYSIS
`
`Randomized patients who received at least one
`dose ofstudy medication madeup the intention-to-
`treat population. Two hundred thirty-one patients
`with tardive dyskinesia were excluded from random
`assignment 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 withouttardive dyskinesia, and
`comparisonsinvolvingthe 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 percentto identify an absolute
`difference of 12 percentin the rates ofdiscontinu-
`ation between two atypical agents; however, it had
`a statistical power of 76 percent for comparisons
`involving perphenazineand of58 percent for com-
`parisonsinvolving 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 adjustmentfor whether
`the patient had had anexacerbation ofschizophre-
`nia in the preceding three months andtardive 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 difference amongthe olanzapine,
`quetiapine,risperidone, and perphenazine groups
`wasevaluated with the use ofa test with 3 degrees
`offreedom (df). Ifthe difference wassignificantat
`a P valueof less than 0.05, the three atypical-drug
`
`N ENGL J MED 353;12 WWW.NEJM.ORG
`
`SEPTEMBER 22, 2005
`
`1211
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`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`groups were compared with each other by means
`of step-downorclosed testing, with a P value of
`less than 0.05 consideredto indicate statistical sig-
`nificance. Each group was then compared with the
`perphenazine group by meansof a Hochberg ad-
`justment for multiple comparisons.3° The smallest
`resulting P value was compared witha value of0.017
`(0.05 + 3). The ziprasidone group wasdirectly com-
`pared with the otherthree atypical-drug groups and
`the perphenazine group withinthe ziprasidone co-
`hort by means of a Hochberg adjustmentfor four
`pairwise comparisons. The smallest resulting P val-
`ue was comparedwitha valueof0.013 (0.05 + 4).
`Successful treatment time was defined as the
`numberof monthsoftreatment during phase 1 in
`which patients had a CGIScale score ofat least 3
`(mildlyill) or a score of 4 (moderately ill) with an
`improvementofat least two points from baseline.
`Treatment groups were compared with use ofpro-
`portional-hazards regression.
`A sensitivity analysis of the Cox model for the
`discontinuation oftreatmentfor anycause evaluat-
`ed the effects ofpotentially important baseline co-
`variates and their interaction with the treatment
`group.
`The PANSS total scores and CGI Scale scores
`over time were compared amongthe groups with
`the use ofa mixed model including the samefixed
`covariatesas for the time to discontinuation, plus
`baseline value, time, the interaction betweentreat-
`ment andtime, and the interaction between base-
`line value and time. Time wasclassified into months
`(1, 3, 6, 9, 12, 15, and 18). The results of assess-
`ments madeatthe end ofphase1 were assigned to
`the next interval. Thecorrelation 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 ofits own drug; they were
`otherwise notinvolved in the design of the study,
`analyses, or interpretation ofresults. The manu-
`script was writtensolely by thelisted authors.
`
`RESULTS
`
`CHARACTERISTICS AND DISPOSITION
`OF PATIENTS
`
`Table 1 showsthe baseline demographic andclini-
`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 randomly assignedto treatment. All data
`from onesite (33 patients) were excluded before
`analysis, owing to concern abouttheintegrity ofdata
`from thatsite before the endofthe study and before
`unblinding. The mean modal doses were 20.1 mg
`per day for olanzapine, 20.8 mg perday for per-
`phenazine, 543.4 mgperday for quetiapine, 3.9mg
`perday for risperidone, and 112.8 mgperdayfor
`ziprasidone (Table 2). Seventy-four percent of pa-
`tients in the intention-to-treat analysis (1061 of
`1432) discontinued their assigned treatmentin
`phase 1 before 18 months(median,6).
`
`DISCONTINUATION OF TREATMENT
`
`The time to the discontinuation of treatment for
`any cause waslongerin 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 wasnotsignificantafter adjustmentfor mul-
`tiple comparisons (required P value, <0.017). With-
`in the cohort of 889 patients who underwentran-
`domization after ziprasidone was addedtothetrial,
`thosereceiving olanzapinehad a longerintervalbe-
`fore discontinuing treatment for any cause than
`did thosein the ziprasidone group (hazardratio,
`0.76; P=0.028). However, this difference was not
`significant after adjustmentfor multiple compari-
`sons(required P value, <0.013).
`The timeto the discontinuation oftreatmentfor
`lack ofefficacy was longerin the olanzapine group
`than in the perphenazine group (hazard ratio, 0.47;
`P<0.001), the quetiapine group (hazardratio, 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 difference between
`the olanzapine and ziprasidone groupswasnotsig-
`nificant after adjustmentfor multiple comparisons
`(required P value, <0.013) (Table 2). There were no
`significant differences betweengroupsin time un-
`til discontinuation owingto 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) wassimilarto that
`for discontinuation for any cause (Table 2).
`The duration of successful treatmentwassig-
`nificantly longer in the olanzapine group than in
`the quetiapine group (hazardratio, 0.53; P<0.001),
`the risperidone group(hazardratio, 0.69; P=0.002),
`or the perphenazine group (hazard ratio, 0.73;
`
`1212
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`N ENGL J MED 353;12 WWW.NEJM.ORG SEPTEMBER 22, 2005
`
`The NewEngland Journal of Medicine
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`Copyright © 2005 Massachusetts Medical Society. All rights reserved.
`
`

`

`EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS IN CHRONIC SCHIZOPHRENIA
`
`Table 1. Baseline Demographic and Clinical Characteristics of Randomized Patients.*
`
`Olanzapine
`(N=336)
`
`Quetiapine
`(N=337)
`
`Risperidone
`(N=341)
`
`Perphenazine
`(N=261)7
`
`Ziprasidone
`(N=185)
`
`Total
`(N=1460)
`
`40.8+10.8
`
`40.9411.2
`
`40.6+11.3
`
`40.0+11.1
`
`40.1+11.0
`
`40.6+11.1
`
`244 (73)
`92 (27)
`
`196 (58)
`119 (35)
`21 (6)
`42 (12)
`12.242.2
`
`36 (11)
`105 (31)
`195 (58)
`281 (85)
`90 (27)
`76.1418.2
`4,041.0
`
`255 (76)
`82 (24)
`
`213 (63)
`114 (34)
`10 (3)
`48 (14)
`12.1+2.4
`
`34 (10)
`90 (27)
`213 (63)
`274 (84)
`89 (26)
`75.7£16.9
`3.9+0.9
`
`253 (74)
`88 (26)
`
`204 (60)
`122 (36)
`15 (4)
`38 (11)
`12.0+2.2
`
`37 (11)
`101 (30)
`203 (60)
`288 (86)
`95 (28)
`76.4+16.6
`4.040.9
`
`199 (76)
`62 (24)
`
`152 (58)
`93 (36)
`16 (6)
`24 (9)
`12.1+2.1
`
`43 (16)
`68 (26)
`150 (57)
`219 (85)
`68 (26)
`74.3+18.1
`3.941.0
`
`129 (70)
`56 (30)
`
`109 (60)
`65 (36)
`9 (5)
`18 (10)
`12.0+2.5
`
`17 (9)
`61 (33)
`107 (58)
`155 (85)
`60 (32)
`75.4418.6
`3.9+0.9
`
`1080 (74)
`380 (26)
`
`874 (60)
`513 (35)
`71 (5)
`170 (12)
`12.1+2.3
`
`167 (11)
`425 (29)
`868 (59)
`1217 (85)
`402 (28)
` 75.7+17.6
`4,020.9
`
`24,1+9.0
`
`23.648.1
`
`23.749.3
`
`24.548.6
`
`24,149.7
`
`24.0£8.9
`
`
`
`
`
`
`
`
`
`289 (20)
`
`Characteristic
`Demographic characteristics
`Age—yr
`Sex — no. (%)
`Male
`Female
`Race — no. (%)+
`White
`Black
`Other
`Spanish, Hispanic, or Latino ethnicity — no. (%)
`Education — yr
`Marital status — no. (9%)
`Married
`Previously married§
`Never married
`Unemployed — no. (%) 4
`Exacerbation in previous 3 mo — no. (%)
`PANSStotal score|
`Clinician-rated CGI severity score**
`Psychiatric history
`Ageat lst treatment for any behavioral
`or emotional problem — yr
`
`Years since 1st antipsychotic medication 14.0410.5=14.4410.714,5411,.0 14.6£10.3 14.8410,7 13.8£11.0
`prescribed
`SCID diagnosis in past 5 yr — no. (%)
`Depression
`Alcoho! dependenceor alcoho! abuse
`Drug dependence or drug abuse
`Obsessive-compulsive disorder
`Other anxiety disorder
`Baseline antipsychotic medications — no. (%) {7
`Olanzapine alone
`Quetiapine alone
`Risperidone alone
`Any combination including olanzapine, quetia-
`pine, or risperidone
`All others
`None
`Baseline medical diagnoses — no. (%)
`Diabetes (type 1 or 2)
`Hyperlipidernia
`Hypertension
`
`86 (26)
`74 (22)
`86 (26)
`10 (3)
`44 (13)
`
`78 (23)
`24 (7)
`57 (17)
`31 (9)
`
`$2 (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 (26)
`
`32 (9)
`42 (12)
`63 (18)
`
`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)
`60 (23)
`
`60 (32)
`37 (20)
`57 (31)
`8 (4)
`28 (15)
`
`41 (22)
`17 (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)
`95 (7)
`275 (19)
`95 (7)
`
`229 (16)
`414 (28)
`
`154 (11)
`204 (14)
`
`* Plus—minus values are means +SD. Because ofrounding, percentages may not sum to 100. SCID denotes Structured Clinical Interview for DSM-IV.
`Patients with tardive dyskinesia were excluded from the perphenazine group.
`oo
`Race was self-reported. “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 numberofpatients 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.
`§ This category includes patients who were widowed, divorced, or separated.
`4 Percentages are based on the numberofpatients with data available: 330 in the olanzapine group, 328 in the quetiapine group, 336in theris-
`peridone group, 259 in the perphenazine group, and 182 in the ziprasidone group.
`| Scores on the Positive and Negative Syndrome Scale (PANSS) for schizophrenia can range from 30 to 210, with higher scores indicating
`more severe psychopathology.
`** The CGI severity score can range from 1 to 7, with higherscores indicating greater severity ofillness.
`Tf Percentages for baseline medications are based on the number of patients with data on concomitant medications: 333 in the olanzapine
`group, 333 in the quetiapine group, 340 in the risperidone group, 259 in the perphenazine group, and 184 in the ziprasidone group.
`
`N ENGL J MED 353;12 WWW.NEJM.ORG
`
`SEPTEMBER 22, 2005
`
`1213
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`The NewEngland Journal! of Medicine
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`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`1894 Screened
`
`401 Excluded
`124 Did not meet study criteria
`109 Declined
`33 Decided against changing
`antipsychotic agent
`135 Had other reasons
`
`All 33 patients from onesite
`excluded before analysis
`because ofconcem about
`integrity ofthe data
`
`1493 Underwent randomization
`
` 333 included in analysis
`
`88 (26%) Completed
`phase 1
`245 (74%) Discontinued
`risperidone
`91 Forlack of efficacy
`34 Owing tointoler-
`ability
`101 Owingto patient's
`decision
`19 For other reasons
`
`185 Assigned to
`ziprasidone
`2 Did not take drug
`
`38 (219%) Completed
`phase 1
`145 (79%) Discontinued
`ziprasidone
`44 Forlack of efficacy
`28 Owingto intoler-
`ability
`63 Owingto patient's
`decision
`10 For other reasons
`
`183 Included in analysis
`
`
`
`
`
`341 Assigned to
`risperidone
`8 Did not take drug
`
`336 Assigned to
`olanzapine
`6 Did not take drug
`
`261 Assigned to
`perphenazine
`4 Did not take drug
`
`337 Assigned to
`quetiapine
`8 Did not take drug
`
`120 (369) Completed
`phase 1
`210 (64%) Discontinued
`olanzapine
`48 Forlack of efficacy
`62 Owing to intoler-
`ability
`78 Owing to patient's
`deasion
`22 For other reasons
`
`65 (259%) Completed
`phase 1
`192 (75%) Discontinued
`perphenazine
`65 For lack ofefficacy
`40 Owing to intoler-
`ability
`77 Owing to patient's
`decision
`10 For other reasons
`
`60 (18%) Completed
`phase ]
`269 (82%) Discontinued
`quetiapine
`92 For lack ofefficacy
`49 Owingto intoler-
`ability
`109 Owing to patient's
`decision
`19 For other reasons
`
`330 Included in analysis
`
`329 Includedin anal
`
`Figure 1. Enrollment and Outcomes.
`Patients with tardive dyskinesia were not assigned to perphenazine. Ziprasidone was added to the study after approximately 40 percent
`of patients had been enrolled.
`
`P=0.013) and wassignificantly 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), andthe an-
`tipsychotic drug taken before study entry (P=0.001).
`Baseline antipsychotic agents were groupedinto six
`categories (Table 1). Patients receiving olanzapine
`or risperidone before enrollment stayed in phase 1
`
`ofthe trial longer than thosetaking no antipsychot-
`ic agents, those taking combinationtreatments, or
`thosereceiving a single antipsychotic agentexclud-
`ing olanzapine, quetiapine, or risperidone; pair-
`wise hazard ratios ranged from 0.68 (P<0.001) to
`0.80 (P<0.02). Nointeractionswith treatmentgroup
`were significantata P value ofless than 0.10. After
`adjustmentfor these predictors ofdiscontinuation,
`the results of treatment-group comparisons were
`similar to the primary results.
`
`EFFICACY MEASURES
`
`Total PANSSscores improved overtimein all groups
`(Fig. 2). The mixed model revealedsignificant vari-
`
`1214
`
`N ENGL J MED 353;12 WWW.NEJM.ORG SEPTEMBER 22, 2005
`
`The NewEngland Journal! of Medicine
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`

`

`EFFECTIVENESS OF ANTIPSYCHOTIC DRUGS IN CHRONIC SCHIZOPHRENIA
`
`ation in treatmenteffects over time (P=0.002). Im-
`provementwasinitially greatest in the olanzapine
`group, butits advantage diminished over time. The
`pattern of change in the scores for the CGI Scale
`was similar to that for the PANSS scores (P=0.004
`for the interaction betweentreatmentand time).
`
`ADVERSE EVENTS
`
`wasassociated with greaterincreasesinglycosylat-
`ed hemoglobin, total cholesterol, and triglycerides
`after randomization than the other study drugs,
`even after adjustment for the duration oftreat-
`ment, Ziprasidone wasthe only study drug associ-
`ated with improvementin each ofthese metabolic
`variables. Only risperidone wasassociated with a
`substantial increasein prolactinlevels.
`
`Therates ofadverse events andside effects arelist-
`Other Potential Adverse Events
`edin Table 3. Fewerpatients in the olanzapine group
`than in the other four groups were hospitalized for
`There were no substantially different effects ofthe
`an exacerbation ofschizophrenia (11 percent vs. 15
`medications on the corrected QIinterval on elec-
`to 20 percent, P<0.001). After adjustmentfor the
`trocardiography, and torsades de pointes did not
`develop in anypatients. There were nosignificant
`different durations of treatment, the olanzapine
`
`group hadariskratio for hospitalization of0.17 per differences amongthe groupsin the incidence of
`person-year of treatment, as compared with risk
`new cataracts. There were no significant differences
`ratios of0.30 to 0.44 in the other groups.
`amongthe groupsin the rates ofsuicide attempts
`The rates of treatment discontinuation due to
`or suicidal ideation reported as serious adverse
`events.
`intolerable side effects differed between treatments
`(P=0.04). Risperidone had the lowestrate (10 per-
`cent), and olanzapinehad the highestrate (18 per-
`cent). Moreover, morepatients discontinued olan-
`zapine owing to weightgain or metabolic effects
`(9 percentvs. 1 percentto 4 percent with the other
`four drugs, P<0.001) and morepatients discontin-
`ued perphenazine owingto extrapyramidal effects
`(8 percentvs, 2 percent to 4 percent, P=0.002).
`Patients in the olanzapine and quetiapine groups
`had lowerrates ofinsomnia (16 and 18percent,re-
`spectively) than did patients in the other groups (24
`percentin the risperidone group, 25 percentin the
`perphenazine group,and 30 percentin the ziprasi-
`done group). Quetiapinewasassociated witha high-
`er rate ofanticholinergic effects than werethe other
`drugs (31 percentys. 20 to 25 percent, P<0.001).
`
`CONCOMITANT MEDICATIONS
`
`There were few substantial differences among the
`groupsintherates or types of medications added
`during the study. Patients in the olanzapineandris-
`peridone groupsweretheleastlikely to have anxio-
`lytic agents added (9 and 10 percent, respectively,
`vs. 14 to 15 percent). Fewer patients receiving que-
`tiapine wereprescribed anticholinergic drugs(3 per-
`cent vs. 8 to 10 percent).
`
`DISCUSSION
`
`All second-generation antipsychotic drugs were in-
`cluded in phase 1 ofthis study exceptaripiprazole
`(which was approved by the FDA in November
`2002) and clozapine, which wasincluded in phase 2
`for patients who discontinued phase 1 oftreatment
`owingto 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 becauseofits lower potency and
`moderateside-effect profile.3!
`Only a minority ofpatients in each group took
`their assigned drug forthe durationofphase1 (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. Althoughtherates ofdiscontinuation may
`have beenincreased bythefact that patients were
`participatingin a blinded,controlledtrial, the rates
`are generally consistent with those previously ob-
`
`Neurologic Side Effects
`There were nosignificant differences among the
`groupsin the incidence of extrapyramidal side ef-
`fects, akathisia, or movementdisordersas reflected
`by rating-scale measures ofseverity.
`
`Weight Gain and Metabolic Changes
`Patients in the olanzapine group gained more
`weightthan patients in any other group,with an ay-
`erage weightgain of2 1b (0.9 kg) per month. A larger
`proportion ofpatients in the olanzapine group than
`in the othergroups gained 7 percent or more oftheir
`baseline body weight(30 percent vs. 7 to 16 percent,
`P<0.001).
`Olanzapine had effects consistent with the po-
`tential developmentofthe metabolic syndrome and
`
`N ENGL J MED 353,12 WWW.NEJM.ORG
`
`SEPTEMBER 22, 2005
`
`1215
`
`The NewEngland Journal of Medicine
`Downloaded from nejm.org on September 14, 2018. For personal use only. No other uses without permission.
`Copyright © 2005 Massachusetts Medical Society. All rights reserved.
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
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