Placebo Response in Antipsychotic Clinical Trials a Meta-Analysis

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Original Investigation | META-ANALYSIS Placebo Response in Antipsychotic Clinical Trials A Meta-analysis

Bret R. Rutherford, MD; Emily Pott, BA; Jane M. Tandler, BA; Melanie M. Wall, PhD; Steven P. Roose, MD; Jeffrey A. Lieberman, MD

Supplemental content at IMPORTANCE Because increasing placebo response rates decrease drug-placebo differences jamapsychiatry.com and increase the number of failed trials, it is imperative to determine what is causing this trend.

OBJECTIVES To investigate the relationship between antipsychotic medication and placebo response by publication year, and to identify associated study design and implementation variables.

DATA SOURCES MEDLINE, PsycINFO, and PubMed were searched to identify randomized clinical trials of antipsychotic medications published from 1960 to July 2013.

STUDY SELECTION Included were randomized clinical trials lasting 4 to 24 weeks, contrasting antipsychotic medication with placebo or an active comparator, and enrolling patients 18 years of age or older with schizophrenia or schizoaffective disorder.

DATA EXTRACTION AND SYNTHESIS Standardized mean change scores were calculated for each treatment arm, plotted against publication year, and tested with Spearman rank correlation coefficients. Hierarchical linear modeling identified factors associated with the standardized mean change across medication and placebo treatment arms.

MAIN OUTCOMES AND MEASURES We hypothesized that the mean change in placebo-treated patients would significantly increase from 1960 to the present, that a greater change would be observed in active comparator vs placebo-controlled trials, and that more protocol visits would increase the symptom change observed.

RESULTS In the 105 trials examined, the mean change observed in placebo arms increased significantly with year of publication (n = 39, r = 0.52, P = .001), while the mean change in effective dose medication arms decreased significantly (n = 208, r =−0.26,P < .001). Significant interactions were found between assignment to effective dose medication and

publication year (t260 = −5.55, P < .001), baseline severity (t260 =5.08,P < .001), and study

duration (t260 =−3.76,P < .001), indicating that the average drug-placebo difference significantly decreased over time, with decreasing baseline severity and with increasing study duration. Medication treatment in comparator studies was associated with significantly more

improvement than medication treatment in placebo-controlled trials (t93 =2.73,P = .008).

CONCLUSIONS AND RELEVANCE The average treatment change associated with placebo treatment in antipsychotic trials increased since 1960, while the change associated with Author Affiliations: Columbia medication treatment decreased. Changes in randomized clinical trials leading to inflation of University College of Physicians and Surgeons, New York, New York baseline scores, enrollment of less severely ill participants, and higher expectations of (Rutherford, Wall, Roose, patients may all be responsible. Lieberman); New York State Psychiatric Institute, New York (Rutherford, Pott, Tandler, Wall, Roose, Lieberman). Corresponding Author: Bret R. Rutherford, MD, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Dr, PO Box 98, JAMA Psychiatry. 2014;71(12):1409-1421. doi:10.1001/jamapsychiatry.2014.1319 NewYork,NY10032 Published online October 8, 2014. ([email protected]).

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lacebo response rates in trials of antipsychotic medica- Figure 1. Literature Review and Selection of Studies tions for acute schizophrenia are increasing, mirroring the increases observed in illnesses such as major de- P 9057 Trials retrieved 1,2 pressive disorder. In 28 atypical antipsychotic trials, Kemp from search et al3 reported that the average symptom improvement among 6731 Excluded after preliminary patients assigned to placebo increased by over 10 points on the review because they were Positive and Negative Syndrome Scale between 1991 and 2006. not clinical trials Agid et al4 found that the standardized mean effect size asso- 2326 Titles reviewed 1699 Excluded because the sample ciated with placebo treatment significantly increased over time. was not of adult patients, the trial Younger age, shorter illness duration, greater baseline illness was not for a psychotic disorder, the medication was not approved severity, shorter trial duration, and more study sites were as- by the FDA, the trial required sociated with greater placebo response.4 a comorbid illness, or it was not 627 Abstracts reviewed a trial of antipsychotic drugs Increasing placebo response rates contribute to decreas-

ing drug-placebo differences and increasing numbers of failed 362 Excluded for the same reasons antipsychotic trials,5 both of which increase the cost of drug already given, after further review development, delay the clinical availability of new antipsy- 265 chotic medications, and even precipitate reductions in phar- Articles reviewed 160 Excluded for the same reasons 6 maceutical company research for psychiatric disorders. Thus, already given or because it is imperative to determine what is causing these increased it was a duplicate or secondary publication, was not a double-blind placebo response rates in antipsychotic trials. The findings of trial, or was unavailable Agid et al4 are of considerable value toward this goal, but their 105 Trials included in meta-analysis interpretation is constrained by their relatively narrow selection of available antipsychotic trials and is limited to examin- ing mean treatment change in participants assigned to pla-

cebo. It also would be of great interest to investigate which trial 39 Placebo-controlled studies 66 Comparator studies designs and which clinical variables are associated with re-

sponse to medication, and to determine whether there exist FDA indicates the US Food and Drug Administration. variable × treatment assignment interactions that directly bear on the observed drug-placebo difference. Consequently, we sought to replicate and build on the results of Agid et al4 by investigating the causes of placebo re- relationships.9 In contrast, a development common to both an- sponse in a much larger selection of randomized clinical trials tidepressant and antipsychotic drug trials has been the ad- (RCTs) of antipsychotic medications using a statistical method vent of larger, multicenter trials in which investigators may (hierarchical linear modeling) permitting the analysis of all have a greater financial incentive to enroll patients.9 This gen- treatment arms (drug and placebo). Rather than examine all eral change in RCT design may result in the inflation of base- possible predictors of treatment change, we selected candi- line scores and increased placebo response rates across date explanatory variables based on an established model of disorders. the causes of placebo response.7 This model, proposed to de- In line with the results of prior analyses, we hypoth- scribe causes of placebo response in antidepressant trials, di- esized that the mean pre-post change observed in placebo- vides its causes between (1) placebo effects based on patient treated patients in RCTs of antipsychotic drugs would signifi- expectancy of improvement and therapeutic contact with cantly increase from 1960 to the present and would be health care professionals, (2) measurement artifacts caused by positively associated with sample size. Similar to findings from rater bias and sampling error, and (3) spontaneous improve- RCTs of antidepressants, we anticipated that a greater mean ment and worsening of symptoms that are unrelated to the change would occur during medication treatment in active study procedures. comparator vs placebo-controlled trials (owing to the in- We were interested in determining to what degree this creased expectation of improvement induced by receiving a model can be generalized to different psychiatric disorders, known active treatment) and in trials with a greater intensity such as schizophrenia, in order to differentiate illness- of therapeutic contact (as measured by the prescribed num- specific causes of placebo response from those common to the ber of protocol visits). conduct of all RCTs. Patients with schizophrenia have baseline cognitive difficulties that may be exacerbated during periods of acute psychosis, which may impair their capacity to Methods form treatment expectancies based on information provided during the informed consent process.8 Moreover, it is unclear Search Strategy and Selection Criteria whether contact with health care professionals has a thera- MEDLINE, PsycINFO, and PubMed were searched to identify peutic effect on patients with schizophrenia comparable to that RCTs published between 1960 and July 2013 that contrasted observed in patients with depression because a cardinal fea- antipsychotics to placebos or active comparators in adults with ture of schizophrenia is a disturbance in interpersonal schizophrenia or schizoaffective disorder (Figure 1; see “Search

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Strategy” in the eAppendix in the Supplement). Inclusion cri- (rather than the Pearson) correlation is used to reduce influ- teria stipulated that articles report an RCT of an antipsychotic ence from any large values from any one study. medication for schizophrenia or schizoaffective disorder that To identify factors significantly associated with the stan- was approved by the US Food and Drug Administration for dardized mean change observed in the treatment arms within adults. Further criteria required trials to last between 4 and 24 our sample, we used a hierarchical linear modeling (HLM) weeks (inclusive), have a comparison group that received pla- approach10-12 similar to the one that we successfully imple- cebo or another antipsychotic medication approved by the US mented in several prior studies, in which the procedures are Food and Drug Administration, be written in English, be pub- described in greater detail.13-15 This approach entails first ex- lished in 1960 or later, and have symptom change measured amining the heterogeneity in treatment outcome within the using a standardized outcome measure. Trials were excluded sample using an unconditional model that contains a single for enrolling treatment-resistant patients or for requiring as in- level 1 (ie, within each study) equation describing the mean clusion criteria specific symptoms, a specific medical illness, change in each treatment arm as equal to a constant. At level or an Axis I disorder other than schizophrenia or schizoaffec- 2 (ie, between studies), this constant can be described as vary- tive disorder. ing around a grand mean with error. The H statistic (H = ͙[χ2/ (df − 1)]) can be used to measure this variability in treatment Data Extraction change, approximating 1 when there is only random varia- Study information such as the year of publication, sample size, tion between studies and progressively exceeding 1 when the and presence of a lead-in period in addition to the clinical and results of a set of studies lack homogeneity.16 The I2 statistic demographic characteristics of participants, details of the treat- (I2 =[H2 − 1]/H2) describes the proportion of total variation in ment conditions, duration of active treatment in each study, treatment change that is attributable to heterogeneity.17 and the number of study visits were entered into a database. If there was significant variability in mean change across We started counting the number of visits prescribed in each studies (ie, when the 95% CI for H did not include 1), we at- study with the initiation of treatment (ie, we began with the tempted to explain this variability by means of our hypoth- week 1 visit and did not count evaluation or screening appoint- esized within-st udy and between-study variables. This yielded ments). We distinguished treatment arms using flexible dos- the final mixed model containing 8 level 1 predictors, 7 level 2 ing or fixed but effective doses of oral antipsychotic medica- predictors, and 9 cross-level interactions. All of the regres- tion from treatment arms using doses of medication believed sion models were estimated using HLM version 6.08 (Scien- to be too low to have an important effect (see “Data Extrac- tific Software International). tion” in the eAppendix in the Supplement). We also sepa- rately classified medications administered intramuscularly in long-acting injectable formulations in order to test whether the Results route and frequency of administration influenced the treatment change observed. Characteristics of Included Studies and Participants Because individual studies used different scales to mea- A total of 105 studies met the inclusion and exclusion criteria sure pre-post change, it was necessary to standardize the (Table 1).18-119 As shown in Table 2, these included 257 treat- change scores published for each treatment condition in the ment groups (25 groups that received low-dose medications, studies comprising our sample. Our primary method was to 208 groups that received effective dose medications, and 24 calculate a standardized mean change score by dividing the pre- groups that received intramuscular medications) comprising post mean difference by the number of total points possible 21 892 participants and 39 placebo groups comprising 2882 par- on the scale used. For example, the standardized change for a ticipants. Sixty-six studies used an active comparator design, treatment arm in which participants improved by 15 points on of which 4 (6.1%) demonstrated significant differences in pre- the 18-item Brief Psychiatric Rating Scale (BPRS, with each item post change between treatment groups. Fifteen of 39 placebo- rated 0-6) was calculated to be 15/108 = 0.139. As discussed in controlled studies (38.5%) demonstrated significant differ- “Search Strategy” in the eAppendix in the Supplement, we also ences in mean change between medication groups and placebo explored alternative methods for calculating standardized groups. See “Clinical Characteristics of Included Patients and mean change. Methodological Features of Studies” in the eAppendix in the Supplement for a comparison of study and clinical character- Data Analyses istics between medication groups and placebo groups. Differences in study characteristics, patient demographics, and clinical features across the different study types were inves- Trajectory of Mean Change Over Time tigated using 2-tailed independent-samples t tests for con- The rank order of the standardized mean change associated tinuous variables and χ2 tests for categorical variables (SPSS with low-dose medication groups, effective dose medication version 21 [IBM Corp]). To investigate the trajectory over time groups, and placebo groups are plotted against year of publi- of the mean change observed in placebo, effective dose, and cation in Figure 2. The mean change observed in patients re- low-dose medication groups, we tested Spearman rank corre- ceiving placebo increased significantly with year of publica- lation coefficients for the relationship between standardized tion (Spearman r =0.52,n=39,P = .001). This correlation mean change and publication year. Plots of the rank order of equates to an average increase in pre-post treatment change standardized mean change are shown, and the Spearman of 1.1 BPRS points (or 2.2 points on the Positive and Negative

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Table 1. Summary of Included Studies and Participants

Countries or Study Patients, No. Outcome Standardized Source, Year Treatment Continents Duration, wk (ITT) Measure Mean Changea Addington et al,18 2004 Ziprasidone, risperidone Canada, Australia 8 149, 147 PANSS −0.12, −0.13 Andersen et al,19 2004 Pimozide, trifluoperazine Sweden 8 19, 19 Martens −0.04, −0.03 S-Scale Arvanitis et al,20 1997 Quetiapine 75, 150, 300, 600, North America 6 53, 48, 52, 51, BPRS −0.02, −0.08, −0.08, −0.07, and 750 mg; haloperidol 12 mg; 54, 52, 51 −0.04, −0.07, 0.01 placebo Astrupetal,21 1974 Flupenthixol decanoate, Norway 8 22, 21 BPRS −0.13, −0.09 pipotiazine undecylenate Atmaca et al,22 2002 Quetiapine, haloperidol Turkey 6 18, 17 PANSS −0.08, −0.08 Bankier et al,23 1972 Generic chlorpromazine, Canada 16 33, 33, 33 BPRS −0.10, −0.03, −0.08 proprietary chlorpromazine, mesoridazine Bankier,24 1973 Trifluoperazine, fluspirilene IM Canada 16 13, 11 BPRS −0.17, −0.12 Beasley et al,25 1997 Olanzapine 1, 5, 10, and 15 mg; Europe, South Africa, 6 83, 85, 83, PANSS −0.04, −0.04,b −0.04,b haloperidol Australia, Israel 85, 79 −0.05,b −0.05 Beasley et al,26 1996 Olanzapine 1 and 10 mg, placebo United States 6 50, 49, 49 BPRS −0.01, −0.06,b 0.01 Beasley et al,27 1996 Low, middle, and high dose of North America 6 36, 37, 36, PANSS −0.06, −0.12, −0.14, olanzapine; haloperidol; placebo 36, 35 −0.12, −0.03 Bechelli et al,28 1983 Pipotiazine, haloperidol, placebo Brazil 4 29, 30, 31 BPRS −0.18, −0.15, −0.03 Bender et al,29 2006 Olanzapine, clozapine Germany 26 54, 54 PANSS −0.21, −0.24 Bressler et al,30 1971 Chlorpromazine, thiothixene United States 4 13, 13 Psychiatric −0.29, −0.30 Rating Scale Brook et al,31 2005 Ziprasidone, haloperidol United States, 6 429, 138 BPRS −0.14, −0.15 Germany, South Africa Buchanan et al,32 2012 Asenapine, olanzapine Europe, South Africa, 16 241, 244 PANSS −0.06, −0.06 (Eastern hemisphere) Australia Buchanan et al,32 2012 Asenapine, olanzapine North America, 16 244, 224 PANSS −0.05, −0.05 (Western hemisphere) South America Ceskova et al,33 1993 Risperidone, haloperidol Czech Republic 8 31, 31 BPRS −0.12, −0.13 Chaudhry et al,34 2007 Amoxapine, haloperidol Pakistan 6 26, 28 PANSS −0.07, −0.06 Chouinard et al,35 1993 Risperidone 2, 6, 10, and 16 mg; Canada 8 24, 22, 22, PANSS −0.05,b −0.12,b −0.05,b haloperidol 20 mg; placebo 24, 21, 22 −0.07,b −0.04, 0.02 Chouinard et al,36 1982 Pimozide, chlorpromazine Canada 4 20, 20 BPRS −0.18, −0.23 Clark et al,37 1968 Trifluperidol, chlorpromazine, United States 4 18, 18, 18 Oklahoma −0.11, −0.01, 0.05 placebo Behavior Scale Clark et al,38 1970 Chlorpromazine 150, 300, and United States 24 16, 15, 17, 17 BPRS −0.08, −0.12, −0.07, −0.00 600 mg; placebo Clark et al,39 1970 Molindone, chlorpromazine, United States 12 15, 15, 14 BPRS −0.05, −0.03, 0.03 placebo Clark et al,40 1972 Chlorpromazine, loxapine, United States 12 19, 18, 18 BPRS −0.02, −0.07, −0.01 placebo Clark et al,41 1975 Trifluoperazine 50 mg, United States 4 12, 13, 12 BPRS −0.13, −0.07, −0.06 loxapine 100 mg, placebo Claus et al,42 1992 Risperidone, haloperidol Belgium 12 21, 21 PANSS −0.07,b −0.03 Conley et al,43 2001 Risperidone, olanzapine Belgium 8 188, 189 PANSS −0.01, −0.01 Copolov et al,44 2000 Quetiapine, haloperidol Europe, Australia, 6 221, 227 PANSS −0.09, −0.11 South Africa Cutleretal,45 2006 Aripiprazole 2, 5, and 10 mg; United States 6 93, 92, 94, 88 PANSS −0.04, −0.05, −0.05,b −0.03 placebo Cutleretal,46 2010 Quetiapine 400, 600, 800 mg, United States 6 113, 101, 110, PANSS −0.05, −0.06, −0.08, and IR; placebo 109, 111 −0.07, −0.07 Daniel et al,47 1999 Ziprasidone 80 and 160 mg, North America 6 106, 104, 92 PANSS −0.06,b −0.08,b −0.03 placebo Davidson et al,48 2007 Paliperidone ER 3, 9, and 15 mg; North America, Europe, 6 123, 123, 113, PANSS −0.07, −0.08, −0.09, olanzapine; placebo Asia, Israel, 126, 120 −0.09, −0.01 Mexico, South Africa Dehnel et al,49 1968 Clopenthixol, perphenazine United States 12 25, 25 BPRS −0.18, −0.14 Dube et al,50 1976 Loxapine, chlorpromazine India 12 26, 26 BPRS −0.25, −0.24 Edwardsetal,51 1980 Sulpiride, trifluoperazine England 6 19, 19 BPRS −0.11, −0.06 Emsley et al,52 1999 Risperidone, haloperidol Australia, Europe, 6 99, 84 PANSS −0.15, −0.14 Canada, Korea, South Africa Filhoetal,53 1975 Loxapine, thiothixene Brazil 13 26, 24 BPRS −0.20, −0.26

(continued)

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Table 1. Summary of Included Studies and Participants (continued)

Countries or Study Patients, No. Outcome Standardized Source, Year Treatment Continents Duration, wk (ITT) Measure Mean Changea Frangos et al,54 1978 Fluspirilene, fluphenazine Greece 16 25, 25 BPRS −0.10, −0.09 decanoate Freeman et al,55 1969 Trifluoperazine, molindone United States 8 20, 20 BPRS −0.17, −0.21 Freeman et al,56 1973 Mesoridazine, chlorpromazine United States 12 25, 25 BPRS −0.41, −0.43 Gelenberg et al,57 1979 Clozapine, chlorpromazine United States 4 7, 8 BPRS −0.17, −0.07 Ghaleiha et al,58 2011 Risperidone, haloperidol, Iran 8 16, 16, 16 PANSS −0.21,b −0.18, −0.23b clozapine Gopal et al,59 2010 Paliperidone 50, 100, and United States, 13 93, 94, 30, PANSS −0.04, −0.05, 150 mg; placebo Europe, Asia 132 −0.05, −0.02 Granacher et al,60 1982 Thioridazine, thiothixene United States 12 27, 27 BPRS −0.14, −0.10 Grootens et al,61 2011 Ziprasidone, olanzapine Europe 8 35, 39 PANSS −0.07, −0.08 Haas et al,62 1982 Pimozide, haloperidol Germany 4 15, 15 BPRS −0.32, −0.22 Harnryd et al,63 1984 Sulpiride 800 mg, Sweden 8 25, 25 CPRS −0.4, −0.33 chlorpromazine 400 mg Heikkilä et al,64 1981 cis(Z)-clopenthixol, haloperidol Finland 8 30, 33 BPRS −0.08, −0.04 Hoyberg et al,65 1993 Risperidone 5 mg, Denmark, 8 55, 52 PANSS −0.11, −0.1 perphenazine 16 mg Norway Ishigooka et al,66 2001 Olanzapine, haloperidol Japan 8 90, 84 PANSS −0.1, −0.04 Itil et al,67 1971 Molindone, trifluoperazine Turkey 13 30, 28 BPRS −0.28, −0.27 Kahn et al,68 2007 Quetiapine 400, 600, 800 mg Europe, Asia, 6 111, 111, 117, PANSS −0.12,b −0.14,b −0.15,b and IR; placebo South Africa 119, 115 −0.13,b −0.09 Kane et al,69 2003 Risperidone 25, 50, and 75 mg; United States 12 99, 103, PANSS −0.11, −0.08, placebo 100, 98 −0.07, −0.03 Kane et al,70 2007 Paliperidone ER 6, 9 and 12 mg; Europe, India 6 123, 122, 129, PANSS −0.09,b −0.08,b −0.11,b olanzapine; placebo 128, 126 −0.09,b −0.02 Kane et al,71 2002 Aripiprazole 15 and 30 mg; United States 4 102, 102, PANSS −0.07,b −0.05,b haloperidol; placebo 104, 106 −0.07,b −0.01 Kane et al,72 2009 Aripiprazole; olanzapine North America, 28 285, 281 PANSS −0.12, −0.10 South America, Australia Keck et al,73 1998 Ziprasidone 40 and 120 mg, United States 4 41, 43, 47 BPRS −0.03, −0.04, −0.08 placebo Kilohetal,74 1976 Loxapine, trifluoperazine Australia 12 17, 10 BRPS −0.35, −0.33 Kinon et al,75 2008 Olanzapine 10, 20, and 40 mg United States 8 199, 200, 200 PANSS −0.11, −0.13, −0.12 Klieser et al,76 1995 Risperidone 4 and 8 mg, Germany 4 18, 17, 18 BPRS −0.23, −0.20, −0.24 clozapine 400 mg Kramer et al,77 2010 Paliperidone 50 and 100 mg, United States, 9 63, 68, 66 PANSS −0.03, −0.04, 0.03 placebo Europe, India Lauriello et al,78 2008 Olanzapine 210 and 300 mg United States, 8 106, 100, PANSS −0.11, −0.13, every 2 wk; olanzapine 405 mg Russia, Croatia 100, 98 −0.11, −0.04 every 4 wk; placebo Linetal,79 2010 Risperidone plus haloperidol, Taiwan 6 46, 42 PANSS −0.10, −0.11 risperidone Luckey et al,80 1967 Trifluoperazine, haloperidol United States 12 13, 13 BPRS −0.05, −0.13 Marder et al,81 1994 Risperidone 2, 6, 10, and 16 mg; United States 8 63, 64, 65, PANSS 0.02, −0.01,b −0.08,b haloperidol; placebo 64, 66, 66 −0.04,b −0.07,b −0.02 Marder et al,82 2007 Paliperidone 6 and 12 mg, United States 6 111, 111, PANSS −0.07, −0.08, olanzapine, placebo 105, 105 −0.09, −0.04 Martin et al,83 2002 Amisulpride, olanzapine Europe, Africa 8 189, 188 PANSS −0.12, −0.11 McIndoo et al,84 1971 Mesoridazine, placebo United States 8 40, 40 BPRS −0.25, 0.01 Meltzer et al,85 2011 Lurasidone 40 and 120 mg, United States, 6 119, 118, PANSS −0.12,b −0.11,b olanzapine, placebo Colombia, 122, 114 −0.14,b −0.08 Lithuania, Asia Mölleretal,86 2008 Risperidone, haloperidol Germany 8 143, 146 PANSS −0.10, −0.11 Moore et al,87 1975 Loxapine, chlorpromazine United States 6 29, 29 BPRS −0.26, −0.17 Moyano et al,88 1975 Loxapine, trifluoperazine United States 12 25, 24 BPRS −0.19, −0.13 Nakamura et al,89 2009 Lurasidone, placebo United States 6 90, 90 PANSS −0.07,b −0.03 Palestine,90 1972 Mesoridazine, chlorpromazine United States 8 29, 26 BPRS −0.19, −0.13 Pandina et al,91 2011 Paliperidone depot, Europe, 13 453, 460 BPRS −0.17, −0.17 risperidone depot United States, India (continued)

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Table 1. Summary of Included Studies and Participants (continued)

Countries or Study Patients, No. Outcome Standardized Source, Year Treatment Continents Duration, wk (ITT) Measure Mean Changea Pandina et al,92 2010 Paliperidone 25, 100, and United States, 13 155, 161, BPRS −0.08, −0.11, 150 mg; placebo Europe, Asia 160, 160 −0.12, −0.03 Pecknold et al,93 1982 Chlorpromazine, pimozide Canada 4 10, 10 BPRS −0.11, −0.20 Peuskens et al,94 1995 Risperidone 1, 4, 8, 12, and South America, 8 229, 227, 230, PANSS −0.06, −0.09, −0.09, 16 mg; haloperidol Europe, 226, 224, 226 −0.08, −0.08, −0.07 South Africa Peuskens et al,95 1997 Quetiapine, chlorpromazine Europe, South Africa 8 101, 100 PANSS −0.17, −0.17 Potkin et al,96 2003 Aripiprazole 20 and 30 mg, United States 4 98, 96, PANSS −0.07,b −0.07,b risperidone, placebo 95, 103 −0.07,b −0.02 Potkin et al,97 2007 Asenapine, risperidone, United States 6 60, 60, 62 PANSS −0.08,b −0.05, −0.03 placebo Potkin et al,98 2008 Iloperidone 4, 8, and 12 mg; United States 6 121, 125, 124, PANSS −0.04, −0.04, −0.05,b haloperidol; placebo 124, 127 −0.07,b −0.02 Potkin et al,98 2008 Risperidone 4-8, 10-16, and United States 6 153, 154, PANSS −0.05,b −0.05,b 4-8 mg; placebo 153, 156 −0.08,b −0.02 Potkin et al,98 2008 Iloperidone 12-16 and United States 6 244, 145, PANSS −0.05, −0.07,b 20-24 mg, risperidone, placebo 157, 160 −0.09,b −0.04 Rickels et al,99 1978 Thiothixene, chlorpromazine United States 4 39, 40 BPRS −0.16, −0.14 Riedel et al,100 2005 Quetiapine, risperidone Germany 12 21, 22 PANSS −0.15, −0.14 Ritter et al,101 1972 Mesoridazine, placebo United States 8 30, 30 BPRS −0.14, −0.01 Russell et al,102 1982 Fluspirilene, fluphenazine Canada 24 18, 10 BPRS −0.1, −0.1 decanoate Selman et al,103 1976 Loxapine, haloperidol, United States 12 28, 26, 25 BPRS −0.13, −0.15, −0.05 placebo Serafetinides et al,104 Clopenthixol, chlorpromazine, United States 12 15, 14, 14, 13 BPRS −0.02, −0.04, 1972 haloperidol, placebo 0.03, 0.07 Shopsin et al,105 1979 Clozapine, chlorpromazine United States 5 13, 12 BPRS −0.24, −0.09 Silverstone et al,106 Pimozide, haloperidol England 4 10, 12 MRS −0.14, −0.10 1984 Simpson et al,107 1967 Ziprasidone, olanzapine United States 6 136, 133 BPRS −0.11, −0.11 Simpson et al,108 1971 Loxapine, trifluoperazine United States 4 24, 19 BPRS −0.16, −0.13 Simpson et al,109 1977 Haloperidol 6 and 30 mg United States 14 8, 5 IMPS −0.27, −0.23 Sirota et al,110 2006 Quetiapine, olanzapine Israel 12 19, 21 PANSS −0.06, −0.05 Small et al,111 1997 Quetiapine 750 and 250 mg, United States, 6 96, 94, 96 BPRS −0.09, −0.04, −0.01 placebo Europe Steinbrook et al,112 Loxapine, chlorpromazine United States 6 27, 27 BPRS −0.20, −0.09 1973 Sugerman et al,113 Trifluoperazine, trifluperidol United States 4 11, 11 BPRS −0.36, −0.26 1965 Tollefson et al,114 1997 Olanzapine, haloperidol United States 6 1312, 636 PANSS −0.08,b −0.04 Tuason et al,115 1984 Chlorpromazine, loxapine United States 4 34, 34 BPRS −0.27, −0.15 Volavka et al,116 2002 Clozapine, olanzapine, United States 14 40, 39, 41, 37 PANSS −0.03, −0.04, risperidone, haloperidol −0.01, −0.01 Wolpertetal,117 1968 Trifluoperazine 60 and United States 12 53, 53, 55 BPRS 0.10, 0.07, 0.04 600 mg, placebo Zhong et al,118 2006 Quetiapine, risperidone United States 8 338, 334 PANSS −0.07, −0.09 Zimbroff et al,119 2007 Ziprasidone, aripiprazole United States 4 121, 126 PANSS −0.10, −0.12

Abbreviations: BPRS, Brief Psychiatric Rating Scale; CPRS, Comprehensive a The pre-post treatment difference in means divided by the number of total Psychopathological Rating Scale; ER, extended release; IM, intramuscularly; points possible on the scale used. IMPRS, Inpatient Multidimensional Psychiatric Scale; IR, immediate release; b P < .05 for comparison with placebo or comparator. ITT, intention to treat; MRS, Montgomery Rating Scale; PANSS, Positive and Negative Syndrome Scale.

Syndrome Scale) per decade since 1960 for patients assigned medication: Spearman r =0.32,n=25,P = .12; intramuscular to placebo. In contrast, the mean change in patients receiving medication: Spearman r =−0.14,n=24,P = .53). We exam- effective dose medication decreased significantly over the same ine correlations between study variables and publication year time period (Spearman r = −0.26, n = 208, P < .001), equating in the eAppendix in the Supplement. to a decrease of 2.0 BPRS points or 3.8 Positive and Negative Syndrome Scale points per decade since 1960. The mean change Multilevel Meta-analysis in patients receiving low-dose or intramuscular medication was In the unconditional model of treatment change, variability was not significantly associated with publication year (low-dose over 3 times greater than expected by chance alone (H =3.3

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Table 2. Clinical Characteristics of Included Patients and Methodological Features of Studies

Medication Treatment Characteristic Placebo Low Dose Effective Dose Intramuscular Treatment groups, No. 39 25 208 24 Patients, No. 2882 1984 17 147 2490 Age, mean (SD), y 39.3 (4.0) 38.0 (2.3) 37.4 (5.8) 38.6 (2.8) Pretreatment score, mean (SD), y PANSS 93.9 (3.9) 94.9 (4.3) 92.4 (7.2) 90.3 (8.0) BPRS 47.0 (14.0) 44.5 (3.7) 49.8 (10.3) 58.4 (23.8) Study duration, mean (SD), wk 8.6 (5.1) 7.2 (3.9) 8.5 (4.8) 12.9 (4.4) Abbreviations: BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Visits, mean (SD), No. 5.7 (2.3) 6.3 (2.0) 5.4 (2.2) 5.8 (2.1) Negative Syndrome Scale. Dropout rate, mean (SD), % 47.4 (21.6)a 47.3 (14.0) 29.1 (19.4) 38.1 (14.8) a P <.05.

[95% CI, 3.0-3.5]), and the proportion of variability in mean native methods of calculating standardized mean change did change caused by heterogeneity rather than random error was not change the overall pattern of results (see “Repeated Multi- 91.8% (I2 = 0.918). Coefficients and accompanying statistical level Models Using Different Methods of Calculating Standard- tests for the predictor variables in the final model of standardized Mean Change” in the eAppendix in the Supplement). ized mean change are presented in Table 3. The primary findings for level 1 main effects were that effective dose medication (t = 14.15, P < .001), low-dose medication (t =4.65, 260 260 Discussion P < .001), and intramuscularly administered medication

(t260 =2.99,P = .004) were each associated with significantly In this meta-analysis of 105 trials of acute antipsychotic drugs more change than placebo. There were no significant main ef- for schizophrenia, the placebo response was shown to be sig-

fects of sample size (t260 =−0.40,P = .69) or standardized nificantly increasing from 1960 to the present (Spearman

baseline severity (t260 = 1.13, P = .26) after accounting for other r = 0.52, P = .001). Strikingly, whereas the average placebo- variables. treated patient in an RCT of antipsychotic drugs from the 1960s The relative benefit of effective dose medication over pla- worsened by 3.5 BPRS points, by the 2000s, the average placebo decreased over time (publication year × effective dose in- cebo-treated patient improved by 3.2 BPRS points. In con-

teraction: t260 = −5.55, P < .001), which was not observed for trast, the treatment change associated with effective dose low-dose or intramuscularly administered medication. More- medication significantly decreased over the same time pe- over, the relative benefit of effective dose medication over pla- riod (r =−0.26,P < .001). The average RCT participant receiv- cebo decreased with increasing study duration (study dura- ing an effective dose of medication in the 1960s improved by

tion × effective dose interaction: t260 = −3.76, P < .001). Baseline 13.8 BPRS points, whereas this difference diminished to 9.7 severity score significantly interacted with both low-dose medi- BPRS points by the 2000s. The consequence of these diver-

cation (t260 =2.30,P = .02) and effective dose medication gent trends was a significant decrease in drug-placebo differ-

(t260 =5.08,P < .001). These interactions indicate that the av- ences from 1960 to the present (effective dose medica-

erage benefit of medication over placebo increased as base- tion × publication year interaction: t260 = −5.55, P < .001). line symptom severity increased. Our analyses suggest that a change in the patient popula- With respect to between-study (level 2) variables, the mean tion enrolling in RCTs of antipsychotic drugs may contribute treatment change significantly increased with year of publica- to the decreasing drug-placebo differences observed over time.

tion (t93 = 2.38, P = .02), although the direction of this effect dif- We found that the benefit of effective dose medication over fered depending on treatment assignment, as already ex- placebo was greater for more severely ill patients (baseline se-

plained. Medication treatment in comparator study designs was verity × effective dose interaction: t260 =5.08,P < .001), yet the associated with significantly more improvement than medica- mean baseline severity in these RCTs appears to be decreas-

tion treatment in placebo-controlled trials (t93 = 2.73, P = .008), ing over time (n = 282, r = −0.13, P = .03). A recent meta- amounting to an average 3.8 BPRS point difference (control- analysis of placebo response in schizophrenia studies by Agid ling for other variables). The use of single-blind lead-ins signifi- et al4 found that the number of study sites significantly in- cantly decreased the average pre-post treatment change creased from a median of 2 sites before 1990 to 38 sites in the

observed (t93 = −2.29, P = .02), but there were no significant 2005-2010 time interval. The same investigators found that the

lead-in × low-dose interactions (t93 =−0.39,P =.70)or percentage of academic sites in antipsychotic drug trials de-

lead-in × effective dose interactions (t93 = −1.79, P = .07), sug- creased from 40% of the total before 1997 to 10% from 1997 gesting that single-blind lead-ins decrease both medication and onward.4 Although we did not directly test the relationship be- placebo response symmetrically. Overall, the final mixed model tween the type and the number of study sites with placebo re- of standardized mean change significantly improved model fit sponse, we did find that the standardized mean change for pla- 2 over the unconditional model (χ 24 = 242.0, P < .001) and ex- cebo-treated patients was significantly associated with sample plained 65.8% of the residual variability in mean change. Alter- size (Pearson r =0.48,n=39,P = .002). Because a larger sample

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Figure 2. Relationship of Standardized Mean Change to Year of Publication for Patients Receiving Placebo or Low-Dose, Effective Dose, or Intramuscular Medication

Placebo arms (n = 39) Low-dose medication arms (n = 25) 40 25

20 30

10 5 Rank Order of Standardized Mean Change Rank Order of Standardized Mean Change

0 0 1960 1970 1980 1990 2000 2010 2020 1960 1970 1980 1990 2000 2010 2020 Year of Publication Year of Publication

Effective dose medication arms (n = 208) Intramuscular medication arms (n = 24) 250 25

200 20

150 15

100 10

50 5 Rank Order of Standardized Mean Change Rank Order of Standardized Mean Change

0 0 1960 1970 1980 1990 2000 2010 2020 1970 1980 1990 2000 2010 2020 Year of Publication Year of Publication

The standardized mean change was significantly positively correlated with year medication arms (Spearman r =−0.26,n=208,P < .001), but not for the of publication for placebo arms (Spearman r =0.52,n=39,P = .001) and was low-dose medication arms (Spearman r =0.32,n=25,P =.12)orthe significantly negatively correlated with year of publication for the effective dose intramuscular medication arms (Spearman r =−0.14,n=24,P = .53).

size generally requires a greater number of study sites, this find- designs or whether criteria for early discontinuation are met) ing appears consistent with the findings of Agid et al.4 or may result in rater bias, thereby contributing to the ob- Another interesting finding in our meta-analysis was that served outcome differences between study types. medication treatment in comparator study designs was asso- Contrary to our hypotheses, the intensity of therapeutic ciated with significantly more improvement than medica- contact (ie, the number of scheduled visits) did not signifi-

tion treatment in placebo-controlled trials (t93 = 2.73, P = .008). cantly influence the pre-post treatment change observed or One possible explanation for these results is that individuals affect average drug-placebo differences in our sample of with schizophrenia become aware of their probability of re- trials of antipsychotic drugs. One reason for this may be that ceiving active medication during the informed consent pro- much of the treatment provided in these trials occurs within cedure in an RCT, and this information generates expecta- an inpatient setting, in which all patients benefit from a tions of improvement that influence treatment response. therapeutic milieu and attention from health care providers Alternatively, the awareness of clinicians and raters of whether regardless of how frequent their visits with research staff. an RCT of antipsychotic drugs uses an active comparator or pla- Alternatively, it may be the case that the supportive provi- cebo control may influence treatment response. In some cases, sion of empathy, a coherent narrative to understand one’s ill- this “investigator expectancy” may influence clinical deci- ness, and a therapeutic relationship are less effective in the sion making (eg, regarding dosage changes in flexible-dosing treatment of schizophrenia.

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Table 3. Multilevel Meta-analysis of Standardized Mean Change and Dropout Ratesa

Model of Standardized Mean Change Fixed Effect Coefficient (SE) t Value df P Value Intercept 0.032 (0.012) 2.55 93 .01 Year 0.0014 (0.0006) 2.38 93 .02 Diagnosis 0.002 (0.013) 0.189 93 .85 Design 0.035 (0.013) 2.73 93 .008 Treatment setting −0.012 (0.014) −0.87 93 .39 Lead-in −0.032 (0.014) −2.29 93 .02 Visits −0.001 (0.004) −0.26 93 .79 Duration 0.001 (0.002) 0.72 93 .47 Baseline severity 0.086 (0.083) 1.04 260 .30 Sample size −0.00001 (0.00003) −0.29 260 .77 Low dose 0.05 (0.011) 4.65 260 <.001 Dose × year −0.0005 (0.001) −0.43 260 .67 Dose × visits 0.004 (0.005) 0.78 260 .43 Dose × duration −0.0014 (0.003) −0.48 260 .63 Dose × baseline severity 0.38 (0.17) 2.30 260 .02 Effective dose 0.075 (0.0053) 14.15 260 <.001 Dose × year −0.0024 (0.0004) −5.55 260 <.001 Dose × visits 0.0038 (0.003) 1.31 260 .19 Dose × duration −0.0048 (0.0013) −3.76 260 <.001 Dose × baseline severity 0.41 (0.080) 5.08 260 <.001 Intramuscular dose 0.076 (0.026) 2.99 260 .004 Dose × year −0.0018 (0.0013) −1.37 260 .17 Dose × visits 0.0041 (0.0090) 0.46 260 .64 Dose × duration −0.0032 (0.0049) −0.64 260 .52 Dose × baseline severity 0.096 (0.080) 1.21 260 .23 Random Effect Variance Component df χ2 Value P Value Intercept 0.0026 93 1317.5 <.001 Level 1 0.00055

a We provide coefficients and statistical tests for the predictor variables provide the difference in mean change between 1 additional week duration examined in the full model of treatment change. “Year” refers to the year of relative to the mean duration. “Baseline severity” is the pretreatment publication for each study in the sample, centered on the earliest year in this symptom score, standardized by dividing by the maximum number of points sample (1960). “Diagnosis” is a dummy variable coded 0 for schizophrenia possible on the scale used and centered on the overall standardized mean in only or 1 for studies enrolling participants with a variety of psychotic disorders the study. “Sample size” is the sample size for each treatment arm, centered (eg, schizophrenia or schizoaffective disorder). “Design” is a dummy variable on the overall mean number for sample size. “Low dose” is a dummy variable coded 1 for comparator trials and 0 otherwise, making the statistics associated coded 1 for ineffectively dosed antipsychotic medication and 0 otherwise. with it relative to placebo-controlled trials. “Treatment setting” was coded 1 for “Effective dose” is a dummy variable coded 1 for effectively dosed studies having any outpatient component and 0 otherwise (ie, for antipsychotic medication and 0 otherwise. “Intramuscular dose” is a dummy inpatient-only studies), and “lead-in” was coded 1 if the study included a variable coded 1 for intramuscularly dosed antipsychotic medication and 0 single-blind placebo lead-in period and 0 otherwise. “Visits” denotes the otherwise. The coefficients associated with low dose, effective dose, and number of clinic visits in each study, centered on the overall mean for visits in intramuscular dose represent the difference in mean change between patients the sample (mean [SD] number of visits, 5.5 [2.2]). The statistics associated receiving medication and patients receiving placebo, controlling for other with “visits” provide the difference in mean change between 1 additional visit study variables. Positive coefficients indicate greater pre-post change (ie, relative to the mean number of visits. “Duration” is the duration of treatment greater improvement relative to baseline), whereas negative coefficients in each study, centered on the overall mean for duration in the sample (mean indicate less pre-post change. [SD] duration, 8.8 [4.9] weeks). The statistics associated with “duration”

Comparing these findings with what is known about pla- smaller, academic, single-site trials to larger, commercial, cebo response in other disorders such as major depressive multicenter trials.4,120 These changes in RCT conduct have disorder, we find that a picture of placebo response emerges significant advantages, such as the increased statistical in which a substantial portion is caused by general method- power conferred by larger samples. However, increased ological factors rather than the nature of the illness under measurement error associated with multicenter clinical study (see “Relevance of Results for Clinical Trial Design” in trials may lead to decreased effect sizes for medication and the eAppendix in the Supplement for further discussion). may partially offset the benefits of a larger sample size.121 For example, a common trend in both antidepressant and Second, whereas academic investigators may be biased by antipsychotic drug trials has been a shift over time from their interest in a positive research outcome, commercial

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sites, particularly those operated by contract research orga- visits that each participant attended. Finally, the time period nizations, have arguably more powerful financial incentives that we examined (1960-2010) encompassed significant to enroll patients, which can result in the inflation of base- changes in the diagnostic criteria used to identify patients (eg, line scores by raters followed by a rapid decrease in scores the publication of DSM-III in 1980),124 and it is possible that once the restrictive entrance criterion has been passed.122 the criteria used to define schizophrenia differed across stud- Some data suggest that using centralized raters may help ies and contributed to the results. control these potential biases and consequently improve inter-rater reliability, reduce biases toward inflation of baseline scores and observing improvement, and eliminate the Conclusions effects of repeated assessments by the same clinician.123 A number of limitations should be considered when in- In summary, the results from our meta-analysis confirm that terpreting the findings of our study. There were relatively few the placebo response rates have been increasing over time in placebo-controlled trials (n = 39) meeting our selection crite- antipsychotic drug trials, while the change observed in medi- ria, which limited the data available for analysis in our study. cation-treated patients has been decreasing. Possible causes The use of trial-level summary data was another limitation be- include decreased baseline symptom severity of study par- cause we were unable to test for associations between pa- ticipants and a change in the treatment settings within which tient characteristics and the effects of study type and fre- studies are conducted. The methodological changes to im- quency of visits. In addition, publication bias may have affected prove signal detection in RCTs of antipsychotic drugs sug- which studies were included in these analyses because RCTs gested by our meta-analysis would be to recruit more se- failing to demonstrate significant differences between medi- verely ill patients, limit study duration to no longer than 8 to cation and placebo may not have been published. Also, we de- 12 weeks, dispense with single-blind placebo lead-in periods, termined the number of visits based on the designed visit and maximize the probability of being assigned to placebo as schedule for each study rather than on the actual number of opposed to active medication.

ARTICLE INFORMATION Correction: This article was corrected on 10. Bryk AS, Raudenbush SW. Hierarchical Linear Submitted for Publication: January 3, 2014; final November 13, 2014, to fix a typographical error in Models. Newbury Park, CA: Sage Publications; 1992. revision received May 27, 2014; accepted June 9, the text. 11.HoxJ.Multilevel Analysis: Techniques and 2014. Applications. Mahwah, NJ: Lawrence Erlbaum REFERENCES Published Online: October 8, 2014. Publishers; 2002. doi:10.1001/jamapsychiatry.2014.1319. 1. Kinon BJ, Potts AJ, Watson SB. Placebo response 12. Haddock CK, Rindskopf D, Shadish WR. Using in clinical trials with schizophrenia patients. Curr odds ratios as effect sizes for meta-analysis of Author Contributions: Dr Rutherford had full Opin Psychiatry. 2011;24(2):107-113. access to all of the data in the study and takes dichotomous data: a primer on methods and issues. responsibility for the integrity of the data and the 2. Walsh BT, Seidman SN, Sysko R, Gould M. Psychol Methods. 1998;3(3):339-353. accuracy of the data analysis. Placebo response in studies of major depression: doi:10.1037/1082-989X.3.3.339. Study concept and design: Rutherford, Wall, Roose, variable, substantial, and growing. JAMA. 2002;287 13. Rutherford BR, Sneed JR, Roose SP. Does study Lieberman. (14):1840-1847. design influence outcome? the effects of placebo Acquisition, analysis, or interpretation of data: 3. Kemp AS, Schooler NR, Kalali AH, et al. What is control and treatment duration in antidepressant Rutherford, Pott, Tandler, Wall, Lieberman. causing the reduced drug-placebo difference in trials. Psychother Psychosom. 2009;78(3):172-181. Drafting of the manuscript: All authors. recent schizophrenia clinical trials and what can be 14. Rutherford BR, Sneed JR, Tandler JM, Critical revision of the manuscript for important done about it? Schizophr Bull. 2010;36(3):504-509. Rindskopf D, Peterson BS, Roose SP. intellectual content: Rutherford, Wall, Lieberman. 4. Agid O, Siu CO, Potkin SG, et al. Meta-regression Deconstructing pediatric depression trials: an Statistical analysis: Rutherford, Wall, Lieberman. analysis of placebo response in antipsychotic trials, analysis of the effects of expectancy and Administrative, technical, or material support: Pott, 1970-2010. Am J Psychiatry. 2013;170(11):1335-1344. therapeutic contact. J Am Acad Child Adolesc Tandler, Lieberman. Psychiatry. 2011;50(8):782-795. Study supervision: Roose, Lieberman. 5. Mallinckrodt CH, Zhang L, Prucka WR, Millen BA. Signal detection and placebo response in 15. Rutherford BR, Tandler J, Brown P, Sneed JR, Conflict of Interest Disclosures: Dr Lieberman schizophrenia: parallels with depression. Roose SP. Clinic visits in late-life depression trials: serves on the advisory board of Intra-Cellular Psychopharmacol Bull. 2010;43(1):53-72. effects on signal detection and therapeutic Therapies. He receives grant support from Allon, outcome [published online November 14, 2013]. Biomarin, Eli Lilly, F. Hoffman–La Roche, 6. Alphs L, Benedetti F, Fleischhacker WW, Kane JM. Placebo-related effects in clinical trials in Am J Geriatr Psychiatry. doi:10.1016/j.jagp.2013.09 Genentech, GlaxoSmithKline, Merck, Novartis, .003. Pfizer, Psychogenics, Sepracor (Sunovion), and schizophrenia: what is driving this phenomenon Targacept and holds a patent from Repligen. No and what can be done to minimize it? Int J 16. Higgins JPT, Thompson SG. Quantifying other disclosures are reported. Neuropsychopharmacol. 2012;15(7):1003-1014. heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-1558. Funding/Support: This work was supported by 7. Rutherford BR, Roose SP. A model of placebo National Institutes of Mental Health grant K23 response in antidepressant clinical trials. Am J 17. Takkouche B, Cadarso-Suárez C, Spiegelman D. MH085236 (Dr Rutherford). Psychiatry. 2013;170(7):723-733. Evaluation of old and new tests of heterogeneity in 8. Meltzer HY, Park S, Kessler R. Cognition, epidemiologic meta-analysis. Am J Epidemiol. 1999; Role of the Funder/Sponsor: The National 150(2):206-215. Institutes of Mental Health had no role in the design schizophrenia, and the atypical antipsychotic drugs. and conduct of the study; collection, management, Proc Natl Acad SciUSA. 1999;96(24):13591-13593. 18. Addington DEN, Pantelis C, Dineen M, Benattia analysis, or interpretation of the data; preparation, 9. Dickerson FB. Cognitive behavioral I, Romano SJ. Efficacy and tolerability of review, or approval of the manuscript; and decision psychotherapy for schizophrenia: a review of recent ziprasidone versus risperidone in patients with to submit the manuscript for publication. empirical studies. Schizophr Res. 2000;43(2-3):71- acute exacerbation of schizophrenia or 90. schizoaffective disorder: an 8-week, double-blind, multicenter trial. J Clin Psychiatry. 2004;65(12): 1624-1633.

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