1042-2587-01-262Copyright 2003 byBaylor University E T P Anne Evans: Assessment of a Biotechnology Market Opportunity Anne G. Evans Nikhil P. Varaiya This case describes Anne Evans’ search for a market opportunity in the biotechnology industry, and examines the feasibility of establishing a new venture to exploit this oppor- tunity. The drug development process in the biopharmaceutical in
7-15-keefe.fmEffects of Olanzapine, Quetiapine, and Risperidone
on Neurocognitive Function in Early Psychosis:
A Randomized, Double-Blind 52-Week Comparison
Richard S.E. Keefe, Ph.D.
Objective: The authors sought to com-
Results: At week 12, there was significant
John A. Sweeney, Ph.D.
treatment (p<0.01), but no significant function in patients with early psychosis.
overall difference between treatments.
Composite z score improvements on the Hongbin Gu, Ph.D.
Method: In a 52-week double-blind,
Robert M. Hamer, Ph.D.
the course of psychotic illness (<5 years) Diana O. Perkins, M.D.
tiapine (100–800 mg/day), or risperidone olanzapine, 0.34 for quetiapine, and 0.22 Joseph P. McEvoy, M.D.
for risperidone. Statistically significant re- Jeffrey A. Lieberman, M.D.
and 2.4 mg (SD=1.0) for risperidone. A to- tal of 224 patients completed neurocogni-tive assessments at baseline and at 12 Conclusions: Olanzapine, quetiapine,
psychosis patients. Although cognitive im- neurocognitive battery used in the Clini- cal Antipsychotic Trials of Intervention Ef- fectiveness (CATIE) and from the Brief As- sessment of Cognition in Schizophrenia.
(Am J Psychiatry 2007; 164:1061–1071)
In patients with schizophrenia, neurocognitive defi- with treatment and functional improvement in patients cits have been established as an important symptom do- main associated with long-term outcome. On average, Treatment with atypical antipsychotics has been found, these patients perform one to two standard deviations in various studies, to produce improvements in neurocog- below healthy individuals on neurocognitive measures, nitive performance in schizophrenia (3, 13–23; see also the such as those assessing attention, executive function, meta-analyses in references 20, 24, 25 and early psychosis memory, and processing speed (1, 2). These deficits are in references 8–10). However, the comparator medication clearly present at the first episode of illness (3–5), even in in many of these studies was a conventional antipsychotic antipsychotic-naive patients (6, 7), and thus are not a administered at doses large enough to produce substan- deleterious effect of treatment. These deficits appear to tial extrapyramidal symptoms requiring treatment with be only marginally corrected with conventional antipsy- anticholinergics, and both of these classes of medication chotic agents in patients early in the course of psychotic are associated with impaired cognition (20). In previous illness, even when medication is administered at lower studies, antipsychotic-naive patients with early psychosis receiving olanzapine (8, 9) or risperidone (10) demon- Because neurocognitive deficits are among the stron- strated greater neurocognitive improvement than those gest predictors of functional outcome in patients with receiving haloperidol, even when haloperidol was given in schizophrenia (5, 11, 12), interventions that reduce these low doses. In this study, we compared the neurocognitive deficits may be particularly useful; neurocognitive im- effects of olanzapine and risperidone and a third atypical provement may enhance patients’ recovery and func- antipsychotic, quetiapine. Our primary hypothesis was tional life outcomes. However, little research has exam- that the three agents would be equivalent in their effects ined the relationship between cognitive improvement This article is featured in this month’s AJP Audio and is discussed in an editorial by Dr. Green on p. 992.
COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
TABLE 1. Neurocognitive Domains Assessed by Tests in the CATIE Neurocognitive Battery and the BACSa
Controlled Oral Word Association Test: F, A, and S words Verbal fluency: letter fluency (F and S words or P Category instances: animals, fruits, and vegetables Wechsler Adult Intelligence Scale—Revised, digit symbol Wisconsin Card Sorting Test, 64-card version Wechsler Intelligence Scale for Children, 3rd ed., mazes Computerized Test of Visuospatial Working Memory Continuous Performance Test—Identical pairs: 2,3, and 4 a CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; BACS=Brief Assessment of Cognition in Schizophrenia.
b MATRICS=Measurement and Treatment Research to Improve Cognition in Schizophrenia.
This study is the first head-to-head comparison of the We excluded patients who did not speak English; had a history cognitive effects of atypical antipsychotics in early psy- of mental retardation; were pregnant or nursing; had a serious,unstable medical illness; had a known allergy to one of the study chosis. In this article, we examine the effects of olanza- medications; were at serious risk of suicide; or had participated in pine, quetiapine, and risperidone on neurocognitive func- an investigational drug trial within 30 days before the first treat- tion in patients early in the course of psychotic illness and the relationship of cognitive changes to changes in func- Study Treatments
tioning and quality of life. In a companion article in thisissue (26), we report results for the primary outcome Patients were randomly assigned to treatment with olanzapine (2.5–20 mg/day), quetiapine (100–800 mg/day), or risperidone measure of all-cause treatment discontinuation and sec- (0.5–4 mg/day). On days 1 and 2, each patient received one cap- ondary measures of psychopathology, quality of life, and sule of olanzapine (2.5 mg), quetiapine (100 mg), or risperidone (0.5 mg) in the evening. At the treating physician’s discretion, thedose could be increased by one capsule every other day—i.e., ondays 3 and 4, one capsule in the morning and one in the evening; on days 5 and 6, one capsule in the morning and two in theevening; and so on, up to a maximum of four capsules twice daily.
This was a 52-week randomized, double-blind, flexible-dose, Any previous antipsychotic therapy was tapered and discontin- multicenter study of patients early in the course of schizophrenia, ued during the first 2 weeks of double-blind treatment, and no schizoaffective disorder, or schizophreniform disorder assigned subsequent use of an additional antipsychotic was permitted.
to treatment with olanzapine, quetiapine, or risperidone.
Treatment with an adjunctive antidepressant or mood stabilizerduring the first 8 weeks of treatment was not allowed unless ap- Study Population
proved by the project medical officer. Anticholinergic medica- Participants were recruited from inpatient, outpatient, and tions for acute extrapyramidal side effects were permitted for up emergency department services for the evaluation and treatment to a total of 2 weeks over the course of the trial. Clinicians were of psychosis. The study was approved by the institutional review encouraged to lower the dose of antipsychotic to relieve extrapy- board at each site, and written informed consent was obtained ramidal side effects. Otherwise, adjunctive and concomitant from the patients or their legally authorized representatives. Con- medications could be used without restriction. This strategy kept senting patients 16–40 years of age were eligible for the study if the frequency of use for benzodiazepines, antidepressants, mood they met DSM-IV criteria for schizophrenia, schizophreniform stabilizers, and anticholinergics below 5% during the study.
disorder, or schizoaffective disorder. Patients had to be in the first Assessments
episode of their psychotic illness and had to have been continu-ously ill for at least 1 month and no more than 60 months. Pa- The screening evaluation included a diagnostic interview (the tients were excluded if a prior psychotic episode had remitted for Structured Clinical Interview for DSM-IV), medical history, physi- 3 months or more or if they had prior antipsychotic drug treat- cal examination, measurement of vital signs, and laboratory tests.
ment for more than 16 cumulative weeks. Several exceptions to Training covering the study protocol and administration of all these criteria were allowed on a case-by-case basis: the study in- study evaluations was provided at an investigator meeting. Cog- cluded nine patients who had been ill for more than 60 months, nitive testers who could not attend the meeting and raters who seven who were over 40 years of age, and 16 who had taken anti- joined the study after the investigator meeting participated in the psychotics for more than 16 weeks. All patients had a score ≥4 on same training using web-based materials, teleconferencing, and at least one psychosis item in the Positive and Negative Syndrome Scale (PANSS; 27) and a score ≥4 (moderately ill) on the severity of Study visits occurred at baseline, at weekly intervals for the first illness item of the Clinical Global Impression scale (CGI) at the 6 weeks, every other week for the next 6 weeks, and monthly point of maximum severity of illness to date. Female participants thereafter. Neurocognitive assessments were conducted at base- of childbearing potential had to be using a medically acceptable line (up to 2 weeks after the start of treatment) and at weeks 12 and 52 (up to 2 weeks before or after the target date) or when the KEEFE, SWEENEY, GU, ET AL.
TABLE 2. Baseline Characteristics of 400 Early-Psychosis Patients Randomly Assigned to Treatment With Olanzapine,
Quetiapine, or Risperidonea
Parents’ highest education level less than Clinical Global Impression scale, severity Calgary Depression Scale for Schizophrenia, Heinrichs-Carpenter Quality of Life Scale a Treatment groups did not differ significantly on any characteristic.
patient terminated the study if it was before week 52. A total of based composite score was defined as the average of the five do- 224 patients completed neurocognitive assessments at baseline main summary scores for the CATIE neurocognitive battery.
and 12 weeks, and 81 patients also completed them at 52 weeks.
An additional neurocognitive outcome measure was the com- Cognitive testers were not blind to adverse event status and use of posite score on the Brief Assessment of Cognition in Schizophre- nia (BACS; 30, 31), a briefer set of tests designed to derive a com- The primary neurocognitive outcome measure for this study posite score. With the BACS, we sought to determine its relative was a composite score derived from the neurocognitive battery sensitivity to treatment-related cognitive changes compared with used in the Clinical Antipsychotic Trials of Intervention Effective- the larger CATIE battery; we also wanted to enable comparisons ness (CATIE). The performance of the 1,331 patients assessed at between this study and other trials using the BACS. The BACS, baseline is described in detail elsewhere (28). For the calculation which takes approximately 35 minutes to administer, includes of the CATIE battery composite score, all test measures were first brief assessments of reasoning and problem solving, verbal flu- converted to standardized z scores by setting the sample mean of ency, processing speed, verbal memory, working memory, and each measure at baseline to zero and the standard deviation to 1.
motor functions. The BACS composite score was calculated by Summary scores for some tests were calculated by averaging z summing the z scores for each of the six measures, obtained by scores from individual measures: a Wisconsin Card Sorting Test comparing each measure with a healthy comparison sample and score was calculated by averaging z scores for preservative errors dividing by the standard deviation of the healthy comparison and categories achieved; a Continuous Performance Test score sample (30). This composite score has high test-retest reliability was calculated by averaging the z score of d-prime for the three in patients with schizophrenia and healthy comparison subjects different Continuous Performance Test conditions; and the Con- (intraclass correlation coefficients >0.80) (30). Pearson correla- trolled Oral Word Association Test and category instances sum- tions between the BACS composite score and CATIE neurocogni- mary measures were averaged together to form one summary test tive composite score in this study were r=0.84 at baseline, r=0.86 score referred to as verbal fluency. For domains with more than at 12 weeks, and r=0.90 at 53 weeks (all p values <0.001). Table 1 one test, summary scores were determined by calculating the summarizes the neurocognitive domains assessed by the CATIE mean of the z scores for the measures that comprised the domain, then converting the mean to a z score with a mean of zero and a Severity of psychopathology was measured with the PANSS standard deviation of 1. This resulted in nine test summary scores and the CGI severity item. Functional outcome was measured and five domain scores corresponding to five of the seven do- with the standard patient interview from the Heinrichs-Carpen- mains in the Measurement and Treatment Research to Improve ter Quality of Life Scale (32), emphasizing the vocational and so- Cognition in Schizophrenia consensus battery (29). A domain- COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
TABLE 3. Use of Adjunctive Medicationsa by Early-Psychosis Patients During Treatment With Olanzapine, Quetiapine, or
a Adjuctive medications include those prescribed to address an aspect of psychopathology inadequately controlled by the assigned antipsy- FIGURE 1. Changes in CATIE Neurocognitive Battery Com-
week 12 at the 0.05 significance level. All subsequent analyses on posite Score From Baseline to Weeks 12 and 52 in Patients
individual cognitive tests and between treatment groups were in- Treated With Olanzapine, Quetiapine, or Risperidonea
tended to expand our major finding and should be considered ex-ploratory. Therefore, no p value adjustments were made for mul-tiple comparisons.
Table 2 presents demographic and clinical characteris- tics for the three treatment groups and the whole cohort.
There were no significant differences between treatment groups. Patients demonstrated moderate levels of psycho- pathology at baseline, as reflected in scores on the PANSS,the CGI severity item, and the Calgary Depression Scale e in Composite Scor
The mean modal prescribed daily doses of study drugs were 11.7 mg (SD=5.3) for olanzapine, 506 mg (SD=215) for quetiapine, and 2.4 mg (SD=1.0) for risperidone; the a CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness.
mean modal numbers of prescribed capsules per day were 4.7 (SD=2.1) for olanzapine, 5.1 (SD=2.2) quetiapine, and 4.7 (SD=2.0) for risperidone. Since adjunctive treatmentswere discouraged, their use was rare after baseline. The Statistical Analysis
use of mood stabilizers, antidepressants, benzodiaz- Analyses of the neurocognitive variables were specified in a epines, and anticholinergics during the study is summa- statistical analysis plan that was finalized before the blind was rized in Table 3. There were no significant differences be- broken. Baseline measures of demographic and clinical charac-teristics were compared using two-sided Kruskal-Wallis tests for tween treatment groups in use of adjunctive medication.
continuous variables and Fisher’s exact test for categorical vari-ables. Separate general linear models provided least square Effects on Neurocognition
means estimates for changes in cognitive scores from baseline to At week 12, each of the treatments significantly im- weeks 12 and 52 for each treatment group, adjusting for baseline proved the composite score on the CATIE neurocognitive and weeks of treatment in cases where neurocognitive testing wascompleted 1 to 2 weeks before or after the scheduled visit. The ef- battery compared with baseline (p<0.01 for olanzapine, fect of group membership on neurocognitive change scores was p<0.001 for quetiapine and risperidone) (Table 4). There tested using the F statistic from the model, followed by pairwise was no significant difference between treatments in the comparisons between treatment groups if overall treatment effect magnitude of cognitive improvement. Mean z score im- was significant. Pearson partial correlation coefficients were used provements in the CATIE composite score were 0.17 for to examine the potential linear relationships between treatment-related changes in the neurocognitive composite scores and olanzapine, 0.33 for quetiapine, and 0.32 for risperidone treatment-related changes in the clinical outcome measures and the social and vocational subscale scores on the Heinrichs-Car- There was considerable attrition at week 52, with only penter Quality of Life Scale from baseline to weeks 12 and 52 in 81 patients providing enough neurocognitive data for the each treatment group and in the cohort as a whole. These correla- calculation of the CATIE composite score. The baseline tions were adjusted for baseline cognitive and clinical measures.
The primary analysis tested the overall treatment effect on and week 12 cognitive measures of patients who remained CATIE neurocognitive battery composite scores from baseline to in the study until week 52 were not significantly different KEEFE, SWEENEY, GU, ET AL.
from those of patients who dropped out of the study. The with a median correlation of –0.25. The correlations be- magnitude of cognitive improvement from baseline to tween cognitive change and change in clinical symptoms endpoint was similar for patients who stayed through to for the study population at week 52 had a range of –0.26 to week 52 (0.09 for olanzapine, 0.24 for quetiapine, and 0.27 –0.44. Correlations between cognitive change and global for risperidone) (Figure 1), but the within-group treatment clinical change within each treatment group were mainly effects on CATIE battery composite scores at week 12 were in the range of medium to large (r=–0.5), with a median correlation of –0.33 (Table 5). The correlations between Exploratory analyses of individual neurocognitive mea- cognitive change and symptom change tended to be larger sures at week 12 suggested differences between treat- ments on the following tests from the CATIE battery: ver-bal fluency, letter-number sequencing, WAIS-R digit Relationship Between Cognitive Change and
symbol subtest, and Continuous Performance Test d- Change in Functional Outcome
prime (Table 4). Subsequent pairwise comparisons of As reported in the companion article (26), changes in the treatment groups showed that at 12 weeks, the improve- vocational and social subscales of the Heinrichs-Carpenter ment in cognition was greater in the quetiapine group Quality of Life Scale were small at 12 weeks (less than 0.2 than in the olanzapine group (p<0.05) on measures of ver- standard deviations) and in the range of medium effects bal fluency, the WAIS-R digit symbol subtest, and the Con- (about 0.5 standard deviations) for each treatment group at tinuous Performance Test d-prime. Compared with the 52 weeks. In analyses of the total study population pooled risperidone group at 12 weeks, the improvement in cogni- across treatment groups at week 12 (N=219), partial corre- tion was greater in the quetiapine group (p<0.05) on mea- lations between change in the CATIE neurocognitive bat- sures of verbal fluency and the WAIS-R digit symbol sub- tery composite score and change in Heinrichs-Carpenter test. The improvement in cognition was greater in the Quality of Life Scale subscores, controlling for baseline risperidone group than in the olanzapine group (p<0.05) CATIE composite score and PANSS total score, were 0.14 on letter-number sequencing at 12 weeks. No other pair- (p=0.04) for vocational outcomes and 0.18 (p=0.009) for oc- wise comparisons were significant, and there were no sig- cupational outcomes. These partial correlations were nificant differences between treatments for individual slightly larger at week 52 (N=77; r=0.22 [p=0.056] to 0.36 [p= 0.001]). Within-treatment correlations between cognitive Relationship Between Cognitive Change and
change and functional change are presented in Figure 2.
Regression analyses conducted to further examine the re-lationship between cognitive, symptom, and functional As reported in the companion article in this issue (26), symptom reduction as rated on the PANSS and the CGI se- change suggested that the variance in social and voca- verity item was substantial in each treatment group, rang- tional functioning predicted by the CATIE composite score ing from 11.6 to 14.3 points on PANSS total score and 0.8 to was not statistically significant when additionally con- 0.9 points on the CGI severity item score at 12 weeks, and trolled for change in PANSS score during treatment.
15.6 to 18.5 points on PANSS total score and 1.2 to 1.3 Relationship Between Cognitive Change and
points on the CGI severity score at 52 weeks. Correlations Changes in Side Effects
between the CATIE neurocognitive battery compositescore and symptom changes at week 12 for the entire Correlations between cognitive change and changes in study population were small, ranging from –0.18 to –0.26.
side effects, as measured by scores at 12 and 52 weeks on Within treatment groups, the majority of the 15 correla- the Abnormal Involuntary Movement Scale (33), the tions between change in CATIE composite score and Barnes Rating Scale for Drug-Induced Akathisia (34), and change in PANSS or CGI severity score at week 12 were in the Simpson-Angus Rating Scale (35), were not statistically the effect size range of small (r=–0.1) to medium (r=–0.3), significant. Use of anticholinergic treatment or presence COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
TABLE 4. Least Square Mean (LSM) Change From Baseline on Neurocognitive Tests in Early-Psychosis Patients at Weeks 12
and 52 of Treatment With Olanzapine, Quetiapine, or Risperidonea
telligence Scale—Revised, digit symbol subtest ing Test, 64-card version, mean z score of persever-ative errors and categories completed gence Scale for Children, 3rd ed., mazes subtest ing Memory Test, mean error, 5 and 15 sec minus no delay (cm) mance Test, iden-tical pairs, mean z score of d-prime for 3 trials score (compared with published healthy comparison data) a Analyzed using a general linear model. Least square mean data are raw scores, adjusting for baseline and weeks of treatment.
b Week 12: A=overall effect between antipsychotic treatment groups, p<0.05; B=improvement from baseline with quetiapine, p<0.05; C=im- provement from baseline with risperidone, p<0.05; D=improvement from baseline with olanzapine, p<0.05; E=quetiapine versus risperi-done, p<0.05; F=quetiapine versus olanzapine, p<0.05; G=olanzapine versus risperidone, p<0.05. Week 52: H=overall effect between anti-psychotic treatment groups, p<0.05; I=improvement from baseline with quetiapine, p<0.05; J=improvement from baseline withrisperidone, p<0.05; K=improvement from baseline with olanzapine, p<0.05; L=quetiapine versus risperidone, p<0.05; M=quetiapine ver-sus olanzapine, p<0.05; N=olanzapine versus risperidone, p<0.05.
c CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; BACS=Brief Assessment of Cognition in Schizophrenia.
KEEFE, SWEENEY, GU, ET AL.
COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
FIGURE 2. Partial Pearson Correlations Between Change in
rocognitive test performance. There were no significant CATIE Neurocognitive Battery Composite Score and Change
differences between treatments in overall cognitive com- in Functional Outcome Measures From Baseline to Weeks
posite scores, which suggests that quetiapine may provide 12 and 52, Controlling for Baseline CATIE Composite Score
and PANSS Total Scorea
modest cognitive benefit to patients with early psychosisthat is in line with that provided by olanzapine and risperi-done. Improvement in the cognitive composite scores was significantly associated with improved social and occupa- tional functioning as measured by the Heinrichs-Carpen- earson r) 0.6
ter Quality of Life Scale. This result is the first direct evi- dence that antipsychotic treatment-related cognitive ith Chang
changes in patients with early psychosis may be clinically relevant for occupational and social functioning. How- ever, interpretation of this relationship is tempered byanalyses indicating that symptom change and baseline ocognitiv
cognitive scores also predicted the variance in functional Composite Scor
outcomes. Thus, cognitive improvement may be a part of a general treatment response that is associated with im- The magnitude of neurocognitive improvement for olanzapine and risperidone in this study is slightly less Heinrichs-Carpenter Quality of Life Scale
than that previously reported in comparisons with conven- a CATIE=Clinical Antipsychotic Trials of Intervention Effectiveness; tional antipsychotics in early-psychosis patients (8–10). In PANSS=Positive and Negative Syndrome Scale earlier studies that used doses similar to those we used in this study (8, 9), the magnitude of the effect of olanzapineon neurocognitive composite scores was 0.36 at 12 weeks of sleepiness or akinesia was not significantly related to and 0.56 at 52 weeks; in this study, olanzapine’s effect was cognitive performance at 12 or 52 weeks.
weaker, with effect sizes of 0.17 and 0.09 at 12 and 52weeks, respectively. The magnitude of the effect of risperi- Relationship Between CATIE Neurocognitive
done on neurocognition in an earlier study (10) was 0.4 at Battery and BACS
12 weeks, whereas in this study, effect sizes for risperidone Treatment effects on the BACS composite score were were 0.32 and 0.27 at 12 and 52 weeks, respectively.
similar to those on the CATIE battery composite score. The The reason for the lesser effect of olanzapine and ris- BACS data are described in more detailed tables and fig- peridone on neurocognition in this study compared with ures in a data supplement that accompanies the online previous studies is not entirely clear. These differences in version of this article. A total of 214 patients completed magnitude are small and could be due to random factors both the CATIE and BACS batteries at baseline and 12 or to methodological advances in the current study that weeks, and 76 completed both batteries at baseline and 52 may have served to refine the estimate of the magnitude of weeks. For the entire cohort, change in the CATIE compos- cognitive treatment effects, such as the inclusion of alter- ite score was highly correlated with change in the BACS nate verbal memory tests, which is likely to yield lower es- composite score at 12 weeks (r=0.57, df=212, p<0.001) and timates of improvement because of repeated test exposure at 52 weeks (r=0.70, df=74, p<0.001). The BACS composite (8–10). Another possible factor is prior exposure to anti- score changes were 0.19 for olanzapine (p<0.01), 0.34 for psychotics. Patients who are antipsychotic-naive when quetiapine (p<0.001), and 0.22 for risperidone (p<0.01), beginning treatment have been shown to obtain particu- similar to those of the CATIE battery. Between-groups larly large benefits from treatment with atypical antipsy- comparisons of individual BACS measures and correla- chotics (9). While about three-quarters of the patients in tions with symptom and side effect change paralleled the this study and in the earlier olanzapine study had briefly CATIE battery findings, with slightly more (4 of 12) signifi- received treatment with antipsychotics prior to random- cant relationships with functional outcomes.
ization, in this more recent study the medications receivedpreviously were more likely to have been atypical antipsy- Discussion
chotics, particularly olanzapine or risperidone. Patientswho were randomly assigned to the same medication that This is the first randomized, double-blind study com- they were receiving at or before baseline may have had a paring the neurocognitive effects of atypical antipsychotic reduced neurocognitive response to further treatment agents in the treatment of patients early in the course of (36). Moreover, patients were given a 2-week window after psychotic illness. Olanzapine, quetiapine, and risperidone treatment initiation to complete baseline neurocognitive produced modest but significant improvements in neu- testing. Thus, very early cognitive effects of antipsychotic KEEFE, SWEENEY, GU, ET AL.
TABLE 5. Pearson Correlations Between Change in CATIE Neurocognitive Battery Composite Score and Change in Clinical
Outcome Measures From Baseline to Weeks 12 and 52 in Early-Psychosis Patients During Treatment With Olanzapine,
Quetiapine, or Risperidonea
Clinical Global Impression, severity item a Negative correlations imply that as cognition improved, symptoms diminished.
*p<0.05. **p<0.01. ***p<0.001.
treatment might have occurred in some of these patients, The course of cognitive improvement with atypical an- which may have minimized measurements of cognitive tipsychotics is controversial. While some long-term stud- ies have reported increasing cognitive improvement over The significant benefit of quetiapine treatment on neu- time (9, 41), others have not (42). Furthermore, the addi- rocognitive measures in patients with early psychosis is a tional cognitive benefit over time may depend on signifi- new observation. Previous work has suggested that olan- cant patient attrition (9). Grouped data from all studies of zapine (8, 9) and risperidone (10) provide greater cognitive atypical antipsychotics suggest little additional cognitive benefit than low doses of haloperidol in patients with early benefit beyond the initial gains in the early phases (6–10 psychosis. Our findings in this study suggest that the effect weeks) of treatment (unpublished 2004 analysis of R.
of quetiapine on cognition may be as beneficial as that of Keefe and J. Cone). Our findings in this study support this olanzapine or risperidone, and thus this agent may be an- view, as the magnitude of cognitive improvements across other evidence-based alternative for clinicians who focus all domains was similar at 12 and 52 weeks, suggesting on cognitive outcomes. However, results from a recent that most of the cognitive benefit of atypical antipsychot- study of 240 schizophrenia patients with stable symptoms ics occurs in the first few months of treatment. This find- treated with donepezil or placebo over a 12-week period ing may be particularly relevant for clinicians deciding suggest that the amount of cognitive change we report whether to keep a patient on an antipsychotic treatment; here is consistent with what may be expected from prac- it suggests that patients who do not demonstrate early tice effects and placebo effects (unpublished 2004 study of cognitive benefit with a particular medication are unlikely R. Keefe et al.). This series of results raises the question of to show benefit with continued treatment. After 12 weeks whether even low doses of haloperidol have a deleterious of treatment, all correlations between cognitive improve- impact on cognition and whether the cognitive benefit of ment and symptom improvement were less than 0.3, atypical antipsychotics derives from their reduced adverse which is considered to be a medium effect, and most were effects rather than procognitive effects. It is noteworthy, closer to 0.1, which is a small effect (43). Thus, it is unlikely however, that this negative effect may not occur with the that the cognitive benefit of these antipsychotic treat- conventional antipsychotic perphenazine, whose cogni- ments was caused by symptom improvement. The corre- tive effects were similar to those of atypical antipsychotics lations with changes in symptoms were larger at 52 weeks, in the CATIE schizophrenia trial (37).
which suggests that patients who were able to continue Although much of our results stem from exploratory treatment to the end of the study may have been more ho- analyses with a large number of outcome measures not mogeneous and were improving across all symptom do- corrected for multiple comparisons, the pattern of results mains or that the clinical impact on cognition may require raises the possibility that quetiapine may have particular benefit on tests of verbal fluency and coding, in both the An important consequence of cognitive deficits in psy- processing speed domain (38) and vigilance. These data chotic disorders is functional impairment (11). However, support previous findings (16, 19, 22) as well as conclu- evidence that cognitive improvement with antipsychotic sions from a meta-analysis suggesting that quetiapine has treatment leads to functional change is limited (44). In this a particularly beneficial impact on verbal fluency and vig- study, patients with early psychosis who demonstrated ilance (24). Perhaps quetiapine’s lack of appreciable affin- cognitive improvement at 52 weeks also demonstrated ity for muscarinic cholinergic receptors (39), which mini- functional benefit in social and occupational domains, mizes anticholinergic effects, and its fast dissociation which suggests a functional relevance for cognitive im- from striatal dopamine D2 receptors (40), which mini- provement. One caveat to this promising conclusion is mizes potential adverse effects on frontostriatal systems that given the high dropout rate in this study, these data (including reduced thalamocortical drive), allow for more apply only to the patients who were able to stay in treat- ment and complete comprehensive assessments for 52 COGNITIVE EFFECTS OF ATYPICAL ANTIPSYCHOTICS
weeks, a group that comprised only 20% of the original ment between University of North Carolina and the following: Wyeth, sample. In addition, cognitive changes were not predictive Allergan, AstraZeneca, Corcept Pharmaceuticals, Epix Pharmaceuti-cals, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Pfizer, SAS Insti- of functional change when the analysis controlled for tute, Schwartz, Solvey, and Somerset Pharmaceuticals. He or his wife symptom change. Therefore, the functional benefits dem- holds shares of stock from Amgen, Bristol-Myers Squibb, Eli Lilly, onstrated in this study may be associated with cognitive Genentech, Proctor & Gamble, and Sepracor. Dr. Perkins has receivedresearch funding from AstraZeneca, Bristol-Myers Squibb, Otsuka, Eli and symptom improvement in patients who remain in Lilly, Janssen, and Pfizer and consulting and educational fees from treatment for substantial periods of time.
AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline,Forest Labs, Pfizer, and Shire. Dr. McEvoy has received research fund- The correlations between cognitive change and change ing or speaking fees from AstraZeneca, Eli Lilly, and Janssen. Dr. Lie- in side effect measures, such as tardive dyskinesia and ex- berman has received research funding from Acadia, Bristol-Myers trapyramidal symptoms, including akathisia, were small Squibb, GlaxoSmithKline, Janssen, Merck, Organon, and Pfizer andholds a patent related to work with Repligen. He has also served and not statistically significant. Furthermore, patients without remuneration as a consultant or on advisory boards for As- who required anticholinergic medications or reported traZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, and Pfizer.
sleepiness did not differ from other patients in cognitive The Comparison of Atypicals in First Episode of Psychosis research program was coordinated by the University of North Carolina. Fund- composite scores. These data suggest that with atypical ing for this program was provided by AstraZeneca Pharmaceuticals antipsychotics, side effects are not an important determi- LP (5077IL/0114). The authors acknowledge the assistance of Anusha nant of cognitive functioning in relatively vulnerable Bolonna, Ph.D., of PAREXEL MMS, who provided medical writing as-sistance on the first draft of the manuscript on behalf of AstraZeneca.
early-psychosis patients with the doses used in this study.
This study is registered at www.clinicaltrials.gov under the title One methodological issue that the data from this study “CAFE: Comparison of Atypicals in First Episode of Psychosis” (gov-Identifier: NCT00034892, Study ID Numbers: 5077IL/0114). All crite- address is the relative sensitivities of the CATIE neurocogni- ria as stated in the Clinical Trial Registration policy have been met.
tive battery, which was designed specifically for the CATIEproject and requires about 90 minutes of testing time, andthe BACS, a 35-minute assessment designed to be sensitive References
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