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Neurocognitive Effects of Clozapine, Olanzapine,
Risperidone, and Haloperidol in Patients With Chronic
Schizophrenia or Schizoaffective Disorder
Robert M. Bilder, Ph.D.
Objective: Newer antipsychotic drugs
Robert S. Goldman, Ph.D.
rocognitive deficits in patients with schizo- Jan Volavka, M.D, Ph.D.
newer antipsychotic drugs with both cloza- both clozapine and haloperidol. Clozapine Pal Czobor, Ph.D.
pine and conventional agents, particularly Matthew Hoptman, Ph.D.
age effect sizes for change were in thesmall to medium range. More than half of Brian Sheitman, M.D.
Method: The authors examined the ef-
fects of clozapine, olanzapine, risperidone,
Jean-Pierre Lindenmayer, M.D.
risperidone experienced “clinically signifi- rocognitive functioning in a double-blind, cant” improvement (changes in score of at Leslie Citrome, M.D., M.P.H.
14-week trial involving 101 patients. A glo- least one-half standard deviation relative to baseline). These findings did not appear Joseph McEvoy, M.D.
to be mediated by changes in symptoms,side effects, or blood levels of medications.
Michal Kunz, M.D.
attention, motor function, and general ex-ecutive and perceptual organization.
Conclusions: Patients with a history of
Miranda Chakos, M.D.
Results: Global neurocognitive function
Thomas B. Cooper, M.A.
Terri L. Horowitz, Ph.D.
superior to those seen with haloperidol.
Patients treated with olanzapine exhibited cal antipsychotic drugs in their patterns of Jeffrey A. Lieberman, M.D.
(Am J Psychiatry 2002; 159:1018–1028)
Neurocognitive deficits are now recognized as an im- conventional treatment in this population. Published trials portant dimension of schizophrenia that may be more involving newer antipsychotic drugs have also been lim- closely linked to functional outcome than are symptoms ited by a range of methodological issues, including small (1). Until recently a spirit of nihilism characterized most patient group sizes and the lack of random assignment to cognition treatment studies of patients with schizophrenia, treatments (reviewed in reference 3). There is so far little since conventional antipsychotic drugs yielded at best evidence suggesting differences among atypical antipsy- limited normalization of selected deficits (2). More recent chotic drugs in their cognitive effects, despite putative dif- studies that have used the atypical antipsychotic drug clo- ferences in mechanisms of action (5, 9, 10). One recent zapine and other newer antipsychotic drugs such as risperi- comparison of atypical agents showed a cognitive advan- done and olanzapine have shown greater promise in treat- tage for olanzapine over risperidone (11), but a larger trial ing neurocognitive deficits (3, 4). There is more information revealed no clear differences (12). If there are differences about clozapine’s effects on cognition than there is for other between the neurocognitive effects of these agents, it could atypical antipsychotic drugs, which reflects clozapine’s ear- be of both clinical and theoretical importance.
lier availability and use (5). So far only a few studies have re- We aimed to assess neurocognitive effects of four treat- ported head-to-head comparisons of clozapine and other ments—clozapine, haloperidol, olanzapine, and risperi- newer antipsychotic drugs on cognitive functions, and done—in a group of patients with schizophrenia or none has used a double-blind design (6–8).
schizoaffective disorder who had not responded fully to Since clozapine has remained the “gold standard” for pa- previous treatments; a 14-week, double-blind design was tients with a history of suboptimal clinical response to used. The primary clinical findings of this study have been treatment, it is important to determine specifically how its previously published (13). In brief, clozapine, olanzapine, cognitive effects compare with those of newer agents and and risperidone (but not haloperidol) yielded significant BILDER, GOLDMAN, VOLAVKA, ET AL.
improvements in symptoms. All three atypical antipsy- 8, and 20 mg/day, respectively) at which they remained fixed until chotic drugs were superior to haloperidol in ameliorating the end of the first study period. We aimed to reach the target level negative symptoms, and this was not attributable to dif- of clozapine (500 mg/day) on day 24; the dose remained fixed atthat level until the end of the first study period. Dosing schedules ferences in extrapyramidal side effects. Clozapine was su- were adjusted depending on the patient’s clinical status, includ- perior to risperidone in its effects on negative symptoms.
ing side effects. Mean dose levels (mg/day) achieved during this We report here the results of neurocognitive assessments first period of the study (last observation carried forward) for pa- conducted at baseline (before random assignment) and at tients included in the neurocognitive analysis were 452 (SD=121) endpoint. We hypothesized that the atypical antipsychotic for clozapine, 20.2 (SD=1.0) for olanzapine, 8.3 (SD=2.2) for ris-peridone, and 19.6 (SD=2.0) for haloperidol.
drugs would yield greater cognitive benefits than would During the last 6 weeks of the study, antipsychotic dose was al- haloperidol and aimed to determine whether there were lowed to vary within the following ranges: clozapine, 200–800 mg/ any differences in neurocognitive effects among the atyp- day; olanzapine, 10–40 mg/day; risperidone, 4–16 mg/day; and haloperidol, 10–30 mg/day. In general, doses were gradually in-creased if adequate improvement was not achieved. Side effectscould preclude dose escalation and could lead to dose reductions.
Psychiatrists who were blind to antipsychotic assignment pre-scribed all dose changes. Participants
Throughout the study, all patients were receiving (double- The participants were 18- to 60-year-old inpatients at four state blind) either benztropine or benztropine placebo or a combina- psychiatric hospitals (two in New York and two in North Caro- tion of both. Benztropine (4 mg/day) was administered prophy- lina). After complete description of the study to the participants, lactically to all patients receiving haloperidol. Patients assigned to written informed consent was obtained in line with each institu- atypical antipsychotic drugs were initially receiving only benz- tropine placebo. If the treating psychiatrist (who was unaware of For inclusion in the study, patients were required to have a antipsychotic assignments) determined clinically that a patient diagnosis of treatment-resistant DSM-IV schizophrenia or schizo- should be treated for extrapyramidal side effects, the psychiatrist affective disorder. Treatment resistance was defined by two crite- could write prescriptions for “benztropine supplements” that ria, both of which had to be present. The first criterion was persis- would result in real benztropine gradually replacing benztropine tent positive symptoms (hallucinations, delusions, or marked placebo (up to 6 mg/day). An analogous arrangement for “sup- thought disorder) after at least 6 contiguous weeks of treatment, plements” was available to raise the dose of benztropine from 4 to presently or documented in the past, with one or more typical an- 6 mg/day in patients assigned to haloperidol for emerging ex- tipsychotics at doses ≥600 mg/day of chlorpromazine. The second trapyramidal symptoms. Propranolol was allowed for the treat- criterion of treatment resistance was a poor level of functioning over the past 2 years, defined by the lack of competitive employ- Lorazepam, diphenhydramine hydrochloride, or chloral hydrate ment or enrollment in an academic or vocational program and not were prescribed open-label (by psychiatrists who were blind to an- having age-expected interpersonal relations with someone out- tipsychotic treatment assignment) as needed for the treatment of side the biological family of origin with whom ongoing regular agitation and insomnia in the dose ranges recommended by the contacts were maintained. In addition, patients were required to manufacturers. No other adjunctive psychotropic medications have a baseline total score ≥60 on the Positive and Negative Syn- (e.g., mood stabilizers and antidepressants) were allowed.
Clinical Assessments
Patients were excluded from the study if they had a history of nonresponse to clozapine, risperidone, or olanzapine, defined as Blind raters performed all clinical research assessments. The an unambiguous lack of improvement despite a contiguous ade- clinical symptom ratings included primarily the Positive and quate trial of at least 6 weeks (for risperidone or olanzapine) or 14 Negative Syndrome Scale (14) as a measure of efficacy, as re- weeks (for clozapine). Patients with a history of clozapine, olanza- ported separately (13). It was administered at baseline and then pine, risperidone, or haloperidol intolerance as well as those who weekly during the first month of the study and every other week received a depot antipsychotic within 30 days before random as- thereafter. Extrapyramidal side effects were assessed by trained raters using the Extrapyramidal Symptom Rating Scale (15). Thetime schedule for administration of the paired and single-rater Treatments
Extrapyramidal Symptom Rating Scale was the same as for the During a baseline period of 1 to 2 weeks, patients’ prestudy an- Positive and Negative Syndrome Scale. Nursing staff rated seda- tipsychotic medications were adjusted so that daily dose did not tion with the Nurses’ Observation Scale for Inpatient Evaluation exceed 750 mg in chlorpromazine equivalents. Other concomi- (NOSIE) (16). Trained raters also used the Quality of Life Scale tant medications such as mood stabilizers and antidepressants (17) to evaluate patients at baseline and endpoint.
were gradually tapered and discontinued before patients received Blood samples for the determination of the antipsychotic study medication. After baseline assessments, patients were ran- plasma levels were drawn at baseline and at weeks 5, 8, and 10–14.
domly assigned to one of four treatment arms: clozapine, olanza- Samples were drawn approximately 12 hours after the last dose of pine, risperidone, or haloperidol. Trial antipsychotics were ad- medication. Clozapine assay used a modification of a published ministered double-blind; all patients had weekly blood tests.
method (18). Olanzapine assay was a modified validated liquid Psychiatrists blind to treatment group assignment changed doses chromatographic procedure with electrochemical detection (19).
by prescribing “levels” of medication (detailed explanation of the Risperidone and 9-hydroxyrisperidone assays used a modified procedures available on request). The 14-week trial consisted of liquid chromatographic method (20). Haloperidol assay was an 8-week escalation and fixed-dose period and a 6-week vari- Neurocognitive Assessments
During the first 8 weeks of the study, the prestudy antipsychotic was gradually discontinued while the doses of olanzapine, ris- The neurocognitive battery was designed to examine func- peridone, and haloperidol were escalated to their target levels (20, tional domains previously considered important by virtue of their ANTIPSYCHOTICS AND COGNITION
TABLE 1. Demographic and Clinical Characteristics of Patients With Treatment-Resistant Schizophrenia or Schizoaffective
Disorder Randomly Assigned to Receive Clozapine, Haloperidol, Olanzapine, or Risperidone
Positive and Negative Syndrome Scale scores a Measure is based on a modified Edinburgh Inventory, for which values >0.70 indicate strong right-hand preference.
b Risperidone plus 9-hydroxyrisperidone level is shown.
c Significantly higher than scores of patients in other treatment groups (F=4.10, df=3, 97, p<0.009).
d Expressed so that positive values indicate improvement.
demonstrated impairment in people with schizophrenia, their re- three tests not considered for scale construction were the Mini- lations to functional outcomes, or their demonstrated change in Mental State Examination, which is a general screening instru- prior studies of antipsychotic treatment. These assessments fo- ment, and the WAIS-R vocabulary and information subtests, cused on measures of general ability, learning and memory, at- which were only administered at baseline to help estimate gen- tention, executive functions, and motor skills. The battery in- eral cognitive ability and index “premorbid” cognitive capacity).
cluded 15 tests that assessed these domains. The specific tests Principal-components analysis on all nonmissing baseline data used have been described extensively in prior research by us and was used to determine whether the 16 neurocognitive test vari- others (1, 22, 23). Patients were assessed at the end of the lead-in ables could be reduced to a smaller number of interpretable do- period before random assignment and at the end of the 14-week main scores. For each test variable, z scores (with mean=0 and trial. In case of premature termination between weeks 4 and 14, SD=1) were computed by using the baseline means and standard endpoint neuropsychological assessments were performed. To deviations from patients who completed that test at both baseline minimize sedation effects, assessments were postponed until at and endpoint. One “global” score (reflecting the equally weighted least 24 hours after the last dose of any treatment for agitation.
mean of all nonmissing scores on the 16 test variables) and do-main scores were then computed by averaging the z scores on Data Analysis
contributing variables; all z scores were computed so that positive Before analysis of neurocognitive data, we examined major de- scores indicate better performance. Analysis of treatment effects mographic variables, treatment, and clinical outcomes in the pa- in each domain used the mixed-models approach to repeated- tients that completed neurocognitive testing compared with measures analysis of variance (SAS Institute, Cary, N.C.) with those who did not. All neurocognitive variables were examined in baseline and endpoint scores as dependent variables, time as a terms of their distribution properties to determine whether base- within-subject repeated measure, and treatment group (cloza- line differences in neurocognitive scores existed between treat- pine, haloperidol, olanzapine, risperidone) as a between-subjects ment groups. Sixteen variables were selected from 12 tests for fixed factor. To control for type I error given the multiplicity of sta- analysis of treatment effects on neurocognitive domains (the tistical tests, we used a step-down Bonferroni procedure that con- BILDER, GOLDMAN, VOLAVKA, ET AL.
TABLE 2. Neuropsychological Tests Constituting Four Neurocognitive Domainsa
Wisconsin Card Sorting Test (perseverative errors) a Principal-components analysis of the 16 neuropsychological test variables resulted in a four-factor solution; variables assigned to each siders the fact that effects of interest may be observed for both the Comparisons of the 101 patients who participated in the main effect of time (since there are four treatment groups, any neurocognitive assessments to the 56 patients who did not one of which can show change) and the interaction effect of treat- revealed no significant differences on any of the demo- ment group with time (yielding six pairwise comparisons be- graphic or clinical variables, including baseline scores on tween the treatment groups) (24). For analysis of the global scalethe family-wise alpha was set at 0.05, and for the tests of the four the Positive and Negative Syndrome Scale (for total score domain scores we divided alpha by the number of scales to set the or positive symptom, negative symptom, or general psy- critical alpha level (0.05/4=0.0125). Individual test scores were chopathology subscale scores, all p>0.15).
not analyzed separately, since with 16 tests we felt the analysiswould suffer either from capitalization on chance (given the Neurocognitive Test Results
number of tests) or from overly conservative alpha levels that Principal-components analysis on the 16 baseline would be needed to control for test multiplicity.
scores yielded four factors with eigenvalues greater than There is no widely accepted method for deciding what are clin- ically significant (as opposed to statistically significant) changes in one that were retained and subjected to varimax rotation neurocognitive performance. Some investigators have suggested (Table 2). While labeling of factors derived from principal- that a change of 0.5 standard deviation units (with respect to base- components analysis is a subjective process, we believe line score and standard deviation) is “clinically meaningful” (12).
the assignment of tests to each domain (indicated by bold To determine whether treatment groups might differ in clinical in Table 2) was interpretable on the basis of existing the- improvement, we examined the proportions of patients within ory. We also conducted a principal-components analysis each treatment group that showed at least a 0.5 standard deviationimprovement on the global scale and tested the significance of dif- that included the baseline WAIS-R Information and Vo- ferences among the treatments by using chi-square analysis.
cabulary scores to determine whether the factor structuremight be influenced by these measures often considered indices of “premorbid” intellectual ability. That analysisyielded the same four factors as the original principal- Demographic and clinical characteristics of the 101 pa- components analysis plus a fifth factor that contained tients who contributed neurocognitive data are shown in only these two WAIS-R variables, which supported the Table 1. There were no significant differences among treat- original principal-components analysis and the four-fac- ment groups in race, sex, or diagnostic composition, nor tor solution. Thus, four domain scores were constructed were there differences in age, duration of illness or age at on the basis of the four-factor principal-components anal- onset, number of previous hospitalizations, or duration of ysis, as the mean of z scores on contributing variables, time spent in the study. There were no differences in base- with each variable weighted equally (i.e., each variable z line psychopathology scores, except that patients in the score was weighted 0 or 1, rather than using the rotated clozapine group had higher baseline scores on the general factor scores). These z scores were based on the mean and psychopathology subscale of the Positive and Negative standard deviation of each test at baseline and used the group of patients who completed each test at both base- ANTIPSYCHOTICS AND COGNITION
TABLE 3. Neurocognitive Global and Domain Scores and Scores on Individual Neuropsychological Tests at Baseline and
Endpoint for Patients With Treatment-Resistant Schizophrenia or Schizoaffective Disorder Randomly Assigned to Receive
Clozapine, Haloperidol, Olanzapine, or Risperidone
a Reflects the equally weighted mean of z scores for all nonmissing scores on the 16 test variables.
b Values represent the average of z scores of contributing variables (see Table 2).
c Only administered at baseline to help estimate general cognitive ability and index “premorbid” cognitive capacity.
d Age-corrected scale score.
line and follow-up. Signs were adjusted so that higher pos- individual neurocognitive tests remained at impaired lev- itive values indicated better performance, while more els with respect to healthy normative standards.
negative values indicated worse performance. The psy- Treatment Effects
chometric properties of the resulting scales were evalu-ated by computing coefficient alpha and test-retest stabil- The main analyses of treatment effects are presented in ity coefficients (global scale: 0.89 and 0.73, respectively; For each score we examined the main effect of time general executive and perceptual organization: 0.81 and (baseline, endpoint) and the group-by-time interaction ef- 0.73; declarative verbal learning and memory: 0.88 and fect. Table 4 shows that there was a significant main effect 0.63; processing speed and attention: 0.81 and 0.66; sim- of time on the global score and on three of the four domain scores, suggesting that some groups showed significant Baseline and endpoint scores for the individual tests changes from baseline to endpoint. Post hoc tests revealed and the neurocognitive domains within each treatment which groups changed: 1) in global score, patients treated group are shown in Table 3. While there was an overall ten- with olanzapine and risperidone improved; 2) in general dency for scores to be higher at endpoint, performance on executive and perceptual organization, patients treated BILDER, GOLDMAN, VOLAVKA, ET AL.
Cohen’s d) tended to be slightly larger, since the standarddeviations of the composite scores tended to be less than1.0. The highest effect size (d=0.74) was seen with olanza-pine treatment for change in processing speed and atten- tion. Medium effect sizes for change on the global scale were seen for olanzapine (d=0.59) and risperidone (d= 0.55), whereas the effect sizes were small for clozapine (d= Relation of Neurocognitive Change
to Clinical and Treatment Variables
A series of additional analyses examined the degree to which changes in neurocognitive scores might relate to clinical rating scale assessments, side effects, and treat- To assess relations to clinical change, the clinical vari- ables were used as time-varying covariates in the mixed-model repeated-measures analyses of variance. Clinical variables included the total score and positive symptom,negative symptom, and general psychopathology sub- scale scores from the Positive and Negative SyndromeScale and the Quality of Life scale scores. These analyses were designed both to assess the degree of association be- tween the clinical variables and the neurocognitive effects and the degree to which the neurocognitive effects mightremain significant even after accounting for the variance We used the step-down Bonferroni procedure to estab- lish the same thresholds for assessing statistical signifi- cance as we did in the main analyses (for the global scale,family-wise alpha=0.05; for the four neurocognitive do- main scores: family-wise alpha=0.0125). The Positive and Negative Syndrome Scale total score was significantly re- lated to the global score (F=6.86, df=1, 95, p<0.01) and the domains of general executive and perceptual organization (F=6.53, df=1, 94, p<0.01) and processing speed and atten-tion (F=6.86, df=1, 90, p<0.01). The positive symptom sub-scale score was not significantly related to any of the neu-rocognitive measures. The negative symptom subscalescore was most robustly associated with the neurocogni- with olanzapine improved; 3) in processing speed and at- tive scores and significantly associated with the global tention, patients treated with olanzapine improved; and 4) score (F=15.27, df=1, 95, p<0.0002) and the domains of in simple motor functioning, patients treated with cloza- general executive and perceptual organization (F=11.31, pine improved. The group-by-time interaction effects df=1, 94, p<0.001) and processing speed and attention (F= were also significant for the global score and for the de- 6.79, df=1, 90, p<0.01). The general psychopathology sub- clarative verbal learning and memory domain. For the glo- scale score was significantly related only to the global neu- bal score, post hoc tests revealed that both olanzapine and rocognitive score (F=4.68, df=1, 95, p<0.03). There were no risperidone treatment resulted in greater improvement significant associations of Quality of Life ratings with any over time than did haloperidol treatment. For the declara- of the neurocognitive scores. Among adverse effects, we tive verbal learning and memory domain, treatment with found no significant relations with ratings of sedation risperidone resulted in greater improvement over time from the NOSIE, but we did find significant effects of Ex- than did treatment with either clozapine or haloperidol.
trapyramidal Symptom Rating Scale ratings on the global Inspection of the least squares means in Table 3 reveals scale (F=4.78, df=1, 95, p<0.03), which appeared to be due that the changes from baseline to endpoint ranged up to to a relatively strong effect on the simple motor function- 0.68 scale score points. The actual effect sizes (i.e., using ing domain (F=14.18, df=1, 74, p<0.0003).
ANTIPSYCHOTICS AND COGNITION
TABLE 4. Changes From Baseline to Endpoint in Neurocognitive Global and Domain Scores for Patients With Treatment-
Resistant Schizophrenia or Schizoaffective Disorder Randomly Assigned to Receive Clozapine, Haloperidol, Olanzapine, or
Risperidone
a Post hoc comparisons revealed significant improvement over time for treatment with olanzapine (t=4.36, df=25, p<0.001) and risperidone (t=4.21, df=25, p<0.002); post hoc pairwise comparisons revealed a significantly greater improvement relative to that seen with haloperidoltreatment for olanzapine (t=3.36, df=49, p<0.006) and risperidone (t=3.15, df=49, p<0.006).
b Bonferroni-corrected alpha set at 0.0125 to control for type I error given the multiplicity of statistical tests.
c Post hoc comparisons revealed significant improvement over time for treatment with olanzapine (t=3.11, df=25, p<0.01) and nearly signifi- cant improvement for risperidone (t=2.73, df=25, p<0.03); post hoc pairwise comparisons revealed a nearly significant greater improvementrelative to that seen with haloperidol treatment for olanzapine (t=2.86, df=49, p<0.03) and risperidone (t=2.64, df=49, p<0.03).
d Post hoc comparisons revealed improvement over time for treatment with risperidone (t=4.62, df=25, p<0.0001) and olanzapine (t=2.46, df= 25, p<0.05); post hoc pairwise comparisons revealed significantly greater improvement seen with risperidone treatment relative to that seenwith haloperidol (t=2.06, df=49, p<0.008) or clozapine (t=3.58, df=48, p<0.003).
Despite the relations of the covariates with neurocogni- motor functioning domain, but the finding did not tive variables, the Positive and Negative Syndrome Scale achieve significance (F=4.45, df=1, 24, p<0.05).
scores had relatively little influence on the significance of “Clinically Significant” Improvement
the main effects of time, the group-by-time interaction in Neurocognitive Function
effects, or the post hoc comparisons among treatmentgroups that were reported in the main analyses. For the Finally, we examined the proportions of patients im- global score, none of these covariates modified the pattern proving by at least 0.5 standard deviation on the global of significant findings as reported in Table 4. Among the scale and found significant differences between treatment other neurocognitive domain scores, the pattern of signif- groups in the proportions improved (χ2=17.5, df=3, icant findings remained, with one exception. There was no p<0.0006) (Figure 1). Pairwise comparisons revealed that longer a main effect of time at the 0.0125 alpha level for the more patients were classified as having improved in the general executive and perceptual organization domain af- olanzapine group than in either the haloperidol group ter the Positive and Negative Syndrome Scale total score (χ2=14.3, df=1, p<0.0002) or the clozapine group (χ2=9.6, (F=3.96, df=1, 94, p<0.05) and the positive symptom (F= df=1, p<0.002); the percentage of patients experiencing 5.75, df=1, 94, p<0.019), negative symptom (F=6.02, df=1, clinically significant improvement did not significantlydiffer between those given olanzapine and those given ris- 94, p=0.016), and general psychopathology (F=5.15, df=1, peridone. Significantly more patients treated with risperi- 94, p<0.03) subscale scores were entered as covariates; all done than with haloperidol met the clinically significant other effects and post hoc comparisons remained signifi- improvement criteria (χ2=6.0, df=1, p<0.02).
cant. Analyses that used benztropine dose as a covariatealso rendered nonsignificant the main effect of time onthe general executive and perceptual organization domain Discussion
(F=2.48, df=1, 54, p<0.12), but other significant effects This study of patients randomly assigned to treatments noted in Table 4 remained. Quality of Life scale, sedation with the atypical antipsychotic agents clozapine, olanza- ratings, and Extrapyramidal Symptom Rating Scale scores pine, and risperidone or the conventional neuroleptic did not alter the pattern of effects in Table 4.
agent haloperidol showed an overall superiority of olan- To examine possible effects of medication blood levels, zapine and risperidone on a range of neurocognitive we used the mixed-model approach separately within functions. When we compared the gains in global cog- each treatment group (since the values were highly unbal- nitive performance, both olanzapine and risperidone anced across the groups) with endpoint dose as a time-in- showed statistically significant changes with treatment, variant covariate. Here again we used family-wise alpha= and both olanzapine and risperidone were superior to ha- 0.05 for global score and family-wise alpha=0.0125 for the loperidol, but their effects did not differ significantly from four neurocognitive domains. There were no significant interactions of blood level with time for any scale within The change in global neurocognitive performance (us- any treatment group. Within the haloperidol group, higher ing standard deviations of the baseline scores as an index blood levels were associated with less improvement on the of effect size) was of medium magnitude for treatment BILDER, GOLDMAN, VOLAVKA, ET AL.
FIGURE 1. Percentages of Subjects Experiencing Significant
Clinical Improvementa Among Patients With Treatment-
Resistant Schizophrenia or Schizoaffective Disorder Ran-
domly Assigned to Receive Clozapine, Haloperidol, Olanza-
pine, or Risperidone
e Post hoc comparisons revealed significant improvement over time for treatment with olanzapine (t=5.46, df=25, p<0.0001) and nearly significant improvement for clozapine (t=2.73, df=23, Significant Improvement (%)
Patients Experiencing Clinically
p<0.03) and risperidone (t=2.66, df=25, p<0.03).
f Post hoc comparisons revealed significant improvement over time for treatment with clozapine (t=3.83, df=23, p<0.002).
Treatment Group
a Change of at least one-half standard deviation in global neurocog- tive antiparkinsonian treatments where indicated. These with olanzapine (0.59) and risperidone (0.55). For com- results might be considered support for the idea that clo- parison to a widely used metric, this would be approxi- zapine exerts its most prominent beneficial cognitive ef- mately eight to nine “IQ-equivalent” points. While our pa- fects by means of reduction in motor and cognitive slow- tients continued to have test scores reflecting significant ing associated with D2 antagonism in the frontostriatal neurocognitive impairment, more than half of the pa- tients who received olanzapine or risperidone showed Olanzapine and risperidone had a similar magnitude of cognitive gains greater than 0.5 standard deviation (i.e., effect on global neurocognitive function, but inspection of 7.5 IQ-equivalent points). These gains were large enough results from individual neurocognitive domains suggests to be considered clinically significant and were larger than that there may be more specific effects of these drugs that would be expected from prior test exposure effects. Over- could be pursued in future investigations. Treatment with all the findings suggest that significant cognitive improve- olanzapine resulted in significant improvement in the do- ments may be possible even among patients who have mains of processing speed and attention and general ex- shown limited response to conventional treatment.
ecutive and perceptual organization. Various explanations One potentially surprising aspect of this study was the for olanzapine-associated benefits have usually centered relatively modest neurocognitive benefit of clozapine on less activity at the D2 receptor, along with more pro- treatment, despite the finding that clozapine had robust nounced serotonergic, adrenergic, histaminic, or effects at effects on clinical symptoms in these patients (13). It is non-D2 dopamine receptors (10). In contrast, risperidone possible that the failure to demonstrate neurocognitive appeared to show more robust effects in the domain of de- benefits of clozapine reflects our failure to test relevant clarative verbal learning and memory, for which it was su- constructs. It was commented previously that clozapine’s perior to both haloperidol and clozapine treatment.
unique mechanism of action may preferentially involve These differences might be explained in part by anti- “paleocortical” systems, particularly those of the ventral cholinergic mechanisms that are known to affect memory.
and orbital frontal regions, that have been linked to social Anticholinergic effects could be associated with the intrin- cognition and response-inhibition functions (5). Assess- sic properties of the antipsychotics or be due to co-admin- ment of these functions has often been incomplete in con- istered benztropine (1, 27, 28). Risperidone might be su- ventional neurocognitive batteries (25, 26).
perior to clozapine because clozapine treatment involves Clozapine only had a significant beneficial impact on high levels of intrinsic anticholinergic activity and has motor performance. This might be explained by cloza- been associated with memory deficit (29). The observa- pine’s relative low affinity for the dopamine-2 (D2) recep- tion that olanzapine was not superior to either haloperi- tor or its unique regional distribution of effects within the dol or clozapine in its effect on memory might also be ex- basal ganglia. The lack of differences between treatments plained by its high levels of intrinsic anticholinergic on motor functioning should be considered in the context activity, which may be higher than those observed with of the treatment algorithm, which was designed to mini- clozapine treatment (30). Anticholinergic effects may also mize adverse motor side effects through prescription (by have led the haloperidol patients to perform worse, since psychiatrists blind to treatment assignment) of adjunc- they received obligatory benztropine. Although we found ANTIPSYCHOTICS AND COGNITION
no statistical association of anticholinergic blood levels the contention that treatment-related modulation of cog- with memory change, paralleling the findings of Green nition and symptoms may proceed with considerable in- and colleagues (31), it is possible that more sensitive mea- dependence. Neurocognitive change also was not clearly sures of anticholinergic activity might detect such effects.
related to a range of other possible mediating factors, in- Our findings might be considered at odds with some cluding extrapyramidal symptoms, sedation, or adjunctive conclusions presented elsewhere in the literature. For ex- medication use (which did not differ among treatment ample, one review suggested different profiles of selective cognitive efficacy for different atypical antipsychotic The use of cognitive domain scores likely increased the drugs (10). On the basis of a survey of 18 publications and sensitivity of this study compared with those that used in- their own open trial of 20 patients switched from typical dividual neurocognitive test scores. First, composite antipsychotics to olanzapine, Meltzer and McGurk sug- scores have higher reliability and stability than do individ- gested that effects were most robust with clozapine for at- ual test scores. Second, reducing the number of variables tention and verbal fluency; risperidone for working mem- examined (in this case from 16 to four) reduces the strin- ory, executive functioning, and attention; and olanzapine gency of corrections for multiple comparisons. The as- for verbal learning/memory, fluency, and executive func- signment of variables to domains, which in this study was tion. While efforts to summarize these findings are laud- informed by factor analysis, would likely differ in other able, it should be noted that the conclusions were based samples or if different tests were used. For this patient on early studies with relatively small study group sizes, group and this set of variables, however, these domain only two of which used double-blind designs, and none of scores appeared to provide an intuitively appealing and which provided head-to-head comparisons among all psychometrically reasonable summary of neurocognitive three agents, as our study did. One recent double-blind study did include head-to-head comparisons of patients Finally, there are limitations of this study that should be randomly assigned to treatment with risperidone, halo- acknowledged. First, it is not clear how well the results peridol, or olanzapine and concluded that olanzapine had may generalize to patients with a more favorable response superior cognitive benefits than both risperidone and ha- to treatment. The findings appear consistent, however, loperidol (11). Some interpretive challenges for that study with other studies of the neurocognitive effects of atypical are posed by the relatively small study group sizes (among antipsychotics in treatment-responsive and first-episode 65 patients completing baseline assessments, 10 termi- patient groups (reviewed in references 3 and 4; see also re- nated before completing a second assessment, and 27 cent presentations [12, 32]). Second, this study used rela- more failed to complete the study). The authors of that tively high doses of all medications, particularly risperi- study highlighted the possible problem of selective attri- done. This might be expected to yield higher levels of tion in both the haloperidol group (which had a dispro- extrapyramidal side effects and higher doses of adjunctive portionate number of early dropouts) and the risperidone anticholinergic treatments and thus either more motor group (for which there were different results from the in- slowing or more memory impairment than might be the tent-to-treat last-observation-carried-forward analyses, case with lower-dose treatment. It should be noted, how- compared with other analyses). Overall, however, we be- ever, that all treatments were adjusted by clinicians who lieve that the findings published so far are relatively con- were blind to treatment assignment, and extrapyramidal sistent in showing cognitive benefits of the newer anti- symptoms actually decreased with all treatments. These psychotics compared with conventional treatments. We patients had not shown good clinical responses to a broad further believe efforts to discern differences in the neu- range of prior treatments, usually reflecting attempts with rocognitive profiles of different agents are likely to require multiple conventional antipsychotic drugs and adjunctive substantial further study with designs that specifically tar- agents. Third, it should be noted that the study inclusion/ get this goal, with perhaps meta-analysis of such studies exclusion criteria permitted patients who had limited to help overcome the necessary limitations of any individ- prior response to haloperidol, but not patients who had demonstrated lack of response to the other treatments.
There were generally modest associations of neurocog- This might have biased the findings toward showing less nitive change with symptom ratings. Paralleling prior improvement in the haloperidol group. Fourth, while the research, negative symptoms showed a more consistent double-blind, random assignment design of this trial had pattern of association with neurocognitive deficits. Of pos- many advantages, we cannot rule out the possibility that sible interest are the observations that these symptoms apparent improvements attributable to some treatments were associated with general, executive, processing speed, (i.e., the newer agents) may instead reflect the effects of and attentional measures but not with verbal learning/ prior exposure or experience with the tests, while other memory or motor functions, suggesting that these might treatments (i.e., haloperidol) might have prevented these constitute unique syndromal elements. The treatment ef- effects. Future trials might incorporate multiple baseline fects on neurocognitive function did not appear to be sub- assessments, additional control groups, or other strategies stantially modulated by symptoms. These findings support to address the possibility that some treatments permit BILDER, GOLDMAN, VOLAVKA, ET AL.
benefit from prior test exposure whereas others do not. In 6. Daniel DG, Goldberg TE, Weinberger DR, Kleinman JE, Pickar D, the meantime we believe the findings reported here reflect Lubick LJ, Williams TS: Different side effect profiles of risperi-done and clozapine in 20 outpatients with schizophrenia or cognitive changes that may be clinically meaningful, re- schizoaffective disorder: a pilot study. Am J Psychiatry 1996; gardless of whether these are due to direct effects of the newer agents or whether the observed changes reflect dif- 7. Meyer-Lindenberg A, Gruppe H, Bauer U, Lis S, Krieger S, Gall- ferences in the capacity to benefit from experience. It re- hofer B: Improvement of cognitive function in schizophrenic mains to be demonstrated whether cognitive changes of patients receiving clozapine or zotepine: results from a dou- this magnitude, in this group of patients, make a substan- ble-blind study. Pharmacopsychiatry 1997; 30:35–42 8. Lindenmayer JP, Iskander A, Park M, Apergi FS, Czobor P, Smith tial difference in patients’ social and vocational function- R, Allen D: Clinical and neurocognitive effects of clozapine and ing or other indices of outcome that were not assessed in risperidone in treatment-refractory schizophrenics: a prospec- our study. It must be remembered that despite cognitive tive study. J Clin Psychiatry 1998; 59:521–527 gains, our patients continued to suffer from significant 9. Meltzer HY: The role of serotonin in antipsychotic drug action.
impairments of cognitive ability and social/vocational Neuropsychopharmacology 1999; 21:106S–115S 10. Meltzer HY, McGurk SR: The effects of clozapine, risperidone, functioning. Overall, however, we believe that these pa- and olanzapine on cognitive function in schizophrenia.
tients represent a large and important population of indi- viduals who may show meaningful neurocognitive bene- 11. Purdon SE, Jones BD, Stip E, Labelle A, Addington D, David SR, fits from treatment with newer antipsychotic agents. We Breier A, Tollefson GD (Canadian Collaborative Group for Re- hope that future research will examine further domains of search in Schizophrenia): Neuropsychological change in earlyphase schizophrenia during 12 months of treatment with olan- neurocognitive and social/emotional functions that may zapine, risperidone, or haloperidol. Arch Gen Psychiatry 2000; be modulated by these treatments and delineate the rela- tions of these effects to both underlying mechanisms and 12. Harvey PD: Cognitive effects of risperidone and olanzapine in patients with schizophrenia or schizoaffective disorder, in 2000Annual Meeting New Research Program and Abstracts. Wash-ington, DC, American Psychiatric Association, 2000, p 149 Presented in part at the eighth International Congress on Schizo- 13. Volavka J, Czobor P, Sheitman B, Lindenmayer J-P, Citrome L, phrenia Research, Whistler, B.C., Canada, April 28–May 2, 2001. Re-ceived June 18, 2001; revision received Dec. 10, 2001; accepted Dec.
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