A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

International Journal of Neuropsychopharmacology (2005), 8, 457–472. Copyright f 2005 CINPdoi :10.1017/S146114570500516X A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and Neil D. Woodward1, Scot E. Purdon2, Herbert Y. Meltzer3 and David H. Zald1 1 Department of Psychology, Vanderbilt University, Nashville, TN, USA2 Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada3 Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocationalrehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypicalantipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement withatypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitivechange to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonlyused neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated,were included. Forty-one studies met these criteria. Neuropsychological test data from each study werecombined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses werecarried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypicalAPD and a typical APD control arm. The second analysis included all prospective investigations ofatypical treatment and the within-group change score divided by its standard deviation served as anestimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improvingoverall cognitive function (ES=0.24). Specific improvements were observed in the learning and pro-cessing speed domains. The second analysis extended the improvements to a broader range of cognitivedomains (ES range=0.17–0.46) and identified significant differences between treatments in attention andverbal fluency. Moderator variables such as study blind and random assignment influence results ofcognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive defi-cits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.
Received 14 July 2004; Reviewed 28 September 2004; Revised 21 October 2004; Accepted 27 October 2004 Key words : Atypical antipsychotics, meta-analysis, neuropsychology, schizophrenia.
to socio-vocational functioning (Green, 1996; Greenet al., 2000), and exerts a greater influence on functional Cognitive dysfunction is fundamental to schizo- outcome than the presence or severity of the positive phrenia (Bleuler, 1950; Kraepelin and Robertson, 1919) or negative symptoms of schizophrenia (Velligan et al., and readily demonstrated on a variety of neuro- 2000). Furthermore, associations between particular psychological instruments (Kolb and Whishaw, 1983).
cognitive skills and specific dimensions of outcome Patients with schizophrenia typically perform one to have been articulated. Thus, the relationships between two standard deviations below normal on a variety of cognitive impairments and psychosocial deficits measures, especially those that assess executive func- may provide a basis for the prediction of functional tions, verbal skills, processing speed, and attention changes that should result from treatment-specific (Bilder et al., 2000; Fuller et al., 2002; Heinrichs and Zakzanis, 1998; Hoff et al., 1992; Saykin et al., 1994).
After many years of null results with typical anti- Cognitive impairment in schizophrenia relates directly psychotic drugs (APDs), and an early negative studyof the effect of clozapine on cognition (Goldberg et al.,1993), a series of studies identified significant im- Address for correspondence : N. D. Woodward, M.A., Department of provements in cognition with other atypical APDs in Psychology, Vanderbilt University, Nashville, TN, 37203, USA.
addition to clozapine (Bilder et al., 2002; Galletly et al., 1999; Hagger et al., 1993; Meltzer and McGurk, 1999; Purdon et al., 2000, 2001a; Rossi et al., 1997). As will be schizophrenia. Two earlier quantitative reviews of discussed, the cognitive enhancement reported in these published studies up to 2000 identified significant early studies could have been artifacts related to re- gains with atypical APDs in several cognitive domains peated testing, study characteristics, or other potential including verbal fluency, vigilance and selective biases. Alternatively, the apparent cognitive enhance- attention, secondary memory, and visuomotor skills ment may be related to one or more of the following (Harvey and Keefe, 2001; Keefe et al., 1999). Effect effects of the atypical APDs which are not shared by sizes, in terms of Cohen’s d, were typically within typical APDs: (1) increased release of dopamine (DA) the range of 0.20–0.40 suggesting that the improve- and acetylcholine (ACh) in the prefrontal cortex and ments may be mild relative to the magnitude of hippocampus (Ichikawa et al., 2002; Kuroki et al., 1999; the cognitive deficits seen in patients with schizo- Parada et al., 1997; Shirazi-Southall et al., 2002) ; (2) phrenia. However, the earlier reviews were hampered antagonism of 5-HT2A, 5-HT2C or 5-HT6 receptors by the relatively small number of studies that (Meltzer, 1999) ; and (3) stimulation of 5-HT1A had been carried out prior to 2000, the limited avail- receptors (Ichikawa et al., 2001). Increased release of ability of data on olanzapine, and the absence of data DA may lead to stimulation of D1 and D3 receptors, in on quetiapine. Since the earlier reviews, the results particular, which might have a beneficial effect on of over 20 studies involving atypical APDs including cognition, assuming that these receptors are under- several large-scale NIMH and industry-sponsored stimulated in schizophrenia. Increased release of ACh clinical trials have been released and there is now a might lead to enhancement of M1, M4, or a7 nicotinic substantial pool of data on olanzapine’s effects on acid post-synaptic receptors, all of which have been cognition and results from several investigations of suggested to be involved in cognitive impairment in quetiapine (Bilder et al., 2002; Harvey et al., 2003; schizophrenia (Bymaster et al., 2003 ; Olincy et al., 1997; Purdon et al., 2001b; Velligan et al., 2002).
Simosky et al., 2003). The atypical APDs also differ The large number of studies that have been from one another in their relative actions on these reported since 2000 make it feasible to examine the systems. Clozapine is an M1 and M4 agonist, an effect effects of relevant methodological characteristics, such which other atypical APDs lack (Olianas et al., 1999; as medication blind, random assignment of subjects, Zorn et al., 1994). Blockade of M2 receptors by cloz- and study duration. Earlier reviews have stressed the apine or olanzapine in vivo would be expected to importance of controlling for these variables to protect increase the release of ACh. Stimulation of M1 and against experimenter bias and demand characteristics.
M4 receptors has been shown to improve memory and However, quantitative comparisons between studies learning in animal models (Felder et al., 2001).
that included these design features and those that Risperidone has a relatively high affinity and long did not are lacking. Additional study variables that dissociation latency period for D2 receptors (Kapur may be relevant include baseline medication status and Seeman, 2001; Lavalaye et al., 1999; Seeman, and medication dosage used in typical control arms.
2002), suggesting that patients receiving risperidone Several investigators have speculated that the cogni- may be more likely to display adverse effects asso- tive improvements observed with atypical APDs ciated with DA antagonism in the striatum including may reflect an avoidance of potentially deleterious greater extrapyramidal symptoms (EPS) and reduced effects associated with typical APD treatments rather procedural learning, especially with doses above than a novel enhancement of cognition (Carpenter 6 mg/d. A recent meta-analysis of EPS prevalence and Gold, 2002). Definitive support for this contention in clinical trials and preliminary evidence of reduced is lacking although recent investigations suggest procedural learning with risperidone, relative to cloz- that haloperidol may indeed interfere with specific apine and olanzapine, provides support for this pre- cognitive skills such as processing speed and pro- diction (Bedard et al., 2000; Leucht et al., 1999; Purdon cedural learning (Bedard et al., 1996, 2000; Blyler et al., 2003). Thus, there are not only neurochemical and Gold, 2000; Purdon et al., 2002, 2003 ; Sharma reasons to expect atypical APDs to improve cognitive and Harvey, 2000; Stevens et al., 2002). In the case function, relative to typical APDs, but differences of within-subjects switch studies, the absence of an between treatments within the atypical APD class unmedicated baseline assessment does not rule out the possibility that the improvements observed fol- The significant methodological differences that lowing a switch to an atypical APD treatment reflect a exist across studies undermine attempts to draw release from the adverse effects associated with a definitive conclusions on the efficacy and differen- typical APD rather than a benefit of atypical APD tial benefits of atypical APDs to cognition in The larger number of studies now available for Table 1. Neuropsychological tests and cognitive domains review also permits a more thorough investigation ofthe unique cognitive benefits for each medication and a preliminary examination of potential differencesbetween them. Although several investigations have directly compared medications within the atypical APD class, with few exceptions (Harvey et al., 2003), interpretation of the results have been limited by the small number of subjects included in treatment groups (Bilder et al., 2002; Purdon et al., 2000). By quantitat- ively analysing effects across studies, meta-analysis can overcome these sample-size limitations, and help identify possible differences between treatments that may warrant further investigation in clinical trials.
At present, over 40 studies have reported on the effects of clozapine, olanzapine, risperidone and que- tiapine on a wide range of neuropsychological tests.
The studies were entered into a meta-analysis to: (1) evaluate and extend the findings of the earlier meta- analyses; (2) identify any differences between atypical APD medications on cognitive processes ; and (3) identify study characteristics that might be relevant to Relevant articles were identified through extensive literature searches of computerized databases includ- ing Medline, PsycInfo, and Dissertation Abstracts.
Key search terms included Schizophrenia, Cognition, Neuropsychology, Neurocognition, Clozapine, Olanz- apine, Risperidone, and Quetiapine. In addition, the bibliographies of several earlier reviews were examined (Harvey and Keefe, 2001; Keefe et al., 1999; Meltzer and McGurk, 1999; Purdon, 1999, 2000).
Studies were included in the meta-analysis if they met the following criteria : (1) inclusion of patients with a diagnosis of schizophrenia or schizoaffective disorder as outlined in DSM-III, DSM-III-R, DSM-IV, or ICD-9, ICD-10; (2) prospective study design with a baseline assessment and at least one follow-up assessment ; (3) trial duration of at least 1 wk ; (4) no antipsychotics, except for the study medications were administered ; (5) a baseline sample size of at * See text for additional information.
least 10; (6) results of neuropsychological change totreatment were reported for at least one of the com-mon tests listed in Table 1; and (7) the study was published or ‘ in press ’ in a peer-reviewed journal as ofApril 2004. Investigations of geriatric, adolescent (age Studies were coded for author and year of publication, <18 yr), or high-risk populations were not included.
corporate sponsorship, schizophrenia subtype classi- Studies included in the meta-analysis are listed in fication, baseline medication status, medication blind, random assignment, trial medications, total subjects Table 2. Studies included in the meta-analysis completing baseline cognitive assessment and the that utilized large cognitive batteries, contemporary number completing the trial, trial duration, and mean neuropsychological domain constructs, and cognitive trial medication dosages. Schizophrenia subtype domains relevant to outcome in schizophrenia (Bilder classification was based on explicit descriptions con- et al., 2000, 2002; Green et al., 2000, 2002; Harvey and tained in each publication and consisted of three Keefe, 2001; Heaton et al., 2001; Purdon et al., 2000, classifications : general schizophrenia, early phase, or treatment refractory. Medication blind was coded The Vigilance and Selective Attention domain as double blind or open label. Open-label extensions included the Continuous Performance/Attention Test, to double-blind studies were not included in this Stroop Test (colour-word score), and Trailmaking A analysis with the exception of Smith et al. (2001) which did not report within-group results at the end The Working Memory domain consisted of tests of of the double-blind phase. The number of subjects verbal or spatial working memory. These included the who completed the study was defined as the total verbal working memory tests Digit Span, Digit Span number of subjects for each medication group that Distraction, Paced Auditory Serial Addition, Letter- completed at least one cognitive test at trial end-point, Number Span, and Consonant Trigrams and spatial or last observation carried forward (LOCF). In working memory tests such as the Visual Span subtest addition, if a study reported statistics based on the of the WAIS-R/III and the Spatial Working Memory LOCF method, then these values were used to The Learning domain included the Rey Serial Design Learning Test (RDLT), paragraph recall tests(WMS-R/III Logical Memory I or the Story Recall Test), verbal list learning tests (California, Crawford, Similar to other meta-analyses of cognition in schizo- Hopkins or Rey Verbal Learning tests, or the Bushcke phrenia (Harvey and Keefe, 2001 ; Heinrichs and Selective Reminding Test), and visual reproduction Zakzanis, 1998) effect sizes were calculated for indi- tests (WMS-R/III Visual Reproduction subtest, the vidual neuropsychological tests, although in several Rey-Osterrieth/Taylor Complex Figure Test (RCFT), cases highly similar tests were combined into a single or the Benton Visual Retention Test).
measure (e.g. verbal list learning). These effect sizes The Cognitive Flexibility and Abstraction domain were then combined into nine domains, as listed in consisted of the Wisconsin Card Sorting Test (perse- Table 1, by averaging effect sizes within studies across verative errors or percent perseverative errors score) tests that putatively tap similar skills. A Global Cog- and the WAIS-R/III Similarities subtest. Timed motor nitive Index was also created by either averaging all tests occasionally considered to tap executive function domain effect sizes within a study or using Global (e.g. Trailmaking B) were not included because dif- Cognitive Index scores in cases where studies reported ferential effects of typical and atypical APDs on motor them. Thus, each study contributed one Global Cog- speed might have unduly influenced effect sizes for nitive Index score and at least one domain effect size. The construction of the domains reported here The Processing Speed domain included the WAIS- was based upon prior reviews and earlier studies R/III Digit Symbol Coding or Digit Symbol Modalities Test, Trailmaking B, and the Wechlser Intelligence to a typical APD control, or multiple dosing arms, the Scale for Children – Revised Mazes subtest.
atypical APD arms were treated as separate samples The Verbal Fluency domain consisted of the and effect sizes for each arm were calculated. Effect Controlled Oral Word Association and Category sizes were combined according to the fixed-effects model (Shadish and Haddock, 1994). Briefly, each The Visuospatial Processing domain included the effect size was weighted by the inverse of its variance WAIS-R/III Block Design subtest, the Rey-Osterrieth/ such that effect sizes calculated from studies with Taylor Complex Figure Test copy score and visual larger sample sizes contributed more to the overall organization tests such as the Hooper Visual Organ- effect size when combined. A weighted average effect ization Test, Mooney Face Closure Test, Benton size, with positive values indicating improvement Judgment of Line Orientation, and Line Drawing.
and negative values indicating a decline in perform- The Motor Skill Domain included the Finger ance, and a corresponding Z statistic was calculated Tapping Test, Grooved Pegboard, and Pin tests.
to determine if the weighted average effect size was The Delayed Recall domain included tests of a significantly greater than zero. Given the large number visual recall (WMS-R/III Visual Reproduction II of Z tests carried out, a Bonferroni correction was and the delayed RCFT), verbal recall (WMS-R/III applied to the critical a. For the domains, the critical Logical Memory II and delayed Story Recall Test), a was p=0.006. In addition, a 95 % confidence interval and verbal list learning (delayed free recall scores from (CI) was calculated for the global and domain effect the verbal list learning tests described above).
sizes. To assess the relevance of predefined moderatorvariables, a measure of effect size homogeneity, the Calculation of effect sizes and data analysis Q statistic, was also calculated for each neuropsycho-logical domain and the Global Cognitive Index Typically, meta-analyses only include controlled stud- (Hedges and Vevea, 1998). The Q statistic has a x2 ies that randomly assigned subjects to either a control distribution with kx1 degrees of freedom, where k is group or an active treatment group. However, this the number of effect sizes being combined. The critical approach would overlook a substantial body of evi- a for the Q statistic was set at 0.05. When the assump- dence from single-sample studies that may be relevant tion of homogeneity was rejected the effect sizes were to the demonstration of cognitive change from atypical combined using the random-effects model. In the APD treatments. In an attempt to preserve scientific moderator variable analysis, the Q statistic was parti- rigour without omitting potentially important results, tioned into a between-groups component, Q two analyses were undertaken, the first with a con- servative approach to the published literature and the way ANOVA). A moderator variable was considered second with less conservative restrictions.
significant if it effectively separated the effect sizesinto separate categories (i.e. Q did not have significant within-group variation (i.e.
The first analysis included only reports from com- QW was not significant). The R2 value was also calcu- parisons of typical APDs and atypical APDs that ran- lated for each significant moderator variable to assess domly assigned patients to treatment. Post-treatment the strength of the relationship between moderator means and standard deviations were used to calculate and dependent variables. Moderator variables in- Hedges’ g, the difference between the means of atypi- cluded the coded study characteristics of baseline cal APD and typical APD groups at study end-point, medication status (typical APDs vs. unmedicated), divided by their pooled standard deviation. Where schizophrenia subtype classification (early phase group means and standard deviations were not combined with general, vs. treatment refractory), explicitly reported, Hedges’ g was calculated using and corporate sponsorship of study (yes vs. no). In appropriate alternative methods based on t or F stat- addition, correlations between effect sizes and the istics (Rosenthal, 1994). Where the t or F statistics were continuous variables haloperidol arm dose at study also not reported, data were solicited from the original end-point and study duration were carried out. To study authors. A weighted average effect-size estimate avoid violations of independence in the moderator was calculated for the Global Cognitive Index and variable analysis, average effect sizes were calculated each domain by combining data from all studies that across groups for the three studies that examined examined cognitive change to clozapine, olanzapine, cognitive change in more than one atypical treatment risperidone, or quetiapine. In cases where a study in- or dosing arm (Bilder et al., 2002; Purdon et al., 2000; cluded more than one atypical APD arm, in addition Velligan et al., 2002) and for four risperidone studies that reported results from the same trial (Green et al., include either were coded as uncontrolled. Pearson’s R 1997; Kern et al., 1998, 1999; McGurk et al., 1997).
correlations were carried out to examine relationshipsbetween domain effect sizes and study duration.
In addition, differences in cognitive change between The second analysis included all prospective studies, medications were examined. Group differences were regardless of whether or not participants were ran- examined in the same manner as moderator variables, domly assigned to treatment, including single-sample by partitioning the Q statistic into a between- and switch studies. Investigations of cognitive change fol- within-groups component where the between-groups lowing a shift from one atypical APD to another were component reflects the difference between medication not included. A single sample, within groups, re- groups and the within-groups component represents peated measures index of effect size, the mean change an overall measure of the variability within medi- score divided by its standard deviation, analogous to cation groups. In cases were QBET was significant, Hedges’ g was used as the estimate of effect size pairwise contrasts were carried out to identify specific (Rosenthal, 1994). It should be noted that this method differences between medication groups. A weighted for calculating effect sizes probably yields different within medication group effect size was not included effect sizes than those reported in Analysis 1 since in the pairwise contrasts if it was calculated under the each group acts as its own control in a repeated- random-effects model. The critical a for the pairwise measures design. Thus, comparisons between Analy- contrasts was Bonferroni corrected to control for Type I ses 1 and 2 should not be made. Paired t tests or alternative repeated-measures values were availableto calculate an effect size for the majority of studies.
In studies that did not report change scores, an esti-mate of effect size was derived using the procedure of Smith et al. (1980), which estimates change from the pre-treatment and post-treatment groupmeans, divided by the standard deviations reported in Seventeen studies from 14 independent, controlled, the original manuscript, and adjusted for test–retest random-assignment clinical trials were included in correlations provided in a compendium of neuro- the analysis. The discrepancy between the number of psychological tests (Spreen and Strauss, 1998).
studies and number of clinical trials is due to the fact Weighted effect sizes, Z statistics, 95 % CIs, and Q that four studies reported on the same clinical trial of statistics were then calculated overall for each domain, cognitive change to risperidone (Green et al., 1997; and again within each medication group. As in Kern et al., 1998, 1999; McGurk et al., 1997). Two Analysis 1, when the Q statistic was rejected, effect studies were open label. Of the 14 independent sizes were combined according to the random-effects trials, two included a clozapine arm, three included an olanzapine arm, four included a risperidone arm, Analysis 2 had a sufficient number of studies to two included a quetiapine arm, one included cloz- allow for a more comprehensive examination of the apine, olanzapine, and risperidone arms, one included influence that study characteristics might have on both a risperidone and an olanzapine arm, and one effect sizes and comparisons between atypical APDs.
included two different dose groups of quetiapine.
Comparisons of the dichotomous variables study Schizophrenia subtype classification for the 14 trials blind or random assignment (controlled vs. uncon- was early phase (n=3), general (n=7), and treatment trolled), corporate sponsorship (yes vs. no), baseline refractory (n=4). Baseline medication status included medication status (typical APDs vs. unmedicated), unmedicated (n=5) or predominantly unmedicated and schizophrenia subtype classification (early phase (n=1), medicated (n=7), and mixed (predominantly combined with general, vs. treatment refractory) were haloperidol, n=1). The reported washout period for carried out as described in Analysis 1. The variables the unmedicated studies typically ranged from 2 to study blind and random assignment were collapsed 7 d. After excluding four reports from the same clini- into a single variable due to the fact that almost every cal trial because of discrepancies in the reported study that randomly assigned subjects to treatment number of enrolled subjects (Green et al., 1997; Kern was also double blind. Thus, in order to avoid the re- et al., 1998, 1999; McGurk et al., 1997), the 13 remain- dundancy of carrying out two comparisons, studies ing (independent) trials reported retention rates of that included at least one of these features in their de- 43–93 % of enrolled patients. As expected, attrition was sign were coded as controlled and those that did not lower in studies with a short duration of treatment and Table 3. Neuropsychological change with atypical antipsychotic drugs: Analysis 1 Number of effect sizes (k) and number of subjects (n) ES, Effect size; CI, confidence interval.
retention improved to a range of 50–93 % of enrolled p<0.024) and Motor Skill (ES=0.21, Z=2.56, p<0.010) subjects when the last observation was carried for- domains. The weighted mean effect sizes for the nine domains and the Global Cognitive Index are presented Mean trial duration was 31 wk (median=23 wk) in Table 3. In addition, the number of subjects within and ranged from 4 to 104 wk. The range of average each atypical medication group, summed across doses used for each medication was consistent studies, is reported for each cognitive domain.
with doses recommended in the various productmonographs ; clozapine (410.5–521.8 mg), olanzapine (10.6–30 mg), risperidone (5.7–11.3 mg), and queti- None of the moderator variables was significantly apine (300–600 mg). The average dose used in the associated with the Global Cognitive Index (all Q haloperidol control arms ranged from 4.5 to 37.9 mg.
values>0.58). Study duration and haloperidol doseused in the control arm were not significantly corre- lated with the Global Cognitive Index score, all Effect sizes for one study could not be computed from Pearson’s p values >0.44. Similarly, none of the the information provided by the author (Kern et al., moderator variables tested was associated with any 1998) and effect sizes for three studies were based on domain score (all QBET <3.28, p>0.070). Effect sizes LOCF data. The effect size for the Global Cognitive for the Cognitive Flexibility and Abstraction domain Index was significant [effect size (ES)=0.24, Z=3.67, were negatively correlated with trial duration ( r= p<0.001] indicating that atypical APDs improved x0.70, p<0.016), however, it was apparent that this overall cognitive function to a greater extent than was due to an outlier (Green et al., 2002), that was typical APDs. The effect sizes for the Learning significantly longer in duration (104 weeks) than the (ES=0.24, Z=3.44, p<0.001) and Processing Speed remaining studies. This correlation was not significant (ES=0.21, Z=3.02, p<0.003) domains were significant after removal of the Green et al. study. There was at the Bonferroni-corrected level. Additional im- evidence that effect sizes for Processing Speed were re- provements at the uncorrected significance level were lated to the average dose used in the haloperidol con- observed for the Verbal Fluency (ES=0.16, Z=2.26, trol arms (r=0.58, p<0.031), however, this correlation did not remain significant when effect sizes were col-lapsed across groups within the studies that includedmultiple atypical treatment arms (r=0.50, p<0.15).
Fifty independent groups from 41 studies met criteria for inclusion in Analysis 2. There were more groupsthan studies because eight studies included more than one atypical treatment arm or group. The schizophrenia subtype classification included earlyphase (n=5), general (n=18), and treatment-refractory (n=18) patients. Baseline medication status included unmedicated (n=11), medicated (n=22), mixed (un-medicated/typicals=1; typicals/atypicals=4), and unknown (n=3). Washout periods for the unmedi-cated studies typically ranged from 1 to 7 d although one study included only neuroleptic-naive subjects.
Eighteen studies either randomly assigned subjects to treatment or were double blind. Eighteen studiesreceived at least partial funding support from a phar- maceutical company. Among the studies that werenot included in Analysis 1, the percentage of subjects completing the trials ranged from 45 % to 100 %. As expected the average percentage was high, 82 %, possibly reflecting the tendency for less controlled studies to infrequently report the number of subjects initially screened or enrolled in a study. Mean trial duration was 25 wk (median=14 wk) and ranged from 1.5 wk to 3 yr. The mean and range (in parentheses) ofdoses under double-blind (DB) conditions tended to be lower than the open-label (OL) doses in studies OL=529.1 (319.3–750)], whereas the reverse was true for olanzapine [DB=16.9 (10–30), OL=13.8 (11–19.9)], and risperidone [DB=7.7 (5.7–11.3), OL=5.5 (2.2–8.9)].
The results for Analysis 2 are shown in Table 4. The Global Cognitive Index for all atypical treatments combined was significantly greater than zero (ES= 0.36, Z=8.87, p<0.001). All cognitive domains dem- onstrated significant improvement on atypical APD medications at the Bonferroni-corrected significance level. The weighted effect sizes for the nine domains ranged from 0.17 to 0.46. The weighted effect sizes for the Vigilance and Selective Attention, Learning, and Delayed Recall domains were calculated under the random-effects model due to the presence of signifi- cant heterogeneity (all x2 p values <0.010). Inspection Flexibility and Abstraction, and Visuospatial Skilldomains calculated from uncontrolled studies were not. The moderator variable baseline medication sta-tus was significantly associated with Delayed Recall domain effect sizes (QBET=5.98, p<0.015; QW=26.29,p<0.240; R2=0.14). Studies that included an un- medicated baseline produced smaller Delayed Recalleffect sizes than those that tested subjects while they were receiving typical APDs at baseline (ES=0.21 vs.
0.54). The moderator variables diagnosis, corporate sponsorship, and schizophrenia subtype were notsignificantly associated with the Global Cognitive Index score or any domain. Trial duration was not correlated with the Global Cognitive Index or any Figure 1. Neuropsychological change to atypical anti- psychotic drugs: controlled (&) vs. uncontrolled studies (%).
* Indicates significant differences between controlled anduncontrolled trials (p<0.05). For abbreviations see Table 1.
Comparison of atypical antipsychotic drugs The QBET statistic revealed significant group differ- of the distribution of effect sizes within the Learning ences within the Vigilance and Selective Attention domain revealed an outlier (ES=1.22) that was sig- domain (QBET=22.53, p<0.001; QW=26.52, p<0.491; nificantly greater than the range of the remaining R2=0.46) and the Verbal Fluency domain (QBET= effect sizes (ES=x0.13–0.84). Removal of this outlier 15.47, p<0.002; QW=25.18, p<0.912; R2=0.32).
significantly reduced the variation within the Learning Within the Vigilance and Selective Attention domain, follow-up contrasts identified a significant advantage size remained significant (ES=0.43, Z=9.94, p< for quetiapine, relative to clozapine (x2df= = 0.001). This outlier is not included in the moderator or comparisons between treatment groups’ analyses a significant advantage for olanzapine, relative to advantages for quetiapine, relative to olanzapine Global Cognitive Index effect sizes from uncontrolled 4.19, p<0.041), and olanzapine, relative to studies (ES=0.43, Z=6.75, p<0.001) were marginally larger than those from controlled studies (ES=0.32, the uncorrected significance level. Pairwise contrasts Z=6.03, p<0.001), however, this difference was not within the Verbal Fluency domain indicated that que- significant, QBET=1.95, p<0.164. The moderator vari- tiapine improved performance to a greater extent than able, control, was significantly associated with Verbal Fluency (QBET=8.19, p<0.005; QW=32.39, p<0.595; improved verbal fluency to a greater extent than R2=0.18) and Processing Speed effect sizes (QBET= 6.82, p<0.009; QW=47.73, p<0.252; R2=0.11). Verbal correction. Additional advantages for quetiapine, Fluency effect sizes calculated from random assign- ment or double-blind studies were significantly less clozapine, compared to olanzapine (x2df= = than those obtained from open-label, uncontrolled 0.050), were observed at the uncorrected significance studies (ES=0.21 vs. 0.45). Similarly, effect sizes for level. The Verbal Fluency pairwise contrasts were Processing Speed were also larger in the uncontrolled repeated after exclusion of the uncontrolled studies relative to controlled studies (ES=0.50 vs. 0.30). The since this moderator variable was associated with weighted mean and 95 % CI for each domain and the verbal fluency effect sizes. After excluding uncon- Global Cognitive Index for controlled and uncon- trolled studies, the quetiapine vs. risperidone and trolled studies are displayed in Figure 1. Within the quetiapine vs. olanzapine contrasts were significant at controlled studies, the weighted mean effect size for the Bonferroni-corrected significance level (x2df= = each domain remained significant after Bonferroni correction, however, the weighted mean effect sizes but the clozapine vs. risperidone contrast was not for the Vigilance and Selective Attention, Cognitive and Selective Attention and Cognitive Flexibility andAbstraction were 0.34 and 0.17.
The within-group effect sizes for each medication are A primary advantage of the meta-analytical strategy presented in Table 4. Because the moderator control involves the ability to analyse moderator variables.
was significant for Verbal Fluency and Processing There was no compelling evidence that moderator Speed, the within-group effect sizes for these two do- variables influenced effect sizes among the set of ran- mains were recalculated after removing uncontrolled domized, controlled trials. However, a trend emerged studies. After excluding the uncontrolled studies, the for a positive correlation between haloperidol dose Verbal Fluency effect sizes for clozapine (ES=0.41, and the degree to which the patients treated with Z=2.87, p<0.005), and quetiapine (ES=0.68, Z=3.92, p<0.001) remained significant. However, the Verbal patients on processing speed tasks. Although this Fluency effect size for olanzapine (ES=0.17, Z=2.54, association failed to reach statistical significance, it p<0.012) and the Processing Speed effect sizes for suggests that some of the advantages of atypical APDs clozapine (ES=0.28, Z=0.99, p<0.322), and risper- relates to an avoidance of the deleterious effects of idone (ES=0.19, Z=2.10, p<0.036) did not. The re- high doses of haloperidol. Alternatively, one might sults for quetiapine should be interpreted cautiously speculate that this association reflects symptom given that the effect sizes for several domains included severity, with the most severe patients requiring the relatively few studies and, in the case of visuospatial highest treatment doses, and the most severe subjects processing, were based on a single study.
showing the greatest relative advantage of atypicalAPDs.
Examination of moderator variables in Analysis 2 revealed that studies that failed to randomly assign The findings from the current set of meta-analyses in- subjects to treatment or utilized open-label designs dicate that atypical APDs improve overall cognitive produced larger verbal fluency and processing speed function in schizophrenia and performance in a num- effect sizes than studies that included either of these ber of cognitive domains. The results obtained from features in their design. However, caution is warran- Analysis 1 of 14 controlled, random-assignment trials ted when interpreting these findings, particularly with indicates that atypical APDs are superior to typical respect to verbal fluency, because the larger number APDs, haloperidol in particular, at improving overall of clozapine studies within the group of open-label cognitive function. This finding is consistent with an studies may have skewed the results. Clozapine, in earlier meta-analysis of three randomized, controlled contrast to olanzapine and risperidone, significantly trials that identified improvement in overall cognitive improves verbal fluency in both open-label and function with atypical APDs. In contrast to the earlier double-blind studies and it is possible that the higher meta-analysis that was based upon a small number of number of open-label clozapine studies may have in- clinical trials conducted prior to 1999, the greater flated the mean effect size. The Global Cognitive Index number of studies in the current meta-analysis al- was not significantly different between controlled and lowed for a closer examination of the improvements.
uncontrolled studies suggesting that study method- After Bonferroni correction, improvements were ident- ology does not systematically bias all results. Rather, ified in learning and processing speed. Additional the effects of study design appear to increase the improvements in verbal fluency and motor skill were variability of effects across studies as evidenced by detected, although these improvements failed to reach the fact that, within any given domain, uncontrolled Bonferroni-corrected significance levels.
studies yielded a broader range of effect sizes than the The inclusion of investigations with single treat- ment arms and uncontrolled designs in Analysis 2 Pairwise contrasts between atypical APDs indicated further supports the benefits of atypical APD treat- that no medication appeared superior or inferior to the ments and indicates improvements occur in a wide other medications in overall cognitive function, but array of cognitive functions. The effect sizes for do- several differences emerged in two domains, Vigilance mains ranged from 0.17 to 0.46 and are remarkably and Selective Attention, and Verbal Fluency. The consistent with Harvey and Keefe’s (2001) earlier findings should be considered preliminary until more review of 20 studies. For example, Harvey and Keefe large-scale, controlled comparisons between atypical (2001) identified improvements, in terms of Cohen’s d, APDs are carried out, particularly with clozapine and of 0.39 and 0.18 for vigilance and executive functions quetiapine. However, the results are generally con- respectively. The results reported here for Vigilance sistent with predictions derived from the assumption that lower dopamine D2 receptor affinity and regard that delayed recall scores showed the largest increased serotonergic effects may be related to cogni- improvements with atypical APDs in studies in tive benefits from novel agents. In contrast the results which subjects were originally assessed while on a are not entirely consistent with the longstanding assumption that the inherent anticholinergic proper- A second artifact relates to the possibility of practice ties of some APDs might limit gains in memory and effects that could occur on neuropsychological meas- attention (McGurk and Powchick, 2000). Risperidone, ures that are repeatedly administered to the same which has the highest affinity for D2 receptors among subject. In atypical APD vs. typical APD studies, the atypical agents (Schotte et al., 1996; Seeman, 2002), practice effects would be expected in both treatment showed the least beneficial profile on measures of arms, thus, a relative advantage of atypical APDs Vigilance and Selective Attention and Verbal Fluency, would probably not be related to practice effects alone.
being outperformed by quetiapine and olanzapine on However, this inference relies on the unsupported Vigilance and Selective Attention, and quetiapine and assumption that there will be no interaction between clozapine on Verbal Fluency. The differences were treatment and practice (Carpenter and Gold, 2002).
quite robust ranging from 0.3 to 0.5 standard devi- To the contrary, emerging evidence suggests that ations and, for Verbal Fluency, remained significant typical APD treatments may have subtle, detrimental even when the analysis was restricted to controlled effects on cognition that may limit the benefit of studies. Clozapine, which may be more cholinomi- repeated exposure to the same materials (Blyler and metic than anticholinergic (Olianas et al., 1999; Zorn Gold, 2000). For example, normalization of procedural et al., 1994), did not significantly improve Vigilance learning following a change from atypical APDs to and Selective Attention and it resulted in less im- clozapine suggest that some improvements in cogni- provement than quetiapine on this domain. Moreover, tive function may relate to a release from impairment although clozapine significantly improved Delayed caused by the typical APD (Purdon et al., 2002).
Recall, improvement in this domain was markedly less Similar demonstrations of a preservation of pro- than that observed in the olanzapine and risperidone cedural learning with olanzapine and clozapine com- groups. However, despite the presumption of signifi- pared to the apparent loss of procedural learning cant inherent anticholinergic activity, olanzapine did induced by haloperidol, and perhaps risperidone not conform to this model. Olanzapine treatment pro- (Bedard et al., 1996, 2000; Purdon et al., 2003; Stevens duced medium to large gains on tests of vigilance and et al., 2002) support the view that some of the im- selective attention and delayed recall. It thus appears provements with atypical APDs might result from an that, at least at clinically relevant dosages, olanzapine avoidance of deleterious effects on learning associated does not appear to behave like an anticholinergic with typical APDs. While typical APDs may limit agent. These conclusions are consistent with the practice effects, the improvements on atypical APDs absence of further cognitive impairment observed in are unlikely to be entirely explained by practice effects.
patients with Alzheimer’s disease treated with very The percentage of patients demonstrating improve- low doses of olanzapine (Kennedy et al., 2001; Street ments at or greater than half a standard deviation, et al., 2000) and the lower incidence of cholinergic- which ranges from 40 % to 75 %, in recent double- related side-effects and serum anticholinergic levels blind, controlled trials (Bilder et al., 2002; Harvey et al., observed with olanzapine relative to clozapine 2003; Velligan et al., 2003) exceeds what one would (Chengappa et al., 2000; Eschweiler et al., 2002).
expect from typical practice effects. Moreover, the The moderator analysis is an effective method differences between atypicals on verbal fluency and for detecting systematic variability between different attention in the current study can not be accounted for studies of cognitive change to novel treatments, but it does not allow an assessment of more systemic chal- As with any meta-analysis, publication bias, es- lenges to the validity of the cognitive benefits reported pecially among studies sponsored by pharmaceutical from atypical APDs relative to typical APDs or to the companies, poses a threat to the validity of the find- validity of differential benefits within the atypical ings. Corporate sponsorship plays a significant role APD class. One factor especially germane to the in the dissemination of results and although there was current review is the adjunctive use of anticholinergic no evidence that sponsored trials reported larger effect medications. In studies with a typical APD control sizes, it remains possible that a number of sponsored, arm, emergent EPS require adjunctive anticholinergic unpublished negative trials exist. Selective reporting medication that may interfere with cognitive skills, of results within published papers can also pose a particularly attention and memory. It is notable in this threat. However, almost all of the trials included in the current review examined multiple dependent as a speaker for Eli Lilly & Co. Dr Herbert Y. Meltzer, measures simultaneously and reported all the results M.D. has served as a consultant, board member and/ within a single article, although there were exceptions or speaker for Janssen, Novartis, and Pfizer and has (see Green et al., 1997; Kern et al., 1998, 1999; McGurk received grant/research support from AstraZeneca, et al., 1997 for exceptions). Thus, while we cannot rule Eli Lilly & Co., Janssen, Novartis, and Pfizer. No out the existence of unpublished negative findings, financial support for this manuscript was received within the published studies analysed here, it seems unlikely that a systematic positive reporting bias The improvements in cognitive performance with atypical APDs are in general encouraging, especiallywhen the potential implications for socio-vocational Bedard MA, Scherer H, Delorimier J, Stip E, Lalonde P re-integration are considered. The gains observed in (1996). Differential effects of D2- and D4-blocking learning may be particularly relevant as this cognitive neuroleptics on the procedural learning of schizophrenic skill has been linked to three major dimensions of patients. Canadian Journal of Psychiatry 41, S21–S24.
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