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Antipsychotics and Cognition: Practice Makes Perfect Confounder

12 October 2007. The question of whether antipsychotic drugs reduce cognitive impairment in schizophrenia has ramifications beyond patient care. Even modest cognitive benefits of these drugs would justify further efforts to maximize effects on the putative molecular mechanisms (see SRF Forum Discussion). Two recent, and prominent, studies, led by Richard Keefe of Duke University, suggest that second-generation antipsychotics, and even a first-generation one, enhance cognition in subjects with schizophrenia. However, in the October Archives of General Psychiatry, Terry E. Goldberg and colleagues at Zucker Hillside Hospital in Glen Oaks, New York, show that practice effects from repeated test taking can masquerade as drug benefits.

The cognitive deficits at issue in schizophrenia cross multiple domains, including attention, working memory, language skills, executive function, and social cognition (for a review, see Bowie and Harvey, 2005). Their importance for functional outcomes has led researchers to examine antipsychotic drugs as possible remedies. According to a 2005 meta-analysis, atypical, or second-generation, antipsychotics improve cognitive functioning more than older, typical antipsychotics (Woodward et al., 2007).

Equal “gains”
Yet the research may be biased by methodological shortcomings and industry sponsorship, Keefe and colleagues write in the June Archives of General Psychiatry. They sought to minimize such problems by comparing the cognitive effects of four atypical and one typical antipsychotic as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (see SRF related news story). Their study randomly assigned subjects with chronic schizophrenia to treatment with an atypical antipsychotic—namely, risperidone, ziprasidone, quetiapine, or olanzapine—or the typical antipsychotic pherphenazine. Analyses included 817 subjects who completed cognitive testing at baseline and after 2 months of treatment.

Over time, all groups in the double-blind study improved their cognitive test performance to a small but statistically significant extent. Unexpectedly, they all did so equally.

The researchers write, “This failure to document a neurocognitive advantage of second-generation antipsychotics suggests that the positive findings from prior reports may not generalize well to the type of everyday clinical practice examined in the CATIE trial.” They contrast their study with others that used “high dosages of first-generation antipsychotics, usually haloperidol, creating an unfair comparison because of the increased risk of extrapyramidal symptoms and anticholinergic treatment, which may impair cognition.”

The other randomized, double-blind study headed by Keefe appeared in the July American Journal of Psychiatry. It compared the cognitive effects of three second-generation antipsychotics in 224 subjects with early schizophrenia who completed cognitive testing after 12 weeks of treatment.

The risperidone, olanzapine, and quetiapine groups initially showed similar, modest gains in performance. However, by week 52, those gains no longer reached statistical significance, perhaps due to attrition. The researchers acknowledge that the cognitive improvement they found could have resulted from subjects’ increased experience with the tests.

Artifact, not drug impact
This need to disentangle practice from medication effects initially inspired the Goldberg study. According to Goldberg and colleagues, “large industry-sponsored controlled trials” in patients with first-episode schizophrenia found that risperidone and olanzapine significantly enhanced cognition, with effect sizes on composite measures ranging from 0.35 to 0.54. “Critically, these studies did not include control groups, raising the possibility that improvements were due to practice effects because patients were tested on multiple occasions,” they write.

In addition, many of the subjects had a history of taking medication. Their test performance may have improved because, at baseline, they were undergoing withdrawal from prior treatment or were taking medication that hampered cognition.

The Goldberg team sought to address these problems by recruiting 104 subjects with first-episode schizophrenia (FES) and randomly assigning them to 16 weeks of treatment with olanzapine or risperidone. They also enrolled a healthy control (HC) group of 84 subjects who received no study medication.

All subjects underwent cognitive testing at baseline, 6 weeks, and 16 weeks. Researchers who were blind to group assignments tested their mental status, processing speed, motor speed and dexterity, episodic memory, working memory, and executive function.

The risperidone and olanzapine groups improved equally over time, so analyses combined them. Cognitive performance improved on nine of the 16 measures. Strikingly, the medicated and control groups made similar gains on most of them. In fact, treated subjects’ rate of improvement surpassed that of controls only on the trail making and memory for visual designs tests.

Across the 16 measures, composite effect sizes—0.33 for unmedicated healthy subjects and 0.36 for medicated subjects with schizophrenia—unearthed little improvement beyond that attributed to practice. “It is sobering to note that the composite effect size in the FES group of 0.36 would be considered moderate and could be attributed to treatment,” Goldberg and colleagues write. Even so, they deem their results “circumstantial” because ethical concerns precluded testing untreated subjects with schizophrenia.

What about social cognition?
Most studies of whether antipsychotics help cognition in schizophrenia have focused on basic cognitive processes such as memory and attention rather than social cognition, the ability to perceive and process information about oneself and others. Since the limited research has yielded unclear results, a study in this month’s American Journal of Psychiatry, led by Mark J. Sergi of California State University at Northridge, assessed the effects of three antipsychotic drugs on both social and basic cognition.

The double-blind study assigned 100 subjects with schizophrenia or schizoaffective disorder to 8 weeks of treatment with risperidone, olanzapine, or haloperidol in a modified random design. They underwent testing at baseline, week 4, and week 8.

The tests of basic cognition covered verbal episodic memory, verbal working memory, executive functioning and problem solving skills, attention, processing speed, motor dexterity, and verbal fluency. A factor analysis revealed two underlying dimensions: general cognitive ability and processing speed.

The social cognition measures probed the ability to perceive interpersonal and emotional cues, like those conveyed by tone of voice, facial expressions, and gestures. Analyses treated them as a single cluster defined a priori.

Neither social cognition nor the processing speed factor showed significant effects of treatment, time, or their interaction. “However, general cognitive ability improved over time for each medication, an effect that may be attributable to the increased test familiarity and practice effects from repeated testing in an 8-week period,” Sergi and colleagues write.

The ramifications
The four new studies agree that none of the tested antipsychotics outshines the others in relieving cognitive deficits in schizophrenia. Actually, the Goldberg and Sergi studies suggest they do little for overall cognitive functioning. These drugs—or at least risperidone and olanzapine—may help only trail making and episodic memory for visual designs. These findings could lead to a rethinking of molecular targets for interventions.

“We hope that our findings increase awareness of practice effects as a potential source of cognitive change in clinical trials,” Goldberg and colleagues write. They call for the development of research methods and tests that minimize practice-related bias. They contend that the drug discovery and approval process could benefit from the inclusion of a healthy control group in trials assessing cognitive change. Beyond future research, the Goldberg team writes, “Our study may have implications for the reinterpretation of several previous trials in which cognition improved because the magnitudes of improvement found in prior trials may not be greater than the practice effect demonstrated by the HC group in our study.“—Victoria L. Wilcox.

Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC, Woerner MG, Schooler NR, Kane JM, Robinson DG. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: Is it a practice effect? Arch Gen Psychiatry. 2007 Oct;64:1115-1122. Abstract

Keefe RSE, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup S, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA, for the CATIE Investigators and the Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry. 2007 June;64:633-647. Abstract

Keefe RSE, Sweeney JA, Gu H, Hamer RM, Perkins DO, McEvoy JP, Lieberman JA. Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: A randomized, double-blind 52-week comparison. Am J Psychiatry. 2007 July;164:1061-1071. Abstract

Sergi MJ, Green MF, Widmark C, Reist C, Erhart S, Braff DL, Kee KS, Marder SR, Mintz J. Cognition and neurocognition: Effects of risperidone, olanzapine, and haloperidol. Am J Psychiatry. 2007 Oct;164:1585-1592. Abstract

Comments on News and Primary Papers
Comment by:  Richard Keefe
Submitted 12 October 2007 Posted 12 October 2007

As stated in the CATIE and CAFÉ neurocognition...  Read more

View all comments by Richard Keefe

Comment by:  Narsimha Pinninti (Disclosure)
Submitted 15 October 2007 Posted 15 October 2007
  I recommend the Primary Papers

This article questions the prevailing notion that...  Read more

View all comments by Narsimha Pinninti

Comment by:  Saurabh Gupta
Submitted 15 October 2007 Posted 15 October 2007
  I recommend the Primary Papers

I propose that future studies should use computational...  Read more

View all comments by Saurabh Gupta

Comment by:  Sebastian Therman
Submitted 17 October 2007 Posted 17 October 2007

One remedy would be repeated practice over time before the...  Read more

View all comments by Sebastian Therman

Comment by:  Andrei Szoke
Submitted 1 November 2007 Posted 5 November 2007
  I recommend the Primary Papers

We recently completed a meta-analysis on "Longitudinal...  Read more

View all comments by Andrei Szoke

Comment by:  Patricia Estani
Submitted 7 November 2007 Posted 8 November 2007
  I recommend the Primary Papers
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