Stability of Cognitive Performance in Older Patients with Schizophrenia: an 8-Week Test-Retest Study

Article Stability of Cognitive Performance in Older Patients With Schizophrenia: An 8-Week Test-Retest Study Philip D. Harvey, Ph.D. Objective: It is important to understand tions, and practice effects were generally the stability of cognitive performance in absent or minimal. Tests administered Barton W. Palmer, Ph.D. schizophrenia in order to understand with alternate forms were no more tem- 1) the potential improvements in perfor- porally stable than tests administered Robert K. Heaton, Ph.D. mance associated with the beneficial ef- twice with the same form. Very few indi- fects of cognitive-enhancing medications vidual cases had substantial variation at and 2) the potential variation in perfor- retest across the 22 test scores. From Somaia Mohamed, M.D., Ph.D. mance on cognitive measures that are these data, “norms for evaluating components of neuroimaging studies. change” were developed and described John Kennedy, M.D. There are several factors that could lead using the reliable change index method. to spurious improvements in cognitive Adam Brickman, M.A. test scores, including practice effects and Conclusions: The data suggest that the random test-retest errors. findings of modest cognitive improve- Method: Forty-five older patients with ments seen in some prior studies of schizophrenia who were receiving conven- schizophrenia patients when treated with tional antipsychotic medications partici- second-generation antipsychotic medica- pated in the study. All subjects completed tions were probably not due to simple re- a comprehensive neuropsychological test testing artifacts. At the same time, be- battery at baseline and again at an 8-week cause of the variance in some of these follow-up evaluation. test-retest performances, relatively sub- Results: Performance on all of the cogni- stantial changes in performance on the tive measures was stable over time, as ev- part of individual patients would be re- idenced by significant test-retest correla- quired to be clearly interpretable. (Am J Psychiatry 2005; 162:110–117) Previous research has focused on cognitive enhance- improved test performance without improvement in the ment in schizophrenia (1). An extensive literature has de- underlying cognitive ability. Test performance may appear veloped on the purported cognitive-enhancing effects of to improve because of the combined influence of normal second-generation (a.k.a. “atypical”) antipsychotic medi- variability in test performance (due to measurement er- cations (2), and in addition there has recently been in- ror) plus examinees’ increased familiarity with the test creased interest in identification of compounds chosen materials and procedures over repeated exposure (“prac- specifically for their cognitive-enhancing potential (3, 4). tice effects”). This issue also applies to nonpharmacologi- These studies have examined cognitive enhancement ef- cal interventions (i.e., cognitive remediation) and to infer- fects on a wide array of cognitive ability areas, including ences regarding the importance of correlations between episodic memory (5), attention/vigilance (6), executive cognitive test performance and the results of neuroimag- functioning (7), psychomotor speed (8), and verbal skills ing studies. Unreliable measurement would reduce the va- (9). While some of these studies have used adequate clini- lidity of inferences associated with correlations between cal trial methodology, the majority have had substantial test performance and imaging results, but few data are methodological limitations. For instance, many of the available to address the stability of performance on these studies did not use blinded designs or random assignment cognitive measures. to treatment conditions (see Harvey and Keefe [1] for a re- One method of addressing practice effects is the use of view of these issues). There has been equivalent interest in alternate forms, yet full equivalence of forms is an ideal developing cognitive-enhancing techniques that are be- that is difficult to achieve, and many of the cognitive tests havioral in nature, with many of the same issues applying that are most widely used in the schizophrenia literature to these studies as well. have only one version. Moreover, alternate forms do not One of the most salient methodologic issues that must fully eliminate practice effects. There appear to be at least be considered in interpreting apparent improvements in two potential components to practice effects: 1) an exam- cognitive test performance is whether such changes actu- inee’s performance may improve with repeated testing be- ally reflect improved cognitive ability or simply result from cause he or she learns the specific item content over re- 110 http://ajp.psychiatryonline.org Am J Psychiatry 162:1, January 2005 HARVEY, PALMER, HEATON, ET AL. peated presentations, and 2) an examinee’s performance This study used a neuropsychological battery (the Aged may improve with repeated testing because he or she be- Schizophrenia Assessment Schedule–Cognitive) that was comes more familiar with performing tasks similar to the originally designed by an advisory team of neuropsy- target assessment battery (method variance) or becomes chological experts for Eli Lilly and Company for use in more familiar or comfortable with being administered multisite studies of the cognitive effects of antipsychotic neurocognitive tests in general. Parallel forms are rarely medications among middle-aged and older patients with perfectly parallel, but even when ideal they correct for ef- psychotic disorders. In the present study, we provide a fects listed under the first component but do not correct comprehensive study of retest effects on cognitive func- for those subsumed under the second. tioning in schizophrenia, performed on 45 clinically and To some degree, interpretive difficulties in clinical trials cognitively stable outpatients who were receiving stable that are due to measurement error and practice effects can doses of conventional antipsychotic medications. Partici- be circumvented by study designs that include double- pants completed the Aged Schizophrenia Assessment blind random assignment of some participants to a pla- Schedule–Cognitive battery at baseline and at an 8-week follow-up evaluation during a period of clinical stability cebo (or other noncognitive enhancing) arm. However, without changes in their treatment status. there have been increasingly frequent concerns expressed about the use of placebo-controlled designs in schizophrenia research. Also, even with an adequately controlled de- Method sign, while one may be able to show differences in group Subjects mean performance, it is difficult to evaluate whether Participants were 45 middle-aged and older patients with changes have occurred on the level of an individual pa- schizophrenia (N=33) or schizoaffective disorder (N=12) who were tient. This level of change is truly the endpoint goal of cog- recruited and evaluated at any of three research sites, the Univer- nitive enhancement treatments, regardless of mechanism. sity of California at San Diego Department of Psychiatry, Mt. Sinai Identification of meaningful changes in performance School of Medicine, or the University of Cincinnati Department of Psychiatry. All participants were 45 years of age or older, each was on the part of schizophrenia patients, either due to im- receiving clinically appropriate doses of conventional neuroleptic provements in performance associated with treatment or medications during the study, and there had been no changes in deterioration in clinical status, requires understanding of their medication treatment during the month preceding the base- normative patterns of test-retest stability (10, 11). Test-re- line evaluation. We excluded patients with a history of other psy- chiatric diagnoses or medical conditions that might impact their test data from healthy comparison subjects may provide cognitive functioning (e.g., substance abuse or dependence, neu- some insight, but norms from cognitively stable schizo- rologic conditions, head trauma with loss of consciousness, sei- phrenia patients are needed because patients may show zure disorder, or degenerative dementia). Patients were also ex- more test-retest error variance than healthy individuals cluded if their current antipsychotic medication dose was greater (12). With the advent of newer antipsychotic medications than 1500 mg/day in chlorpromazine equivalents, they were receiving selective serotonin reuptake inhibitor antidepressants, or with reduced severity of side effects (13) and greater effi- they had a current diagnosis of major depression. These criteria cacy in critical symptom domains (14), it is difficult to per- were intended to ensure that the patients in the sample were clin- form clinical trials in which patients have the possibility of ically stable over the test-retest interval. being randomly assigned to receive older antipsychotic Measures treatments. If normative data were collected on clinically Psychopathology and motor symptoms. Level and changes stable individuals receiving older medications, these data in severity of psychopathology were assessed with the positive might be helpful in evaluating changes seen in future and negative subscale scores of the Positive and Negative Syn- studies examining compounds with purported cognitive- drome Scale (15) and the Montgomery-Åsberg Depression Rating enhancing effects. The purpose of the present study was Scale (16). Severity of extrapyramidal symptoms was assessed

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