Psychiatric Annals

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Pharmacologic Treatments in Schizophrenia and Their Effect on Cognitive Function 

Do Novel Antipsychotics Improve Cognition? A Report of a Meta-Analysis

Richard S E Keefe, PhD; Anna M Bollini, BA; Susan G Silva, PhD

Abstract

Sebastian is 28 years old and has chronic schizophrenia. Five years ago he moved from Chile to New York City, where he became a taxi driver. After a few months, he began to experience anxiety as a result of the chaotic traffic, rude passengers, arid his demanding boss. He tried to schedule his shifts so that he could avoid working during the rush hours, but he still found himself overcome with stress. In addition to his growing anxiety, Sebastian was having problems remembering the passengers' destinations and planning which route was the most time and distance efficient. Twice he ran through red lights because he was not paying attention to his driving. Many passengers felt endangered and bothered by his circuitous routes. Several complained to his employer or refused to pay the fare. After 6 months, Sebastian was fired. He sought employment at other taxi companies, but found that he had the same difficulties driving for them and eventually gave up driving a taxi altogether.

Like many patients with schizophrenia, Sebastian has significant cognitive deficits. A neuropsychological testing battery suggests that his working memory, which refers to his ability to keep information in mind during brief periods of time, is poor, falling in the bottom 25%, compared with non-schizophrenic individuals his age. In addition, his ability to categorize information, make decisions, and construct plans is poor, with scores in the bottom 10%, compared with normal individuals. Tests show that his attention and verbal memory are also substandard, with scores in the bottom 10% to 15%, compared with normal individuals. Anyone involved in Sebastian's treatment would be concerned about these cognitive deficits and would be inclined to ask the following questions: To what degree do these cognitive deficits affect Sebastian's life? Are they a result of his other symptoms of schizophrenia, such as his negative symptoms, or are they independent, warranting a treatment regimen aimed specifically at ameliorating them? Are medications available to treat these cognitive deficits? Will the improvements caused by these medications be clinically meaningful? What changes can Sebastian and his physician expect?

It is important to consider these questions because they concern areas that are central to the quality of life of individuals with schizophrenia. As reviewed by Green et al.,1 cognitive impairment in schizophrenia is strongly related to poor outcome and poor everyday functioning. Employment status is strongly related to performance on cognitive tests (S. McGurk and H. Meltzer, unpublished data, April 16, 1999). Many studies conducted during the past 40 years have addressed the question of whether typical antipsychotics improve cognitive function in patients with schizophrenia. Numerous literature reviews, including a recent review of data collected during the past 9 years,2 have arrived at the same basic conclusions: long-term treatment with conventional antipsychotic medications improves symptoms, but appears to have limited cognitive benefits. In fact, the literature examining the cognitive effects of typical antipsychotics provides some of the clearest demonstrations of the recalcitrant nature of cognitive impairment despite symptom change. The results of several studies may be interpreted to suggest that typical antipsychotic medications actually prevent adequate learning effects and worsen motor skills,3 memory function,4 and executive abilities, such as problem solving and performance assessment.5

Table

STATISTICAL PROCEDURE

The statistical meta-analytic procedures used to examine the results of these studies are described in detail by Keefe et al.6 Briefly, Fisher's method for combining P values was used. It provides a summary of the statistical significance of the results and a test of the null hypothesis that there is no difference between the effects of novel antipsychotics and conventional antipsychotics. When a given study included multiple test…

Sebastian is 28 years old and has chronic schizophrenia. Five years ago he moved from Chile to New York City, where he became a taxi driver. After a few months, he began to experience anxiety as a result of the chaotic traffic, rude passengers, arid his demanding boss. He tried to schedule his shifts so that he could avoid working during the rush hours, but he still found himself overcome with stress. In addition to his growing anxiety, Sebastian was having problems remembering the passengers' destinations and planning which route was the most time and distance efficient. Twice he ran through red lights because he was not paying attention to his driving. Many passengers felt endangered and bothered by his circuitous routes. Several complained to his employer or refused to pay the fare. After 6 months, Sebastian was fired. He sought employment at other taxi companies, but found that he had the same difficulties driving for them and eventually gave up driving a taxi altogether.

Like many patients with schizophrenia, Sebastian has significant cognitive deficits. A neuropsychological testing battery suggests that his working memory, which refers to his ability to keep information in mind during brief periods of time, is poor, falling in the bottom 25%, compared with non-schizophrenic individuals his age. In addition, his ability to categorize information, make decisions, and construct plans is poor, with scores in the bottom 10%, compared with normal individuals. Tests show that his attention and verbal memory are also substandard, with scores in the bottom 10% to 15%, compared with normal individuals. Anyone involved in Sebastian's treatment would be concerned about these cognitive deficits and would be inclined to ask the following questions: To what degree do these cognitive deficits affect Sebastian's life? Are they a result of his other symptoms of schizophrenia, such as his negative symptoms, or are they independent, warranting a treatment regimen aimed specifically at ameliorating them? Are medications available to treat these cognitive deficits? Will the improvements caused by these medications be clinically meaningful? What changes can Sebastian and his physician expect?

It is important to consider these questions because they concern areas that are central to the quality of life of individuals with schizophrenia. As reviewed by Green et al.,1 cognitive impairment in schizophrenia is strongly related to poor outcome and poor everyday functioning. Employment status is strongly related to performance on cognitive tests (S. McGurk and H. Meltzer, unpublished data, April 16, 1999). Many studies conducted during the past 40 years have addressed the question of whether typical antipsychotics improve cognitive function in patients with schizophrenia. Numerous literature reviews, including a recent review of data collected during the past 9 years,2 have arrived at the same basic conclusions: long-term treatment with conventional antipsychotic medications improves symptoms, but appears to have limited cognitive benefits. In fact, the literature examining the cognitive effects of typical antipsychotics provides some of the clearest demonstrations of the recalcitrant nature of cognitive impairment despite symptom change. The results of several studies may be interpreted to suggest that typical antipsychotic medications actually prevent adequate learning effects and worsen motor skills,3 memory function,4 and executive abilities, such as problem solving and performance assessment.5

Table

TABLE 1Methodologies of 15 Studies of the Effect of Novel Antipsychotlc Medication on Cognitive Functions In Patients With Schizophrenia

TABLE 1

Methodologies of 15 Studies of the Effect of Novel Antipsychotlc Medication on Cognitive Functions In Patients With Schizophrenia

Table

TABLE 1Methodologies of 15 Studies of the Effect of Novel Antipsychotlc Medication on Cognitive Functions In Patients With Schizophrenia

TABLE 1

Methodologies of 15 Studies of the Effect of Novel Antipsychotlc Medication on Cognitive Functions In Patients With Schizophrenia

META-ANALYSIS METHODS

The advent of novel antipsychotics has motivated researchers to examine how these medications affect cognitive impairments compared with conventional medications. To address this question empirically, a meta-analysis was conducted including the 15 studies that, as of June 30, 1998, had investigated the impact of novel antipsychotic medication on cognitive dysfunction in patients with schizophrenia.6 The methodology used in each of the 15 studies is listed in Table 1. The analysis was not restricted to studies investigating a particular novel antipsychotic medication. Three of the studies were randomized and double-blind, and 11 were open-label studies. In 1 study,19 the patients who received novel antipsychotics and a portion of the patients who received haloperidol were assessed in a double-blind manner; however, several of the patients who received haloperidol were not. One of the open-label studies13 used multiple study arms with random assignment. The numbers of studies that included the various novel antipsychotics are as follows: clozapine, 11; risperidone, 4; zotepine, 1; ziprazidone, 1; and aripiprazole, 1.

The 15 studies used a wide range of test measures. Some studies examined only a few neurocognitive measures, whereas others conducted a more comprehensive neuropsychological assessment. The number of different neurocognitive tests given to subjects ranged from 1 to 13. Because of the variability in the type and the number of measures used to assess neurocognitive effects, test results were grouped into the following categories: (1) attention subprocesses; (2) executive function; (3) working memory; (4) learning and memory; (5) visuospatial analysis; (6) verbal fluency; (7) digit symbol substitution; and (8) fine motor function.

Each study was examined to determine improvement in performance on a single test after treatment with novel antipsychotic medication compared with after conventional antipsychotic treatment (atypical vs typical) or a significant positive change in performance after treatment with novel antipsychotic medication relative to baseline. Our definition of improvement was conservative. We corrected for multiple comparisons in each study using an experimentwise P value of less than .05, even if the study authors did not complete this statistical procedure. For instance, if 10 measures were reported in a study, we assigned a significance criterion of .05/10 = .005 for each measure.

The cognitive domains in which each investigator reported improvement with novel antipsychotic treatment are displayed in Table 2, along with the improved cognitive domains resulting from our multiple comparison analysis. After we corrected for multiple comparisons, 9 of the 15 studies demonstrated significant neurocognitive improvement on at least 1 test measure following treatment with novel antipsychotic medication compared with conventional antipsychotics.

Table

TABLE 2Meta-Analysis Results of Impaired Cognitive Functions in 15 Studies

TABLE 2

Meta-Analysis Results of Impaired Cognitive Functions in 15 Studies

STATISTICAL PROCEDURE

The statistical meta-analytic procedures used to examine the results of these studies are described in detail by Keefe et al.6 Briefly, Fisher's method for combining P values was used. It provides a summary of the statistical significance of the results and a test of the null hypothesis that there is no difference between the effects of novel antipsychotics and conventional antipsychotics. When a given study included multiple test measures, the average P value for that study was used in the statistical procedure. If multiple test measures were included in a single domain of cognitive functioning, the average P value for that domain was used in the statistical procedure. When P values were not available, we calculated them using the published means and standard deviations. In one case, we contacted the authors to obtain unpublished means and standard deviations.

RESULTS OF THE META-ANALYSIS

The meta-analysis of the 15 studies indicated that there was a significant effect of novel antipsychotics compared with typical antipsychotics in their ability to improve cognitive functioning (chi-square = 62.41, P = .0004). The effect of novel antipsychotic medication on specific domains of cognitive function was also examined by combining all studies that reported data for each domain. Corrections were not made for multiple comparisons because this would have required setting a variable P value for each domain. Meta-analyses indicated significant improvement with novel antipsychotics in each of the aforementioned categories: attention, executive functions, working memory, visuospatial analysis, verbal fluency, digit symbol substitution, and fine motor functions.6

Despite a conservative statistical approach of correcting the results of each study for the number of statistical comparisons made, the metaanalysis strongly suggests that hovel antipsychotics, when compared with conventional antipsychotics, improve cognitive functions in patients with schizophrenia. The measures that responded the most strongly to novel antipsychotics were verbal fluency, digit symbol substitution, fine motor functions, and executive functions. Attention subprocesses were also responsive. Learning and memory functions were the least responsive.

CONCLUSION

Because of the limited number of studies included in the meta-analysis, it is difficult to conclusively determine the pattern of cognitive improvements that can be expected with any specific novel antipsychotic treatment. There is, however, preliminary support for the notion that verbal fluency, attention, and motor speed improve with clozapine. It has been shown that risperidone has beneficial effects on verbal working memory, selective attention and alertness,1 and executive functions.15 A study conducted by Rossi et al.18 suggests that negative symptoms correlate with performance on the Wisconsin Card Sorting Test before and after treatment with risperidone, implying that cognitive deficits and negative symptoms have a common substrate targeted by risperidone. Data published since our metaanalysis was completed suggest that quetiapine may have beneficial effects on attention,22 shortterm memory, and explicit memory.23 As reviewed by Meltzer and McGurk,24 preliminary data suggest that olanzapine also has beneficial effects on a variety of cognitive functions.

None of the 15 studies met all of the recently developed standards for the assessment of cognitive change in schizophrenia.6 Only 3 of the 15 studies used double-blind methodology and the impact of the various rater biases inherent to open-label studies of patients with schizophrenia, described recently in the Veterans' Administration collaborative study of clozapine,25 may be strong. However, these 15 studies serve an important function - they support the relatively recent notion that cognitive deficits can be improved in patients with schizophrenia. As a result of these initial studies, several large-scale comprehensive investigations of the effect of novel antipsychotics on cognitive impairment in schizophrenia are currently under way. The results of these studies will be of great interest because the possibility of improved cognitive functions in individuals with schizophrenia will help to further enhance their quality of life.

REFERENCES

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15. Gallhofer B, Bauer U, Lis S, Krieger S, Gruppe H. Cognitive dysfunction in schizophrenia: comparison of treatment with atypical antipsychotic agents and conventional neuroleptic drugs. Eur Neuropsychopharmacol. 1996;6(suppl 2):13-20.

16. Hoff AL, Faustman WO, Wieneke M, et al The effects of clozapine on symptom reduction, neurocognitive function, and clinical management in treatment-refractory state hospital schizophrenic inpatients. Neuropsychopharmacology. 1996;15:361-369.

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20. Galletly CA, Clark RC, McFarlane AC, Weber DL. The relationship between changes in symptom ratings, neuropsychological test performance, and quality of life in schizophrenic patients treated with clozapine. Psychiatry Res. 1997;72:161-166.

21. Fujii DEM, Ahmed I, Jokumsen M, Compton JM. The effects of clozapine on cognitive functioning in treatmentresistant schizophrenic patients. J Neuropsychiatry Clin Neurosci. 1997;9:240-245.

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24. Meltzer HY, McGurk SR. The effect of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull. 1999;25:233-255.

25. Rosenheck R, Cramer J, Xu W, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia: Department of Veterans' Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. N Engl J Med. 1997;337:809-815.

TABLE 1

Methodologies of 15 Studies of the Effect of Novel Antipsychotlc Medication on Cognitive Functions In Patients With Schizophrenia

TABLE 1

Methodologies of 15 Studies of the Effect of Novel Antipsychotlc Medication on Cognitive Functions In Patients With Schizophrenia

TABLE 2

Meta-Analysis Results of Impaired Cognitive Functions in 15 Studies

10.3928/0048-5713-19991101-08

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