Cognitive Effects of Olanzapine Treatment in Schizophrenia

Susan R. McGurk, Ph.D. (1) and Herbert Y. Meltzer, M.D. (2)

1. Assistant Professor of Psychiatry, Mount Sinai School of Medicine 2. Professor and Director, Division of Psychopharmacology, Department of Psychiatry Vanderbilt University School of Medicine Key Words: Schizophrenia; Cognition; Olanzapine; Anticholinergic, Verbal Memory; Executive Functioning Funding: NARSAD grant to S.R. McGurk Grants from Warren Foundation and a grant from Eli Lilly to H. Y. Meltzer

Running Title: Cognitive Effects of Olanzapine Corresponding Author: Susan R. McGurk, Ph.D. PO Box 591 Northport, New York 11768 Phone: 631-761-2686 Fax: 631-761-2718 susanrmcgurk@compuserve.com

Abstract Improvement in some but not all domains of cognition during treatment with the atypical antipsychotic drugs clozapine, quetiapine, olanzapine and risperidone has been reported in some but not all studies. It has been recently suggested that these reports are an artifact, related to lessening of the impairment due to typical neuroleptic drugs and anticholinergic agents. The purpose of this study was to further test the hypotheses that olanzapine, an atypical antipsychotic drugs reported to have anticholinergic properties, improves cognition in patients with schizophrenia, including domains of cognition related closely to work and social function, i.e. verbal learning and memory, and, that this improvement was independent of improvement in psychopathology. Thirty-four patients with schizophrenia who were partial responders to typical antipsychotic drug treatment were evaluated with a comprehensive neurocognitive battery, including measures of executive functioning, verbal and visual learning and memory, working memory, immediate, selective and sustained attention, perceptual/motor processing, and motor skills prior to, and following, treatment with olanzapine for 6 weeks. The Brief Psychiatric Rating Scale was used to assess psychopathology in patients treated with typical antipsychotic drugs. Subjects were to olanzapine (average dose 13.4 mg, range 520) and were reassessed following six weeks and six months of treatment. Significant improvement was noted in nine of 19 cognitive tests, including measures of selective attention, verbal learning and memory, and verbal fluency. No cognitive test was worsened by olanzapine treatment. Improvements in the BPRS Total and Positive symptom subscale scores were noted. Improvements in verbal learning and memory, sustained attention and psychomotor tracking were independent of improvement in psychopathology. These data suggest that olanzapine improved some but not all cognitive deficits in schizophrenia, including verbal memory, a cognitive domain impaired by anticholinergic drugs. The basis for the improvement in cognitive scores, which should lead to improvement in role functioning if real, is discussed.

Introduction The vast majority of people with schizophrenia, as many as 85%, have significant impairment in most domains of cognitive functioning (Palmer et al, 1997). This impairment has been reported to be present shortly after recovery from the first period of psychosis and to persist (Saykin et al., 1994). It is likely that significant components of this cognitive impairment precede the development of psychotic symptoms, becoming manifest, and contributing to the loss in function, during the prodromal period (Cornblatt and Kimling, 1985; Neuchterlein et al., 1991; Byrne et al., 1999; Bilder et al., 2000). The cognitive disturbance is slowly progressive in most patients, but a small proportion shows severe deterioration as the duration of illness increases (Friedman et al., 1999). However, in one recent study which evaluated cognitive functioning in the five years subsequent to illness onset, only secondary verbal memory deteriorated (Hoff et al., 1999). The degree of impairment in various domains of cognition differs in patients with schizophrenia, with some studies suggesting that the most severe cognitive impairments occurs in measures of attention, verbal fluency, motor speed, and executive function (Gold and Harvey, 1993; Kenny and Meltzer, 1991). Moderate impairments in working memory, immediate memory span, and verbal learning and memory have been reported most frequently. All of these impairments are disproportionate to the mild intellectual decline demonstrated in patients with schizophrenia as a group (Braff et al., 1991; Saykin et al., 1994). In addition to the disease-related impairment in cognition in schizophrenia, there is considerable evidence that anticholinergic drugs such as atropine can impair memory function in laboratory animals and man, and that anticholinergic drugs, such as benztropine and trihexyphenidyl, which are used to prevent or to lessen extrapyramidal side (EPS) effects from antipsychotic drugs, or antipsychotic drugs such as thiordazine and mesoridazine, which are strongly anticholinergic, can impair various cognitive function, especially memory (Tune et al., 1982; McEvoy et al., 1987; McEvoy and Freter, 1989; Spohn and Strauss, 1989). It has been suggested that the apparent improvement in cognition due to atypical antipsychotic drugs (see below) could be related, in part, to the lesser use of anticholinergic medications with these agents than is needed with typical neuroleptic drugs (Carpenter and Gold, 2002). However, an adverse

effect of anticholinergic drugs on cognition has not been found in all studies (Calev et al.1987). Recently, Mori et al (2002) studied the effect of anticholinergic drugs on immediate memory and working memory in patients with schizophrenia by withdrawal of anticholinergic drugs in 21 schizophrenic inpatients. Improvement in immediate memory, verbal working memory, and psychopathology, as well as an increase in regional cerebral blood flow after withdrawal from anticholinergic drugs was noted, with no changes in EPS. Olanzapine has been reported to have low-high antagonist affinities for all five cloned rat and human muscarinic receptors in vitro (Bymaster et al., 1996; 1999 and ex vivo (Bymaster et al., 1996) and was initially thought to be at least moderately anticholinergic in vivo (Bymaster et al., 1999). Consistent with this, clinical trials reported anticholinergic side effects and relatively high serum anticholinergic levels (Chengappa et al., 2000). Two SPECT studies reported high occupancy of brain muscarinic receptors in patients treated with olanzapine and suggested that it was strongly anticholinergic (Raedler et al., 2000; Lavalaye et al., 2001). However, subsequent studies reported no anticholinergic side effects in patients with Alzheimers disease (Kennedy et al., 2001), that its apparent in vivo potency as an antimuscarinic was overestimated (Zhang and Bymaster, 1999), and that it can increase release of acetylcholine in the prefrontal cortex (Ichikawa et al., 2002) and hippocampus (ShiraziSouthall et al., 2002) of rats, which would be expected to diminish its anticholinergic effects. Thus, there is a need to determine whether olanzapine has the effects on memory in man which would be expected of an anticholinergic agent. Numerous studies reports that novel antipsychotic agents, including clozapine, risperidone, olanzapine, and quetiapine, improve cognitive function in patients with schizophrenia with small to moderate effect sizes (Meltzer and McGurk, 1999; Keefe et al., 1999; Cuesta et al., 2001; Harvey and Keefe, 2001). This is in contrast to typical antipsychotic medications that have only occasionally been reported to produce cognitive improvement (Cassens et al., 1990; Lee et al., 1999). However, there are some studies which fail to find any differences between typical and atypical antipsychotic drugs on cognition (e.g., Green et al 2002), which has led some to suggest that the atypical agents are without any significant effect on cognition (Carpenter and Gold, 2002). The

cognitive deficit in schizophrenia has been suggested to be a better predictor of good outcome in social and work function than positive symptoms (Green, 1996; McGurk and Meltzer, 2000; Green et al., 2000), suggesting that the lack of improvement in cognitive function during typical antipsychotic drug treatment could likely contribute to poor functional outcome in schizophrenic patients treated with these agents, despite adequate control of psychotic symptoms.

Published reports of cognitive effects of olanzapine in schizophrenia report inconsistent improvement with olanzapine, particularly on cognitive domains that are worsened by anticholinergicdrugs. In a preliminary report of the results presented in full here, Meltzer and McGurk (1999) reported significant improvements following six weeks of olanzapine treatment on selective attention, verbal learning and memory, verbal fluency, and reaction time in 20 outpatients with schizophrenia or schizoaffective disorder. No improvements were noted in immediate and sustained attention, verbal and spatial working memory, visual memory, motor speed, or executive functioning. In a double-blind, 52 week comparison of olanzapine, risperidone, and haloperidol, Purdon et al. (2000) reported significant within-group improvements in 21 patients with schizophrenia treated with olanzapine at the six, 30, and 52 week assessment. Exploratory analyses demonstrated significant improvements after six weeks of treatment with olanzapine on five separate cognitive domains, including attention span, motor skills, nonverbal fluency and construction, executive functioning, and immediate recall, but following Bonferroni adjustment, significant improvements were limited to the immediate recall cognitive domain and only one of the 17 total tests administered, the Hooper Visual Organization Test. The improvements evident at the six-week assessment remained significant at the 30 and 52-week assessment. However, no cognitive test performance was worsened by treatment with olanzapine. No other cognitive improvements, or worsening, occurred during the year follow-up. There was no evidence of a practice effect in this study. Cuesta (2001) reported that following the switch in 21 patients with chronic schizophrenia of various antipsychotic medications to olanzapine, verbal memory was significantly improved compared to a comparison group of 17 patients, half of whom

received risperidone and half, typical neuroleptic drugs. Similarly, Smith et al. (2001) found no significant differences on a brief cognitive battery between olanzapine and haloperidol following 8 weeks of treatment in chronically-hospitalized, treatmentrefractory patients, but noted improved verbal and visual memory after 3 months of continued, open label treatment with olanzapine. Recent results from a multi-site, double-blind, randomized, 14 week study comparing olanzapine, risperidone, clozapine, and haloperidol in treatment-refractory inpatients demonstrated significant improvement in olanzapine treated patients in processing speed, attention, and general executive and perceptual organization whereas risperidone improved verbal memory (Bilder et al., 2002). The authors suggest that further investigations would help indicate if olanzapine had a unique ability, among the novel antipsychotic drugs, to improve these, or other cognitive domains. Thus, despite a number of cognitive evaluations of olanzapine on chronically ill inpatients and community dwelling outpatients, there is yet no consensus regarding the effects of olanzapine on cognition, and in particular, those cognitive areas that are sensitive to anticholinergics, such as memory. The present study reports cognitive and clinical response to a six-month openlabel olanzapine treatment trial which was prospectively designed to study its effects on cognition in 34 patients with schizophrenia [14 more than the preliminary results previously reported in 20 patients following six weeks of olanzapine treatment reported elsewhere (Metzer and McGurk, 1999)]. Patients were evaluated on a comprehensive cognitive battery while receiving typical antipsychotic medications and again following six-weeks and six-months of treatment with olanzapine. Cognitive domains known to be sensitive to anticholinergic drugs included visual, verbal, and working memory were evaluated (Spohn et al., 1989; Tune et al., 1982). The effect of olanzapine on cognitive domains believed to be important in functional outcome, including sustained attention, executive functioning, and psychomotor speed, were also evaluated (Green et al., 2000; Bellack et al., 1999; McGurk and Meltzer, 2000).

Methods Subjects Thirty-four schizophrenia patients (27 males) completed baseline assessments, ten of whom were hospitalized on a psychiatric acute-care inpatient unit, and 24 outpatients. All met DSM-III-R (APA, 1987) criteria for schizophrenia or schizoaffective disorder. The mean age of the subjects was 41.4 years (SD= 12.0 yrs), the mean age of illness onset was 24 years (SD= 6.5 yrs), the mean duration of psychiatric illness was 17.0 years (SD= 11.0 yrs), and the average education of the subjects was 12.9 years (SD=2.8 yrs). Fourteen subjects with persistent positive symptoms despite three adequate trials with other antipsychotic drugs met criteria for neuroleptic resistance (Kane et al., 1989). Procedures The diagnosis of schizophrenia or schizoaffective disorder was determined using the Structured Clinical Interview for DSM III-R. Subjects were then evaluated on a comprehensive clinical and cognitive battery while receiving typical antipsychotic medications, following which they were switched to olanzapine. Antipsychotic medications at baseline were haloperidol (N=23); loxitane (N=4); prolixin (N=4); thorazine (N=2) trilafon (N=1); Ancillary medication at baseline included lorazepam and/or benztropine in a total of twelve subjects. For the six month period of olanzapine treatment, the mean dose of olanzapine was 13.4 S.D. 7.8 (range 5-20) mg/day. No other antipsychotic drug was given. At the 6 weeks and 6 month reassessments, four subjects were receiving lorazepam, two sertraline, two benztropine, and one valproate. This protocol was approved by the Institutional Review Board of Vanderbilt University. Following a full explanation of study procedures, a written informed consent was obtained from all subjects before admission to the study. Measures The Brief Psychiatric Rating Scale, 24 items, 0-6 scoring (BPRS, Overall and Gorham, 1962) was used to assess current clinical symptoms. The dependent measures were BPRS Total scores, BPRS Positive Symptoms subscale (hallucinations, unusual thought, suspiciousness and conceptual disorganization), and BPRS Withdrawal/Retardation subscale (blunted affect, emotional withdrawal, and motor retardation), a measure of negative symptoms.

Nine neurocognitive domains were assessed (listed in Table 1): 1) executive functioning (Wisconsin Card Sort (Berg, 1968) (WCST) Categories (CAT) and Percent Perseveration (PP)); b) Stroop Test (28); c) Trail Making B (Reitan, 1979); 2) working memory: verbal working memory (Auditory Consonant Trigrams) (Peterson and Peterson, 1959) (ACT); spatial working memory [Spatial Working Memory Test) (McGurk et al., 1996) (SWMT), 5 sec delay and 15 sec delay)]; 3)verbal fluency (Controlled Word Oral Association Test (CWAT); Animal Naming) (Benton and Hamsher, 1989); 4) immediate attention (WAIS-R Digit Span Subtest) (Wechsler, 1981); 5) sustained attention (Continuous Performance Test, Repeating Digits subtest) (Cornblatt et al., 1988) (CPT); 6)visual motor tracking (Trail Making A (Reitan, 1979); Digit Symbol Substitution Test, WAIS R (Wechsler, 1981); Mazes, WISC-R (Wechsler, 1991); 7)verbal learning and memory (California Verbal Learning and Memory Test (Delis et al., 1987) (CVLT), total words recalled for list A 1-5 (List A1-5), and long delay free recall (LDFR)); 8)visual memory (Visual Reproduction subtest, Wechsler Memory Scale-Revised (Wechsler, 1974); Immediate Recall (VRIR) and Delayed Recall (VRDR 2) and 9) fine motor control (Finger Tapping) (Halstead, 1947). Neuropsychological assessment was conducted in two, two-hour sessions that occurred on the same day, or two consecutive days. The order of the tests was standardized for all subjects. Statistical Methods A mixed model analysis of variance (ANOVA) using the least squared difference to control for multiple post-hoc comparisons was used to evaluate cognitive and clinical measures at baseline, six weeks and six months. The effect of change in positive symptoms on cognition was evaluated by an analysis of covariance (ANCOVA) using change in BPRS Positive symptom subscale as the covariate. The effect of age, duration of illness and neuroleptic-resistance status on cognitive measures was determined by regression analysis, which included the initial score level and these factors in the model. Results The means and standard deviations of all clinical and cognitive measures are given in Table 2. Following six weeks of treatment, significant improvements were

demonstrated for the 1) Stroop Interference Trial, 2) two measures of verbal fluency, Animal Naming and CWAT, 3) Trail Making A, 4) CVLT, Immediate and Delayed Recall, and, 5) Visual Reproduction, Immediate and Delayed Recall. Following six months of olanzapine treatment, significant improvements were noted in the 1) Digit Span, 2) CPT-D, 3) Auditory Consonant Trigrams, 4) Digit Symbol Substitution test, 5) Trail Making A, and 6) CVLT, Immediate and Delayed Recall. The Digit Symbol Substitution and Digit Span tests, in contrast with ACT and CPT-D Prime, were the only two cognitive tests in which inspection of the data revealed no evidence for improvement at 6 weeks, followed by significant improvement at 6 months. For the ACT and CPT-D Prime, there was non-significant improvement at the 6-week assessment which reached significance at 6 months. Performance on Digit Symbol significantly improved between six weeks and six months of treatment (F(1,23=8.50, p<0.01). There was no evidence of an across the board improvement in performance between baseline and 6 weeks, or between 6 weeks and 6 months, which would suggest an overall practice effect. No cognitive test performance was impaired by olanzapine treatment at either time interval. The BPRS Total score, and Positive Symptom subscale of the BPRS were significantly improved at the six-week and six month follow-up. The change in the BPRS Withdrawal-Retardation subscale score was not statistically significant. In order to determine if cognitive improvements were related to improvement in positive symptoms, ANCOVA were performed to determine the influence of covarying the change in positive symptoms on the change in each cognitive measure. Improvements in the Stroop Interference Trial, the CVLT Immediate and Delayed Recall, CPT-D, Digit Symbol Substitution, Animal Naming and CWAT remained significant but not the Visual Reproduction, Trail Making A, Auditory Consonant Trigrams, and Digit Span. Performance on Animal Naming, CWAT, and Digit Symbol remained significant after controlling for positive symptom change. Regression analyses were conducted to determine significant predictors of cognitive improvement with olanzapine. Age of subjects, gender, duration of illness, and neuroleptic resistance were entered into the model, and change scores from baseline to 6 weeks for each cognitive test was entered as the dependent variable. Age, gender,

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duration of illness, and neuroleptic resistance did not significantly predict cognitive response to olanzapine for any of these measures. The early termination sample (N=24) was compared to the six-month, prospective group (N=10) and were not found to differ on any demographic (age, gender, years of education, age of illness onset, duration of illness), clinical or cognitive measure. Reasons for study discontinuation included move out of region (N=8), consent withdrawal (N=4), unable to locate (N=6), treatment non-response (N=3), medication side-effects including weight gain and/or EPS (N=3). Discussion The two main hypotheses of this study were confirmed: olanzapine improved multiple cognitive domains, including those known to be important in functional outcome such as verbal learning and memory and attention, and olanzapine did not impair measures sensitive to anticholinergic drugs, including verbal and spatial memory. Treatment with olanzapine for six months was associated with significant improvement on measures of attention, verbal fluency, selective attention, executive functioning, verbal and visual learning and memory, and psychomotor tracking. Performance on the Digit Span, Animal Naming, CWAT, CPT D, the Stroop Interference trial, the CVLT, immediate and delayed recall, Visual Reproduction, immediate and delayed recall, Trail Making A and Digit Symbol Substitution were improved. Secondly, improvement in positive symptoms, contributed to some of the cognitive improvements: after adjustment for positive symptom improvement, improvements in assessments of attention (Digit Span), psychomotor tracking (Trail Making A), working memory (Auditory Consonant Trigrams), and visual learning and memory (Visual Reproduction test, immediate and delayed recall) became non-significant. However, the majority of the tests which improved with olanzapine treatment were not related to the concomitant improvement in positive symptoms: the Stroop Interference Trial, the CVLT Immediate and Delayed Recall, CPT-D, Digit Symbol Substitution, Animal Naming and CWAT. Improvements in cognition after switching to olanzapine were not uniform across domains of cognition. Although performance was numerically the same or better on every cognitive test after switching to olanzapine, the improvement was significant in

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12 of 19 cognitive tests. Seven of these 12 tests, including verbal learning and memory, CPT D, Stroop, Animal Naming, CWAT and Digit Symbol, remained significant after controlling for positive symptoms. No significant effects were found on most measures of executive functioning, including the WCST-Categories and Perseveration, the WISCR Mazes, Trail Making B, or spatial working memory. After switch from typical antipsychotic treatment to treatment with olanzapine, none of the cognitive measures showed a worsening after six weeks or six months of treatment. These findings are in contrast with those for clozapine which worsened working memory following 6 weeks, but not six months, of treatment (Hagger et al., 1993; Lee et al., 1994). The basis for the difference between clozapine and olanzapine with regard to short term effect on working memory could be related to differences in the release of DA in the mPFC or possibly differences in cholinergic function. It is known that working memory is highly sensitive to too little or too much DA (Williams and Goldman-Rakic, 1995) and there is extensive evidence that M1 and M4 muscarinic receptor have a strong effect on DA release in multiple brain areas (Bymaster et al, 2002). There was no indication from the data reported here that olanzapine had the adverse profile on cognition associated with strongly anticholinergic drugs. Improvements occurring in this study in verbal list learning and memory are consistent with improvement previously reported with olanzapine (Purdon et al., 2000: Cuesta et al. 2001; Smith et al., 2001; Bilder et al., 2002). Performance in verbal learning and memory was improved from approximately 3 SDs below normal (for normative scores, Delis et al., 1987), to approximately 2 SDs below normal. This improvement is particularly noteworthy given the findings of Hoff et al. (1992) where verbal memory deficits were the only cognitive area noted to worsen during the first five years of illness. It has been reported that olanzapine caused widespread changes of cerebellar functional connectivity, especially in the prefrontal cortex and mediodorsal thalamus, which have important roles in verbal learning and attention (Stephan et al. 2001). This may provide part of the functional basis for some of the cognitive improvement noted here. Performance on the Stroop Interference trial was raised from 2 SDs below normal to the normal range. This result is particularly important given that the Stroop Interference trial is a measure of selective attention (Braver et al., 1999), a

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fundamental cognitive capacity that is essential for every day functioning. Disturbances in selective attention are among the earliest described cognitive deficits that are present in schizophrenia and are highly associated with social skills deficits in patients with schizophrenia (Green, 1996; Green et al., 2000). The anterior cingulate cortex is activated in healthy control subjects, but not in schizophrenia subjects, while performing the Stroop test (Carter et al., 1997). Improvements on the Stroop test seen after switching to olanzapine may be related to its ability to increase extracellular dopamine and acetylcholine levels in the cingulate cortex (Meltzer and McGurk, 1999; Ichikawa et al., 2001) or to increase central noradrenergic neurotransmission (Dawe et al., 2001). Further studies evaluating functional impact of treatment with olanzapine are indicated. Changes in verbal fluency scores were more modest. Baseline fluency scores were approximately 3 SDs below normal, and improved by one SD, thus remaining in the impaired range. Purdon et al. (2000) also found a one SD improvement on fluency scores with olanzapine treatment, with performance in that subject sample remaining in the impaired range. The ability of olanzapine to improve fluency performance parallels that of clozapine, which has also been shown to improve performance on the CWAT by one standard deviation (e.g., Hagger et al., 1993; Hoff et al., 1996). Verbal fluency has also been shown to be significantly associated with functional outcome but on a more restricted basis than verbal learning and memory (Green, 1996). Measures of verbal fluency (Animal Naming, CWAT) and visuo-motor tracking (Digit Symbol) significantly improved between six weeks to six months of treatment. This effect of time is of interest because improvements in each of these tests were already significant at six weeks of treatment and continued to improve through 6 months of treatment. Thus, olanzapines beneficial effect on measures involving processing speed, consistent with Bilder et al., either continues through six months of treatment, or, the detrimental motor effects of baseline typical antipsychotic treatment continue to diminish following discontinuation. These explanations are not mutually exclusive. The cognitive results of the final sample of 34 subjects presented here are consistent with data presented for the first 20 subjects in this study (Meltzer and McGurk, 1999). Significant improvements in selective attention (Stroop), verbal learning

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and memory (CVLT), and verbal fluency (CWAT, Animal Naming) in the early sample remained significant in the full sample. Therefore, the majority of the effects demonstrated in 20 subjects were confirmed after inclusion of 14 additional subjects and extension of follow-up to six months. A potential drawback of the current study is that it was open-label and that there was no randomization to a comparator. Open-label studies been suggested by Keefe et al. (1999, 2001) to introduce the possibility of subjective biases by clinical and cognitive raters, but it must be noted that this conclusion is not firmly based in empirical data. We have argued that the assessment of cognitive performance in an open trial does not necessarily introduce a systematic bias (Meltzer and McGurk, 1999). The consistency in the results of the current open-label study with the Purdon et al. and Bilder et al., studies which were blinded, argues against the open-label design of the current study systematically biasing results. The raters in this study had no knowledge of any specific pattern of cognitive changes to be expected from olanzapine treatment. The fact that the results reported here are highly consistent with those of the double-blind trial of olanzapine discussed above provides additional support for the conclusion that open-trials of the effect of cognition in schizophrenia can produce reliable results. Another design weakness in this study was the lack of a typical neuroleptictreated group to control for possible effects of repeated measurement. However, practice effects are an unlikely explanation for the cognitive improvements associated with olanzapine treatment. Firstly, cognitive tests that have been reported to be improved by practice in patients with schizophrenia (e.g., WCST (e.g., Goldman et al., 1992); CPT (Harvey et al., 2000)), or from treatment with risperidone (e.g., working memory (Green et al., 1997)), or clozapine (e.g., Finger Tapping (Goldberg et al., 1993), were not improved by olanzapine in this study. Conversely, performance on the CVLT in patients with schizophrenia, which was improved in this study with olanzapine treatment, and in another study with risperidone treatment (Kern et al., 1999), was worsened by clozapine treatment (Hoff et al., 1996), and was unimproved by treatment with haloperidol (Kern et al., 1999). Thus, improvement on the CVLT is unlikely to be simply the result of practice. Similarly, the effects of clozapine have been evaluated on the same visual memory test used here (WMS-R Visual Reproduction). Clozapine was found to have

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either no effect on performance of these measures, or a deleterious effect (Goldberg et al., 1993), whereas we found olanzapine improved performance on this test. Verbal fluency, as measured by the CWAT and Animal Naming, was improved by olanzapine in this study, and has also been shown to be improved by clozapine in patients with schizophrenia (Hoff et al., 1996; Lee et al., 1994; Grace et al., 1996; Galletly et al., 1997; Hagger et al., 1993; Buchanan, et al., 1994) and risperidone (Purdon et al., 2000), but not haloperidol (Purdon et al., 2000). These considerations suggest that improvements in the current study are a result of a direct effect of olanzapine. In summary, current findings indicate that six months of treatment with olanzapine favorably impacts cognitive functioning in schizophrenia, with strong beneficial effects independent of symptom changes noted in the areas of selective attention, verbal learning and memory, and psychomotor tracking, which are cognitive domains known to be important in functional outcome. These results add further evidence to our previous contention (Meltzer and McGurk, 1999) that there are differences in the pattern, as well as the extent of improvement, in cognition in the atypical antipsychotic drugs. The pattern of improvement with olanzapine is most similar to that of clozapine but superior in that there was no worsening of working memory.

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REFERENCES Bellack AS, Gold JM, Buchanan RW. Cognitive rehabilitation for schizophrenia: problems, prospects, and strategies. Schizophr Bull, 25(2):257-74, 1999. Benton, A.L. and Hamsher, K.deS. Multilingual Aphasia Examination. Iowa City, Iowa: AJA Associates, 1989. Berg, E.A. A simple objective test for measuring flexibility in thinking. Journal of General Psychology, 39:15-22, 1968. Berman, K.F., Zec, R.F., and Weinberger, D.R. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia: 2. Regional cerebral blood flow (rCBF) evidence. Archives of General Psychiatry, 43:126-135, 1986. Bilder, R. M., Goldman, R.S., Robinson, D., Reiter, G., Bell, L., Bates, J.A., Pappadopulos, E., Willson, D.F., Alvir, J.M., Woerner, M.G., Geisler, S., Kane J.M., and Lieberman, J.A. Neuropsychology of first episode of schizophrenia: Initial characterization and clinical correlates. American Journal of Psychiatry, 157: 549559, 2000. Bilder, R.M., Goldman, R.S., Volavka, J., Czobor, P., Hoptman, M., Sheitman, R., Lindenmayer, J.P., Citrome, L., McEvoy, J., Kunz, M., Chakos, M., Cooper, T.B., Horowitz, T.L., Lieberman, J.A. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. American Journal of Pyschiatry, 159:6, 2002. Braff, D.L.,Heaton, R., Kuck, J., Cullum, M., Moranville, J., Grant, I.,and Zisook, S. The generalized pattern of neuropsychological deficits in outpatients with chronic schizophrenia with heterogeneous Wisconsin Card Sorting Test results. Archives of General Psychiatry, 48:891-898, 1991. Braver, T.S., Barch, D.M., and Cohen, J.D. Cognition and control in schizophrenia: a computational model of dopamine and prefrontal function. Biol Psychiatry Aug 1;46(3):312-28, 1999. Buchanan, R.W.; Holstein, C.; and Breier, A. The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. Biological Psychiatry, 36:717-725, 1994. Bymaster, F.P., Felder, C., Ahmed, S. and McKinizie, D. Muscarinic Receptors as a Target for Drugs Treating Schizophrenia Current Drug Targets. CNS & Neurological Disorders,1: 147-164, 2002. Bymaster, F.P., Hemrick-Luecke, S.K., Perry, F.W., and Fuller, F.W. Neurochemical evidence for antagonism by olanzapine of dopamine, serotonin, alpha 1-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology, 124:87-94, 1996. Bymaster, F.P., Nelson, D.L., DeLapp, N.W., Falcone, J.F., Eckols, K. Truex, L.L., Foreman, M.M. Lucaites, V.L., Calligaro, D.O. Antagonism by olanzapine of dopamine D1, serotonin 2, muscarinic, histamine H1, and alpha 1-adrenergic receptors in vitro. Schizophrenia Research, 37:107-22, 1999. Byrne, M. Hodges A., Grant, E., Owens, D.C. and Johnstone, E.Cj. Neuropsychological assessment of young people at high gentic risk for developing schizophrenia compared with controls: preliminary findings of the Edinbugh High Risk Study (EHRS) Psychological Medicine, 29 1161-1175, 1999. Carpenter WT, Gold JM. Letter. Biol Psychiatry, Feb 1;53(3):267-8, 2003.

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Calev A, Berlin H, Lerer B. Remote and recent memory in long-hospitalized chronic schizophrenics. Biol Psychiatry, Jan;22(1):79-85, 1987. Carter CS, MacDonald AW 3rd, Ross LL, Stenger VA. Anterior cingulate cortex activity and impaired self-monitoring of performance in patients with schizophrenia: an event-related fMRI study. Am J Psychiatry, Sep;158(9):1423-8, 2001. Carter CS, Mintun M, Nichols T, Cohen JD. Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during singletrial Stroop task performance. Am J Psychiatry Dec;154(12):1670-5, 1997. Cassens, G.; Inglis, A.K.; Appelbaum, P.S.; and Guthell, T.G. Neuropsychological function in chronic schizophrenic patients. Schizophrenia Bulletin, 16:477-499, 1990. Chengappa, K.N., Pollock, B.G., Parepally, H., Levine, J., Kirshner, M.A., Brar, J.S., and Zoretich, R.A. J Clin Psychopharmacol, 20(3):311-6, 2000. Cornblatt, B.A., Erlenmeyer-Kimling, L. Global attentional deviance as a marker of risk for schizophrenia: specificity and predictive validity. Journal of Abnormal Psychology, 9:470-486, 1985. Cornblatt, B., Risch, N.J., Faris, G., Friedman, D., and Erlenmeyer-Kimling, L., The Continuous Performance Test, Identical Paris Version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Research, 26, 223-238, 1988. Cuesta, M.J., Peralta V., Zarauela A., Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schiz Res 48 1728, 2001. Dawe, GS., Huff, KD, Vandergriff, JL, Sharp T, O'Neill MJ, and Rasmussen K: Olanzapine activates the rat locus coeruleus (2001): In Vivo Electrophysiology and c-fost Immunoreactivity, Biol Psychiatry 50:510-520, 2001. Delis, D.C., Kramer, J.H., Kaplan, E., and Ober, B.A. California Verbal Learning and Memory Test (Manual). San Antonio, TX: Psychological Corp., 1987. Friedman, J.I., Harvey, P.D., Kemether, E., Byne, W., Davis, K.L. Cognitive and functional changes with aging in schizophrenia. Biological Psychiatry, 46(7):921928, 1999. Galletly, C.A.; Clark, C.R.; McFarlane, A.C.; and Weber, D.L. Relationships between changes in symptoms ratings, neuropsychological test performance and quality of life in schizophrenic patients with clozapine. Psychiatry Research, 72:161-166, 1997. Gold, J.M. and Harvey, P.D. Cognitive deficits in schizophrenia. Psychiatr Clin North Am;16:295-312, 1993. Goldman RS, Axelrod BN, Tandon R, Ribeiro SC, Craig K, Berent S. Neuropsychological prediction of treatment efficacy and one-year outcome in schizophrenia. Psychopathology;26(3-4):122-6, 1993. Goldberg, T.E.; Greenberg, R.D.; Griffin, S.J.; Gold, J.M.; Kleinman, J.E.; Pickar, D.; Shulz, S.C.; and Weinberger, D.R. The effect of clozapine on cognition and psychiatric symptoms in patients with schizophrenia. British Journal of Psychiatry, 162:43-48, 1993. Grace, J.; Bellus, S.P.; Raulin, M.L.; Herz, M.L.; Priest, B.L.; Brenner, V.; Donnelly, K.; Smith, P.; and Gunn, S. Long-term impact of clozapine and psychosocial treatment

17

of psychiatric symptoms and cognitive functioning. Psychiatric Service, 4:41-45, 1996. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the right stuff? Schizophr Bull;26:11936, 2000. Green MF, Marshall BD Jr, Wirshing WC, Ames D, Marder SR, McGurk S, Kern RS, Mintz J. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry Jun;154(6):799-804, 1997. Green, M.F. What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry, 153:321-330, 1996. Green MF. Marder SR. Glynn SM. McGurk SR. Wirshing WC. Wirshing DA. Liberman RP. Mintz J. The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone Biol Psychiatry; 51:972-8, 2002. Hagger, C.; Buckley, P.; Kenny, J.T.; Freidman, L.; Ubogy, D.; and Meltzer, H.Y. Improvement in cognitive function and psychiatric symptoms in treatmentrefractory schizophrenic patients receiving clozapine. Biological Psychiatry, 34(10):702-712, 1993. Halstead, W.C. Brain and Intelligence. Chicago: University of Chicago Press, 1947. Harvey, P.D., Moriarty, P.J., Serper, M.R., Schnur, E. Lieber, D., Practice-related improvement in information processing with novel antipsychotic treatment. Schizophrenia Research, Dec 15;46(2-3):139-48, 2000. Harvey, P.D. and Keefe, R.S. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry, Feb;158(2):176-84, 2001. Heaton, R., Paulsen, J.S., McAdams, L.A., Kuck, J., Zisook, S., Braff, D., Harris, J., Jeste, D.V. Neuropsychological deficits in schizophrenia. Archives of General Psychiatry, 51:469-476, 1994. Heaton, R.K., and Crowley, T.J. Effect of psychiatric disorders and their somatic treatments on neuropsychological test results. In Filskov, S., and Boll, T.J., eds. Handbook of Clinical Neuropsychology, New York: John Wiley & Sons, 1981. pp 481-525. Hoff, A.L.; Riordan, H.; ODonnell, D.W.; Morris, L.; and DeLisi, L.E. Neuropsychological functioning of first-episode schizophreniform patients. American Journal of Psychiatry, 149:898-903, 1992. Hoff, A.L.; Faustman, W.O.; Wieneke, M.; Espinoza, S.; Costa, M.; Wolkowitz, O.; and Csernansky, J.C. The effects of clozapine on symptom reduction, neurocognitive function, and clinical management in treatment-refractory state hospital schizophrenic inpatients. Neuropsychopharmacology, 15:361-369, 1996. Hoff, A.L., Sakuma, M., Wieneke, M., Horon, R., Kushner, M., and DeLisi, L.E. Longitudinal neuropsychological follow-up study of patients with first episode schizophrenia. American Journal of Psychiatry, 156:1336-1341, 1999. Ichikawa J, Li Z, Dai J, Meltzer HY. Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT(1A) receptor agonism. Brain Res, Nov 29;956(2):349-57, 2002. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY.

18

5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem, Mar;76(5):1521-31, 2001. Jensen, A.R. and Rohwer, W.D. The Stroop Color-Word Test: a review. Acta Psychologica, 25:36-93, 1966. Kane, J., Honigfeld, G., Singer, J., Meltzer, H.Y. and the Clozaril Collaborative Study Group. Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Archives of General Psychiatry, 45:789-796, 1989. Keefe, R.S.E.; Silva, S.C.; Perkins, D.O.; and Lieberman, J.A. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia. Schizophrenia Bulletin, 25:201-222, 1999. Kennedy JS, Bymaster FP, Schuh L, Calligaro DO, Nomikos G, Felder CC, Bernauer M, Kinon BJ, Baker RW, Hay D, Roth HJ, Dossenbach M, Kaiser C, Beasley CM, Holcombe JH, Effron MB, Breier A. A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data. Int J Geriatr Psychiatry, Dec;16 Suppl 1:S33-61, 2001. Kenny JT, Meltzer HY. Attention and higher cortical functions in schizophrenia. J Neuropsychiatry Clin Neurosci, 3(3):269-75, 1991. King, D.J. The effect of neuroleptics on cognitive and psychomotor function. British Journal of Psychiatry, 157:799-811, 1990. Lavalaye J, Booij J, Linszen DH, Reneman L, van Royen EA. Higher occupancy of muscarinic receptors by olanzapine than risperidone in patients with schizophrenia. A[123I]-IDEX SPECT study. Psychopharmacology (Berl) 2001 Jun;156(1):53-7. Lee, M.A.; Thompson, P.; and Meltzer, H.Y. Effects of clozapine on cognitive function in schizophrenia. Journal of Clinical Psychiatry, 55 (Supplement B): 8-14, 1994. Lee, M.A., Jayathilake, K., Meltzer, H.Y. A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schiz Res 37: 1-12, 1999. Lindenmayer, J.P.; Iskander, A.; Park, M.; Apergi, F.S.; Czobor, P.; Smith, R.; and Allen, D. Clinical and neurocognitive effects of clozapine and risperidone in treatmentrefractory patients: A prospective study. Journal of Clinical Psychiatry, 1998. McGurk, S.R.; Green, M.F.; Wirshing, W.C.; Ames, D.; Marshall, B.D.; Marder, M.D.; and Mintz, J. The effects of risperidone vs. haloperidol on cognitive functioning in treatment-resistant schizophrenia: The Trail Making Test. CNS Spectrums, 2:6064, 1997. Meltzer, HY and McGurk, SR. The effects of clozapine, risperidone and olanzapine on cognitive functioning in schizophrenia. Schizophrenia Bulletin, 25 (2):233255.1999. McEvoy JP, McCue M, Spring B, Mohs RC, Lavori PW, Farr R. The effects of amantadine vs. trihexyphenidyl on memory in elderly normal volunteers. Psychopharmacol Bull,23(1):30-

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