Psychopharmacology (2003) 169:398403 DOI 10.

1007/s00213-003-1506-y

ORIGINAL INVESTIGATION

Tonmoy Sharma Catherine Hughes William Soni Veena Kumari

Cognitive effects of olanzapine and clozapine treatment in chronic schizophrenia

Received: 5 March 2002 / Accepted: 4 April 2003 / Published online: 4 July 2003  Springer-Verlag 2003

Abstract Rationale: Schizophrenia patients are known to manifest widespread, multifaceted cognitive deficits. There is now an increasing emphasis on the critical importance of cognitive deficits for the functional outcome in schizophrenia. Typical antipsychotics, although effective in reducing positive symptoms of the illness, have not shown much effect on cognitive functions. Atypical antipsychotics have shown promise of improving some cognitive functions. Objectives: This naturalistic study aimed to determine whether olanzapine and clozapine improve cognitive functioning in a sample of 48 patients with chronic schizophrenia who had either failed to show sufficient clinical improvements or suffered from distressing side effects with conventional antipsychotics and were switched to either olanzapine or clozapine for clinical reasons and, if so, whether the two drugs produce similar or different cognitive effects. Methods: All patients completed a comprehensive battery of neuropsychological tests designed to index executive functioning, verbal learning, verbal and visual and memory, attention, working memory, and psychomotor speed at: (i) baseline, (ii) after 6 weeks and (iii) after 6 months of treatment with olanzapine or clozapine. Results: From the initial 48 patients who remained on olanzapine (n=16) or clozapine (n=14) for the entire duration with continuous participation, 30 provided data for this study. There were improvements over time (i.e.
T. Sharma ()) W. Soni Clinical Neuroscience Research Centre, 7 Twisleton Court, Priory Hill, Dartford, Kent, DA1 2EN, UK e-mail: t.sharma@psychmed.org.uk Tel.: +44-1322-286862 Fax: +44-1322-286861 C. Hughes V. Kumari Section of Cognitive Psychopharmacology, Institute of Psychiatry, Kings College London, De Crespigny Park, London, SE5 8AF, UK V. Kumari Department of Psychology, Institute of Psychiatry, Kings College London, De Crespigny Park, London, SE5 8AF, UK

from baseline through 6 weeks to 6 months) in both treatment groups on verbal fluency, verbal learning and verbal and visual memory measures. Conclusions: The findings indicate similar beneficial effects of olanzapine and clozapine on verbal learning and memory measures in patients showing a favourable clinical response to these drugs. Keywords Schizophrenia Cognitive effects Clozapine Olanzapine Verbal learning Verbal memory Visual memory

Introduction
Schizophrenia is a chronic and debilitating disorder characterised by a heterogeneous group of symptoms, including positive symptoms (delusions, hallucinations, disorganised thought), negative symptoms (flattened affect, stereotyped thinking, difficulty in abstract thinking) and multifaceted cognitive deficits, most prominently in the areas of attention, memory and executive functioning (Rund and Borg 1999). Cognitive deficits are present prior to the manifestation of clinical symptoms (Cornblatt et al. 1999), at the first presentation of symptoms (Riley et al. 2000) and tend to persist in chronic patients regardless of change in symptoms (Rund 1998; Hughes et al. 2003). An association has been found between cognitive abilities and social functioning such that pervasive cognitive deficits have a limiting effect on the quality of life of patients with schizophrenia including social interaction and problem solving, community living and employment prospects (Green 1996; Velligan et al. 1997; Addington and Addington 1999). Treatment of schizophrenia has traditionally taken the form of typical antipsychotic medication, which is effective in treating positive symptoms, but has little or no effects on negative symptoms or cognitive deficits (Sharma 1999). Furthermore, some patients do not respond to this treatment or suffer from severe extra pyramidal symptoms (EPS) (Kane et al. 1988). The new

399

generation of atypical drugs, such as clozapine and olanzapine, are more effective in treating negative symptoms and produce limited EPS (Arnt and Skarsfeldt 1998). They have also been associated with improvements in cognitive functioning (Gallhofer et al. 1999; Keefe et al. 1999; Manschreck et al. 1999; Pallanti et al. 1999) independent of their effects on EPS (Weiser et al. 2000). Recent reviews (Meltzer and McGurk 1999) have suggested strong evidence for improvements with clozapine treatment on attention and verbal fluency and moderate evidence for improvements on some types of executive functioning. Improvements in verbal fluency, reaction time and set shifting have also been found with clozapine (Manschreck et al. 1999), while the effects on working memory and secondary verbal and spatial memory have been rather inconclusive (Meltzer and McGurk 1999). Meltzer and McGurk (1999) reported evidence that suggested olanzapine improves verbal learning and memory, verbal fluency and executive function but not attention, working memory or visual learning and memory. In one of the first studies to be published on neuropsychological change in early phase schizophrenia with olanzapine treatment, Purdon and colleagues (2000) found some superior benefits, particularly on immediate recall and visual organisation measures, relative to haloperidol and risperidone. Continuing the above line of enquiry, the present study aimed to determine whether olanzapine and clozapine improve cognitive functioning in a sample of patients with chronic schizophrenia who had either failed to show sufficient clinical improvements or suffered from distressing EPS with conventional antipsychotics and, if so, to what extent they show similar or different cognitive improvements. Both clozapine and olanzapine have distinct pharmacological profiles from conventional antipsychotics and show significant affinities for dopamine (DA)-D1, DA-D2, (olanzapine > clozapine), alpha1 (clozapine > olanzapine), 5-HT2A, 5-HT2C, muscarinic and histaminergic (comparable affinities) receptors (Arnt and Skarsfeldt 1998; Mortimer 2001). In addition, clozapine also has affinities for alpha2 receptors (Mortimer 2001). Since clozapine continues to be seen as the gold standard for patients with a history of sub-optimal clinical response to treatment, it is important to determine how its cognitive efficacy compares with newer agents in this population.

psychotic symptoms or intolerable side effects with this treatment based on clinical judgement and patient reports and thus were switched to clozapine or olanzaine. Of the initial sample, 16 patients remained on olanzapine and 14 remained on clozapine with continued consent to take part in the study. The main reasons for the patients to drop out of olanzapine treatment was the lack of efficacy (n=6) and unwanted side effects (n=4). For the clozapine group, four patients discontinued treatment because of side effects. Four patients (two on olanzapine and two on clozapine) withdrew consent and thus had to be excluded. The final sample size thus comprised of 30 patients of a total of 48 initially enrolled in the study (see below). The study was approved by the (research) ethics committee of the Institute of Psychiatry and Maudsley Hospital, London. Written informed consent was obtained from all patients after the study procedures had been explained to them. Design and procedure Patients completed a comprehensive neuropsychological test battery on three occasions, once at baseline and again after 6 weeks and 6 months later. Within 1 week of the baseline assessment, 28 patients started treatment with olanzapine and 20 patients started treatment with clozapine. The assignment of patients to olanzapine or clozapine for the duration of the study was decided by the clinicians responsible for their care, based on clinical judgements. No specific instructions or requests were made by the research team to allocate a patient to one or the other study drugs. Doses were determined by their treating clinicians and titrated over a period of 4 weeks. Patients were maintained at a stable dose, determined by their treating clinicians, until the follow-up assessments. For the olanzapine group, daily drug doses were between 10 mg and 20 mg (4 patients on 10 mg, 6 patients on 15 mg, and 6 patients on 20 mg); for the clozapine group, between 350 mg daily and 650 mg daily (2 patients on 350 mg, 2 patients on 375 mg, 4 patients on 500 mg, and 6 patients on 650 mg). No patient was on any anticholinergic treatment at the time of follow-up assessments. The neuropsychological battery (Table 1) included measures of executive/frontal lobe functioning, attention, verbal and visual memory, working memory and psychomotor processing. The battery was administered to all patients on all three occasions in a fixed order. Patients were allowed to take breaks as needed in order to obtain maximal performance at all times. The assessment took between 1.5 h and 2 h to complete. Tests were administered and scored by trained psychologists who were blind to patients group affiliations and were not involved in patients treatment plans in any way. On each occasion, patients were also assessed for symptoms using the positive and negative syndrome scale (PANSS) (Kay et al. 1987). Statistical analyses First, we compared patients who remained in the study with those who dropped out after the baseline assessments on demographic, clinical and cognitive variables using independent sample t-tests. Next, olanzapine and clozapine groups were compared for the demographic and symptoms ratings at the baseline using independent sample t-tests. Non-parametric demographic variables were analysed using chi-square tests. The change in positive symptoms, negative symptoms, psychopathology and total PANSS scores with olanzapine and clozapine treatments were examined using mixedmodel analyses of variance (ANOVA), performed separately for each variable, with time (baseline, 6 weeks, 6 months) as a withinsubjects factor and group (olanzapine, clozapine) as a betweensubjects factor. All cognitive variables were first examined for their distribution properties, i.e. to ensure normality. The cognitive effects of olanzapine and clozapine over time were then evaluated using mixed-model ANOVA, performed separately for each variable, with time as a within-subjects factor and group as a between-

Materials and methods

Subjects Forty-eight patients with chronic schizophrenia (DSM IV) were recruited from the Bethlem Royal and Maudsley National Health Service Trust, London. All patients had been hospitalised on at least one occasion. They had no history of neurological disease or alcohol or other substance abuse in the preceding 6 months. They had been receiving stable doses of typical antipsychotic drugs for at least 28 days prior to participation but had shown uncontrolled

400 Table 1 Details of the neuropsychological test battery Cognitive domain Premorbid functioning Intellectual assessment Executive functioning
a a

Tests National adult reading test premorbid IQ (NART, Nelson 1991) Wechsler adult intelligence scale-revised verbal, performance and Fullscale IQ (WAIS-R, Wechsler 1981) Wisconsin card sorting task categories and perseverative errors (WCST, Heaton 1993); verbal fluency (Benton et al. 1983); Computerised trails B (Morris 1995) Logical memory immediate and delayed recall, Wechsler memory scale (WMS, Wechsler 1945) b Hopkins serial learning test immediate and delayed recall (Brandt 1991) Visual reproduction immediate and delayed recall, Wechsler memory scale (WMS, Wechsler 1945) Continuous performance test reaction time and attentiveness (Connors 1995) Digit symbol age scaled score (DSST, Wechsler 1981) Finger tapping test total score (Halstead 1947)

Verbal learning and memory Visual memory Attention Working memory Psychomotor processing
a Administered b

only at baseline Same form used on all occasions

Table 2 Baseline characteristics of patients classified by completers and non-completers Demographics Completers n=30 Means (SD) Non-completers n=18 Means (SD)

Table 3 Demographic characteristics of patients classified by drug group Olanzapine n=16 Clozapine n=14

Age (years) 34.53 (10.09) 36.39 (7.56) Age of onset (years) 23.22 (7.22) 25.22 (5.24) Education (years) 12.60 (1.83) 12.22(2.07) Illness duration (years) 11.32 (9.36) 11.17 (8.23) Premorbid IQ 110.03 (11.73) 100.89 (15.08) Full scale IQ 93.57 (13.71) 87.44 (12.16) Gender 17 Male, 13 Female 14 Male, 4 Female Ethnicity Afro-Caribbean 5 7 Caucasian 21 11 Asian 3 0 Handedness 25 Right, 5 Left 17 Right, 1 Left PANNS Positive symptoms 15.88 (5.97) 18.65 (8.87) Negative symptoms 19.27 (6.65) 17.47 (7.39) Psychopathology 35.15 (9.70) 34.47 (10.76) Total score 70.31 (19.40) 70.59 (25.15) Executive function WCST categories 4.41 (2.06) 3.83 (2.38) completed WCST perseverative 17.55 (13.83) 21.39 (9.70) errors Verbal fluency 34.07 (13.39) 25.61 (6.80) Trails B 83.15 (65.56) 104.33 (51.75) Memory Immediate verbal 12.17 (6.40) 10.69 (5.09) memory Delayed verbal memory 6.77 (6.18) 5.89 (4.53) HSLT immediate recall 21.17 (5.82) 20.61 (3.55) HSLT delayed recall 6.03 (3.44) 5.72 (2.65) Immediate visual 6.80 (3.02) 6.28 (2.40) memory Delayed visual memory 5.53 (3.58) 5.22 (2.84) Attention CPT reaction time 454.86 (123.21) 475.20 (138.45) CPT attentiveness 2.56 (1.17) 1.97 (0.85) Working memory DSST 7.40 (2.22) 6.41 (1.80) Psychomotor processing FTT total 78.32 (14.09) 80.03 (16.54)

Age (years) 39.81 (10.81) 28.50 (4.33) Age at illness onset 26.787.59 19.144.05 (years) Education (years) 12.25 (1.44) 13.0 (2.18) Illness duration (years) 13.03 (11.12) 9.36 (6.70) Premorbid IQ 107.38 (12.81) 107.43 (12.80) Full scale IQ 96.75 (13.13) 89.93 (13.92) Gender 10 Male, 6 Female 7 Male, 7 Female Ethnicity Afro-Caribbean 2 4 Caucasian 11 10 Asian 3 0 Handedness 15 Right, 1 Left 10 Right, 4 Left

subjects factor. All cognitive effects were re-evaluated using analyses of co-variance (ANCOVA) after co-varying for age, age at illness onset and negative symptoms at baseline (these factors differentiated groups at baseline; Table 2 and Table 3) and also after co-varying for baseline performance. No subject had missing data for any cognitive variable for the baseline assessment. Any missing data (less than three observations for any cognitive variable) for the 6 weeks or 6 months assessments were replaced with the values observed for the previous assessment (last observation carried forward). All subjects had undergone all three assessments and were tested on the entire battery. The missing data had resulted mainly from equipment failure. Finally, data were analysed with and without the missing data (replaced with the values obtained for the last assessment) and found to produce the same pattern of effects. The results for the analyses with missing data are thus not reported any further. All data analyses were performed using Statistical Package for the Social Sciences (SPSS version 8.0). Alpha level for significance testing was kept at 0.05 unless specified otherwise.

Results
Patients who continued in the study (n=30) were not significantly differentfor any demographic, clinical or cognitive variablesfrom those who had to be excluded (n=16) after the baseline assessment (Table 2). Of those remaining in the study, patients assigned to olanzapine

401 Table 4 Positive and negative syndrome scale (PANSS) ratings at baseline, 6 weeks and 6 months, classified by drug group Olanzapine n=16 Positive symptoms Baseline 6 Weeks 6 Months Negative symptoms Baseline 6 Weeks 6 Months Psychopathology Baseline 6 Weeks 6 Months Total score Baseline 6 Weeks 6 Months 14.676.73 11.294.36 9.754.46 16.836.19 12.574.07 10.624.21 33.0010.63 24.296.98 23.758.26 64.5021.52 48.1413.11 44.1215.24 Clozapine n=14 16.695.30 11.935.23 10.503.21 22.386.31 15.577.43 14.406.67 37.388.95 25.296.99 23.305.21 76.4616.81 52.7917.53 48.2013.62

treatment were significantly older (t28=3.66, P<0.001) and had a later onset of illness (t28=3.36, P<0.001) than those assigned to clozapine treatment (Table 3). No differences were found for the premorbid or current IQ. Patients in the olanzapine group had less severe negative symptoms than the clozapine group at the baseline (t28=2.56, P<0.001; Table 4), but both groups improved on positive symptoms, negative symptoms, psychopathology and total PANSS scores from baseline to 6 weeks assessments, with further improvements over

6 months as indicated by significant main effects of time (positive symptoms: F2,56=19.54, P<0.001; negative symptoms: F2,56=29.77, P<0.001; psychopathology: F2,56=34.25, P<0.001; total PANSS score: F2,56=35.62, P<0.001), but there were no significant time group effects. There were significant main effects of time indicating improvements with both olanzapine and clozapine treatments for verbal fluency (F2,56=4.65, P=0.01), immediate verbal memory (F2,56=12.66, P<0.001), delayed verbal memory (F2,56=19.65, P<0.001), Hopkins immediate recall (F2,56=12.90, P=0.001), Hopkins delayed recall (F2,56=20.41, P<0.001), immediate visual memory (F2,56=3.59, P=0.03) and delayed visual memory (F2,56=9.02, P=0.001). The improvement on WCST perseverative errors over time with both olanzapine and clozapine treatments failed to reach accepted level of significance (F2,56=2.29, P=0.11). The main effect of time was not significant for WCST categories, trails B, CPT reaction time, CPT attentiveness, DSST or the fingertapping measures. Time group effect was not significant for any measure and remained non-significant after the analyses controlled for the age, age at the onset of illness, negative symptoms at the baseline. The effects remained the same when evaluated with ANCOVA using the baseline cognitive performance as a co-variate. The means (SDs) for all cognitive variables at the three occasions of testing for both olanzapine and clozapine groups are presented in Table 5.

Table 5 Neuropsychological performance by group at baseline, 6 weeks and 6 months. WCST Wisconsin card sorting task, HSLT Hopkins serial learning test, CPT continuous performance test, DSST digit symbol age scaled score, FTT finger tapping test Olanzapine n=16 Baseline Executive functioning WCST categories completed 4.33 (2.06) WCST perseverative errors 17.40 (12.49) Verbal fluency 38.00 (12.69) Trails B 77.05 (46.05) Memory Immediate verbal memory 13.50 (6.42) Delayed verbal memory 7.59 (6.66) HSLT immediate recall 21.32 (5.41) HSLT delayed recall 6.19 (3.21) Immediate visual memory 6.13 (2.70) Delayed visual memory 5.13 (3.50) Attention CPT reaction time 432.27 (59.84) CPT attentiveness 2.51 (0.96) Working memory DSST 7.05 (2.07) Psychomotor processing FTT total 78.22 (16.18) 6 Weeks 4.57 17.14 35.50 74.76 14.59 11.44 25.25 8.63 8.56 7.33 (2.06) (13.54) (9.69) (46.45) (7.11) (8.31) (5.87) (2.83) (3.69) (3.85) 6 Months 4.87 13.81 41.56 68.47 17.69 12.47 24.37 8.81 7.81 7.25 (1.89) (9.99) (10.49) (42.08) (6.65) (7.82) (7.37) (2.90) (3.51) (3.57) Clozapine n=14 Baseline 4.50 17.71 29.57 72.78 10.64 5.82 20.93 5.86 7.57 6.00 (2.14) (15.63) (13.16) (43.32) (6.25) (5.67) (6.45) (3.80) (3.27) (3.74) 6 Weeks 4.43 12.43 32.00 64.96 12.07 7.68 25.36 8.57 7.71 7.57 (2.34) (8.86) (14.01) (33.23) (7.58) (5.37) (5.33) (3.03) (3.17) (3.03) 6 Months 4.79 11.50 34.14 69.90 14.38 9.50 23.57 8.36 7.86 7.29 (2.15) (7.22) (16.90) (49.12) (5.86) (6.39) (6.32) (2.76) (2.93) (3.45)

446.62 (66.96) 2.87 (0.93) 7.75 (2.52) 78.82 (13.56)

470.25 (92.98) 2.97 (0.93) 8.31 (2.18) 81.35 (17.32)

479.07 (166.21) 464.71 (138.55) 482.21 (122.20) 2.62 (1.39) 2.57 (1.60) 2.53 (1.19) 7.29 (2.46) 78.42 (11.87) 7.79 (2.75) 83.60 (11.56) 7.57 (3.37) 86.04 (8.94)

402

Discussion
This present study examined the effects of olanzapine and clozapine treatments on cognitive functioning in a cohort of schizophrenia patients who had shown insufficient clinical responses to conventional antipsychotics and found evidence for similar rates of improvements with both treatments on measures of verbal fluency, verbal learning and verbal and visual memory. It is possible that the effects on HSLT were confounded by practice and did not truly reflect enhanced memory as a function of olanzapine or clozapine treatment, since the same form was used on all occasions of testing. The positive effects were, however, seen also on other memory tasks. This would suggest beneficial effects of olanzapine and clozapine treatment in general on learning and memory functions. Executive functioning showed weak evidence for improvement. In general, our findings fit well with previous data in showing cognitive improvements with clozapine and olanzapine (Gallhofer et al. 1999; Keefe et al. 1999; Manschreck et al. 1999; Meltzer and McGurk 1999; Pallanti et al. 1999; Purdon et al. 2001). Given the broad pharmacological profile of these drugs, it is difficult to determine exact pharmacological mechanisms for their cognitive effects, but it is plausible that their beneficial effects, specifically on learning and memory measures, may at least in part be mediated via their targeted actions on the serotonergic and cholinergic systems within the hippocampal formation (Scarr et al. 2001). This study is important in directly comparing the effects of clozapine and olanzapine, which have relatively comparable pharmacological profiles, in a homogeneous sample of patients who responded clinically and continued to be treated with these compounds in a naturalistic setting for a minimum period of 6 months and found no significant evidence for qualitative or quantitative differences in cognitive improvements with olanzapine and clozapine. It must, however, be noted that there was a hint of the beneficial effect of olanzapine, but not of clozapine, on attention and working memory (>0.5 standard deviation improvement on CPT distractibility and DSST; Table 5). It remains to be seen whether these were chance observations (given that they failed to reach significance) or simply failed to reach significance (i.e. did not emerge as a time group interaction) because of small sample sizes for both olanzapine and clozapine groups. There have been previous data (Meltzer and McGurk 1999) suggesting different profiles of cognitive improvements with olanzapine and clozapine. Yet other studies have mostly used conventional antipsychotics or risperidone as comparator drugs while evaluating the effects of clozapine (Buchanan et al. 1994; Lee et al. 1994; Meyer-Lindenberg et al. 1997; Meltzer and McGurk 1999; Sharma 1999; no control group, Purdon et al. 2001) or olanzapine (Purdon et al. 2000; Weiser et al. 2000; Cuesta et al. 2001). The only published study (Bilder et al. 2002) to have examined the effects of 14 weeks of treatment of clozapine, risperidone and

olanzapine in a single double-blind trial in patients with schizophrenia or schizoaffective disorder has reported comparable improvements in global cognitive functioning with all three atypical antipsychotics, relative to haloperidol treatment. Even when examined in terms of specific cognitive domains, olanzapine and clozapine treatments did not produce significantly different rates of improvement over a 14-week period in this study, suggesting that olanzapine and clozapine produce broadly similar (but not identical) patterns of cognitive improvements in patients with schizophrenia. In summary, this study suggests that treatment with olanzapine and clozapine produces beneficial effects on learning and memory functions in schizophrenia patients who show a favourable clinical response to these drugs. There were, however, a few limitations to this study. First, the study did not use a double-blind methodology though it is unlikely that this would account for the cognitive improvements seen for clozapine or olanzapine. Second, cognitive functioning may continue to improve over a longer (than 6 months) period and there may emerge a differential profile of cognitive improvements with olanzapine and clozapine in a relatively longer term. Longterm evaluation of cognitive functions is important especially given the role of cognitive status in functional outcome of schizophrenia (Green 1996). Third, this study involved a small number of patients treated with olanzapine and clozapine, so might have lacked the power to detect differential effects of these drugs in cognitive improvements. Future research is required to replicate the present findings and extend them to examine further domains of neurocognitive and social-emotional functions that may be modulated by these treatments, and delineate the relationship of these effects to functional outcomes.
Acknowledgements This study was supported by Novartis Pharmaceuticals, UK. Veena Kumari holds a Wellcome Trust Senior Fellowship in Basic Biomedical Science. We thank Mr. S. ONeil and Ms. S. Drozd for their help in cognitive testing and Drs. M. Das and B. Binneman for help with clinical assessments of the patients.

References
Addington J, Addington D (1999) Neurocognitive and social functioning in schizophrenia. Schizophr Bull 25:173182 Arnt J, Skarsfeldt T (1998) Do novel antipsychotics have similar pharmacological characteristics? A review. Neuropsychopharmacology 18:63101 Bilder RM, Goldman RS, Bolavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunj M, Chakos M, Cooper T, Horowitz T, Lieberman J (2002) Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Benton AL, Hamsher K, Varney NR, Spreen O (1983) Contributions to neuropsychological assessment. Oxford University Press, New York Brandt J (1991) The Hopkins selective memory test: development of a new memory test with six equivalent forms. Clin Neuropsychol 5:125142 Buchanan RW, Holstein C, Brier A (1994) The comparative efficacy and long term effect of clozapine treatment on

403 neuropsychological test performance. Biol Psychiatry 36:717 725 Connors continuous performance test computer program (1995) Multi-Health Systems Inc. Cornblatt B, Obuchowski M, Roberts S, Pollack S, ErlenmeyerKimling L (1999) Cognitive and behavioural precursors of schizophrenia. Dev Psychopathol 11:487508 Cuesta MJ, Peralta V, Zarzuela A (2001) Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study. Schizophr Res 48:1728 Gallhofer B, Lis S, Meyer-Lindenberg A, Krieger S (1999) Cognitive dysfunction in schizophrenia: a new set of tools for the assessment of cognition and drug effects. Acta Psychiatr Scand Suppl 395:118128 Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321330 Halstead WC (1947) Brain and cognition. University of Chicago Press, Chicago Heaton RK (1993) Wisconsin card sorting test: computer version-2 research edition. Psychological Assessment Resources Inc Hughes C, Kumari V, Soni W, Das M, Binneman B, Drozd S, ONeil S, Mathew V, Sharma T (2003) Longitudinal study of symptoms and cognitive function in chronic schizophrenia. Schizophr Res 59:137146 Kane JM, Woerner M, Lieberman J (1988) Tardive dyskinesia: prevalence, incidence, and risk factors. J Clin Psychopharmacol 8[Suppl 4]: 52S56S Kay SR, Fiszbein PS, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261276 Keefe RS, Silva SG, Perkins DO, Lieberman JA (1999) The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 25:201222 Lee MA, Thompson PA, Meltzer HY (1994) Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 55[Suppl B]: 8287 Manschreck TC, Redmond DA, Candela SF, Maher BA (1999) Effects of clozapine on psychiatric symptoms, cognition and functional outcome in schizophrenia. J Neuropsychiatry Clin Neurosci 11:481489 Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233255 Meyer-Lindenberg A, Gruppe H, Bauer U, Lis S, Krieger S, Gallhofer B (1997) Improvement of cognitive function in schizophrenic patients receiving clozapine or zotepine: results from a double-blind study. Pharmacopsychiatry 30:3542 Mortimer AM (2001) Newer antipsychotics drugsa review. J Ad Schizophr Brain Res 3:111120 Morris RG (1995) The Computerised Trail Making Test. Institute of Psychiatry, London Nelson HE, Willison JR (1991) National adult reading test (part II): test manual. NFER-NELSON, Windsor Pallanti S, Quercioli L, Pazzagli A (1999) Effects of clozapine on awareness of illness and cognition in schizophrenia. Psychiatry Res 86:239249 Purdon SE, Jones BDW, Stip E, Labelle A, Addington D, David SR, Breier A, Tollefson GD (2000) Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone or Haloperidol. Arch Gen Psychiatry 57:249258 Purdon SE, Labelle A, Boulay L (2001) Neuropsychological change in schizophrenia after 6 weeks of clozapine. Schizophr Res 48:5767 Riley EM, McGovern D, Mockler D, Doku VCK, OCeallaigh S, Fannon DG, Tenakoon L Santamarie M, Soni W, Morris RG, Sharma T (2000) Neuropsychological functioning in firstepisode psychosisevidence of specific deficits. Schizophr Res 43:4755 Rund BR (1998) A review of longitudinal studies of cognitive functions in schizophrenia patients. Schizophr Bull 24:425435 Rund BR, Borg NE (1999) Cognitive deficits and cognitive training in schizophrenic patients: a review. Acta Psychiatr Scand 100:8595 Scarr E, Copolov DL, Dean B (2001) A proposed pathological model in the hippocampus of subjects with schizophrenia. Clin Exp Pharmacol Physiol 28:7073 Sharma T (1999) Cognitive effects of conventional and atypical antipsychotics in schizophrenia. Br J Psychiatry Suppl 38:44 51 Velligan DI, Mahurin RK, Diamond PL, Hazleton BC, Stacey LE, Miller AL (1997) The functional significance of symptomatology and cognitive function in schizophrenia. Schizophr Res 25:2131 Wechsler D (1945) Wechsler memory scale. The Psychological Corporation, New York Wechsler D (1981) Wechsler adult intelligence scalerevised, manual. The Psychological Corporation, New York Weiser M, Shneider-Beeri M, Nakash N, Brill N, Bawnik O, Reiss S, Hocherman S, Davidson M (2000) Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS? Schizophr Res 46:8189