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From Medscape General Medicine > MedGenMed Psychiatry and Mental Health

Cognitive Effects of Olanzapine Treatment in SchizophreniaSusan R. McGurk, PhD; M.A. Lee, MD; K. Jayathilake, PhD; Herbert Y. Meltzer, MD

Posted: 05/10/2004; Medscape General Medicine. 2004;6(2):27 © 2004 Medscape

Abstract and Introduction

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 hypothesis that olanzapine, an atypical antipsychotic drug reported to have

anticholinergic properties, improves cognition in patients with schizophrenia, including domains of

cognition related closely to work and social function (ie, verbal learning and memory) and that this

improvement is 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 (BPRS) was

used to assess psychopathology in patients treated with typical antipsychotic drugs. Subjects were

switched to olanzapine (average dose 13.4 mg, range 5-20 mg) and reassessed following 6 weeks

and 6 months of treatment. Significant improvement was noted in 9 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.[1] This impairment has been reported to be present shortly after

recovery from the first period of psychosis and to persist.[2] It is likely that significant components of

this cognitive impairment precede the development of psychotic symptoms, becoming manifest, andcontributing to the loss in function, during the prodromal period.[3-6] The cognitive disturbance is slowly

progressive in most patients, but a small proportion shows severe deterioration as the duration of

illness increases.[7] However, in one recent study that evaluated cognitive functioning in the 5 years

subsequent to illness onset, only secondary verbal memory deteriorated.[8]

The degree of impairment in various domains of cognition differs in patients with schizophrenia, with

some studies suggesting that the most severe cognitive impairments occur in measures of attention,

verbal fluency, motor speed, and executive function.[9,10] 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.[2,11]

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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. Other anticholinergic drugs, such as benztropine and trihexyphenidyl, which are

used to prevent or to lessen extrapyramidal symptoms (EPS) from antipsychotic drugs, or

antipsychotic drugs such as thioridazine and mesoridazine, which are strongly anticholinergic, can

impair various cognitive functions, especially memory.[12-15]

It has been suggested that the apparentimprovement 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.[16] However, an adverse effect of anticholinergic drugs on cognition has not been

found in all studies.[17] Recently, Mori and colleagues[18] 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 5 cloned rat and human muscarinic receptors in

vitro[19,20] and ex vivo[19] and was initially thought to be at least moderately anticholinergic in vivo.[20]

Consistent with this, clinical trials reported anticholinergic side effects and relatively high serumanticholinergic levels.[21] Two single-photon emission computed tomography studies reported high

occupancy of brain muscarinic receptors in patients treated with olanzapine and suggested that it

was strongly anticholinergic.[22,23] However, subsequent studies reported no anticholinergic side

effects in patients with Alzheimer's disease,[24] that its apparent in vivo potency as an antimuscarinic

was overestimated,[25] and that it can increase release of acetylcholine in the prefrontal cortex[26] and

hippocampus[27] 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 that would be expected

of an anticholinergic agent.

Numerous studies report that novel antipsychotic agents, including clozapine, risperidone,

olanzapine, and quetiapine, improve cognitive function in patients with schizophrenia with small tomoderate effect sizes.[28-31] This is in contrast to typical antipsychotic medications that have only

occasionally been reported to produce cognitive improvement.[32,33] However, there are some studies

that fail to find any differences between typical and atypical antipsychotic drugs on cognition,[34] which

has led some to suggest that the atypical agents are without any significant effect on cognition.[16] The

cognitive deficit in schizophrenia has been suggested to be a better predictor of good outcome in

social and work function than positive symptoms,[35-37] 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 anticholinergic drugs. In a

preliminary report of the results presented in full here, Meltzer and McGurk[28] reported significant

improvements following 6 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 and colleagues[38] reported significant

within-group improvements in 21 patients with schizophrenia treated with olanzapine at the 6-, 30-,

and 52-week assessment. Exploratory analyses demonstrated significant improvements after 6

weeks of treatment with olanzapine on 5 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 1 of the 17 total tests administered, the Hooper Visual Organization Test. The



improvements evident at the 6-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 1-year follow-up. There was no

evidence of a practice effect in this study.

Cuesta and colleagues[30]

reported that following the switch from various antipsychotic medications toolanzapine in 21 patients with chronic schizophrenia, verbal memory was significantly improved

compared with a comparison group of 17 patients, half of whom received risperidone and half typical

neuroleptic drugs. Similarly, Smith and colleagues[39] found no significant differences on a brief

cognitive battery between olanzapine and haloperidol following 8 weeks of treatment in chronically

hospitalized, treatment-refractory 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.[40] The authors suggested that further investigations would help

indicate whether olanzapine had a unique ability, among the novel antipsychotic drugs, to improvethese or other cognitive domains. Thus, despite a number of cognitive evaluations of olanzapine in

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 6-month open-label olanzapine

treatment trial that 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 6

weeks of olanzapine treatment reported elsewhere).[28] Patients were evaluated on a comprehensive

cognitive battery while receiving typical antipsychotic medications and again following 6 weeks and 6

months of treatment with olanzapine. Cognitive domains known to be sensitive to anticholinergic

drugs, including visual, verbal, and working memory, were evaluated.[12,15] 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.[36,37,41]

Methods

Subjects

Thirty-four schizophrenia patients (27 males) completed baseline assessments, 10 of whom were

hospitalized on a psychiatric acute-care inpatient unit, and 24 of whom were outpatients. All met

DSM-III-R criteria for schizophrenia or schizoaffective disorder. The mean age of the subjects was

41.4 years (standard deviation [SD] = 12.0 years), the mean age of illness onset was 24 years (SD =6.5 years), the mean duration of psychiatric illness was 17.0 years (SD = 11.0 years), and the

average education of the subjects was 12.9 years (SD = 2.8 years). Fourteen subjects with persistent

positive symptoms despite 3 adequate trials with other antipsychotic drugs met criteria for neuroleptic

resistance.[42]

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), and trilafon (n = 1); ancillary medication at baseline included

lorazepam and/or benztropine in a total of 12 subjects. For the 6-month period of olanzapine



treatment, the mean dose of olanzapine was 13.4 ± SD 7.8 (range 5-20) mg/day. No other

antipsychotic drug was given. At the 6-week and 6-month reassessments, 4 subjects were receiving

lorazepam, 2 sertraline, 2 benztropine, and 1 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 subjectsbefore admission to the study.

Measures

The BPRS, 24 items, 0-6 scoring 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 ( Table 1 ): (1) executive functioning (Wisconsin Card

Sort Test [WCST] Categories and Percent Perseveration[43]

; Stroop Test[28]

; Trail Making B[44]

); (2)working memory: verbal working memory (Auditory Consonant Trigrams [ACT])[45]; spatial working

memory (Spatial Working Memory Test, 5 sec delay and 15 sec delay)[46]; (3) verbal fluency

(Controlled Word Oral Association Test [CWAT]; Animal Naming)[47]; (4) immediate attention

(Wechsler Adult Intelligence Scale-Revised [WAIS-R] Digit Span Subtest)[48]; (5) sustained attention

(Continuous Performance Test [CPT], Repeating Digits subtest)[49]; (6) visual motor tracking (Trail

Making A[44]; Digit Symbol Substitution Test, WAIS-R[48]; Mazes, WISC-R[50]; (7) verbal learning and

memory (California Verbal Learning and Memory Test (CVLT)[51], total words recalled for list A 1-5

(List A1-5), and long delay free recall); (8) visual memory (Visual Reproduction subtest, Wechsler

Memory Scale-Revised[52]; Immediate Recall and Delayed Recall; and (9) fine motor control (Finger

Tapping).[53]

Table 1. Neuropsychological Assessments Listed by Cognitive Domain

1. Executive Functioning

WCST Categories; PerseverationTrail Making BStroop Test, Interference Trial

2. Working Memory

Spatial Working Memory: Spatial Working Memory Test:5 and 15 second delay

Verbal Working Memory: Auditory Consonant Trigrams

3. Verbal Fluency

Phonological Fluency: FAS testSemantic Fluency: Animal Naming

4. Immediate Attention Digit Span (WAIS-R)

5. Sustained Attention

CPT, Repeating Digits; D Prime

6. Visual Motor Tracking

Mazes (WISC-R)Trail Making A

Digit Symbol Substitution (WAIS-R)



7. Verbal Memory

California Verbal Learning and Memory Test:Immediate Recall (Trials 1-5);Delayed Recall (List A)

8. Visual Learning and Memory

Visual Reproduction (WMS-R)Figure Recall, Immediate RecallFigure Recall, Delayed Recall

9. Fine Motor Control

Finger Tapping

WCST = Wisconsin Card Sort Test; FAS = verbal fluency test; WAIS-R = Wechsler Adult Intelligence

Scale-Revised; WISC-R = Wechsler Intelligence Scales for Children-Revised; WMS-R = Wechsler

Memory Scale Revised

Neuropsychological assessment was conducted in two 2-hour sessions that occurred on the same

day, or 2 consecutive days. The order of the tests was standardized for all subjects.

Statistical Methods

A mixed model analysis of variance using the least squared difference to control for multiple post-hoc

comparisons was used to evaluate cognitive and clinical measures at baseline, 6 weeks, and 6

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 SDs of all clinical and cognitive measures are given in Table 2 . Following 6 weeks

of treatment, significant improvements were demonstrated for: (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 6 months of

olanzapine treatment, significant improvements were noted in: (1) Digit Span, (2) CPT-D Prime, (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 2 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 nonsignificant improvement at the 6-week assessment, which reached

significance at 6 months. Performance on Digit Symbol significantly improved between 6 weeks and

6 months of treatment (F(1,23 = 8.50, P < .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.

Table 2. Summary of Symptom and Cognitive Measures at Baseline, 6 Weeks, and 6

Months of Treatment with Olanzapine

Baseline

Mean (SD)

6 Weeks

Mean (SD)

6 Months

Mean (SD)

ANOVA

Base-6Wks

ANCOVA

Base-6Wks

ANOVA

Base-6 moF (DF)

ANCOVA

Base-6 moF†



F (DF) F†

Total BPRS 28.61(9.58)

23.44(7.86)

21.45(13.1)

8.83**(1,32)

7.49**(1,26)

BPRSPOSITIVE

8.30 (4.71) 6.13 (3.95) 5.6 (4.8) 5.38*(1,32)

6.74*(126)

BPRSNEGATIVE

2.70 (2.34) 2.28 (2.43) 3.6 (3.5) 1.01 (1,32) 2.1 (1,26)

WCSTCategories

2.23 (2.14) 2.42 (2.09) 2.8 (2.2) 1.00 (1,28) 1.3 (1,24)

WCSTPreservation

32.32(20.88)

29.35(16.91)

26.1(13.9)

3.52 (1,28) 1.68 (1,24)

Trails-B 145.06(87.10)

128.94(48.2)

124.6(57.6)

3.23 (1,29) 1.3 (1,26)

StroopInterference

141.23(64.55)

110.33(33.70)

112 (30.3) 14.31***(1,25)

13.03*** 2.10 (1,20)

ACT 39.58(11.63)

42.16(8.49)

43.9 (7.9) 3.22 (1,30) 5.35*(1,25)

3.89

SWM 5 sec. 23.93(6.38)

24.55(4.69)

24.9 (4.4) 0.34 (1,25) 1.03 (1,25)

SWM 15 sec. 21.34(6.64)

22.28(5.44)

23.1 (4.8) 1.40 (1,26) 1.69 (1,24)

Animal Naming 15.15(5.46)

18.03(4.83)

18.0 (5.5) 9.32**(1,31)

7.24** 2.67 (1,26)

ControlledWord

27.24(13.62)

31.91(12.10)

31.7 11.8 13.42***(1,31)

6.8** 1.01 (1,26)

Mazes 18.48(5.73)

19.36(5.07)

19.6 (3.9) 0.28 (1,20) .67 (1,18)

Digit Symbol 32.83(14.63)

32.75(17.93)

44.0(12.9)

0.35 (1,28) 13.87**(1,23)

13.81**

Digit Span 12.23(4.36)

12.17(4.83)

13.4 (4.1) 0.41 (1,28) 3.99*(1,22)

2.58

CPT-D Prime 0.28 (0.49) 0.86 (0.54) 0.99(0.91)

0.92 (1,18) 9.80**(1,16)

6.52*

Trails-A 56.75(30.90)

45.88(21.64)

44.61(23.4)

7.02*(1,31)

2.94 4.76*(1,29)

2.32

Finger Tapping 46.78(9.36) 47.91(8.86) 45.78(8.52) 0.67 (1,26) 0.35 (1,22)

VLIR 35.76(12.02)

43.90(11.02)

47.01(13.13)

17.30***(1,24)

18.82*** 5.53*(1,21)

5.94*

VLDR 7.31 (3.06) 9.55 (2.90) 10.25(3.69)

23.07***(1,24)

22.00*** 5.34*(1,21)

5.21*

Figure Recall - I 25.88(8.56)

28.45(7.79)

27.33(9.47)

7.80**(1,29)

3.84 .37 (1,22)

Figure Recall -D

18.00(11.53)

21.93(9.76)

21.44(9.38)

8.02**(1,28)

2.78 .35 (1,22)

ANOVA = analysis of variance; ANCOVA = analysis of covariance; SD = standard deviation; F =fixed effects; DF = degrees of freedom; BPRS = Brief Psychiatric Rating Scale; WCST = Wisconsin

Card Sort Test; ACT = Auditory Consonant Trigrams; SWM = Spatial Working Memory; CPT =



Continuous Performance Test; VLIR = Visual Learning, Immediate Recall; VLDR = Visual Learning,

Delayed Recall

*P < .05

**P < .01

***P < .001†

ANCOVA DF = 2 less than ANOVA DF

The BPRS Total score, and Positive Symptom subscale of the BPRS were significantly improved at

the 6-week and 6-month follow-up. The change in the BPRS Withdrawal-Retardation subscale score

was not statistically significant. In order to determine whether 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 Prime, Digit

Symbol Substitution, Animal Naming, and CWAT remained significant but the Visual Reproduction,

Trail Making A, Auditory Consonant Trigrams, and Digit Span did not. 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, sex, duration of illness, and neuroleptic resistance were entered

into the model, and change scores from baseline to 6 weeks for each cognitive test were entered as

the dependent variable. Age, sex, 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 with the 6-month, prospective group (N = 10)

and was not found to differ on any demographic (age, sex, 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 nonresponse (N

= 3), and medication side effects including weight gain and/or EPS (N = 3).

Discussion

The 2 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 6 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. Performances on the

Digit Span; Animal Naming; CWAT; CPT D Prime; Stroop Interference trial; CVLT, Immediate and

Delayed Recall; Visual Reproduction, Immediate and Delayed Recall; Trail Making A; and Digit

Symbol Substitution were improved. Additionally, 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 nonsignificant. However, the majority of

the tests that improved with olanzapine treatment were not related to the concomitant improvement

in positive symptoms: Stroop Interference Trial, CVLT Immediate and Delayed Recall, CPT-D Prime,

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 12 of 19 cognitive tests. Seven of these12 tests, including verbal learning and memory, CPT D Prime, 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 WISC-R 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 6 weeks or 6 months of treatment. These findings are in contrast with those for

clozapine, which worsened working memory following 6 weeks, but not 6 months, of treatment.[54,55]

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 dopamine (DA) in the medial

prefrontal cortex or possibly differences in cholinergic function. It is known that working memory is

highly sensitive to too little or too much DA,[56] and there is extensive evidence that M1 and M4

muscarinic receptors have a strong effect on DA release in multiple brain areas.[57] There was no

indication from the data reported here that olanzapine had the adverse profile on cognition

associated with strongly anticholinergic drugs, perhaps due to enhanced release of acetylcholine in

brain areas associated with memory suggested by studies in rats.[26,27]

Improvements occurring in this study in verbal list learning and memory are consistent with

improvement previously reported with olanzapine.[30,38-40]

Performance in verbal learning and memorywas improved from approximately 3 SDs below normal (for normative scores),[51] to approximately 2

SDs below normal. This improvement is particularly noteworthy given the findings of Hoff and

colleagues,[58] where verbal memory deficits were the only cognitive area noted to worsen during the

first 5 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.[59] 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,[60] a fundamental cognitive capacity that is essential for everyday 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.[35,37] The anterior cingulate cortex is activated in healthy control subjects, but not in

schizophrenia subjects, while performing the Stroop test.[61] Improvements on the Stroop test seen

after switching to olanzapine may be related to its ability to increase extracellular DA and

acetylcholine levels in the cingulate cortex[28,62] or to increase central noradrenergic

neurotransmission.[63] 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 1 SD, thus remaining in the impaired range. Purdon and

colleagues[38] also found a 1-SD improvement in 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 1 SD.[54,58] Verbal fluency has also been shown to be significantly

associated with functional outcome but on a more restricted basis than verbal learning and memory.[35]

Measures of verbal fluency (Animal Naming, CWAT) and visual-motor tracking (Digit Symbol)

significantly improved between 6 weeks and 6 months of treatment. This effect of time is of interest

because improvements in each of these tests were already significant at 6 weeks of treatment and

continued to improve through 6 months of treatment. Thus, olanzapine's beneficial effect on

measures involving processing speed, consistent with Bilder and colleagues,[40] either continues

through 6 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.[28] Significant improvements in selective attention

(Stroop), verbal learning and memory (CVLT), and verbal fluency (CWAT, Animal Naming) in theearly 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 6 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 have been suggested by Keefe and

colleagues[29,31] 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.[28] The consistency in the results of the current open-label study with the blinded studies by

Purdon and colleagues[38] and Bilder and colleagues[6] 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 neuroleptic-treated group to control

for possible effects of repeated measurement. However, practice effects are an unlikely explanation

for the cognitive improvements associated with olanzapine treatment. First, cognitive tests that have

been reported to be improved by practice in patients with schizophrenia (eg, WCST[64]; CPT[65]), or

from treatment with risperidone (eg, working memory[66]) or clozapine (eg, Finger Tapping[67]), 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,[68] was worsened by clozapine treatment,[69] and was unimproved by treatment

with haloperidol.[68] 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

(Wechsler Memory Scale Revised [WMS-R] Visual Reproduction). Clozapine was found to have

either no effect on performance of these measures, or a deleterious effect,[67] 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[54,55,69-72] and risperidone, but not haloperidol.[38] These

considerations suggest that improvements in the current study are a result of a direct effect of

olanzapine.

In summary, current findings indicate that 6 months of treatment with olanzapine favorably affects

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[28] 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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Authors and Disclosures

Susan R. McGurk, PhD, Department of Psychiatry, Mount Sinai School of Medicine, New York City,

NY

M.A. Lee, MD, K. Jayathilake, PhD, and Herbert Y. Meltzer, MD, Division of Psychopharmacology,

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee

Disclosure: Susan R. McGurk, PhD, M.A. Lee, MD, and K. Jayathilake, PhD, have no significant

financial interests or relationships to disclose.

Disclosure: Herbert Y. Meltzer, MD, has disclosed that he serves as a consultant to GlaxoSmithKline,

Eli Lilly & Company, Novartis, Janssen, AstraZeneca, and Roche.

Funding Information This article is supported by a NARSAD grant to S.R. McGurk and by grants from Warren Foundation and a grant fromEli Lilly to H.Y. Meltzer.

1. Executive Functioning

WCST Categories; PerseverationTrail Making BStroop Test, Interference Trial

2. Working Memory



















Spatial Working Memory: Spatial Working Memory Test:5 and 15 second delay

Verbal Working Memory: Auditory Consonant Trigrams

3. Verbal Fluency

Phonological Fluency: FAS test

Semantic Fluency: Animal Naming

4. Immediate Attention Digit Span (WAIS-R)

5. Sustained Attention

CPT, Repeating Digits; D Prime

6. Visual Motor Tracking

Mazes (WISC-R)Trail Making ADigit Symbol Substitution (WAIS-R)

7. Verbal Memory

California Verbal Learning and Memory Test:Immediate Recall (Trials 1-5);Delayed Recall (List A)

8. Visual Learning and Memory

Visual Reproduction (WMS-R)Figure Recall, Immediate RecallFigure Recall, Delayed Recall

9. Fine Motor Control

Finger Tapping

Baseline

Mean (SD)6 Weeks

Mean (SD)6 MonthsMean (SD)

ANOVABase-6

WksF (DF)

ANCOVABase-6

WksF†

ANOVABase-6 mo

F (DF)

ANCOVABase-6 mo

F†

Total BPRS 28.61(9.58)

23.44(7.86)

21.45(13.1)

8.83**(1,32)

7.49**(1,26)

BPRSPOSITIVE

8.30 (4.71) 6.13 (3.95) 5.6 (4.8) 5.38*(1,32)

6.74*(126)

BPRSNEGATIVE

2.70 (2.34) 2.28 (2.43) 3.6 (3.5) 1.01 (1,32) 2.1 (1,26)

WCST

Categories

2.23 (2.14) 2.42 (2.09) 2.8 (2.2) 1.00 (1,28) 1.3 (1,24)

WCSTPreservation

32.32(20.88)

29.35(16.91)

26.1(13.9)

3.52 (1,28) 1.68 (1,24)

Trails-B 145.06(87.10)

128.94(48.2)

124.6(57.6)

3.23 (1,29) 1.3 (1,26)

StroopInterference

141.23(64.55)

110.33(33.70)

112 (30.3) 14.31***(1,25)

13.03*** 2.10 (1,20)

ACT 39.58(11.63)

42.16(8.49)

43.9 (7.9) 3.22 (1,30) 5.35*(1,25)

3.89

SWM 5 sec. 23.93(6.38)

24.55(4.69)

24.9 (4.4) 0.34 (1,25) 1.03 (1,25)

SWM 15 sec. 21.34 22.28 23.1 (4.8) 1.40 (1,26) 1.69 (1,24)



(6.64) (5.44)

Animal Naming 15.15(5.46)

18.03(4.83)

18.0 (5.5) 9.32**(1,31)

7.24** 2.67 (1,26)

ControlledWord

27.24(13.62)

31.91(12.10)

31.7 11.8 13.42***(1,31)

6.8** 1.01 (1,26)

Mazes 18.48(5.73)

19.36(5.07)

19.6 (3.9) 0.28 (1,20) .67 (1,18)

Digit Symbol 32.83(14.63)

32.75(17.93)

44.0(12.9)

0.35 (1,28) 13.87**(1,23)

13.81**

Digit Span 12.23(4.36)

12.17(4.83)

13.4 (4.1) 0.41 (1,28) 3.99*(1,22)

2.58

CPT-D Prime 0.28 (0.49) 0.86 (0.54) 0.99(0.91)

0.92 (1,18) 9.80**(1,16)

6.52*

Trails-A 56.75(30.90)

45.88(21.64)

44.61(23.4)

7.02*(1,31)

2.94 4.76*(1,29)

2.32

Finger Tapping 46.78(9.36)

47.91(8.86)

45.78(8.52)

0.67 (1,26) 0.35 (1,22)

VLIR 35.76(12.02)

43.90(11.02)

47.01(13.13)

17.30***(1,24)

18.82*** 5.53*(1,21)

5.94*

VLDR 7.31 (3.06) 9.55 (2.90) 10.25(3.69)

23.07***(1,24)

22.00*** 5.34*(1,21)

5.21*

Figure Recall - I 25.88(8.56)

28.45(7.79)

27.33(9.47)

7.80**(1,29)

3.84 .37 (1,22)

Figure Recall -D

18.00(11.53)

21.93(9.76)

21.44(9.38)

8.02**(1,28)

2.78 .35 (1,22)

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