Cognitive Effects of Olanzapine Treatment in Schizophrenia

Susan R. McGurk, PhD; M.A. Lee, MD; K. Jayathilake, PhD; Herbert Y. Meltzer, MD

Disclosures
In This Article

Abstract and Introduction

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.

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, and contributing to the loss in function, during the prodromal period.[3,4,5,6] 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]

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.[12,13,14,15] 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.[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 serum anticholinergic 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 to moderate effect sizes.[28,29,30,31] 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,[35,36,37] 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 to olanzapine 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 improve these 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]

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