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

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 these 12 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.[30,38,39,40] Performance in verbal learning and memory was 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 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 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[54,55,69,70,71,72] 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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