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

Methods

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]

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 subjects before admission to the study.

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]

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.

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.

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