A Randomized Controlled Trial of Olanzapine Versus Haloperidol in the Treatment of Primary Negative Symptoms and Neurocognitive Deficits in Schizophrenia

Objective: Primary negative symptoms are intrinsic to the pathology of schizophrenia and are associated with significant deficits in motivation, verbal and nonverbal communication, affect, and cognitive and social functioning. Overall, atypical antipsychotic medications have been found to be more efficacious than conventional antipsychotics in the treatment of negative symptoms, based on studies with acute patients. Results have been confounded by concomitant improvements in positive, depressive, and extrapyramidal symptoms. This 12-week, double-blind, controlled study aimed to examine the effects of the atypical antipsychotic olanzapine versus haloperidol on persistent, primary negative symptoms and neurocognitive functions in stable schizophrenic patients with the deficit syndrome and low levels of concomitant positive, depressive, and extrapyramidal symptoms.

Method: Thirty-five patients with DSM-IV-TR schizophrenia and predominant negative symptoms were randomly assigned in a 12-week double-blind study to either olanzapine (15-20 mg/day) or haloperidol (15-20 mg/day). Patients taking haloperidol received additional blinded benztropine. Inclusion criteria were Positive and Negative Syndrome Scale (PANSS) negative score of >= 20, PANSS positive score < 20, and fulfilling the criteria for the Schedule for the Deficit Syndrome. The PANSS, Clinical Global Impressions, Hamilton Rating Scale for Depression (HAM-D), Simpson-Angus Scale, and Abnormal Involuntary Movement Scale were assessed at regular subsequent intervals. A neuropsychological battery examining declarative verbal learning memory, attention and processing speed, executive functioning, and simple motor functioning domains of cognition was assessed at baseline and endpoint. The study ran from September 1998 through May 2005.

Results: Clinical Results: There was a statistically significant difference for PANSS negative symptoms (F = 5.44, df = 1,15; p <= .05), with an 8.63-point decrease in the olanzapine group (t = 5.66, df = 1,33; p <= .05), and PANSS total score (t = 9.304, df = 1,33; p <= .05). Linear mixed model for repeated measures indicated that the olanzapine group showed a statistically significant change in negative symptom scores (F = 9.70, df = 1,15; p <= .05). There were no significant differences for change in PANSS positive score, PANSS general psychopathology score, and HAM-D score. Using a criterion of 40% decrease in the PANSS negative subscale score, 31.25% of patients were classified as responders in the olanzapine group, while only 10.53% were responders in the haloperidol group. There were no significant between-treatment differences in the incidence of extrapyramidal side effects. Olanzapine-treated patients experienced more weight gain than the haloperidol-treated group (F = 7.044, df = 1,33; p <= .05). Neuropsychological Results: Significant differences in change from baseline to endpoint for the olanzapine-treated group were seen for declarative verbal learning memory (F = 11.499, df = 1,14; p = .021) and the motor functioning domain (F = 4.405, df = 1,31; p = .044).

Conclusions: The results of this study suggest that olanzapine treatment was associated with significant improvement in primary negative symptoms, overall symptomatic improvement as measured by the PANSS total score, and improvement in some areas of neurocognition as compared with haloperidol/benztropine mesylate treatment.