Olanzapine induced reductions in frontal lobe lactate levels correlate with treatment response in first episode psychosis

Abstract

Purpose: Typical and atypical antipsychotic medications differ in the extent to which they inhibit respiratory enzyme activity, with typical neuroleptics producing greater degrees of inhibition. Lactate is a neurochemical marker that increases with mitochondrial dysfunction and which can be detected using proton magnetic resonance spectroscopy (1H MRS). We hypothesized that olanzapine treatment would result in a greater reduction of brain lactate levels than haloperidol treatment in subjects with a first episode of psychosis. Design: Subjects with a first episode of psychosis (N = 263) were era'oiled in a multi-site, double blind treatment trial of either olanzapine or haloperidol. Single voxel, 6 era3, 1H MR spectra of the left frontal lobe (FC), basal ganglia (BG), and hippocampal (HC) regions were acquired both before and following 12 weeks of treatment for 156 subjects. The weak lactate doublet at 1.4 PPM was fit using an automated fitting method and the intensity of this resonance was normalized using a replacement phantom. Results: An acceptable fit of the lactate resonance was obtained on both occasions for approximately one fourth of the study subjects (N = 81). During 12 weeks of treatment, mean lactate reductions in the FC, BG, and HC were 12%, 18%, and 13% for the olanzapine cohort and 1%, 3%, and 8% for the haloperidol cohort. These differences did not reach statistical significance. However, reductions in frontal cortex lactate were strongly correlated with reductions in PANSS scores (p = 0.00t 1) and BPRS scores (p = 0.0017) for the entire subject population as well as for the olanzapine cohort (p = 0.0035 and p = 0.017, respectively; N = 42). These correlations were much weaker in the hatoperidol cohort (p = 0.17 and p = 0.043, respectively; N = 39). Conclusions: Reductions in frontal cortex lact'~,te during olanzapine treatment are strongly associated with resolution of psychotic symptoms. This relationship is weaker with haloperidol treatment, which has been associated with inhibition of complex 1. Lactate appears to be a chemical marker fo1 the frontal hypometabolism that has been reported in prior studies; strategies to reduce brain lactate levels may present novel therapeutic opportunities for the treatment of schizophrenia. These findings are also consistent with the lower incidence of depression associated with olanzapine therapy, as we have recently observed elevated brain lactate levels in depressed, umnedicated bipolar subjects.