Could grey matter loss in the superior temporal gyrus contribute to treatment resistance?

The DSM 5 abandoned classifying schizophrenia by psychopathology subtype, but the heterogeneity of the disorder still requires explanation. A more pragmatic approach advocated by some researchers is classification according to treatment response: antipsychotic responsive, clozapine responsive, and clozapine non-responsive. Investigators are looking at the biologic correlates of these subtypes, and a group from New Zealand recently examined differences in brain volume. Using a 3-Tesla scanner, they obtained T1-weighted images of the brains of 18 antipsychotic responders, 19 clozapine responders (for whom other antipsychotics failed), 15 clozapine nonresponders, and 20 controls. All subjects were 18 to 45 years old, and patients with neurologic or active addictive disorders were excluded. The clozapine responsive and non-responsive patients had failed to respond to at least two trials of other antipsychotics, and the PANSS was used to assess symptoms.

The groups of patients did not differ by mean age, PANSS scores or illness duration. The groups had some differences in substance use history; the clozapine-resistant patients had more use of hallucinogens, and the antipsychotic responsive group had more use of cannabis, but the groups did not differ in stimulant use history.

Compared with controls, all patient groups had a reduction in whole-brain and white-matter volumes, and the clozapine-resistant group had a significant increase in ventricular volume. The treatment-resistant and clozapine-resistant patients had smaller grey matter volumes compared with controls and antipsychotic-responsive patients. In analysis using voxel-based morphometry, a technique to examine the volume of specific brain regions, the clozapine-resistant patients, compared with controls, showed bilateral grey matter reductions in the superior and middle temporal gyri, ventromedial prefrontal cortex, anterior cingulate gyrus, and postcentral gyrus. The left cerebellum and right occipital cortex also showed grey matter reduction. Compared with controls, the treatment-resistant group had a similar magnitude of grey matter volume reduction which especially affected the right perisylvian region.

Compared with the antipsychotic-responsive group, both clozapine-resistant and clozapine-responsive groups had reduction in grey matter volume with somewhat differing patterns. Only the clozapine-resistant patients had a relative reduction in the left cerebellum and left anterior cingulate gyrus. No differences were seen in comparing the clozapine-resistant and clozapine-responsive groups.

A controversy in the field of neuroimaging of schizophrenia is the role of antipsychotic exposure in cerebral volume loss; previous research has shown conflicting results. In this study, the clozapine-resistant group had a higher mean daily dose of antipsychotic compared with the other groups, but the researchers found no overall correlation between daily dose and grey matter volume. The study did not look at lifetime antipsychotic exposure.

The investigators highlight the finding of prominent volume reduction in the superior temporal gyrus in the clozapine-resistant group, which was seen in a number of prior studies including longitudinal investigations and in first-episode patients. This brain structure is crucial for auditory processing and language, which are highly implicated in schizophrenia; perhaps tissue loss in this region contributes to poor medication response. However, as the researchers state, in this kind of observational study we are unable to draw conclusions about cause and effect.

Anderson VM, Goldstein ME, Kydd RR, Russell BR. Extensive grey matter volume reduction in treatment-resistant schizophrenia. Int J Neuropsychopharmacol. Published online Feb 25, 2015. Abstract

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