Hippocampal Shape and Volume Changes with Antipsychotics in Early Stage Psychotic Illness

Abstract

Progression of hippocampal shape and volume abnormalities has been described in psychotic disorders such as schizophrenia. However it is unclear how specific antipsychotic medications influence the development of hippocampal structure. We conducted a longitudinal, randomized, controlled, multisite, double-blind study involving 14 academic medical centers (United States 11, Canada 1, Netherlands 1, and England 1). One hundred thirty-four first-episode psychosis patients (receiving either haloperidol [HAL] or olanzapine [OLZ]) and 51 healthy controls were followed for up to 104 weeks using magnetic resonance imaging and large-deformation high-dimensional brain mapping of the hippocampus. Changes in hippocampal volume and shape metrics (i.e., percentage of negative surface vertex slopes, and surface deformation) were evaluated. Mixed-models analysis did not show a significant group-by-time interaction for hippocampal volume. However, the cumulative distribution function of hippocampal surface vertex slopes showed a notable left shift with HAL treatment compared to OLZ treatment and to controls. OLZ treatment was associated with a significantly lower percentage of “large magnitude” negative surface vertex slopes compared to HAL treatment (p = 0.004). Surface deformation maps however did not localize any hippocampal regions that differentially contracted over time with OLZ treatment, after FDR correction. These results indicate that surface analysis provides supplementary information to volumetry in detecting differential treatment effects of the hippocampus. Our results suggest that OLZ is associated with less longitudinal hippocampal surface deformation than HAL, however the hippocampal regions affected appear to be variable across patients.

Much ado about much: Stress, dynamic biomarkers and HPA axis dysregulation along the trajectory to psychosis

“…Those conducted with prospectively identified populations would reduce confounding factors such as the provision of medications (especially atypical antipsychotic medications, which are known to influence the HPA axis by reducing daytime cortisol levels (Cohrs et al, 2006;Mondelli et al, 2010a) and increasing PV Pariante, 2008) although their effect on HV remains inconclusive (Mamah et al, 2012;McClure et al, 2013;Schobel et al, 2009)) and the a priori presence of psychotic symptoms, which are often experienced as stressful and therein may themselves activate the HPA axis. In doing so, they would enhance the study of the HPA axis as well as its interaction with additional neuroendocrine, autonomic or other mechanistic pathways.…”

The traumagenic neurodevelopmental model of psychosis revisited

“…Furthermore, psychotic samples also demonstrate increased regional blood flow in the hippocampus in response to exogenous cortisol administration [110]. Less is known about relative changes in the various hippocampal subfields; although some studies emphasize the anterior parts, CA1 and the densely interconnected subiculum [111,112]. Post-mortem studies of individuals with a schizophrenia diagnosis find decreased GR mRNA expression throughout all hippocampal subfields [80,113].…”

The use of clinical and biological characteristics to predict outcome following First Episode Psychosis

“…Accounting for the global medication effects on brain imaging parameters that have been associated with the use of antipsychotics (Mamah et al, 2012), longitudinal imaging data now suggest that progressive volume loss following FEP occurs in a subset of patients, particularly during the early years following illness onset (Andreasen et al, 2011). One might speculate that this subgroup, showing progressive grey matter loss beyond global medication effects, is particularly vulnerable to prolonged psychotic relapses and to the gradual development of treatment resistance (Andreasen et al, 2013).…”