Lipid effects during antipsychotic drug treatment and their relevance for clinical outcomes

Abstract

Schizophrenia is a devastating mental disorder with disease mechanisms that are still poorly understood. Evidence has emerged that lipid dysregulations and myelination abnormalities might contribute to the pathophysiology of schizophrenia. Antipsychotic drugs often induce severe metabolic adverse effects, such as weight gain, dyslipidemias, and diabetes. However, several studies in chronic patients have indicated that some antipsychotic drug-related metabolic changes may be associated with improvements in psychotic symptoms. The main aim of this doctoral thesis was to combine clinical, biological, and imaging data to increase our current understanding of the relationship between serum lipid changes and various outcomes in antipsychotic-treated patients earlier in their illness course with emphasis on first-episode psychosis (FEP) patients. The clinical samples included FEP patients using antipsychotic drug treatment, olanzapine-treated, and unmedicated patients with broad schizophrenia spectrum disorders, along with a group of healthy controls from the Thematically Organized Psychosis project in Oslo. The participants underwent a thorough clinical evaluation, structural imaging, analyses of serum lipids, and physical examination, including assessment of body mass index (BMI). The severity of positive and negative symptoms and cognitive performances were assessed at inclusion and after a one-year follow-up, along with serum lipids. Linear mixed-effects models were used to examine associations between changes in serum lipids versus changes in positive, negative, and cognitive symptoms. General linear models were used to investigate associations between serum lipids and cortical thickness and gray/white matter intensity contrast, which were used as proxy measures for intracortical myelin. Our results indicate that an increase in serum HDL-C during antipsychotic drug treatment is associated with improvements in negative symptoms and verbal learning, independent of changes in BMI. Moreover, OLZ treatment was linked to normalized cortical intensity contrast, and a higher serum level of HDL-C in OLZ-treated patients was related to thicker cortices suggesting a lipid-mediated effect on intracortical myelin. Together, our results may indicate that the therapeutic effect of antipsychotic drug treatment could in parts be linked to lipid biosynthesis.