Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Abstract

Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform 'lipidomics' that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2-3 weeks with olanzapine (n = 20), risperidone (n = 14) or aripiprazole (n = 16). Patients were recruited in two cohorts (study I, n = 27 and study II, n = 23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.

Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol

“…Lipids and defects in lipid metabolism are an emerging facet of the neurodevelopmental theory of schizophrenia. 5,44,45 Thus, it has been proposed that some APDs may have a beneficial effect on cognitive dysfunction in schizophrenia through lipogenic activation and myelination of the brain. 4,45,46 Our results indicate that although APDs induce lipogenic gene expression, this may not necessarily translate to increased synthesis of myelin, which comprises 70-80% of brain cholesterol.…”

Application of fatty acid and lipid measurements in neuropsychiatry

“…It would seem that to find biomarkers it is crucial to understand the mechanisms of a given disorder [29]. However, new analytical platforms, -omics techniques, such as proteomics [30][31][32], metabolomics [33][34][35] or genomics [36][37][38][39] are proving to be extremely helpful in this area as they do not require the knowledge of the disease's pathoaetiology [29,40].…”

Biomarker discovery in neurological diseases: a metabolomic approach

“…57,69 The metabolic profile of children diagnosed with autistic disorder with regressive onset was found to be severely abnormal. 70 The autistic children were found to have significant decreases in methionine levels and in the ratio of plasma S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAM/SAH ratio), an index of methylation capacity.…”