Abstract
The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and UHMK1 (ubiquitin-mediated proteolysis). Finally, focusing analysis on brain structure volumes revealed significantly lower bilateral hippocampal volumes in MAP subjects. Overall, these results suggest similar molecular and neurocognitive mechanisms underlying the pathophysiology of psychosis and SCZ regardless of substance abuse and provide preliminary evidence supporting the MAP paradigm as an exemplar for SCZ biomarker discovery.
Highlights
Methamphetamine (METH) is an N-methyl derivative of amphetamine and a highly addictive psychostimulant severely affecting the central nervous system.[1]
METH use is at epidemic levels in several areas of the world and its global prevalence is estimated at 15–16 million people with several pockets of increased use in the USA, Europe and Africa.[2,3]
Several challenges currently exist in terms of accurately diagnosing Methamphetamine-associated psychosis (MAP) on a molecular and cognitive level before the MAP model can contribute to the discovery of SCZ biomarkers
Summary
Methamphetamine (METH) is an N-methyl derivative of amphetamine and a highly addictive psychostimulant severely affecting the central nervous system.[1]. Methamphetamine-associated psychosis (MAP) has been considered a pharmacological and environmental model of schizophrenia (SCZ) due to similarities in clinical presentation (that is, paranoia, hallucinations, disorganized speech and negative symptoms), response to treatment (neuroleptics) and presumed neuromechanisms (central dopaminergic neurotransmission).[7,8,9] It is hypothesized that a better understanding of the molecular mechanisms underlying SCZ may be accelerated via examination of human models related to the disease. In this context, the MAP model could quicken the discovery of risk biomarkers, screening for subclinical disease, prognostics, diagnostics or disease staging. Several challenges currently exist in terms of accurately diagnosing MAP on a molecular and cognitive level before the MAP model can contribute to the discovery of SCZ biomarkers
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