Abstract
Topiramate (TPM) is suggested to be a promising medication for treatment of methamphetamine (METH) dependence, but the molecular basis remains to be elucidated. Among 140 METH-dependent participants randomly assigned to receive either TPM (N = 69) or placebo (N = 71) in a previously conducted randomized controlled trial, 50 TPM- and 49 placebo-treated participants had a total 212 RNA samples available at baseline, week 8, and week 12 time points. Following our primary analysis of gene expression data, we reanalyzed the microarray expression data based on a latent class analysis of binary secondary outcomes during weeks 1-12 that provided a classification of 21 responders and 31 non-responders with consistent responses at both time points. Based on secondary outcomes, 1,381, 576, 905, and 711 differentially expressed genes at nominal P values < 0.05 were identified in responders versus non-responders for week 8 TPM, week 8 placebo, week 12 TPM, and week 12 placebo groups, respectively. Among 1,381 genes identified in week 8 TPM responders, 359 genes were identified in both week 8 and week 12 TPM groups, of which 300 genes were exclusively detected in TPM responders. Of them, 32 genes had nominal P values < 5 × 10-3 at either week 8 or week 12 and false discovery rates < 0.15 at both time points with consistent directions of gene expression changes, which include GABARAPL1, GPR155, and IL15RA in GABA receptor signaling that represent direct targets for TPM. Analyses of these 300 genes revealed 7 enriched pathways belonging to neuronal function/synaptic plasticity, signal transduction, inflammation/immune function, and oxidative stress response categories. No pathways were enriched for 72 genes exclusively detected in both week 8 and week 12 placebo groups. This secondary analysis study of gene expression data from a TPM clinical trial not only yielded consistent results with those of primary analysis but also identified additional new genes and pathways on TPM response to METH addiction.
Highlights
Methamphetamine (METH), a synthetic derivative of amphetamine, is a highly addictive psychostimulant, with escalating rates of use worldwide [1], in East and Southeast Asia, Australia, various regions of Great Britain, as well as Western and Midwestern areas of United States [1]
In a previous gene expression study based on the primary outcome of the clinical trial [30], we identified a set of differentially expressed (DE) genes associated with the treatment of TPM on METH dependence, as well as enriched biochemical pathways
The main objective of this study was to continue a primary analysis of gene expression data based on only primary outcome [30] by conducting a secondary analysis study using the same gene expression data of the same TPM randomized clinical trial [25] but with more samples classified as either responders or non-responders by applying a latent class analysis (LCA) of binary secondary outcomes during weeks 1–12 [31] to obtain a better understanding of the molecular mechanisms associated with the differences between responders and non-responders for TPM
Summary
Methamphetamine (METH), a synthetic derivative of amphetamine, is a highly addictive psychostimulant, with escalating rates of use worldwide [1], in East and Southeast Asia, Australia, various regions of Great Britain, as well as Western and Midwestern areas of United States [1]. 45% of METH is metabolized into amphetamine, and both highly addictive drugs are mostly excreted in renal system [4]. The half-life of METH is approximately 8–12 h, and during this time, acute effects of METH take place, which include an ecstatic rush that is nearly immediate in those who either smoke or inject this drug [5]. Chronic effects of METH include significant functional impairments in a range of cognitive processes, in attention/psychomotor speed, verbal learning and memory, and fluency-based measures of executive systems functioning [6]. Topiramate (TPM) is suggested to be a promising medication for treatment of methamphetamine (METH) dependence, but the molecular basis remains to be elucidated
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