Dataset Information

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder.

ABSTRACT: Background/Aim:Although individuals with substance use disorder (SUD) are at high risk of committing suicide, most studies of postmortem gene expression exclude subjects with SUD due to the potential confounding effect of drugs in the transcriptome. Thus, little is known about the gene expression profile in suicides with SUD. The identification of altered biological processes in suicides with SUD is crucial in the comprehension of the interaction between both pathologies. Methods:We evaluated the gene expression profile in the dorsolateral prefrontal area of suicides and nonsuicides with and without SUD by microarrays. Results:We identified 222 differentially expressed genes, predominately enriched in cell proliferation in the comparison between suicides with and without SUD. When comparing the transcriptome of suicides with SUD to nonsuicides with SUD, we identified 550 differentially expressed genes, mainly enriched in oxidative phosphorylation. Differentially expressed genes (1,417) between suicides and nonsuicides without SUD were detected. Most of them were related to mitochondrial function. Conclusion:Interaction between suicide and SUD seems to influence the expression of genes involved in glial proliferation and glutamatergic neurotransmission. These results highlight, for the first time, that suicides with SUD have a gene expression profile distinct from that of subjects with only one of these disorders.

SUBMITTER: Cabrera B

PROVIDER: S-EPMC6465692 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder.

Cabrera Brenda B Monroy-Jaramillo Nancy N Fries Gabriel Rodrigo GR Mendoza-Morales Roberto Cuauhtemoc RC García-Dolores Fernando F Mendoza-Larios Alejandra A Diaz-Otañez Carlos C Walss-Bass Consuelo C Glahn David Colin DC Ostrosky-Wegman Patricia P Fresno Cristobal C Nicolini Humberto H

Molecular neuropsychiatry 20181112 1

<h4>Background/aim</h4>Although individuals with substance use disorder (SUD) are at high risk of committing suicide, most studies of postmortem gene expression exclude subjects with SUD due to the potential confounding effect of drugs in the transcriptome. Thus, little is known about the gene expression profile in suicides with SUD. The identification of altered biological processes in suicides with SUD is crucial in the comprehension of the interaction between both pathologies.<h4>Methods</h4> ...[more]

PMID: 31019919

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Project description:ObjectiveClinical practice guidelines recommend concurrent treatment of co-occurring depression and substance use disorders; however, the degree to which patients with substance use disorders receive guideline-concordant treatment for depression is unknown. The authors investigated the provision of guideline-concordant depression treatment to patients with and without substance use disorders in a large integrated health care system.MethodsIn a retrospective cohort study of 53,034 patients diagnosed with a depressive disorder in fiscal year 2017 in the U.S. Veterans Health Administration, the authors assessed the association of comorbid substance use disorders with guideline-concordant depression treatment, including both medication and psychotherapy, while adjusting for patient demographic and clinical characteristics.ResultsGuideline-concordant depression treatment was lower across metrics for patients with co-occurring depression and substance use disorders compared to those without substance use disorders. Consistent findings emerged in covariate-adjusted models of antidepressant treatment, such that patients with substance use disorders had 21% lower odds of guideline-concordant acute treatment (adjusted odds ratio=0.79, 95% CI=0.73, 0.84) and 26% lower odds of continuation of treatment (adjusted odds ratio=0.74, 95% CI=0.69, 0.79). With regard to psychotherapy, patients with co-occurring depression and substance use disorders had 13% lower odds (adjusted odds ratio=0.87, 95% CI=0.82, 0.91) of adequate acute-phase treatment and 19% lower odds (adjusted odds ratio=0.81; 95% CI=0.73, 0.89) of psychotherapy continuation.ConclusionsDespite the availability of effective treatments for depression, patients with co-occurring substance use disorders are less likely to receive guideline-concordant depression treatment. Efforts to improve the provision of care to those with co-occurring substance use disorders should focus on clinician-based interventions and use of integrated care models to improve the quality of depression treatment.

Project description:Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is currently a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased expression of the ECM protease matrix metalloproteinase 9 (Mmp9), and increased expression for the excitatory synaptic marker vesicle associated membrane protein 2 (Vamp2). Similar increases in PNNs were observed in monkeys with chronic alcohol self-administration. Subjects with MDD displayed changes opposite to SUD, and subjects with SUD and comorbid MDD had minimal changes in any of the outcome measures examined. Our findings demonstrate that PNNs are increased in SUD, possibly contributing to stabilizing contextual reward memories as suggested by preclinical studies. Our results also point to a previously unsuspected role for CSPG expression in glial cells in SUD. Evidence for increased hippocampal PNNs in SUD suggests that targeting PNNs to weaken contextual reward memories is a promising therapeutic approach for SUD, however comorbidity with MDD is a significant consideration.

Dataset Information

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder.

Publications

Brain Gene Expression Pattern of Subjects with Completed Suicide and Comorbid Substance Use Disorder.

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