Network science approach elucidates integrative genomic-metabolomic signature of antidepressant response and lifetime history of attempted suicide in adults with major depressive disorder

Abstract

Background: Individuals with major depressive disorder (MDD) and a lifetime history of attempted suicide demonstrate lower antidepressant response rates than those without a prior suicide attempt. Identifying biomarkers of antidepressant response and lifetime history of attempted suicide may help augment pharmacotherapy selection and improve the objectivity of suicide risk assessments. Towards this goal, this study sought to use network science approaches to establish a multi-omics (genomic and metabolomic) signature of antidepressant response and lifetime history of attempted suicide in adults with MDD.Methods: Single nucleotide variants (SNVs) which associated with suicide attempt(s) in the literature were identified and then integrated with a) p180-assayed metabolites collected prior to antidepressant pharmacotherapy and b) a binary measure of antidepressant response at 8 weeks of treatment using penalized regression-based networks in 245 ‘Pharmacogenomics Research Network Antidepressant Medication Study (PGRN-AMPS)’ and 103 ‘Combining Medications to Enhance Depression Outcomes (CO-MED)’ patients with major depressive disorder. This approach enabled characterization and comparison of biological profiles and associated antidepressant treatment outcomes of those with (N = 46) and without (N = 302) a self-reported lifetime history of suicide attempt.Results: 351 SNVs were associated with suicide attempt(s) in the literature. Intronic SNVs in the circadian genes CLOCK and ARNTL (encoding the CLOCK:BMAL1 heterodimer) were amongst the top network analysis features to differentiate patients with and without a prior suicide attempt. CLOCK and ARNTL differed in their correlations with plasma phosphatidylcholines, kynurenine, amino acids, and carnitines between groups. CLOCK and ARNTL-associated phosphatidylcholines showed a positive correlation with antidepressant response in individuals without a prior suicide attempt which was not observed in the group with a prior suicide attempt.Conclusion: Results provide evidence for a disturbance between CLOCK:BMAL1 circadian processes and circulating phosphatidylcholines, kynurenine, amino acids, and carnitines in individuals with MDD who have attempted suicide. This disturbance may provide mechanistic insights for differential antidepressant pharmacotherapy outcomes between patients with MDD with versus without a lifetime history of attempted suicide. Future investigations of CLOCK:BMAL1 metabolic regulation in the context of suicide attempts may help move towards biologically-augmented pharmacotherapy selection and stratification of suicide risk for subgroups of patients with MDD and a lifetime history of attempted suicide.

Potential links between brown adipose tissue, circadian dysregulation, and suicide risk

“…Chronobiological alterations were associated with passive and active suicidal ideation or preparation (Palagini et al, 2021) and with suicide attempts (Grant et al, 2022). Circadian rhythm disturbances are a common symptom among individuals with mood disorders (Vadnie and McClung, 2017) and can be a mood disorder phenotype (Carpenter et al, 2021).…”

Recent Progress in Mass Spectrometry-Based Metabolomics in Major Depressive Disorder Research

“…Due to the complexity of the pathogenesis of MDD, the integration of metabolomics with other "omics" technologies is becoming increasingly necessary. Recent studies have combined genomics and metabolomics to characterize various aspects of early-and adultonset MDD, including adult MDD suicide attempts [160][161][162][163]. Integrated proteomics and metabolomics were used to explore antidepressant treatments in animal models and MDD patients [164,165].…”