Neural and molecular correlates of psychological pain during major depression, and its link with suicidal ideas.

OBJECTIVES: Psychological pain increases the risk of suicidal ideas and acts, and represents a potential therapeutic target. However, the mechanisms of mental pain remain unclear. Here, we assessed the peripheral transcriptomic and central neural correlates of mental pain during a depressive episode. METHODS: 172 adult un-medicated depressed patients were recruited. Leucocytes were extracted for RNA quantification at baseline (T0) and after 8 weeks (T8) of an antidepressant treatment. Ninety-nine genes of the cortisol, immune, opioid, serotonergic, and kynurenine systems were a priori selected, and 41 were sufficiently expressed to be analyzed. At both T0 and T8, mean level of mental pain over the last 15 days was measured with a visual analog scale. A subset of 38 patients was additionally scanned with Magnetic Resonance Imaging at T0. Resting-state sequences of 4 networks (default-mode, basal ganglia, central executive, salience) were examined. RESULTS: Mean psychological pain scores significantly decreased between T0 and T8. At conservative p-corrected levels, T0 mental pain was significantly correlated with 11 brain clusters encompassing the prefrontal, parietal, and temporal cortices, the striatum, and the cerebellum. There was no direct association between peripheral gene expression and mean mental pain at any time points or in terms of temporal changes. However, expressions of 5HTR2B at p-corrected levels, and 5HTR3A, TPH1, and OPRL1 were correlated with the activity of several identified brain clusters at T0. Finally, while suicidal ideas and mental pain were correlated, the neural and molecular correlates of suicidal ideas were not the same. CONCLUSION: Our study suggests that the serotonergic and nociceptin systems are associated with the activity of a cortico-subcortical brain network underlying the perception of mental pain during depression. Mental pain may be a necessary but insufficient condition for the emergence of suicidal ideation during depression.