In vivo probing of purinergic P2X7 as a potential biomarker for suicide risk: a hypothesis

Suicide claims over 720,000 lives annually worldwide and for every suicide there are many more people who attempt suicide and with suicidal ideation being even more prevalent. To improve the identification of individuals at high risk for suicidal behavior, there is a need to study risk factors in relation to neurobiological mechanisms. This paper proposes an integrative neurobiological hypothesis linking childhood adversity as a known risk factor for suicide attempts and the experience of mental pain in individuals with childhood adversity in their background. The ideation-to-action theory proposes that psychological pain, in addition to hopelessness, is associated with suicide ideation, whereas the acquired capability to attempt suicide enables the progression from suicidal thought to suicidal behavior. A psychological paradox is suggested wherein childhood adversity exposed individuals are more vulnerable for psychological pain, a driver for suicidal ideation, alongside increased physical pain tolerance and fearlessness about death fostering suicide capability. Pain perception may be neurobiologically regulated. Dysregulation of the purinergic pathway and purinergic receptors, such as overactivation of the P2X7 receptor, may contribute to suicidality through at least three parallel mechanisms: neuroinflammation via NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, glutamatergic dysregulation in the anterior cingulate cortex, and disruption of inhibitory pain and fear circuits via brain-derived neurotrophic factor (BDNF) -mediated potassium chloride cotransporter 2 (KCC2) downregulation. Purinergic dysregulation is associated with increased risk for suicidal behavior, which has been demonstrated in bipolar and depressive disorders and schizophrenia. Converging evidence from genetic studies, peripheral inflammatory biomarkers, and postmortem brain tissue indicates that P2X7 dysregulation in suicidality is cell-type and region-specific, with the most direct evidence coming from postmortem findings in individuals who died by suicide independent of psychiatric diagnosis. These neurobiological changes may lower barriers to suicidal behavior during acute crises. In vivo PET with [¹¹C]SMW139 or [¹¹C]JNJ717 can visualize the purinergic pathway through high-affinity binding to the P2X7 receptor. We hypothesize that in vivo receptor overactivation is associated with acute suicidality, hence psychological pain. This approach offers potential for biomarker development and targeted therapeutic interventions addressing the neuro-immune substrate of suicidality.