Hippocampal neuropathology in suicide: Gaps in our knowledge and opportunities for a breakthrough

Suicide is a major global hazard. There is a need for increasing suicide awareness and effective and evidence-based interventions, targeting both suicidal ideation and conduct. However, anti-suicide pharmacological effects are unsatisfactory. The human hippocampus is vulnerable to neuropsychiatric damages and subsequently releases psychobiological signals. Human hippocampal studies of suicide completers have shown mechanistic changes in neurobiology, which, however, could not reflect the neuropathological 'fingerprints' of fatal suicide ideations and suicide attempts. In this review, we provide several leading theories of suicide, including the serotoninergic system, Wnt pathway and brain-derived neurotrophic factor/tropomyosin receptor kinase B signalling, and discuss the evidence for their roles in suicide and treatment. Moreover, the cognitive dysfunctions associated with suicide risk are discussed, as well as the novel evidence on cognitive therapies that decrease suicidal ideation. We highlight the need to apply multi-omics techniques (including single-nucleus RNA sequencing and mass spectrometry histochemistry) on hippocampal samples from donors who died by suicide or legal euthanasia, to clarify the aetiology of suicide and propose novel therapeutic strategies.