Social and Biological Parameters Involved in Suicide Ideation During the COVID-19 Pandemic: A Narrative Review

Abstract

Fear is an indispensable characteristic of any infectious disease, and the alarm will be further amplified when the infection spreads uncontrollable, unpredictable, and global. The novel corona virus (SARS CoV-2) lead Covid-19, has been declared as a global emergency by WHO as it has affected millions of people with a high mortality rate. The non-availability of medicine for Covid-19 and the various control measures such as social distancing, self-isolation, house quarantine, and the new normal implementation by different nations across the world to control the spread of Covid-19 made people vulnerable to fear and anxiety. As a result, considerable number of Covid-19-related suicidal deaths has been reported across the world during this pandemic. There have been several studies which describe the psychosocial aspects of suicidal ideation. However, the research on the biological aspects of suicidal ideation/suicidal risk factors that are related to pandemic are unreported. Hence this review article is intended to provide a comprehensive analysis of suicidal deaths during Covid-19 and also aimed to addresses the possible link between suicidal ideation and different factors, including psycho-social, behavioral, neurobiological factors (proximal, distal, and inflammatory) and immunity. The alterations in glutamatergic and GABAergic neurotransmitters had upregulated the GABARB3, GABARA4, GABARA3, GABARR1, GABARG2, and GAD2 gene expressions in suicidal victims. The changes in the Kynurenine (KYN) pathway, Hypothalamus-Pituitary-Adrenal axis (HPA axis) hyperactivation, and dysregulation of serotonin biosynthesis would significantly alter the brain chemistry in people with suicide ideation.

Keywords: Covid-19; inflammatory cytokines; neurobiological factors; psychiatric disorder; suicidal behavior; suicidal death.

Figure 1.

Role of distal factor in suicidal behavior. Distal risk factor predisposition to suicide. Brain-derived neurotrophic factor (BDNF) is synthesized as a precursor known as proBDNF, which later undergoes proteolytic cleavage to form a mature BDNF. The proBDNF preferentially binds to p75^NTR and mature BDNF to TrkB. The binding of BDF with high affinity receptor TrkB activates various signaling pathways such as P13K, MAPK and PLC-γ, which are required for proper synaptic functioning, cell survival and maintaining neural plasticity. A single nucleotide (G196A) polymorphism (SNP) of BDNF gene produce Val to Met substitution in the proBDNF protein at codon 66 (Val66Met). This SNP (SNP ID: rs6265) decreases the activity dependent secretion of BDNF protein in the brain and results in lower trafficking of BDNF. In addition, the BDNF actively binds with lower affinity receptor p75^NTR that activates NF-κB and c-Jun N-terminal kinase pathways and it induces apoptosis. The presence of excess levels results in neurodegeneration and mood disorders that can cause suicidal behavior. The abnormality in BDNF signaling pathway function is considered a vital biological risk factor in the pathological process of suicide.

Figure 2.

An overview of the proximal contributors to suicidal behavior: (A) Under normal condition, serotonin (a monoamine neurotransmitter) is synthesized from the hydroxylation of tryptophan (TRP) by the enzymes TPH1 and TPH2. However, increased inflammatory cytokines deviates the tryptophan pathway to produce kynurenine (KYN) hindering the serotonin biosynthesis. Reduced level of serotonin and 5-hydroxyindoleacetic acid (5-HIAA), and changes in the kinetics of serotonin and its receptor interaction leads to impaired decision making which results in suicidal ideation, (B) Suicidal ideation and behavior have pronounced inflammatory changes in both blood and cerebrospinal fluid (CSF). In suicide attempters the levels of plasma IL-6 and TNF- α are increased and IL-2 level is decreased, (C) The impaired glutamate recycling results in dysregulated glutamatergic and/or GABAergic neurotransmission, which leads to mood disorders and suicide. Under normal conditions, the glutamate that is released into the pre synaptic cleft is taken up by the surrounding astrocytes. GS present in the astrocytes plays a major role in glutamate re-uptake from the synaptic cleft. The dysfunction of glial cells results in the down regulation of GS that result in the deposition of glutamate in the presynaptic cleft. This activates the NMDA receptor consequently resulting in cell death. In addition, it inhibits the BDNF pathway leading to suicidal behavior. (Red arrow indicates inhibition, while green indicates activation), and (D) Altered expression of glial fibrillary associated protein (GFAP), glial-specific excitatory amino-acid transporters (EAATs) in tissue, suggests that the glial cell abnormalities include changes in astrocytic cell functions of depressed individuals who engaged in suicidal activities.

Figure 3.

Schematic representation of pathways involved in inflammatory responses causing suicidal behavior. In case of kynurenine (KYN) pathway, tryptophan (TRP) is converted to KYN with the help of the enzyme indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO), which is activated by the inflammatory cytokines. Further, downstream activations lead to the formation of quinolinic acid (QUIN), which increases the extracellular glutamate level resulting in suicidal behavior. Non-availability of TRP for the biosynthesis of serotonin also causes mood related disorders. Increased pro-inflammatory cytokines in the CNS can also desensitize glucocorticoid receptor thereby inhibiting the negative feedback mechanism for activation of HPA axis leading to hyper-activation of HPA axis.