A Brain-Centric Model of Suicidal Behavior
Publication: American Journal of Psychiatry
The suicide death toll is alarmingly high, outnumbering deaths from war and homicide worldwide (1). Many factors contribute to suicide death, making it difficult to prevent because it is much more than a response to life stressors. Campaigns to lower U.S. suicide rates by 20% by 2025, and even to zero, confront hard realities such as not knowing why the annual suicide rate in the United States has risen every year since 2000 (2). The concurrent fall in suicide rates worldwide (1) is largely driven by restricting access to one highly lethal suicide method, namely, pesticides, which are commonly used in a few very populous countries, including China, India, and Sri Lanka (3–5). That approach saves lives without addressing the reasons people want to die by suicide. Currently empirically proven suicide prevention methods (Figure 1) include 1) better training of nonpsychiatrist physicians in the diagnosis and treatment of depression, the most common psychiatric disorder associated with suicide (6); 2) better outreach during the highest risk period, after suicidal patients are discharged from hospital or the emergency department (7); and 3) means restriction, focused on the commonest methods in each country (8). To prevent suicide in the short term, we need to scale up the use of these proven methods. To use these methods more effectively, we need to know who is at risk and when the risk is greater. Progress in both domains has stalled.
FIGURE 1. The stress-diathesis model of suicidal behaviora
a CBT=cognitive-behavioral therapy; BDNF=brain-derived neurotrophic factor; dACC=dorsal anterior cingulate cortex; DBT=dialectical behavioral therapy; dlPFC=dorsolateral prefrontal cortex; dmPFC=dorsomedial prefrontal cortex; DST=dexamethasone suppression test; GR=glucocorticoid receptor; HPA axis=hypothalamic-pituitary-adrenal axis; IFG=inferior frontal gyrus; mOFC=medial orbitofrontal cortex; MR=mineralocorticoid receptor; OFC=orbitofrontal cortex; rACC=rostral anterior cingulate cortex; rTMS=repetitive transcranial magnetic stimulation; SNRIs=serotonin-norepinephrine reuptake inhibitors; SSRIs=selective serotonin reuptake inhibitors; tDCS=transcranial direct current stimulation; TrkB=Tropomyosin-related kinase B; TSST=Trier Social Stress Test; vlPFC=ventrolateral prefrontal cortex; vmPFC=ventromedial prefrontal cortex.
Rehashing older approaches does not improve suicide risk assessment or prevention (9). While universal approaches like training primary care physicians to manage depression and means restriction work (10), for targeted prevention approaches we need to find new risk detection methods. The explosion of new information about the causes of suicidal behavior (11) needs to be built into a heuristic descriptive model that integrates potential predictors and prevention targets with a hypothetical explanatory model. A model for suicidal behavior must reconcile two major observations. First, suicidal behavior is found in many psychiatric disorders and not just in mood disorders and borderline personality disorder, where it is part of the diagnostic symptom list. Second, only a minority of psychiatric patients make suicide attempts, and the presence or absence of suicidal behavior is not simply determined by the presence of a psychiatric illness or the overall severity of illness (12–14).
Suicidal ideation is much more prevalent than suicidal behavior, and it often does not progress to suicidal behavior (15). Suicide prevention measures might prevent the transitioning from ideation to behavior if we understood the factors involved (13, 16). Suicidal behavior risk is moderated by a set of psychopathological and cognitive traits that are different from the psychopathology of associated psychiatric illnesses. We term the interaction of internal and external stressors with the traits that form a diathesis for suicide risk the stress-diathesis model of suicidal behavior (13, 14). In this model, we seek to integrate clinical and cognitive correlates of suicidal behavior with their neural circuitry and the biological basis of abnormalities in this circuitry to help explain the pathogenesis of the diathesis elements. We then link these elements to pharmacologic, psychotherapeutic, and brain modulatory approaches to suicide prevention (Figure 1).
Pathways to Suicidal Behavior: a Stress-Diathesis Model
The stress-diathesis model (13, 14) depicts suicidal behavior as a consequence of an interaction between acute stressors or proximal risk factors and a diathesis or distal factors (Figure 1). Stressors can be external, in the form of relationship or financial problems, or internal, such as a major depressive episode. The diathesis refers to a set of suicide-related traits that moderates the likelihood of suicidal behavior in response to stressors. The neurobiological correlates of these traits may be potential biomarkers for suicide risk, separate from biomarkers of co-occurring psychiatric disorders. Identified suicide-related, risk-moderating traits (Figure 1) include 1) excessive subjective distress when depressed and attentional bias toward negative stimuli; 2) altered decision making involving less delayed discounting and less executive control resulting in impulsive-aggressive tendencies and favoring acting on emotions; 3) an array of neuropsychological abnormalities, including learning difficulties, cognitive rigidity, and memory problems; and 4) social distortions (17–26).
1.
Subjective distress is linked to familial transmission of suicidal behavior and encompasses hopelessness and subjective depression, which are more severe in depressed suicide attempters compared with depressed nonattempters (27). Others use terms like psych-ache and emotional pain to refer to a similar phenomenon (28, 29). Joiner’s tripartite model of suicidal behavior (30) describes a tolerance to the pain involved in suicide, sometimes developed by prior nonfatal suicide attempts, that could encompass weighing the emotional pain being suffered against the anticipated pain of a suicide attempt. Other models of suicide, like the integrated motivational-volitional model (16), examine the threshold between ideation and action, also emphasizing the role of emotion and cognition.
2.
Decision making is multifaceted. Linked to suicidal behavior are impaired probabilistic learning assessed by monetary reward and punishments (31), risky decision tendency under uncertainty (32), and a bias for active responding when escaping an aversive state (33). Decision making differs in high-lethality suicide attempters relative to low-lethality attempters because the former are generally more deliberate and planned. High-lethality attempters have greater impairment of reward learning, hampering the search for alternative solutions (34), but they have less delayed discounting (i.e., they can suppress the desire for immediate satisfaction in favor of delayed reward) (35) and perform better on an object alternation task, indicating greater executive control and response organization (25). Impaired decision making (36) and related brain circuit changes (37) are also observed in healthy relatives of suicide decedents, consistent with familial transmission of an endophenotype for suicide risk.
3.
Suicide attempters exhibit less language fluency and learning (38) and impaired deterministic learning in the context of complex unambiguous environments (39). These learning deficits scale with attempt lethality and are partially explained by impaired cognitive control (34), the most consistent deficit found in suicide attempters (17, 22, 24). Memory deficits in suicide attempters include impaired working memory and long-term memory and a shift from specific to more general autobiographical memory (18, 23).
4.
Suicide risk is increased by cognitive distortions related to social reward and exclusion (40). A perceived lack of reciprocally caring relationships, also known as thwarted belongingness, may deter help-seeking (41), amplify sensitivity to social rejection (42), and impair social integration (43), and all enhance suicidal ideation and behavior.
Genetic and Epigenetic Causes of the Diathesis in the Stress-Diathesis Model
Human genetic studies have made three major observations: 1) heritability of fatal or nonfatal suicidal behavior and even ideation is moderate; 2) heritability of suicidal behavior is independent of major psychiatric syndromes; and 3) heritability of suicidal behavior is mediated by many gene variants of small effect (44–47). After candidate gene studies stalled because effects were too small and difficult to replicate, rapidly expanding sample sizes for genome-wide association studies (GWASs) have identified some suicide-specific candidate genes that also mostly remain to be replicated (48, 49). A recent review reported 40 genes associated with suicidal behavior, independently of psychiatric diagnoses (50). Combining GWASs with transcriptome data indicates that suicide-related genes are associated with inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, γ-aminobutyric acid (GABA) and glutamate neurotransmission, and neurogenesis (51–56). Severity of suicide attempts is associated with genes involved in anerobic energy production, circadian clock regulation, and tyrosine catabolism (57). Suicide risk may be mediated by genetic and epigenetic effects of stress response genes (58–61). Altered genome-wide DNA methylation reveals alteration at several genetic loci in the prefrontal cortex (PFC) and cerebellum, and more globally in the brain in suicide decedents compared with control subjects (62–64).
Neurobiological Correlates of Suicide Risk–Related Diathesis Traits
Genetic and epigenetic effects are mediated through biological effects that are currently being discovered (Figure 1). The four major suicide risk–moderating trait domains are linked to different combinations of neural circuitry and neurotransmitter system abnormalities. These, in turn, are the results of altered stress responses, trophic/apoptotic effects, and inflammation.
Neural Circuitry of Suicidal Behavior and Suicidal Ideation
Although neuroimaging studies of suicidal behavior and ideation disagree about details, the main features of dysfunctional neural circuitry (Figure 1) include 1) a relationship of enhanced negative affective and self-referential processing networks (ventromedial prefrontal cortex [vmPFC], medial orbitofrontal cortex [OFC], rostral anterior cingulate cortex [rACC], insula, and ventral striatum) to suicidal ideation (65) that may also underlie excessive subjective distress; 2) structural and functional deficits in the dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and dorsal anterior cingulate cortex (dACC) that correlate with severity of subjective depression (66) and contribute to less top-down control over vmPFC regions, resulting in impaired decision making and, in turn, suicidal behavior (67); 3) differential activation of the OFC to pleasant versus negative facial expressions, perhaps related to excessive distress and social distortions; 4) serotonergic release deficits in the ventral PFC and ACC that are more prominent in high-lethality suicidal behavior and suicide death; and 5) abnormalities of glutamate and opioid systems that may affect memory, learning, and reward mechanisms.
Structural Brain Findings.
Suicide decedents have smaller gray matter volume in the dlPFC (68) and hippocampus (69, 70), perhaps related to impaired decision making and learning/memory functions, respectively. Gray matter volume changes in nonfatal suicidal behavior are less consistently reported (14, 71, 72) and may be confined to subgroups of suicide attempters. Higher-lethality suicide attempters have larger PFC and insula volumes compared with lower-lethality attempters and nonattempters (73), potentially related to superior planning abilities. Violent attempters have greater caudate volume, and suicide attempters with familial suicidal behavior have smaller volumes in temporal regions, dlPFC, and putamen, compared with other subgroups of attempters (72). Adolescent suicidal behavior mostly involves smaller ventral PFC regions, particularly the OFC (74), which correlates with greater attempt lethality (75).
Diffusion tensor imaging (DTI) examines fractional anisotropy (FA) as an index of white matter integrity. In mood disorders, a prior suicide attempt is associated with lower FA in frontal-subcortical connections (76–79). Such findings may indicate impaired top-down executive control, explaining a correlation with attempt-related impulsivity (80) and number of suicide attempts (81, 82). DTI studies of suicidal ideation are inconclusive (77, 83, 84).
Functional Brain Activity and Connectivity.
Resting-state functional MRI (rs-fMRI) indicates lower functional connectivity in adolescent and adult suicide attempters, predominantly in the default mode network, which is implicated in self-referential processing and social cognition (85–87). This functional circuitry deficit maps onto the DTI-identified structural connectivity deficits in default mode network hubs (e.g., vmPFC) and connections (e.g., genu of corpus callosum) (80–82). Suicidal ideation relates to greater rs-fMRI activity in the vmPFC (88) and greater resting functional connectivity between the OFC and amygdala (89) and between the posterior cingulate cortex and middle temporal gyrus (90), perhaps related to negative self-reflection or rumination (91). However, other studies have reported lower rs-fMRI activity and functional connectivity (85, 86, 92, 93), probably due to use of different outcome measures of rs-fMRI activity, for example, regional homogeneity, fractional amplitude of low-frequency fluctuations among studies, and heterogeneity of suicidal ideation. Suicidal ideation–related increased frontal-subcortical connectivity may be confined to suicidal ideators who do not attempt suicide (94), because better executive control prevents acting on suicidal thoughts.
Task-based fMRI studies add the specificity of a task but also add variance as a result of the details of task implementation. Task-based fMRI studies are able to identify deficits in brain regions related to the suicide diathesis. Compared with suicide nonattempters, suicide attempters having the same diagnosis manifest less activity in the dlPFC, rACC, dACC, thalamus, and insula while performing decision-making tasks (e.g., the Iowa Gambling Task) (95–99). Lower activity in the dACC and dlPFC is also detected in attempters during tasks evaluating executive function (e.g., the go/no-go task) (100). Recall of suicide episodes (mental pain and suicide action) is associated with less activity in the dlPFC and dmPFC and greater activity in the parahippocampal gyrus and cuneus (101). Immersion and reappraisal of negative autobiographical memories are associated with greater OFC activity in suicide attempters (102). Suicide attempters have lower activity in the supramarginal gyrus and posterior insula during the cyberball task, an fMRI experiment evoking reaction to social exclusion (103), perhaps reflecting distorted social perception. Suicide attempters also have less OFC and rACC activity in response to positive facial expressions (78) and greater lateral OFC activity in response to angry facial expressions (95, 97, 104). This may underlie excessive subjective distress in suicide attempters and may also explain poorer help-seeking (41), susceptibility to bullying (105), and admonishment from parents or teachers (106), all of which are suicide risk factors.
Neurotransmitter Systems.
Deficient serotonin release as a potential suicide biomarker was discovered over 40 years ago (107). Low cerebrospinal fluid (CSF) serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) predicts suicide risk in depressed individuals, with an odds ratio of 4.6 (see reference 108 for a review). Deficient serotonin release is not due to serotonin biosynthesis, because suicide decedents have greater tryptophan hydroxylase 2 (the rate-limiting enzyme of serotonin synthesis) expression per neuron, and there are more brainstem serotonin neuron cell bodies (109, 110). The serotonin deficit likely involves less serotonin neuron firing and less release, because fatal and nonfatal suicide attempts are associated with up-regulated serotonin 1A autoreceptors that are located on serotonin neuron cell bodies and proximal dendrites (111, 112). Mouse studies show that greater expression of these autoreceptors produces a biological phenotype of less serotonin neuron firing and release and a behavioral phenotype manifesting giving-up behavior in the tail suspension test and the forced swim test (113). Other studies report up-regulated postsynaptic cortical serotonin 2A receptors that correlate with lifetime aggression severity (114). Less presynaptic serotonin transporter binding in major depression is seen throughout most of the PFC, but in suicide an additional deficit is confined to the ventral PFC and ACC, suggesting a role in decision making (115, 116). Serotonin dysfunction is more prominent in higher-lethality suicidal behavior (117), indicating localized PFC hypofunction (118). Greater raphe nucleus serotonin 1A receptor binding correlates with prior and future higher-lethality suicidal behavior (112, 119). Up-regulated serotonin 1A receptors may result from a 5-HT1A gene promoter polymorphism that causes overexpression of autoreceptors as a result of less binding of inhibitory transcription factors in serotonin neurons (120, 121). Childhood adversity may produce a phenocopy by epigenetic effects in the promotor and thereby mediate the effect on suicidal behavior risk via less serotonin release (108). Complex relationships also exist between the serotonin system and stress response. Childhood adversity may both up-regulate HPA stress responses (122) and reduce serotonin neuron firing (108) in parallel (123), the former amplifying neuroinflammation (124) and the latter dampening neurotrophic factors (125).
Less is known about the role of norepinephrine in suicide risk (reviewed in reference 126). Depressed suicide decedents have fewer brain-projecting noradrenergic neurons in the rostral locus coeruleus and higher β-adrenergic receptor binding in the PFC, both consistent with less noradrenergic activity. Moreover, depressed suicide attempters have lower urinary and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHGP), a major metabolite of norepinephrine, compared with control subjects, and CSF 3-methoxy-4-hydroxphenylglycol (MHPG) levels correlate negatively with lethality of future suicide attempts (127). Childhood adversity may sensitize norepinephrine release in response to a stressor in adulthood, as shown in rodents (128). Perhaps this excessive norepinephrine release, when combined with fewer noradrenergic neurons, is more likely to result in a depletion of norepinephrine and lower CSF MHPG in future suicide attempters (127).
Altered expression of glutamate receptor N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainite glutamate receptors is linked to suicidal behavior (129) and may play a role in the rapid-onset antidepressant and antisuicidal effects of ketamine (130–135). Enhanced glutamatergic NMDA-mediated transmission may improve memory consolidation (136) but in excess may be neurotoxic (137). Expression of some glutamatergic genes is greater in suicide decedents with a history of major depression (138).
The kappa opioid receptor system may play a role in negative affect associated with suicidal ideation and may explain the possible antisuicidal effects of the kappa antagonist buprenorphine (139, 140). Kappa receptor agonists induce anxiogenic and dysphoric effects in humans (141–143) and depressive-like behavior in animals (i.e., increased immobility in the forced swim test) (144, 145). Prodynorphin, the precursor to endogenous kappa opioid dynorphin, is elevated in the caudate nucleus in suicide decedents (146). Altered mu opioid receptor binding is also related to suicide risk (40, 147), perhaps via dysregulation of reward circuitry and social function (40).
Stress Response Systems
Response to stress involves a more immediate short-term noradrenergic system response and a more enduring HPA axis response. Feedback inhibition of resting cortisol level is through high-affinity mineralocorticoid receptors, and lower-affinity glucocorticoid receptors regulate stress-induced peaks of cortisol (123). Glucocorticoid receptors are subject to genetic effects via chaperone proteins like SKA1 and FKBP5 (58, 148, 149), as well as epigenetic changes (i.e., methylation) observed in response to maternal deprivation in rats (150) and in suicide decedents with a history of childhood adversity (60). Nonsuppression on the dexamethasone suppression test, which assesses this HPA axis glucocorticoid receptor feedback loop, predicts suicide (151–153), but there is disagreement about nonfatal attempts (154–158). Laboratory-induced psychosocial stressors, like the Trier Social Stress Test (TSST) (159), evaluate HPA axis response to social and environmental stressors (160). TSST studies find lower pretask baseline cortisol (161, 162) and blunted total cortisol output (162, 163) in suicide attempters compared with nonattempters, while heightened cortisol response to stress appears confined to suicide attempters exhibiting higher levels of impulsivity and aggression (164). Mixed results exist for the association between HPA axis abnormalities and suicidal ideation (163, 165–167). Some authors attribute these inconsistencies to the heterogeneity of patterns and severity of suicidal thoughts, such that fluctuating patterns of suicidal ideation are associated with greater cortisol response to stress compared with more stable and chronic ideation patterns (168).
Neurotrophic and Apoptotic Pathways
Brain-derived neurotrophic factor (BDNF) regulates neuron survival, plasticity, and synaptic function (169–174), plays an integral role in differentiation during development (175, 176), is affected by stress (177), and is associated with major depression and suicidal behavior (178). Expression of BDNF and BDNF receptor tyrosine kinase B genes is lower in suicide decedents (179–181), and plasma BDNF levels are low in suicide attempters (182), perhaps reflecting a systemic genomic effect on BDNF expression. The BDNF gene Met allele, a part of BDNF functional polymorphism (rs6265), increases the risk for suicidal behavior (183, 184), particularly in depressed individuals (185) and in those exposed to early-life stress (186, 187), where it may do so by loss of ACC volume (188) and altered decision-making or depression circuitry. BDNF promoter/exon IV, which plays a critical role in BDNF gene regulation (189), is hypermethylated in Wernicke’s area in suicide decedents (190). Infant maltreatment increases DNA methylation and reduces BDNF gene expression in the PFC (191). Further, epigenetic regulation of TrkB-T1 (an astrocyte-specific variant of the BDNF receptor) is reported in suicide decedents through promoter methylation affecting regulation by miRNA miR-185 (192, 193). Low brain BDNF in the hippocampus of suicide decedents (180) may underlie its smaller size in suicide decedents (69) and attempters (194) and fewer mature granule neurons in its dentate gyrus (70). This may partly explain learning and memory components of suicide diathesis. Moreover, the dentate gyrus plays a role in emotion regulation through its connection to the PFC—which also shows lower neuron density and serotonin receptor binding in suicide decedents (68). These suicide risk–related neuron deficits may also be attributed to toxic effects of the excessive allostatic load due to glucocorticoids and abnormal stress response (137). Elevated glucocorticoids may result in loss of astrocytes and glutamate transporters. This, in turn, leads to a pathological accumulation of glutamate, with subsequent loss of neuronal density (137).
Neuroinflammation
Peripheral inflammatory biomarkers linked to suicide risk include elevated C-reactive protein (CRP), neutrophil-to-lymphocyte ratio, proinflammatory interleukins (IL), cytokines that regulate the immune response (e.g., IL-1β and IL-6), tumor necrosis factor-α (TNF-α), tissue growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF) and low levels of the anti-inflammatory IL-2, IL-4, and interferon-γ (IFN-γ) in suicidal individuals (generally suicide attempters) (195–202). Elevated IL-6 correlates positively with suicide attempters’ impulsivity (203), thereby linking proinflammatory responses to an impulsive, reactive endophenotype for suicidal behavior. IL-1β negatively correlates, whereas IL-2 positively correlates, with OFC activation during experimental social exclusion (204), a known trigger of suicidal ideation and behavior. Quinolinic and kynurenic acids (which serve as an agonist and an antagonist of the excitotoxic glutamate receptors, respectively) are related to suicidal behavior (205–207). Activated microglia (208, 209), the primary immune response cells in the brain, and brain translocator protein (TSPO) found in mitochondria of activated glial cells (210) are linked to suicide risk, independently of the presence of psychiatric disorders. Chronic inflammatory processes associated with latent Toxoplasma gondii (T. gondii) infection may increase suicide risk (211, 212), perhaps through amplification of impulsive aggressive traits (213), or accumulation of T. gondii in the amygdala (214), which is involved in emotional and physiological responses to stress.
Greater suicidal ideation severity is associated with higher CRP (197), IL-6, and IL-10 levels (215) and with activated microglia-related alterations of the tryptophan-kynurenine pathway (216). This suggests that regulation of inflammatory pathways may change with level of suicidal ideation and therefore risk (208). However, a recent study reports no association between suicidal ideation severity and cytokine pathway marker mRNA expression (217), and longitudinal studies are needed to determine whether fluctuating suicide risk correlates with severity of inflammation.
Stress-Diathesis-Model-Informed Suicide Prevention
Approaches targeting different components of the stress-diathesis model can help suicide prevention and treatment efforts. Targets for suicide prevention may be found in the domain of the stressors or in the processing and response to the stressors that involve the diathesis component (Figure 1), and include the perception of the stressor, the formulation of the response, and the actual response. The treatment or prevention target may be described in clinical or cognitive terms or in neurobiological or circuitry terms (Figure 1).
Stressors and Prevention
The amelioration of external stressors may be the goal of interventions by mental health professionals and social workers seeking to improve personal, family, and workplace relationships and to improve housing, nutrition, and employment status, but these approaches have not been shown to prospectively influence risk of suicidal behavior (10). Targeting internal stressors by training primary care providers in the management of major depressive episodes prevents suicide (6). Major depressive episodes account for about 60% of psychiatric diagnoses in suicide decedents (218), and major depressive episodes are mostly untreated at the time of death (219).
Diathesis and Prevention
Pharmacotherapy.
Antidepressants generally act on serotonergic and noradrenergic systems (220) and may help prevent suicide by effects on both the internal stressors of depression and anxiety and the diathesis by reducing hopelessness, reducing propensity for impulsive behavior in response to aggressive or suicidal urges and enhancing cognition. Lithium (221, 222) and clozapine (223, 224) have effects on the internal stressors of depression and acute psychosis. Because both medications reduce the risk of suicidal behavior independently of how effective they are for mood and psychosis (225), this indicates potential effects via the diathesis. The specific mechanisms of their antisuicidal diathesis effects are unknown and are not readily discoverable because lithium and clozapine have many different pharmacologic effects. Antiapoptotic effects of lithium (226) may increase gray matter volume in the dlPFC, where hypoactivity and cortical thinning are implicated in suicide risk. Clozapine blocks dopamine 2 and serotonin 2A receptors, potentially mediating antiaggressive and anti-impulsive properties (227).
Intravenous ketamine is a rapidly acting treatment that robustly reduces depressive symptoms and suicidal ideation in hours instead of weeks (130–133). Intranasal ketamine (or esketamine) also shows promise as anti–suicidal ideation treatment (134) and is less invasive, but its absorption is more erratic, and, like intravenous ketamine, it must be administered in medical settings. The anti–suicidal ideation effect of ketamine is only partly explained by its antidepressant action, and effects on memory and cognition may also play a role (131–133). The relative importance of ketamine diverting glutamatergic transmission to AMPA from NMDA glutamate receptors, opioid system activation (228), alteration of BDNF release (229), or up-regulation of insulin-like growth factor 2 in the hippocampus (230) in its lowering suicidal ideation is unknown. Ketamine has never been tested in terms of preventing suicidal behavior.
Psychotherapy.
Most studied are cognitive-behavioral therapy (CBT) and dialectical behavior therapy, and both can prevent suicide attempts (231, 232). CBT improves capacities for cognitive regulation of emotion and is associated with decreased activity in the amygdala-associated negative emotional reactivity (233) and enhanced activity of the emotion regulation network, including the subgenual ACC, medial PFC, and lingual gyrus (234). Dialectical behavior therapy prevents suicidal behavior without proven antidepressant benefit, indicating that it works via problem-solving and stress management or elements of the diathesis such as dampening amygdala reactivity to negative emotions (235).
Brief Interventions and Active Postdischarge Outreach in the Emergency Department or From Inpatient Units
After seeking help for suicidal thoughts or low-lethality suicide attempts in the emergency department, discharged patients have an elevated suicide attempt rate. The suicide death rate is 300 times higher in the first week and 200 times higher in the first month among patients discharged from inpatient psychiatric care compared with the general population (236). Suicide prediction models based on computational analyses of electronic health records may help identify individuals with the highest risk for suicide at time of discharge, the subgroup that would potentially benefit most from intensive treatment and follow-up (237, 238). A number of brief psychological and educational interventions are now available for use with individuals presenting to the emergency department with acute suicidal crisis (239). These brief interventions are inexpensive, easy to implement, and require limited staff resources. They seek to project a helpful option to a patient who gets into a crisis and overcome the social cognitive distortion that the social network is more hostile than helpful. Active outreach after discharge seeks the same goal, and both have been shown to reduce the postdischarge risk of suicidal behavior (7, 240–242).
Restriction of Lethal Means
Means restriction works because it seeks to make access to the most popular higher-lethality methods more difficult. It takes advantage of two key observations. The acute risk of acting on suicidal thoughts is brief, and the flexibility of the suicidal person in changing from one method to another is surprisingly limited. Studies of survivors of suicide attempts indicate that most suicide attempts are the result of a decision to act that was made minutes earlier, even if the method was planned months or more ahead (243, 244). Switching methods is known to be difficult because restricting access to a common method—such as household coal gas in the United Kingdom (245–247) and firearms in Switzerland (248)—was followed by large reductions in suicide rates, mainly due to those methods, and very little method substitution even over several years. Forcing individuals to use a less lethal method may work because over 80% of suicide attempt survivors do not end up dying by suicide (249). So even after the combination of stress and diathesis leads to a suicide attempt, there are still interventions that can help.
The Future of Research and Suicide Prevention
Suicide as a Distinct Mental Disorder
Suicide is moderately heritable independently of the heritability of major psychiatric disorders (45, 46). This suicide-specific heritability is associated with suicide diathesis–related traits (36, 250). Further, the body of observations linking the suicide-related diathesis components to neurobiological abnormalities as described above supports the idea that suicidal behavior is not merely a symptom of a subset of psychiatric disorders, but should be coded as a distinct mental disorder (251). As a distinct diagnosis, it will be coded more consistently in medical records, raising clinician awareness of risk in individual patients, enhancing suicide research, and motivating the targeting of the suicide-related diathesis for prevention and treatment in suicidal patients.
Real-Time Monitoring of Acute Suicidal Crisis
While many of the distal or trait risk and protective factors for suicide and their underlying biological processes are extensively studied, we know little of the very short-term risk factors. Recent technological advances have begun to elucidate factors associated with acute suicidal processes that were difficult to observe by conventional assessment measures. Suicidal ideation, which usually precedes and may represent an alarm for imminent risk of a suicide attempt, goes unrecognized by even systematic periodic evaluation of outpatients. Around 60% of individuals denying suicidal ideation on weekly self-report measures reported suicidal thoughts using an ecological momentary assessment (EMA) technology that delivered questions on their smartphones six times a day over the same 1-week period (252). EMA also identifies a subgroup of suicidal individuals who report a more highly variable severity pattern of suicidal thoughts and spikes of suicidal thoughts when stressed (253). This pattern of suicidal ideation variability is associated with mood instability (254, 255) and a heightened stress response system (168), and it is a stable trait because it persists for 2 years (256). The suicidal behavior in this reactive group is just as lethal as in patients with stable but pronounced suicidal ideation (257). Different patterns of suicidal ideation suggest that a more nuanced approach to risk detection and prevention is needed (258) because otherwise suicidal ideation has modest sensitivity and low predictive value for suicide (259).
Combining EMA-collected real-time data on suicidal thoughts and behavior with “passive sensing,” which collects data from individuals’ smartphones, allows examination of the very short-term risk factors of suicide in multiple domains: emotional distress (via acoustic voice, sentiment in communicative language [e.g., via social media, text messaging], facial expression [in selfies], and music choice), and social dysfunction (self and social content in communications and language, patterns of online communication [frequency and diversity of online contacts], and geographic movement) (260). The wide availability of smartphones allows accumulation of massive amounts of such personal-level data that may lead to identification of a “phonotype” (261) or “screenotype” (262). These approaches have promise, but they lack replicated data on prediction of suicidal behavior risk (263). If successful, they may permit calibration of suicide prevention to fluctuating levels of risk, but much work remains to be done before this becomes a reality. In addition, smartphones have introduced self-guided digital interventions as novel suicide prevention methods that may prove as effective as face-to-face interventions (264).
Implicit Cognitions and Neuroimaging for Suicide Risk Detection
Future suicide decedents may deny suicidal thoughts as inpatients (265), and more so in initial evaluations and emergency department settings, when patients and clinicians are less known to each other (266). This may be done intentionally to thwart any intervention to prevent suicide, or because the person does not perceive a need for care (267). Others may be unconsciously using the defense mechanism of denial regarding suicidal impulses (268). The death/suicide implicit association test (IAT) has been proposed in such situations. The IAT predicts suicidal behavior in some prospective studies (269, 270), but not others (271). Neural decoding is an approach where machine-learning methods have been used to identify the neural activity pattern involved in the mental representation of a deceased loved one and to track unconscious deceased-related thinking (272). fMRI-measured neural representation of mental concept representations differentiates suicidal ideators from suicide attempters and healthy control subjects (273). The identification of a neural signature of suicidal ideation could be a biomarker for suicide risk even when suicidal ideation is denied or unrecognized.
Medication and Neuromodulation
Buprenorphine, a mu opioid receptor partial agonist (274–276) and a kappa opioid receptor antagonist (277), is used for relapse prevention in opioid use disorder (278). Buprenorphine has antidepressant effects when used for both opioid use disorder and treatment-resistant depression (279–284) and may also reduce suicidal ideation (139, 140, 283, 285, 286). Compared with placebo, low-dose buprenorphine reduces suicidal ideation in 2 weeks in individuals who have never used opioids (140), probably through modulating emotional pain/psych-ache. Few case reports demonstrate similar effect in individuals with opioid use disorder using higher dosages (139, 285, 286). By addressing both opioid relapse and comorbid depression and suicidality, buprenorphine should be further evaluated in reducing suicide risk via opioid overdose, which has been spiking in the United States over the past two decades.
Neuroimaging-delineated brain regions and networks involved in suicide risk represent plausible targets for neuromodulatory interventions. Some researchers report a decrease of suicidal ideation following treatment with repetitive transcranial magnetic stimulation (rTMS) (287), but results are preliminary because most studies have small sample sizes and lack control groups. Inhibition of the dlPFC by low-frequency rTMS can increase risky decision making in males (288), suggesting that enhancing dlPFC activity may reduce suicide risk by improved top-down cognitive control. Transcranial direct current stimulation (tDCS) is another promising, low-risk, noninvasive neuromodulation technique that has effects on inhibitory control, planning, delay discounting, and risk taking in healthy individuals (289–291). It remains to be seen whether tDCS applied to the PFC can modulate impulsivity and suicide risk (292).
The role of inflammation in the pathogenesis of depression and suicidal behavior suggests use of anti-inflammatory drugs for depressive symptoms and suicidal ideation. None have been shown to improve suicidal ideation, but minocycline decreases microglial activation in the PFC and depressive and anxiety-like traits in animals (293) and may reduce depressive symptoms (294). Celecoxib, a selective inhibitor of the cyclo-oxygenase 2 enzyme, may be effective as an add-on treatment for unipolar depression (295). Glycogen synthase kinase-3 (GSK3), an enzyme that promotes inflammation, is linked to animal stress and aggression models, is elevated in the ventral PFC of depressed suicide decedents, and is inhibited by lithium (296).
No drugs targeting HPA axis dysregulation have been evaluated for suicide prevention. The glucocorticoid receptor antagonist mifepristone (297) and cortisol synthesis inhibitors such as metyrapone and ketoconazole (298) do not show distinct benefit for depression but may warrant testing in suicidal individuals with glucocorticoid hypofunction.
Conclusions
New suicide prevention targets may be identified in seeking clinical and cognitive correlates of suicidal behavior and by an understanding of the altered brain circuitry and pathogenesis underlying the stress-diathesis model of suicidal behavior. The goal is to enhance identification of high-risk patients and to determine when their risk spikes in order to focus prevention on those patients at those times. A biological approach offers biomarkers to guide a personalized medical approach to prevention of suicide, a way to track fluctuating risk, and a way to track treatment effects. Such biomarkers assume greater importance if they can detect risk when very suicidal patients choose to withhold information of a plan and intent to suicide in order to avoid being thwarted.
Acknowledgments
Dr. Rizk is supported by the Paul Janssen Postdoctoral Fellowship in Translational Neuroscience from Columbia University and a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation.
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Accepted: 14 August 2020
Published online: 1 October 2020
Published in print: October 01, 2020
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Supported by NIMH grant P50MH090964 (principal investigator, Dr. Mann).Dr. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale from the Research Foundation for Mental Hygiene. Dr. Rizk reports no financial relationships with commercial interests.
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