Due to the heterogeneity in molecular pathways and clinical presentations associated with suicide, an endophenotypic approach may be beneficial for identifying treatment targets. An endophenotype represents an intermediary step from genes-to-clinical phenotype, which can simplify intermediate players in multifactorial disorders and identify mediators/moderators underpinning complex clinical presentations (Gottesman and Gould 2003). Several proposed suicide-salient endophenotypes, using criteria set forward by Gottesman and Gould (2003), include impulsive and aggressive traits, early onset of major depression, neurocognitive dysfunction (including executive functioning and impaired decision-making), and cortisol response to psychosocial stress (Mann et al. 2009; Courtet et al. 2011). Other proposed candidate endophenotypes for suicidal behavior with relatively less research evidence are dysfunctional serotonergic neurotransmission, second-messenger systems aberrations, and traits consistent with borderline personality disorder, including affective dysregulation and difficulties in interpersonal relationships. Each of these constructs could be used to identify treatment targets for experimental therapeutics for suicidal behavior, with allopurinol as a case example discussed in the following section.

The purinergic system has been implicated in the impulsive and aggressive behavior associated with mania (Machado-Vieira 2012) and has therefore been targeted in drug development. Purinergic metabolism is involved in the regulation of neurotransmitters (ATP and adenosine) and affects sleep, motor activity, appetite, cognition, and social interaction (Machado-Vieira 2012). An adenosine antagonist, caffeine is also a GABA receptor antagonist and phosphodiesterase inhibitor; excessive consumption is associated with irritability, anxiety, tachycardia, and increased blood pressure (presumably via its effects on GABA). In contrast, increased caffeine consumption has been linked with a lower risk of death by suicide (Lucas et al. 2014). The end product of purinergic metabolism is uric acid, which has been positively associated with increased drive/motivation, disinhibition, hyperthymia, and irritable temperament (Lorenzi et al. 2010). As a syndrome model, Lesch-Nyhan Disease is a congenital disorder associated with the overproduction of uric acid associated with increased de novo purine synthesis and deficient salvage of purine bases. Among the characteristics associated with this disorder is intense self-injurious behavior, including self-biting and self-hitting (Torres et al. 2012). Therefore, the purinergic system may be a potential target for suicidal/self-injurious behaviors and a model for the study of impulsivity.

Allopurinol is a xanthine oxidase inhibitor, which decreases production of uric acid, superoxide, and hydrogen peroxide and is widely used as a treatment for gout. Because of its role in the purinergic system, it has been proposed as a possible treatment for acute mania. In a randomized placebo-controlled trial of 180 bipolar I patients in a current manic episode, adjunctive allopurinol to lithium was associated with greater Young Mania Rating Scale (YMRS) (Young et al. 1978) score reductions when compared to adjunctive dipyridamole, another agent that regulates purine metabolism, plus lithium, or lithium plus placebo (Machado-Vieira et al. 2008). Similar results were found in a randomized clinical trial of lithium, haloperidol, and allopurinol compared to lithium, haloperidol, and placebo (Akhondzadeh et al. 2006). While the relationship of allopurinol to suicidal behavior has yet to be evaluated, it has a theoretical therapeutic role for patients with high impulsivity and aggression.

The recent interest in glutamatergic pathways in depression has been led by promising results with subanesthetic doses of the non-competitive N-methyl-D-aspartate receptor antagonist ketamine. Originally used clinically as a dissociative anesthetic and analgesic, recent research on ketamine’s rapid and potent antidepressant properties has opened promising avenues for future development of treatments for acutely suicidal patients (Zarate et al. 2006, 2013b; Murrough et al. 2013). After initial reports as an antidepressant, an open-label single subanesthetic infusion of ketamine (0.5 mg/kg given intravenously over 40 min) in 33 major depressive disorder (MDD) patients decreased suicidal ideation (as assessed by the decreased mean SSI) immediately following infusion, which continued over the next 4 h. Suicide items from the MADRS, Hamilton Depression Rating Scale (HDRS) (Hamilton 1960), and Beck Depression Inventory (BDI) (Beck and Beamesderfer 1974), as well as indicators of anxiety and hopelessness also significantly decreased over the same time period (DiazGranados et al. 2010). Analogous reductions in suicidal ideation were further demonstrated in a double-blind, placebo-controlled study of the glutamatergic modulator riluzole or placebo following a single open-label ketamine infusion in treatment-resistant unipolar depression (Ibrahim et al. 2012). Similarly, in a double-blind, randomized, crossover study of 15 participants with bipolar I or II depression, suicidal ideation (assessed by the MADRS) significantly improved within 40 min after a single infusion of ketamine (Zarate et al. 2006). A comparable decrease in suicidal ideation was demonstrated 24 h after ketamine infusion in 25 participants with treatment-resistant depression (Price et al. 2009), a finding which has been replicated in a trial of ketamine compared to midazolam (Price et al. 2014). A subset of the participants (n = 9) received multiple infusions over 12 days, and the antisuicidal effects were maintained. Similar results have been found in a study involving patients in India with treatment-resistant depression (Thakurta et al. 2012). When collapsing across multiple ketamine clinical trials, the effect of ketamine on suicidal ideation is independent of its effect on depression and anxiety (Ballard et al. In Press).