An Overview of the Neurobiology of Suicidal Behaviors As One Meta-System
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Molecular Psychiatry (2015) 20, 56–71 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp EXPERT REVIEW An overview of the neurobiology of suicidal behaviors as one meta-system M Sokolowski1, J Wasserman1 and D Wasserman1,2 Suicidal behaviors (SB) may be regarded as the outmost consequence of mental illnesses, or as a distinct entity per se. Regardless, the consequences of SB are very large to both society and affected individuals. The path leading to SB is clearly a complex one involving interactions between the subject’s biology and environmental influences throughout life. With the aim to generate a representative and diversified overview of the different neurobiological components hypothesized or shown implicated across the entire SB field up to date by any approach, we selected and compiled a list of 212 gene symbols from the literature. An increasing number of novel gene (products) have been introduced as candidates, with half being implicated in SB in only the last 4 years. These candidates represent different neurosystems and functions and might therefore be regarded as competing or redundant explanations. We then adopted a unifying approach by treating them all as parts of the same meta-system, using bioinformatic tools. We present a network of all components connected by physical protein–protein interactions (the SB interactome). We proceeded by exploring the differences between the highly connected core (~30% of the candidate genes) and its peripheral parts, observing more functional homogeneity at the core, with multiple signal transduction pathways and actin- interacting proteins connecting a subset of receptors in nerve cell compartments as well as development/morphology phenotypes and the stress-sensitive synaptic plasticity processes of long term potentiation/depression. We suggest that SB neurobiology might also be viewed as one meta-system and perhaps be explained as intrinsic unbalances acting within the core or as imbalances arising between core and specific peripheral components. Molecular Psychiatry (2015) 20, 56–71; doi:10.1038/mp.2014.101; published online 2 September 2014 Suicide is the act of dying by one’s own efforts. Suicides may often necessary precondition for SB, as seemingly healthy subjects can be preceded by non-letal suicidal events, that is, suicide attempts engage in SB. As an alternative, SB can also be characterized by (SA), representing an important clinical predictor of increased certain transdiagnostic properties not restricted to any one diagnosis, suicide risk.1–3 A previous SA performed with high intent to die but being present among many of them.10 Poor impulse control (for example, by using a violent method) or resulting in a high (usually coupled with anger/aggresssion)11,12 and certain types of – lethality is also an important sign of the suicide propensity.4,5 The comorbid anxiety and depression appear important overall.13 15 In focus here is on completed suicides and serious SA, termed parallel, there is an increasing focus on certain endophenotypes, suicidal behaviors (SB). Studies focusing on suicide ideation as which prevail relating to stress regulation and neurocognitive outcomes are not primarily covered here, although ideation and changes.14,16,17 Recent studies, for example, confirm certain cognitive desire for death are in turn a major risk factor for SB.6 deficits in decision making, category verbal fluency and the Stroop One can however delineate SB further by using different risk interference test (for example, altered working memory and factors and assessments, which unravels both a substantial hetero- attention),18 in addition to reduced impulse control.19 One may also geneity as well as certain common denominators. These aspects delineate SB by biochemical11,20 or genetic21 correlates as summar- have been fully reviewed elsewhere and are only briefly mentioned ized herein. The integrative study of those correlates with various here.3,5,7,8 Different risk factors have been observed, for example, to endophenotypic delineations of SB appears as a particularly be a male, living alone, exposure to stressful life events/trauma, to promising way forward,14,16 forexample,inthecontextofaneuro- own a handgun or being under chronic pain, while protective factors genetic approach.22 The stress-diathesis model initially introduced for can be, for example, religiousness, spirituality, healthy lifestyles and SB by Mann and Arango23 has also evolved into a developmental social support. It has since long also been known that mental framework of neurogenetic interactions with lifetime stress 24–27 illnesses, for example, as assessed by psychiatric diagnoses, have a exposures. majorroleroleinSB;9 the risk of suicide appears to be elevated in particular among persons with mood disorders, schizophrenia and alcohol/substance use disorders, often during a state of clinical HERITABILITY OF SB worsening of symptoms.3 However, psychiatric disorders are not a A family history of SB is a major risk factor. Indeed, SB aggregates sufficient explanation, as the majority of psychiatrically ill do not in families and involves a substantial genetic component.28,29 A engage in SB. Furthermore, psychiatric disorders are not always a heritability has been observed in the range of 30–55%. This 1National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute (KI), Stockholm, Sweden and 2WHO Collaborating Centre for Research, Methods Development and Training in Suicide Prevention, Stockholm, Sweden. Correspondence: Dr M Sokolowski, National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP), Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail: [email protected] Received 14 March 2014; revised 19 June 2014; accepted 22 July 2014; published online 2 September 2014 The neurosystem of suicidal behaviors M Sokolowski et al 57 heritability is however a completely relative and fluent measure, to the increasing sets of candidate genes of psychiatric depending on, for example, the environmental risk burden.30,31 disorders.52–56 The aim here was to explore further the proposition Regardless, it is clear from a qualitative standpoint that the of thinking about SB neurobiology (as approximated by Table 1) genetic diathesis can often have a probabilistic influence on SB, by using a polygenetic ‘meta-’system perspective, with the help of which has led to a hunt for the genes that may be involved. bioinformatic tools. In the biochemical paradigm, all biological functions mediated by proteins (for example, metabolic, structural, regulatory) depend on the physical binding between molecules.57 THE SB GENOME-CANDIDATE GENES Physical PPIs may thus be regarded as a stable generic The gene (products) and neurosystems most frequently studied ‘endophenotype’ or ‘trait’ of any protein. Proteins that interact in have been reviewed in detail elsewhere and represent a highly larger groups may represent the mediating of different functions recommended reading list.7,24,25,32–38 With the aim to generate a by, for example, larger complexes, chain reactions or signal representative and diversified overview of the different neurobio- propagation, involving molecular, cellular or even systemic levels. logical components hypothesized and/or shown implicated across Therefore, certain PPI networks might even depict a simultaneous the entire SB field up to date by any approach, we selected and transversal of the four scenarios recently suggested to be of compiled a list of 212 gene symbols (Table 1). The evidence base interest in psychiatric disorders (that is, the ‘biochemical, cellular, for each gene (product) was not a primary selection criterion, neural network and brain circuit’ levels).58 A PPI network may thus albeit it was used if selecting a subset from many more genes show both vertical (within one level/pathway/neurosystem) and hypothesized or implicated in the one and same neurosystem/ horizontal (between levels/pathways/neurosystems) integration, pathway (aiming at, for example, maximum 5–10 receptor the latter being similar in spirit to functional gene ‘groups’.59 subtypes and transporters from each). We excluded all studies Interestingly, networks of PPIs have been used to identify new, that had not used SB as an outcome. The starting point was the common biology among genes of several complex disorders.60,61 previous review articles.7,24,25,32–38 As ambiguous names of PPI contacts are themselves also important targets for drug proteins cannot be used in, for example, the protein–protein development.62 interaction (PPI) or enrichment analyses performed here, we also We therefore submitted all genes in Table 1 to the online translated all biological findings into official Human Genome Disease Association Protein-Protein Link Evaluator (DAPPLE),60 to Organisation gene symbols. We used PubMed to gain more investigate the PPIs among the genes in Table 1. Figure 2 (upper) insight about all studies up to date for each such gene (product), depicts the large PPI network of proteins encoded by the SB by combining with the ‘suicid*’ search item as well as by browsing candidate genes, as well as other common interacting proteins for novel articles, which had cited older articles on this topic. among them (the ‘indirect’ interactions of the first degree, that is, Because of space concerns, we often did not cite all the their nearest neighbors), with 1793 genes in total. We can call this publications found about each gene (product), providing