The Neurobiological Basis of Suicide PDF

Preface

The act of suicide has been defined as a "fatal self-inflicted destructive act with explicit or inferred intent to die" (Institute of Medicine of the National Academies, 2002). Suicide is a major public health concern not only in the United States but throughout the world. According to World Health Organization studies, approximately 2% of people commit suicide worldwide every year. Recent data released in 2011 from the Centers for Disease Control and Prevention state that suicide is the 10th leading cause of death in the United States. When accounting for all age groups, 36,035 people committed suicide in 2008. When different age groups were factored, suicide was the second leading cause of death among those aged 25 to 34 years and the third leading cause of death among those aged 10–24 years. Although approximately 90% of suicides are associated with mental disorders, several studies suggest that suicidal behavior has distinct psychiatric phenotypes and that suicidal patients have a certain predisposition that is different from other psychiatric illnesses. This is based on the argument that 10% of people who commit suicide do not have any diagnosed psychiatric illness and that 95% of people who have some form of psychiatric illness do not commit suicide. Moreover, the therapeutic approaches and their outcomes appear to be different between suicidal patients and patients with associated mental disorders. Psychological, psychosocial, and cultural factors are important in determining the risk factors for suicide; however, they offer weak prediction and can be of less clinical use. Also, the clinical history of a patient provides low specificity in predicting suicide. Interestingly, cognitive characteristics are different among depressed suicidal and depressed nonsuicidal subjects, and could be involved in the development of suicidal behavior. Thus, characterizing neurobiological basis will be key in delineating the risk factors associated with suicide. In recent years, research has been initiated to develop the neurobiological basis of suicide. This book aims to focus on the recent neurobiological findings associated with suicide.

Suicide is not predictable in the individual and results from a complex series of factors that may differ across individuals; yet 30%–70% of suicides occur in patients who are receiving some treatment. Learning more about the interacting biological, clinical, and situational factors that lead to suicide can help the clinician to recognize risk factors and initiate clinical interventions to reduce suicide risk. In Chapter 1, Fawcett describes diagnosis, traits, states, and co-morbidity in suicide.

Because of its key role in aggression and impulsivity, the role of the serotonergic system in suicidal behavior has been the focus of attention for a long time. Several clinical and postmortem brain studies have consistently shown that an abnormal serotonergic system is critical in the development of suicidal behavior. In Chapter 2, Bach and Arango discuss the neuroanatomical basis of serotonergic abnormalities that are specific to suicide. This is consistent with a homeostatic brain response, in both source 5-hydroxytryptamine synthesizing neurons in the raphe nuclei and in postsynaptic target neurons in the cortex, to deficits in serotonergic neurotransmission.

In addition to the serotonergic system, evidence indicates a dysfunctional central noradrenergic system in suicide and suggests that deficits in noradrenergic signaling may contribute to suicide. In Chapter 3, Chandley and Ordway review the neurobiological features and functional output of the brain noradrenergic system in relation to the potential involvement of the noradrenergic system in suicide.

Although γ-aminobutyric acid (GABA) was previously implicated in depression and suicidal behavior, there has not been much research on this aspect. In recent years, interest has renewed regarding the role of GABA in suicide. In Chapter 4, Anisman and colleagues review how GABA is involved in depressive behavior and provide evidence that, in depressive illness, it works in collaboration with serotonin, and corticotropinreleasing hormone and that these actions are moderated by neurosteroids. They further discuss that the coordination in the appearance of the subunits that comprise GABAA receptors may be fundamental in the timing and synchronization of neuronal activity and might, thus, influence depressive illness.

The brain endocannabinoid (eCB) system modulates several neurobiological processes, and its dysfunction is suggested to be involved in the pathophysiological characteristics of mood and drug use disorders. CB1 receptor–mediated signaling, in particular, has played a critical role in the neural circuitry that mediates mood, motivation, and emotional behaviors. The association of the eCB system with alcohol addiction and the existence of a high incidence rate of suicide in cannabis and alcohol abusers indicate that dysfunction of the eCB system might be one of the contributing factors for suicidal behavior. In Chapter 5, by using preclinical and clinical evidence, Vinod describes in detail how the eCB system may be involved in suicidal behavior.

Stress is one of the major risk factors in suicide. In Chapter 6, by using the stressdiathesis model, van Heeringen reviews how stress can play a role in suicidal behavior. He also discusses the advantages of using stress-diathesis models for treating and preventing suicide risk. In Chapter 7, on a related issue, Coryell discusses the association of hypothalamic–pituitary–adrenal axis hyperactivity and a low serum cholesterol level to a heightened risk for suicide and provides evidence showing that serum cholesterol concentrations and dexamethasone suppression test results are clinically useful tools for the assessment of risks in suicide.

An emerging hypothesis suggests that the pathogenesis of suicidal behavior and depression involves altered neural plasticity, resulting in the inability of the brain to make appropriate adaptive responses to environmental stimuli. Furthermore, stress, a major factor in suicide, hinders performance on hippocampal-dependent memory tasks and impairs induction of hippocampal long-term potentiation. The brainderived neurotrophic factor plays a critical role in regulating structural, synaptic, and morphological plasticity and in modulating the strength and number of synaptic connections and neurotransmission. In Chapter 8, Dwivedi provides a detailed account of how a brain-derived neurotrophic factor and its cognate receptors may be involved in the development of suicidal behavior.

Neuroimaging methods provide a great opportunity to improve our understanding of the pathway between adverse environmental conditions and suicide. Because neuroimaging is completed in vivo, it is tailored to investigate the intermediary links between neuropathological characteristics and the symptoms or traits associated with suicide.

Such symptoms and traits may be measured at brain scanning. In Chapter 9, Meyer describes neuroimaging studies of 5-HT2A receptors, serotonin transporters, monoamine oxidase A, dopamine D2 receptor binding, and μ-opioid receptors in suicide. He also discusses how environmental conditions lead to alterations in brain neurochemistry that can increase the risk for suicide with neuroimaging studies of monoamine oxidase A in the early postpartum period.

The etiology of suicide has been considered to be a complex combination of genetic and environmental components. Studies have increasingly shown that gene–environment interactions are crucial in the development of suicidal behavior. Approximately 30%–40% of the variance in suicidal behavior is related to genetic risk factors. Given the importance of genetics and gene–environment interactions, several chapters discuss this issue. In Chapter 10, Roy elaborates on this aspect in much greater detail. In this chapter, he describes the importance of both the environment and genes in suicidal behavior and reviews clinical studies of gene–environment interactions in relation to suicide attempts. In Chapter 11, using a similar approach, Zai and colleagues discuss genetic findings in suicidal behavior in greater detail. They discuss the twin, family, and adoption studies that establish a genetic basis for suicidal behavior. They review the results from studies of candidate genes in the neurotransmitter systems, neurotrophin pathways, and hypothalamic–pituitary–adrenal axis. They further discuss recent developments in whole genome association studies, epigenetics, and gene–environment interactions.

To expand its focus, suicide research has moved toward high-throughput gene expression microarrays in an effort to identify novel biological pathways and molecular mechanisms associated with suicide. By analyzing tissues obtained from suicide completers and examining the expression of many genes in parallel, these technologies allow researchers to obtain a functional profile of gene expression, thus providing valuable insight into the overall biological processes underlying suicide. In Chapter 12, Fiori and Turecki discuss the methods that have been used to profile gene expression alterations and examine several of the neurobiological mechanisms implicated in suicide. They also discuss the future uses of gene expression profiling technologies in suicide research.

Gene expression is highly regulated through an epigenetic mechanism. Epigenetic changes regulate gene function via alternative mechanisms to the coding DNA sequence. Until recently, it was believed that only physical and chemical environmental factors altered epigenetic markings; more recently, studies have indicated that the social environment can also induce epigenetic changes. Suicide is frequently associated with a history of early-life adversity, and recent studies have suggested that epigenetic changes are present in specific areas of the brain from individuals who died by suicide. In Chapter 13, Labonté and Turecki discuss this aspect and review the growing body of literature examining epigenetic alterations associated with early-life environment and suicide.

The neurobiological characteristics of suicide in adolescents may be different than in adults because adolescent suicide is more associated with impulsive and aggressive behavior. Suicide in adolescents has been studied much less than in adults. Three chapters are devoted to adolescent suicide. In Chapter 14, Zalsman provides a detailed account of various aspects of adolescent suicide, including peripheral blood and postmortem brain studies; however, the main focus of this chapter is the genetics and gene–environment interaction studies linked to adolescent suicidality. In another chapter (Chapter 15) devoted to adolescent suicide, Pandey and Dwivedi discuss the findings of postmortem brain studies, with emphasis on neurotransmitter receptors, cellular signaling, and neurotrophins. With a similar theme, in Chapter 16, Nanayakkara and colleagues discuss suicidal behavior in the pediatric population, assessing risk among pediatric patients with bipolar disorder.

Another important age group that is vulnerable to suicide is the elderly population. Suicide rates are highest in elderly persons in most countries around the world, and suicide has a more severe impact in this demographic group. In Chapter 17, Ajilore and Kumar discuss the clinical and neurobiological risk factors among the elderly suicidal population. They also discuss how cognitive neuroscience can be used to understand impaired decision making in elderly suicidal patients.

The identification of personality features related to suicide attempts may be useful to prevent suicide mortality. This is because of their strong correlation with attempted and completed suicide. In Chapter 18, Rujescu and Giegling devote a chapter on the issue and discuss that personality trait is a crucial intermediate phenotype of suicidal behavior. They also discuss that aggression, impulsivity, anger, temperament, and neuroticism are important risk factors in suicidal behavior and show how a genetic component is involved in suicidal behavior in relation to personality.

Okusaga and Postolache have been studying triggers and vulnerabilities for suicide originating in the natural environment. More specifically, they have shown that during certain seasons there is a consistent peak of suicide. In Chapter 19, Okusaga and Postolache review the evidence connecting immune activation to Toxoplasma gondii infection and suicidal behavior.

Because of the inaccessibility of the human brain, peripheral tissues such as serum, blood cells, saliva, or urine may provide information regarding biological abnormalities. Pandey and Dwivedi discuss this approach in Chapter 20 and critically assess whether abnormalities in peripheral tissues can serve as biomarkers for suicidal behavior.

Finally, in Chapter 21, Mann and Currier outline the main alterations in neurobiological functions in suicide attempters and in individuals who died by suicide and describe the putative mechanisms of action by which different classes of medications may help prevent suicidal behavior.

In summary, this book covers a wide array of neurobiological abnormalities associated with suicide in a comprehensive manner. From various studies described in this book, it can be inferred that neurobiological correlates are important substrates in identifying the risk factors associated with suicidal behavior and that these neurobiological correlates may provide a promising approach to improve old approaches and develop new treatment modalities in the prevention of suicidal behavior.