Inflammation in Psychiatry

A. Halaris, B. E. Leonard

• Publisher: S. Karger
• Year: 2013
• ISBN:
  9783318023114
• Topic: Medicine
• Subtopic: Psychiatry & Mental Health

Psychoimmunology is a rapidly maturing area of scientific endeavor that provides a compelling integrative link between the immune system and its response to stress and psychiatric illness. Stress initiates pathological changes by activating the immune and endocrine systems. Inflammation is at the core of the complex and interactive systems that both contribute to and result from psychopathology. Consequently, inflammation research advances our knowledge of the pathology of depression, schizophrenia, chronic fatigue syndrome, posttraumatic stress disorder and a host of co-morbid conditions, notably diabetes, cardiovascular disease and cerebrovascular disease. The possible mechanisms underlying the bidirectionality of co-morbid medical and psychiatric disorders can be viewed as a consequence of inflammatory changes. These emerging novel concepts illustrate how the knowledge of inflammation can enable meaningful integration of psychopathology with physical co-morbidity. The innovative articles in this volume highlight the intricate link between psychiatry and psychoimmunology and underscore the central role of inflammation in furthering our understanding of the pathophysiology underlying mental health and illness.

Halaris A, Leonard BE (eds): Inflammation in Psychiatry.
Mod Trends Pharmacopsychiatry. Basel, Karger, 2013, vol 28, pp 188-202 (DOI: 10.1159/000346085)

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Inflammation in Suicidality: Implications for Novel Treatment Options

Shorena Janelidze^a · Lena Brundin^a,b

^aPsychoimmunology Unit, Section for Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden; ^bDepartment of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Mich., USA

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Abstract

Suicide is an increasing health problem worldwide and the most severe complication of multiple psychiatric disorders. It is also prevalent in several somatic conditions. In recent years, significant advances have been made in understanding the neurobiology of suicidal behaviors. Several lines of evidence have emerged suggesting that inflammation may contribute to the pathophysiology of suicide. Basic and clinical data indicate that the effects of inflammation on mood and behavior are likely to be mediated by the kynurenine pathway metabolites and glutamatergic neurotransmission. At the same time, the triggers of inflammatory changes observed in suicidal patients are largely unknown but may include stress, infectious agents and autoimmune diseases. As available treatment options against suicidality are only moderately effective, targeting the inflammatory system may provide novel therapeutic opportunities. For this goal to be achieved, however, we need to gain better insight into the origin, mechanisms and outcomes of inflammation in suicidal behavior.

Copyright © 2013 S. Karger AG, Basel

Suicide, the termination of ones own life on purpose, is a global health problem. At least 1 million deaths by suicide take place around the world each year [1]. The number of suicide attempts is generally 10-20 times higher than the number of completed suicides. Suicide is the tenth leading cause of death worldwide with a higher prevalence in men than in women [2], although suicide statistics vary considerably from country to country [3]. The phenomenon is sometimes the subject of cultural taboos that could cause an underestimation of true suicide rates. Both the deaths by suicide and the attempts are signs of extreme psychological suffering that unaffected persons find difficult to comprehend. Each completed suicide carries with it deep emotional pain and grief that stand to impact family members for years to come.

A previous suicide attempt [4] and mental illness are the strongest risk factors for suicidal behavior. Suicide rates are high among patients with major depressive disorders (MDD) [5], bipolar disorders [6], anxiety disorders [7], alcohol abuse [8], schizophrenia [9] and several other psychiatric conditions [2]. The percentage of patients with a diagnosis of MDD who will attempt suicide is about 14-17% [10-12], and the corresponding number for completed suicide is 4-6% [13, 14]. Certain personality traits, including aggressiveness, impulsivity [15, 16] and hopelessness/ helplessness [17, 18], are also associated with increased risk of suicide. However, frequent psychiatric comorbidity complicates the identification of true associations between specific mental disorders and suicidality [19].

Despite increased pharmacological treatment of suicidal individuals over the past decade, the incidence rates of suicide and suicide attempts have been increasing. It is estimated that 1.5 million people will die from suicide yearly in 2020, if current trends remain unchanged [20]. Moreover, the health care system is often unable to accurately detect suicidality, in spite of the fact that almost half of these patients contact primary care providers in the month prior to their attempt [21]. Consequently, there is a great need for both improved methods for detection of suicide risk and for specific treatments of suicidal patients [22].

Treatment of Suicidality

Currently there is no treatment of choice for suicidal patients. Treatment depends on the primary psychiatric diagnosis, if any, and often includes serotonin reuptake inhibitors and anxiolytic medication [23]. Severe cases can be treated with electroconvulsive therapy in many countries, in addition to the pharmacological treatment. Interestingly, there is a known increase in the risk for suicidal behavior during the first few weeks of treatment with antidepressants, especially in children and adolescents [24]. This has been attributed to reduced psychomotor retardation and elevated energy levels, which may occur prior to the improvement of mood [25]. At the neurobiological level, there is no explanation so far as to why there is approximately a 1-month time lag from the initiation of treatment with an antidepressant to the improvement of mood given that neurotransmitter levels normalize almost immediately.

A number of recent studies have found a strikingly rapid anti-suicidal effect of the N-methyl-d-aspartate (NMDA)-receptor antagonist, ketamine, in MDD and bipolar depression. In contrast to conventional antidepressants, ketamine reduces suicidal ideation and depressive symptoms within minutes or hours after intravenous administration [26-29]. In the study by Price et al. [26], treatment-resistant medication-free depressed patients were given a single dose or five repeated iv infusions of ketamine. In the single-dose regimen, suicidality, rated using the suicidality item on the Montgomery-Asberg Depression Rating Scale (MADRS-SI) and Implicit Association Test, was reduced in 8 of 13 patients 24 h postinfusion. The reduction in suicidal ideation was also observed in 9 of 10 patients who had received repeated ketamine infusions. In a similar group of 33 patients, DiazGranados et al. [27] showed that the anti-suicidal effects of ketamine, assessed with the Scale for Suicide Ideation, were already detectable 40 min after the initiation of treatment and lasted for at least 4 h. Moreover, it has been later demonstrated by Larkin and Beautrais [28] that reduction in the MADRS-SI was maintained for 10 days following a singe intravenous ketamine bolus injection in 13 of 14 MDD patients. As reported by Zarate et al. [29], ketamine also resolved suicidal ideation in patients with treatment-resistant bipolar depression. These findings suggest enhanced NMDA-receptor signaling as part of the pathophysiology of suicidal behavior, especially when considering the rapid onset of antisuicidal effects of ketamine administration.

Neurobiology of Suicidality

It is well accepted that suicidal behavior is driven by highly complex interactions between genetic and environmental factors. Nevertheless, the neurobiological substrates of suicide are poorly understood. To date, the most commonly reported changes in the neurobiology of suicidal behavior are abnormalities in serotonergic neurotransmission [30] and hypothalamic-pituitary-adrenal (HPA) axis activity [31]. Accumulating evidence also suggests that inflammation contributes to the pathophysiology of suicidality. The mediators of inflammation are known to interact closely and reciprocally with the HPA axis, and can also induce substantial changes in the serotonin system, as will be described below.

Serotonin System and Suicidality

The idea of deficient serotonergic neurotransmission in suicidality emerged in the 1970s when Asberg et al. [32] described reduced levels of the serotonin metabolite, 5-hydroxy-indole-acetic acid in violent suicide attempters. Numerous subsequent studies focusing on suicidal patients further uncovered impairments in various aspects of serotonergic function. Low serotonin synthesis was demonstrated in the ventromedial and orbital prefrontal cortex (PFC) of suicide attempters [33]. Hypofunction of the serotonergic system in suicidality was further supported by findings of a blunted prolactin response following fenfluramine challenge in suicide attempters [34-36]. Prolactin levels are used as an index of serotonergic function as its release increases dose-dependently in response to activation by serotonin agonists, such as fenfluramine. In addition, binding of the serotonin transporter (SERT) is reduced in suicide victims in the ventral PFC [37-39] indicating lower serotonergic innervation in this area. Previous studies also demonstrated upregulation of serotonin receptors, 5-HT_1A and 5-HT_2A, in the PFC cortex of individuals who died by suicide [40, 41]. Upregulation of 5-HT receptors in suicidal behavior is thought to represent a feedback mechanism compensating for deficient serotonergic function [31]. Finally, genetic evidence has implicated polymorphisms in SERT and in tryptophan hydroxylase, the rate-limiting enzyme catalyzing serotonin synthesis from tryptophan, in suicidal behavior [42, 43]. However, postmortem microarray studies revealed no change in the expression of genes related to serotonergic neurotransmission in suicide victims compared to non-suicidal patients with matching psychiatric diagnosis [44, 45], suggesting regulation of serotonin-related genes at the posttranslational level [46].

It should be noted that findings concerning serotonergic dysfunction in suicide and in depression are sometimes conflicting. Several investigatio...

Table of contents

• Cover Page
• Front Matter
• Basic Aspects of the Immunology of Neuroinflammation
• Stress and Neuroinflammation
• Role of Inflammation in Depression: Implications for Phenomenology, Pathophysiology and Treatment
• Virus Infection as a Cause of Inflammation in Psychiatric Disorders
• Inflammation, Neurotoxins and Psychiatric Disorders
• Essential Fatty Acids as Potential Anti-Inflammatory Agents in the Treatment of Affective Disorders
• The Brain-Gut Axis: A Target for Treating Stress-Related Disorders
• The Question of Pro-Inflammatory Immune Activity in Schizophrenia and the Potential Importance of Anti-Inflammatory Drugs
• Inflammation as the Cause of the Metabolic Syndrome in Depression
• Glucocorticoids and Inflammation: A Double-Headed Sword in Depression?
• Co-Morbidity between Cardiovascular Pathology and Depression: Role of Inflammation
• Inflammatory and Oxidative and Nitrosative Stress Cascades as New Drug Targets in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome
• Peripheral Inflammation and Cognitive Aging
• Inflammation in Suicidality: Implications for Novel Treatment Options
• Author Index
• Subject Index