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## **Meet the editor**

Mario Francisco Juruena graduated in medicine from the Pontifical Catholic University - RS, Brazil. He did his training in psychiatry at the Sao Pedro Hospital, and specialization in mental health at School of Public Health - RS. He received his master degree at the Department of Psychobiology, Federal University of São Paulo, and in Affective Neuroscience, Universiteit Maastricht, the

Netherlands. He got his PhD degree in Psychiatry from the University of London, and training in cognitive psychotherapy at Beck Institute for Cognitive Behavior Therapy - USA. He is a specialist in adult psychiatry in the UK according to the Medical Royal Colleges and has published over 80 original research articles, reviews and book chapters, editing four books. British Association for Psychopharmacology awarded him the "Senior Clinical Psychopharmacology Award 2007". He also received the "Robert W. Kerwin Prize in 2010" from the Royal College of Psychiatrists for the best article published in the British Journal of Psychiatry. Juruena is currently a professor at the Department of Neurosciences and Behavior, University of São Paulo (USP-FMRP) and Honorary Senior Lecturer at the Institute of Psychiatry, Kings College London.

Contents

**Preface IX**

Yong-Ku Kim

Chapter 2 **Self-Reported Symptoms Related**

Chapter 1 **Biological Prediction of Suicidal Behavior**

**to Depression and Suicidal Risk 19**  Kouichi Yoshimasu, Shigeki Takemura, Jin Fukumoto and Kazuhisa Miyashita

Chapter 3 **Chronobiological Aspects of Mood Disorders 35**  Rosa Levandovski, Ana Harb, Fabiana Bernardi

Maria Cristina Triguero Veloz Teixeira,

Chapter 5 **Mood Disorders and Cardiovascular Disease 73**

Blaine Ditto and Simon L. Bacon

**Part 2 Childhood and Adolescence 103**

Chapter 6 **Mood Disorders in Childhood and**

Ulf Engqvist

Alessandra Alciati

Chapter 7 **Different Types of**

and Maria Paz Loayza Hidalgo

Chapter 4 **Mood Disorders in Individuals with**

**in Patients with Major Depressive Disorder 3**

**Genetic Syndromes and Intellectual Disability 49**

Jennifer L. Gordon, Kim L. Lavoie, André Arsenault,

**Adolescence and Their Outcome in Adulthood 105**

**Childhood Adverse Experiences and Mood Disorders 143**

Maria Luiza Guedes de Mesquita, Marcos Vinícius de Araújo, Laís Pereira Khoury and Luiz Renato Rodrigues Carreiro

**Part 1 Clinical 1**

### Contents

**Part 1 Clinical 1**

	- **Part 2 Childhood and Adolescence 103**

#### X Contents

#### **Part 3 Neurobiology 165**

#### **Part 4 Treatment 281**

### Preface

A fundamental problem in diagnosis is the fact that elaborate classification systems that exist today are solely based on subjective descriptions of symptoms. Such detailed phenomenology includes the description of multiple clinical subtypes; however, there is no biological feature that distinguishes one subtype from another. Moreover, it is recognized that a variety of disorders can exhibit similar clinical symptoms and that one disorder can manifest with distinct patterns in different people.

The Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Disease (ICD), the manuals that specify these diagnoses and the criteria for making them, are currently undergoing revision. These processes are involving a huge numbers of researchers from around the world; it is thus an appropriate time to question if neuroscience is prepared for the DSM-V and the ICD-11, and if they in turn are set for neuroscience. The presence of merely a few number of well-validated biomarkers and the early stage in which our understanding of neurobiology and genetics finds itself have obstructed the integration of neuroscience into psychiatric diagnosis to date. If we integrate a neurobiological approach that describes reliable neurobiological findings based on psychopathological syndrome, it will be more solid contrasted to a non-etiological system of classification. A future diagnostic criteria system in which aetiology and pathophysiology are essential in diagnostic decision-making would bring psychiatry closer to other specialties of medicine.

The relationship between stress and affective disorders is a strong example of a field of study that can be more fully understood from an integrative perspective. The potential of an integrative approach to contribute to improvements in human health and well being are more important than historical biases that have been associated with an integrative science approach. Approximately 60% of cases of depressive episodes are preceded by exposure to stressors, especially psychosocial stressors. Among the factors associated with depression in adulthood are exposure to childhood stressors such as the death of a parent or substitute, maternal deprivation, paternal abandonment, parental separation, and divorce. Psychological stress may change the internal homeostatic state of an individual. During acute stress, adaptive physiological responses occur, including increased adrenocortical hormone secretion, primarily cortisol. Whenever an acute interruption of this balance occurs, illness may result.

#### X Preface

Particularly interesting are psychological stress (i.e., stress in the mind) and the interactions with the nervous, endocrine, and immune systems. For example childhood maltreatment is a major social problem. It is a complex global phenomenon that does not respect boundaries of class, race, religion, age, or educational level and can occur both publicly and privately, resulting in serious physical injury or even death. Moreover, its psychological consequences can acutely affect a child's mental health well into adulthood.

Preface XI

Generally, HPA axis changes appear in chronic depressive and more severe episodes. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has

There is an increasing data supporting that depressive disorders include a group of conditions which may be different with regard to the activity of the HPA axis, immune functions and treatment response. Melancholia, for instance, a syndrome with a long history and distinctive psychopathological features, is differentiated from major depression by the DSM-IV specifiers and partly described in the ICD-10th edition. Nevertheless, it has a distinctive psychopathology and biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions according to international studies. In the last few years an important movement proposes to reinstitute the definition of melancholia, set a duration criterion and add as secondary criteria the associated laboratory findings of dexamethasone non-suppression of cortisol, high night-time cortisol levels, or

The lack of correlations between clinical and biological data continues to be, according to several authors, one of the great unsolved problems of psychiatry today and could be solved by recovering the value of traditional psychopathological analysis based on fundamental and thorough clinical assessment, which should support aetiological

Therefore, I am greatly pleased to edit this book where the authors achieve a balance among diagnostic, research, clinical and new treatment approaches to Affective

**Mario Francisco Juruena, MD, MSc, MPhil, PhD**

Department of Neurosciences and Behaviour

Brazil

Stress and Affective Disorders Programme (SAD Programme)

Faculty of Medicine Ribeirao Preto, University of Sao Paulo

decreased REM latency or other characteristic sleep abnormalities.

been associated with higher rates of relapse.

research and treatment decisions.

Disorders.

This approach says very clearly and without a doubt that the causes, development and outcomes of affective disorders are determined by the relationship of psychological, social and cultural factors with biochemistry and physiology. Biochemistry and physiology are not disconnected and different from the rest of our experiences and life events. This system is based on current studies that reported that the brain and its cognitive processes show a fantastic synchronization. Consequently, accepting the brain–body–mind complex is possible only when the three systems – nervous, endocrine and immune – have receptors on critical cells that can receive information (through messenger molecules) from each of the other systems. The fourth system, the mind (our thoughts, our feelings, our beliefs and our hopes), is part of the functioning of the brain integrating the paradigm. The interaction of the mind, an explicit functioning of the brain, with other body systems is critical for the maintenance of homeostasis and well being.

It is now broadly accepted that psychological stress may change the internal homeostatical state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behaviour, and they influence the process of adaptation or 'allostasis'. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Of special interest are the psychological stress (stress in the mind) and the interactions of the nervous, endocrine and immune systems. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in psychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol (the endogenous glucocorticoid in humans) in the plasma, urine, saliva and cerebrospinal fluid (CSF); an exaggerated cortisol response to adrenocorticotropic hormone (ACTH); and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Generally, HPA axis changes appear in chronic depressive and more severe episodes. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse.

X Preface

health well into adulthood.

homeostasis and well being.

Particularly interesting are psychological stress (i.e., stress in the mind) and the interactions with the nervous, endocrine, and immune systems. For example childhood maltreatment is a major social problem. It is a complex global phenomenon that does not respect boundaries of class, race, religion, age, or educational level and can occur both publicly and privately, resulting in serious physical injury or even death. Moreover, its psychological consequences can acutely affect a child's mental

This approach says very clearly and without a doubt that the causes, development and outcomes of affective disorders are determined by the relationship of psychological, social and cultural factors with biochemistry and physiology. Biochemistry and physiology are not disconnected and different from the rest of our experiences and life events. This system is based on current studies that reported that the brain and its cognitive processes show a fantastic synchronization. Consequently, accepting the brain–body–mind complex is possible only when the three systems – nervous, endocrine and immune – have receptors on critical cells that can receive information (through messenger molecules) from each of the other systems. The fourth system, the mind (our thoughts, our feelings, our beliefs and our hopes), is part of the functioning of the brain integrating the paradigm. The interaction of the mind, an explicit functioning of the brain, with other body systems is critical for the maintenance of

It is now broadly accepted that psychological stress may change the internal homeostatical state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behaviour, and they influence the process of adaptation or 'allostasis'. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Of special interest are the psychological stress (stress in the mind) and the interactions of the nervous, endocrine and immune systems. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in psychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol (the endogenous glucocorticoid in humans) in the plasma, urine, saliva and cerebrospinal fluid (CSF); an exaggerated cortisol response to adrenocorticotropic hormone (ACTH); and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. There is an increasing data supporting that depressive disorders include a group of conditions which may be different with regard to the activity of the HPA axis, immune functions and treatment response. Melancholia, for instance, a syndrome with a long history and distinctive psychopathological features, is differentiated from major depression by the DSM-IV specifiers and partly described in the ICD-10th edition. Nevertheless, it has a distinctive psychopathology and biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions according to international studies. In the last few years an important movement proposes to reinstitute the definition of melancholia, set a duration criterion and add as secondary criteria the associated laboratory findings of dexamethasone non-suppression of cortisol, high night-time cortisol levels, or decreased REM latency or other characteristic sleep abnormalities.

The lack of correlations between clinical and biological data continues to be, according to several authors, one of the great unsolved problems of psychiatry today and could be solved by recovering the value of traditional psychopathological analysis based on fundamental and thorough clinical assessment, which should support aetiological research and treatment decisions.

Therefore, I am greatly pleased to edit this book where the authors achieve a balance among diagnostic, research, clinical and new treatment approaches to Affective Disorders.

> **Mario Francisco Juruena, MD, MSc, MPhil, PhD**  Stress and Affective Disorders Programme (SAD Programme) Department of Neurosciences and Behaviour Faculty of Medicine Ribeirao Preto, University of Sao Paulo Brazil

**Part 1**

**Clinical**

**Part 1**

**Clinical**

**1**

Yong-Ku Kim

*Republic of Korea*

**Biological Prediction of Suicidal Behavior**

**in Patients with Major Depressive Disorder**

Suicide is a major public health issue and a significant cause of death worldwide. Most suicides (about 90%) occur in the context of psychiatric disorders, most commonly major depressive disorder, which is associated with approximately 60% of all suicides (Carlson et al. 1991). Prediction of suicidal risk in major depressive disorder is very important for preventing suicide, but current approaches to predicting suicidal behavior are based on clinical history and have low specificity. Accordingly, biological markers may provide a more specific means of identifying individuals at high risk of suicide with major depressive disorder (Lee and Kim 2011). Despite the high lifetime rate of suicide in patients with major depressive disorder (estimated to be 10-15%; Wulsin et al. 1999), most never attempt suicide. This raises the question of why some people with major depression are at risk of suicide and others are not, and suggests that the predisposition toward suicidal behavior is independent of psychiatric disorders. Other factors that increase the risk of suicidal behavior include psychosocial stressors, aggressive and impulsive traits, hopelessness, pessimism, substance abuse and dependence, physical or sexual abuse during childhood, and a history of head injury or neurological disorders. In considerations of these risk factors, suicidal behavior has been conceptualized into stress-diathesis and state-trait interaction models (Mann et al. 1999; Van Heeringen and Marusic 2003). Figure 1 illustrates the stress-diathesis model of

These models suggest that acute psychological stressors act on the diathesis, or traits of suicidal behavior, and that the complicated interactions between stress and diathesis gradually evolve into suicidal behavior over time. Previous research has explored potential biological markers and predictors of suicide and suicidal behavior, especially in the context of major depression. Although work in this area has been inconclusive, many animal, postmortem, clinical, and genetic studies have produced results implicating at least 3 neurobiological systems in the pathogenesis of suicidal behavior in major depression: deficiency in the serotonergic system, hyperactivity of the hypothalamic-pituitary-adrenal axis, and decreased brain derived neurotrophic factor (BDNF) metabolism. Additionally, other neurotransmitters, cholesterol, nitric oxide (NO) and cytokines may be associated with suicide and suicidal behavior in major depression. Specifically, diathesis or trait-dependent risk factors are associated with dysfunctions in the serotonin system; however, the stress response (i.e., state-dependent factors) is related to hypothalamic-pituitary adrenal(HPA)

**1. Introduction**

suicidal behavior.

*Department of Psychiatry, College of Medicine, Korea University*

## **Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder**

Yong-Ku Kim

*Department of Psychiatry, College of Medicine, Korea University Republic of Korea*

#### **1. Introduction**

Suicide is a major public health issue and a significant cause of death worldwide. Most suicides (about 90%) occur in the context of psychiatric disorders, most commonly major depressive disorder, which is associated with approximately 60% of all suicides (Carlson et al. 1991). Prediction of suicidal risk in major depressive disorder is very important for preventing suicide, but current approaches to predicting suicidal behavior are based on clinical history and have low specificity. Accordingly, biological markers may provide a more specific means of identifying individuals at high risk of suicide with major depressive disorder (Lee and Kim 2011). Despite the high lifetime rate of suicide in patients with major depressive disorder (estimated to be 10-15%; Wulsin et al. 1999), most never attempt suicide. This raises the question of why some people with major depression are at risk of suicide and others are not, and suggests that the predisposition toward suicidal behavior is independent of psychiatric disorders. Other factors that increase the risk of suicidal behavior include psychosocial stressors, aggressive and impulsive traits, hopelessness, pessimism, substance abuse and dependence, physical or sexual abuse during childhood, and a history of head injury or neurological disorders. In considerations of these risk factors, suicidal behavior has been conceptualized into stress-diathesis and state-trait interaction models (Mann et al. 1999; Van Heeringen and Marusic 2003). Figure 1 illustrates the stress-diathesis model of suicidal behavior.

These models suggest that acute psychological stressors act on the diathesis, or traits of suicidal behavior, and that the complicated interactions between stress and diathesis gradually evolve into suicidal behavior over time. Previous research has explored potential biological markers and predictors of suicide and suicidal behavior, especially in the context of major depression. Although work in this area has been inconclusive, many animal, postmortem, clinical, and genetic studies have produced results implicating at least 3 neurobiological systems in the pathogenesis of suicidal behavior in major depression: deficiency in the serotonergic system, hyperactivity of the hypothalamic-pituitary-adrenal axis, and decreased brain derived neurotrophic factor (BDNF) metabolism. Additionally, other neurotransmitters, cholesterol, nitric oxide (NO) and cytokines may be associated with suicide and suicidal behavior in major depression. Specifically, diathesis or trait-dependent risk factors are associated with dysfunctions in the serotonin system; however, the stress response (i.e., state-dependent factors) is related to hypothalamic-pituitary adrenal(HPA)

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 5

Tryptophan hydroxylase (TPH), which has two isoforms (TPH1 and TPH2), is one of the rate limiting factors in serotonin synthesis, Postmortem studies have reported significantly higher numbers and higher densities of TPH immunoreactive neurons in the dorsal raphe nuclei of depressed suicide victims (Underwood et al. 1999) and in the same regions of alcohol dependent, depressed suicide victims (Bonkale et al. 2006) when compared to controls. We have found that the TPH2 -703G/T SNP may have an important effect on susceptibility to suicidal behavior in those with major depressive disorder. Additionally, an increased frequency of the G allele of the TPH2 SNP is associated with elevated risk of suicidal behavior itself rather than with the diagnosis of major depression, and may increase the risk of suicidality, independent of diagnosis (Yoon and Kim 2009). Collectively, TPH, serotonin transporter, and serotonin receptor studies suggest that deficient or impaired serotonin activity is involved in suicidal behavior. Increased activity in TPH and postsynaptic 5-HT2A receptors may be compensatory results of decreased central levels of serotonin. Notably, serotonin dysfunction appears to be localized in the ventral prefrontal cortex among suicide victims (Mann et al. 2000), as well as in individuals who make suicide

The prefrontal cortex has been implicated in both behavioral and cognitive inhibition, as well as in willed action and decision-making. A meta-analysis examining 27 prospective and retrospective reports found that individuals who attempt suicide, and particularly those who use violent methods, had lower cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5- HIAA) levels when compared to psychiatric controls (Lester 1995). Additionally, a metaanalysis of prospective biological studies estimated the odds ratio for the prediction of suicide completion to be 4.5-fold greater for individuals with low levels of CSF 5-HIAA than individuals with high levels of CSF 5-HIAA among patients with mood disorders (Mann et al. 2006). CSF 5-HIAA may serve as a predictor of future suicide attempts and completions, as findings associating CSF 5-HIAA levels with suicidal behavior have been relatively consistent. Additionally, levels of CSF 5-HIAA are relatively stable and therefore believed to be under substantial genetic control (Rogers et al. 2004). Blunted prolactin response to the fenfluramine challenge test has been observed among young (<30 years) inpatients with major depression and histories of suicide attempts (Mann et al. 1995). Other work has shown significantly lower prolactin responses to fenfluramine challenge tests among depressed patients with histories of suicide attempts than among patients without such histories or healthy controls (Correa et al. 2000; Mann et al. 1995). Further, decreased prolactin response has been reported among patients with histories of high-lethality suicide attempts (Malone et al. 1996). These results suggest that blunted prolactin response to fenfluramine, which indicates reduced serotonin function, may serve as a marker for

Few post-mortem studies have examined alterations in the noradrenergic or dopaminergic systems in suicide victims. Studies have found decreased noradrenalin (NA) levels in the brainstem and increased α2-adrenergic receptor densities in suicide victims (Ordway et al. 1994a). One study found that tyrosine hydroxylase (TH), the rate-limiting enzyme for NA and dopamine (DA) synthesis, is higher in suicide victims (Ordway et al. 1994b), however another study found the opposite (Biegon and Fieldust 1992). Increased TH and α2-

suicidality among individuals with major depressive disorder.

**2.2 The noradrenergic and dopaminergic systems**

attempts (Leyton et al. 2006).

Fig. 1. Stress-diathesis model of suicidal behavior

axis hyperactivity. Decreases in cholesterol and BDNF levels are associated with impaired brain plasticity among individuals with suicidal behavior in major depressive disorder. In this chapter, I discuss peripheral biological markers involved in the pathogenesis of suicidal behavior in major depressive disorder and propose a model to predict the risk of suicidal behavior in these patients.

#### **2. The neurotransmitter system**

#### **2.1 Serotonin**

The serotonin system has been widely investigated in studies of major depression and suicide. The innervations of the serotonin system project from the dorsal raphe nucleus to all of the regions of the brain, including the cerebral cortex and hippocampus. Decreased function and activity of the serotonergic system in suicide victims and patients with major depression who attempt suicide have been confirmed in postmortem, serotonin transporter, serotonin receptor and cerebrospinal fluid (CSF) studies and neuroendocrine challenge tests. Post-mortem studies of the brains of suicide victims provide evidence of reduced serotonin transporter sites in the prefrontal cortex, hypothalamus, occipital cortex and brainstem (Purselle and Nemeroff 2003). In an autoradiographic study, this abnormality was found to be localized to the ventromedial prefrontal cortex (Arango et al. 1995). Abnormalities were also observed at the receptor level, as postsynaptic 5-HT1A and 5-HT2A receptors were found to be upregulated in the prefrontal cortex. It has been hypothesized that this increase may be a compensatory mechanism to counter the low activity of serotonergic neurons (Mann 2003). It is interesting to note that this serotonin dysfunction appears to be localized to the ventral prefrontal cortex, a region that is involved in behavioral and cognitive inhibition. Thus, low serotonergic input may contribute to impaired inhibition, creating a greater propensity to act on suicidal or aggressive feelings (Mann 2003).

axis hyperactivity. Decreases in cholesterol and BDNF levels are associated with impaired brain plasticity among individuals with suicidal behavior in major depressive disorder. In this chapter, I discuss peripheral biological markers involved in the pathogenesis of suicidal behavior in major depressive disorder and propose a model to predict the risk of suicidal

The serotonin system has been widely investigated in studies of major depression and suicide. The innervations of the serotonin system project from the dorsal raphe nucleus to all of the regions of the brain, including the cerebral cortex and hippocampus. Decreased function and activity of the serotonergic system in suicide victims and patients with major depression who attempt suicide have been confirmed in postmortem, serotonin transporter, serotonin receptor and cerebrospinal fluid (CSF) studies and neuroendocrine challenge tests. Post-mortem studies of the brains of suicide victims provide evidence of reduced serotonin transporter sites in the prefrontal cortex, hypothalamus, occipital cortex and brainstem (Purselle and Nemeroff 2003). In an autoradiographic study, this abnormality was found to be localized to the ventromedial prefrontal cortex (Arango et al. 1995). Abnormalities were also observed at the receptor level, as postsynaptic 5-HT1A and 5-HT2A receptors were found to be upregulated in the prefrontal cortex. It has been hypothesized that this increase may be a compensatory mechanism to counter the low activity of serotonergic neurons (Mann 2003). It is interesting to note that this serotonin dysfunction appears to be localized to the ventral prefrontal cortex, a region that is involved in behavioral and cognitive inhibition. Thus, low serotonergic input may contribute to impaired inhibition, creating a

greater propensity to act on suicidal or aggressive feelings (Mann 2003).

Fig. 1. Stress-diathesis model of suicidal behavior

behavior in these patients.

**2.1 Serotonin**

**2. The neurotransmitter system**

Tryptophan hydroxylase (TPH), which has two isoforms (TPH1 and TPH2), is one of the rate limiting factors in serotonin synthesis, Postmortem studies have reported significantly higher numbers and higher densities of TPH immunoreactive neurons in the dorsal raphe nuclei of depressed suicide victims (Underwood et al. 1999) and in the same regions of alcohol dependent, depressed suicide victims (Bonkale et al. 2006) when compared to controls. We have found that the TPH2 -703G/T SNP may have an important effect on susceptibility to suicidal behavior in those with major depressive disorder. Additionally, an increased frequency of the G allele of the TPH2 SNP is associated with elevated risk of suicidal behavior itself rather than with the diagnosis of major depression, and may increase the risk of suicidality, independent of diagnosis (Yoon and Kim 2009). Collectively, TPH, serotonin transporter, and serotonin receptor studies suggest that deficient or impaired serotonin activity is involved in suicidal behavior. Increased activity in TPH and postsynaptic 5-HT2A receptors may be compensatory results of decreased central levels of serotonin. Notably, serotonin dysfunction appears to be localized in the ventral prefrontal cortex among suicide victims (Mann et al. 2000), as well as in individuals who make suicide attempts (Leyton et al. 2006).

The prefrontal cortex has been implicated in both behavioral and cognitive inhibition, as well as in willed action and decision-making. A meta-analysis examining 27 prospective and retrospective reports found that individuals who attempt suicide, and particularly those who use violent methods, had lower cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5- HIAA) levels when compared to psychiatric controls (Lester 1995). Additionally, a metaanalysis of prospective biological studies estimated the odds ratio for the prediction of suicide completion to be 4.5-fold greater for individuals with low levels of CSF 5-HIAA than individuals with high levels of CSF 5-HIAA among patients with mood disorders (Mann et al. 2006). CSF 5-HIAA may serve as a predictor of future suicide attempts and completions, as findings associating CSF 5-HIAA levels with suicidal behavior have been relatively consistent. Additionally, levels of CSF 5-HIAA are relatively stable and therefore believed to be under substantial genetic control (Rogers et al. 2004). Blunted prolactin response to the fenfluramine challenge test has been observed among young (<30 years) inpatients with major depression and histories of suicide attempts (Mann et al. 1995). Other work has shown significantly lower prolactin responses to fenfluramine challenge tests among depressed patients with histories of suicide attempts than among patients without such histories or healthy controls (Correa et al. 2000; Mann et al. 1995). Further, decreased prolactin response has been reported among patients with histories of high-lethality suicide attempts (Malone et al. 1996). These results suggest that blunted prolactin response to fenfluramine, which indicates reduced serotonin function, may serve as a marker for suicidality among individuals with major depressive disorder.

#### **2.2 The noradrenergic and dopaminergic systems**

Few post-mortem studies have examined alterations in the noradrenergic or dopaminergic systems in suicide victims. Studies have found decreased noradrenalin (NA) levels in the brainstem and increased α2-adrenergic receptor densities in suicide victims (Ordway et al. 1994a). One study found that tyrosine hydroxylase (TH), the rate-limiting enzyme for NA and dopamine (DA) synthesis, is higher in suicide victims (Ordway et al. 1994b), however another study found the opposite (Biegon and Fieldust 1992). Increased TH and α2-

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 7

found that veno-arterial BDNF plasma concentration gradient acts as an index of brain BDNF production. Based on this determination, the veno-arterial BDNF concentration gradient was shown to be significantly reduced among patients at medium to high suicide risk compared to those at low risk. Additionally, this gradient was negatively correlated with suicide risk among untreated patients with depression. As such, BDNF level in sera or plasma appears to be decreased among suicidal individuals soon after attempted suicide, which is consistent with the changes observed in brain BDNF levels that have been reported in postmortem studies. These results suggest that BDNF may play an important role in the

One study has found that BDNF and neurotrophin-3 (NT-3) levels are decreased in postmortem brains of suicide victims (Karege et al. 2005). Additionally, mRNA levels of nerve growth factor (NGF), NT-3, NT-4/5, cyclophilin, and neuron-specific enolase are decreased in the hippocampi of suicide victims (Dwivedi et al. 2005). Few studies have investigated other neurotropic factors, and further studies in suicidal depression are

The HPA axis is the major biological system involved in the acute stress response. The stress-related theory of depression states that chronic stress may lead to long-term activation of the HPA axis, which may then result in reductions in the volume or impairments to the function of the hippocampus (Holsboer 1988). Corticotropin-releasing hormone (CRH) levels in the CSF tend to be increased among suicide victims, suggesting an increase in HPA axis activity among individuals with suicidal behaviors (Arato et al. 1989). However, this association remains controversial and other research has shown that patients who make repeated suicide attempts may have even lower CSF CRH levels than patients who do not

The dexamethasone suppression test (DST) is one of the most useful assessments of HPA axis activity. During normal HPA axis activity, administration of dexamethasone, an exogenous synthetic glucocorticoid hormone, leads to negative feedback to the HPA axis. This negative feedback results in suppression of the release of adrenocorticotropic hormone (ACTH) from the hypothalamus, which results in suppression of the release of cortisol from the adrenal gland. The reduction in cortisol levels as measured in plasma results in a positive result on the DST test. Many studies have shown that cortisol non-suppression in response to the DST is a strong predictor of suicidal behavior (Coryell and Schlesser 2001; Kunugi et al. 2004; Yerevanian et al. 2004). Specifically, some reports have demonstrated that patients with non-suppression engage in more serious suicide attempts (Coryell 1990; Norman et al. 1990) or use more violent methods (Roy 1992) than those who do not exhibit non-suppression. Jokinen and Nordström (2008) found that DST non-suppression is associated with suicide attempts among young adult and elderly inpatients with mood disorders. However, Black and colleagues (2002) found no significant differences in the frequency of suicidal ideation or completed suicides between patients demonstrating DST suppression and those demonstrating non-suppression (Black et al. 2002). A long-term follow-up study spanning 15 years has shown that patients with depression and DST non-

neurobiology of suicide and suicidal behavior in major depression.

**4. The hypothalamic–pituitary–adrenal (HPA) axis and cortisol**

**3.2 Other neurotrophic factors**

(Traskman-Bendz et al. 1992).

necessary.

adrenergic receptor densities could be indicative of noradrenergic depletion compensatory to increased NA release. Increased NA release may be explained by the relationship between the noradrenergic system and stress response, as severe anxiety and agitation are associated with noradrenergic overactivity, higher suicide risk, and overactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Mann 2003).

Few studies have examined the dopaminergic system. Overall, no alterations were found in mRNA levels of the D1, D2 and D4 receptors that bind in the caudate nuclei of suicide victims (Hurd et al. 1997; Sumiyoshi et al. 1995). A recent investigation exploring homovanillinic acid (HVA) in the CSF of depressed suicide attempters found reduced HVA levels in attempters, but not in depressed non-attempters (Sher et al. 2006). Thus, the dopamine system seems to be hypofunctional in major depression (Kapur and Mann 1992).

#### **3. Neurotrophic factors**

#### **3.1 Brain derived neurotrophic factor (BDNF)**

Neurotrophic factors including BDNF, nerve growth factor (NGF) and neurotrophin (NT)- 3, 4/5, play an important physiological role in the maintenance and growth of neurons and synaptic plasticity in the adult brain (Lewin and Barde 1996) and are known to be involved in the pathogenesis of depression and suicide (Duman et al. 1997; Nestler et al. 2002). In particular, BDNF mRNA expression levels are significantly decreased in animals subjected to forced swimming and chronic immobilization stress (Russo-Neustadt et al. 2001; Xu et al. 2002). Moreover, chronic antidepressant treatment increases the expression of BDNF and neurogenesis in adult rat hippocampi (Duman et al. 1997; Malberg et al. 2000). Several clinical studies have found differing BDNF levels in the blood sera or plasma of patients with major depression and patients who have attempted suicide. Deveci and colleagues (2007) investigated serum BDNF levels among suicide attempters without major psychiatric disorders, patients with major depression, and healthy subjects. They found that serum BDNF levels were lower among both suicide attempters and depressed patients than among healthy controls. Our research group has also examined plasma BDNF levels among patients with major depression who both have and have not attempted suicide. One study found that plasma BDNF levels were significantly lower among depressed patients than among normal controls (Lee et al. 2007). Plasma BDNF levels were also significantly lower among suicidal patients than non-suicidal patients with major depression, and that suicidal patients had the lowest levels of BDNF among all of the groups assessed (Lee et al. 2007). Further, Kim and colleagues (2007b) measured plasma BDNF levels in patients with depression who had recently attempted suicide, non-suicidal patients with depression, and healthy controls. BDNF levels were significantly lower among suicidal patients with depression than non-suicidal patients with depression and healthy controls. However, BDNF levels did not differ between individuals who made fatal and nonfatal suicide attempts (Kim et al. 2007b). One study examining BDNF mRNA expression in peripheral blood mononuclear cells revealed that patients with major depression and recent suicide attempts had decreased BDNF mRNA expression, compared to patients who had not attempted suicide (Lee and Kim 2010). Measurements of BDNF levels in sera or plasma in previous studies have been challenged, as it is questionable whether BDNF in the blood is released from the brain or from other sources. To address this issue, Dawood and colleagues (2007) used direct blood sampling from the internal jugular vein and the brachial artery and found that veno-arterial BDNF plasma concentration gradient acts as an index of brain BDNF production. Based on this determination, the veno-arterial BDNF concentration gradient was shown to be significantly reduced among patients at medium to high suicide risk compared to those at low risk. Additionally, this gradient was negatively correlated with suicide risk among untreated patients with depression. As such, BDNF level in sera or plasma appears to be decreased among suicidal individuals soon after attempted suicide, which is consistent with the changes observed in brain BDNF levels that have been reported in postmortem studies. These results suggest that BDNF may play an important role in the neurobiology of suicide and suicidal behavior in major depression.

#### **3.2 Other neurotrophic factors**

6 Clinical, Research and Treatment Approaches to Affective Disorders

adrenergic receptor densities could be indicative of noradrenergic depletion compensatory to increased NA release. Increased NA release may be explained by the relationship between the noradrenergic system and stress response, as severe anxiety and agitation are associated with noradrenergic overactivity, higher suicide risk, and overactivity of the

Few studies have examined the dopaminergic system. Overall, no alterations were found in mRNA levels of the D1, D2 and D4 receptors that bind in the caudate nuclei of suicide victims (Hurd et al. 1997; Sumiyoshi et al. 1995). A recent investigation exploring homovanillinic acid (HVA) in the CSF of depressed suicide attempters found reduced HVA levels in attempters, but not in depressed non-attempters (Sher et al. 2006). Thus, the dopamine system seems to be hypofunctional in major depression (Kapur and Mann 1992).

Neurotrophic factors including BDNF, nerve growth factor (NGF) and neurotrophin (NT)- 3, 4/5, play an important physiological role in the maintenance and growth of neurons and synaptic plasticity in the adult brain (Lewin and Barde 1996) and are known to be involved in the pathogenesis of depression and suicide (Duman et al. 1997; Nestler et al. 2002). In particular, BDNF mRNA expression levels are significantly decreased in animals subjected to forced swimming and chronic immobilization stress (Russo-Neustadt et al. 2001; Xu et al. 2002). Moreover, chronic antidepressant treatment increases the expression of BDNF and neurogenesis in adult rat hippocampi (Duman et al. 1997; Malberg et al. 2000). Several clinical studies have found differing BDNF levels in the blood sera or plasma of patients with major depression and patients who have attempted suicide. Deveci and colleagues (2007) investigated serum BDNF levels among suicide attempters without major psychiatric disorders, patients with major depression, and healthy subjects. They found that serum BDNF levels were lower among both suicide attempters and depressed patients than among healthy controls. Our research group has also examined plasma BDNF levels among patients with major depression who both have and have not attempted suicide. One study found that plasma BDNF levels were significantly lower among depressed patients than among normal controls (Lee et al. 2007). Plasma BDNF levels were also significantly lower among suicidal patients than non-suicidal patients with major depression, and that suicidal patients had the lowest levels of BDNF among all of the groups assessed (Lee et al. 2007). Further, Kim and colleagues (2007b) measured plasma BDNF levels in patients with depression who had recently attempted suicide, non-suicidal patients with depression, and healthy controls. BDNF levels were significantly lower among suicidal patients with depression than non-suicidal patients with depression and healthy controls. However, BDNF levels did not differ between individuals who made fatal and nonfatal suicide attempts (Kim et al. 2007b). One study examining BDNF mRNA expression in peripheral blood mononuclear cells revealed that patients with major depression and recent suicide attempts had decreased BDNF mRNA expression, compared to patients who had not attempted suicide (Lee and Kim 2010). Measurements of BDNF levels in sera or plasma in previous studies have been challenged, as it is questionable whether BDNF in the blood is released from the brain or from other sources. To address this issue, Dawood and colleagues (2007) used direct blood sampling from the internal jugular vein and the brachial artery and

hypothalamic-pituitary-adrenal (HPA) axis (Mann 2003).

**3.1 Brain derived neurotrophic factor (BDNF)**

**3. Neurotrophic factors**

One study has found that BDNF and neurotrophin-3 (NT-3) levels are decreased in postmortem brains of suicide victims (Karege et al. 2005). Additionally, mRNA levels of nerve growth factor (NGF), NT-3, NT-4/5, cyclophilin, and neuron-specific enolase are decreased in the hippocampi of suicide victims (Dwivedi et al. 2005). Few studies have investigated other neurotropic factors, and further studies in suicidal depression are necessary.

#### **4. The hypothalamic–pituitary–adrenal (HPA) axis and cortisol**

The HPA axis is the major biological system involved in the acute stress response. The stress-related theory of depression states that chronic stress may lead to long-term activation of the HPA axis, which may then result in reductions in the volume or impairments to the function of the hippocampus (Holsboer 1988). Corticotropin-releasing hormone (CRH) levels in the CSF tend to be increased among suicide victims, suggesting an increase in HPA axis activity among individuals with suicidal behaviors (Arato et al. 1989). However, this association remains controversial and other research has shown that patients who make repeated suicide attempts may have even lower CSF CRH levels than patients who do not (Traskman-Bendz et al. 1992).

The dexamethasone suppression test (DST) is one of the most useful assessments of HPA axis activity. During normal HPA axis activity, administration of dexamethasone, an exogenous synthetic glucocorticoid hormone, leads to negative feedback to the HPA axis. This negative feedback results in suppression of the release of adrenocorticotropic hormone (ACTH) from the hypothalamus, which results in suppression of the release of cortisol from the adrenal gland. The reduction in cortisol levels as measured in plasma results in a positive result on the DST test. Many studies have shown that cortisol non-suppression in response to the DST is a strong predictor of suicidal behavior (Coryell and Schlesser 2001; Kunugi et al. 2004; Yerevanian et al. 2004). Specifically, some reports have demonstrated that patients with non-suppression engage in more serious suicide attempts (Coryell 1990; Norman et al. 1990) or use more violent methods (Roy 1992) than those who do not exhibit non-suppression. Jokinen and Nordström (2008) found that DST non-suppression is associated with suicide attempts among young adult and elderly inpatients with mood disorders. However, Black and colleagues (2002) found no significant differences in the frequency of suicidal ideation or completed suicides between patients demonstrating DST suppression and those demonstrating non-suppression (Black et al. 2002). A long-term follow-up study spanning 15 years has shown that patients with depression and DST non-

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 9

Kaplan et al. 1997; Ringo et al. 1994). Another possible explanation is that decreased cholesterol in peripheral blood may reduce cholesterol levels in the brain, which may lead to reduced synaptic plasticity and brain dysfunction associated with impaired neurobehavioral

Nitric oxide (NO) is an endogenous gas that is known to influence cerebral monoaminergic activity, including serotonin activity (Montague et al. 1994; Yamada et al. 1995). In patients with major depression, the total amount and density of neurons with immunoreactivity to nitric acid synthase (NOS) were reduced in paraventricular neurons (Bernstein et al. 1998), and NOS activity was decreased in the prefrontal cortex (Xing et al. 2002). A previous study revealed that plasma NO levels were dramatically lower in patients with major depressive disorder compared to healthy controls (Chrapko et al. 2004). However, another study detected elevated NO levels in patients with major depression compared to patients with anxiety disorder and normal control subjects (Jozuka et al. 2003). We found that increased NO production in plasma is associated with suicide attempts in depressed patients (Kim et

It has been postulated that major depression is accompanied by significant changes in cellmediated and humoral immunity and that these changes are related to the pathophysiology or pathogenesis of the illness (Miller and O'Callaghan 2005; Myint and Kim 2003; Schiepers et al. 2005). Pro-inflammatory cytokines including IL-1, IL-6, IL-12, and TNF- are increased in the blood in major depression (Kim et al. 2002b; Thomas et al. 2005; Tuglu et al. 2003; Viljoen and Panzer 2005). These findings suggest that innate immunity is activated by secretion from monocytes and macrophages during major depression. A previous study measured cytokine secretion of T-cells of suicidal and non-suicidal depressed patients and healthy controls and found that the T-cells of suicidal depressed patients have Th1 characteristics, while the T-cells of non-suicidal depressed patients have Th2 characteristics (Mendlovic et al. 1999). A new hypothesis concerning the relationships between serum lipids, depression, suicide and atherosclerosis suggests that IL-2 plays important roles in lipid metabolism, depression, suicide and atherosclerosis (Colin et al. 2003; Penttinen 1995). Our group found that Th1 and Th2 cytokine imbalances are observed in a subpopulation of depressed patients (Myint et al. 2005). We also found that Th1 cytokine (IL-2 and IL-6) levels were significantly lower in suicidal depressed patients than in non-suicidal depressive patients and normal controls (Kim et al. 2007a). Collectively, NO and cytokines may be candidates for biological markers of suicidal behavior in major depression, but they have

Many studies have tried to identify biological etiologies and predictors of suicidal behavior in major depression, but this task has been difficult because most suicide risk factors have low specificity and the rate of suicide completion is relatively low the in the general population (Cohen 1986). These difficulties can be addressed when combinations of risk factors for suicide are used to estimate the suicide risk of individuals. For instance, several researchers have examined combinations of two biological risk factors for suicide simultaneously. Specifically, researchers have studied the coupling of CSF 5-HIAA and DST

consequences (Mauch et al. 2001; Pfrieger 2003).

**6. Nitric oxide and cytokines**

not yet been investigated extensively.

**7. Can we predict suicidal behavior in major depression?**

al. 2006).

suppression have a roughly 14-fold higher risk of suicide than do patients with DST suppression (Coryell and Schlesser 2001). A meta-analysis estimated the odds ratio of suicide completion to be 4.5-fold greater among non-suppressors than suppressors in patients with mood disorders (Mann et al. 2006). Moreover, other long-term follow-up studies have suggested that the DST is a useful predictor of suicidal behaviors and attempts among individuals with mood disorders, depressed inpatients, and patients with manifest suicidality, but not among the general population (Jokinen et al. 2007) or in patients displaying DST suppression (Coryell et al. 2006). Further, Jokinen and colleagues (2008b) suggested that a different threshold for cortisol levels following dexamethasone may require defining DST non-suppression for the prediction of suicide among individuals experiencing melancholic depression. Yerevanian and colleagues (2004) also reported that DST nonsuppression identifies unipolar depressed patients at higher risk of future suicide completion or hospitalization for suicidality. Overall, evidence suggests that HPA axis hyperactivity may influence the overactivity of the adrenergic system and alternations of the serotonergic system (Mann 2003; Meijer and de Kloet 1998).

#### **5. Cholesterol**

Trials of cholesterol-lowering drugs revealed increased mortality due to accidents, violence, and suicide among subjects who received the drugs (Kaplan et al. 1997; Muldoon et al. 1990). Kaplan and colleagues (1997) suggest that serum cholesterol reduction achieved by changing the serum composition or concentration of lipoproteins, could affect brain levels of fat-soluble micronutrient supply, structural lipids, cellular communication, or neurotransmitters, including serotonin. However, a second meta-analysis revealed only a modest, non-significant increase in deaths due to suicide and violence among patients receiving trials of dietary interventions and non-statin drugs (Muldoon et al. 2001).

Clinical studies of psychiatric subjects indicate a relationship between lower total cholesterol levels and suicidal behavior. Specifically, it has been reported that suicide attempters tend to have significantly lower cholesterol levels than non-suicidal psychiatric inpatients and individuals experiencing accidental injuries (Kunugi et al. 1997). Plasma cholesterol levels among acutely suicidal patients with mood disorders were found to be lower than among non-suicidal inpatients with mood disorders and healthy subjects (Papassotiropoulos et al. 1999). Additionally, a study of serum cholesterol levels showed that serum cholesterol is 30% lower among violent suicide attempters, in comparison to non-violent suicide attempters and healthy subjects (Alvarez et al. 2000). Of note, studies of Korean subjects found that serum total cholesterol levels and densities of lipoproteins tend to be lower among parasuicidal individuals, and that serum triglyceride levels tend to be lower among suicide attempters than non-suicidal patients with major depressive disorder (Kim et al. 2002a; Lee and Kim 2003). Moreover, our data suggest two cut-off points for serum cholesterol levels in patients with depression: 180 mg/dl, which may serve as a point for high sensitivity of possible risk of suicide, and 150 mg/dl, a point with a high specificity of probable risk of suicide (Kim and Myint 2004). However, studies in the general Korean population have failed to report consistent findings linking low cholesterol levels and suicidal behavior (Ellison and Morrison 2001; Iribarren et al. 1995). If suicidal behavior is associated with reductions in serum or plasma cholesterol levels, this may be explained because low cholesterol levels are related to decreased serotonin activity, which may increase tendencies toward impulsive, aggressive, and suicidal behavior (Heron et al. 1980; Kaplan et al. 1997; Ringo et al. 1994). Another possible explanation is that decreased cholesterol in peripheral blood may reduce cholesterol levels in the brain, which may lead to reduced synaptic plasticity and brain dysfunction associated with impaired neurobehavioral consequences (Mauch et al. 2001; Pfrieger 2003).

#### **6. Nitric oxide and cytokines**

8 Clinical, Research and Treatment Approaches to Affective Disorders

suppression have a roughly 14-fold higher risk of suicide than do patients with DST suppression (Coryell and Schlesser 2001). A meta-analysis estimated the odds ratio of suicide completion to be 4.5-fold greater among non-suppressors than suppressors in patients with mood disorders (Mann et al. 2006). Moreover, other long-term follow-up studies have suggested that the DST is a useful predictor of suicidal behaviors and attempts among individuals with mood disorders, depressed inpatients, and patients with manifest suicidality, but not among the general population (Jokinen et al. 2007) or in patients displaying DST suppression (Coryell et al. 2006). Further, Jokinen and colleagues (2008b) suggested that a different threshold for cortisol levels following dexamethasone may require defining DST non-suppression for the prediction of suicide among individuals experiencing melancholic depression. Yerevanian and colleagues (2004) also reported that DST nonsuppression identifies unipolar depressed patients at higher risk of future suicide completion or hospitalization for suicidality. Overall, evidence suggests that HPA axis hyperactivity may influence the overactivity of the adrenergic system and alternations of the

Trials of cholesterol-lowering drugs revealed increased mortality due to accidents, violence, and suicide among subjects who received the drugs (Kaplan et al. 1997; Muldoon et al. 1990). Kaplan and colleagues (1997) suggest that serum cholesterol reduction achieved by changing the serum composition or concentration of lipoproteins, could affect brain levels of fat-soluble micronutrient supply, structural lipids, cellular communication, or neurotransmitters, including serotonin. However, a second meta-analysis revealed only a modest, non-significant increase in deaths due to suicide and violence among patients

Clinical studies of psychiatric subjects indicate a relationship between lower total cholesterol levels and suicidal behavior. Specifically, it has been reported that suicide attempters tend to have significantly lower cholesterol levels than non-suicidal psychiatric inpatients and individuals experiencing accidental injuries (Kunugi et al. 1997). Plasma cholesterol levels among acutely suicidal patients with mood disorders were found to be lower than among non-suicidal inpatients with mood disorders and healthy subjects (Papassotiropoulos et al. 1999). Additionally, a study of serum cholesterol levels showed that serum cholesterol is 30% lower among violent suicide attempters, in comparison to non-violent suicide attempters and healthy subjects (Alvarez et al. 2000). Of note, studies of Korean subjects found that serum total cholesterol levels and densities of lipoproteins tend to be lower among parasuicidal individuals, and that serum triglyceride levels tend to be lower among suicide attempters than non-suicidal patients with major depressive disorder (Kim et al. 2002a; Lee and Kim 2003). Moreover, our data suggest two cut-off points for serum cholesterol levels in patients with depression: 180 mg/dl, which may serve as a point for high sensitivity of possible risk of suicide, and 150 mg/dl, a point with a high specificity of probable risk of suicide (Kim and Myint 2004). However, studies in the general Korean population have failed to report consistent findings linking low cholesterol levels and suicidal behavior (Ellison and Morrison 2001; Iribarren et al. 1995). If suicidal behavior is associated with reductions in serum or plasma cholesterol levels, this may be explained because low cholesterol levels are related to decreased serotonin activity, which may increase tendencies toward impulsive, aggressive, and suicidal behavior (Heron et al. 1980;

receiving trials of dietary interventions and non-statin drugs (Muldoon et al. 2001).

serotonergic system (Mann 2003; Meijer and de Kloet 1998).

**5. Cholesterol**

Nitric oxide (NO) is an endogenous gas that is known to influence cerebral monoaminergic activity, including serotonin activity (Montague et al. 1994; Yamada et al. 1995). In patients with major depression, the total amount and density of neurons with immunoreactivity to nitric acid synthase (NOS) were reduced in paraventricular neurons (Bernstein et al. 1998), and NOS activity was decreased in the prefrontal cortex (Xing et al. 2002). A previous study revealed that plasma NO levels were dramatically lower in patients with major depressive disorder compared to healthy controls (Chrapko et al. 2004). However, another study detected elevated NO levels in patients with major depression compared to patients with anxiety disorder and normal control subjects (Jozuka et al. 2003). We found that increased NO production in plasma is associated with suicide attempts in depressed patients (Kim et al. 2006).

It has been postulated that major depression is accompanied by significant changes in cellmediated and humoral immunity and that these changes are related to the pathophysiology or pathogenesis of the illness (Miller and O'Callaghan 2005; Myint and Kim 2003; Schiepers et al. 2005). Pro-inflammatory cytokines including IL-1, IL-6, IL-12, and TNF- are increased in the blood in major depression (Kim et al. 2002b; Thomas et al. 2005; Tuglu et al. 2003; Viljoen and Panzer 2005). These findings suggest that innate immunity is activated by secretion from monocytes and macrophages during major depression. A previous study measured cytokine secretion of T-cells of suicidal and non-suicidal depressed patients and healthy controls and found that the T-cells of suicidal depressed patients have Th1 characteristics, while the T-cells of non-suicidal depressed patients have Th2 characteristics (Mendlovic et al. 1999). A new hypothesis concerning the relationships between serum lipids, depression, suicide and atherosclerosis suggests that IL-2 plays important roles in lipid metabolism, depression, suicide and atherosclerosis (Colin et al. 2003; Penttinen 1995). Our group found that Th1 and Th2 cytokine imbalances are observed in a subpopulation of depressed patients (Myint et al. 2005). We also found that Th1 cytokine (IL-2 and IL-6) levels were significantly lower in suicidal depressed patients than in non-suicidal depressive patients and normal controls (Kim et al. 2007a). Collectively, NO and cytokines may be candidates for biological markers of suicidal behavior in major depression, but they have not yet been investigated extensively.

#### **7. Can we predict suicidal behavior in major depression?**

Many studies have tried to identify biological etiologies and predictors of suicidal behavior in major depression, but this task has been difficult because most suicide risk factors have low specificity and the rate of suicide completion is relatively low the in the general population (Cohen 1986). These difficulties can be addressed when combinations of risk factors for suicide are used to estimate the suicide risk of individuals. For instance, several researchers have examined combinations of two biological risk factors for suicide simultaneously. Specifically, researchers have studied the coupling of CSF 5-HIAA and DST

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 11

Wisconsin Card Sorting Test, and reported deficits in executive functioning are associated with high-lethality suicidal attempts among individuals with major depression (Keilp et al. 2001). Table 1 outlines nine risk factors for suicidal behavior and assigns one point to each factor. It is hypothesized that the total score of these risk factors is correlated with current

Suicide is a complicated phenomenon that results from the interaction of several factors, including neurobiological changes, genetic predisposition, and psychological factors. Postmortem and clinical studies suggest that serotonin dysfunction is a form of diathesis or trait style-risk factor while HPA dysfunction is associated with stress response or statedependency. Decreased cholesterol and BDNF levels are also related to brain dysfunction among suicidal individuals. Decreased serotonin functioning among suicidal individuals has been measured with CSF 5-HIAA, fenfluramine challenge studies, and levels of platelet 5-HT2A receptors. HPA axis dysfunction has been evaluated using the DST. Cholesterol and BDNF levels can be measured in blood serum or plasma. Additionally, serotonin dysfunction and lower BDNF activity has been found in the prefrontal cortex of the brain in suicidal individuals. Impairment in this region may be associated with behavioral disinhibition and executive dysfunctions, which is often examined with neurocognitive tests. We have proposed a model that incorporates present research on biological factors that may contribute to suicide risk. Clinical studies are needed to evaluate the validity of our risk scale for suicide, but we believe that based on current evidence, this provides a

It remains challenging to identify neurobiological predictors of suicidal behavior that are promising and easily assessable. Since suicidal behavior is a complex phenomenon, a multidimensional approach, including the above assessments, may be required to predict suicide risk, especially among individuals with major depression. A better understanding of the neurobiology of suicide in major depression will help detect at risk individuals or

Alvarez, J.C., Cremniter, D., Gluck, N., Quintin, P., Leboyer, M., Berlin, I., Therond, P.,

Arango, V., Underwood, M.D., Gubbi, A.V., Mann, J.J. (1995). Localized alterations in pre-

suicide victims. *Brain Research*, Vol.688, No.1-2, pp. 121-133, ISSN 0006-8993 Arato, M., Banki, C.M., Bissette, G., Nemeroff, C.B. (1989). Elevated CSF CRF in suicide victims. *Biological Psychiatry*, Vol.25, No.3, pp. 355-359, ISSN 0006-3223 Bernstein, H.G., Stanarius, A., Baumann, B., Henning, H., Krell, D., Danos, P., Falkai, P.,

Spreux-Varoquaux, O. (2000). Low serum cholesterol in violent but not in nonviolent suicide attempters. *Psychiatry Research*, Vol.95, No.2, pp. 103-108, ISSN 0165-

and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of

Bogerts, B. (1998). Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular

populations, and help develop better treatment interventions.

risk of suicide.

**8. Conclusions**

comprehensive screen.

**9. References**

1781

non-suppression (Jokinen et al. 2008a; Jokinen et al. 2009; Mann et al. 2006) and the coupling of serum cholesterol and DST non-suppression (Coryell and Schlesser 2007). These combined factors may be useful because they reflect diverse aspects of suicidal phenomena. Specifically, Jokinen and colleagues (2008a) suggest that CSF 5-HIAA and DST nonsuppression are independent biomarkers and that CSF 5-HIAA may reflect short-term suicide risk, while dysregulation of the HPA axis may be a more long-term predictor of suicidal behavior. These findings appear to be even better predictors among individuals with major depression or with previous histories of attempted suicide. Mann and colleagues (2006) also suggested that low CSF 5-HIAA and serotonin dysfunction are markers of the diathesis and that DST non-suppression and HPA axis hyperactivity are markers of the acute stress response.

Additionally, reduced cholesterol and BDNF levels in blood serum or plasma may be associated with impaired brain plasticity among individuals with suicidal behavior and ideation. In the future, it will be useful to examine multiple tests and risk factors, including CSF 5-HIAA, DST, cholesterol, and BDNF levels, as well as patient history of attempted suicide, in the prediction of suicide risk, especially among patients with depression.

We propose a model that predicts suicide risk that also considers several factors. We based this model on the Child-Pugh classification system of severity of chronic liver disease (Pugh et al. 1973) and the model is presented in Table 1. Abnormal findings associated with serotonin or HPA activity are more significant among individuals with major depression or with previous histories of attempted suicide (Coryell and Schlesser 2007; Coryell et al. 2006). Additionally, an interaction effect of childhood abuse and gene polymorphisms of serotonin transporters and BDNF has also been reported to influence the risk for suicidal behavior (Currier and Mann 2008). Suicide is associated with dysfunction in the prefrontal cortex, which is related to poor executive function. Such dysfunction can be measured with the

BDNF, brain-derived neurotrophic factor, DST, dexamethasone suppression test, CSF, cerebrospinal fluid, 5-HIAA, 5-hydroxyindoleacetic acid. Our hypothesis is that the total score of these parameters is correlated with current risk of suicide in major depression.

Table 1. Proposed classification of multiple factors to explain risk of suicide in major depression.

Wisconsin Card Sorting Test, and reported deficits in executive functioning are associated with high-lethality suicidal attempts among individuals with major depression (Keilp et al. 2001). Table 1 outlines nine risk factors for suicidal behavior and assigns one point to each factor. It is hypothesized that the total score of these risk factors is correlated with current risk of suicide.

#### **8. Conclusions**

10 Clinical, Research and Treatment Approaches to Affective Disorders

non-suppression (Jokinen et al. 2008a; Jokinen et al. 2009; Mann et al. 2006) and the coupling of serum cholesterol and DST non-suppression (Coryell and Schlesser 2007). These combined factors may be useful because they reflect diverse aspects of suicidal phenomena. Specifically, Jokinen and colleagues (2008a) suggest that CSF 5-HIAA and DST nonsuppression are independent biomarkers and that CSF 5-HIAA may reflect short-term suicide risk, while dysregulation of the HPA axis may be a more long-term predictor of suicidal behavior. These findings appear to be even better predictors among individuals with major depression or with previous histories of attempted suicide. Mann and colleagues (2006) also suggested that low CSF 5-HIAA and serotonin dysfunction are markers of the diathesis and that DST non-suppression and HPA axis hyperactivity are markers of the

Additionally, reduced cholesterol and BDNF levels in blood serum or plasma may be associated with impaired brain plasticity among individuals with suicidal behavior and ideation. In the future, it will be useful to examine multiple tests and risk factors, including CSF 5-HIAA, DST, cholesterol, and BDNF levels, as well as patient history of attempted

We propose a model that predicts suicide risk that also considers several factors. We based this model on the Child-Pugh classification system of severity of chronic liver disease (Pugh et al. 1973) and the model is presented in Table 1. Abnormal findings associated with serotonin or HPA activity are more significant among individuals with major depression or with previous histories of attempted suicide (Coryell and Schlesser 2007; Coryell et al. 2006). Additionally, an interaction effect of childhood abuse and gene polymorphisms of serotonin transporters and BDNF has also been reported to influence the risk for suicidal behavior (Currier and Mann 2008). Suicide is associated with dysfunction in the prefrontal cortex, which is related to poor executive function. Such dysfunction can be measured with the

**0 1 2 3**

suicide, in the prediction of suicide risk, especially among patients with depression.

Parameter Points assigned

Current depression negative positive

correlated with current risk of suicide in major depression.

depression.

Childhood abuse history negative positive

Genetic factors negative positive CSF 5-HIAA > cut-off ≤ cut-off

BDNF levels normal decreased

BDNF, brain-derived neurotrophic factor, DST, dexamethasone suppression test, CSF, cerebrospinal fluid, 5-HIAA, 5-hydroxyindoleacetic acid. Our hypothesis is that the total score of these parameters is

Table 1. Proposed classification of multiple factors to explain risk of suicide in major

Cholesterol levels (mg/dl) ≥ 180 180-150 < 150 Wisconsin Card Sort Test Normal Abnormal

Previous attempt 0 1 ≥ 2

DST suppression Non-suppression

acute stress response.

Suicide is a complicated phenomenon that results from the interaction of several factors, including neurobiological changes, genetic predisposition, and psychological factors. Postmortem and clinical studies suggest that serotonin dysfunction is a form of diathesis or trait style-risk factor while HPA dysfunction is associated with stress response or statedependency. Decreased cholesterol and BDNF levels are also related to brain dysfunction among suicidal individuals. Decreased serotonin functioning among suicidal individuals has been measured with CSF 5-HIAA, fenfluramine challenge studies, and levels of platelet 5-HT2A receptors. HPA axis dysfunction has been evaluated using the DST. Cholesterol and BDNF levels can be measured in blood serum or plasma. Additionally, serotonin dysfunction and lower BDNF activity has been found in the prefrontal cortex of the brain in suicidal individuals. Impairment in this region may be associated with behavioral disinhibition and executive dysfunctions, which is often examined with neurocognitive tests. We have proposed a model that incorporates present research on biological factors that may contribute to suicide risk. Clinical studies are needed to evaluate the validity of our risk scale for suicide, but we believe that based on current evidence, this provides a comprehensive screen.

It remains challenging to identify neurobiological predictors of suicidal behavior that are promising and easily assessable. Since suicidal behavior is a complex phenomenon, a multidimensional approach, including the above assessments, may be required to predict suicide risk, especially among individuals with major depression. A better understanding of the neurobiology of suicide in major depression will help detect at risk individuals or populations, and help develop better treatment interventions.

#### **9. References**

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 13

Duman, R.S., Heninger, G.R., Nestler, E.J. (1997). A molecular and cellular theory of

Dwivedi, Y., Mondal, A.C., Rizavi, H.S., Conley, R.R. (2005).  Low serum cholesterol concentration and risk of suicide.

Heron, D.S., Shinitzky, M., Hershkowitz, M., Samuel, D. (1980). Lipid fluidity markedly

Holsboer, F. (1988). Implications of altered limbic-hypothalamic-pituitary-adrenocortical

Hurd, Y.L., Herman, M.M., Hyde, T.M., Bigelow, L.B., Weinberger, D.R., Kleinman, J.E.

Iribarren, C., Reed, D.M., Wergowske, G., Burchfiel, C.M., Dwyer, J.H. (1995). Serum

Jokinen, J., Carlborg, A., Martensson, B., Forslund, K., Nordstrom, A.L., Nordstrom, P.

Jokinen, J., Martensson, B., Nordstrom, A.L., Nordstrom, P. (2008a). CSF 5-HIAA and DST

Jokinen, J., Nordstrom, A.L., Nordstrom, P. (2008b). ROC analysis of dexamethasone

Jokinen, J., Nordstrom, A.L., Nordstrom, P. (2009). CSF 5-HIAA and DST non-suppression--

Jokinen, J., Nordstrom, P. (2008). HPA axis hyperactivity as suicide predictor in elderly

Jozuka, H., Jozuka, E., Suzuki, M., Takeuchi, S., Takatsu, Y. (2003). Psycho-neuro-

Kaplan, J.R., Muldoon, M.F., Manuck, S.B., Mann, J.J. (1997). Assessing the observed

*Epidemiology*, Vol.12, No.2, pp. 168-172, ISSN 1044-3983

*Supplementum*, Vol.341, pp. 72-111, ISSN 0065-1591

*Research*, Vol.150, No.3, pp. 297-303, ISSN 0165-1781

*Disorders*, Vol.105, No.1-3, pp. 241-245, ISSN 0165-0327

*Affective Disorders*, Vol.106, No.1-2, pp. 145-152, ISSN 0165-0327

*Psychiatry Research*, Vol.165, No.1-2, pp. 96-102, ISSN 0165-1781

324, ISSN 0006-3223

7467, ISSN 0027-8424

9926

ISSN 0306-4530

ISSN 0300-7995

0077-8923

No.6, pp. 495-500, ISSN 1359-4184

depression. *Archives of General Psychiatry*, Vol.54, No.7, pp. 597-606, ISSN 0003-990X

decreased expression of neurotrophins. *Biological Psychiatry*, Vol.58, No.4, pp. 315-

modulates the binding of serotonin to mouse brain membranes. *Proceedings of the National Academy of Sciences of the United States of America*, Vol.77, No.12, pp. 7463-

(LHPA)-function for neurobiology of depression. *Acta Psychiatrica Scandinavica*

(1997). Prodynorphin mRNA expression is increased in the patch vs matrix compartment of the caudate nucleus in suicide subjects. *Molecular Psychiatry*, Vol.2,

cholesterol level and mortality due to suicide and trauma in the Honolulu Heart Program. *Archives of Internal Medicine*, Vol.155, No.7, pp. 695-700, ISSN 0003-

(2007). DST non-suppression predicts suicide after attempted suicide. *Psychiatry*

non-suppression -independent biomarkers in suicide attempters? *Journal of Affective*

suppression test threshold in suicide prediction after attempted suicide. *Journal of*

orthogonal biologic risk factors for suicide in male mood disorder inpatients.

mood disorder inpatients. *Psychoneuroendocrinology*, Vol.33, No.10, pp. 1387-1393,

immunological treatment of hepatocellular carcinoma with major depression--a single case report. *Current Medical Research and Opinion*, Vol.19, No.1, pp. 59-63,

relationship between low cholesterol and violence-related mortality. Implications for suicide risk. *Annals of the New York Academy of Sciences*, Vol.836, pp. 57-80, ISSN

nucleus of depressive patients and schizophrenics. *Neuroscience*, Vol.83, No.3, pp. 867-875, ISSN 0306-4522

Biegon, A., Fieldust, S. (1992). Reduced tyrosine hydroxylase immunoreactivity in locus coeruleus of suicide victims. *Synapse*, Vol.10, No.1, pp. 79-82, ISSN 0887-4476 Black, D.W., Monahan, P.O., Winokur, G. (2002). The relationship between DST results and

Bonkale, W.L., Turecki, G., Austin, M.C. (2006). Increased tryptophan hydroxylase

Carlson, G.A., Rich, C.L., Grayson, P., Fowler, R.C. (1991). Secular trends in psychiatric

Chrapko, W.E., Jurasz, P., Radomski, M.W., Lara, N., Archer, S.L., Le Melledo, J.M. (2004).

Cohen, J. (1986). Statistical approaches to suicidal risk factor analysis. *Annals of the New York*

Colin, A., Reggers, J., Castronovo, V., Ansseau, M. (2003). [Lipids, depression and suicide].

Correa, H., Duval, F., Mokrani, M., Bailey, P., Tremeau, F., Staner, L., Diep, T.S., Hode, Y.,

Coryell, W. (1990). DST abnormality as a predictor of course in major depression. *Journal of*

Coryell, W., Schlesser, M. (2001). The dexamethasone suppression test and suicide

Coryell, W., Schlesser, M. (2007). Combined biological tests for suicide prediction. *Psychiatry*

Coryell, W., Young, E., Carroll, B. (2006).Hyperactivity of the hypothalamic-pituitary-

Currier, D., Mann, J.J. (2008). Stress, genes and the biology of suicidal behavior. *The Psychiatric Clinics of North America*, Vol.31, No.2, pp. 247-269, ISSN 1558-3147 Dawood, T., Anderson, J., Barton, D., Lambert, E., Esler, M., Hotchkin, E., Haikerwal, D.,

Deveci, A., Aydemir, O., Taskin, O., Taneli, F., Esen-Danaci, A. (2007). Serum BDNF levels in

depression. *Neuropsychobiology*, Vol.56, No.2-3, pp. 93-97, ISSN 1423-0224

*Academy of Sciences*, Vol.487, pp. 34-41, ISSN 0077-8923

*Affective Disorders*, Vol.19, No.3, pp. 163-169, ISSN 0165-0327

*L'Encephale*, Vol.29, No.1, pp. 49-58, ISSN 0013-7006

*Research*, Vol.150, No.2, pp. 187-191, ISSN 0165-1781

Vol.142, No.1, pp. 99-104, ISSN 0165-1781

867-875, ISSN 0306-4522

85, ISSN 0887-4476

ISSN 0165-0327

0165-1781

953X

983, ISSN 1359-4184

129-134, ISSN 0006-3223

1237

nucleus of depressive patients and schizophrenics. *Neuroscience*, Vol.83, No.3, pp.

suicidal behavior. *Annals of Clinical Psychiatry* Vol.14, No.2, pp. 83-88, ISSN 1040-

immunoreactivity in the dorsal raphe nucleus of alcohol-dependent, depressed suicide subjects is restricted to the dorsal subnucleus. *Synapse*, Vol.60, No.1, pp. 81-

diagnoses of suicide victims. *Journal of Affective Disorders*, Vol.21, No.2, pp. 127-132,

Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. *Biological Psychiatry*, Vol.56, No.2, pp.

Crocq, M.A., Macher, J.P. (2000). Prolactin response to D-fenfluramine and suicidal behavior in depressed patients. *Psychiatry Research*, Vol.93, No.3, pp. 189-199, ISSN

prediction. *The American Journal of Psychiatry*, Vol.158, No.5, pp. 748-753, ISSN 0002-

adrenal axis and mortality in major depressive disorder. *Psychiatry Research*,

Kaye, D., Lambert, G. (2007). Reduced overflow of BDNF from the brain is linked with suicide risk in depressive illness. *Molecular Psychiatry*, Vol.12, No.11, pp. 981-

suicide attempters related to psychosocial stressors: a comparative study with

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 15

Lester, D. (1995). The concentration of neurotransmitter metabolites in the cerebrospinal

Lewin, G.R., Barde, Y.A. (1996). Physiology of the neurotrophins. *Annual Review of*

Leyton, M., Paquette, V., Gravel, P., Rosa-Neto, P., Weston, F., Diksic, M., Benkelfat, C.

Malberg, J.E., Eisch, A.J., Nestler, E.J., Duman, R.S. (2000). Chronic antidepressant treatment

Malone, K.M., Corbitt, E.M., Li, S., Mann, J.J. (1996). Prolactin response to fenfluramine and

Mann, J.J. (2003). Neurobiology of suicidal behaviour. *Nature Reviews Neuroscience*, Vol.4,

Mann, J.J., Currier, D., Stanley, B., Oquendo, M.A., Amsel, L.V., Ellis, S.P. (2006). Can

*Journal of Neuropsychopharmacology* Vol.9, No.4, pp. 465-474, ISSN 1461-1457 Mann, J.J., Huang, Y.Y., Underwood, M.D., Kassir, S.A., Oppenheim, S., Kelly, T.M., Dwork,

Mann, J.J., McBride, P.A., Malone, K.M., DeMeo, M., Keilp, J. (1995). Blunted serotonergic

Mann, J.J., Waternaux, C., Haas, G.L., Malone, K.M. (1999). Toward a clinical model of

Mauch, D.H., Nagler, K., Schumacher, S., Goritz, C., Muller, E.C., Otto, A., Pfrieger, F.W.

Meijer, O.C., de Kloet, E.R. (1998). Corticosterone and serotonergic neurotransmission in the

Miller, D.B., O'Callaghan, J.P. (2005). Depression, cytokines, and glial function. *Metabolism: Clinical and Experimental*, Vol.54, No.5 Suppl 1, pp. 33-38, ISSN 0026-0495 Montague, P.R., Gancayco, C.D., Winn, M.J., Marchase, R.B., Friedlander, M.J. (1994). Role of

cortex. *Science*, Vol.263, No.5149, pp. 973-977, ISSN 0036-8075

*Critical Reviews in Neurobiology*, Vol.12, No.1-2, pp. 1-20, ISSN 0892-0915 Mendlovic, S., Mozes, E., Eilat, E., Doron, A., Lereya, J., Zakuth, V., Spirer, Z. (1999).

*of General Psychiatry*, Vol.57, No.8, pp. 729-738, ISSN 0003-990X

*Neuroscience*, Vol.19, pp. 289-317, ISSN 0147-006X

45-50, ISSN 0176-3679

No.3, pp. 220-223, ISSN 0924-977X

No.24, pp. 9104-9110, ISSN 1529-2401

No.10, pp. 819-828, ISSN 1471-003X

No.2, pp. 181-189, ISSN 0002-953X

No.5545, pp. 1354-1357, ISSN 0036-8075

Vol.67, No.2, pp. 105-108, ISSN 0165-2478

64, ISSN 0893-133X

Vol.168, No.3, pp. 324-329, ISSN 0007-1250

fluid of suicidal individuals: a meta-analysis. *Pharmacopsychiatry*, Vol.28, No.2, pp.

(2006). alpha-[11C]Methyl-L-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters. *European Neuropsychopharmacology* Vol.16,

increases neurogenesis in adult rat hippocampus. *The Journal of Neuroscience* Vol.20,

suicide attempt lethality in major depression. *The British Journal of Psychiatry*

biological tests assist prediction of suicide in mood disorders? *The International*

A.J., Arango, V. (2000). A serotonin transporter gene promoter polymorphism (5- HTTLPR) and prefrontal cortical binding in major depression and suicide. *Archives*

responsivity in depressed inpatients. *Neuropsychopharmacology* Vol.13, No.1, pp. 53-

suicidal behavior in psychiatric patients. *The American Journal of Psychiatry*, Vol.156,

(2001). CNS synaptogenesis promoted by glia-derived cholesterol. *Science*, Vol.294,

hippocampus: functional implications of central corticosteroid receptor diversity.

Immune activation in non-treated suicidal major depression. *Immunology Letters*,

NO production in NMDA receptor-mediated neurotransmitter release in cerebral

Kapur, S., Mann, J.J. (1992). Role of the dopaminergic system in depression. *Biological*

Karege, F., Vaudan, G., Schwald, M., Perroud, N., La Harpe, R. (2005). Neurotrophin levels

Keilp, J.G., Sackeim, H.A., Brodsky, B.S., Oquendo, M.A., Malone, K.M., Mann, J.J. (2001).

Kim, Y.K., Jung, H.G., Myint, A.M., Kim, H., Park, S.H. (2007a). Imbalance between pro-

Kim, Y.K., Lee, H.J., Kim, J.Y., Yoon, D.K., Choi, S.H., Lee, M.S. (2002a). Low serum

Kim, Y.K., Lee, H.P., Won, S.D., Park, E.Y., Lee, H.Y., Lee, B.H., Lee, S.W., Yoon, D., Han, C.,

Kim, Y.K., Myint, A.M. (2004). Clinical application of low serum cholesterol as an indicator

Kim, Y.K., Paik, J.W., Lee, S.W., Yoon, D., Han, C., Lee, B.H. (2006). Increased plasma nitric

Kim, Y.K., Suh, I.B., Kim, H., Han, C.S., Lim, C.S., Choi, S.H., Licinio, J. (2002b). The plasma

Kunugi, H., Takei, N., Aoki, H., Nanko, S. (1997). Low serum cholesterol in suicide attempters. *Biological Psychiatry*, Vol.41, No.2, pp. 196-200, ISSN 0006-3223 Kunugi, H., Urushibara, T., Nanko, S. (2004). Combined DEX/CRH test among Japanese

Lee, B.H., Kim, H., Park, S.H., Kim, Y.K. (2007). Decreased plasma BDNF level in depressive patients. *Journal of Affective Disorders*, Vol.101, No.1-3, pp. 239-244, ISSN 0165-0327 Lee, B.H., Kim, Y.K. (2010). BDNF mRNA expression of peripheral blood mononuclear

Lee, B.H., Kim, Y.K. (2011). Potential peripheral biological predictors of suicidal behavior in

Lee, H.J., Kim, Y.K. (2003). Serum lipid levels and suicide attempts. *Acta Psychiatrica*

*Psychiatry*, Vol.35, No.4, pp. 842-847, ISSN 1878-4216

*Scandinavica*, Vol.108, No.3, pp. 215-221, ISSN 0001-690X

*Journal of Psychiatry*, Vol.158, No.5, pp. 735-741, ISSN 0002-953X

*Affective Disorders*, Vol.104, No.1-3, pp. 91-95, ISSN 0165-0327

*Scandinavica*, Vol.105, No.2, pp. 141-148, ISSN 0001-690X

*Psychiatry*, Vol.31, No.1, pp. 78-85, ISSN 0278-5846

in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. *Brain Research Molecular Brain Research*, Vol.136, No.1-2,

Neuropsychological dysfunction in depressed suicide attempters. *The American*

inflammatory and anti-inflammatory cytokines in bipolar disorder. *Journal of*

cholesterol is correlated to suicidality in a Korean sample. *Acta Psychiatrica*

Kim, D.J., Choi, S.H. (2007b). Low plasma BDNF is associated with suicidal behavior in major depression. *Progress in Neuro-Psychopharmacology & Biological*

for suicide risk in major depression. *Journal of Affective Disorders*, Vol.81, No.2, pp.

oxide level associated with suicide attempt in depressive patients. *Progress in Neuro-Psychopharmacology & Biological Psychiatry*, Vol.30, No.6, pp. 1091-1096, ISSN

levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. *Molecular Psychiatry*, Vol.7, No.10, pp. 1107-1114,

patients with major depression. *Journal of Psychiatric Research*, Vol.38, No.2, pp. 123-

cells was decreased in depressive patients who had or had not recently attempted suicide. *Journal of Affective Disorders*, Vol.125, No.1-3, pp. 369-373,

major depressive disorder. *Progress in Neuro-Psychopharmacology & Biological*

*Psychiatry*, Vol.32, No.1, pp. 1-17, ISSN 0006-3223

pp. 29-37, ISSN 0169-328X

161-166, ISSN 0165-0327

0278-5846

ISSN 1359-4184

128, ISSN 0022-3956

ISSN 1573-2517

Biological Prediction of Suicidal Behavior in Patients with Major Depressive Disorder 17

Roy, A. (1992). Hypothalamic-pituitary-adrenal axis function and suicidal behavior in depression. *Biological Psychiatry*, Vol.32, No.9, pp. 812-816, ISSN 0006-3223 Russo-Neustadt, A., Ha, T., Ramirez, R., Kesslak, J.P. (2001). Physical activity-antidepressant

Schiepers, O.J., Wichers, M.C., Maes, M. (2005). Cytokines and major depression. *Progress in*

Sher, L., Mann, J.J., Traskman-Bendz, L., Winchel, R., Huang, Y.Y., Fertuck, E., Stanley, B.H.

depression. *Brain Research*, Vol.681, No.1-2, pp. 109-116, ISSN 0006-8993 Thomas, A.J., Davis, S., Morris, C., Jackson, E., Harrison, R., O'Brien, J.T. (2005). Increase in

Traskman-Bendz, L., Ekman, R., Regnell, G., Ohman, R. (1992). HPA-related CSF

Tuglu, C., Kara, S.H., Caliyurt, O., Vardar, E., Abay, E. (2003). Increased serum tumor

Underwood, M.D., Khaibulina, A.A., Ellis, S.P., Moran, A., Rice, P.M., Mann, J.J., Arango, V.

Viljoen, M., Panzer, A. (2005). Proinflammatory cytokines: a common denominator in

Wulsin, L.R., Vaillant, G.E., Wells, V.E. (1999). A systematic review of the mortality of depression. *Psychosomatic Medicine*, Vol.61, No.1, pp. 6-17, ISSN 0033-3174 Xing, G., Chavko, M., Zhang, L.X., Yang, S., Post, R.M. (2002). Decreased calcium-dependent

Xu, H., Qing, H., Lu, W., Keegan, D., Richardson, J.S., Chlan-Fourney, J., Li, X.M. (2002).

Yamada, K., Noda, Y., Nakayama, S., Komori, Y., Sugihara, H., Hasegawa, T., Nabeshima, T.

victims. *Biological Psychiatry*, Vol.46, No.4, pp. 473-483, ISSN 0006-3223 Van Heeringen, C., Marusic, A. (2003). Understanding the suicidal brain. *The British Journal*

*Psychopharmacology*, Vol.170, No.4, pp. 429-433, ISSN 0033-3158

*of Psychiatry,* Vol.183, pp. 282-284, ISSN 0007-1250

4328

0278-5846

No.1, pp. 175-177, ISSN 0002-953X

No.2, pp. 99-106, ISSN 0924-977X

No.1-2, pp. 65-68, ISSN 0304-3940

128, ISSN 0706-7437

0920-9964

treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model. *Behavioural Brain Research*, Vol.120, No.1, pp. 87-95, ISSN 0166-

*Neuro-Psychopharmacology & Biological Psychiatry*, Vol.29, No.2, pp. 201-217, ISSN

(2006). Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters. *Journal of Affective Disorders*, Vol.90, No.1, pp. 83-89, ISSN 0165-0327 Sumiyoshi, T., Stockmeier, C.A., Overholser, J.C., Thompson, P.A., Meltzer, H.Y. (1995).

Dopamine D4 receptors and effects of guanine nucleotides on [3H]raclopride binding in postmortem caudate nucleus of subjects with schizophrenia or major

interleukin-1beta in late-life depression. *The American Journal of Psychiatry*, Vol.162,

neuropeptides in suicide attempters. *European Neuropsychopharmacology,* Vol.2,

necrosis factor-alpha levels and treatment response in major depressive disorder.

(1999). Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide

depression and somatic symptoms? *Canadian Journal of Psychiatry,* Vol.50, No.2, pp.

constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression. *Schizophrenia Research*, Vol.58, No.1, pp. 21-30, ISSN

Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. *Neuroscience Letters*, Vol.321,

(1995). Role of nitric oxide in learning and memory and in monoamine metabolism

Muldoon, M.F., Manuck, S.B., Matthews, K.A. (1990). Lowering cholesterol concentrations

Muldoon, M.F., Manuck, S.B., Mendelsohn, A.B., Kaplan, J.R., Belle, S.H. (2001). Cholesterol

Myint, A.M., Kim, Y.K. (2003). Cytokine-serotonin interaction through IDO: a

Myint, A.M., Leonard, B.E., Steinbusch, H.W., Kim, Y.K. (2005). Th1, Th2, and Th3 cytokine

Nestler, E.J., Barrot, M., DiLeone, R.J., Eisch, A.J., Gold, S.J., Monteggia, L.M. (2002). Neurobiology of depression. *Neuron*, Vol.34, No.1, pp. 13-25, ISSN 0896-6273 Norman, W.H., Brown, W.A., Miller, I.W., Keitner, G.I., Overholser, J.C. (1990). The

Ordway, G.A., Smith, K.S., Haycock, J.W. (1994a). Elevated tyrosine hydroxylase in the locus

Ordway, G.A., Widdowson, P.S., Smith, K.S., Halaris, A. (1994b). Agonist binding to alpha

Papassotiropoulos, A., Hawellek, B., Frahnert, C., Rao, G.S., Rao, M.L. (1999). The risk of

Penttinen, J. (1995). Hypothesis: low serum cholesterol, suicide, and interleukin-2. *American*

Pfrieger, F.W. (2003). Cholesterol homeostasis and function in neurons of the central

Pugh, R.N., Murray-Lyon, I.M., Dawson, J.L., Pietroni, M.C., Williams, R. (1973). Transection

Purselle, D.C., Nemeroff, C.B. (2003). Serotonin transporter: a potential substrate in the

Ringo, D.L., Lindley, S.E., Faull, K.F., Faustman, W.O. (1994). Cholesterol and serotonin:

Rogers, J., Martin, L.J., Comuzzie, A.G., Mann, J.J., Manuck, S.B., Leland, M., Kaplan, J.R.

*Journal of Epidemiology*, Vol.141, No.8, pp. 716-718, ISSN 0002-9262

No.6747, pp. 309-314, ISSN 0959-8138

519-525, ISSN 0306-9877

173, ISSN 0165-0327

ISSN 0022-3042

ISSN 1420-682X

133X

3223

*BMJ*, Vol.322, No.7277, pp. 11-15, ISSN 0959-8138

*Scandinavica*, Vol.81, No.2, pp. 120-125, ISSN 0001-690X

*Neurochemistry*, Vol.63, No.2, pp. 617-624, ISSN 0022-3042

*Pharmacopsychiatry*, Vol.32, No.1, pp. 1-4, ISSN 0176-3679

Vol.60, No.8, pp. 646-649, ISSN 0007-1323

*Psychiatry*, Vol.35, No.12, pp. 957-959, ISSN 0006-3223

and mortality: a quantitative review of primary prevention trials. *BMJ*, Vol.301,

reduction and non-illness mortality: meta-analysis of randomised clinical trials.

neurodegeneration hypothesis of depression. *Medical hypotheses*, Vol.61, No.5-6, pp.

alterations in major depression. *Journal of Affective Disorders*, Vol.88, No.2, pp. 167-

dexamethasone suppression test and completed suicide. *Acta Psychiatrica*

coeruleus of suicide victims. *Journal of Neurochemistry*, Vol.62, No.2, pp. 680-685,

2-adrenoceptors is elevated in the locus coeruleus from victims of suicide. *Journal of*

acute suicidality in psychiatric inpatients increases with low plasma cholesterol.

nervous system. *Cellular and Molecular Life Sciences* Vol.60, No.6, pp. 1158-1171,

of the oesophagus for bleeding oesophageal varices. *The British Journal of Surgery*,

biology of suicide. *Neuropsychopharmacology* Vol.28, No.4, pp. 613-619, ISSN 0893-

seeking a possible link between blood cholesterol and CSF 5-HIAA. *Biological*

(2004). Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid. *Biological Psychiatry*, Vol.55, No.7, pp. 739-744, ISSN 0006-

**2**

*Japan*

**Self-Reported Symptoms Related**

Depression is often accompanied by a wide variety of somatic symptoms even when there is no evidence of any organic disorder that can cause such symptoms. Though the underlying mechanism still remains unclear, there are two assumptions explaining the associations between somatic symptoms and depression. One is that depression itself causes several somatic symptoms. That is, people with depression may express their mental conflicts in various somatic symptoms. This hypothesis could apply especially to those who have a vague feeling of stigma or prejudice against mental disorders, and who are reluctant to frankly express their mental symptoms. From another point of view, this might mean that some chronic somatic symptoms are magnified due to the person's depressive state. Another possible hypothesis is that those who have had chronic somatic symptoms of unknown origin, in other words, functional somatic symptoms, are likely to be depressed since they cannot always receive effective medical treatment for such

Likewise, people at risk of suicide sometimes express somatic symptoms instead of obvious psychiatric symptoms, such as depressive moods, loss of interest, anxiety, or irritation. Since depression is strongly associated with suicidal risk, it may often be that those who do not show any signs of a depressive state suddenly attempt suicide, especially when they harbor strong feelings against expressing emotional conflicts of the kind described above. Therefore, general physicians should pay close attention to such suicide-related somatic symptoms as possible signs of suicide, and if necessary, take appropriate action, including

Previous epidemiological studies suggest that Japanese are generally more likely than Westerners to share a strong prejudice against mental disorders or suicidal ideation and to suppress their emotions and mental symptoms accordingly (Griffiths et al., 2006; Kawakami et al., 2008). Police officers are considered to have this tendency more strongly than the general population (Royle, Keenan, & Farrell, 2009). In such populations, some particular self-reported somatic symptoms may serve as an alternative for detecting depressive disorders or suicidal signs. Furthermore, if such people have a prejudice against mental

**1. Introduction**

symptoms.

referring such patients to a psychiatrist.

**to Depression and Suicidal Risk**

Kouichi Yoshimasu, Shigeki Takemura, Jin Fukumoto and Kazuhisa Miyashita *Department of Hygiene, School of Medicine,*

*Wakayama Medical University*

in the rat brain. *British Journal of Pharmacology*, Vol.115, No.5, pp. 852-858, ISSN 0007-1188

## **Self-Reported Symptoms Related to Depression and Suicidal Risk**

Kouichi Yoshimasu, Shigeki Takemura, Jin Fukumoto and Kazuhisa Miyashita *Department of Hygiene, School of Medicine, Wakayama Medical University Japan*

#### **1. Introduction**

18 Clinical, Research and Treatment Approaches to Affective Disorders

Yerevanian, B.I., Feusner, J.D., Koek, R.J., Mintz, J. (2004). The dexamethasone suppression

Yoon, H.K., Kim, Y.K. (2009). TPH2 -703G/T SNP may have important effect on

*Disorders*, Vol.83, No.2-3, pp. 103-108, ISSN 0165-0327

0007-1188

5846

in the rat brain. *British Journal of Pharmacology*, Vol.115, No.5, pp. 852-858, ISSN

test as a predictor of suicidal behavior in unipolar depression. *Journal of Affective*

susceptibility to suicidal behavior in major depression. *Progress in Neuro-Psychopharmacology & Biological Psychiatry*, Vol.33, No.3, pp. 403-409, ISSN 0278-

> Depression is often accompanied by a wide variety of somatic symptoms even when there is no evidence of any organic disorder that can cause such symptoms. Though the underlying mechanism still remains unclear, there are two assumptions explaining the associations between somatic symptoms and depression. One is that depression itself causes several somatic symptoms. That is, people with depression may express their mental conflicts in various somatic symptoms. This hypothesis could apply especially to those who have a vague feeling of stigma or prejudice against mental disorders, and who are reluctant to frankly express their mental symptoms. From another point of view, this might mean that some chronic somatic symptoms are magnified due to the person's depressive state. Another possible hypothesis is that those who have had chronic somatic symptoms of unknown origin, in other words, functional somatic symptoms, are likely to be depressed since they cannot always receive effective medical treatment for such symptoms.

> Likewise, people at risk of suicide sometimes express somatic symptoms instead of obvious psychiatric symptoms, such as depressive moods, loss of interest, anxiety, or irritation. Since depression is strongly associated with suicidal risk, it may often be that those who do not show any signs of a depressive state suddenly attempt suicide, especially when they harbor strong feelings against expressing emotional conflicts of the kind described above. Therefore, general physicians should pay close attention to such suicide-related somatic symptoms as possible signs of suicide, and if necessary, take appropriate action, including referring such patients to a psychiatrist.

> Previous epidemiological studies suggest that Japanese are generally more likely than Westerners to share a strong prejudice against mental disorders or suicidal ideation and to suppress their emotions and mental symptoms accordingly (Griffiths et al., 2006; Kawakami et al., 2008). Police officers are considered to have this tendency more strongly than the general population (Royle, Keenan, & Farrell, 2009). In such populations, some particular self-reported somatic symptoms may serve as an alternative for detecting depressive disorders or suicidal signs. Furthermore, if such people have a prejudice against mental

Self-Reported Symptoms Related to Depression and Suicidal Risk 21

A total of 914 consecutive new patients had check-ups at the Department of Psychosomatic Medicine in a university hospital in the Kyushu area of Japan during the period from June 2000 to March 2001. The Department usually treats primary cases with psychosomatic disorders or mild psychiatric disorders. Patients with psychotic diseases such as schizophrenia or severe depression are not treated in the Department. Those with such disorders are rather treated in the Department of Neuropsychiatry, which is distinct from the Department of Psychosomatic Medicine. In the first stage, an admitting physician interviewed the outpatients. After the interview, the patients were assigned a separate physician (physician in charge). Both the admitting physician and the physician in charge diagnosed each patient independently based on the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) (American Psychiatric Association, 1994;

Patients were diagnosed with depression if both the admitting physician and the physician in charge confirmed that their symptoms met the diagnostic criteria of major depressive disorder based on the DSM-IV. A total of 335 patients were diagnosed with depression according to those criteria. If both physicians did not diagnose the patients with a major depressive disorder, they were classified in a non-depression group (n = 423). The remaining patients (n = 156) were excluded from the analysis since a definitive diagnosis of

The patients were requested to answer questions based on the Kyudai Medical Index (KMI), Kyushu University's original medical index (Matsuoka, 1990), which was developed as a modification of the Cornell Medical Index Health Questionnaire for rapid screening. Each patient was requested to choose between dichotomous answers (yes/no), and to reveal their true intentions with a guarantee of confidentiality. They were also requested to give intuitive responses since prolonged thinking might confuse them. The question regarding suicidal ideation was included in the KMI that asked: "Do you often think you want to die?" If the patients answered "yes," they were regarded as having suicidal ideation. McNemar's test did not reveal any significant differences between this question and the corresponding suicide-related question included in the SDS (data not shown). After patients with missing data of suicidal ideation were excluded, 820 (304 men and 516 women) remained in the

KMI includes questions for 45 subjective somatic symptoms (two concerning menstruation were added for women). The patients confirmed the presence of each symptom by yes/no answers to the corresponding questions. At the same time, they were asked to note the three symptoms that were causing them the most distress, and how long they had been suffering from these symptoms, since information regarding chief complaints is important in clinical setting. The three most distressing symptoms were checked with the original health

**2.1 Outpatients visiting a psychosomatic clinic**

a major depressive disorder could not be obtained.

**2.1.2 Assessment of suicidal ideation**

**2.1.3 Assessment of somatic symptoms**

Japanese edition, 1996).

analyses.

**2.1.1 Diagnosis of depression**

disorders, rather than visit a psychiatric clinic, they are more likely to visit a psychosomatic clinic of the kind that has become popular in Japan.

Although many studies have evaluated the associations between somatic symptoms and depression or suicidal risk (Smolderen et al., 2009; Spiegel, Schoenfeld & Naliboff, 2007; Wang et al., 2007, 2009; Yoon et al., 2011), few have evaluated gender differences of such symptoms (Silverstein, 1999, 2002). Likewise, few investigations have evaluated the associations between a wide range of somatic symptoms and depression in both general and clinical populations (Haug, Mykletun & Dahl, 2004; Simon et al., 1999). In one of these reports (Simon et al., 1999), Japanese patients were reported to show the lowest number of depression-related psychological and somatic symptoms among those of 14 countries at the primary care setting. Thus, Japanese cultural characteristics may exert some influence on the relationship between somatic symptoms and depression.

We have conducted a series of epidemiological studies regarding this issue using separate samples of new outpatients visiting a psychosomatic clinic, community residents, and a working population (male police officers). The purpose of the present study is to evaluate the associations among various subjective somatic symptoms and depression as well as the suicidal risk among Japanese clinical, community and working populations. That involves establishing the key contributing elements that might aid in discovering depressive/suicidal signs in the pre-clinical or primary care stage by extracting key somatic symptoms associated with such risk in those populations. Furthermore, focusing on the outpatients who have a major depressive disorder, we evaluated the gender differences in psychiatric symptoms related to suicidal ideation.

#### **2. Methods**

Three separate samples were included in the present study; i.e., new outpatients of a psychosomatic clinic, community dwellers aged 40 or older, and male police officers in one prefectural police organization. In previously published studies of outpatients (Sugahara et al., 2004; Yoshimasu et al., 2006, 2009), we used several psychological tests, such as State-Trait Anxiety Inventory (STAI) (Spielberger, 1972) or Zung's self-rating depression scale (SDS) (Zung, Richards & Short, 1965), for evaluating their mental and physical status. Since outpatients had too many mental and somatic symptoms, those related to depression or suicidal ideation were narrowed down by an appropriate statistical method (i.e., stepwise selection).

Annual health check-up data were available for the latter two samples (community dwellers and male police officers). In those samples, the relation between each symptom (both mental and somatic) and depression or suicidal risk was assessed. Because depressive symptoms were regarded as confounding factors between somatic symptoms and suicidal risk, we adjusted for depression in multivariate analyses when suicidal risk/ideation was used as an outcome variable.

We also examined the gender differences of somatic symptoms related to suicidal ideation in outpatients visiting the psychosomatic clinic. Furthermore, focusing on the patients who have a major depressive disorder, the gender differences in psychiatric symptoms related to suicidal ideation were evaluated. Those studies were generally approved by the institutional review boards of each corresponding institution.

#### **2.1 Outpatients visiting a psychosomatic clinic**

A total of 914 consecutive new patients had check-ups at the Department of Psychosomatic Medicine in a university hospital in the Kyushu area of Japan during the period from June 2000 to March 2001. The Department usually treats primary cases with psychosomatic disorders or mild psychiatric disorders. Patients with psychotic diseases such as schizophrenia or severe depression are not treated in the Department. Those with such disorders are rather treated in the Department of Neuropsychiatry, which is distinct from the Department of Psychosomatic Medicine. In the first stage, an admitting physician interviewed the outpatients. After the interview, the patients were assigned a separate physician (physician in charge). Both the admitting physician and the physician in charge diagnosed each patient independently based on the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) (American Psychiatric Association, 1994; Japanese edition, 1996).

#### **2.1.1 Diagnosis of depression**

20 Clinical, Research and Treatment Approaches to Affective Disorders

disorders, rather than visit a psychiatric clinic, they are more likely to visit a psychosomatic

Although many studies have evaluated the associations between somatic symptoms and depression or suicidal risk (Smolderen et al., 2009; Spiegel, Schoenfeld & Naliboff, 2007; Wang et al., 2007, 2009; Yoon et al., 2011), few have evaluated gender differences of such symptoms (Silverstein, 1999, 2002). Likewise, few investigations have evaluated the associations between a wide range of somatic symptoms and depression in both general and clinical populations (Haug, Mykletun & Dahl, 2004; Simon et al., 1999). In one of these reports (Simon et al., 1999), Japanese patients were reported to show the lowest number of depression-related psychological and somatic symptoms among those of 14 countries at the primary care setting. Thus, Japanese cultural characteristics may exert some influence on the

We have conducted a series of epidemiological studies regarding this issue using separate samples of new outpatients visiting a psychosomatic clinic, community residents, and a working population (male police officers). The purpose of the present study is to evaluate the associations among various subjective somatic symptoms and depression as well as the suicidal risk among Japanese clinical, community and working populations. That involves establishing the key contributing elements that might aid in discovering depressive/suicidal signs in the pre-clinical or primary care stage by extracting key somatic symptoms associated with such risk in those populations. Furthermore, focusing on the outpatients who have a major depressive disorder, we evaluated the gender differences in psychiatric

Three separate samples were included in the present study; i.e., new outpatients of a psychosomatic clinic, community dwellers aged 40 or older, and male police officers in one prefectural police organization. In previously published studies of outpatients (Sugahara et al., 2004; Yoshimasu et al., 2006, 2009), we used several psychological tests, such as State-Trait Anxiety Inventory (STAI) (Spielberger, 1972) or Zung's self-rating depression scale (SDS) (Zung, Richards & Short, 1965), for evaluating their mental and physical status. Since outpatients had too many mental and somatic symptoms, those related to depression or suicidal ideation were narrowed down by an appropriate statistical method (i.e., stepwise

Annual health check-up data were available for the latter two samples (community dwellers and male police officers). In those samples, the relation between each symptom (both mental and somatic) and depression or suicidal risk was assessed. Because depressive symptoms were regarded as confounding factors between somatic symptoms and suicidal risk, we adjusted for depression in multivariate analyses when suicidal risk/ideation was used as an

We also examined the gender differences of somatic symptoms related to suicidal ideation in outpatients visiting the psychosomatic clinic. Furthermore, focusing on the patients who have a major depressive disorder, the gender differences in psychiatric symptoms related to suicidal ideation were evaluated. Those studies were generally approved by the institutional

clinic of the kind that has become popular in Japan.

relationship between somatic symptoms and depression.

symptoms related to suicidal ideation.

**2. Methods**

selection).

outcome variable.

review boards of each corresponding institution.

Patients were diagnosed with depression if both the admitting physician and the physician in charge confirmed that their symptoms met the diagnostic criteria of major depressive disorder based on the DSM-IV. A total of 335 patients were diagnosed with depression according to those criteria. If both physicians did not diagnose the patients with a major depressive disorder, they were classified in a non-depression group (n = 423). The remaining patients (n = 156) were excluded from the analysis since a definitive diagnosis of a major depressive disorder could not be obtained.

#### **2.1.2 Assessment of suicidal ideation**

The patients were requested to answer questions based on the Kyudai Medical Index (KMI), Kyushu University's original medical index (Matsuoka, 1990), which was developed as a modification of the Cornell Medical Index Health Questionnaire for rapid screening. Each patient was requested to choose between dichotomous answers (yes/no), and to reveal their true intentions with a guarantee of confidentiality. They were also requested to give intuitive responses since prolonged thinking might confuse them. The question regarding suicidal ideation was included in the KMI that asked: "Do you often think you want to die?" If the patients answered "yes," they were regarded as having suicidal ideation. McNemar's test did not reveal any significant differences between this question and the corresponding suicide-related question included in the SDS (data not shown). After patients with missing data of suicidal ideation were excluded, 820 (304 men and 516 women) remained in the analyses.

#### **2.1.3 Assessment of somatic symptoms**

KMI includes questions for 45 subjective somatic symptoms (two concerning menstruation were added for women). The patients confirmed the presence of each symptom by yes/no answers to the corresponding questions. At the same time, they were asked to note the three symptoms that were causing them the most distress, and how long they had been suffering from these symptoms, since information regarding chief complaints is important in clinical setting. The three most distressing symptoms were checked with the original health

Self-Reported Symptoms Related to Depression and Suicidal Risk 23

weighted value of each question; points 1, 2, 6, and 10 (comprising two questions) were allotted for each response to the former five questions, and point 4 was allotted to the last response regarding lifetime experiences of suicidal attempts. More concretely, they were: a wish to die (point 1), a desire to harm oneself (point 2), suicidal thoughts (point 6), having a suicide plan (point 10), suicide attempts (point 10) (all five of which were events occurring in the past month), and life-time suicide attempts (point 4). This scoring system is in accordance with the M.I.N.I. 5.0.0 (January 1, 2003). Thus, a total score of 33 showed the maximum points for suicidal risk. All questions included in the M.I.N.I. were coded as two categories according to the respondents' yes/no answers. Subjects who scored more than 0

An annual health examination for self-employed community dwellers in those towns was conducted during the period from May to July 2008. The health examination was comprised of several basic examinations and a doctor's check-up based on one's self-reported medical history and symptoms as confirmed by a self-administered questionnaire. The questionnaire included items regarding lifestyle factors, past and current illnesses as well as their current treatment status and self-reported symptoms. Because this health examination mainly focused on the secondary prevention of lifestyle-related diseases, a checklist included in the questionnaire for such symptoms contained a variety of 18 current physical symptoms, including those of the respiratory, cardiovascular, or digestive organs. Based on the information from this checklist, any associations between self-reported physical symptoms

Logistic regression analyses were conducted using depression and suicidal risk as outcome variables and somatic symptoms as explanatory variables. Age, sex, and two basic depressive symptoms that were used for the screening of major depressive disorders were controlled when suicidal risk was used as an outcome variable. Using logistic regression analysis, we also evaluated the associations between psychiatric symptoms of major

A total of 2399 employees at 18 stations of one prefectural police organization in the Kinki area of Japan underwent annual health checkups from May to July 2008. The number of police officers amounted to approximately 1% of all Japanese police officers. However, the characteristics of each prefectural police organization in Japan are standardized and strictly controlled by the National Police Agency. Thus, our sample would be representative of the entire Japanese police organization. Of these, 2100 (87.5%) agreed to participate in the study. After excluding female police officers whose suicidal rate is negligibly few, and clerical workers that might impede the homogenous characteristic of the study sample, 1718 male police officers remained in the analyses. Further 33 officers with missing information regarding suicidal risk were excluded in the analyses for evaluating the associations

were regarded as possibly having a suicidal risk.

and depression as well as suicidal risk were assessed.

depressive disorder as well as dysthymia and suicidal risk.

between somatic symptoms and suicidal risk.

**2.2.3 Statistical analysis**

**2.3 Male police officers**

**2.2.2 Assessment of somatic symptoms**

questionnaire, and were also later identified by the admitting physician at the first interview.

#### **2.1.4 Statistical analysis**

In our analyses of the associations between somatic symptoms and depression, those somatic symptoms identified as the three most distressing ones were used. Since some of the three most distressing symptoms were psychiatric, we also evaluated the associations between those symptoms and depression. Somatic symptoms included in the KMI were used in the analyses for associations between those somatic symptoms and suicidal ideation. In the multivariate logistic regression models, depression and suicidal ideation were used as outcome variables, while somatic symptoms were used as the explanatory variables. A stepwise method was applied to narrow down the somatic symptoms that were significantly associated with depression or suicidal ideation. The number of subjects included in the regression models varied according to each calculating algorithm due to the missing values of the relevant factors to be adjusted for. In addition, the gender differences in psychiatric symptoms related to suicidal ideation were assessed in patients with major depressive disorders by logistic regression analysis using the stepwise method. In this analysis, the candidates' psychiatric symptoms considered to be related to suicidal ideation were chosen from the KMI.

#### **2.2 Community dwellers**

Town A (total population, approximately 8000) and Town B (total population, approximately 7000) are both located in the middle of Wakayama Prefecture, the Kinki area in Japan. To detect lifestyle-related diseases such as metabolic syndrome, those towns provided an annual health check-up program for self-employed community dwellers and their family members aged 40-74 years. In 2008, a total of 3656 people aged 40-74 years were eligible for the annual health check-up program, and 686 underwent a health check-up from May through August. Among those, 452 agreed to participate in the study.

#### **2.2.1 Assessment of depression and suicidal risk**

The Mini-International Neuropsychiatric Interview (M.I.N.I.), Japanese version 5.0.0 (2003) (Sheehan et al., 1998; Sheehan & Lecrubier, 2003), a conveniently structured tool designed to identify cases of mental disorder, was used for the present interview survey. The reliability and validity of the Japanese version of the M.I.N.I. were reported to be satisfactory (Otsubo et al., 2005). A total of nine interviewers, all of whom were licensed doctors or nurses, were enrolled as competent to conduct the interviews. The first author (KY), a psychiatrist, trained them in essential interview skills, including didactic sessions of a general interview, or reviews of the instrument sections. The first author also checked the interviewers and corrected them as the need arose during the sessions so that the interview could be appropriately conducted. Thus, the diagnosis of major depressive disorder was conducted according to the diagnostic criteria of DSM-IV.

The suicidal risk of each person was measured by six relevant items included in the M.I.N.I., five of which were concerned with suicidal thoughts or behaviors within the previous onemonth, while one item dealt with lifetime experiences of suicidal attempts according to the weighted value of each question; points 1, 2, 6, and 10 (comprising two questions) were allotted for each response to the former five questions, and point 4 was allotted to the last response regarding lifetime experiences of suicidal attempts. More concretely, they were: a wish to die (point 1), a desire to harm oneself (point 2), suicidal thoughts (point 6), having a suicide plan (point 10), suicide attempts (point 10) (all five of which were events occurring in the past month), and life-time suicide attempts (point 4). This scoring system is in accordance with the M.I.N.I. 5.0.0 (January 1, 2003). Thus, a total score of 33 showed the maximum points for suicidal risk. All questions included in the M.I.N.I. were coded as two categories according to the respondents' yes/no answers. Subjects who scored more than 0 were regarded as possibly having a suicidal risk.

#### **2.2.2 Assessment of somatic symptoms**

An annual health examination for self-employed community dwellers in those towns was conducted during the period from May to July 2008. The health examination was comprised of several basic examinations and a doctor's check-up based on one's self-reported medical history and symptoms as confirmed by a self-administered questionnaire. The questionnaire included items regarding lifestyle factors, past and current illnesses as well as their current treatment status and self-reported symptoms. Because this health examination mainly focused on the secondary prevention of lifestyle-related diseases, a checklist included in the questionnaire for such symptoms contained a variety of 18 current physical symptoms, including those of the respiratory, cardiovascular, or digestive organs. Based on the information from this checklist, any associations between self-reported physical symptoms and depression as well as suicidal risk were assessed.

#### **2.2.3 Statistical analysis**

22 Clinical, Research and Treatment Approaches to Affective Disorders

questionnaire, and were also later identified by the admitting physician at the first

In our analyses of the associations between somatic symptoms and depression, those somatic symptoms identified as the three most distressing ones were used. Since some of the three most distressing symptoms were psychiatric, we also evaluated the associations between those symptoms and depression. Somatic symptoms included in the KMI were used in the analyses for associations between those somatic symptoms and suicidal ideation. In the multivariate logistic regression models, depression and suicidal ideation were used as outcome variables, while somatic symptoms were used as the explanatory variables. A stepwise method was applied to narrow down the somatic symptoms that were significantly associated with depression or suicidal ideation. The number of subjects included in the regression models varied according to each calculating algorithm due to the missing values of the relevant factors to be adjusted for. In addition, the gender differences in psychiatric symptoms related to suicidal ideation were assessed in patients with major depressive disorders by logistic regression analysis using the stepwise method. In this analysis, the candidates' psychiatric symptoms considered to be related to suicidal ideation were chosen

Town A (total population, approximately 8000) and Town B (total population, approximately 7000) are both located in the middle of Wakayama Prefecture, the Kinki area in Japan. To detect lifestyle-related diseases such as metabolic syndrome, those towns provided an annual health check-up program for self-employed community dwellers and their family members aged 40-74 years. In 2008, a total of 3656 people aged 40-74 years were eligible for the annual health check-up program, and 686 underwent a health check-up from

The Mini-International Neuropsychiatric Interview (M.I.N.I.), Japanese version 5.0.0 (2003) (Sheehan et al., 1998; Sheehan & Lecrubier, 2003), a conveniently structured tool designed to identify cases of mental disorder, was used for the present interview survey. The reliability and validity of the Japanese version of the M.I.N.I. were reported to be satisfactory (Otsubo et al., 2005). A total of nine interviewers, all of whom were licensed doctors or nurses, were enrolled as competent to conduct the interviews. The first author (KY), a psychiatrist, trained them in essential interview skills, including didactic sessions of a general interview, or reviews of the instrument sections. The first author also checked the interviewers and corrected them as the need arose during the sessions so that the interview could be appropriately conducted. Thus, the diagnosis of major depressive disorder was conducted

The suicidal risk of each person was measured by six relevant items included in the M.I.N.I., five of which were concerned with suicidal thoughts or behaviors within the previous onemonth, while one item dealt with lifetime experiences of suicidal attempts according to the

May through August. Among those, 452 agreed to participate in the study.

**2.2.1 Assessment of depression and suicidal risk**

according to the diagnostic criteria of DSM-IV.

interview.

from the KMI.

**2.2 Community dwellers**

**2.1.4 Statistical analysis**

Logistic regression analyses were conducted using depression and suicidal risk as outcome variables and somatic symptoms as explanatory variables. Age, sex, and two basic depressive symptoms that were used for the screening of major depressive disorders were controlled when suicidal risk was used as an outcome variable. Using logistic regression analysis, we also evaluated the associations between psychiatric symptoms of major depressive disorder as well as dysthymia and suicidal risk.

#### **2.3 Male police officers**