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Stress, Genes and the Biology of Suicidal Behavior
Abstract
Suicidal behavior is partly heritable. Studies seeking the responsible candidate genes have examined genes involved in neurotransmitter systems shown to have altered function in suicide and attempted suicide. These neurotransmitter systems include the serotonergic, noradrenergic, and dopaminergic systems and the hypothalamic-pituitary-adrenal axis. With some exceptions, most notably the serotonin transporter gene promoter polymorphism (HTTLPR), replication of candidate gene association studies findings has been difficult. This article reviews current knowledge of specific gene effects and gene-environment interactions that influence risk for suicidal behavior. Effects of childhood stress on development and how it influences adult responses to current stress are shown to be relevant for mood disorders, aggressive/impulsive traits, and suicidal behavior.
... Известно, что суицидальное поведение отчасти генетически детерминировано [3,7] . Предрасположенность к суицидальному поведению определяется несколькими генами, контролирующими серотонинергическую, норадренергическую, а также дофаминергическую нейромедиацию и ответственными за синтез протеинов различных нейротрансмиттерных систем, таких как транспортер серотонина, транспортер дофамина, изоформы триптофангидроксилазы, семейство рецепторов серотонина, катехол-О-метилтрансферразы (КОМТ) [9,11,12] . ...
... КОМТ является одним из главных ферментов, вовлечённых в деградацию катехоламинов [9] . Его активность контролируется геном КОМТ, который имеет около 300 сайтов нуклеотидного полиморфизма, наиболее известным из которых является Val108/158Met [11] . ...
... Функциональный полиморфизм гена КОМТ ассоциируется с высокой агрессивностью, импульсивностью, депрессией и суицидальным поведением, хотя данные литературы относительно этой связи достаточно противоречивы [9] . Метаанализ исследований, посвящённых данной проблеме, показал, что Val108/158Met полиморфизм КОМТ не ассоциируется с суицидальным поведением в общей популяции, однако является фактором риска ...
Суицидальное поведение отчасти детерминировано генетически. Предрасположенность к суицидальному поведению определяется несколькими генами, контролирующими серотонинергическую, норадренергическую,
а также дофаминергическую нейромедиацию. Катехол-О-метилтрансферраза (КОМТ) является одним из главных ферментов, вовлечённых в деградацию катехоламинов. Среди парасуицидентов СПРС преобладают мужчины с генотипом КОМТ GA (70,3%), в то время, как среди парасуицидентов СПВС относительно чаще
встречаются мужчины с генотипом КОМТ АA (33,3%). Полученные данные позволяют говорить о существовании связи между генотип КОМТ GA, вероятностью совершения суицидальной попытки различными способами
и риском развития связанных с алкоголем проблем.
... Therefore, alcohol use and suicidality might represent likelier ways of problem solving or coping with stress reactivity in this group (Gierski et al., 2022;Muddle, Jones, Taylor, & Jacobsen, 2022). Finally, alcohol can induce long-term biological changes, such as neuro-inflammation (Hillemacher, Bachmann, Kahl, & Frieling, 2018), alterations to the hypothalamic-pituitary-adrenal axis (Sudol & Mann, 2017), and reduction to the volume and density of cortices in the frontal and parieto-occipital regions of the brain (Lange et al., 2017), all of which are recognized biological markers for suicidality (Courtet et al., 2016;Currier & Mann, 2008). ...
Suicide is the leading cause of unnatural death among people with a diagnosis of schizophrenia. Alcohol use is a prevalent comorbid feature of schizophrenia and a modifiable risk factor for suicide. We conducted a prospectively registered (PROSPERO, CRD42022358214) systematic review and meta-analysis to quantify the relationship between alcohol use and suicide-related outcomes in schizophrenia.
We searched Medline, Embase, and PsycINFO for cross-sectional, case–control and longitudinal studies using exhaustive terms from database inception to December 2022 inclusive. Computation of odds ratios (ORs) and hazard ratios (HRs) were performed using a random-effects model with DerSimonian–Laird estimation. We also evaluated publication bias, study quality, and performed subgroup analysis and meta-regression. Fifty studies, comprising 65 samples, met eligibility criteria. Overall, alcohol use was associated with suicide (OR 1.38, 95% CI 1.21–1.58; HR = 1.32, 95% CI 1.00–1.74), attempted suicide (OR 1.69, 95% CI 1.45–1.98), and suicidal ideation (OR 1.69, 95% CI 1.22–2.34). While there was no evidence of publication bias, between-sample heterogeneity was moderate in analyses of attempted suicide ( I ² = 39.6%, p = 0.01) and suicidal ideation ( I ² = 56.0%, p = 0.01). Summary effects were significant in all subgroups except for longitudinal studies of attempted suicide (OR 1.60, 95% CI 0.86–3.00) and studies of suicidal ideation using gender combined samples (OR 1.63, 95% CI 0.99–2.67). Alcohol use is significantly associated with suicide-related outcomes in schizophrenia. Clinicians should routinely inquire about alcohol use in mental health services to focus preventative treatment efforts.
... On the other hand adoption family studies shows that the suicidal rates higher among the adoptees' biological parents who committed suicide (Roy, 1983;Schulsinger et al., 1979;Wender et al., 1986). Stress diathesis of suicide explained how psychiatric disorder like depression leads to suicide and suicide behavior, role of endophenotypes like aggression, impulsivity, hopelessness and other psychiatric disorders (Brent and Mann, 2005;Currier and Mann, 2008;Mann et al., 1999). This stress diathesis theory of suicide can be biologically understood by two biological pathways of neurotransmitters including dopaminergic and noradrenergic systems and HPA axis deregulation. ...
Background: This paper highlights the shifting notion of suicide with time zone. This review of literature is an attempt to understand the multifaceted concept of suicide by various thinkers with changing time in context of culture. The studies include this paper from historical view of suicide and its different concepts in various cultures through which psychologist; sociologists, Psychiatrist and biologist try to explain the definition of suicide and because of this how the identification of rate of suicide is difficult. With advancement of technology in the present time and increase use of social media leads new scenario to malaise of suicide. Moreover the sudden break of Pandemic Covid 19 evolves as the new risk factor for suicidal behavior. Method: This review incorporated with the studies related to definition of suicide and history of suicide and its worldwide incident of suicide. It also includes recent studies on social media and covid 19 pandemic as risk factors of suicide. In addition of it comprised the studies on suicide prevention strategy. Suggested by WHO. Conclusion: Suicide is as old as human and with evolution of human with society the phenomenon of suicide is also changing the behavior of suicide among the people is also changing with the time. Moreover with advancement of technology like social media and outbreaks of pandemic COVID-19 give rise new kind of challenges for the researchers and scientists for understanding and dealing with suicide. So there is a need to make new kind of multisectorial strategy with time to deals with this public health problem.
... Many efforts have been made in research to identify risk factors that drive people to suicide. Biology might play a key role determining a certain degree of familiarity for specific genes that predispose individuals to suicide [3,4]. Together with the heritability of suicide behaviors, psychosocial risk factors have a huge impact on the complexity of suicidality [5], highlighting the importance of the psychological vulnerability [6] as well as the relationship between personality traits and the neurophysiological functioning [7,8]. ...
Background:
Suicide methods chosen by victims are particularly critical in suicide risk research. To differentiate suicide deaths, it is usual to categorize them as violent and nonviolent depending on the detrimental method chosen by the victims. Caustic ingestion, for example, is traditionally considered as a nonviolent suicide method. It results in severe consequences for the human body and it is associated with high levels of lethality.
Methods:
In this study, we retrospectively analyzed suicides that occurred between 1993 and 2021 in Milan (Italy) and that underwent autopsy. We compared a sample of 40 victims that ingested caustic substances with a sample of 460 victims of other chemical ingestion, and a sample of 3962 victims from violent suicide. Univariate analyses and univariate logistic regression models were performed. Suicides from caustic poisoning were significantly older, had a higher mean number of diseases and were more affected by psychiatric diseases compared to other chemical ingestion victims. By contrast, caustic suicides, compared to violent suicides, had a more balanced gender ratio, a higher mean number of diseases, were more affected by psychiatric diseases, had a higher rate of complex suicides (more than one modality), and had victims who died more frequently inside instead of outside. In logistic regression models, age was the only feature differentiating caustic from other chemical ingestion suicides while the features differentiating caustic from violent suicides were gender, mean number of diseases and suicide place.
Conclusions:
Suicides by caustic ingestion showed substantial differences compared to violent suicides, with a higher severe profile. However, some differences were reported comparing caustic ingestion to other chemical ingestion as well. Thus, we argue whether it is more appropriate to differentiate the suicidal ingestion of caustics from both violent and nonviolent suicide methods.
... While few studies have endeavored to identify biological markers of this higher-intent subgroup, a recent study suggests that individuals with high suicidal intent exhibit cortisol non-suppression in response to the dexamethasone suppression test (DST) [27] , suggesting GR-mediated dysfunction in the HPA-axis negative feedback loop. To date, however, no study has examined cortisol reactivity to a standardized acute laboratory stress in individuals with a history of high intent SA, despite the centrality of stress to suicidal behavior [28] . ...
Higher intent suicide attempts carry elevated risk of future suicidal behavior. Abnormal functioning of the hypothalamic-pituitary-adrenal (HPA) axis is both linked to nonfatal suicidal behavior and suicide deaths in major depressive disorder. Few studies, however, have identified biological markers of a high-intent suicidal subgroup. We examined HPA axis output and reactivity to the Trier Social Stress Test (TSST) via salivary cortisol in depressed individuals (N=68) with a suicide attempt (SA) history. A median split of higher and lower suicidal intent scores was used to define groups. Individuals with high intent SA had attenuated total cortisol output (AUCg), F(1,60)=10.04, SE=5.095, p=.003, and lower HPA-axis stress responsivity to the TSST (AUCi), F(1,60)=4.50, SE=4.604, p=.039, compared with the low intent SA group. The high intent group also reported more pronounced negative affect than the low intent group (F[1,61]=6.413, SE=10.55, p=.014) both at baseline (meandiff=22.32, p=.038) and in response to the stressor task (meandiff=37.62, p=.003). Vulnerability to suicidal behavior in high-intent individuals may be related to the combined profile of impaired physiological responses to stress and greater negative affectivity. This clinical and biologic subgroup may benefit from targeted suicide prevention interventions.
... Recent life stress (RLS) is also shown to be a risk factor for developing mood disorders (Ancelin et al., 2017), suicidal thoughts (Hwang et al., 2020), suicide attempt (Roy et al., 2007;Moskowitz et al., 2013;McLafferty et al., 2019) and suicide death (Litman, 1989), in interaction with, or independently from ELA (Labonte and Turecki, 2010;Raleva, 2018;Rabbany et A c c e p t e d M a n u s c r i p t al., 2022). RLS has been linked to HPA axis dysfunction (Currier and Mann, 2008;Sublette et al., 2016;Young et al., 2021) and lower BDNF levels in MDD with recent life stress (Elzinga et al., 2011). ...
Background
The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early life adversity (ELA), recent life stress (RLS), suicide, and corticotropin releasing hormone (CRH), CRH binding protein (CRHBP), FK506-binding protein (FKBP5), glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9) and anterior cingulate cortex (BA24).
Methods
Thirteen quadruplets, matched for sex, age and postmortem interval, consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by Western blots.
Results
There were no suicide- or ELA-related differences in CRH, CRHBP, GR, or FKBP5 in BA9 or BA24, and no interaction between suicide and ELA (p>0.05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in ACC correlated negatively with RLS. LASSO logistic regression with cross-validation found combining BDNF, GR and FKBP5 BA24 levels predicted suicide but ELA did not contribute. A calculated “suicide risk score” using these measures had 71% sensitivity and 71% specificity.
Conclusion
A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears dysregulated in a region-specific way with ELA and suicide.
... Globally, it is the fourth leading cause of death in people aged 15-29 years [2]. The factors associated with the development of suicidal behavior are diverse and complex; in the last years, the HPA axis alterations have been highly related to suicide [5,26,27]. This axis responds to situations that generate stress and alter homeostasis [28]. ...
DNA methylation in genes of the hypothalamic–pituitary–adrenal (HPA) axis has been associated with suicide behavior. Through a systematic review, we aimed to evaluate DNA methylation levels of the genes involved in the HPA pathway and their association with suicide behavior. A search of articles was performed using PubMed and Science Direct, EBSCO. The terms included were “DNA methylation”, “suicide”, “epigenetics”, “HPA axis” and “suicide behavior”. This systematic review was performed by the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. Six studies comprising 743 cases and 761 controls were included in this systematic review. The studies included individuals with suicide ideation, suicide attempts or completed suicide and childhood trauma, post-traumatic stress disorder (PTSD), or depression. One study reported hypermethylation in GR in childhood trauma, while two studies found hypermethylation of NR3C1 in childhood trauma and major depressive disorder (MDD). Only one study reported hypermethylation in BNDF in people with MDD. FKBP5 was found to be hypermethylated in people with MDD. Another study reported hypermethylation in CRHBP. SKA2 was reported to be hypermethylated in one study and another study found hypomethylated both in populations with PTSD. CRHR1 was found to be hypermethylated in people with MDD, and the last study found hypomethylation in CRH. Our result showed that patients with suicidal behavior showed a DNA methylation state of genes of the HPA axis in association with psychiatric comorbidity and with adverse events. Genes of the HPA axis could play a role in suicidal behavior associated with adverse events and pathologies. As a result, DNA methylation levels, proteins, and genes involved in the HPA axis could be considered for the search for biomarkers for the prevention of suicidal behavior in future studies.
... 27 Norepinefrin dan katekolamin disebutkan berhubungan dengan respons stres tubuh dan berperan dalam munculnya psikopatologi dan perilaku bunuh diri. 28 Pada korban bunuh diri ditemukan juga peningkatan ekpsresi mRNA reseptor alfa-2 adrenergik, 29 juga ditemukannya konsentrasi norepinefrin tinggi di hipokampus. 30 Rendahnya kadar norepinefrin dalam darah dapat memberikan efek protektif terhadap perkembangan perilaku agresivitas dan impulsivitas masa kanak-kanak dan dewasa muda pada laki-laki. ...
Sejumlah 50% pelaku bunuh diri pernah melakukan percobaan bunuh diri sebelumnya. Sulitnya prediktor klinis dan tidak terdapatnya biomarker spesifik, menyulitkan prediksi perilaku bunuh diri. Perkembangan neurobiologi dan neuroimaging dapat memprediksi terjadinya upaya bunuh diri. Fifty percent individuals who committed suicide have previously conducted suicide attempts. Rare clinical predictors and the absence of specific biomarkers, lead to difficulties in predicting suicidal behavior. Neurobiology and neuroimaging may predict the occurrence of suicide.
... Finally, in the HPA axis, the dexamethasone suppression test has been extensively studied as a suicide risk biomarker. Non-suppression on the dexamethasone suppression test (DST) predicted significantly higher suicide risk in those diagnosed with depression or who had made a previous suicide attempt, though this finding was not always consistent (reviewed in Currier and Mann 2008). ...
Background
Suicide is a global health crisis. However, no objective biomarkers of suicide risk currently exist, and self-report data can be unreliable, which limits prediction, diagnostic, and treatment efforts. Reliable biomarkers that can differentiate between diagnostic subgroups, predict worsening symptoms, or suggest novel therapeutic targets would be extremely valuable for patients, researchers, and clinicians.
Methods
MEDLINE was searched for reports published between 2016 and 2021 using search terms (suicid*) AND (biomarker*) OR (indicat*). Reports that compared biomarkers between suicidal ideation, suicide attempt, death from suicide, or any suicide subgroup against other neuropsychiatric disorders were included. Studies exclusively comparing suicidal behavior or death from suicide to healthy controls were not included in order to ensure that biomarkers were specific to suicide and not other psychopathology.
Results
This review summarizes the last five years of research into suicide-associated biomarkers and provides a comprehensive guide for promising and novel biomarkers that encompass varying presentations of suicidal ideation, suicide attempt, and death by suicide. The serotonergic system, inflammation, the hypothalamic-pituitary-adrenal (HPA) axis, lipids, and endocannabinoids emerged as the most promising diagnostic, predictive, and therapeutic indicators.
Conclusions
The utility of diagnostic and predictive biomarkers is evident, particularly for suicide prevention. While larger-scale studies and further in-depth research are required, the last five years of research has uncovered essential biomarkers that could ultimately improve predictive strategies, aid diagnostics, and help develop future therapeutic targets.
... However, we realize that they matter and require future consideration (16). Similarly, we did not analyze for suicidality, which is associated with all psychiatric disorders and has, to some degree, its own genetic and experiential determinants (36,37). The sample population was examined cross-sectionally. ...
Objective:
Despite research demonstrating the value of dimensional approaches, standard systems for classifying psychotic disorders rely primarily on categorization of patients into distinct diagnoses. We present the first study comparing analyses of dimensional features, categories, and standard diagnoses, all derived from the same sample.
Methods:
Using symptom ratings from 934 patients hospitalized for psychosis, we examined dimensional models, fit using factor analysis, categorical models, fit to factor-based scores from the dimensional model, and their correspondence with DSM-defined diagnoses. We compared the ability of each model to discriminate patients' assignment to medication regimen as a clinical validator.
Results:
Dimensional modeling identified four factors (manic, depressive, negative symptoms, and positive symptoms), which corresponded to factors in prior studies and appeared robust to statistical approach. Scores based on these factors overlapped substantially among DSM diagnoses. Patients assigned to clusters had less overlap in factor-based scores. However, categorical models were sensitive to statistical approach. The addition of DSM diagnoses, but not cluster assignments, improved the fits of models with dimensional scores alone as the clinical predictors for some medication classes.
Conclusions:
The results highlight the variability of symptom presentation within DSM-defined diagnostic categories, the utility of symptom dimensions or factors, and a potential lack of robustness of data-driven categorical approaches. Findings support initiatives to develop updated diagnostic systems that complement categorical classification of psychotic illness with factors representing dimensional ratings of symptoms.
... FEV is a transcription factor exclusively involved in the differentiation and maintenance of serotonin neurons [34,43]. Previous studies have reported that FEV plays a significant role in normal anxiety-related behaviors [34,44], and impaired serotonergic function in CNS leads to psychiatric diseases, including aggressiveness and impulsive behaviors [34,45,46]. In light of the function of FEV and the potential role of the serotonergic system in psychiatric diseases, the authors speculated that the serotonergic system has functional significance in elite athletic performance. ...
Recent remarkable advances in genetic technologies have allowed for the identification of genetic factors potentially related to a predisposition to elite athletic performance. Most of these genetic variants seem to be implicated in musculoskeletal and cardiopulmonary functions. Conversely, it remains unclear whether functions of the central nervous system (CNS) genetically contribute to elite athletic traits, although the CNS plays critical roles in exercise performance. Accumulating evidence has highlighted the emerging implications of CNS-related genes in the modulation of brain activities, including mental performance and motor-related traits, thereby potentially contributing to high levels of exercise performance. In this review, recent advances are summarized, and future research directions are discussed in regard to CNS-related genes with potential roles in a predisposition to elite athletic traits.
... The "S" allele of the promoter region of serotonin transporter gene (5 HTTLPR) has lower transcriptional ability compared to its longer counterpart the "L" allele. The presence of one or two short allele "S" in promoter region of the 5HTT gene has been implicated in impaired ability to respond to stressful situations, thereby increasing the risk of depression and suicide behaviour in response to stress (Caspi et al., 2003;Currier & Mann, 2008). ...
... It is well-known that a family history of depression and suicidal ideation can predispose succeeding generations to develop these as well. [10] Hence, it is likely that the diagnosis of valvular heart disease increased the likelihood of developing major depressive illness in the victim who was already at high risk. ...
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Suicide rates continue to increase globally. The volume of research in this field has also expanded rapidly. In A Concise Guide to Understanding Suicide, leading researchers and clinicians provide a concise review of recent literature, report solutions achieved and give practical guidance for patient care to aid understanding and help prevent suicide. Each chapter is highly focused to provide pertinent information covering all major aspects of the field, from epidemiology and theories of causation through to treatment and prevention. This text will educate practising clinicians (psychologists, psychiatrists, nurses, counsellors, and emergency room personnel) and other health care workers and researchers, as well as providing a pathway for undergraduate and graduate students interested in furthering their understanding of the complexities surrounding suicide. Further, mental health professionals and those in the social sciences will be extremely interested in this monograph, as will the University community, armed forces and interested lay public.
Aims:
This study was designed to detect the association between the history of alcohol drinking and suicidality in schizophrenia (SCZ) inpatients in a Chinese population.
Methods:
We recruited 616 male SCZ inpatients and collected demographic and clinical data. Five-factor model of the Positive and Negative Syndrome Scale (PANSS) was used to assess their psychopathological symptoms.
Results:
Our results showed that 31.33% of SCZ patients had a history of alcohol drinking. They had higher rates of lifetime suicide attempt and suicidal ideation than those without a history of alcohol drinking. Moreover, patients with a history of drinking were more likely to attempt suicide (14.51% vs. 7.09%; χ2 = 7.70, df = 1, p = 0.006), with an odds ratio (OR) of 2.22 and have suicidal ideation (29.02% vs. 17.49%; χ2 = 9.89, df = 1, p = 0.002), with an OR of 1.93. In addition, patients who used to drink alcohol were more likely to be smokers and had more severe positive and depressive symptoms (all p < 0.05).
Conclusions:
Our study indicates that history of alcohol drinking may increase the prevalence of lifetime suicide attempt and suicidal ideation in male patients with chronic SCZ. Moreover, the history of alcohol drinking may be associated with some demographic data and clinical symptoms.
Standard diagnostic systems, the predominantly categorical DSM-5 and ICD-11, have limitations in validity, utility, and predictive and descriptive power. For psychotic disorders, these issues were partly addressed in current versions, but additional modifications are thought to be needed. Changes should be evidence based. We reviewed categorical, modified-categorical, and continuum-based models versus factor-based models of psychosis. Factors are clusters of symptoms or single prominent aspects of illness. Consistent evidence from studies of the genetics, pathobiology, and clinical presentation of psychotic disorders all support an underlying structure of factors, not categories, as best characterizing psychoses. Factors are not only the best fit but also comprehensive, as they can encompass any key feature of illness, including symptoms and course, as well as determinants of risk or response. Factors are inherently dimensional, even multidimensional, as are the psychoses themselves, and they provide the detail needed for either grouping or distinguishing patients for treatment decisions. The tools for making factor-based diagnoses are available, reliable, and concordant with actual practices used for clinical assessments. If needed, factors can be employed to create categories similar to those in current use. In addition, they can be used to define unique groupings of patients relevant to specific treatments or studies of the psychoses. Lastly, factor-based classifications are concordant with other comprehensive approaches to psychiatric nosology, including personalized (precision treatment) models and hierarchical models, both of which are currently being explored. Factors might be considered as the right primary structural choice for future versions of standard diagnostic systems, both DSM and ICD.
Suicidality presents a major global health concern and its association with epilepsy has been suggested. The body of evidence is growing due to targeted epidemiological studies, genetic findings, and neuroimaging data, use of specific neuropsychiatric inventories, neuropsychological tests, and metabolic and immunological studies.Suicide tendencies and psychiatric comorbidity such as depression are not uncommon in chronic diseases, especially in epilepsy. Suicide is an important cause of death in epilepsy, and is usually underestimated. Persons with epilepsy have higher risk for suicide than healthy controls. It appears that some epilepsy types have stronger tendencies for suicide, in particular temporal lobe epilepsy. The suicidal risk factors in persons with epilepsy include difficult to treat epilepsies, onset of epilepsy at an earlier age, and comorbid depression.This clinical evidence is mostly based on observational studies in which we found an increased risk of suicidal ideation, suicidal attempts, and completed suicides in persons with epilepsy. However, we lack prospective and longitudinal studies on suicide in epilepsy. In this chapter we will examine recent research in neurobiological mechanisms between suicidality and epilepsy, and comorbid depression.
This chapter focuses on a variety of deliberate self‐harm (DSH) behaviors of children and adolescents and differentiates between nonsuicidal self‐injury (NSSI) and suicidal self‐injurious behaviors. It analyses the youth at risk for engaging in these behaviors and describes etiologies attributed to DSH behaviors. The chapter presents evidence‐based management strategies for use when working with these youth. NSSI has been seen as a negative coping behavior used to end dissociative experiences. Self‐injurers have also reported engaging in NSSI in order to feel “high” or obtain a sense of “excitement” from the act itself. Suicide is a serious and growing public health concern and remains the second cause of death in youth worldwide. The chapter also presents the risk factors frequently attributed to those who pose the highest risk for suicide.
Suicide by self-immolation is a common method of suicide among young, married women in India. The associated socio-cultural beliefs and unique historical context make self-immolation an important public health concern. The practice of Sati and Jauhar were prevalent during the medieval period and vivid descriptions of these accounts exist in ancient scriptures. In the post-independence era, the majority of these incidents occurred in the form of a symbolic protest against radical social changes or as a part of glorification of the ancient tradition of Sati. Some of the risk factors associated with suicide by self-immolation in India are lower educational levels, female gender, intimate partner violence, loss or alienation. Only a handful of research studies in India examine relevant psychosocial factors predisposing to suicide. However, research limitations include small sample size and the lack of reliable measures to understand the unique social and cultural context in which self-immolation suicides occur. We describe essential components of suicide prevention programmes, including active surveillance, training and education, reducing access to means and efforts by nongovernmental and governmental organisations that could help address the problem of self-immolation in a coordinated and effective manner.
Understanding the neurobiology of suicide, in particular gene-environment interactions, could be relevant in the clinical assessment of suicide risk and prevention. Although there are no studies examining the neurobiology of suicide by self-immolation, we will demonstrate how general findings from suicide research may prove relevant in the care of persons at risk for self-immolation who experienced early trauma and retraumatization during young adulthood. The neurobiology and pathogenesis of suicide is complex and involves multiple neurotransmitter systems (serotonergic, noradrenergic, dopaminergic, glutamatergic) and different regions of the brain (brainstem, prefrontal cortex, anterior cingulate cortex, amygdala and hippocampus). Biomarkers of suicide include levels of CSF 5-HIAA, MHPG, quinolinic acid and kynurenic acid. The intergenerational transmission and a positive family history of suicide results from a combination of factors, including modeling and imitation, contagion, the transmission of an impulsive aggression phenotype, child rearing styles and concomitant environmental stressors, a shared genetic makeup and epigenetic changes. Adverse childhood experiences and a chaotic family environment increase suicide risk. Violent trauma during young adulthood also triggers suicidal behavior. Traumatic events, in particular during these sensitive periods of brain development, may trigger enduring epigenetic changes. We will review how epigenetics may be an important underlying mechanism for the pathogenesis of suicide. Epigenetic mechanisms associated with suicide include DNA methylation, histone modifications and non-coding RNA interference and silencing. Lastly, we will summarize data showing that psychosocial interventions, including brief psychotherapy interventions, may reverse epigenetic changes associated major depression, PTSD and stressor related disorders, decreasing suicide risk.
Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.
Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.
Nonhuman primates offer unique opportunities to study the effects of genes, environments, and their interaction, on physiology and complex behavior. We examined genotype and early environment contributions to CNS function in a large sample of rhesus monkeys. In humans, length variation of the serotonin (5-HT) transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) that results in allelic variation in 5-HTT expression is associated with decreased serotonergic function and 5-HT-mediated psychopathology. We report that an analogous variation of the gene's regulatory region in monkeys interacts with early experience to affect central 5-HT functioning. Monkeys with deleterious early rearing experiences were differentiated by genotype in cerebrospinal fluid concentrations of the 5-HT metabolite, 5-hydroxyindoleacetic acid, while monkeys reared normally were not. These findings demonstrate an environment-dependent effect of the rh5-HTTLPR genotype on CNS 5-HT function and suggest nonhuman primates may provide an important avenue for investigating gene/environment interactions using candidate genes for physiological and behavioral traits.
Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats.
As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed
reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid
receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing
hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all
r's > −0.6). These findings suggest that maternal behavior serves to “program” hypothalamic-pituitary-adrenal responses to
stress in the offspring.
Corticotropin-releasing hormone (CRH), somatostatin (SOM), delta-sleep-inducing peptide (DSIP), neuropeptide Y (NPY), beta-endorphin (beta-END), and vasopressin (AVP), which are regarded as being involved in the HPA-regulation were investigated in lumbar CSF of 44 suicide attempters. The patients were diagnosed according to the DSM-III-R, and rated with the MADRS. The neuropeptides were compared with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF and with post-dexamethasone plasma cortisol. We found strong correlations between CRH and the peptides SOM and beta-END. The latter also correlated positively with SOM. There were no differences between men and women. Patients with major depressive disorders had significantly lower SOM, CRH, and DSIP than other patients. Both SOM and beta-END correlated negatively with post dexamethasone plasma cortisol in all patients. We found no significant relationships between neuropeptides and CSF 5-HIAA. Patients who had made previous suicide attempts had significantly lower CRH than those who had not. No other significant associations between neuropeptides and suicidal subgroups of patients appeared, and there was no indication of specific neuropeptide patterns in patients who later completed suicide. Intercorrelations of some neuropeptides and low SOM and DSIP in major depressed patients are findings in line with those by others.
Suicidal behavior has been linked to a deficiency in serotonin neurotransmission, but it is not known which brain regions are involved. We determined the pattern of alteration in serotonin 5-HT2 (5-HT2) receptor binding sites in suicide victims in prefrontal cortex compared with temporal cortex using a matched-pairs design to study 11 suicide victims and 11 matched controls, by both membrane binding and quantitative receptor autoradiography. Since a relationship between the serotonergic and noradrenergic systems has been proposed, we also examined beta-adrenergic receptor binding sites. Binding to 5-HT2 and beta-adrenergic sites in slide-mounted sections correlated strongly with binding site number in membrane preparations. A specific laminar distribution of 5-HT2 binding sites was found in both the control and suicide groups, whereas beta-adrenergic binding sites did not differ across cortical layers. A significant increase was found in suicide victims across all cortical layers in both receptor subpopulations in the prefrontal cortex, but only beta-adrenergic sites were increased in the temporal cortex. We conclude that suicide is associated with a localized increase in 5-HT2 binding sites.
Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0.0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36–42, 2000 © 2000 Wiley‐Liss, Inc.
To assess the relationship between two phenotypes in an extremely well-characterized population of personality disorder patients–impulsive aggression and prolactin response to fenfluramine–and tryptophan hydroxylase (TPH) genotype, TPH genotype (at an intronic polymorphic site) and prolactin response to fenfluramine were assessed in 40 Caucasian patients with personality disorder. Impulsive aggression was assessed by using the Buss-Durkee Hostility Inventory (BDHI). Twenty-one male patients with the “LL” genotype had higher BDHI scores than men with the “UL” or the “UU” genotype. No relationship between genotype and prolactin response to fenfluramine was found. It was concluded that impulsive-aggressive behavior in male personality disorder patients may be associated with the TPH genotype. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:13–17, 1998. © 1998 Wiley-Liss, Inc.
Early-life experiences, including maternal interaction, profoundly influence hormonal stress responses during adulthood. In rats, daily handling during a critical neonatal period leads to a significant and permanent modulation of key molecules that govern hormonal secretion in response to stress. Thus, hippocampal glucocorticoid receptor (GR) expression is increased, whereas hypothalamic CRH-messenger RNA (mRNA) levels and stress-induced glucocorticoid release are reduced in adult rats handled early in life. Recent studies have highlighted the role of augmented maternal sensory input to handled rats as a key determinant of these changes. However, the molecular mechanisms, and particularly the critical, early events leading from enhanced sensory experience to long-lasting modulation of GR and CRH gene expression, remain largely unresolved.
To elucidate the critical primary genes governing this molecular cascade, we determined the sequence of changes in GR-mRNA levels and in hypothalamic and amygdala CRH-mRNA expression at three developmental ages, and the temporal relationship between each of these changes and the emergence of reduced hormonal stress-responses.
Down-regulation of hypothalamic CRH-mRNA levels in daily-handled rats was evident already by postnatal day 9, and was sustained through postnatal days 23 and 45, i.e. beyond puberty. In contrast, handling-related up-regulation of hippocampal GR-mRNA expression emerged subsequent to the 23rd postnatal day, i.e. much later than changes in hypothalamic CRH expression. The hormonal stress response of handled rats was reduced starting before postnatal day 23. These findings indicate that early, rapid, and persistent changes of hypothalamic CRH gene expression may play a critical role in the mechanism(s) by which early-life experience influences the hormonal stress-response long-term.
These findings support the hypothesis that the functional polymorphism in the COMT gene may modify the phenotype of suicide attempts and anger-related traits. This, however, being a novel finding, should warrant further investigation.
Background
Evidence exists for an association between aggression and schizophrenia. Although the aetiology of aggression is multifactorial, three studies have reported associations between polymorphisms of the catechol- O -methyltransferase (COMT) gene and aggression in schizophrenia.
Aims
To replicate these findings in a larger sample using the Overt Aggression Scale (OAS).
Method
A sample of 180 people with DSM–IV schizophrenia were rated for aggression using the OAS. Kruskal–Wallis and contingency table analyses were applied to the OAS results.
Results
The high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03–4.15), whereas that for the heterozygotes was 0.54 (95% CI=0. 30–1.00).
Conclusions
The high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage.
• Suicidal behavior has been linked to a deficiency in serotonin neurotransmission, but it is not known which brain regions are involved. We determined the pattern of alteration in serotonin 5-HT2 (5-HT2) receptor binding sites in suicide victims in prefrontal cortex compared with temporal cortex using a matched-pairs design to study 11 suicide victims and 11 matched controls, by both membrane binding and quantitative receptor autoradiography. Since a relationship between the serotonergic and noradrenergic systems has been proposed, we also examined β-adrenergic receptor binding sites. Binding to 5-HT2 and β-adrenergic sites in slide-mounted sections correlated strongly with binding site number in membrane preparations. A specific laminar distribution of 5-HT2 binding sites was found in both the control and suicide groups, whereas β-adrenergic binding sites did not differ across cortical layers. A significant increase was found in suicide victims across all cortical layers in both receptor subpopulations in the prefrontal cortex, but only β-adrenergic sites were increased in the temporal cortex. We conclude that suicide is associated with a localized increase in 5-HT2 binding sites.
• The cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria for major depressive episode, 15 of whom also met criteria for melancholia. Life events during the six-month period before the onset of depression were recorded using Paykel's method. There was no difference in Hamilton depression ratings between patients with life events and those without. However, depressed patients who did not have a life event in the six months before the onset of depression had significantly lower levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events. The incidence of nonsuppression on the dexamethasone suppression test was also greater in patients with a major depressive episode who did not have an undesirable life event than in those who did. Thus, the presence or absence of life events led to a separation into biologically distinct groups.
In patients with Alzheimer-type dementia, in addition to the well-known losses of cholinergic neurones, there is evidence of degeneration of the noradrenergic and serotonergic innervation of the cerebral cortex. While noradrenergic and cholinergic receptors are preserved there is a loss of serotonin S1 and S2 receptors, particularly in the temporal lobe. The loss of serotonin S2 receptors may occur at an early stage of the disease and, in temporal and frontal cortex, is correlated with the loss of somatostatin immunoreactivity. In patients dying in hospital with depression, and in individuals committing suicide, there are no consistent changes in monoamine metabolites. Noradrenergic, serotonergic, and other neurotransmitter receptors were found to be unchanged, although there was a moderate decrease in imipramine binding in a small group (n = 6) of subjects with a history of depression, who had committed suicide.
We report on 5-HT1A, 5-HT1D, and 5-HT2 binding sites in 23 control subjects and 18 suicide victims subdivided according to the method of death and the previous existence of depressive symptoms. No difference in maximum binding (Bmax) or binding affinity (Kd) was found between the control and overall suicide groups for the binding sites studied. The drug overdose subgroup showed, however, a significant decrease in the 5-HT1A binding affinity, probably explained by the higher sensitivity of this binding site to the acute administration of tricyclic antidepressants. A significant decrease in 5-HT1D binding affinity was also found in the depressed suicides, together with a significant decrease in the number of 5-HT1D binding sites in the nondepressed suicides. Further studies should be carried out on the 5-HT1D binding site as it might represent a new tool in the understanding of the depressive illness.
This article presents a series of experiments that involves the development of three novel strategies for human stress research and the utilization of these strategies to examine neurobehavioral processes of stress in healthy volunteers, schizophrenia, and affective illness. The first strategy involved intravenous 2-deoxy-d-glucose (2DG) administration, a glucoprivic Stressor. We found that glucoprivic stress results in dissociation of hypothalamus-pituitary-adrenal (HPA), adrenomedullary, and sympathoneural activity. In addition, glucoprivic stress in neuroleptic-treated schizophrenic patients caused heightened dopamine activity, as reflected by increased plasma homovanillic acid (HVA) levels and decreased adaptive responses as assessed by decreased food consumption following 2DG administration. These data suggest that neuroleptics do not prevent stress-related increases in dopamine activity and that schizophrenia may be associated with abnormalities in the stress response. The second strategy assessed effects of uncontrollable and identical amounts of controllable stress in volunteers and depressed patients. In volunteers, it was found that uncontrollable in comparison to controllable stress results in specific behavioral and neuroendocrine alterations. Moreover, uncontrollable stress exposure in depressed patients in comparison to volunteers produced greater alterations in behavioral ratings and plasma cortisol levels and that the uncontrollable stress related increases in helplessness ratings and cortisol levels were significantly correlated. These data suggest that depressed patients may have increased sensitivity to uncontrollable stress and that there may be an important interrelationship between the cognitive deficits of depression and the heightened HPA axis activity observed in these patients. Lastly, we used a naturalistic strategy to examine mechanisms relating childhood parental loss and the development of adult affective illness and found that among subjects with early parental loss histories, those who developed adult psychiatric illness had increased resting plasma levels of cortisol and beta-endorphin (ir) as compared with subjects with early loss and no adult history of psychiatric illness. Moreover, increased HPA activity in adulthood was significantly related to poor childhood adjustment to parental loss. The implications of the results of these studies are discussed.
Background
In mice, quantitative trait locus studies and behavioral evaluation of animals deleted for 5-HT1B have implicated this serotonin autoreceptor in alcohol consumption and aggressive behavior. We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism.Methods
Linkage was first tested in 640 Finnish subjects, including 166 alcoholic criminal offenders, 261 relatives, and 213 healthy controls. This was followed by a study in a large multigenerational family derived from a Southwestern American Indian tribe (n=418) with a high rate of alcoholism. All subjects were psychiatrically interviewed, blind-rated for psychiatric diagnoses, and typed for a HTR1B G861C polymorphism and for a closely linked short-tandem repeat locus, D6S284. Linkage was evaluated in sib pairs, and by using an association approach in which pedigree randomization corrects for nonindependence of observations on related subjects.Results
In Finnish sib pairs, antisocial alcoholism showed significant evidence of linkage to HTR1B G861C (P=.04) and weak evidence with D6S284 (P=.06). By association analysis, the 183 Finnish antisocial alcoholics had a significantly higher HTR1B-86IC allele frequency than the other 457 Finns we studied (P=.005). In the Southwestern American Indian tribe, significant sib pair linkage of antisocial alcoholism to HTR1B G861C (P=.01) was again observed, and there was also significant linkage to D6S284 (P=.01).Conclusion
These results suggest that a locus predisposing to antisocial alcoholism may be linked to HTR1B at 6q13-15.
Context
Evidence suggests that early adverse experiences play a preeminent role
in development of mood and anxiety disorders and that corticotropin-releasing
factor (CRF) systems may mediate this association.Objective
To determine whether early-life stress results in a persistent sensitization
of the hypothalamic-pituitary-adrenal axis to mild stress in adulthood, thereby
contributing to vulnerability to psychopathological conditions.Design and Setting
Prospective controlled study conducted from May 1997 to July 1999 at
the General Clinical Research Center of Emory University Hospital, Atlanta,
Ga.Participants
Forty-nine healthy women aged 18 to 45 years with regular menses, with
no history of mania or psychosis, with no active substance abuse or eating
disorder within 6 months, and who were free of hormonal and psychotropic medications
were recruited into 4 study groups (n = 12 with no history of childhood abuse
or psychiatric disorder [controls]; n = 13 with diagnosis of current major
depression who were sexually or physically abused as children; n = 14 without
current major depression who were sexually or physically abused as children;
and n = 10 with diagnosis of current major depression and no history of childhood
abuse).Main Outcome Measures
Adrenocorticotropic hormone (ACTH) and cortisol levels and heart rate
responses to a standardized psychosocial laboratory stressor compared among
the 4 study groups.Results
Women with a history of childhood abuse exhibited increased pituitary-adrenal
and autonomic responses to stress compared with controls. This effect was
particularly robust in women with current symptoms of depression and anxiety.
Women with a history of childhood abuse and a current major depression diagnosis
exhibited a more than 6-fold greater ACTH response to stress than age-matched
controls (net peak of 9.0 pmol/L [41.0 pg/mL]; 95% confidence interval [CI],
4.7-13.3 pmol/L [21.6-60.4 pg/mL]; vs net peak of 1.4 pmol/L [6.19 pg/mL];
95% CI, 0.2-2.5 pmol/L [1.0-11.4 pg/mL]; difference, 8.6 pmol/L [38.9 pg/mL];
95% CI, 4.6-12.6 pmol/L [20.8-57.1 pg/mL]; P<.001).Conclusions
Our findings suggest that hypothalamic-pituitary-adrenal axis and autonomic
nervous system hyperreactivity, presumably due to CRF hypersecretion, is a
persistent consequence of childhood abuse that may contribute to the diathesis
for adulthood psychopathological conditions. Furthermore, these results imply
a role for CRF receptor antagonists in the prevention and treatment of psychopathological
conditions related to early-life stress.
Figures in this Article
The relative contribution of genetic and environmental factors in the
etiology of psychiatric disorders has long been a hotly debated area of investigation.
Considerable evidence from a variety of studies suggests a preeminent role
of early adverse experiences in the development of mood and anxiety disorders.
One study1 composed of almost 2000 women revealed
that those with a history of childhood sexual or physical abuse exhibited
more symptoms of depression and anxiety and had more frequently attempted
suicide than women without a history of childhood abuse. Women who have been
abused in childhood are 4 times more likely to develop syndromal major depression
in adulthood than women who have not been abused, and the magnitude of the
abuse is correlated with the severity of depression.2
Early parental loss predominantly due to parental separation has also
been found to increase the risk for major depression in case-control and epidemiological
studies.3- 8
Twin studies9- 10 have provided
concordant findings. Childhood abuse also predisposes to the development of
anxiety disorders in adulthood, including panic disorder and generalized anxiety
disorder.11- 12 In addition, posttraumatic
stress disorder (PTSD) may be a direct consequence of childhood abuse, and,
moreover, such trauma early in life also appears to increase an individual's
risk of developing PTSD in response to other traumas in adulthood.13 Depression and anxiety disorders, including PTSD,
are often comorbid in individuals with a history of diverse early adversities.14
There is evidence that central nervous system (CNS) corticotropin-releasing
factor (CRF) systems are likely to mediate the association between early-life
stress and the development of mood and anxiety disorders in adulthood. Corticotropin-releasing
factor neurons are found not only in the hypothalamus, but also in the neocortex
and the central nucleus of the amygdala, which are believed to be involved
in cognitive and emotional processing and in brainstem nuclei that contain
the bulk of the noradrenergic and serotonergic perikarya that project to the
forebrain.
These CNS CRF systems have also been strongly implicated in the pathophysiology
of both depression and anxiety disorders.15
Thus, when administered directly into the CNS of laboratory animals, CRF produces
many physiological and behavioral changes that closely parallel symptoms of
depression and anxiety, such as elevations of peripheral adrenocorticotropic
hormone (ACTH), corticosterone, and catecholamine concentrations, increases
in heart rate and mean arterial pressure, changes in gastrointestinal activity,
decreased reproductive behavior, decreased appetite, disruption of sleep,
increased grooming behavior, increased locomotor activity in a familiar environment,
suppression of exploratory behavior in a novel environment, potentiation of
acoustic startle responses, facilitation of fear conditioning, and enhancement
of shock-induced freezing and fighting behavior.16- 20
Enhanced release of CRF from 1 or more CNS circuits may, thus, account
for many of the symptoms of depression and anxiety and for the frequent comorbidity
between these disorders.21- 22
Indeed, our group and others have repeatedly measured increased CRF-like immunoreactivity
in cerebrospinal fluid (CSF) of untreated depressed patients compared with
healthy controls and patients with other psychiatric disorders.23- 26
Moreover, increased numbers of CRF-positive neurons and increased CRF messenger
RNA (mRNA) expression have recently been measured in the paraventricular nucleus
(PVN) in postmortem hypothalamic tissue of untreated depressed patients.27- 28 Similar to findings in depression,
increased CSF CRF concentrations have been reported in patients with PTSD
and obsessive-compulsive disorder.29- 31
Of particular relevance to the current study is evidence from preclinical
studies that suggests that increased activity of CRF circuits may be the persisting
neurobiological consequence of stress early in development. Adult rats repeatedly
separated from their dams for 180 min/d on postnatal days 2 to 14 demonstrate
increased CRF concentrations in the median eminence, hypothalamohypophysial
portal blood, and CSF and increased CRF mRNA expression in the hypothalamic
PVN under resting conditions. In response to a variety of stressors, these
maternally separated rats exhibit increased CRF mRNA expression in the hypothalamic
PVN and increased ACTH and corticosterone responses.32- 33
Similarly, nonhuman primates reared as neonates with their mothers in a variable
foraging demand condition for 12 weeks demonstrate significantly elevated
CSF CRF concentrations along with stable traits of anxiety as adults.34- 35 We hypothesize that stress early
in life results in a persistent sensitization or hyperactivity of CNS CRF
systems to even mild stress in adulthood, contributing to the development
of mood and anxiety disorders. This study sought to test this hypothesis in
human subjects.
The present study was performed to test the hypotheses that allelic variants at the human dopamine D2 receptor gene locus (DRD2) confer susceptibility to alcoholism or are associated with clinical subtypes of alcoholism. We investigated anA^G substitution polymorphism in the 3'-untranslated region of exon 8 (E8) of DRD2 with allele frequencies of/G=0.295 - 0.329. No significant association of the DRD2 genotype or allele frequencies with alcoholism was found in an association study including 283 alcoholics and 146 non-alcoholic controls. However, the frequent homozygous E8 A/A genotype with fAA=0.47 - 0.48 was associated with increased anxiety and depression scores in alcoholics during the follow up after clinical detoxification treatment. In addition, E8 A/A was associated with increased suicide attempts and showed a tendency towards more severe withdrawal symptoms, early relapse and reduced responsiveness to the dopaminergic agonist apomorphine. Regression analysis revealed the DRD2 E8 genotype as the only significant factor determining withdrawal severity in female alcoholics. The findings suggest an influence of the DRD2 genotype on the neuropharmacological effects of chronic alcohol exposure and the clinical course of alcoholism.
(C) Lippincott-Raven Publishers.
Abstract An association between serotonergic dysfunction in the brain and suicidal behavior has previously been suggested. The high affinity of some antipsychotic and antidepressant drugs to serotonin 6 (5-HT6) receptors, and the predominant localization of 5-HT6 receptors in some limbic regions, suggest that 5-HT6 receptors play a role in the pathogenesis of suicide. The objective of the present study was to examine the association between suicide victims and two polymorphisms of the 5-HT6 receptor gene: a biallelic polymorphism (267C/T) in exon 1 and a trinucleotide repeat polymorphism ([GCC]2/3) in the 5′-upstream region of the gene. The two polymorphisms were genotyped in 163 suicide victims and 166 controls, and the distribution of genotype and allele frequencies between the two groups were compared. Haplotype frequencies of these two polymorphisms were estimated from genotypic data by the maximum-likelihood method. In both polymorphisms, there were no significant differences in genotype or allele frequencies between the suicide victims and the controls. Moreover, there were no significant differences in the haplotype distributions of these polymorphisms between the two groups. These findings suggest that it is unlikely that the 5-HT6 receptor gene is involved in the susceptibility to suicide.
Serotonergic systems have been reported to mediate the control of aggression and/or impulsivity in humans and to be involved in suicidal behavior. Neurochemical studies showing serotonergic dysfunction in suicide appear to support the functional alteration of serotonergic systems due to gene polymorphisms. Knock-out mice of the 5HT1B receptor gene have been reported to result in increased aggression. We hypothesized that the 5HT1B receptor-mediated serotonergic dysfunction was implicated in suicide through disinhibition of aggression and/or impulsivity. To explore this hypothesis, we examined the association between suicide victims who completed suicide and the 5HT1B receptor gene G861C polymorphism. No significant differences in genotype distribution and allele frequencies were found between suicide victims and controls. Though there is the possibility of failing to detect small effects, these results show no evidence of an association between the 5HT1B receptor gene G861C polymorphism and suicide victims in a Japanese population and indicate that it is unlikely that the 5HT1B receptor is implicated in the susceptibility to suicide. © 2001 Wiley-Liss, Inc.
Addictive drugs, including ethanol, increase the brain's dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (χ2 = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1–8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:348–352, 2000. © 2000 Wiley-Liss, Inc.
Serotonergic dysfunction has been implicated in the pathophysiology of affective disorders and suicidality. Especially the density of the 5-HT2A receptor was claimed as being increased in suicidality, proposed as an adaptive upregulation due to reduced serotonergic transmission. Recent studies have shown an association of allele C of the 5-HT2A-T102C polymorphism with suicidal ideation in patients with major depression. The purpose of this study was to test whether this proposed marker indicates susceptibility not only to suicidal ideation in depressed patients but also to suicidality as a syndrome. We investigated the 5-HT2A-T102C polymorphism in 131 suicide victims with unknown underlying psychiatric diagnoses, 84 patients with major depression with or without suicidal ideation, and 125 healthy controls. We were unable to find any association of genotype or allele frequencies to major depression, suicidal ideation, or suicide as a syndrome. Thus, our results suggest that this polymorphism may not commonly be involved in the susceptibility to suicidality. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:831–835, 2000. © 2000 Wiley-Liss, Inc.
Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0.0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36–42, 2000 © 2000 Wiley-Liss, Inc.
Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5-HT2A-C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5-HT2A-102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5-HT2A receptor gene was analyzed in 159 patients with major depression (DSM-IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi-square = 4.13, df = 1, P = 0.04) and genotype (chi-square = 6.19, df = 2, P = 0.04) distributions were found between non–suicide attempters and suicide attempters. Moreover, those patients carrying 5-HT2A-C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18–35.20, P = 0.01). Our results replicate the proposed association between 5HT2A-C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5-HT2A-C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself. © 2001 Wiley-Liss, Inc.
To assess the relationship between two phenotypes in an extremely well-characterized population of personality disorder patients–impulsive aggression and prolactin response to fenfluramine–and tryptophan hydroxylase (TPH) genotype, TPH genotype (at an intronic polymorphic site) and prolactin response to fenfluramine were assessed in 40 Caucasian patients with personality disorder. Impulsive aggression was assessed by using the Buss-Durkee Hostility Inventory (BDHI). Twenty-one male patients with the “LL” genotype had higher BDHI scores than men with the “UL” or the “UU” genotype. No relationship between genotype and prolactin response to fenfluramine was found. It was concluded that impulsive-aggressive behavior in male personality disorder patients may be associated with the TPH genotype. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:13–17, 1998. © 1998 Wiley-Liss, Inc.
The amounts of tyrosine hydroxylase protein in locus coeruleus from nine pairs of antidepressant-free suicide victims and age-matched, sudden-death control cases were determined by quantitative blot immunolabeling of cryostat-cut sections from the caudal portion of the nucleus. In each of the nine age-matched pairs, the concentration of tyrosine hydroxylase was greater in the sample from the suicide victim, with values ranging from 108 to 172% of the matched control value (\-x = 136%). By contrast, there were no differences in the concentrations of neuron-specific enolase protein in the same set of samples. Similarly, the number of neuromelanin-containing cells, counted in sections of locus coeruleus adjacent to those taken for blot immunolabeling analyses, did not differ between the two groups. These data indicate that locus coeruleus neurons from suicide victims contain higher than normal concentrations of tyrosine hydroxylase, thus raising the possibility that the expression of tyrosine hydroxylase in locus coeruleus may be relevant in the pathophysiology of suicide.
Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5′-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.
5-HT2 receptor binding sites were measured (by saturation binding of [3H]ketanserin) in brain tissue obtained at postmortem from 19 suicide victims with definite evidence of depression and 19 sex and age-matched control subjects. Five of the suicide victims were receiving antidepressant drugs prior to death; 13 suicide victims had not been prescribed antidepressant or other psychoactive drugs recently and none were found in their blood at postmortem. The number of serotonin-2 (5-HT2) binding sites in frontal, temporal and occipital cortex and amygdala did not differ significantly between the depressed suicide victims and controls, either in the total suicide group or in the antidepressant drug-free suicides. The number of 5-HT2 binding sites in the hippocampus did not differ from controls in the total suicide group but was significantly lower (by 23%) in the antidepressant-free suicide group. The affinity of [3H]ketanserin binding did not differ from controls in the antidepressant-free suicides but was lower (increased Kd) in those subjects receiving antidepressant drugs. No correlation was found between the time of death and storage of tissue or the duration of tissue storage prior to assay and the number or affinity of 5-HT2 binding sites. A significant negative correlation was found between age of the subject and the number of 5-HT2 binding sites in the frontal and occipital cortex. The present study of suicide victims with definite evidence of depression do not confirm previous studies of increased numbers of 5-HT2 binding sites in suicide victims and suggest that these previous findings may be related to factors other than depression.
We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans. A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site. Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists. Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors. We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 10.43; P = 0.003).
In a previous study, increased weight of the adrenal glands was found in a small group of persons who committed violent suicides. This finding was confirmed in our study, which comprised a group of 42 suicide cases and 37 control cases. Further analysis with special consideration toward a "relative adrenal weight" (weight/body surface) revealed that a relative combined adrenal weight >6 g/m2 may be a morphologic sign of a depressive disorder prior to death if no other disease with a known effect on the adrenals is present. These results are consistent with clinical computed tomographic findings of enlarged adrenals in depressed patients. In all suicide cases the police records were reviewed and a postmortem psychiatric diagnosis conducted to investigate whether a correlation between adrenal weight and the "severity" of depression or type of psychiatric disorder exists. In thirteen cases, psychiatric treatment prior to death was known, and a postmortem severity score of depressive disease was formed. No influence of this score or the postmortem diagnosis on the adrenal weight, however, could be detected. Also, the increase in weight of adrenal glands could not be explained by a suspected or proven preceding drug therapy or use. The effect on the pituitary-adrenal-axis by depressive disorders and changes in serotonin metabolism have been investigated repeatedly; mainly reported are increased levels of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in the depressive interval, which may lead to a growth of the adrenal glands.
The tryptophan hydroxylase 1 (TPH1) gene is reported to be associated with suicidal behavior. This has not been confirmed by prospective studies of suicide and clinical or biological mediators of this genetic risk have not been identified.
343 subjects (Caucasian, African-American, Hispanic) presenting with a Major Depressive Episode were genotyped for polymorphisms A218C in intron 7 and A-6526G in the promoter region of TPH1, and monitored for suicide attempts for up to one year. Clinical correlates of suicidal behavior and CSF-HIAA, HVA and MHPG levels were explored as possible mediators of genetic risk. Analyses were adjusted for ethnicity.
The AA genotype on intron 7 and the AA genotype on the promoter (both more prevalent in Caucasians) predicted suicide attempts during the 1 year follow-up, and were associated with past attempts of high medical lethality, regardless of ethnicity. The intron 7 genotype was associated with fewer reported reasons for living, and lower impulsivity. Haplotype analysis indicated significant increase in risk of suicide attempts for subjects with four risk alleles. TPH1 genotype was not associated with CSF metabolite levels.
The TPH1 gene is likely one of several genes associated with suicidal behavior. Power to detect differential genotype effects by ethnicity is low.
Polymorphisms of TPH1 may assist in identifying a subgroup of mood disorder patients that is at higher risk for suicidal behavior.
Different nuclei and regions of the brain from patients who had committed suicide and from controls were analysed for their content of monoamine and monoamine metabolites.
There was a post mortem breakdown of 5-hydroxyindoleacetic acid (5-HIAA) which could be correlated to the time elapsed between the occurrence of death and autopsy. Homovanillic acid (HVA) and the monoamines did not decrease post mortem during the time observed (6–148 hours). There was no significant correlation between age and chemical variables in this investigation.
There were no significant group differences between suicides and controls concerning dopamine, noradrenaline, 5-hydroxytryptamine, and HVA, 5-HIAA levels were significantly lower in the suicide group in six out of eight parts of the brain investigated. It was, however, also demonstrated that there was a longer time elapse between the occurrence of death and autopsy in the suicide group. The suicides came on average 48 hours later to autopsy than the controls. As there was a post mortem decrease of 5-HIAA, this time variable had to be kept constant when group differences were analysed. When the influence of this time variable had to be kept constant when group differences were analysed. When the influence of this time variable was eliminated there were no longer any differences between suicides and controls.
According to this investigation, there seem to be no differences in levels of monoamines and their metabolites between suicides and controls.
Cerebrospinal fluid studies have reported that low concentrations of the dopamine metabolite homovanillic acid are associated with suicidal behavior in depression. Although only a small proportion of homovanillic acid in the urine derives from the brain, we decided to examine 24-hour urinary outputs of homovanillic acid in relation to suicidal behavior in depression. Patients with depression who had attempted suicide had significantly smaller urinary outputs of homovanillic acid, dihydroxyphenylacetic acid, and total body output of dopamine (sum dopamine) than did patients with depression who had not attempted suicide. Patients with depression who reattempted suicide during 5-year follow-up had significantly smaller urinary outputs of homovanillic acid and sum dopamine than did patients who did not reattempt suicide, patients who never attempted suicide, and normal control subjects, and had significantly smaller outputs of dihydroxyphenylacetic acid than patients who never attempted suicide or control subjects. These data suggest that urinary outputs of homovanillic acid may be peripheral correlates of suicidality in depression. These data add to data on the low levels of homovanillic acid in cerebrospinal fluid in suggesting that diminished dopaminergic neurotransmission may play a part in suicidal behavior in depression.
Hypothalamic-pituitary-adrenal (HPA) axis function was examined in relation to suicidal behavior in depression. There were no significant differences between depressed patients who had or had not attempted suicide for either cerebrospinal fluid concentrations of corticotropin-releasing hormone, plasma cortisol levels predexamethasone or postdexamethasone, or for urinary-free cortisol outputs. However, depressed patients who had made a violent suicide attempt had significantly higher 4 PM and maximum postdexamethasone plasma cortisol levels, and significantly more of them were cortisol nonsuppressors than patients who had made nonviolent suicide attempts. A 5-year follow-up was carried out. There were no significant differences on indices of HPA function between depressed patients who did or did not reattempt suicide during the follow-up or who had never attempted suicide. These results suggest the possibility that dysregulation of the HPA axis may be a determinant of violent suicidal behavior in depression.
To determine whether the well-documented hyperactivity of the hypothalamic-pituitary-adrenal axis in depressed patients includes adrenal gland hypertrophy, adrenal gland size was evaluated by computed tomography. Assessments consisted of (1) global ratings by two radiologists ignorant of the diagnostic identity of the subjects and (2) calculation of adrenal volume. Of the 38 patients with major depression, 12 were rated as exhibiting adrenal hypertrophy. Adrenal volumes in the depressed patients were significantly increased when compared with those of normal controls. Adrenal gland size was not correlated with dexamethasone suppression test results, patient age, duration of the depressive episode, or depression severity. These results are concordant with the hypothesis that chronic corticotropin hypersecretion in depression results in adrenocortical hypertrophy. Adrenal gland enlargement may be a measure of cumulative lifetime depression.
The monoaminergic innervation of the amygdala of the squirrel monkey (Saimiri sciureus) was studied by using immunohistochemical methods with primary antisera raised against serotonin, and the catecholamine synthesizing enzymes tyrosine hydroxylase, dopamine-beta-hydroxylase and phenylethanolamine-N-methyltransferase. Serotonin was widely distributed within the amygdala including profuse terminal labeling in central, basolateral and cortical nuclear groups. The accessory basal and medial nuclei were the only two areas receiving relatively poor serotoninergic innervation. Tyrosine hydroxylase was more discretely distributed, with very dense to moderate terminal labeling in central, basal and lateral nuclei, but only scant labeling within accessory basal and corticomedial nuclei, except at the cortical transitional area where dense terminal labeling was noted. Dopamine-beta-hydroxylase immunoreactivity was moderate in central and corticomedial nuclei, but comparatively light in other nuclear groups. Phenylethanolamine-N-methyltransferase was only sparsely distributed in the amygdala. The findings of the present study reveal that the monoaminergic innervation of the primate amygdala is similar to that reported in rodents, although some conspicuous exceptions do exist. Whereas the noradrenergic and serotoninergic neuronal systems ramify profusely within the amygdala, the dopaminergic system appears to be more discretely and topographically organized.
The present study was undertaken to further explore the relationship between the dexamethasone suppression test (DST) and suicide. Depressed inpatients who had undergone the DST at index admission and later committed suicide (n = 13) were matched for age, gender, diagnosis, and type of DST (1 mg, 2 mg) with depressed inpatients from the same hospital and study time period to form 2 groups: a suicide attempter group (n = 25) and a nonattempter group (n = 28). The suicide completers group had significantly higher 1600 postdexamethasone cortisol levels than the suicide attempters group and a significantly higher 1600 rate of DST nonsuppression compared with the suicide attempter + nonattempter combined group. Although the rate of DST nonsuppression did not differ between the suicide attempter and nonattempter groups, serious attempters had significantly higher 1600 cortisol levels and a statistically higher proportion of patients who completed suicide than nonserious attempters.(ABSTRACT TRUNCATED AT 250 WORDS)
Serotonergic mechanisms have been investigated in postmortem brain samples from controls and suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus and the high-affinity binding of ligands to the 5-HT1, 5-HT2 and imipramine-binding sites was assessed in frontal cortex, occipital cortex and hippocampus. The only significant difference between the two groups was a modest increase in 5-HIAA levels in the hippocampus of suicide victims. There was no evidence to suggest that those suicide victims with a clinical history of depression represented a subgroup with altered metabolite levels or binding values. The storage conditions of the samples were not related to the metabolite levels or binding values. There was, however, a significant positive correlation between [3H]imipramine binding and age in some brain regions. The results do not provide any evidence of gross alterations in 5-HT mechanisms in suicide or depression.
This chapter has reviewed biochemical and morphological studies of the human and monkey serotonergic system. In addition, the serotonin-producing neurons of M fascicularis were analyzed, using immunocytochemistry, radioautography, and measurements of synaptosomal serotonin reuptake and supernatant tryptophan hydroxylase activity. The major sections of the chapter covered cell bodies, pathways, subcortical distribution, and cortical distribution, and a gross brain dissection guide of M fascicularis is included. An atlas of the 5-HT-IR cell bodies was presented in Figures 7 to 33. Rostral and caudal groups of nuclei were discussed. The rostral group consists principally of the nuclei raphe dorsalis (B7 and B6), centralis superior (B8, B5, and part of B7), and prosupralemniscus (B9). These groups ascend mainly in tracts lying outside the medial forebrain bundle (MFB). In M fascicularis, 25% of the fibers within the MFB are myelinated. The caudal 5-HT-IR nuclei consist principally of the nuclei in a dorsal cluster (raphe obscurus, B2) and in a ventral cluster (pallidus, B1, and magnus B3). The dorsal 5-HT-IR cells in raphe obscurus are associated with the MLF, and cells extend into cervical spinal cord (lamina IX and X) with the descending MLF and the TTS. Fibers from the raphe obscurus innervate the motoneurons in both the cranial nuclei (X, XII) and the ventral horn. The ventral 5-HT-IR cells lie mainly medial to the medial leminiscal fibers. A large number of these cells extend laterally into paragigantocellularis lateralis and here extend caudally lying below the lateral reticular nuclei. Cells from this group are seen dorsally joining the internal arcuate fibers. The raphe magnus of the ventral cluster projects to the dorsal horn and is believed to mediate the serotonin-induced analgesia. The descending fibers from both of these clusters are occasionally myelinated. Also, in our tryptophan- and pargyline-pretreated monkeys, small 5 HT-IR cells were visible in the area postrema. Human and monkey biochemical data (detailed summary in Tables 1-6) provide evidence for the presence of serotonin fibers in all cortical and subcortical regions. In subcortical regions, the midbrain, medulla, amygdala, and substantia nigra have the highest, whereas the cerebellum, spinal cord, and ventral pons have the lowest amount of serotonin and its metabolite, 5-HIAA. In the basal ganglion, the globus pallidus has the highest rate of 5-HT synthesis. The temporal lobe receives the most serotonin of the major cortical lobes.(ABSTRACT TRUNCATED AT 400 WORDS)
The cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria for major depressive episode, 15 of whom also met criteria for melancholia. Life events during the six-month period before the onset of depression were recorded using Paykel's method. There was no difference in Hamilton depression ratings between patients with life events and those without. However, depressed patients who did not have a life event in the six months before the onset of depression had significantly lower levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events. The incidence of nonsuppression on the dexamethasone suppression test was also greater in patients with a major depressive episode who did not have an undesirable life event than in those who did. Thus, the presence or absence of life events led to a separation into biologically distinct groups.
Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.
This article presents a series of experiments that involves the development of three novel strategies for human stress research and the utilization of these strategies to examine neurobehavioral processes of stress in healthy volunteers, schizophrenia, and affective illness. The first strategy involved intravenous 2-deoxy-D-glucose (2DG) administration, a glucoprivic stressor. We found that glucoprivic stress results in dissociation of hypothalamus-pituitary-adrenal (HPA), adrenomedullary, and sympathoneural activity. In addition, glucoprivic stress in neuroleptic-treated schizophrenic patients caused heightened dopamine activity, as reflected by increased plasma homovanillic acid (HVA) levels and decreased adaptive responses as assessed by decreased food consumption following 2DG administration. These data suggest that neuroleptics do not prevent stress-related increases in dopamine activity and that schizophrenia may be associated with abnormalities in the stress response. The second strategy assessed effects of uncontrollable and identical amounts of controllable stress in volunteers and depressed patients. In volunteers, it was found that uncontrollable in comparison to controllable stress results in specific behavioral and neuroendocrine alterations. Moreover, uncontrollable stress exposure in depressed patients in comparison to volunteers produced greater alterations in behavioral ratings and plasma cortisol levels and that the uncontrollable stress related increases in helplessness ratings and cortisol levels were significantly correlated. These data suggest that depressed patients may have increased sensitivity to uncontrollable stress and that there may be an important interrelationship between the cognitive deficits of depression and the heightened HPA axis activity observed in these patients. Lastly, we used a naturalistic strategy to examine mechanisms relating childhood parental loss and the development of adult affective illness and found that among subjects with early parental loss histories, those who developed adult psychiatric illness had increased resting plasma levels of cortisol and beta-endorphin (ir) as compared with subjects with early loss and no adult history of psychiatric illness. Moreover, increased HPA activity in adulthood was significantly related to poor childhood adjustment to parental loss. The implications of the results of these studies are discussed.
The authors determined serotonin2 (5-HT2) binding in the frontal cortex of 32 suicide victims and 37 subjects who died from nonpsychiatric causes. The maximum number of binding sites (Bmax) and the affinity (Kd) were significantly higher in subjects who had committed suicide than in control subjects. However, there was no difference in Kd between these two groups after the influence of age, race, sex, and postmortem delay was covaried. The Bmax of subjects who had committed violent suicide was significantly greater than that of control subjects.