Dianne Currier

Candidate Endophenotypes for Genetic Studies of Suicidal Behavior

Twin, adoption, and family studies have established the heritability of suicide attempts and suicide. Identifying specific suicide diathesis-related genes has proven more difficult. As with psychiatric disorders in general, methodological difficulties include complexity of the phenotype for suicidal behavior and distinguishing suicide diathesis-related genes from genes associated with mood disorders and other suicide-associated psychiatric illness. Adopting an endophenotype approach involving identification of genes associated with heritable intermediate phenotypes, including biological and/or behavioral markers more proximal to genes, is an approach being used for other psychiatric disorders. Therefore, a workshop convened by the American Foundation for Suicide Prevention, the Department of Psychiatry at Columbia University, and the National Institute of Mental Health sought to identify potential target endophenotypes for genetic studies of suicidal behavior. The most promising endophenotypes were trait aggression/impulsivity, early-onset major depression, neurocognitive function, and cortisol social stress response. Other candidate endophenotypes requiring further investigation include serotonergic neurotransmission, second messenger systems, and borderline personality disorder traits.

Prospective studies of suicidal behavior in major depressive and bipolar disorders: what is the evidence for predictive risk factors?

Objective:  Prospective studies over the past 30 years have identified an array of predictive indicators for suicidal acts in mood disorders. However, prediction of suicidal behavior remains an elusive goal. This paper reviewed evidence from prospective studies for clinical factors that elevate risk of suicidal acts in that group.

Can biological tests assist prediction of suicide in mood disorders

Predicting suicide is difficult due to its low base-rate and the limited specificity of clinical predictors. Prospective biological studies suggest that dysfunctions in the serotonergic system and hypothalamic-pituitary-adrenal axis have some predictive power for completed suicide in mood disorders. A prediction model that incorporates biological testing to increase specificity and sensitivity of prediction of suicide is of potential clinical value. Meta-analyses of prospective biological studies of suicide and cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and suicide and the dexamethasone suppression test (DST) in mood disorders using the penalized quasi-likelihood (PQL) and bootstrap method yield odds ratios for prediction of suicide of 4.48 and 4.65 respectively. Two combinatory prediction models, the first requiring positive results on more than one test, and the second requiring a positive result on either one of two tests, were tested to assess their sensitivity, specificity, and predictive power using biological data from published and unpublished studies. The prediction model that requires both DST and CSF 5-HIAA tests to be positive results in 37.5% sensitivity, 88% specificity, and has a positive predictive value of 23%. The prediction model that requires either DST or CSF 5-HIAA tests to be positive results in 87.5% sensitivity, 28% specificity, and has a positive predictive value of 10%. Thus, models attempting to predict a lethal outcome that is uncommon perform very differently making model choice of major importance. Further work on refining biological predictors and integration with clinical predictors is needed to optimize a model to predict suicide in the clinic.

A Review of Prospective Studies of Biologic Predictors of Suicidal Behavior in Mood Disorders.

Predicting suicide is difficult due to the low base rate, even in high-risk groups, and the multi-causal nature of suicidal behavior. Clinical predictors have shown low specificity. Retrospective and cross-sectional studies have identified a number of biologic anomalies associated with suicide and suicide attempt. Prospective studies provide estimates of the predictive utility of biologic measures. Here we review prospective studies of suicidal behavior and serotonergic, noradrenergic, dopaminergic and hypothalamic-pituitary-adrenocortical axis function in mood disorders. The most promising biologic predictors are low CSF 5-HIAA and HPA axis dysfunction as demonstrated by dexamethasone non-suppression that are each associated with about 4.5 fold greater risk of suicide.

Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression

Alterations in a number of neurobiological systems have been associated with suicidal behavior including the serotonergic and noradrenergic systems and the hypothalamic-pituitary-adrenal axis. Altered functioning of these systems may stem from both genetic and developmental causes. Adversity in early-life has developmental consequences on these systems that persist into adulthood. Genetic differences may also contribute to alterations in functioning of neurobiological systems. Moreover, the interaction of early-life experiences of adversity and genetic vulnerability is increasingly thought to play a role, including via epigenetic mechanisms.

Stress, genes and the biology of suicidal behavior.

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.

Increased risk for suicidal behavior in comorbid bipolar disorder and alcohol use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)

OBJECTIVE Bipolar disorder is associated with a high rate of suicide attempt, and alcohol use disorders have also been associated with elevated risk for suicidal behavior. Whether risk for suicidal behavior is elevated when these conditions are comorbid has not been addressed in epidemiologic studies. METHOD 1,643 individuals with a DSM-IV lifetime diagnosis of bipolar disorder were identified from 43,093 general-population respondents who were interviewed in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions. Assessments were made using the National Institute on Alcohol Abuse and Alcoholism Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version (AUDADIS-IV). Lifetime prevalence of reported history of suicide attempt and suicidal thoughts among bipolar disorder respondents with and without DSM-IV lifetime alcohol use disorders (abuse or dependence) was assessed using chi-squared and adjusted odds ratios with confidence intervals. Logistic regression was used to test the relevance of other comorbid clinical conditions to suicide risk in bipolar respondents with and without comorbid alcohol use disorders. RESULTS More than half of the respondents (54%) who met criteria for bipolar disorder also reported alcohol use disorder. Bipolar individuals with comorbid alcohol use disorder were at greater risk for suicide attempt than those individuals without alcohol use disorder (adjusted odds ratio=2.25; 95% CI, 1.61-3.14) and were more likely to have comorbid nicotine dependence and drug use disorders. Nicotine dependence and drug use disorders did not increase risk for suicidal behavior among those with bipolar disorder, nor did they confer additional risk among bipolar respondents who also reported alcohol use disorder. Despite greater psychopathological burden, individuals with comorbid bipolar disorder and alcohol use disorder did not receive more treatment or more intensive treatment. CONCLUSIONS Suicidal behavior is more likely to occur in bipolar respondents who also suffer from alcohol use disorder. Interventions to reduce suicide risk in bipolar disorder need to address the common and high-risk comorbidity with alcohol use disorders.

Protective factors against suicidal behavior in latinos

Latinos appear to be relatively protected against suicidal behavior, but the factors that mediate this effect are not known. Some protective factors may be related to cultural constructs that provide a buffer against suicidal behavior in the face of psychiatric illness. We sought to determine whether the Reasons for Living Inventory (RFLI) might capture protective factors against suicidal behavior in Latinos and non-Latinos. Patients with major depression, bipolar disorder, or schizophrenia were interviewed regarding their depressive symptomatology and lifetime history of suicidal behavior. The RFLI, which measures protective factors against suicidal acts, was also administered. Multivariate analyses were used to assess the relationship between suicide measures, ethnicity, and selected clinical and demographic variables. Although Latinos and non-Latinos did not differ significantly in attempter status (attempter/nonattempter), number of attempts, or suicide intent, Latinos reported significantly less suicidal ideation and made less lethal attempts. On the RFLI, Latinos scored significantly higher on subscales regarding survival and coping beliefs, responsibility to family, and moral objections to suicide, possibly reflective of cultural norms endorsed by Latino groups. Multivariate analyses suggested that although being Latino was independently associated with less suicidal ideation, other suicidal behaviors held a stronger relationship to moral objections to suicide and survival and coping skills than to ethnicity. Self-identification as Latino may be associated with espousing cultural constructs that mediate protective effects against suicidal behavior. Constructs identified in the RFLI may protect Latinos from acting on suicidal thoughts, affecting moral objections to suicide and survival and coping beliefs. Further studies to elucidate the impact of these factors on suicidal behavior and their relationship to specific cultural constructs would be of interest.

Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior.

OBJECTIVE Bipolar disorder is associated with high risk for suicidal acts. Observational studies suggest a protective effect of lithium against suicidal behavior. However, testing this effect in randomized clinical trials is logistically and ethically challenging. The authors tested the hypothesis that lithium offers bipolar patients with a history of suicide attempt greater protection against suicidal behavior compared to valproate. METHOD Patients with bipolar disorder and past suicide attempts (N=98) were randomly assigned to treatment with lithium or valproate, plus adjunctive medications as indicated, in a double-blind 2.5-year trial. An intent-to-treat analysis was performed using the log-rank test for survival data. Two models were fitted: time to suicide attempt and time to suicide event (attempt or hospitalization or change in medication in response to suicide plans). RESULTS There were 45 suicide events in 35 participants, including 18 suicide attempts made by 14 participants, six from the lithium group and eight from the valproate group. There were no suicides. Intent-to-treat analysis using the log-rank test showed no differences between treatment groups in time to suicide attempt or to suicide event. Post hoc power calculations revealed that the modest sample size, reflective of challenges in recruitment, only permits detection of a relative risk of 5 or greater. CONCLUSIONS Despite the high frequency of suicide events during the study, this randomized controlled trial detected no difference between lithium and valproate in time to suicide attempt or suicide event in a sample of suicide attempters with bipolar disorder. However, smaller clinically significant differences between the two drugs were not ruled out.

Feminist Technological Futures Deleuze and Body/Technology Assemblages

The figure of Donna Haraway’s cyborg continues to loom large over contemporary feminist engagements with questions of technology. Across a range of analytical projects ranging from cosmetic surgery to employment practices it has come to be one of the defining figurations through which the social and discursive construction of bodies in a technological age are theorized. Indeed, it has become a widely accepted and largely unquestioned orthodoxy of postmodern feminist thinking. Not only has the cyborg offered a theoretical framework for exploring the feminist possibilities of technologies, it has provided a focus for situating questions of technology and bodies into broader feminist theoretical considerations of the structures of knowledge, particularly those of binary oppositions and the logic of identity. While a productive and influential intervention into feminist theorizing, the cyborg is not without limitations. One of these is pointed out by Kirby (1997) as a failure to break convincingly with the logic ofidentity in the way Haraway theorizes the intersection of bodies and technologies in the fabrication of the cyborg. This article examines that criticism and then explores the possibilities which Deleuze and Guattari’s concept of assemblageoffers as a mean of thinking the meetings of bodies and technologies beyond binary oppositions.