Michael F. Grunebaum

Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder.

BACKGROUND Inflammation has been linked to depression and suicide risk. One inflammatory process that has been minimally investigated in this regard is cytokine-stimulated production of kynurenine (KYN) from tryptophan (TRP). Recent data suggest that KYN increases in cerebrospinal fluid (CSF) are associated with depressive symptoms secondary to immune activation. KYN may alter dopaminergic and glutamatergic tone, thereby contributing to increased arousal, agitation and impulsivity - important risk factors in suicide. We hypothesized that patients with major depressive disorder (MDD) and a history of suicide attempt would have higher levels of KYN than depressed nonattempters, who in turn would have higher levels than healthy volunteers. METHODS Plasma KYN, TRP, and neopterin were assayed by high performance liquid chromatography in three groups: healthy volunteers (n=31) and patients with MDD with (n=14) and without (n=16) history of suicide attempt. Analysis of variance tested for group differences in KYN levels. RESULTS KYN levels differed across groups (F=4.03, df=(2,58), and p=0.023): a priori planned contrasts showed that KYN was higher in the MDD suicide attempter subgroup compared with MDD non-attempters (t=2.105, df=58, and p=0.040), who did not differ from healthy volunteers (t=0.418, df=58, and p=0.677). In post hoc testing, KYN but not TRP was associated with attempt status, and only suicide attempters exhibited a positive correlation of the cytokine activation marker neopterin with the KYN:TRP ratio, suggesting that KYN production may be influenced by inflammatory processes among suicide attempters. CONCLUSION These preliminary results suggest that KYN and related molecular pathways may be implicated in the pathophysiology of suicidal behavior.

Lower Cortisol Levels in Depressed Patients with Comorbid Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is often comorbid with major depressive episodes (MDEs) and both conditions carry a higher rate of suicidal behavior. Hypothalamic–pituitary–adrenal (HPA) axis and serotonin abnormalities are associated with both conditions and suicidal behavior, but their inter-relation is not known. We determined cortisol response to placebo or fenfluramine in MDE, MDE and PTSD (MDE+PTSD), and healthy volunteers (HVs) and examined the relation of cortisol responses to suicidal behavior. A total of 58 medication-free patients with MDE (13 had MDE+PTSD) and 24 HVs were studied. They received placebo on the first day and fenfluramine on the second day. Cortisol levels were drawn before challenge and for 5 h thereafter. The MDE+PTSD group had the lowest plasma cortisol, the MDE group had the highest, and HVs had intermediate levels. There were no group differences in cortisol response to fenfluramine. Suicidal behavior, sex, and childhood history of abuse were not predictors of baseline or postchallenge plasma cortisol. Cortisol levels increased with age. This study finds elevated cortisol levels in MDE and is the first report of lower cortisol levels in MDE+PTSD. The findings underscore the impact of comorbidity of PTSD with MDE and highlight the importance of considering comorbidity in psychobiology.

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.

Family history of suicidal behavior and early traumatic experiences : Additive effect on suicidality and course of bipolar illness?

BACKGROUND Bipolar disorder (BD) is associated with a high prevalence of suicide attempt and completion. Family history of suicidal behavior and personal history of childhood abuse are reported risk factors for suicide among BD subjects. METHODS BD individuals with family history of suicidal behavior and personal history of childhood abuse (BD-BOTH), BD individuals with family history of suicidal behavior or personal history of childhood abuse (BD-ONE), and BD individuals with neither of these two risk factors (BD-NONE) were compared with regard to demographic variables and clinical measures. RESULTS Almost 70% of the sample had a history of a previous suicide attempt. There were significantly higher rates of previous suicide attempts in the BD-BOTH and BD-ONE relative to the BD-NONE group. BD-BOTH were significantly younger at the time of their first suicide attempt and had higher number of suicide attempts compared with BD-NONE. BD-BOTH were significantly younger at the time of their first episode of mood disorder and first psychiatric hospitalization and had significantly higher rates of substance use and borderline personality disorders compared to BD-NONE. LIMITATIONS Retrospective study. Use of semi-structured interview for the assessment of risk factors. CONCLUSIONS BD individuals with a familial liability for suicidal behavior and exposed to physical and/or sexual abuse during childhood are at a greater risk to have a more impaired course of bipolar illness and greater suicidality compared to those subjects with either only one or none of these risk factors. Prospective studies are needed to confirm these findings.

Suicidal behavior and mild Traumatic brain injury in major depression

Traumatic brain injury (TBI) is associated with psychiatric illness, suicidal ideation, suicide attempts, and completed suicide. We investigated the relationship between mild TBI and other risk factors for suicidal behavior in major depressive episode. We hypothesized that mild TBI would be associated with suicidal behavior at least partly because of shared risk factors that contribute to the diathesis for suicidal acts. Depressed patients (N = 325) presenting for treatment were evaluated for psychopathology, traumatic history, and suicidal behavior. Data were analyzed using Student t -test, chi-square statistic, or Fisher exact test. A backward stepwise logistic regression model (N = 255) examined the relationship between attempter status and variables that differed in the TBI and non-TBI patients. Forty-four percent of all subjects reported mild TBI. Subjects with TBI were more likely to be male, have a history of substance abuse, have cluster B personality disorder, and be more aggressive and hostile compared with subjects without TBI. They were also more likely to be suicide attempters, although their suicidal behavior was not different from that of suicide attempters without TBI. Attempt status was mostly predicted by aggression and hostility, but not the presence of TBI. Of note, for males, a history of TBI increased the likelihood of being a suicide attempter, whereas the risk was elevated for females regardless of TBI history. Our data suggest that suicidal behavior and TBI share antecedent risk factors: hostility and aggression. Future studies may yield confirmation using a prospective design.

Lower CSF Homovanillic Acid Levels in Depressed Patients with a History of Alcoholism

Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.

Attachment and social adjustment: relationships to suicide attempt and major depressive episode in a prospective study

OBJECTIVE To study two aspects of interpersonal function - attachment security and social adjustment - in relation to suicide attempt and major depressive episode (MDE) during naturalistic follow-up of up to one year after presentation with MDE. METHOD 136 adults who presented with a DSM-IV MDE completed the Adult Attachment Scale and the Social Adjustment Scale-Self Report at study entry. Based on follow-up interviews at three months and one year, we used survival analysis to investigate the relationship of scores on these measures with time to a suicide attempt and time to recurrent MDE. RESULTS Less secure/more avoidant attachment predicted increased risk of suicide attempt during the 1-year follow-up (Wald chi(2)=9.14, df=1, p=0.003, HR=1.16, 95% CI=1.05 to 1.27). Poorer social adjustment predicted increased risk of recurrent MDE (Wald chi(2)=6.95, df=1, p=0.008, HR=2.36, 95% CI=1.25 to 4.46), and that in turn increased the risk of a suicide attempt (z=4.19, df=1, p<0.001, HR=17.3, 95% CI=4.6 to 65.5). CONCLUSIONS Avoidant attachment in the setting of major depressive disorder is a potential therapeutic target to prevent suicidal behavior. Enhancing social adjustment may reduce relapse in major depressive disorder and thereby reduce risk of a suicide attempt. Study limitations include small sample size and use of a self-report attachment scale.

Protective factors against suicidal behavior in depressed adults reporting childhood abuse.

Most previous studies compared suicidal behavior in subjects with and without a history of childhood abuse, whereas less attention was paid to the comparison of suicide attempters and nonattempters among subjects reporting childhood abuse. To identify risk and protective factors against suicidal behavior, we compared suicide attempters with nonattempters among the sample of 119 depressed inpatients who reported childhood abuse. Compared with nonattempters, suicide attempters were younger, had more self-rated depression severity and suicidal ideation, higher trait aggression and more cluster B personality disorder comorbidity, less coping potential, and fewer moral objections to suicide (MOS)/religious beliefs. Logistic regression showed that more severe suicidal ideation and fewer MOS/religious beliefs were associated with suicidal acts in subjects with reported childhood abuse. Furthermore, suicidal ideation and MOS/religious beliefs were significantly inversely correlated. The results of this clinical study add support to previous reports that religious/spiritual coping could serve as an additional resource in prevention of suicidal behavior for subjects with reported childhood abuse.

Omega-3 Polyunsaturated Fatty Acid (PUFA) Status in Major Depressive Disorder With Comorbid Anxiety Disorders

BACKGROUND Although lower levels of omega-3 polyunsaturated fatty acids (PUFAs) are found in major depressive disorder, less is known about PUFA status and anxiety disorders. METHOD Medication-free participants with DSM-IV-defined major depressive disorder (MDD), with (n = 18) and without (n = 41) comorbid DSM-IV anxiety disorders, and healthy volunteers (n = 62) were recruited from October 2006 to May 2010 for mood disorder studies at the New York State Psychiatric Institute. Participants were 18-73 years of age (mean age, 35.8 ± 12.6 years). Depression and anxiety severity was assessed using depression and anxiety subscales from the 17-item Hamilton Depression Rating Scale. Plasma PUFAs eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) and the ratio of arachidonic acid (AA; 22:4n-6) to EPA (AA:EPA) were quantified. This secondary analysis employed analysis of variance with a priori planned contrasts to test for diagnostic group differences in log-transformed PUFA levels (logDHA, logEPA, and logAA:EPA). RESULTS Plasma levels of logDHA (F(2,118) = 4.923, P = .009), logEPA (F(2,118) = 6.442, P = .002), and logAA:EPA (F(2,118) = 3.806, P = .025) differed across groups. Participants with MDD had lower logDHA (t(118) = 2.324, P = .022) and logEPA (t(118) = 3.175, P = .002) levels and higher logAA:EPA levels (t(118) = -2.099, P = .038) compared with healthy volunteers. Lower logDHA (t(118) = 2.692, P = .008) and logEPA (t(118) = 2.524, P = .013) levels and higher logAA:EPA levels (t(118) = -2.322, P = .022) distinguished anxious from nonanxious MDD. Depression severity was not associated with PUFA plasma levels; however, anxiety severity across the entire sample correlated negatively with logDHA (r(p) = -0.22, P = .015) and logEPA (r(p) = -0.25, P = .005) levels and positively with logAA:EPA levels (r(p) = 0.18, P = .043). CONCLUSIONS The presence and severity of comorbid anxiety were associated with the lowest EPA and DHA levels. Further studies are needed to elucidate whether omega-3 PUFA supplementation may preferentially alleviate MDD with more severe anxiety.