Wolframin gene polymorphisms, including the H611R polymorphism, are reportedly associated with mood disorders and psychiatric hospitalization, but there is disagreement about the association of this specific variant with suicidality and impulsive traits. This study tested the association of the H611R polymorphism with mood disorders, suicidal behavior, and aggressive–impulsive traits. Two hundred and one subjects with mood disorders and 113 healthy volunteers were genotyped for the H611R polymorphism and underwent structured interviews for diagnosis and clinical ratings. All were Caucasians. The H611R polymorphism was associated with mood disorders but not suicidal behavior, aggressive/impulsive traits or suicidality in first-degree relatives. The HR heterozygote genotype was more frequent in mood disorder (χ2=7.505; df=2; p=.023). If this finding will be replicated, the H611R polymorphism may be a possible marker for mood disorders in a psychiatric population, and not just in relatives of Wolfram syndrome probands.
Depression; Genetics; Mood disorders; Polymorphism; Suicide; Wolfram syndrome
We examined the relationship of increasing prescription volume of newer antidepressants, introduced in Japan in 1999, to national rates of suicide.
The relationship between annual changes in rates of suicide (obtained from the Japanese Ministry of Health, Labor, and Welfare Vital Statistics Database) and prescription volume of the newer antidepressants paroxetine, fluvoxamine, and milnacipran (obtained from the database of IMS Japan K.K.), stratified by gender and age groups, was modeled statistically for the years 1999 through 2003. Effects of unemployment and alcohol consumption and the interaction of gender and age with antidepressant prescribing were assessed.
From 1999 through 2003 in Japan, total antidepressant prescriptions increased 57% among males and 50% among females. Approximately 80% of this increase involved the selective serotonin reuptake inhibitors (SSRIs). To reduce a limitation of ecological analysis, we compared annual change in prescription and suicide rates, which eliminates the effect of long-term (secular) linear trends. We found an inverse association between year-to-year changes in the suicide rate and prescription volume of newer antidepressants (fluvoxamine, paroxetine, and milnacipran) (β = −1.34, p = .008) and SSRIs specifically (fluvoxamine, paroxetine) (β = −1.41, p = .019). An increase of 1 defined daily dose of SSRI use/1000 population/day was associated with a 6% decrease in suicide rate. Exploratory analysis suggested a stronger association in males, who experienced a greater increase in antidepressant use. Changes in unemployment and alcohol consumption rates did not explain the association.
In Japan during 1999 through 2003, absent long-term linear trend effects, annual increases in prescribing of newer antidepressant medications, mainly SSRIs, were associated with annual decreases in suicide rates, particularly among males.
Backward masking is a measure of early visual information processing usually abnormal in psychotic disorders. Previous studies of subjects with Borderline Personality Disorder have been inconsistent regarding their impairment or lack of impairment on backward masking. We examined visual backward masking performance in samples of unmedicated depressed patients with (n=12) and without (n=16) Borderline Personality Disorder, and healthy volunteers (n=18). Accuracy was poorer in depressed BPD patients, relative to both non-BPD depressed and healthy comparison subjects. As in previous studies, no differences in accuracy were found between non-BPD depressed patients and healthy comparison subjects. Differences in BPD subjects’ accuracy were most evident at the fastest ISI and were not attributable to intercurrent psychotic symptoms. Beyond these group differences, accuracy at faster ISI’s correlated with self-ratings of impulsiveness in all patients, and may be a general correlate of this trait. Poor early information processing appears to be a feature of Borderline Personality Disorder, and may play a role in the impulsive behavior that is characteristic of the disorder.
Backward masking; Borderline Personality Disorder; Depression; Information processing; Impulsiveness; Impulsiveness assessment
In order to test the hypotheses that pretreatment metabolic activity in
the midbrain and the rostral anterior cingulate may predict remission in
response to medications enhancing monoaminergic transmission, we compared
relative regional cerebral metabolic rate of glucose (rCMRglu) using positron
emission tomography (PET) in medication-free patients with major depression who
remitted after 3 months of monoaminergic medication, with non-remitters on the
same treatment. [18F]-FDG PET was conducted in a group of 33
drug-free DSM-IV major depression subjects prior to antidepressant treatment.
Patients were prescribed paroxetine initially (61%) unless they had failed
paroxetine previously. Treatment was then managed by the subjects’ own
physician with 91% receiving a selective serotonin reuptake inhibitor and 78%
another non-selective monoamine reuptake inhibitor during the 3 months of
treatment. Voxel-based parametric brain maps of remitters were compared with
maps of non-remitters using SPM2. Remission was defined as a N50% decrease in
and a final score of ≤10 on the 24-item Hamilton Depression Rating Scale.
We found that treatment remitters have lower activity in a single contiguous
brain region (with global maxima in the midbrain, cluster level
P=0.013, corrected for multiple comparison (CMC)), prior to
treatment, compared with non-remitters to 3 months of community-based
monoaminergic antidepressant treatment. Degree of improvement correlated with
pretreatment midbrain activity. Pretreatment clinical picture and intensity of
treatment did not distinguish remitters. No other area of the brain showed a
significant difference between remitters and non-remitters even with CMC
completely disabled. Lower relative regional brain activity in the region of
monoaminergic nuclei prior to treatment predicts remission in response to 3
months of antidepressant treatment, despite no clinical differences at baseline
and no difference in treatment intensity. Brain imaging is a potential objective
laboratory technique that may guide treatment selection where clinical methods
have not shown promise. Prospective studies are needed to replicate these
findings and determine whether outcome prediction is limited to a specific class
Depression; PET; FDG; Brain regions; Remission; Antidepressant treatment; Outcome; Positron emission tomography
The authors sought to identify clinical predictors of new-onset suicidal behavior in children of parents with a history of mood disorder and suicidal behavior.
In a prospective study of offspring of parents with mood disorders, 365 offspring (average age, 20 years) of 203 parents were followed for up to 6 years. Offspring with incident suicide attempts or emergency referrals for suicidal ideation or behavior (“incident events”) were compared with offspring without such events on demographic and clinical characteristics. Multivariate analyses were conducted to examine predictors of incident events and predictors of time to incident event.
Offspring of probands who had made suicide attempts, compared with offspring of parents with mood disorders who had not made attempts, had a higher rate of incident suicide attempts (4.1% versus 0.6%, relative risk=6.5) as well as overall suicidal events (8.3% versus 1.9%, relative risk=4.4). Mood disorder and self-reported impulsive aggression in offspring and a history of sexual abuse and self-reported depression in parents predicted earlier time to, and greater hazard of, an incident suicidal event.
In offspring of parents with mood disorders, precursors of early-onset suicidal behavior include mood disorder and impulsive aggression as well as parental history of suicide attempt, sexual abuse, and self-reported depression. These results suggest that efforts to prevent the familial transmission of early-onset suicidal behavior by targeting these domains could reduce the morbidity of suicidal behavior in high-risk youths.
To determine how intraoperative microelectrode recordings (MER) and intraoperative lead placement acutely influence tremor, rigidity, and bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead placement effects were influenced by target location (subthalamic nucleus (STN) or globus pallidus interna (GPi)).
Currently most groups who perform deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as macrostimulation (test stimulation), to refine DBS lead position. Following MER and/or test stimulation, however, there may be a resultant “collision/implantation” or “microlesion” effect, thought to result from disruption of cells and/or fibres within the penetrated region. These effects have not been carefully quantified.
47 consecutive patients with PD undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function was measured at six time points with a modified motor Unified Parkinson Disease Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3) immediately after lead implantation/collision, (4) 4 months following surgery—off medications, on DBS (12 h medication washout), (5) 6 months postoperatively—off medication and off DBS (12 h washout) and (6) 6 months—on medication and off DBS (12 h washout).
Significant improvements in motor scores (p<0.05) (tremor, rigidity, bradykinesia) were observed as a result of MER and lead placement. The improvements were similar in magnitude to what was observed at 4 and 6 months post-DBS following programming and medication optimisation. When washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved compared with preoperative testing. There was a larger improvement in STN compared with GPi following MER (p<0.05) and a trend for significance following lead placement (p<0.08) but long term outcome was similar.
This study demonstrated significant acute intraoperative penetration effects resulting from MER and lead placement/collision in PD. Clinicians rating patients in the operating suite should be aware of these effects, and should consider pre- and post-lead placement rating scales prior to activating DBS. The collision/implantation effects were greater intraoperatively with STN compared with GPi, and with greater disease duration there was a larger effect.
Adult neurogenesis is coupled to angiogenesis in neurogenic niches in the dentate gyrus (DG) and increased by antidepressants in rodents. We hypothesized that, in major depressive disorder (MDD), antidepressants increase neural progenitor cells (NPCs) and capillaries in the human DG.
NPCs and capillaries, detected on hippocampal sections by immunohistochemistry for nestin, were quantified by stereology in matched MDDs (untreated, n=12), MDD treated with selective serotonin reuptake inhibitors (MDD*SSRI, n=6) or tricyclic antidepressants (MDD*TCA, n=6) and nonpsychiatric controls (n=12), all confirmed by psychological autopsy.
MDD*SSRI had a larger capillary area and more NPCs versus MDDs (p=.034 and p=.008, respectively) and controls (p=.010 and p=.002, respectively) in the whole DG, more NPCs in the anterior (pes, p=.042) and central (mid-body, p=.004) DG, and greater capillary area in the pes (p=.002) and mid-body (p=.021). NPC number and capillary area correlated positively in the whole sample (R2=.454, p<.001) and in treated subjects (R2=.749, p=.001). We found no NPCs or antidepressant-related angiogenesis in CA1 and parahippocampal gyrus. DG volume correlated positively with NPC number (p=.004) and capillary area (p<.001), and differed between groups in whole hippocampus (p=.013) and mid-body (p=.036). Age negatively correlated with NPC number (p=.042), capillary area (p=.037) and bifurcations (p=.030). No sex effect was detected.
Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.
neural progenitor cells; nestin; dentate gyrus; postmortem; stereology; immunohistochemistry
Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimer’s dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.
Linoleic acid; HODE; hydroxy-octadecadienoic acid; oxoODE; oxo-octadecadienoic acid; oxidation; OXLAM; PUFA; polyunsaturated fatty acid
Prior studies examining the relationship between social adjustment and suicidal ideation or behaviour have not examined attachment. This study examines the effect of attachment on the association between current social adjustment and suicide attempt risk.
Attachment, social adjustment, and history of suicide attempt were assessed in patients participating in research on major depressive disorder (N = 524). Suicide attempters and non-attempters were compared with attachment style and social adjustment using hierarchical logistic regression models. The two factor scoring method of the Adult Attachment Scale (secure vs. avoidant) was utilized as each measures unique aspects of attachment.
Anxious attachment (OR = 1.33; 95%CI = 1.016–1.728; P = 0.038) but not overall social adjustment (P = 0.14) was associated with a history of a past suicide attempt when both attachment and social adjustment were assessed in the same model. Among subtypes of social adjustment, work adjustment was associated with past history of suicide attempt (OR = 1.25; 95%CI = 1.019–1.540; P = 0.033). As impairment in work adjustment increased by 1 unit, the likelihood of reporting a suicide attempt increased by approximately 25%. There was no interaction between anxious attachment and work adjustment (P = 0.81).
Anxious attachment and work adjustment warrant further study as potential treatment targets in depressed suicidal patients.
attachment; social adjustment; suicide attempt
Dysfunction of serotonergic neurotransmission has been implicated in the etiopathogenesis of major depression (MDD) and alcohol use disorders (AUD). To compare serotonin function in MDD with co-occurring AUD (MDD/AUD), MDD without co-occurring AUD (MDD only) and healthy controls (HC) we sought to study differences in prolactin responses to fenfluramine administration in patients with MDD/AUD, patients with MDD only and HC. In all, 169 subjects (62 MDD/AUD, 75 MDD only, and 32 HC) were entered into the study. Controlling for gender, prolactin responses were lower in the MDD/AUD group compared to the MDD only or the HC group. Controlling for gender and aggression, prolactin responses in the MDD/AUD group remained significantly lower compared to the HC group but the difference between the MDD/AUD and the MDD only groups disappeared. The difference in prolactin responses between MDD/AUD and MDD only could be attributed to higher aggression scores in the MDD/AUD group compared to the MDD group.
Serotonin; Prolactin; Fenfluramine; Depression; Alcohol; Aggression
Whether sex differences exist in clinical risk factors associated with suicidal behavior is unknown. The authors postulated that among men with a major depressive episode, aggression, hostility, and history of substance misuse increase risk for future suicidal behavior, while depressive symptoms, childhood history of abuse, fewer reasons for living, and borderline personality disorder do so in depressed women.
Patients with DSM-III-R major depression or bipolar disorder seeking treatment for a major depressive episode (N=314) were followed for 2 years. Putative predictors were tested with Cox proportional hazards regression analysis.
During follow-up, 16.6% of the patients attempted or committed suicide. Family history of suicidal acts, past drug use, cigarette smoking, borderline personality disorder, and early parental separation each more than tripled the risk of future suicidal acts in men. For women, the risk for future suicidal acts was sixfold greater for prior suicide attempters; each past attempt increased future risk threefold. Suicidal ideation, lethality of past attempts, hostility, subjective depressive symptoms, fewer reasons for living, comorbid borderline personality disorder, and cigarette smoking also increased the risk of future suicidal acts for women.
These findings suggest that the importance of risk factors for suicidal acts differs in depressed men and women. This knowledge may improve suicide risk evaluation and guide future research on suicide assessment and prevention.
Brain serotonin-1A receptors (5-HT1A) are implicated in anxiety. We compared regional brain 5-HT1A binding in medication-free participants with posttraumatic stress disorder (PTSD) and healthy volunteers using fully quantitative positron emission tomography (PET) methods.
Twenty patients with DSM-IV PTSD (13 with comorbid major depressive disorder, [MDD]) and 49 healthy volunteers underwent PET imaging with 5-HT1A antagonist radioligand [C-11]WAY100635. Arterial blood sampling provided a metabolite-corrected input function and the concentration of free ligand in plasma (fP) for estimation of regional binding potential, BPF ( = Bavailable /KD). Linear mixed modeling compared BPF between groups across regions of interest (ROIs).
The PTSD group had higher 5-HT1A BPF across brain ROIs (P = .0006). Post hoc comparisons showed higher 5-HT1A BPF in PTSD in all cortical ROIs (26–33%), amygdala (34%), and brainstem raphe nuclei (43%), but not hippocampus. The subgroup of seven PTSD patients without comorbid MDD had higher 5-HT1A BPF compared with healthy volunteers (P = .03).
This is the first report of higher brainstem and forebrain 5-HT1A binding in vivo in PTSD. The finding is independent of MDD. PTSD and MDD have in common an upregulation of 5-HT1A binding including midbrain autoreceptors that would favor less firing and serotonin release. This abnormality may represent a common biomarker of these stress-associated brain disorders.
posttraumatic stress disorder (PTSD); serotonin-1A (5-HT1A); positron emission tomography; WAY100635; major depressive disorder
Patients with bipolar disorder are prone to suicidal behavior, yet possible protective mechanisms are rarely studied. We investigated a possible protective role for moral or religious objections to suicide against suicidal ideation and attempts in depressed bipolar patients.
A retrospective case control study of 149 depressed bipolar patients (DSM-III-R criteria) in a tertiary care university research clinic was conducted. Patients who reported religious affiliation were compared with 51 patients without religious affiliation in terms of sociodemographic and clinical characteristics and history of suicidal behavior. The primary outcome measure was the moral or religious objections to suicide subscale of the Reasons for Living Inventory (RFLI).
Religiously affiliated patients had more children and more family-oriented social networks than nonaffiliated patients. As for clinical variables, religiously affiliated patients had fewer past suicide attempts, had fewer suicides in first-degree relatives, and were older at the time of first suicide attempt than unaffiliated patients. Furthermore, patients with religious affiliation had comparatively higher scores on the moral or religious objections to suicide subscale of the RFLI, lower lifetime aggression, and less comorbid alcohol and substance abuse and childhood abuse experience. After controlling for confounders, higher aggression scores (P = .001) and lower score on the moral or religious objections to suicide subscale of the RFLI (P < .001) were significantly associated with suicidal behavior in depressed bipolar patients. Moral or religious objections to suicide mediated the effects of religious affiliation on suicidal behavior in this sample.
Higher score on the moral or religious objections to suicide subscale of the RFLI is associated with fewer suicidal acts in depressed bipolar patients. The strength of this association was comparable to that of aggression scores and suicidal behavior, and had an independent effect. A possible protective role of moral or religious objections to suicide deserves consideration in the assessment and treatment of suicidality in bipolar disorder.
Positron emission tomography (PET) studies of the serotonin transporter (5-HTT) in the human brain are increasingly using the radioligand [11C]N, N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine. A variety of models have been applied to such data in several published articles; however to date, these models have not been validated with test–retest data. We recruited 11 healthy subjects and conducted two identical scans on each subject on the same day. We considered four different models (one- and two-tissue compartment kinetic models, likelihood estimation in graphical analysis (LEGA; a bias-free alternative to the graphical method), and basis pursuit) along with fast noniterative approximations to the kinetic models. We considered four different outcome measures (total volume of distribution (VT), binding potential with (BP) and without (BP1), free-fraction adjustment, and specific-to-nonspecific equilibrium partition coefficient (BP2)). To assess the performance of each model, we compared results using six different metrics (percent difference (PD) and within-subject mean sum of squares for reproducibility, interclass coefficient for reliability, variance across subjects, identifiability based on bootstrap resampling of residuals for each method, and time stability analysis to determine minimal required scanning time). We considered analysis of both at the voxel level and at the region of interest (ROI) level and compared results from these two approaches to assess agreement. We determined that 100 mins of scanning time is adequate and that for ROI-level analysis, LEGA gives best results. Average PD is 5.51 for VT, 20.7 for BP, 17.2 for BP1, and 16.5 for BP2 across all regions. For voxel-level analysis we determined that the one-tissue compartment noniterative model is best.
bootstrap; compartment; kinetic; test–retest reproducibility; voxel
There is some evidence for an association between Cluster C Personality Disorders (CCPD) and suicidal behavior. We compared depressed inpatients with and without CCPD in terms of suicidal behavior and associated psychopathology. Cluster A or B personality disorder co-morbidity were exclusion criteria for both groups (cases and controls). Depressed inpatients with “pure” CCPD had higher levels of suicidal ideation but not more previous suicide attempts compared with patients without CCPD. Greater suicidal ideation in depressed patients with CCPD in our study was associated with more hostility. Future studies examining the relationship between suicidal ideation and hostility in CCPD may clarify whether treatment focused on hostility might be of use for decreasing suicidal ideation in depressed patients with CCPD (Spitzer, Williams, Gibbon et al., 1990).
cluster C personality disorders; depression; hostility; suicide
This is the first study contrasting regional glucose metabolic rate (rCMRglu) responses to a serotonergic challenge in major depressive disorder (MDD) with and without comorbid alcohol dependence. In a university hospital, patients with MDD without a history of alcohol dependence (MDD only) and patients with MDD and comorbid alcohol dependence (MDD/ALC) were enrolled in this study. Subjects with comorbid borderline personality disorder were excluded. A bolus injection of approximately 5 mCi of 18fluorodeoxyglucose was administered 3 h after the administration of placebo or fenfluramine. We found an anterior medial prefrontal cortical area where MDD/ALC subjects had more severe hypofrontality than MDD only patients. This area encompassed the left medial frontal and left and right anterior cingulate gyri. This group difference disappeared after fenfluramine administration. The fact that the observed group difference disappeared after the fenfluramine challenge suggests that serotonergic mechanisms play a role in the observed differences between the groups.
Depression; Alcohol dependence; Fenfluramine; Serotonin; Positron emission tomography
To determine whether borderline personality disorder (BPD) and bipolar II disorder can be differentiated from each other and from major depressive disorder (MDD) by comparing depression severity, impulsiveness, and hostility in mood disorder patients with and without BPD.
One hundred seventy-three patients with either MDD or bipolar II disorder were enrolled from a larger sample admitted to a multisite project on mood disorders and suicidal behavior conducted from June 1996 through June 2006. Patients were divided into 4 groups: MDD with BPD, MDD without an Axis II diagnosis, bipolar II disorder with BPD, and bipolar II disorder without an Axis II diagnosis. All diagnoses were based on DSM-IV criteria. Depression was assessed using the 17-item Hamilton Rating Scale for Depression (HAM-D) and the self-rated Beck Depression Inventory (BDI). Impulsiveness was assessed using the Barratt Impulsiveness Scale, and hostility was assessed using the Buss-Durkee Hostility Inventory.
Patients with BPD reported higher levels of impulsiveness (p = .004) and hostility (p = .001), independent of Axis I diagnosis. Bipolar II patients reported greater attentional impulsiveness (p = .008) than MDD patients, independent of BPD status, while BPD patients reported greater nonplanning impulsiveness than patients without BPD, independent of Axis I diagnosis (p = .02). For motor impulsiveness, there was a main effect for Axis I diagnosis (p = .05) and Axis II diagnosis (p = .002). The bipolar II + BPD group scored the highest, suggesting a compound effect of comorbidity. There were no differences in depression severity when measured with the HAM-D, although the BPD groups reported more severe depression on the BDI, independent of their Axis I diagnosis (p = .05). The BPD groups scored higher on the cognitive factor (p = .01) and anxiety factor (p = .03) of the HAM-D.
Results suggest that there is a unique symptom and trait profile associated with BPD that distinguishes the diagnosis from bipolar II disorder. Results also suggest that impulsiveness is an important aspect of both disorders and that there is a compounding effect associated with a diagnosis of bipolar II disorder with comorbid BPD.
Suicide attempters with major depression are at risk for repeat attempts and often do not utilize treatment. Identifying predictors of treatment non-utilization could inform interventions to motivate treatment use and reduce suicide risk in major depression. Two hundred and seventy three participants with a major depressive episode as part of a major depressive disorder or bipolar disorder, were assessed for socio-demographic and clinical characteristics at baseline and again 1 year later to identify predictors of treatment utilization. Treatment utilization rate was high 1 year after initial evaluation (72.5%). Severity of baseline depression, baseline treatment status, and education were associated with treatment utilization at 1 year. Interventions focused on increasing knowledge about depression and treatment efficacy may improve treatment adherence when treating depression.
major depression; psychiatric treatment; suicide attempt; utilization
Post-mortem studies document alterations in the central noradrenergic system in suicide. However, studies of non-fatal suicide attempts have, thus far, found no consistent relationship to the noradrenaline metabolite 3-methoxy-4-hydroxphenylglycol (MHPG) in cerebrospinal fluid (CSF). We therefore conducted a prospective study of CSF MHPG and suicidal acts in major depression and bipolar depression. CSF MHPG was assayed in 184 drug-free patients with DSM-IV major depressive disorder or bipolar disorder, presenting for treatment of a current depressive episode, who were then followed-up for up to 12 months. Survival analysis was conducted using Cox proportional hazards modelling to test association of CSF MHPG and future suicidal behaviour, and potential clinical mediators. Twenty-seven individuals made a suicide attempt (two fatal) in the follow-up period. Lower CSF MHPG predicted future suicide attempt or suicide (22% increase in hazard for each 10 pmol/ml lower MHPG, p=0.045). Lower CSF MHPG also correlated with higher medical lethality of future suicidal act (mean MHPG: 49±18 vs. 32±12 pmol/ml for low- vs. high-lethality, t=2.8, d.f.=25, p=0.009). Smoking and self-rated depression severity were also associated with lower CSF MHPG and with future suicide attempt, but were not statistically significant mediators in multivariate models. In conclusion, lower CSF MHPG is associated with short-term risk for future suicidal behaviour in the 12 months following a major depressive episode. Psychopathology that mediates the relationship between lower CSF MHPG and future suicidal behaviour needs to be identified.
CSF MHPG; depression; mediation model; smoking; suicide attempt
In this study, we compare the performance of prognostic models of increasing complexity for prediction of future suicide attempt.
Using data from a 2-year prospective study of 304 depressed subjects, a series of Cox proportional hazard regression models were developed to predict future suicide attempt. The models were evaluated in terms of discrimination (the ability to rank subjects in order of risk), calibration (accuracy of predicted probabilities of attempt), and sensitivity and specificity of risk group stratification based on cross-validated predicted probabilities.
Although an additive model with past attempt, smoking status, and suicidal ideation achieved 75% (cross-validated) sensitivity and specificity, models that performed best in terms of discrimination included interactions between predictor variables.
As several models had similar predictive power, clinical considerations and ease of interpretation may have a significant role in the final stage of model selection for assessing future suicide attempt risk.
attempted suicide; prediction; Cox proportional hazards models
The Met allele of the Catechol-O-Methyltransferase (COMT) gene functional polymorphism (COMT-V158M) is associated with lower enzymatic activity than the Val allele and is reported to be associated with aggression, depression, and suicidal behavior. Since depression and impulsive-aggressive behavior may mediate risk for suicidal behavior, we assessed the association of this polymorphism with suicidal behavior. Clinical (impulsive aggression) and biological (CSF monoamine metabolites) endophenotypes were tested as potential mediators of the effect of genotype on suicide risk. Subjects with mood disorders (N=486) and healthy volunteers (N=119), all European Caucasian, were genotyped for COMT-V158M and assessed for DSM IV diagnoses, lifetime suicidal behavior, lifetime impulsivity, hostility, and aggression. CSF monoamine metabolites were assayed in a sub-sample of mood disorder patients (N=111). We found no association between genotype and mood disorder diagnosis or with reported history of suicide attempt in mood disorder subjects. There was no association between genotype and lethality or method of suicide attempt, or with aggressive/impulsive traits. Further, there was no difference in monoamine metabolites by genotype. The COMT-V158M polymorphism was not associated with suicidal behavior in a Caucasian sample of mood disorder subjects, or with possible clinical or biological endophenotypes.
aggression; catechol o-methyltransferase; depression; genetics; mood disorders; suicide
Moral and religious objections to suicide (MOS) are reported to be associated with less suicidal behavior in depressed patients, and are proposed to act as a protective factor against suicidal behavior. It is unclear whether MOS are a protective factor against suicide attempt per se, or if this effect is mediated through other variables.
Depressed inpatients (n = 265) reporting low or high MOS were compared on history of suicidal behaviour, demographic and clinical characteristics.
Patients with low MOS had significantly more lifetime suicide attempts, were more often without religious affiliation, had greater depression severity, hopelessness and trait impulsivity, less anxiety and fewer reasons for living. Logistic regression revealed that lower MOS was independently associated with suicide attempt.
Moral and religious objections to suicide may serve as a protective factor against suicidal acts given their unique association with less suicidal behavior in depressed inpatients.
Suicide; Moral objections; Protective factors