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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. [ABSTRACT FROM AUTHOR]

In recent years there has been considerable concern that certain classes of drugs, for example antidepressants, may increase the risk of suicide. In this current opinion article, we examine the literature on methodological and statistical approaches to the design and analysis of suicidal event studies. Experimental, ecological and observational studies of the relationship between drugs and suicidal events (thoughts, attempts and completion) are discussed. Areas considered include analysis of spontaneous reporting system data, ecological trends in national and/or small area (e.g. county) suicide rates, meta-analyses of randomized clinical trials, and large-scale medical claims data. New statistical and experimental strategies for investigating possible associations between drugs and suicide are highlighted, and we suggest directions for future statistical/methodological research. To put this into context, we then review the most recent literature on the relationship between drugs (antidepressants, antiepileptics, varenicline, montelukast and antipsychotics) and suicidal events. Overall, there appears to be little evidence that drugs increase the risk of suicide and related behaviour. Numerous lines of evidence in adults clearly demonstrate that inadequate treatment of depression (pharmacotherapy and/or psychotherapy) is associated with increased risk of suicidal behaviour. In children, the results are less clear and further study is required to better delineate which children benefit from treatment and who may be at increased risk as a consequence of treatment. From a statistical and methodological perspective, the field of pharmacoepidemiology is a fertile area for statistical research, both in theory and in application. In general, methods have been adopted from other areas such as general epidemiology, despite the singular nature of many of the problems that are unique to drug safety in general, in particular the study of rare events. Finally, there is considerable debate concerning the communication of risk. For suicide, regulatory action has been taken largely on the basis of evidence suggesting increased risk of suicidal thoughts. However, suicidal thoughts are quite common, particularly among patients with depression, and may have little relationship to suicidal behaviour and/or completion. [ABSTRACT FROM AUTHOR]

Objective: To examine the utility of single-photon emission computed tomography (SPECT) to predict conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).Design: Longitudinal, prospective study.Setting: University-based memory disorders clinic.Participants: One hundred twenty seven patients with MCI and 59 healthy comparison subjects followed up for 1-9 years.Measurements: Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, magnetic resonance imaging, and brain Tc hexamethyl-propylene-aminoxime SPECT scan with visual ratings, and region of interest (ROI) analyses were done.Results: Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), but the global rating predicted conversion (41.9% sensitivity and 82.3% specificity, Fisher's exact test p = 0.013). Blood flow in each ROI was not predictive, but when dichotomized at the median value of the patients with MCI, low flow increased the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% confidence interval: 1.16-7.53, p = 0.023) and medial temporal regions (hazard ratio: 3.12, 95% confidence interval: 1.14-8.56, p = 0.027). In the 3-year follow-up sample, low parietal (p <0.05) and medial temporal (p <0.01) flow predicted conversion to AD, with or without controlling for age, Mini-Mental State Examination, and apolipoprotein E ε4 genotype. These measures lost significance when other strong predictors were included in logistic regression analyses: verbal memory, social/cognitive functioning, olfactory identification deficits, hippocampal, and entorhinal cortex volumes.Conclusions: SPECT visual ratings showed limited utility in predicting MCI conversion to AD. The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available. [ABSTRACT FROM AUTHOR]

Amyloid load in the brain using Pittsburgh compound B ((11)C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose ((18)F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). ( 11)C-PIB binding potential (BP(ND)) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For (18)F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI-CTR differences. For the AD-CTR comparison, precuneus BP(ND) area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. ( 11)C-PIB PET BP(ND) clearly distinguished diagnostic groups and combined with (18)F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies. [ABSTRACT FROM AUTHOR]

Following the drug-approval process, concerns remain regarding the safety of new drugs that are introduced into the marketplace. In the case of rare adverse events, the number of subjects that are treated in randomized controlled trials is invariably inadequate to determine the safety of the new pharmaceutical. Identifying safety signals for new and/or existing drugs is a major priority in the protection of public health. Unfortunately, design, analysis, and available data are often quite limited for detecting in a timely fashion any potentially harmful effects of drugs. In this review, we examine a variety of approaches for determining the possibility of adverse drug reactions. Our review includes spontaneous reports, meta-analysis of randomized controlled clinical trials, ecological studies, and analysis of medical claims data. We consider both experimental design and analytic problems as well as potential solutions. Many of these methodologies are then illustrated through application to data on the possible relationship between taking antidepressants and increased risk of suicidality. [ABSTRACT FROM AUTHOR]

Objective and Participants: From 2002 to 2005, the authors tested an interactive, Web-based method to encourage college students at risk for suicide to seek treatment. Methods: The authors invited students at 2 universities to complete an online questionnaire that screened for depression and other suicide risk factors. Respondents received a personalized assessment and were able to communicate anonymously with a clinical counselor online. At-risk students were urged to attend in-person evaluation and treatment. Results: A total of 1,162 students (8% of those invited) completed the screening questionnaire; 981 (84.4%) were designated as at high or moderate risk. Among this group, 190 (19.4%) attended an inperson evaluation session with the counselor, and 132 (13.5%) entered treatment. Students who engaged in online dialogues with the counselor were 3 times more likely than were those who did not to come for evaluation and enter treatment. Conclusions: The method has considerable promise for encouraging previously untreated, at-risk college students to get help. [ABSTRACT FROM AUTHOR]

Objective: 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.Method: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The lower expressing allele of the serotonin transporter gene 5' promoter region (5-HTTLPR) polymorphism is reported to be associated with susceptibility to depression and suicidality in response to stressful life events. The authors examined the relationship of a triallelic 5-HTTLPR polymorphism to stressful life events, severity of major depression, and suicidality. METHOD: Mood disorder subjects (N=191) and healthy volunteers (N=125), all Caucasian subjects of European origin, were genotyped for the triallelic 5-HTTLPR polymorphism (higher expressing allele: L(A); lower expressing alleles: L(G), S). All subjects underwent structured clinical interviews to determine DSM-IV diagnoses, ratings of psychopathology, stressful life events, developmental history, and suicidal behavior. CSF 5-HIAA was assayed in a subgroup of subjects. RESULTS: Lower expressing alleles independently predicted greater depression severity and predicted greater severity of major depression with moderate to severe life events compared with the higher expressing L(A) allele. No associations with suicidal behavior and CSF 5-HIAA were found. CONCLUSIONS: Lower expressing transporter alleles, directly and by increasing the impact of stressful life events on severity, explain 31% of the variance in major depression severity. The biological phenotype responsible for these effects remains to be elucidated. [ABSTRACT FROM AUTHOR]

OBJECTIVE: First-degree relatives of persons with mood disorder who attempt suicide are at greater risk for mood disorders and attempted or completed suicide. This study examined the shared and distinctive factors associated with familial mood disorders and familial suicidal behavior. METHOD: First-degree relatives' history of DSM-IV--defined mood disorder and suicidal behavior was recorded for 457 mood disorder probands, of whom 81% were inpatients and 62% were female. Probands' lifetime severity of aggression and impulsivity were rated, and probands' reports of childhood physical or sexual abuse, suicide attempts, and age at onset of mood disorder were recorded. Univariate and multivariate analyses were carried out to identify predictors of suicidal acts in first-degree relatives. RESULTS: A total of 23.2% of the probands with mood disorder who had attempted suicide had a first-degree relative with a history of suicidal behavior, compared with 13.2% of the probands with mood disorder who had not attempted suicide (odds ratio=1.99, 95% CI=1.21-3.26). Thirty percent (30.8%) of the first-degree relatives with a diagnosis of mood disorder also manifested suicidal behavior, compared with 6.6% of the first-degree relatives with no mood disorder diagnosis (odds ratio=6.25, 95% CI=3.44-11.35). Probands with and without a history of suicide attempts did not differ in the incidence of mood disorder in first-degree relatives (50.6% versus 48.1%). Rates of reported childhood abuse and severity of lifetime aggression were higher in probands with a family history of suicidal behavior. Earlier age at onset of mood disorder in probands was associated with greater lifetime severity of aggression and higher rates of reported childhood abuse, mood disorder in first-degree relatives, and suicidal behavior in first-degree relatives. CONCLUSIONS: Risk for suicidal behavior in families of probands with mood disorders appears related to early onset of mood disorders, aggressive/impulsive traits, and reported childhood abuse in probands. Studies of such clinical features in at-risk relatives are under way to determine the relative transmission of these clinical features. [ABSTRACT FROM AUTHOR]

BACKGROUND: We reported previously that the socio-economic status (SES) of individuals predicts variation in brain serotonergic responsivity, as assessed by neuropharmacological challenge in an adult community sample, and that this association is qualified by allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Here we examine whether serotonergic responsivity covaries similarly with the SES of communities, as indexed by US Census data in the same study sample. METHOD: Community SES was defined by levels of income, economic disadvantage, housing costs, and educational attainment of census tracts in which 249 locally recruited study participants (54% male) resided. Serotonergic responsivity was assessed as the baseline-adjusted, peak plasma prolactin (Prl) concentration following acute administration of the serotonin-releasing agent, fenfluramine; tissue for DNA extraction and 5-HTTLPR genotyping was available on 131 participants. RESULTS: Subjects residing in census tracts of lower SES showed a blunted Prl response to fenfluramine (diminished serotonergic responsivity) relative to individuals living in more affluent neighborhoods. When adjusted for personal income and education, SES at the community level continued to predict fenfluramine-stimulated Prl responses and did so independently of 5-HTTLPR genotype. CONCLUSIONS: Area-level indices of relative social and economic disadvantage covary with individual differences in brain serotonergic responsivity, and this association is, in part, independent of individually defined SES. These findings may be relevant to reported effects of low community SES on the prevalence of psychiatric disorders or behaviors associated with dysregulation of central serotonergic function, such as depression, impulsive aggression, and suicide. [ABSTRACT FROM AUTHOR]

Context: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT.Objective: To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse.Design: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode.Setting: Two university-based hospitals and 1 private psychiatric hospital.Patients: Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study.Interventions: Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28).Main Outcome Measure: Relapse of major depressive episode, compared among the 3 continuation groups.Results: Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse.Conclusions: Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to determine whether aggression and serotonergic dysfunction are related in the absence of a history of suicidal behavior. Although serotonergic dysfunction has been implicated in aggressive and impulsive behavior, most studies of such behavior have included individuals with a history of suicide attempts. Low concentrations of CSF 5-hydroxyindoleacetic acid (5-HIAA) have been consistently associated with suicidal behavior, presenting a potential confound in the link between aggression and serotonergic dysfunction. METHOD: The authors examined the association between aggression and CSF 5-HIAA concentrations in a group of 64 patients who had different DSM-III-R axis I diagnoses and no past suicidal behavior. Aggressive (N=35) and nonaggressive (N=29) groups were defined by a median split on a six-item history of adulthood aggressive behavior. RESULTS: The aggressive group had significantly lower CSF 5-HIAA concentrations than the nonaggressive group. Aggressive individuals also scored significantly higher on self-report measures of hostility, impulsiveness, and sensation seeking. CSF 5-HIAA concentrations, however, did not correlate with self-reported hostility and impulsivity. CONCLUSIONS: There is an association between aggressive behavior and serotonergic dysfunction independent of suicidal behavior in patients with axis I disorders who exhibit relatively milder forms of aggressive behavior. Analogous to findings with suicidal behavior, a low concentration of CSF 5-HIAA is related to aggressive behavior but does not show the same relationship to the continuum of aggressive feelings and thoughts. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Suicidal behavior is highly prevalent in borderline personality disorder and major depressive episode, although the characteristics of suicide attempts in the two disorders are believed to differ. Comorbidity of borderline personality disorder and major depressive episode may obscure characteristics of suicide attempts that are uniquely related to the psychopathology of each disorder. We compared suicidal behavior in patients with borderline personality disorder, major depressive episode, and borderline personality disorder plus major depressive episode to determine whether characteristics of suicide attempts differed between groups and if aspects of core psychopathology predicted specific attempt characteristics. METHOD: Eighty-one inpatients with borderline personality disorder, including 49 patients with borderline personality disorder plus major depressive episode, were compared to 77 inpatients with major depressive episode alone on measures of depressed mood, hopelessness, impulsive aggression, and suicidal behavior, including lifetime number of attempts, degree of lethal intent, objective planning, medical damage, and degree of violence of suicide methods. RESULTS: No significant differences were found in the characteristics of suicide attempts between patients with borderline personality disorder and those with major depressive episode. However, patients with both disorders had the greatest number of suicide attempts and the highest level of objective planning. An increase in either impulsive aggression or hopelessness or a diagnosis of borderline personality disorder predicted a greater number of attempts. Hopelessness predicted lethal intent in all three groups and predicted objective planning in the group with both disorders. Medical damage resulting from the most serious lifetime suicide attempt was predicted by number of attempts. CONCLUSIONS: Comorbidity of borderline personality disorder with major depressive episode increases the number and seriousness of suicide attempts. Hopelessness and impulsive aggression independently increase the risk of suicidal behavior in patients with borderline personality disorder and in patients with major depressive episode. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Low levels of docosahexaenoic acid, a polyunsaturated fatty acid, and elevated ratios of omega-6/omega-3 fatty acids are associated with major depression and, possibly, suicidal behavior. Predicting risk of future suicidal behaviors by essential fatty acid status merits examination. METHOD: Plasma polyunsaturated fatty acid levels in phospholipids were measured in 33 medication-free depressed subjects monitored for suicide attempt over a 2-year period. Survival analysis examined the association of plasma polyunsaturated fatty acid status and pathological outcome. RESULTS: Seven subjects attempted suicide on follow-up. A lower docosahexaenoic acid percentage of total plasma polyunsaturated fatty acids and a higher omega-6/omega-3 ratio predicted suicide attempt. CONCLUSIONS: A low docosahexaenoic acid percentage and low omega-3 proportions of lipid profile predicted risk of suicidal behavior among depressed patients over the 2-year period. If confirmed, this finding would have implications for the neurobiology of suicide and reduction of suicide risk. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alcoholism is associated with alterations in the serotonergic and noradrenergic systems. Alcoholics are at a significantly higher risk for suicide than the general population. Altered serotonin (5-HT) function is associated with suicide and serious suicide attempts. We hypothesized patterns of abnormality associated independently with suicide and with alcoholism. METHODS: Quantitative autoradiographic experiments were performed in human postmortem brain tissue sections from alcoholics, alcoholic-suicide decedents, nonalcoholic suicide decedents, and normal controls diagnosed by psychological autopsy. RESULTS: Binding to 5-HT1A receptors is lower in both alcoholic suicides and alcoholic nonsuicides, suggesting that this effect is related to alcoholism and not suicide. In nonalcoholic suicides, there is a localized increase in 5-HT1A binding in ventral prefrontal cortex, hypothesized to be a response to less serotonin input. Therefore, alcoholic suicides may fail to up-regulate ventral prefrontal 5-HT1A receptors in response to decreased serotonergic transmission, failing to mitigate the impact of less serotonin upon signal transduction and thereby increasing the risk of suicidal behavior. Binding to the serotonin transporter is low in alcoholic suicides but not in alcoholic nonsuicides, suggesting an association with suicide, as nonalcoholic suicides also have decreased binding compared with controls. Evidence of impaired serotonergic innervation associated with alcoholism is also manifested by less 5-HT1D terminal autoreceptor binding in alcoholics. Nonalcoholic suicides do not have lower 5-HT1D binding.In the noradrenergic system, alcoholics (suicide and nonsuicide) and nonalcoholic suicide victims all have fewer pigmented locus ceruleus neurons compared with controls, yet beta1-adrenergic binding is low in both alcoholic groups, whereas alpha1-and alpha2-adrenergic binding decreases are more pronounced in the alcoholic suicide group. These noradrenergic findings differ from those in nonalcoholic suicides, which have a common feature with alcoholics in having less alpha2-and beta1-adrenergic binding but more alpha1-adrenergic binding in ventrolateral and orbital cortex. CONCLUSION: Extensive but different abnormalities in both the serotonergic and noradrenergic systems have been identified in alcoholics and suicides, suggesting two separate patterns: one related to alcoholism and the other related to suicide. The different patterns suggest different causes and homeostatic responses for alcoholism and suicide. [ABSTRACT FROM AUTHOR]

Objective: Exposure to suicidal behavior in peers and relatives is thought to increase risk for suicidal behavior in vulnerable individuals, possibly as a result of imitation or modeling. This study examines exposure to suicidal behavior and likelihood of suicide attempt in a high-risk cohort of offspring of a depressed parent.Method: A total of 449 offspring of 255 probands with a mood disorder were enrolled in a family study. Probands and offspring were assessed for psychopathology and suicide attempt history, and offspring for suicide exposure. Generalized estimating equations (GEE) and generalized least squares models were used to compare suicide attempt history in exposed and nonexposed offspring as well as characteristics of exposure in exposed offspring suicide attempters and exposed nonattempters. GEE was used to compare exposure occurring before first attempt in attempter offspring and exposure occurring before the same age in matched nonattempter offspring.Results: Offspring reporting exposure to suicidal behavior were four times more likely to report a lifetime suicide attempt compared with unexposed offspring, controlling for age. Suicide attempt status was not associated with age at first exposure, total number or degree (attempt or threat) of exposures, or relationship. Analysis of exposure occurring before age at first suicide attempt found no association between exposure and suicide attempt.Conclusions: Offspring exposed to suicidal behavior are more likely to report a lifetime suicide attempt than nonexposed offspring. However, when examining the temporal sequence of exposure and attempt, the association is no longer significant, suggesting that imitation is not sufficient explanation. [ABSTRACT FROM AUTHOR]