Antidepressant medication exposure and 5-HT1A autoreceptor binding in major depressive disorder.

OBJECTIVE: We have previously reported higher brain serotonin 1A (5-HT1A ) autoreceptor binding in antidepressant-naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5-HT1A receptor binding after medication discontinuation. METHODS: Positron emission tomography (PET) imaging with the 5-HT1A receptor radioligand [11 C]WAY-100635 was performed in 66 individuals with current DSM-IV MDD to examine relationships between 5-HT1A binding and time since most recent antidepressant treatment. All subjects were medication-free for at least 2 weeks prior to scanning. Thirty-two additional MDD comparison subjects were antidepressant naïve. RESULTS: No differences in [11 C]WAY-100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [11 C]WAY-100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. CONCLUSION: These results indicate that any antidepressant-associated downregulation of 5-HT1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness-related binding levels.

Are comorbid anxiety disorders a risk factor for suicide attempts in patients with mood disorders? A two-year prospective study.

BACKGROUND: Comorbid anxiety disorders have been considered a risk factor for suicidal behavior in patients with mood disorders, although results are controversial. The aim of this two-year prospective study was to determine if lifetime and current comorbid anxiety disorders at baseline were risk factors for suicide attempts during the two-year follow-up. METHODS: We evaluated 667 patients with mood disorders (504 with major depression and 167 with bipolar disorder) divided in two groups: those with lifetime comorbid anxiety disorders (n=229) and those without (n=438). Assessments were performed at baseline and at 3, 12, and 24 months. Kaplan-Meier survival analysis and log-rank test were used to evaluate the relationship between anxiety disorders and suicide attempts. Cox proportional hazard regression was performed to investigate clinical and demographic variables that were associated with suicide attempts during follow-up. RESULTS: Of the initial sample of 667 patients, 480 had all three follow-up interviews. During the follow-up, 63 patients (13.1%) attempted suicide at least once. There was no significant difference in survival curves for patients with and without comorbid anxiety disorders (log-rank test=0.269; P=0.604). Female gender (HR=3.66, P=0.001), previous suicide attempts (HR=3.27, P=0.001) and higher scores in the Buss-Durkee Hostility Inventory (HR=1.05, P≤0.001) were associated with future suicide attempts. CONCLUSIONS: Our results suggest that comorbid anxiety disorders were not risk factors for suicide attempts. Further studies were needed to determine the role of anxiety disorders as risk factors for suicide attempts.

Addressing the tuberculosis-depression syndemic to end the tuberculosis epidemic.

Tuberculosis (TB) and depression act synergistically via social, behavioral, and biological mechanisms to magnify the burden of disease. Clinical depression is a common, under-recognized, yet treatable condition that, if comorbid with TB, is associated with increased morbidity, mortality, community TB transmission, and drug resistance. Depression may increase risk of TB reactivation, contribute to disease progression, and/or inhibit the physiological response to anti-tuberculosis treatment because of poverty, undernutrition, immunosuppression, and/or negative coping behaviors, including substance abuse. Tuberculous infection and/or disease reactivation may precipitate depression as a result of the inflammatory response and/or dysregulation of the hypothalamic-pituitary-adrenal axis. Clinical depression may also be triggered by TB-related stigma, exacerbating other underlying social vulnerabilities, and/or may be attributed to the side effects of anti-tuberculosis treatment. Depression may negatively impact health behaviors such as diet, health care seeking, medication adherence, and/or treatment completion, posing a significant challenge for global TB elimination. As several of the core symptoms of TB and depression overlap, depression often goes unrecognized in individuals with active TB, or is dismissed as a normative reaction to situational stress. We used evidence to reframe TB and depression comorbidity as the 'TB-depression syndemic', and identified critical research gaps to further elucidate the underlying mechanisms. The World Health Organization's Global End TB Strategy calls for integrated patient-centered care and prevention linked to social protection and innovative research. It will require multidisciplinary approaches that consider conditions such as TB and depression together, rather than as separate problems and diseases, to end the global TB epidemic.

Clinical features, impulsivity, temperament and functioning and their role in suicidality in patients with bipolar disorder.

OBJECTIVE: Our aim was to analyse sociodemographic and clinical differences between non-suicidal (NS) bipolar patients (BP), BP reporting only suicidal ideation (SI) and BP suicide attempters according to Columbia-Suicide Severity Rating Scale (C-SRSS) criteria. Secondarily, we also investigated whether the C-SRSS Intensity Scale was associated with emergence of suicidal behaviour (SB). METHOD: A total of 215 euthymic bipolar out-patients were recruited. Semistructured interviews including the C-SRSS were used to assess sociodemographic and clinical data. Patients were grouped according to C-SRSS criteria: patients who scored ≤1 on the Severity Scale were classified as NS. The remaining patients were grouped into two groups: 'patients with history of SI' and 'patients with history of SI and SB' according to whether they did or did not have a past actual suicide attempt respectively. RESULTS: Patients from the three groups differed in illness onset, diagnosis, number of episodes and admissions, family history, comorbidities, rapid cycling and medication, as well as level of education, functioning, impulsivity and temperamental profile. CONCLUSION: Our results suggest that increased impulsivity, higher rates of psychiatric admissions and a reported poor controllability of SI significantly increased the risk for suicidal acts among patients presenting SI.

A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine's antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg(-1) intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score ⩽10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=-0.78, P=0.023), but no other measures.

Mental disorders and risk of suicide attempt: a national prospective study.

Most mental disorders, when examined independently, are associated with an elevated risk for suicide attempt. However, mental disorders often co-occur, and that co-occurrence is well explained by models where specific mental disorders are understood as manifestations of latent dimensions of psychopathology. To date, it remains unclear whether the risk of suicide attempt is due to specific mental disorders, to specific dimensions of psychopathology (that is, internalizing and externalizing dimensions), to a general psychopathology factor or to a combination of these explanations. In a large nationally representative prospective survey, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we used structural equation modeling to examine the shared and specific effects of Axis I and Axis II disorders on the occurrence of suicide attempts in the general population and among individuals with a lifetime history of suicidal ideation. Effects of mental disorders on the risk of suicide attempt were exerted almost exclusively through a general psychopathology factor representing the shared effect across all mental disorders. Effects of remitted psychiatric disorders on the risk of suicide attempt were fully mediated by current mental disorders. Similar patterns of associations were found in individuals with suicidal ideation. These results held when using different approaches to modeling psychiatric comorbidity. Our findings underscore the importance of adopting dimensional approaches to comorbidity in the study of suicidal behavior. Because mental disorders increase the risk of suicide attempt through a general psychopathology liability, this dimension should be considered as an important therapeutic target to substantially advance suicide prevention.

A computational analysis of flanker interference in depression.

BACKGROUND: Depression is characterized by poor executive function, but - counterintuitively - in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study. METHOD: One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials). RESULTS: Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = -0.28, p = 0.007). CONCLUSIONS: Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.

Bipolar I and II versus unipolar depression: clinical differences and impulsivity/aggression traits.

OBJECTIVE: To investigate distinguishing features between bipolar I, II and unipolar depression, and impulsivity/aggression traits in particular. METHODS: Six hundred and eighty-five (n=685) patients in a major depressive episode with lifetime Unipolar (UP) depression (n=455), Bipolar I (BP-I) disorder (n=151), and Bipolar II (BP-II) (n=79) disorder were compared in terms of their socio-demographic and clinical characteristics. RESULTS: Compared to unipolar patients, BP-I and BP-II depressed patients were significantly younger at onset of their first depressive episode, and were more likely to experience their first depressive episode before/at age of 15. They also had more previous affective episodes, more first- and second-degree relatives with history of mania, more current psychotic and subsyndromal manic symptoms, and received psychopharmacological and psychotherapy treatment at an earlier age. Furthermore, BP-I and BP-II depressed patients had higher lifetime impulsivity, aggression, and hostility scores. With regard to bipolar subtypes, BP-I patients had more trait-impulsivity and lifetime aggression than BP-II patients whereas the latter had more hostility than BP-I patients. As for co-morbid disorders, Cluster A and B Personality Disorders, alcohol and substance abuse/dependence and anxiety disorders were more prevalent in BP-I and BP-II than in unipolar patients. Whereas the three groups did not differ on other socio-demographic variables, BP-I patients were significantly more often unemployed that UP patients. CONCLUSION: Our findings comport with major previous findings on differences between bipolar and unipolar depression. As for trait characteristics, bipolar I and II depressed patients had more life-time impulsivity and aggression/hostility than unipolar patients. In addition, bipolar I and II patients also differed on these trait characteristics.

Neuropsychological deficits in past suicide attempters with varying levels of depression severity.

BACKGROUND: Our previous work identified deficits in interference processing and learning/memory in past suicide attempters who were currently depressed and medication-free. In this study, we extend this work to an independent sample studied at various stages of illness and treatment (mild symptoms, on average) to determine if these deficits in past suicide attempters are evident during a less severe clinical state. METHOD: A total of 80 individuals with a past history of major depression and suicide attempt were compared with 81 individuals with a history of major depression and no lifetime suicide attempts on a battery of neurocognitive measures assessing attention, memory, abstract/contingent learning, working memory, language fluency and impulse control. RESULTS: Past attempters performed more poorly in attention, memory and working memory domains, but also in an estimate of pre-morbid intelligence. After correction for this estimate, tests that had previously distinguished past attempters - a computerized Stroop task and the Buschke Selective Reminding Test - remained significantly worse in attempters. In a secondary analysis, similar differences were found among those with the lowest levels of depression (Hamilton Depression Rating Scale score <10), suggesting that these deficits may be trait markers independent of current symptomatology. CONCLUSIONS: Deficits in interference processing and learning/memory constitute an enduring defect in information processing that may contribute to poor adaptation, other higher-order cognitive impairments and risk for suicidal behavior.

Life events: a complex role in the timing of suicidal behavior among depressed patients.

Suicidal behavior is often conceptualized as a response to overwhelming stress. Our model posits that given a propensity for acting on suicidal urges, stressors such as life events or major depressive episodes (MDEs) determine the timing of suicidal acts. Depressed patients (n=415) were assessed prospectively for suicide attempts and suicide, life events and MDE over 2 years. Longitudinal data were divided into 1-month intervals characterized by MDE (yes/no), suicidal behavior (yes/no) and life event scores. Marginal logistic regression models were fit, with suicidal behavior as the response variable and MDE and life event score in either the same or previous month, respectively, as time-varying covariates. Among 7843 person-months, 33% had MDE and 73% had life events. MDE increased the risk for suicidal behavior (odds ratio (OR)=4.83, P⩽0.0001). Life event scores were unrelated to the timing of suicidal behavior (OR=1.06 per 100 point increase, P=0.32), even during a MDE (OR=1.12, P=0.15). However, among those without borderline personality disorder (BPD), both health- and work-related life events were key precipitants, as was recurrent MDE, with a 13-fold effect. The relationship of life events to suicidal behavior among those with BPD was more complex. Recurrent MDE was a robust precipitant for suicidal behavior, regardless of BPD comorbidity. The specific nature of life events is key to understanding the timing of suicidal behavior. Given unanticipated results regarding the role of BPD and study limitations, these findings require replication. Of note, that MDE, a treatable risk factor, strongly predicts suicidal behaviors is cause for hope.

Genetic variability at IMPA2, INPP1 and GSK3ß increases the risk of suicidal behavior in bipolar patients.

Bipolar patients (BP) are at high risk of suicide. Causal factors underlying suicidal behavior are still unclear. However, it has been shown that lithium has antisuicidal properties. Genes involved in its putative mechanism of action such as the phosphoinositol and the Wnt/ß-catenine pathways could be considered candidates for suicidal behavior (SB). Our aim was to investigate the association of the IMPA1 and 2, INPP1, GSK3α and ß genes with suicidal behavior in BP. 199 BP were recruited. Polymorphisms at the IMPA1 (rs915, rs1058401 and rs2268432) and IMPA2 (rs66938, rs1020294, rs1250171 and rs630110), INPP1 (rs3791809, rs4853694 and 909270), GSK3α (rs3745233) and GSK3ß (rs334558, rs1732170 and rs11921360) genes were genotyped. All patients were grouped and compared according to the presence or not of history of SB (defined as the presence of at least one previous suicidal attempt). Single SNP analyses showed that suicide attempters had higher frequencies of AA genotype of the rs669838-IMPA2 and GG genotype of the rs4853694-INPP1gene compared to non-attempters. Results also revealed that T-allele carriers of the rs1732170-GSK3ß gene and A-allele carriers of the rs11921360-GSK3ß gene had a higher risk for attempting suicide. Haplotype analysis showed that attempters had lower frequencies of A:A haplotype (rs4853694:rs909270) at the INPP1 gene. Higher frequencies of the C:A haplotype and lower frequencies of the A:C haplotype at the GSK-3ß gene (rs1732170:rs11921360) were also found to be associated to SB in BP. Therefore, our results suggest that genetic variability at IMPA2, INPP1 and GSK3ß genes is associated with the emergence of SB in BP.

Neuropsychological function and suicidal behavior: attention control, memory and executive dysfunction in suicide attempt.

BACKGROUND: Executive dysfunction, distinct from other cognitive deficits in depression, has been associated with suicidal behavior. However, this dysfunction is not found consistently across samples. METHOD: Medication-free subjects with DSM-IV major depressive episode (major depressive disorder and bipolar type I disorder) and a past history of suicidal behavior (n = 72) were compared to medication-free depressed subjects with no history of suicidal behavior (n = 80) and healthy volunteers (n = 56) on a battery of tests assessing neuropsychological functions typically affected by depression (motor and psychomotor speed, attention, memory) and executive functions reportedly impaired in suicide attempters (abstract/contingent learning, working memory, language fluency, impulse control). RESULTS: All of the depressed subjects performed worse than healthy volunteers on motor, psychomotor and language fluency tasks. Past suicide attempters, in turn, performed worse than depressed non-attempters on attention and memory/working memory tasks [a computerized Stroop task, the Buschke Selective Reminding Task (SRT), the Benton Visual Retention Test (VRT) and an N-back task] but not on other executive function measures, including a task associated with ventral prefrontal function (Object Alternation). Deficits were not accounted for by current suicidal ideation or the lethality of past attempts. A small subsample of those using a violent method in their most lethal attempt showed a pattern of poor executive performance. CONCLUSIONS: Deficits in specific components of attention control, memory and working memory were associated with suicidal behavior in a sample where non-violent attempt predominated. Broader executive dysfunction in depression may be associated with specific forms of suicidal behavior, rather than suicidal behavior per se.

Machine learning and data mining: strategies for hypothesis generation.

Strategies for generating knowledge in medicine have included observation of associations in clinical or research settings and more recently, development of pathophysiological models based on molecular biology. Although critically important, they limit hypothesis generation to an incremental pace. Machine learning and data mining are alternative approaches to identifying new vistas to pursue, as is already evident in the literature. In concert with these analytic strategies, novel approaches to data collection can enhance the hypothesis pipeline as well. In data farming, data are obtained in an 'organic' way, in the sense that it is entered by patients themselves and available for harvesting. In contrast, in evidence farming (EF), it is the provider who enters medical data about individual patients. EF differs from regular electronic medical record systems because frontline providers can use it to learn from their own past experience. In addition to the possibility of generating large databases with farming approaches, it is likely that we can further harness the power of large data sets collected using either farming or more standard techniques through implementation of data-mining and machine-learning strategies. Exploiting large databases to develop new hypotheses regarding neurobiological and genetic underpinnings of psychiatric illness is useful in itself, but also affords the opportunity to identify novel mechanisms to be targeted in drug discovery and development.

Genetic repositories for the study of major psychiatric conditions: what do we know about ethnic minorities' genetic vulnerability?

In spite of considerable efforts, no genes of major effect have been found across an entire diagnostic category in psychiatry. Possible reasons for this may include difficulties in defining the phenotype, the complex relationship between genotype and gene expression and population stratification. This last problem has often been managed by restricting genetic sampling to only one ethnic group. An unintended consequence of using this strategy is that the major repositories of genetic material for the study of psychiatric conditions in the United States suffer from a paucity of genetic samples from non-Caucasian groups. Thus, these groups are being relatively understudied in terms of the genetic antecedents to psychiatric disease. The authors provide solutions including the need to augment the representation of African-American, Latino and Asian-Americans among research participants; a more nuanced approach to identify ancestry; and the development of analytic and genetic strategies to handle the issue of ethnic heterogeneity in samples.

Suicidal ideation and suicide attempts in the United States: 1991-1992 and 2001-2002.

The aim of the study is to compare the prevalence of suicidal ideation and attempts in the United States in 1991-1992 and 2001-2002, and identify sociodemographic groups at increased risk for suicidal ideation and attempts. Data were drawn from the National Institute on Alcohol Abuse and Alcoholism 1991-1992 National Longitudinal Alcohol Epidemiologic Survey (n=42,862) and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n=43,093), two nationally representative household surveys of non-institutionalized civilians aged 18 years and older, residing in the United States. The lifetime prevalence of suicide attempts remained unchanged in the United States between 1991-1992 and 2001-2002. Specific groups, namely 18- to 24-year-old white and black women, 25- to 44-year-old white women and 45- to 64-year-old Native American men were identified as being at high risk for suicide attempts. Despite prevention and treatment efforts, the lifetime prevalence of suicide attempts remains unchanged. Given the morbidity and mortality associated with suicide attempts, urgent action is needed to decrease the prevalence of suicide attempts in the United States.

Association between familial suicidal behavior and frequency of attempts among depressed suicide attempters.

OBJECTIVE: Only a few studies have examined whether a family history of suicide influences the severity of suicidal acts and the results have been inconsistent. The current study aimed to examine whether a family history of suicidal acts predicts severity of suicide attempts. METHOD: 190 suicide attempters aged 18-75 years with a lifetime history of major depression were assessed for first-degree family history of suicidality and severity of suicide attempts (number and lethality of prior suicide attempts and age at first attempt). RESULTS: Regression analyses indicate that a positive family history of suicidal behaviors predicts a greater number of suicide attempts. Reasons for living predict number and lethality of prior attempts. CONCLUSION: It is critical to assess for family history of suicidal behavior when treating depressed suicide attempters as it may serve as an indicator of the risk of repeat suicide attempt and as a guide for treatment.

Severity of personality disorders and suicide attempt.

OBJECTIVE: Severity of personality disorders (PDs) may be more useful in estimating suicide risk than the diagnosis of specific PDs. We hypothesized that suicide attempters with severe PD would present more attempts and attempts of greater severity/lethality. METHOD: Four hundred and forty-six suicide attempters were assessed. PD diagnosis was made using the International Personality Disorder Questionnaire--Screening Questionnaire. PDs were classified using Tyrer and Johnson's classification of severity (no PD, simple PD, diffuse PD). Severity/lethality of attempts was measured with the Suicide Intent Scale, Risk-Rescue Rating Scale and Lethality Rating Scale. RESULTS: Attempters with severe (diffuse) PD had more attempts than the other groups. After controlling for age and gender, this difference remained significant only for the younger age group and women. There was no relationship between severity of PDs and severity/lethality of attempts. CONCLUSION: Younger female attempters with severe PD are prone to repeated attempts. However, the severity of PD was not related to the severity/lethality of suicide attempts.

Evaluation of clinical prognostic models for suicide attempts after a major depressive episode.

OBJECTIVE: In this study, we compare the performance of prognostic models of increasing complexity for prediction of future suicide attempt. METHOD: 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. RESULTS: 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. CONCLUSION: 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.