Biomarkers of Bipolar Disorder in Late Life: An Evidence-Based Systematic Review.

PURPOSE OF REVIEW: Review the current evidence on biomarkers for bipolar disorder in the older adults. We conducted a systematic search of PubMed MEDLINE, PsycINFO, and Web of Science databases using the MeSH search terms "Biomarkers", "Bipolar Disorder", "Aged" and and "Aged, 80 and over". Studies were included if they met the following criteria: (1) the mean age of the study population was 50 years old or older, (2) the study included patients with bipolar disorder, and (3) the study examined one type of biomarkers or more including genetic, neuroimaging, and biochemical biomarkers. Reviews, case reports, studies not in English and studies for which no full text was available were excluded. A total of 26 papers were included in the final analysis. RECENT FINDINGS: Genomic markers of bipolar disorder in older adults highlighted the implication of serotonin metabolism, while the expression of genes involved in angiogenesis was dysregulated. Peripheral blood markers were mainly related with low grade inflammation, axonal damage, endothelial dysfunction, and the dysregulation of the HPA axis. Neuroanatomical markers reflected a dysfunction of the frontal cortex, a loss of neurones in the anterior cingulate cortex and a reduction of the hippocampal volume (in patients older than 50 years old). While not necessarily limited to older adults, some of them may be useful for differential diagnosis (neurofilaments), disease staging (homocysteine, BDNF) and the monitoring of treatment outcomes (matrix metalloproteinases). Our review provides a comprehensive overview of the current evidence on biomarkers for bipolar disorder in the older adults. The identification of biomarkers may aid in the diagnosis, treatment selection, and monitoring of bipolar disorder in older adults, ultimately leading to improved outcomes for this population. Further research is needed to validate and further explore the potential clinical utility of biomarkers in this population.

Predictors of psychological distress in advanced cancer patients under palliative treatments.

This work aims to investigate the factors associated with psychological distress in advanced cancer patients under palliative treatment. We comprehensively assessed the demographic, psychosocial and health factors of 158 advanced cancer patients. Patients with high and low distress, according to the Hospital Anxiety and Depression Scale, were compared. A regression analysis was built to identify the best predictors of distress. Patients with high psychological distress (81%) were more likely to have lung cancer, suicidal ideation, hopelessness, low quality of life and poor body image than those without. In the multivariate model, only poor emotional functioning (OR = .89; 95% CI = .83-.95; p ≤ .001), hopelessness (OR = .86; 95% CI = .78-.94; p ≤ .001) and body image distortions (OR = .77; 95% CI = .68-.85; p = .005) were retained. High levels of hopelessness, impaired emotional functioning and body image distortions are the main factors associated with psychological distress in patients with advanced cancer. Potential interventions to modify these factors in palliative units are discussed.

Suicide ideation among oncologic patients in a Spanish ward.

Oncologic patients are exposed to a higher risk of suicidal behaviors than the general population. In this study, we aim to examine the severity of suicidal ideation in a sample of oncologic patients considering different psychological and clinical features. We interviewed 202 inpatients receiving curative or palliative treatment in a medical oncology ward of a Spanish hospital during the period 2012-2014. A complete assessment of psychosocial factors, cancer diagnoses (lung, colon rectum, and genitourinary system), and suicidal behaviors were made during admission, including validated questionnaires about depression, anxiety, personality, quality of life, body image, life threatening events, hopelessness, and suicidal ideation. The characteristics of inpatients with high and low suicidal ideation were retrospectively compared. A logistic regression model was constructed to examine the relationship between the significant factors retained after the univariate analyses. One of every four patients (n = 51; 25.24%) presented high scores of suicidal ideation. Logistic regression analyses retained depression (OR = 3.55; 95% CI = 1.25-11.68; p = .016), hopelessness (OR = 8.78; 95% CI = 3.44-25.88; p ≤ .001), personality (OR = .44; 95% CI = .2-.96; p = .038), and advanced age (OR = 2.60; 95% CI = 1.18-5.98; p = .016) as the main risk factors for high suicidal ideation. Suicidal ideation was frequent among oncologic patients. These patients should receive closer monitoring, especially, when old, retired, or severely depressed.

Increased severity of suicidal behavior in impulsive aggressive patients exposed to familial adversities.

BACKGROUND: The mechanisms by which childhood abuse and family history of suicidal behavior (FHS) lead to an increased risk of suicidal behavior are still unknown. Impulsive aggression may play an intermediate role. We investigated whether greater scores for aggression and impulsivity might be associated with the effects of FHS and/or childhood abuse on the severity of suicidal behavior. METHOD: We examined the scores of three scales measuring impulsive aggression in a sample of 696 suicide attempters. We compared the highest and lowest scores with regard to reports of childhood abuse and FHS using adjusted multinomial regression models. Genetic polymorphisms of the serotonergic system known to be associated with impulsive aggression were also analyzed. RESULTS: Patients with high impulsive aggressive scores showed significant differences in sociodemographic, clinical and suicidal features compared with patients with low impulsive aggressive scores. Adjusted results showed that combinations of some types of childhood abuse and FHS, particularly emotional abuse and emotional neglect, are associated with high impulsivity and hostility scores. The SS genotype of the serotonin transporter gene (5-HTTLPR) was associated with high levels of impulsivity when the subjects reported emotional abuse [odds ratio (OR) 5.55, 95% confidence interval (CI) 1.75-17.5] or physical abuse (OR 5.03, 95% CI 1.50-16.9) in their childhood. CONCLUSIONS: Our results support the role of impulsive aggression as one of the links that may connect childhood abuse and FHS with severity of suicidal behavior.

Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population.

Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.

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.

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.

Endophenotypes and suicide behaviour.

BACKGROUND: Recent studies have suggested that genetic predisposition to suicidal behavior may be independent of the risk of suicide associated to mental disorders, such as affective disorders, schizophrenia or alcohol dependence. Given the suicidal behavior heterogeneity and its hereditary complexity, the need to find demonstrable intermediate phenotypes that may make it possible to establish links between genes and suicide behaviors (endophenotypes) seems to be necessary. The main objective is to review which are the candidate endophenotypes of suicidal behaviors. METHODS: We carried out a non-systematic review of all published literature in English, French and Spanish in MEDLINE. The search terms were endophenotypes and suicide behaviors. CONCLUSIONS: The main candidate endophenotypes of suicidal behaviors are neuropsychological (decision-making, executive functions), personality traits (impulsivity, aggressiveness, and neuroticism), neurochemistry (5-HIAA in CNS) and neuroimaging (fMRI of cerebral amygdala or PET of prefrontal cortex metabolism).

[Electronic calendar as an organization element in Internal Medicine services]. / Los calendarios electrónicos como herramientas de organización de los servicios de Medicina Interna.

The growing volume of information and introduction of new technologies in the Internal Medicine hospital department mare making the traditional updating «methods¼ of knowledge and organization obsolete. The development of new tools could help the management of information and organization of the medical departments is outdated. Electronic calendar such as the Google calendar facilitate adequate coordination among health care professionals. Our experience suggests that the Google calendar is a simple and useful tool that helps planning and organization of the clinical, educational, and research activities of the different medical departments, limits loss of information and improves efficacy with a close to zero cost of infrastructure.

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.

Mood changes after delivery: role of the serotonin transporter gene.

BACKGROUND: Polymorphic variations in the serotonin transporter gene (5-HTT) moderate the depressogenic effects of tryptophan depletion. After childbirth there is a sharp reduction in brain tryptophan availability, thus polymorphic variations in 5-HTT may play a similar role in the post-partum period. AIMS: To study the role of 5-HTT polymorphic variations in mood changes after delivery. METHOD: One thousand, eight hundred and four depression-free Spanish women were studied post-partum. We evaluated depressive symptoms at 2-3 days, 8 weeks and 32 weeks post-partum. We used diagnostic interview to confirm major depression for all probable cases. Based on two polymorphisms of 5-HTT (5-HTTLPR and STin2 VNTR), three genotype combinations were created to reflect different levels of 5-HTT expression. RESULTS: One hundred and seventy-three women (12.7%) experienced major depression during the 32-week post-partum period. Depressive symptoms were associated with the high-expression 5-HTT genotypes in a dose-response fashion at 8 weeks post-partum, but not at 32 weeks. CONCLUSIONS: High-expression 5-HTT genotypes may render women more vulnerable to depressive symptoms after childbirth.

Association of plasma nitrite levels with obesity and metabolic syndrome in the Old Order Amish.

OBJECTIVES: Plasma nitrite is a metabolite of nitric oxide and reflects endogenous nitric oxide synthase (NOS) activity. Although plasma nitrites were previously linked with obesity and metabolic syndrome (MetS), the direction of association remains inconsistent, possibly due to sample heterogeneity. In a relatively homogeneous population, we hypothesized that nitrite levels will be positively associated with overweight/obesity and MetS. METHODS: Fasting nitrite levels were measured in 116 Old Order Amish (78% women). We performed age-and-sex-adjusted ancovas to compare nitrite levels between three groups (a) overweight/obese(-)MetS(-), (b) overweight/obese(+)MetS(-) and (c) overweight/obese(+)MetS)(+). Multivariate linear regressions were conducted on nitrite associations with continuous metabolic variables, with successive adjustments for demographics, body mass index, C-reactive protein and neopterin. RESULTS: Nitrite levels were higher in the obese/overweight(+)MetS(+) group than in the other two groups (p < 0.001). Nitrites were positively associated with levels of triglycerides (p < 0.0001), total cholesterol (p = 0.048), high-density lipoprotein/cholesterol ratio (p < 0.0001) and fasting glucose (p < 0.0001), and negatively correlated with high-density lipoprotein-cholesterol (p < 0.0001). These associations were robust to adjustments for body mass index and inflammatory markers. CONCLUSION: Further investigation of the connection between obesity/MetS and plasma nitrite levels may lead to novel dietary and pharmacological approaches that ultimately may contribute to reducing the increasing burden of obesity, MetS and cardiovascular morbidity and mortality.

Computerized Adaptive Test vs. decision trees: Development of a support decision system to identify suicidal behavior.

BACKGROUND: Several Computerized Adaptive Tests (CATs) have been proposed to facilitate assessments in mental health. These tests are built in a standard way, disregarding useful and usually available information not included in the assessment scales that could increase the precision and utility of CATs, such as the history of suicide attempts. METHODS: Using the items of a previously developed scale for suicidal risk, we compared the performance of a standard CAT and a decision tree in a support decision system to identify suicidal behavior. We included the history of past suicide attempts as a class for the separation of patients in the decision tree. RESULTS: The decision tree needed an average of four items to achieve a similar accuracy than a standard CAT with nine items. The accuracy of the decision tree, obtained after 25 cross-validations, was 81.4%. A shortened test adapted for the separation of suicidal and non-suicidal patients was developed. CONCLUSION: CATs can be very useful tools for the assessment of suicidal risk. However, standard CATs do not use all the information that is available. A decision tree can improve the precision of the assessment since they are constructed using a priori information.

Suicide mortality trends in Galicia, Spain and their relationship with economic indicators.

BACKGROUND: Recent research has shown an association between unemployment and suicide, but the mediating factors in this relationship are still unknown. In this study, we investigated the effect of unemployment and economic recession on suicide rates in the Spanish region of Galicia between 1975 and 2012 Method. We analysed age-standardised suicide rates in men and women and in four age groups: less than 25 years, 25-45 years, 45-65 years and more than 65 years and performed a joinpoint analysis to determine trend changes throughout 1975-2012 period. Also we analysed the association between suicide, recession and unemployment by means of a temporal trend model with a Generalised Additive Model. RESULTS: Suicide rates increased from 145 suicides in 1975 to a high in 1993, with 377 deaths by suicide, representing 1.38% of all causes of death, and thereafter they tend to decrease to 335 suicides in 2012. Joinpoint analyses revealed that suicide rates changed differently across sex and age groups. For men, the annual percentage of change (APC) between 1975 and 1988 (CI 95% 1986-1994) was 5.45 (CI 95% = 3.5, -7.2) but from 1988 the APC became negative [-0.66 (CI 95% = -1.3, -0.1)]. For women, APC between 1974 and 1990 (CI 95% 1986-1992) was 4.86 (CI 95% = 3.2, -6.4) and -1.46 subsequently (CI 95% = -2.2, -0.5). Women aged 24 years or less showed stable suicide rates while men from 45-65 years showed two incidence peaks. When we studied the independent correlation between unemployment, recession and suicide, we found a significant association between unemployment and suicide, but not between recession and suicide for both sexes together and for men while for women there was no significant correlation between suicide and unemployment or recession. Finally, when we studied the effect of the interaction between unemployment and recession on suicide we found economic recession and unemployment interacted with regards to suicide rates (F = 5.902; df = 4.167; p = 0.00098) and after adjusting by sex, the effect was confirmed among men (F = 4.827; df = 2.823; p = 0.0087), but not among women (F = 0.001; df = 1.000; p = 0.979). CONCLUSIONS: Although suicide rates in Galicia are gradually decreasing in the last decades, there are important sex and age differences. Unemployment was related with suicide during economic recession periods according to our results.

The additive effect on suicidality of family history of suicidal behavior and early traumatic experiences.

Family history of suicidal behavior and personal history of childhood abuse are reported risk factors for suicide attempts and suicide completion. We aim to quantify the additive effect of family history of suicidal behavior and different subtypes of childhood abuse on suicidal behavior. We examined a sample of 496 suicide attempters, comparing individuals with family history of suicidal behavior and personal history of childhood (physical or sexual) abuse, individuals with family history of suicidal behavior only, individuals with history of early traumatic experiences only, and individuals with none of these two risk factors with regards to suicidal features. An additive effect was found for the age at the first attempt in suicide attempters with both family history of suicidal behavior and either physical or sexual abuse. No significant interactions were found between family history of suicidal behavior and childhood trauma in relation to any characteristics of suicidal behavior. Subjects presenting family history of suicidal behavior and childhood abuse attempt suicide earlier in life than subjects with just one or none of them, particularly if they were sexually abused. Other suicidality indexes were only partially or not associated with this combination of risk factors. A careful assessment of patients with both family history of suicidal behavior and childhood abuse could help to prevent future suicide attempts, particularly in young people.

A prospective study of the paradoxical relationship between impulsivity and lethality of suicide attempts.

BACKGROUND: Biological studies suggest that lower serotonergic activity is associated with both greater suicide lethality and impulsive personality traits. These results may lead to the conclusion that impulsivity in the attempt should be associated with greater lethality. However, Klerman's review of epidemiologic suicide studies suggests an inverse relationship between impulsivity and lethality. This seemingly paradoxical relationship between impulsivity and lethality has not been explored in large representative clinical samples of suicide attempts. METHOD: During 1996 to 1998, 478 individuals who attempted suicide were studied in a general hospital in Madrid, Spain. Impulsivity was measured as described in the literature by combining 2 items of Beck's Suicidal Intent Scale (active preparation for attempt and degree of premeditation). Lethality of the attempt was assigned 1 of 4 levels according to the need for medical and/or psychiatric treatment. RESULTS: More than half of the attempts were impulsive (55%; 95% confidence interval [CI], 51% to 59%), approximately one fourth of the attempts had an intermediate level of impulsivity (28%; 95% CI, 24% to 32%), and approximately one sixth of the attempts were not impulsive (17%, 95% CI, 13% to 21%). There was an inverse association between the impulsivity and lethality of the suicide attempt (chi2 = 62.639, df = 6, p < .0001). The most impulsive attempts tended to result in less morbidity, while the less impulsive attempts tended to be more lethal. CONCLUSION: If the inverse relationship between impulsivity and lethality is replicated in other large and representative samples, new studies will be needed to clarify the complex interactions between the clinical dimensions (lethality, impulsivity as a state, and impulsivity as a personality trait) and the biological correlates (particularly serotonergic function) of suicidal behavior.

Plasma testosterone and pathological gambling.

The authors studied plasma testosterone levels and psychological characteristics of male pathological gamblers. Twenty-nine male pathological gamblers and a group of healthy volunteers matched for age and gender were compared on levels of plasma testosterone and scores on the Eysenck Personality Questionnaire (EPQ) and the Psychopathic Deviance scale of the Minnesota Multiphasic Personality Inventory (MMPI). Plasma testosterone levels were similar in the pathological gambling and comparison group (476.06 ng/100 ml vs. 560.71 ng/100 ml). Patients had higher scores on the Neuroticism subscales of the EPQ (13.83 vs. 10.83) and the Psychopathic Deviance scale of the MMPI (27.03 vs. 21.03), but not on any of the other subscales of the EPQ. Testosterone levels did not correlate with the psychological ratings. Testosterone levels are probably not related to impulsivity in pathological gambling.

Assessment of reliability in the clinical evaluation of depressive symptoms among multiple investigators in a multicenter clinical trial.

The objective of this work was to determine the severity of depressive symptoms when multiple clinical examiners evaluate a single subject, as preparatory to their participation as evaluators in a clinical trial. Using the 17-item Hamilton Depression Rating Scale (HDRS), 37 psychiatrists independently assessed the videotape of a patient with symptoms of depression. A new measure for the detection of multiple examiners not in consensus (DOMENIC) was used to identify scale items with low reliability and raters with low inter-rater reliability, from among the remaining raters. Overall inter-rater agreement on the full HDRS was 'excellent' (97%). All raters but one showed adequate agreement both on individual items and on total scores. Two of the 17 HDRS symptomatology items had unacceptable levels of inter-rater scoring variability (<70% agreement). The use of DOMENIC allows for the detection of items of low inter-rater reliability and identification of raters that deviate from the group's ratings prior to the beginning of a clinical trial.