Early life stress unravels epistatic genetic associations of cortisol pathway genes with depression.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of the most consistent pathophysiological findings in depressive disorders. Cortisol signaling is affected by proteins that mediate its cellular responses or alters its availability to mineralocorticoid and glucocorticoid receptors. In our study, we evaluated candidate genes that may influence the risk for depression and suicide due to its involvement in cortisol signaling. The aim of the study was to assess whether the genotypes of these genes are associated with the risk for depression, severity of depressive symptoms, suicidal ideation, and suicide attempts. And whether there is interaction between genes and early-life stress. In this study, 100 healthy controls and 140 individuals with depression were included. The subjects were clinically assessed using the 21-item GRID-Hamilton questionnaires (GRID-HAMD-21), Beck Scale for Suicidal Ideation (BSI), and the Childhood Trauma Questionnaire (CTQ). A robust multifactorial dimensionality reduction analysis was used to characterize the interactions between the genes HSD11B1, NR3C1, NR3C2, and MDR1 and early-life stress. It was found a significant association of the heterozygous genotype of the MDR1 gene rs1128503 polymorphism with reduced risk of at least one suicide attempt (OR: 0.08, p = 0.003*) and a reduction in the number of suicide attempts (ß = -0.79, p = 0.006*). Furthermore, it was found that the MDR1 rs1228503 and NR3C2 rs2070951 genes interact with early-life stress resulting in a strong association with depression (p = 0.001). Our findings suggest that polymorphisms in the MDR1 and NR3C2 genes and their interaction with childhood trauma may be important biomarkers for depression and suicidal behaviors.

Minocycline as adjunctive treatment for major depressive disorder: Pooled data from two randomized controlled trials.

BACKGROUND: Randomized controlled clinical trials that have investigated minocycline as an adjunctive treatment for major depressive disorder have proved promising. Data from two studies were pooled to evaluate more definitively whether the addition of minocycline to standard treatment for major depressive disorder leads to an improvement of depressive symptoms when compared with placebo. METHODS: Both studies were multi-site, double-blinded, placebo-controlled trials of minocycline 200 mg/day added to treatment as usual during a 12-week period. The primary outcome measure was change in depressive symptoms (Montgomery-Asberg Depression Rating Scale in Dean et al. and Hamilton Depression Rating Scale in Husain et al.). Secondary outcomes were change in depression severity (Montgomery-Asberg Depression Rating Scale for Dean et al. and 9-item Patient Health Questionnaire in Husain et al.), anxiety severity (Hamilton Anxiety Rating Scale in Dean et al. and Generalized Anxiety Disorder 7-item scale in Husain et al.) and functional status, which were also evaluated as potential mediators on the primary outcome. RESULTS: A total of 112 participants were included in the pooled data (Dean et al., n = 71; Husain et al., n = 41). A significant change from baseline to week 12 was noted in depressive symptoms - differential change (Placebo vs Minocycline): 9.0, 95% confidence interval = [4.2, 13.9], Cohen's D (95% confidence interval): 0.71 [0.29, 1.14], p < 0.001 - anxiety severity - differential change (Placebo vs Minocycline): 0.38, confidence interval = [0.00, 0.75], Cohen's D (95% confidence interval): 0.41 [0.00, 0.82], p = 0.050) and functional status - differential change (Placebo vs Minocycline): 1.0, 95% confidence interval = [0.4, 1.5], Cohen's D (95% confidence interval): 0.76 [0.34, 1.19], p = 0.001). Duration of illness, current use of benzodiazepine and pain medication were identified as moderators, whereas functional status as a mediator/predictor. CONCLUSION: The improvement of depressive symptoms, anxiety severity and functional status is promising and suggests that minocycline has potential as an adjunctive treatment for major depressive disorder. However, further studies are warranted to confirm therapeutic effects of minocycline in major depressive disorder. TRIAL REGISTRATIONS: NCT02263872, registered October 2014, and ACTRN12612000283875, registered March 2012.

The pharmacological interaction of compounds in ayahuasca: a systematic review

Ayahuasca is a South American psychoactive plant brew used as traditional medicine in spiritual and in cultural rituals. This is a review of the current understanding about the pharmacological mechanisms that may be interacting in ayahuasca. Searches were performed using PubMed, PsycINFO, and Web of Science databases and 16 papers were selected. As hypothesized, the primary narrative in existing research revolved around prevention of deamination of N,N-dimethyltryptamine (N,N-DMT, also referred to as DMT) by monoamine oxidase inhibitors (MAOIs) in ayahuasca. Two of the constituents, DMT and harmine, have been studied more than the secondary harmala alkaloids. At present, it is unclear whether the pharmacological interactions in ayahuasca act synergistically or additively to produce psychoactive drug effects. The included studies suggest that our current understanding of the preparation's synergistic mechanisms is limited and that more complex processes may be involved; there is not yet enough data to determine any potential synergistic interaction between the known compounds in ayahuasca. Our pharmacological understanding of its compounds must be increased to avoid the potential risks of ayahuasca use.

The pharmacological interaction of compounds in ayahuasca: a systematic review.

Ayahuasca is a South American psychoactive plant brew used as traditional medicine in spiritual and in cultural rituals. This is a review of the current understanding about the pharmacological mechanisms that may be interacting in ayahuasca. Searches were performed using PubMed, PsycINFO, and Web of Science databases and 16 papers were selected. As hypothesized, the primary narrative in existing research revolved around prevention of deamination of N,N-dimethyltryptamine (N,N-DMT, also referred to as DMT) by monoamine oxidase inhibitors (MAOIs) in ayahuasca. Two of the constituents, DMT and harmine, have been studied more than the secondary harmala alkaloids. At present, it is unclear whether the pharmacological interactions in ayahuasca act synergistically or additively to produce psychoactive drug effects. The included studies suggest that our current understanding of the preparation's synergistic mechanisms is limited and that more complex processes may be involved; there is not yet enough data to determine any potential synergistic interaction between the known compounds in ayahuasca. Our pharmacological understanding of its compounds must be increased to avoid the potential risks of ayahuasca use.

Association of 11ß-hydroxysteroid dehydrogenase type1 (HSD11b1) gene polymorphisms with outcome of antidepressant therapy and suicide attempts.

The hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depressive disorders. HSD11B1 encodes 11ß-hydroxysteroid dehydrogenase type1 enzyme, responsible for converting cortisone to cortisol. Genetic polymorphisms in HSD11B1 may impact in depression outcome and risk of suicide. This study aimed to assess whether HSD11B1 genotypes and haplotypes are associated with depression risk, severity of symptoms and suicidal attempts, considering early-life stress as an environmental factor. Here, 142 depressive patients and 103 healthy controls were included. Patients were enrolled from the Affective Disorders ambulatory and day hospital units, both within the University General Hospital of Ribeirao Preto. All subjects were clinically assessed applying the Mini-PLUS International Neuropsychiatric Interview, followed by the 21-item GRID-Hamilton Depression Scale, Childhood Trauma Questionnaire and Beck Scale for Suicidal Ideation (BSI). All subjects underwent antecubital vein puncture to obtain blood for DNA extraction. Genotyping of rs11119328 and rs11811440 were performed using allele-specific oligonucleotide polymerase chain reaction. We found a significant association of rs11119328 variant genotypes with increased risk for at least one suicide attempt (OR: 7.10, p = 0.049) and an association of variant genotypes of rs11811440 with euthymic mood under optimized pharmacological treatment (OR: 0.05, P = 0.014). These tests included correction for confounding factors. The association of genetic markers with depression risk, GRID-HAM-D21 and BSI scores and the number of suicidal attempts were nonsignificant. Haplotypes combining both markers were not associated with the studied phenotypes. We conclude that HSD11B1 polymorphisms may be relevant biomarkers for detecting subjects genetically vulnerable to poorer antidepressant response and higher risk of suicide attempts.

Bipolar affective disorder and borderline personality disorder: Differentiation based on the history of early life stress and psychoneuroendocrine measures.

INTRODUCTION: Borderline Personality Disorder (BPD) and Bipolar Affective Disorder (BD) have clinical characteristics in common which often make their differential diagnosis difficult. The history of early life stress (ELS) may be a differentiating factor between BPD and BD, as well as its association with clinical manifestations and specific neuroendocrine responses in each of these diagnoses. OBJECTIVE: Assessing and comparing patients with BD and BPD for factors related to symptomatology, etiopathogenesis and neuroendocrine markers. METHODOLOGY: The study sample consisted of 51 women, divided into 3 groups: patients with a clinical diagnosis of BPD (n = 20) and BD (n = 16) and healthy controls (HC, n = 15). Standardized instruments were used for the clinical evaluation, while the history of ELS was quantified with the Childhood Trauma Questionnaire (CTQ), and classified according to the subtypes: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. The functioning of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by measuring a single plasma cortisol sample. RESULTS: Patients with BPD presented with more severe psychiatric symptoms of: anxiety, impulsivity, depression, hopelessness and suicidal ideation than those with BD. The history of ELS was identified as significantly more prevalent and more severe in patients (BPD and BP) than in HC. Emotional abuse, emotional neglect and physical neglect also showed differences and were higher in BPD than BD patients. BPD patients had greater severity of ELS overall and in the subtypes of emotional abuse, emotional neglect and physical neglect than BD patients. The presence of ELS in patients with BPD and BP showed significant difference with lower cortisol levels when compared to HC. The endocrine evaluation showed no significant differences between the diagnoses of BPD and BD. Cortisol measured in patients with BPD was significantly lower compared to HC in the presence of emotional neglect and physical neglect. A significant negative correlation between the severity of hopelessness vs cortisol; and physical neglect vs cortisol were found in BPD with ELS. The single cortisol sample showed a significant and opposite correlations in the sexual abuse diagnosis-related groups, being a negative correlation in BD and positive in BPD. DISCUSSION: Considering the need for a multi-factorial analysis, the differential diagnosis between BPD and BD can be facilitated by the study of psychiatric symptoms, which are more severe in the BPD patients with a history of early life stress. The function of the HPA axis assessed by this cortisol measure suggests differences between BPD and BP with ELS history. CONCLUSION: The integrated analysis of psychopathology, ELS and neuroendocrine function may provide useful indicators to differentiate BPD and BD diagnoses. These preliminary data need to be replicated in a more significant sample with improved and multiple assessments of HPA axis activity.

Neuropsychological changes in melancholic and atypical depression: A systematic review.

There is not a consensus as to whether neuropsychological profiling can distinguish depressive subtypes. We aimed to systematically review and critically analyse the literature on cognitive function in patients with melancholic and atypical depression. We searched in databases PubMed, SCOPUS, Web of Knowledge and PsycInfo for papers comparing the neuropsychological performance of melancholic patients (MEL) to non-melancholic depressive patients (NMEL), including atypical depressives, and healthy controls (HC). All studies were scrutinised to determine the main methodological characteristics and particularly possible sources of bias influencing the results reported, using the STROBE statement checklist. We also provide effect size of the results reported for contrasts between MEL; patients and NMEL patients. Seventeen studies were included; most of them demonstrated higher neuropsychological impairments of MEL patients compared to both NMEL patients and HC on tasks requiring memory, executive function, attention and reaction time. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the participants' sociodemographic characteristics, clinical characteristics of patients and differences in neuropsychological assessment. These findings suggest that MEL may have a distinct and impaired cognitive performance compared to NMEL depressive patients on tasks involving verbal and visual memory, executive function, sustained attention and span, as well as psychomotor speed, this last especially when cognitive load is increased. Additional studies with adequate control of potentially confounding variables will help to clarify further differences in the neuropsychological functioning of depressive subtypes.

Environmental lithium exposure in the north of Chile--II. Natural food sources.

Lithium, generally, occurs in barely trace amounts in ground water with few major exceptions. One of these is the northern area of Chile where all potable water and many of the food stuffs contain high levels of lithium. Surface water can contain between 100 and 10,000 times more than most rivers in North America. Inevitably, food, both animal and vegetable, contains higher lithium levels than found elsewhere. In consequence, the local population has been exposed to high levels of lithium in their food and drinking water for as long as the region has been populated. The present report details lithium levels in a variety of food stuffs from several locations in Northern Chile and compares these with those found elsewhere. The implications for the local population have been discussed in our earlier paper.