Can loss of agency and oppositional perturbation associated with antidepressant monotherapy and low-fidelity psychological treatment dilute the benefits of guideline-consistent depression treatment at the population level?

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The associations of CNR1 SNPs and haplotypes with vulnerability and treatment response phenotypes in Han Chinese with major depressive disorder:A case-control association study

BACKGROUND: Understanding how genetic polymorphisms are associated with the pathophysiology of major depressive disorder (MDD) may aid in diagnosis and the development of personalized treatment strategies. CNR1 is the gene coding Cannabinoid type 1 receptor which is highly involved in emotional processing and in regulating neurotransmitter releases. We aimed to investigate the associations of CNR1 single‐nucleotide polymorphisms (SNPs) with MDD susceptibility and treatment response. METHODS: The study reported data on 181 Han Chinese with MDD and 80 healthy controls. The associations of CNR1 genetic polymorphisms with MDD susceptibility and treatment response were examined, wherein the MDD patients were subgrouped further by responding to antidepressant treatment, compared with healthy controls separately. RESULTS: The CNR1 SNPs rs806367 and rs6454674 and haplotype C‐T‐T‐C of rs806366, rs806367, rs806368, and rs806370 were associated with increased susceptibility for MDD and antidepressant treatment resistance, but the association was not detected in other SNPs or the haplotype block of rs806368 and rs806370. CONCLUSION: The CNR1 is a promising candidate for the genetic association study of MDD. Larger and well‐characterized samples are required to confirm the genetic association of CNR1 with MDD because of the limitations such as relatively small sample size and lack of information for correcting confounding factors

N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity:study protocol of a double-blind randomized placebo-controlled trial

Abstract Background A subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. Methods/design A double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10 mg/L will be included. Discussion This is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD. Trial registration The trial protocol has been registered on “ClinicalTrials.gov“with protocol ID “NAC-2015-TJAH” and ClinicalTrials.gov ID “NCT02972398”

Oxazepam and temazepam attenuate paroxetine-induced elevation of serotonin levels in guinea-pig hippocampus

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are used as a first-line treatment in depression. However, many depressed patients are also treated with benzodiazepines to alleviate increased anxiety and sleep disturbances normally associated with depression. Since benzodiazepines inhibit 5-HT neuronal firing activity, they might attenuate SSRI-induced increase in extracellular 5-HT levels. This study aimed to assess, using in-vivo microdialysis, the effects of the benzodiazepines oxazepam or temazepan on the SSRI paroxetine-induced 5-HT increase in the hippocampus of freely moving guinea-pigs. It was found that the acute systemic administration of paroxetine increased extracellular 5-HT levels. Pre-administration of oxazepam or temazepam significantly diminished the paroxetine-induced elevation of extracellular 5-HT levels (from 350% to 200% of baseline). It was concluded that benzodiazepines attenuate the ability of SSRIs to elevate hippocampal 5-HT levels. Thus, co-administration of benzodiazepines might affect the therapeutic efficacy of SSRI treatment

Associations of plasma androgens with suicidality among men and women:A 9-year longitudinal cohort study

BACKGROUND: Testosterone has been implicated in suicidality in cross-sectional studies. Stress that coincides with a suicide attempt may alter androgen levels, so prospective studies are needed to exclude reverse causation. We aimed to examine the associations of plasma androgens with concurrent and future suicidality, and if present, whether these associations were mediated by a behavioral trait like reactive aggression. METHODS: Baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate with a radioimmunoassay. Suicidality was assessed using the Suicidal Ideation Scale at baseline and after 2-, 4-, 6-, and 9-year follow-up. Men and women were analyzed separately, and potential confounders were considered. RESULTS: Participants (N = 2861; 66.3% women) had a mean age of 42.0 years (range 18-65) and almost half (46.9%) fulfilled criteria for a major depressive or anxiety disorder. At baseline 13.2% of men and 11.2% of women reported current suicidal ideation. In participants who were non-suicidal at baseline, slightly more men than women reported suicidal ideation during follow-up (14.7% vs. 12.5%), whereas the reverse pattern was observed for suicide attempts (3.6% vs. 4.2%). None of the associations between androgens and current and future suicidality were significant. LIMITATIONS: Androgens were determined once, which may have been insufficient to predict suicidality over longer periods. DISCUSSION: The lack of associations between plasma levels of androgens determined by 'gold-standard' laboratory methods with suicidality do not support previous cross-sectional and smaller studies in adult men and women with values within the physiological range

Plasma androgens and the presence and course of depression in a large cohort of men

Background: Hypoandrogenic men showed a higher prevalence of major depressive disorder (MDD), which could be ascribed to overlapping symptoms such as sexual dysfunction, or additionally to core emotional symptoms such as sadness and anhedonia. We examined whether androgen levels 1) differ between men with and without MDD cross-sectionally, 2) are associated with an elevated risk for onset of MDD prospectively, and 3) associate with all individual MDD symptoms, or only with hypogonadism overlapping symptoms. Methods: In 823 men (mean age 43.5 years), baseline plasma levels of total testosterone, 5α-dihydrotestosterone (5α-DHT), and androstenedione were determined with liquid chromatography–tandem mass spectrometry, and dehydroepiandrosterone-sulphate (DHEAS) and sex hormone binding globulin with radioimmunoassay, whereas free testosterone was calculated. MDD status was assessed at baseline and after two years using structured interviews and individual MDD symptoms were self-rated at baseline, and after one and two years. Results: None of the androgen levels were associated with current or onset (incidence or recurrence) of MDD. Free testosterone was only inversely associated with interest in sex. Also, androstenedione and DHEAS were positively associated with some individual MDD symptoms, and 5α-DHT levels showed non-linear associations (both with low and high levels) with MDD symptom severity and several individual MDD symptoms. Conclusions: These results support the idea that circulating androgens synthesised by the testes are of limited clinical relevance to MDD in adult men, but levels of androstenedione, DHEAS and 5α-DHT may be associated with some individual MDD symptoms

Mouse repeated electroconvulsive seizure (ECS) does not reverse social stress effects but does induce behavioral and hippocampal changes relevant to electroconvulsive therapy (ECT) side-effects in the treatment of depression

Electroconvulsive therapy (ECT) is an effective treatment for depression, but can have negative side effects including amnesia. The mechanisms of action underlying both the antidepressant and side effects of ECT are not well understood. An equivalent manipulation that is conducted in experimental animals is electroconvulsive seizure (ECS). Rodent studies have provided valuable insights into potential mechanisms underlying the antidepressant and side effects of ECT. However, relatively few studies have investigated the effects of ECS in animal models with a depression-relevant manipulation such as chronic stress. In the present study, mice were first exposed to chronic social stress (CSS) or a control procedure for 15 days followed by ECS or a sham procedure for 10 days. Behavioral effects were investigated using an auditory fear conditioning (learning) and expression (memory) test and a treadmill-running fatigue test. Thereafter, immunohistochemistry was conducted on brain material using the microglial marker Iba-1 and the cholinergic fibre marker ChAT. CSS did not increase fear learning and memory in the present experimental design; in both the control and CSS mice ECS reduced fear learning and fear memory expression. CSS induced the expected fatigue-like effect in the treadmill-running test; ECS induced increased fatigue in CSS and control mice. In CSS and control mice ECS induced inflammation in hippocampus in terms of increased expression of Iba-1 in radiatum of CA1 and CA3. CSS and ECS both reduced acetylcholine function in hippocampus as indicated by decreased expression of ChAT in several hippocampal sub-regions. Therefore, CSS increased fatigue and reduced hippocampal ChAT activity and, rather than reversing these effects, a repeated ECS regimen resulted in impaired fear learning-memory, increased fatigue, increased hippocampal Iba-1 expression, and decreased hippocampal ChAT expression. As such, the current model does not provide insights into the mechanism of ECT antidepressant function but does provide evidence for pathophysiological mechanisms that might contribute to important ECT side-effects.</p