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

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

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

Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and androgen levels in the physiological range, is unknown. This study examined if women with current MDD have higher androgen levels compared to women who have never had MDD, and if androgen levels are associated with onset and remission of MDD. In 1659 women (513 current MDD, 754 remitted MDD, and 392 never MDD), baseline plasma levels of total testosterone, 5 alpha-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) with radioimmunoassays. Free testosterone was calculated. MDD status was assessed at baseline, and at 2 and 4 years follow-up. Women were aged between 18 and 65 years (mean age 41) with total testosterone levels in the physiological range (geometric mean 0.72 nmol/L [95% CI 0.27-1.93]). After adjusting for covariates and multiple testing, women with current MDD had a higher mean free testosterone than women who never had MDD (adjusted geometric mean 8.50 vs. 7.55 pmol/L, p = 0.0005), but this difference was not large enough to be considered clinically meaningful as it was consistent with statistical equivalence. Levels of other androgens and SHBG did not differ and were also statistically equivalent between the groups. None of the androgens or SHBG levels predicted onset or remission of MDD. Our findings support the idea that plasma androgens within the physiological range have no or only limited effects on depressive disorders in women

Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients:A prospective inception cohort study in treatment-free patients

Background: Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. Objectives: To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. Methods: Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (Delta HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and Delta HAM-D. Results: Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in postmenopausal women found a similar comparison between alleles. Limitations: Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. Conclusions: Patients taking tricylic antidepressants were noted to have a significant improvement in Delta HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment

Association Between BDNF Gene Variant Rs6265 and the Severity of Depression in Antidepressant Treatment-Free Depressed Patients

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms. Aim: To investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression. Methods: Participants of 18–70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model. Results: A total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 −0.042 ln(pg/ml) (95%CI −0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI −0.117; 0.130). No other association reached statistical significance. Conclusion: We observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes