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Background: Depression is the leading cause of global disability and can develop following the change in body image and functional capacity associated with stoma surgery. However, reported prevalence across the literature is unknown. Accordingly, we performed a systematic review and meta-analysis aiming to characterise depressive symptoms after stoma surgery and potential predictive factors. Methods: PubMed/MEDLINE, Embase, CINAHL and Cochrane Library were searched from respective database inception to 6 March 2023 for studies reporting rates of depressive symptoms after stoma surgery. Risk of bias was assessed using the Downs and Black checklist for non-randomised studies of interventions (NRSIs), and Cochrane RoB2 tool for randomised controlled trials (RCTs). Meta-analysis incorporated meta-regressions and a random-effects model. Registration: PROSPERO, CRD42021262345. Results: From 5,742 records, 68 studies were included. According to Downs and Black checklist, the 65 NRSIs were of low to moderate methodological quality. According to Cochrane RoB2, the three RCTs ranged from low risk of bias to some concerns of bias. Thirty-eight studies reported rates of depressive symptoms after stoma surgery as a proportion of the respective study populations, and from these, the median rate across all timepoints was 42.9% 42.9% (IQR: 24.2–58.9%). Pooled scores for respective validated depression measures (Hospital Anxiety and Depression Score (HADS), Beck Depression Inventory (BDI), and Patient Health Questionnaire-9 (PHQ-9)) across studies reporting those scores were below clinical thresholds for major depressive disorder according to severity criteria of the respective scores. In the three studies that used the HADS to compare non-stoma versus stoma surgical populations, depressive symptoms were 58% less frequent in non-stoma populations. Region (Asia–Pacific; Europe; Middle East/Africa; North America) was significantly associated with postoperative depressive symptoms (p = 0.002), whereas age (p = 0.592) and sex (p = 0.069) were not. Conclusions: Depressive symptoms occur in almost half of stoma surgery patients, which is higher than the general population, and many inflammatory bowel disease and colorectal cancer populations outlined in the literature. However, validated measures suggest this is mostly at a level of clinical severity below major depressive disorder. Stoma patient outcomes and postoperative psychosocial adjustment may be enhanced by increased psychological evaluation and care in the perioperative period. [ABSTRACT FROM AUTHOR]

Introduction: Rare genetic functional variants can contribute to 30-40% of functional variability in genes relevant to drug action. Therefore, we investigated the role of rare functional variants in antidepressant response.Method: Mexican-American individuals meeting the Diagnostic and Statistical Manual-IV criteria for major depressive disorder (MDD) participated in a prospective randomized, double-blind study with desipramine or fluoxetine. The rare variant analysis was performed using whole-exome genotyping data. Network and pathway analyses were carried out with the list of significant genes.Results: The Kernel-Based Adaptive Cluster method identified functional rare variants in 35 genes significantly associated with treatment remission (False discovery rate, FDR <0.01). Pathway analysis of these genes supports the involvement of the following gene ontology processes: olfactory/sensory transduction, regulation of response to cytokine stimulus, and meiotic cell cycleprocess.Limitations: Our study did not have a placebo arm. We were not able to use antidepressant blood level as a covariate. Our study is based on a small sample size of only 65 Mexican-American individuals. Further studies using larger cohorts are warranted.Conclusion: Our data identified several rare functional variants in antidepressant drug response in MDD patients. These have the potential to serve as genetic markers for predicting drug response.Trial Registration: ClinicalTrials.gov NCT00265291. [ABSTRACT FROM AUTHOR]

We propose the “microbiota‐inflammasome” hypothesis of major depressive disorder (MDD, a mental illness affecting the way a person feels and thinks, characterized by long‐lasting feelings of sadness). We hypothesize that pathological shifts in gut microbiota composition (dysbiosis) caused by stress and gut conditions result in the upregulation of pro‐inflammatory pathways mediated by the Nod‐like receptors family pyrin domain containing 3 (NLRP3) inflammasome (an intracellular platform involved in the activation of inflammatory processes). This upregulation exacerbates depressive symptomatology and further compounds gut dysbiosis. In this review we describe MDD/chronic stress‐induced changes in: 1) NLRP3 inflammasome; 2) gut microbiota; and 3) metabolic pathways; and how inflammasome signaling may affect depressive‐like behavior and gut microbiota composition. The implication is that novel therapeutic strategies could emerge for MDD and co‐morbid conditions. A number of testable predictions surface from this microbiota‐gut‐inflammasome‐brain hypothesis of MDD, using approaches that modulate gut microbiota composition via inflammasome modulation, fecal microbiota transplantation, psychobiotics supplementation, or dietary change. [ABSTRACT FROM AUTHOR]

Objective: The authors compared the effectiveness of fluoxetine and desipramine treatment in a prospective double-blind pharmacogenetics study in first-generation Mexican Americans and examined the role of whole-exome functional gene variations in the patients' antidepressant response.Method: A total of 232 Mexican Americans who met DSM-IV criteria for major depressive disorder were randomly assigned to receive 8 weeks of double-blind treatment with desipramine (50-200 mg/day) or fluoxetine (10-40 mg/day) after a 1-week placebo lead-in period. Outcome measures included the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale, and the Beck Depression Inventory. At week 8, whole-exome genotyping data were obtained for 36 participants who remitted and 29 who did not respond to treatment.Results: Compared with desipramine treatment, fluoxetine treatment was associated with a greater reduction in HAM-D score, higher response and remission rates, shorter time to response and remission, and lower incidences of anticholinergic and cardiovascular side effects. Pharmacogenetics analysis showed that exm-rs1321744 achieved exome-wide significance for treatment remission. This variant is located in a brain methylated DNA immunoprecipitation sequencing site, which suggests that it may be involved in epigenetic regulation of neuronal gene expression. This and two other common gene variants provided a highly accurate cross-validated predictive model for treatment remission of major depression (receiver operating characteristic integral=0.95).Conclusions: Compared with desipramine, fluoxetine treatment showed a more rapid reduction of HAM-D score and a lower incidence of side effects in a population comprising primarily first-generation Mexican Americans with major depression. This study's pharmacogenetics approach strongly implicates the role of functional variants in antidepressant treatment response. [ABSTRACT FROM AUTHOR]

Abstract: Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th  weeks were significantly better for the s/s genotype of the 5-HTTLPR polymorphism than for l-allele carriers. These results support our hypothesis that the response to noradrenergic and specific serotonergic antidepressants is significantly associated with the 5-HTTLPR polymorphism. [Copyright &y& Elsevier]

Depression, a complex psychiatric disorder that affects ~15% of the population, has an enormous social cost. Although the disorder is thought to be the outcome of gene-environmental interactions, the causative genes and environmental factors underlying depression remain to be identified. All the antidepressant drugs now in use -- the forerunner of which was discovered serendipitously 50 years ago -- modulate monoamine neurotransmission, and take six to eight weeks to exert their effects, but each drug is efficacious in only 60-70% of patients. A conceptually novel antidepressant that acted rapidly and safely in a high proportion of patients would almost certainly become the world’s bestselling drug. Yet such a drug is not on the horizon. Here, we cover the different phases of antidepressant drug discovery in the past, present and future, and comment on the challenges and opportunities for antidepressant research. INSETS: The phenotype of major depression;Aims for an ideal antidepressant drug;Criteria for the development of animal models of depression. [ABSTRACT FROM AUTHOR]

Depression is a major cause of disability worldwide, but we know little about the underlying fundamental biology. Research is hindered by the difficulties of modelling a disorder of higher cognitive functions in animals. Depression can be understood as the interaction of genetic susceptibility and environmental factors; however, current classifications are purely descriptive. The complexity of this field is best approached by rigorous explorations of known candidate systems in conjunction with the use of genomic tools to discover new targets for antidepressants and to predict therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Highlights from the article: B Background: b Approximately 12% of Americans are currently taking antidepressants; thus, the ability to predict antidepressant drug response may have significant public health impact. B Methods: b We obtained whole exome genotyping data in Mexican-Americans individuals who met DSM-IV criteria of major depressive disorder and completed 8 weeks of double-blind treatment with desipramine or fluoxetine in a prospective randomized double-blind pharmacogenetics trial. B Discussion: b Our results support the involvement of rare functional variants in antidepressant drug response, and enriched pathways were in sensory, immune mediation and growth processes.

Background: To study the potential association of antidepressant use and suicide at a population level, we analyzed the associations between suicide rates and dispensing of the prototypic SSRI antidepressant fluoxetine in the United States during the period 1960-2002.Methods and Findings: Sources of data included Centers of Disease Control and US Census Bureau age-adjusted suicide rates since 1960 and numbers of fluoxetine sales in the US, since its introduction in 1988. We conducted statistical analysis of age-adjusted population data and prescription numbers. Suicide rates fluctuated between 12.2 and 13.7 per 100,000 for the entire population from the early 1960s until 1988. Since then, suicide rates have gradually declined, with the lowest value of 10.4 per 100,000 in 2000. This steady decline is significantly associated with increased numbers of fluoxetine prescriptions dispensed from 2,469,000 in 1988 to 33,320,000 in 2002 (r(s) = -0.92; p < 0.001). Mathematical modeling of what suicide rates would have been during the 1988-2002 period based on pre-1988 data indicates that since the introduction of fluoxetine in 1988 through 2002 there has been a cumulative decrease in expected suicide mortality of 33,600 individuals (posterior median, 95% Bayesian credible interval 22,400-45,000).Conclusions: The introduction of SSRIs in 1988 has been temporally associated with a substantial reduction in the number of suicides. This effect may have been more apparent in the female population, whom we postulate might have particularly benefited from SSRI treatment. While these types of data cannot lead to conclusions on causality, we suggest here that in the context of untreated depression being the major cause of suicide, antidepressant treatment could have had a contributory role in the reduction of suicide rates in the period 1988-2002. [ABSTRACT FROM AUTHOR]

Comments on an article about classification of antidepressants and antiobesity drugs as 'lifestyle drugs,' in the September 2002 issue of the 'Nature Medicine'. Definition of depression; Origin of melancholia; Effects of depression.

Summary: Disturbance of each of the three hypothalamic–pituitary-end organ systems [hypothalamic–pituitary–thyroid (HPT), –adrenal (HPA), and –gonadal (HPG)] has been reported in depressive disorders. Little is known about potential reciprocal interaction among the three HP-end organ systems in patients with depressive disorders. The present pilot study examined selective HPA and HPG hormones in a detailed time series in women with bipolar disorder (depressed type) before and after treatment with levothyroxine (L-T4), and in matched control subjects. Six medically stable, euthyroid, premenopausal women with bipolar depression, and 5 age-matched controls underwent overnight blood sampling from 2100 to 0900h for measurement of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), and estradiol every 15min. Bipolar patients underwent a second overnight blood sampling procedure following 7-weeks of open-label add-on treatment with L-T4. Results revealed lower baseline cortisol parameters in bipolar patients in comparison to control subjects, while ACTH, LH, and estradiol parameters were similar. Thyroid hormones (TSH, free and total T4) were not correlated with any of the HPA or HPG hormones. ACTH and cortisol levels were correlated in control subjects, but not in bipolar patients. After L-T4 treatment, thyroid hormones increased significantly and depression scores significantly declined. No significant changes in HPA or HPG hormones parameters were observed, although the small sample size may have limited results. Upon visual inspection, ACTH and cortisol appeared to decrease after L-T4 treatment, while estradiol appeared to increase. These pilot data suggest lower levels of cortisol in women with bipolar depression, unlike previously published studies that reported higher cortisol in patients with depression. The data also suggest reciprocal changes in the HPA and HPG axes upon pharmacological modulation of the HPT system, although whether this change was due to the L-T4 treatment or the improvement of depression is unknown. The results are preliminary, and require replication in larger samples. [Copyright &y& Elsevier]