Project description:Genetic factors are believed to play a major role in the variation of treatment response and the incidence of adverse effects to medication. The aim of pharmacogenetics is to elucidate this variability according to hereditary differences. Considering current hypotheses for the mechanisms of action of antidepressants, most investigations to date have concentrated on mutations in genes coding either for the pathways in the serotonergic and noradrenergic systems or for drug-metabolizing enzymes. Recent studies shifted the emphasis on the main mechanism of drug action from changes in neurotransmitter concentration or receptor function toward long-lasting adaptive processes within the neurons. Although the results are controversial, many studies support the hypothesis that psychopharmacogenetics will help predict an individual's drug response, while minimizing the side effects. The inclusion of functional genomics, which investigates the complex gene and/or protein expression in response to a given drug, may lead to the development of novel and safer drugs.
Project description:BackgroundThe observation that some patients appear to respond better to antidepressants for depression than others encourages the assumption that the effect of antidepressants differs between individuals and that treatment can be personalized.ObjectiveTo compare the outcome variance in patients receiving antidepressants with the outcome variance in patients receiving placebo in randomized controlled trials (RCTs) of adults with major depressive disorder (MDD) and to illustrate, using simulated data, components of variation of RCTs.MethodsFrom a dataset comprising 522 RCTs of antidepressants for adult MDD, we selected the placebo-controlled RCTs reporting outcomes on the 17 or 21 item Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale and extracted the means and SDs of raw endpoint scores or baseline to endpoint changes scores on eligible depression symptom rating scales. We conducted inverse variance random-effects meta-analysis with the variability ratio (VR), the ratio between the outcome variance in the group of patients receiving antidepressants and the outcome variance in the group receiving placebo, as the primary outcome. An increased variance in the antidepressant group would indicate individual differences in response to antidepressants.ResultsWe analysed 222 RCTs that investigated 19 different antidepressants compared with placebo in 345 comparisons, comprising a total of 61144 adults with an MDD diagnosis. Across all comparisons, the VR for raw endpoint scores was 0.98 (95% CI 0.96 to 1.00, I2 = 0%) and 1.00 (95% CI 0.99 to 1.02, I2 = 0%) for baseline-to-endpoint change scores.ConclusionBased on these data, we cannot reject the null hypothesis of equal variances in the antidepressant group and the placebo group. Given that RCTs cannot provide direct evidence for individual treatment effects, it may be most reasonable to assume that the average effect of antidepressants applies also to the individual patient.
Project description:BackgroundObesity, depressive disorders and antidepressant drugs are associated with increased mortality, cardiovascular disease, diabetes, fractures and falls. We explored outcomes associated with the most commonly prescribed antidepressants in overweight or obese people with depression.Methods and findingsWe identified a cohort of overweight or obese adults (≥18 years) in primary care from the UK Clinical Practice Research Datalink, linked with hospital and mortality data, between 1 January 2000 and 31 December 2016 who developed incident depression to January 2019. Cox proportional hazards models and 99% confidence intervals were used to estimate hazard ratios (HR) for mortality, cardiovascular disease, diabetes, and falls/fractures associated with exposure to selective serotonin reuptake inhibitors (SSRIs), tricyclic (TCA)/other, combination antidepressants, citalopram, fluoxetine, sertraline, amitriptyline and mirtazapine, adjusting for potential confounding variables. In 519,513 adults, 32,350 (9.2 per 1,000 years) displayed incident depression and 21,436 (66.3%) were prescribed ≥1 antidepressant. Compared with no antidepressants, all antidepressant classes were associated with increased relative risks of cardiovascular disorders [SSRI HR: 1.32 (1.14-1.53), TCA/Other HR: 1.26 (1.01-1.58)], and diabetes (any type) [SSRI HR: 1.28 (1.10-1.49), TCA/Other: 1.52 (1.19-1.94)]. All commonly prescribed antidepressants except citalopram were associated with increased mortality compared with no antidepressants. However, prescription ≥1 year of ≥40mg citalopram was associated with increased mortality and falls/fractures and ≥1 year 100mg sertraline with increased falls/fractures.ConclusionsIn overweight/obese people with depression, antidepressants may be overall and differentially associated with increased risks of some adverse outcomes. Further research is required to exclude indication bias and residual confounding.
Project description:OBJECTIVE:Depression is highly prevalent among people living with HIV/AIDS (PLWHA) and has deleterious effects on HIV clinical outcomes. We examined changes in depression symptoms, viral suppression, and CD4 T cells/?l among PLWHA diagnosed with depression who initiated antidepressant treatment during routine care, and compared the effectiveness of dual-action and single-action antidepressants for improving those outcomes. DESIGN:Comparative effectiveness study of new user dual-action or single-action antidepressant treatment episodes occurring from 2004 to 2014 obtained from the Center for AIDS Research Network of Integrated Clinical Systems. METHODS:We identified new user treatment episodes with no antidepressant use in the preceding 90 days. We completed intent-to-treat and per protocol evaluations for the main analysis. Primary outcomes, were viral suppression (HIV viral load <200 copies/ml) and CD4 T cells/?l. In a secondary analysis, we used the Patient Health Questionnaire-9 (PHQ-9) to evaluate changes in depression symptoms and remission (PHQ <5). Generalized estimating equations with inverse probability of treatment weights were fitted to estimate treatment effects. RESULTS:In weighted intent-to-treat analyses, the probability of viral suppression increased 16% after initiating antidepressants [95% confidence interval?=?(1.12, 1.20)]. We observed an increase of 39 CD4T cells/?l after initiating antidepressants (30, 48). Both the frequency of remission from depression and PHQ-9 scores improved after antidepressant initiation. Comparative effectiveness estimates were null in all models. CONCLUSION:Initiating antidepressant treatment was associated with improvements in depression, viral suppression, and CD4 T cells/?l, highlighting the health benefits of treating depression in PLWHA. Dual and single-action antidepressants had comparable effectiveness.
Project description:Depression, commonly treated with antidepressants, is associated with an increased risk of dementia, especially in older adults. However, the association between antidepressant use and dementia risk is unclear. We searched for randomized controlled trials and observational studies from PubMed, Embase, and Cochrane on 1 February 2022, restricting to full texts in English. Since dementia is a chronic disease requiring a long induction time, we restricted studies with ≥1 year follow-up. We extracted the relative risk (RR) adjusted for the most variables from each study and evaluated the heterogeneity using I square (I2). The protocol was registered in the PROSPERO International Register of Systematic Reviews (CRD42022338038). We included six articles in the systematic review, of which the sample size ranged from 716 to 141,740, and the median length of follow-up was 5 years. The pooled RR was 1.21 (95% CI = 1.12-1.29) with an I2 of 71%. Our findings suggest that antidepressant use was associated with an increased risk of dementia in older adults with depression, yet moderate to high heterogeneity existed across studies. Future work accounting for the depression progression is needed to differentiate the effect of depression and antidepressants on dementia risk.
Project description:This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota effects on functional and behavioral effects of antidepressants in human and animal models were identified from PubMed up to December 2022. Risk of bias was assessed, and results are presented as a systematic review following PRISMA guidelines. A total of 28 (21 animal, 7 human) studies were included in the review. The reviewed papers converged on three themes: (1) Antidepressants can alter the composition and metabolites of gut microbiota, (2) gut microbiota can alter the bioavailability of certain antidepressants, and (3) gut microbiota may modulate the clinical or modeled mood modifying effects of antidepressants. The majority (n = 22) of studies had at least moderate levels of bias present. While strong evidence is still lacking to understand the clinical role of antidepressant PMx in human health, there is evidence for interactions among antidepressants, microbiota changes, microbiota metabolite changes, and behavior. Well-controlled studies of the mediating and moderating effects of baseline and treatment-emergent changes in microbiota on therapeutic and adverse responses to antidepressants are needed to better establish a potential role of PMx in personalizing antidepressant treatment selection and response prediction.
Project description:A previous study suggested an increased risk of preeclampsia among women treated with selective serotonin reuptake inhibitors (SSRIs). Using population-based health-care utilization databases from British Columbia (1997-2006), the authors conducted a study of 69,448 pregnancies in women with depression. They compared risk of preeclampsia in women using SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) between gestational weeks 10 and 20 with risk in depressed women not using antidepressants. Among prepregnancy antidepressant users, the authors compared the risk in women who continued antidepressants between gestational weeks 10 and 24 with the risk in those who discontinued. Relative risks and 95% confidence intervals were estimated. The risk of preeclampsia in depressed women not treated with antidepressants (2.4%) was similar to that in women without depression (2.3%). Compared with women with untreated depression, women treated with SSRI, SNRI, and TCA monotherapy had adjusted relative risks of 1.22 (95% confidence interval (CI): 0.97, 1.54), 1.95 (95% CI: 1.25, 3.03), and 3.23 (95% CI: 1.87, 5.59), respectively. Within prepregnancy antidepressant users, the relative risk for preeclampsia among continuers compared with discontinuers was 1.32 (95% CI: 0.95, 1.84) for SSRI, 3.43 (95% CI: 1.77, 6.65) for SNRI, and 3.26 (95% CI: 1.04, 10.24) for TCA monotherapy. Study results suggest that women who use antidepressants during pregnancy, especially SNRIs and TCAs, have an elevated risk of preeclampsia. These associations may reflect drug effects or more severe depression.