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Introduction: Selective Serotonin Reuptake Inhibitors (SSRIs) are recommended as first-line anti-depressants in Major Depressive Disorder (MDD) because of their relatively benign safety profile. Hyponatremia is under reported and notorious adverse effect of SSRIs shown by few Randomised Clinical Trials (RCTs). There are only few published studies of SSRIs on serum sodium level in human and animal model. Aim: To determine SSRI induced hyponatremia in human and its correlation with age. Materials and Methods: The clinical part is a prospective cohort study whereas second part is experimental study involving animals. In clinical part-Patients of either sex, aged above 18 years, attending the Out-Patient Department (OPD) of Psychiatry of a tertiary hospital and diagnosed as MDD Diagnostic and Statistical Manual (DSM) V with the help of a senior psychiatrist, were screened and recruited in the study after satisfying the inclusion and exclusion criteria by consecutive sampling. Patients were prescribed fluoxetine (n=90), sertraline (n=55), paroxetine (n=30) and escitalopram (n=25). Parameters recorded (serum sodium) at baseline, 4th week, 8th week and 12th week. Symptoms due to hyponatremia and Adverse Drug Reactions (ADR) were also checked. Multiple group comparison at different visits for sodium level was done using one-way ANOVA and repeated measures ANOVA test and relationship of blood sodium level with age were estimated with bivariate correlation. Animal experiment was done in Pharmacology Department, animals were randomised into 5 groups control, fluoxetine, sertraline, paroxetine and escitalopram (n=6). Blood sodium checked at baseline, 2nd week and 4th week. Kruskal Wallis test and Friedman’s test done to detect changes in sodium level in follow-up period. Results: Mean age ranged between 40-50 years with equal gender distribution. Both within group and between group analysis revealed significant difference in blood sodium level (p-value< 0.0001). Hyponatremia was strongly correlated with age (correlation coefficient >-0.783). Most participants (184 out of 200) developed asymptomatic hyponatremia. Two among sertraline developed seizure leading to discontinuation to therapy. About 72 (38.09%) ADRs belonged to probable, mostly belonging to fluoxetine and sertraline group, developement of hyponatremia was 9 days (median) from starting SSRI. In animal part within group analysis revealed significant change of sodium from baseline in all drug treated animals (p-value