Response to Antidepressant Treatment and Risk of Later Metabolic Syndrome


Will this medication make me gain weight? Researchers analyzed response to antidepressant treatment as a predictor of incident metabolic syndrome in a cohort of patients with depression.




“James” is a 22-year-old African American male with a history of moderate, single-episode major depressive disorder (MDD). He is a senior in college. This is his first lifetime episode of depression, and he is antidepressant naïve. He does not have any medical comorbidities.

His body mass index (BMI) is normal at 22 kg/m2 and he has a normal fasting glucose. His lipid panel is unremarkable except for mildly low HDL cholesterol (35 mg/dL). He has a family history of paternal hypertension and hyperlipidemia, and his paternal grandmother died from a stroke.

James is agreeable to a trial of sertraline for his depression. He asks about the risks of weight gain and metabolic dysfunction with this medication. As his psychiatrist, how would you respond?

MDD is associated with an increased risk of cardiometabolic morbidity and mortality.1 The metabolic syndrome (MetS) is a cluster of 5 risk factors for cardiovascular disease and type 2 diabetes mellitus, including high waist circumference, high triglycerides, high blood pressure, elevated fasting glucose, and low HDL cholesterol. There is evidence of weight gain with antidepressant treatment, which confers increased risk of MetS.2,3

In the METADAP cohort study, the incidence of MetS in patients with MDD was 12% and 17% after 3 and 6 months, respectively.4 In the same cohort, early weight gain (after 30 days of antidepressant treatment) was associated with a 5.5-fold increased odds of MetS.5 Although response to antidepressant is associated with genetic and environmental factors, no previous studies have investigated response to antidepressant treatment and MetS.

The Current Study

El Asmar and colleagues6 analyzed data from METADAP, a 6-month prospective, multi-center, effectiveness study. MetS before and after antidepressant treatment for MDD were assessed between June 2008 and March 2013 for 6 university psychiatry departments in France. Participants were aged 18 to 65 years with a current major depressive episode diagnosed by the MINI and a minimum depression score of 18 on the Hamilton Depression Rating Scale.

Participants were required to begin a new or switch from another antidepressant monotherapy. Other inclusion criteria were a BMI <24 kg/m2 and the absence of MetS at study baseline. Exclusion criteria were bipolar disorders, psychotic disorders or symptoms, eating disorders, current substance use disorder, pregnancy, breastfeeding, organic brain syndromes, unstable medical conditions, and treatment with mood stabilizers or antipsychotics. Other exclusionary medical comorbidities were diabetes, thyroid disorders, and polycystic ovarian syndrome.

Response to treatment (RTT) was defined as a 50% decrease from baseline in the HDRS scale and was measured at 3 and 6 months. MetS and its individual criteria were also measured at 3 and 6 months. MetS (present/absent) was defined according to the International Federation of Diabetes,7 which requires meeting criteria for at least 3 of the 5 components (waist circumference, triglycerides, blood pressure, glucose, and HDL cholesterol). Data were also obtained on 5% weight gain after 1 month of treatment, the duration of depression, and antidepressant class.

The primary outcome measure was incident MetS, and he primary exposure variable was RTT at 3 months. Associations between metabolic parameters at baseline and 3 and 6 months and RTT at 3 months were tested using univariate logistic regression. Longitudinal associations between RTT and metabolic parameters were tested using mixed-effect logit and Poisson models. All analyses were adjusted for age, sex, duration of depression, baseline HDRS, baseline antidepressant dose, increase in appetite after 3 months, and 5% weight gain at 1 month.

The cohort consisted of 169 patients. The mean participant age was 42 years, 68% of participants were female, the average duration of MDD was 10 years, and the mean baseline HDRS score was 25. The most common antidepressant classes were SSRIs (46%), SNRIs (32%), and TCAs (7%). After 1 month, 17% of participants had 5% weight gain. Responders (vs non-responders) were more likely to report an increase in appetite (28% vs 20%), but did not differ on age and sex. Completers (vs non-completers) did not differ on demographic or baseline clinical variables.

In the entire cohort, the incidence of MetS was 9% at 3 months and 10% at 6 months. Participants with RTT at 3 months had a higher incidence of MetS after 6 months than non-responders (13% vs 3%), translating to an almost 9-fold increase in the regression models (OR=8.6, 95% CI 3.9-18.9). This increase was driven primarily by increases in fasting glucose (OR=3.1, 95% CI 1.6-6.0) and, to a lesser extent, blood pressure (OR=1.7, 95% CI 0.7-4.1). Interestingly, responders were 5 times less likely to have low HDL levels (OR=0.2, 95% CI 0.1-0.4). There were no significant changes in metabolic parameters in non-responders.

Study Conclusions

The investigators concluded that antidepressant response at 3 months was associated with an almost 9-fold increased odds of incident MetS at 6 months, driven primarily by elevated fasting glucose. Interestingly, antidepressant non-responders were 5 times more likely to have low HDL at 6 months.

Study strengths include that this was the first study of antidepressant response and incident MetS in non-obese adults. The investigators controlled for multiple potential confounding or moderating factors in the analyses. Study limitations include generalizability of the study sample, which was limited to patients from university psychiatry departments; potential changes in nutrition and physical activity; non-random antidepressant selection; and weight-related data prior to depression.

The Bottom Line

Antidepressant response at 3 months is associated with significantly increased odds of developing MetS at 6 months. Metabolic monitoring of this patient population is warranted. Further studies are needed to evaluate if these changes are a pharmacological and/or a recovery effect.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Vancampfort D, Correll CU, Wampers M, et al. Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variablesPsychol Med. 2014;44(10):2017-2028.

2. Delacrétaz A, Lagares Santos P, Saigi Morgui N, et al. Influence of polygenic risk scores on lipid levels and dyslipidemia in a psychiatric population receiving weight gain-inducing psychotropic drugsPharmacogenet Genomics. 2017;27(12):464-472.

3. Salvi V, Mencacci C, Barone-Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressantsEur Neuropsychopharmacol. 2016;26(10):1673-1677.

4. Corruble E, El Asmar K, Trabado S, et al. Treating major depressive episodes with antidepressants can induce or worsen metabolic syndrome: results of the METADAP cohortWorld Psychiatry. 2015;14(3):366-367.

5. El Asmar K, Fève B, Colle R, et al. Early weight gain predicts later metabolic syndrome in depressed patients treated with antidepressants: findings from the METADAP cohortJ Psychiatr Res. 2018;107:120-127.

6. El Asmar K, Annan NB, Khoury R, et al. Non-overweight depressed patients who respond to antidepressant treatment have a higher risk of later metabolic syndrome: findings from the METADAP cohortPsychol Med.

7. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome—a new world-wide definition. A consensus statement from the International Diabetes FederationDiabet Med. 2006;23(5):469-480.

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