Why Antidepressants Should be Personalized

By Irene Yeh

The physiological side effects of antidepressants can present differently in each individual patient, including weight gain and blood pressure disturbance. These side effects can lead to greater consequences, such as worsening mental health conditions. However, it is unclear to what degree these side effects occur. To answer that, The Lancet (DOI: 10.1016/S0140-6736(25)01293-0) published a systemic review and meta-analysis that investigated the side effects of antidepressants in each individual’s treatment—and argued for considering personal health and preferences when prescribing these medications.

The team searched various results from databases such as ClinicalTrials.gov, MEDLINE, EMBASE, PsycINFO, and the U.S. Food and Drug Administration (FDA), combing through 151 studies and 17 FDA reports that met inclusion criteria. Overall, the team analyzed a total of 58,534 participants, comparing 30 antidepressants with placebo. They analyzed single-blinded and double-blinded randomized controlled trials (RCTs) that compared antidepressants with a placebo or with another antidepressant used for acute treatment (eight weeks) of adults with a psychiatric disorder, including major depressive disorder (MDD), anxiety disorders, bipolar disorder, sleep disorders, schizophrenia, and behavioral addictions, as well as fibromyalgia for co-occurring affective symptoms for patients in this population. For the study, the team only examined patients with MDD to avoid inconsistencies and heterogeneity in the analyses.

The team found that antidepressants can cause cardiometabolic and physiological alterations, such as changes in weight, heart rate, and blood pressure. Some antidepressants (e.g. maprotiline and amitriptyline) cause weight gain in 48% of patients, and other antidepressants (e.g. agomelatine) cause weight loss in around 55% of patients. A 21-bpm difference in heart rate change was found between fluvoxamine and nortriptyline, and over 11 mmHg difference in systolic blood pressure between nortriptyline and doxepin. Notably, compared to patients with schizophrenia, there were no correlations between changes in depressive symptoms and metabolic alterations in individuals with MDD.

Increased weight can lead to cardiovascular risks and high blood pressure. Using amitriptyline as an example, typical short-term increases in weight, heart rate, and blood pressure could add up to a notable rise in long-term health risk, though the impact varies from person to person.

Though the study sheds light on the side effects and impact of antidepressants, there were limitations. For one, there were inconsistencies across many network meta-analyses, most likely caused by the imbalances in effect-modifying factors, small-study effects, and publication bias. And though the analyses were limited to MDD studies, it still did not completely resolve the inconsistencies. For several important health measures, especially metabolic ones, there were very few data available, and some clinical trial data could not be obtained.

Additionally, while there is the possibility that a few findings may reflect real differences between medications, they could also just be errors in the data. The study also relied more on the averages of each trial rather than individual patient data, which can lead to misconstrued results. Finally, most trials did not report results separately for men and women, limiting assessment of sex-specific effects, nor provide clear data on clinically meaningful thresholds in trials, which can limit analyses. Other side effects, such as sexual dysfunction, emotional blunting, gastrointestinal issues, and differences in antidepressant efficacy were not considered. It is also unknown if side effects persist over time.

Despite the limitations, the results of the study bring up correlation of side effects with antidepressants. This information can be useful for clinicians and patients as a guide to determine more personalized treatment options. The study also points out that people with depression who take antidepressants tend to have lower risks of suicide and overall death, which is important to keep in mind when interpreting these results.