Physiologic and cardiometabolic effects of antidepressants vary widely, particularly in terms of weight, heart rate, and blood pressure — differences that may influence treatment adherence and long-term health outcomes, a large-scale analysis showed.

The report, considered the first in-depth, comparative survey of the physical effects of antidepressant treatment, analyzed dozens of randomized controlled trials and regulatory reports to rank 30 agents across multiple physiologic measures, from metabolism to cardiovascular function.

The results confirm what many clinicians have observed: Not all antidepressants are built the same.

Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) were linked to increases in weight, heart rate, and blood pressure. In contrast, selective serotonin reuptake inhibitors (SSRIs) showed little to no physiologic impact.

Although most short-term changes were modest, the patterns were consistent. TCAs and SNRIs produced the greatest elevations in blood pressure and heart rate, effects that could accumulate over time. 

Investigators said the results highlight the need for closer physical health monitoring and a more individualized approach to prescribing and also called for updated treatment guidelines to reflect these differences among drugs.

“These aren’t trivial changes. We found substantial variation between drugs in weight, heart rate, and blood pressure — three parameters that directly relate to cardiometabolic risk. Even small changes can add up to meaningful cardiovascular differences over time,” Toby Pillinger, PhD, of the Institute of Psychiatry, Psychology and Neuroscience at King’s College London and the study’s senior author, said at a media briefing.

The study was published on October 21, 2025, in The Lancet.

Side Effects Matter 

Up to 1 in 5 adults in Europe and North America take an antidepressant to treat depression, anxiety, or related disorders, and the numbers continue to climb. While these medications are known to cause physical side effects, the extent to which those effects differ among drugs has remained unclear.

Adverse effects are also one of the main reasons patients stop taking their medication. In one study, 36% of individuals who discontinued antidepressants cited side effects as the cause. 

The new analysis was designed to quantify those differences, providing clinicians with more precise data to guide treatment choices, investigators said. 

Drawing on data from more than 58,000 participants across 151 randomized trials and 17 FDA reports, the researchers compared 30 antidepressants used to treat depression, anxiety, obsessive-compulsive disorder, and bipolar disorder. 

Most trials lasted about 8 weeks, yet the review still found clear short-term physiologic differences among drugs, particularly in weight and cardiovascular measures, where effects ranged from negligible to clinically meaningful.

Physiologic Effects At-a-Glance

On average, there was about a 4-kg gap between agents associated with weight gain and those linked to weight loss. Maprotiline amitriptyline, and mirtazapine produced the largest increases, while agomelatine, bupropion, fluoxetine and sertraline were tied to small but consistent reductions. 

Roughly half of patients taking amitriptyline or maprotiline gained at least 2 kg, whereas more than half taking agomelatine lost that much.

Cardiovascular changes showed similar variation. Researchers noted a heart rate difference of 21 beats/min between fluvoxamine and nortriptyline and a difference of about 11 mm Hg in systolic blood pressure between nortriptyline and doxepin.

Researchers found evidence of clinically relevant increases in blood pressure with duloxetine, desvenlafaxine, venlafaxine, levomilnacipran, imipramine, maprotiline, and amitriptyline.

Other measurable shifts were less pronounced: Duloxetine, venlafaxine, and desvenlafaxine modestly raised total cholesterol and occasionally glucose levels, while mild, transient increases in liver enzymes were noted but were not clinically significant.

The analysis also found no link between symptom improvement and metabolic change, suggesting that the physical effects stemmed from the medications themselves rather than from recovery.

Clinical Implications 

The authors said the findings give clinicians a clearer evidence base for comparing antidepressants’ physical effects and reinforce the need to consider both mental and physical health when prescribing antidepressants, particularly for patients with metabolic syndrome, hypertension, or obesity. 

Small physiologic changes can accumulate over time, affecting adherence and long-term outcomes. Better tolerability, they emphasized, often leads to longer treatment duration and improved recovery.

“This doesn’t mean certain drugs shouldn’t be used, but that clinicians need to weigh trade-offs and monitor patients accordingly,” co-senior author Andrea Cipriani, MD, PhD, professor of psychiatry at the University of Oxford, United Kingdom, said at the briefing.

The findings also underscore the importance of involving patients in treatment decisions, Cipriani noted. 

“Physicians still make most clinical choices in mental health with little input from patients. Our results emphasize the importance of shared decision-making, the collaborative process through which patients are supported by clinicians to decide on their treatment, bringing together their preferences, personal circumstances, goals, values, and beliefs,” Cipriani said.

The authors added that these data should help guide individualized prescribing and routine physical health monitoring, especially early in treatment. 

They recommended that treatment guidelines integrate physiologic tolerability with efficacy and that longer-term studies assess whether short-term physical changes during roughly 8 weeks of treatment foreshadow cardiovascular events or affect adherence and treatment response over time.

Real-World vs Trial Data 

Clinicians who reviewed the study said it offers crucial insight into how antidepressants differ in their physical effects but cautioned that the short-term, placebo-controlled data may not reflect what happens in day-to-day care.

Jason P. Block, MD, MPH, an internal medicine physician and associate professor in the Department of Population Medicine at Harvard Medical School, Boston, called the analysis “impressive in scope” and “methodologically sound” but noted that most of the trials it drew on were brief and highly controlled. 

“They give us valuable information about physiologic differences, but not necessarily what happens in real-world practice, where patients are older, have comorbidities, and stay on these drugs for months or years,” Block told Medscape Medical News. 

Block was senior author of a 2024 Annals of Internal Medicine study that used electronic health records to track weight changes over 2 years in patients prescribed eight antidepressants. He said his findings align with the overall conclusions of the new study. 

“In our real-world data, the differences were small for the most commonly used medications, but even modest weight gain can affect adherence and satisfaction. Studies like this help clinicians and patients have more informed conversations about what to expect,” he said.

Other experts weighed in on the study in a statement from the UK nonprofit Science Media Centre, suggesting the findings should be interpreted with care.

Cardiovascular changes seen during antidepressant use can also reflect behavioral or lifestyle factors linked to depression itself, such as delayed healthcare seeking or poor baseline heart health, Dervla Kelly, PhD, associate professor of medicine at the University of Limerick in Ireland, noted.

“Randomized trials usually recruit younger adults without other illnesses,” she said. “In practice, these drugs are often prescribed to people with complex health profiles; the true risks may look different.”

Keith Murphy, PhD, of University College Dublin in Ireland, said the results suggest a practical takeaway. 

“A more structured approach to monitoring may be warranted, perhaps similar to what’s recommended for antipsychotic medications,” he said. 

“Regular checks of weight, blood pressure, and metabolic labs can identify early signs of change, especially in patients taking higher-risk drugs or on long-term treatment,” so that antidepressant therapy supports overall well-being, Murphy added.

The study was funded by the National Institute for Health Research, Maudsley Charity, Wellcome Trust, and Medical Research Council. Pillinger and Cipriani reported no relevant financial relationships. Other author declarations are available in the full article. Block, Kelly, and Murphy reported no conflicts of interest.