Antidepressants can have significant side effects on physical health – even after just weeks of use – according to an international study. The systematic review and meta-analysis, published in the medical journal The Lancet Tuesday, drew conclusions from the results of 151 clinical trials and 17 U.S. Food and Drug Administration reports, involving a combined total of more than 58,000 participants and 30 antidepressant drugs. Data was analyzed from existing clinical trials, most of which measured outcomes over the first eight weeks of treatment. Researchers at the U.K.’s King’s College London found a wide variation in how these medications influence body weight, blood pressure and heart rate, suggesting that the choice of antidepressant should be tailored to each patient’s overall health profile. Lead author Toby Pillinger, academic clinical lecturer at King’s College London Institute of Psychiatry, Psychology and Neuroscience, said the findings challenge the idea that antidepressants are interchangeable. “We set out to address that evidence gap, because if you know which ones are better for weight gain, weight loss, blood pressure changes, changes in cholesterol, then you can start to choose certain medications preferentially,” he said in a Zoom interview with CTVNews.ca on Thursday. The research team ranked medications based on changes noted in the trials analyzed in weight, blood pressure, cholesterol and heart rate. The ranking is the first at this scale, those behind the study said. “The output of the analysis was very similar to … a football league table of treatments from best to worst,” Pillinger said. The key takeaway, he said: not all antidepressants are the same, something prescribing doctors should take into account. “We need to move away from a one-size-fits-all approach for use of antidepressants. We need to be more precise in our prescribing and matching the medication to the person, rather than the other way around,” he added. On a practical level, matching patients with dozens of antidepressants is impossible in a 20- to 30-minute consultation, he said. But the freely accessible digital tool developed alongside this research allows doctors and patients to collaborate together, choosing which side effects they are most and least concerned about, and generating a personalized league of antidepressant options from best to worst. “If you’re happy with the treatment that you’re going to get, and you understand why it’s been chosen, you know exactly what you’re going to expect, it promises to have much better outcomes… Your mental health will be better as well,” Pillinger said. Mapping weight gain and other side effects The analysis found a four-kilogram difference in weight change between two drugs over an eight-week period. Participants taking maprotiline, a tetracyclic antidepressant, gained an average of 1.82 kg, while those on agomelatine, a melatonin receptor agonist, lost an average of 2.44 kg. Several antidepressants were strongly linked to weight gain compared to placebo, including amitriptyline (+1.6 kg), milnacipran (+1.16 kg) and mianserin (+1.15 kg). Nearly half of participants prescribed maprotiline or amitriptyline experienced clinically important weight increases, the study found. Changes were not limited to weight. There was a 21-beat-per-minute (bpm) difference in the heart rates of people on certain antidepressants. The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine reduced heart rates by 8.18 bpm on average, while nortriptyline increased rates by an average of 13.77 bpm. Blood pressure varied by 11 mmHg between drugs – dropping by an average of 6.68 mmHg with nortriptyline, but rising by 4.94 mmHg with doxepin. “Some side effects are really important to people. If you develop a side effect, you might decide to stop your medication,” Pillinger said. On the other hand, Pillinger said, some side effects can cause increased risk of heart disease and stroke over time. He noted people with depression are already at a higher risk of heart disease and stroke compared to the general population. Why this matters for Canada In Canada, the stakes are tangible. According to the Centre for Addiction and Mental Health (CAMH) about five per cent of Canadians aged 15 and older have experienced a major depressive episode in the past year. In any given year, 1 in 5 Canadians experience a mental illness. According to data from IQVIA, a U.S.-based global provider of clinical research services that operates in Canada, the prevalence of community-pharmacy-dispensed antidepressants in Canada rose from 15.4 per cent in 2019 to 16.4 per cent in 2023. Despite the study’s findings, Pillinger stressed that the goal is not to alarm patients or discourage use of these medications, but to encourage informed decision making around treatment. “The last thing we wanted this paper to cause was panic,” he said. “Across medicine, it is pretty hard to find any pharmacological treatment that doesn’t have a side effect (or) at least some form of (one). It doesn’t matter if you’re prescribed a blood pressure pill, an antibiotic or antidepressant -- there are side effects.” Pillinger said that taking any medication is a “judgment call” for patients. “Someone struggling with low mood, anxiety or post-traumatic stress may decide that a small weight gain or change in blood pressure is worth it if treatment helps them function and feel better,” he said. Pillinger added that patients worried about side effects should not stop or switch medications without consulting their doctor. Instead, the research should serve as a tool to support shared decision-making, ensuring treatment plans balance mental health needs with physical health considerations. Limitations Pillinger also acknowledged key limitations in the study’s design – including that data primarily came from relatively young, healthy participants who were on average in their early 40s. “To enter a clinical trial, you need to be in good health,” he explained. That means findings may not fully reflect how antidepressants affect the general population, older adults or those managing multiple conditions. The research also focused on short-term outcomes of typically eight-week trials, which Pillinger said reflects the data most readily available. However, many people take antidepressants for months or even years and the long-term physical effects remain less understood. “If you gain weight within the first two months of treatment, it’s unlikely that you’ll lose it again over the next year,” he noted. “In fact, some of those changes may worsen over time.” Pillinger said his team is examining longer-term data to better understand how extended antidepressants use influences physical health markers.
