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A systematic review and network meta-analysis published in The Lancet looks at the physical side effects of antidepressants.
Dr Lade Smith CBE, President of the Royal College of Psychiatrists, said:
“We know that more than 7 million adults have depression in England alone and that severe depression can devastate people’s lives if left untreated.
“Antidepressants play a key role in the treatment of more severe depression and are particularly effective when used in combination with talking therapies.
“As with all drugs, antidepressants have side effects, and we very much welcome this study which helps improve our understanding of some of the physical side effects that can be caused by different types of antidepressants. These findings will help patients and clinicians choose the medication that is best suited to their personal needs. It is vital that these decisions are informed by the best available evidence.
“Research such as this, is and should be used to inform guidance for clinicians and is taken into consideration during discussions with patients on the benefits, risks and side effects of these medications.”
(from our friends at the All Ireland SMC) Dr Brian O’Donoghue, Professor of Psychiatry, University College Dublin, said:
“This is an important study by Pillinger and colleagues that compared the side effects of 30 different antidepressant medications by combining over 150 studies, which included more than 58,000 participants in total.
“The effectiveness of different antidepressant medications that are used as first line treatments for depression or anxiety do not vary substantially. Therefore, the selection of antidepressant medication should be based on the anticipated side-effects. This review by Pillinger et al helps inform individuals about the likely side-effects associated with each antidepressant medication, which in turn will facilitate making an informed decision about which antidepressant medication is most suitable. For example, the study highlights that different antidepressants have varying effects on weight gain, heart rate, blood pressure, cholesterol and blood glucose levels. Therefore, individuals with pre-existing conditions, vulnerabilities from family history of certain disorders or if they have a concern about a specific side effect, they can now make a more informed and individualised decision in relation to what antidepressant medication would be best suited for them.
“Although not mentioned in the article, members of this research group have also developed an online tool that can be used, in consultation with a clinician, to support people to make an informed decision about selecting an antidepressant medication; www.psymatik.com“
(from our friends at the All Ireland SMC) Prof Frank Moriarty, Associate Professor, School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, said:
“This review of evidence was conducted in a thorough way, and notably, the researchers looked at sources where unpublished trials might be found. This is important as previous work has shown that not all antidepressant trials have been published, and focusing on only the published research can skew the evidence.
“These findings do not show major new physical side effects of antidepressants, and so should not be a cause for concern. Rather the results should help to personalise the choice of therapy for patients starting on antidepressant medicine. They may also help tailor advice and monitoring of side effects, going beyond the overall drug class effects. However it is worth bearing in mind that these are the average effect in groups of patients, and so there may be differences between individuals in their experience of using a medicine. If a patient thinks they may be experiencing a side effect of their medicine, they should let their healthcare professional know and discuss this with them.
“For patients and their healthcare professionals in Ireland, most of the medicines identified as having strongest side effects, e.g. the biggest decrease in heart rate or increase in blood pressure, are older drugs that are used less often, or only when other medicines have not been effective.
“It’s also important to bear in mind that this study only looked at physical side effects of these medicines. It does not provide any evidence on their possible benefits, nor on other possible harms, including the effects when a patient stops taking these medicines. These factors, as well as non-drug treatment options where available and accessible, are important for patients to discuss with their prescriber in making a decision to start an antidepressant.”
(from our friends at the All Ireland SMC) Prof Keith Murphy, Professor of Neuropharmacology, University College Dublin, said:
“In a very recent meta-analysis published this week in The Lancet, Pillinger and colleagues (2025) report the first comprehensive comparative review of how different antidepressants affect the body beyond the central nervous system and their mood-related benefits. They analysed data from over 58,000 participants across 151 clinical trials, and report clear differences between antidepressant drugs in their effects on weight, blood pressure, heart rate, and metabolism, factors with important impacts on cardiovascular health. Tricyclic antidepressants and certain SNRIs (serotonin and noradrenaline reuptake inhibitors), such as amitriptyline, venlafaxine, and duloxetine, were associated with, for example, increased heart rate and blood pressure. In contrast, medications like agomelatine and bupropion appeared to have fewer measurable physiological effects. While most of these effects were relatively small over the short term, they have the potential to become more significant with long-term use, especially for people already at risk of cardiovascular disease.
“These findings have potentially important implications for prescribing practice in Ireland, where antidepressant use is relatively high by European standards. At present, doctors generally monitor weight and blood pressure, but systematic checks for other metabolic changes are not routine. The results of this new study suggest that a more structured approach may be beneficial, perhaps similar to the monitoring already recommended for antipsychotic medications. Regular reviews of weight, blood pressure, and blood tests for glucose and cholesterol could help identify early signs of metabolic disturbance. This would be particularly useful in patients on higher-risk drugs or long-term treatment.
“The research highlights the potential for physical side effects of antidepressants. It is essential, however, to note that the appropriate use of these medicines remains effective and generally safe. The Lancet study reinforces the importance of open discussion between patients and prescribers about the mental health benefits and the potential physical side effects of antidepressants. Such dialogue can ensure that antidepressant treatment decisions can be best tailored to support the whole person’s wellbeing.”
(from our friends at the All Ireland SMC) Dr Dervla Kelly, Associate Professor, School of Medicine, University of Limerick, said:
Do antidepressants cause weight gain and increase risk of heart problems?
“Results from a new systematic review of 30 different antidepressant medicines suggest that some antidepressants may cause problematic weight gain and heart problems. Antidepressants are available by prescription and have proven to be effective in treating depression. Beyond depression, they have proven useful in other conditions such as anxiety, OCD, eating disorders, incontinence and chronic pain. Because there are lots of antidepressant to choose from, it is really important to have comparative studies like this to differentiate between antidepressants, in terms of side effects.
“It has been known for some time that certain antidepressants cause weight gain and others may be unsafe for people with chronic heart disease and arrythmias. It is also accepted that people with diabetes need to monitor their blood glucose more closely and may need to adjust their diabetes medications when taking an antidepressant. This new study brings back to the spotlight the side effects of antidepressants.”
What is known about the link between antidepressants and weight gain?
“Regarding weight gain, it is thought that the neurotransmitters, dopamine and noradrenaline which can be altered by antidepressants are also involved in the regulation of appetite, satiety, craving, and eating behaviours. We know from previous research than antidepressants paroxetine, mirtazapine and amitriptylline are associated with increased weight gain. The new study calls out maprotiline as having the worst effect on weight, however this drug is not routinely used in Ireland.
“Weight gain, cholesterol and metabolic changes are typically a gradual health issues, where small changes over time can, sometimes without symptoms, can lead to health problems. The duration of a randomised controlled trial (3-12 weeks in this study) may not always give time to monitor for these issues.”
What is known about cardiovascular health and antidepressants?
“Heart problems previously linked with antidepressants include increased heart rate, arrhythmia, conduction problems, hypertension and postural hypotension. Indeed, guidelines currently recommend sertraline as the first line treatment for people with existing cardiovascular problems. While tricyclic antidepressants, duloxetine, reboxetine, and venlafaxine and citalopram and escitalopram are less preferred or generally avoided in people with heart disease.
“In this study, amitriptyline, venlafaxine, fluoxetine and duloxetine are associated with increased blood pressure compared to placebo. However, it is important to be cautious when interpreting the study findings as sometimes cardiovascular problems that coincide with antidepressant use could be influenced by behavioural or lifestyle factors associated with depression, such as delayed healthcare seeking, and poor cardiovascular health. In addition, randomised controlled trials typically recruit younger adults without other illnesses, so this study likely does not reflect the risks of antidepressant use in practice, where they are prescribed in people with other illnesses.”
So given all of this, should people worry about how safe antidepressants are?
“This new study should not create a panic about the safety of antidepressants. For patients with existing obesity or heart problems , the findings from the study are an important piece of information for prescribers to have to hand.
“Given how common heart disease and heart disease risk factors are, such as high blood pressure, obesity and diabetes (which are often unrecognised), it is important to select antidepressant treatments, considering an individual’s weight, cardiovascular health status, family history and lifestyle factors.
“Sometimes the cardiovascular side effects may be dose related and a baseline test a called an ECG may be used in people with cardiac disease before starting them on antidepressants such as citalopram or escitalopram.
“Once someone is started on these medicines, they need to have follow up monitoring to check blood pressure, blood sugars and cholesterol. How often monitoring takes place can vary a lot for people, often depending on their doctor. This study suggests that weight, cholesterol, blood pressure, blood sugars may need to be routinely monitored when people are taking antidepressants. It’s important to talk with your pharmacist or doctor if you have questions about taking an antidepressant you’ve been prescribed.”
Dr Alison Cave, MHRA Chief Safety Officer, said:
“We continuously monitor the safety of all medicines in the UK, including antidepressants.
“This study compares short-term physiological changes across a range of antidepressants. We will examine the full findings in detail and consider them alongside other available evidence as part of our ongoing safety monitoring.
“All antidepressants have known side effects, and these are clearly outlined in the product information. Patients should always read the Patient Information Leaflet (PIL) that comes with their medicine, as it contains important details on how to take their medicine safely and what side effects to look out for.
“Anyone who has questions or experiences symptoms while taking antidepressants should speak to a healthcare professional and report suspected side effects via the Yellow Card scheme. Patients should not stop taking any medication without talking to their healthcare professional.”
Dr Prasad Nishtala, Reader in Pharmacy and Epidemiology, University of Bath, said:
“This large network meta-analysis, compared the physiological effects of 30 antidepressants across 151 randomised controlled trials involving more than 58,000 participants. The study revealed substantial differences between antidepressants in their impact on cardiometabolic and other physiological parameters, including weight, blood pressure, heart rate, cholesterol, and glucose. While some agents such as maprotiline, amitriptyline, and mirtazapine were associated with weight gain and increased blood pressure or heart rate, others like agomelatine, fluoxetine, and bupropion tended to cause weight loss or minimal metabolic disruption. Drugs including duloxetine, venlafaxine, and paroxetine raised cholesterol and glucose despite modest weight loss, but no clinically meaningful changes were observed in QTc interval, electrolytes, or renal function. Notably, these physiological changes were not linked to antidepressant efficacy, and dose-related effects were not assessed.
“This is the first comprehensive study to quantify changes in physiological parameters following antidepressant treatment. Although the cardiometabolic risks of some antidepressants were already recognised, quantifying these effects across different antidepressants is a novel and valuable contribution. The average treatment duration in the included trials was around eight weeks, yet in real-world setting, where patients often receive antidepressants for months or years, the cumulative risks are likely to be higher, particularly among those with chronic depression or existing metabolic comorbidities. Therefore, understanding the differential cardiometabolic profiles of antidepressants can help clinicians make more informed decisions when tailoring therapy to an individual’s comorbidity profile.
“Currently, the UK’s QRISK calculator, used to estimate a person’s 10-year risk of heart attack or stroke, considers the use of antipsychotic medications because of their known cardiometabolic risks. Given the evidence from this meta-analysis that several antidepressants also significantly alter cardiometabolic parameters, incorporating antidepressant use into QRISK assessments for patients with mental illness could improve cardiovascular risk estimation and preventive care in this population. Such an update would better reflect the true metabolic burden of psychiatric pharmacotherapy and support safer, more personalised prescribing.”
Prof Azeem Majeed, Chair of Primary Care and Public Health & Head of Department, Imperial College London, said:
“The study confirms that antidepressants vary significantly in their impact on key cardiometabolic parameters, such as weight gain, blood pressure, heart rate, cholesterol and glucose levels. This finding is particularly important for individuals with pre-existing conditions like heart disease or diabetes. For patients and clinicians, the results underscore the need for routine physical health checks in those treated with antidepressants. Moreover, awareness of these side effects is essential to support shared decision-making about the risks and benefits of treatment with antidepressants.”
Prof Hamish McAllister-Williams, Strategic Research Advisor, Newcastle University, said:
“The findings of the well conducted study adds increased precision to what we previously knew about antidepressants. It is important to note that the study did not consider rare side effects (e.g. hepatic failure with agomelatine). In addition, side effects may get better or worse in long term treatment beyond 8 weeks. More research is also needed to understand the impact of pre-existing physical illnesses on the likelihood and severity of side effects with antidepressants.”
Additional information below:
Background information from the MHRA:
‘The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis’ by Toby Pillinger et al. was published in The Lancet at 23:30 UK time on Tuesday 21st October 2025.
DOI: 10.1016/S0140-6736(25)01293-0
Declared interests
Dr Lade Smith CBE: None
Prof Keith Murphy: No conflict of interest
Dr Brian O’Donoghue: No conflicts of interest, except that I have collaborated with researchers involved in this study.
Prof Frank Moriarty: My research focuses on the effects of reducing or stopping medications, and is funded by national research funders or charitable foundations (Health Research Board, Wellcome Trust). I have no other conflicts of interest.
Dr Dervla Kelly: Nothing to declare.
Dr Alison Cave: No declarations of interest
Dr Prasad Nishtala: No COI
Prof Azeem Majeed: I don’t have any conflicts of interest.
Prof Hamish McAllister-Williams: In the last 5 years I have done work with J&J in relation to esketamine for mood disorders.
This Roundup was accompanied by an SMC Briefing.