Which Antidepressants Have the Most Side Effects?

Antidepressants are a lifeline for millions of people living with depression, anxiety, and other mental health conditions. But while these medications can be highly effective, they can also sometimes come with physical side effects that can impact a person’s overall health and wellbeing. Until now, there hasn’t been a clear picture of how different antidepressants compare when it comes to these side effects.

The Petrushka Trial is a major research project led by Professor Andrea Cipriani at the University of Oxford. He and his team conducted a systematic review and network meta-analysis, which means they carefully analysed and compared data from dozens of previous studies involving over 58,000 people. They used this data to rank commonly prescribed antidepressants based on their physical side effects, such as weight gain, changes in blood pressure, and heart rate.

Why This Matters

In the UK, around 15–20% of adults are prescribed antidepressants. While we know a lot about how well these drugs work to improve mood, sleep, and pain, their physical effects have been less studied. This new research helps fill that gap and could lead to more personalised prescribing, where doctors choose medications not just based on mental health symptoms, but also on how they affect the body.

Different antidepressants are not ‘good’ or ‘bad’ but different and have different physical effects on the body. For people with underlaying physical conditions such as high-blood pressure or stomach issues, receiving the anti-depressants which won’t make these conditions worse is important.

What Did the Study Find?

The researchers found that some antidepressants are more likely to cause weight gain and cardiovascular changes than others. For example, older drugs like amitriptyline and mirtazapine were linked to higher risks of these side effects, while newer medications like sertraline and fluoxetine tended to have a more favourable profile.

This doesn’t mean one drug is “better” than another—it means that side effects should be part of the conversation when choosing a treatment.

For some people, a medication that causes weight gain might be manageable. For others, especially those with heart conditions or diabetes, it could be a serious concern.

What Do These Side Effects Mean?

• Weight gain: Can affect self-esteem and physical health, especially for people with diabetes or heart conditions.
• Sexual dysfunction: Includes reduced libido or difficulty achieving orgasm, which can impact relationships.
• Sedation: Feeling overly sleepy or sluggish, which may interfere with daily activities.
• Dry mouth and constipation: Common with older antidepressants, these can be uncomfortable and affect quality of life.
• Blood pressure changes: Important to monitor, especially for people with cardiovascular conditions.

The study was welcomed by experts across the field.

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.

What’s Next?

The Petrushka Trial is part of a growing movement in mental health research to make treatments more tailored and transparent. By understanding how different drugs affect the body, doctors can help patients make informed choices and hopefully improve both mental and physical health outcomes.

The recently awarded PRADA study (funded by Wellcome and supported by MQ) is the next step after PETRUSHKA. This project aims to add genetic predictors to an evidence-based multimodal web-tool, to help patients and clinicians choose the best pharmacological treatment for depression jointly.

Andrea Cipriani is also leading the GALENOS study, which is also supported by MQ, which aims to review the published evidence and data in order to answer specific questions about depression, anxiety and psychosis.

If you’re currently taking antidepressants and have concerns about side effects, it’s important to speak with your doctor. This study doesn’t suggest stopping medication, but it does highlight the need for open conversations and individualised care.