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new review ranks antidepressants by their physical health side effects

October 22, 2025
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Common mental health problems like depression and anxiety impact about 20% of the adult population (NHS Digital, 2025). These conditions can cause extreme emotional pain and can make it difficult to function in everyday life.

Antidepressant medication can be effective in reducing both depression (Cipriani et al, 2018) and anxiety symptoms (Slee et al, 2019), but one of the biggest concerns people may have about starting treatment is the potential risk of side effects (An et al, 2025). This is particularly relevant for people who already have, or are at risk of, long-term physical health conditions, as side effects in these individuals could be more dangerous. Clinicians may be reluctant to prescribe antidepressants in such scenarios.

We know that different antidepressant medications can have different side effects (British National Formulary, 2025), but there is limited evidence regarding the extent to which these side effects might occur. This means that the choice of antidepressant medication can often be based on prescriber preferences or habits, rather than evidence.

A new systematic review by Toby Pillinger et al. (2025), out today in The Lancet, gathered information from antidepressant drug trials where physical health side effects were reported. Their aim was to compare and rank antidepressants based on their physical health effects.

1

Antidepressants are an effective treatment for depression and anxiety, but side effects can vary, and the choice of antidepressant medication can often be based on prescriber habits, rather than person-centred evidence.

Methods

Pillinger et al. searched online databases to identify all relevant randomised controlled trials (RCTs). They included trials that met the following criteria:

  • Compared any single antidepressant either to a placebo or to another antidepressant.
  • Included adults with a psychiatric disorder or fibromyalgia (as antidepressants can be prescribed to treat mental health symptoms in these individuals).
  • Included at least one of the following physical health measurements: weight, blood pressure, heart rate, qt interval (time taken for heart to contract and reset), cholesterol, blood sugar, blood electrolytes, kidney and liver function tests.

The authors combined trial results using a network meta-analysis to compare the effects of different antidepressant medications. A network meta-analysis is a way to compare many treatments at once, even if some of them have never been directly tested against each other, by connecting the results of studies that share a common treatment for comparison. They then looked at whether the effects were different based on people’s sex, age and weight at the start of the study.

Results

Pillinger et al. identified 168 RCTs that measured physical health effects of antidepressants. These included a total of 58,534 participants and compared 30 different antidepressant medications. However, not all antidepressant medications were covered by a large number of trials: the medication with the most trials was fluoxetine (32 trials) and the medications with the least number of trials were desipramine, phenelzine and selegeline (1 trial each). The duration of the trials lasted from 3-12 weeks, with the average being 8 weeks. The average age of participants was 45 years, 62% were female and 75% were white.

Clinically relevant effects

The effect on physical health after 8 weeks varied considerably between different antidepressant medications. Of all the side effects measured, clinically relevant effects (meaning the effects were potentially big enough to make a difference to someone’s health) were found in those related to long-term heart health. The clinically relevant effects were as follows:

  • Amitriptyline increased weight, heart rate and blood pressure.
  • Duloxetine increased total cholesterol, blood glucose, heart rate, and blood pressure.
  • Desvenlafaxine and venlafaxine increased total cholesterol, heart rate and blood pressure.
  • Imipramine, levomilnacipran, and maprotiline increased heart rate and blood pressure.
  • Clomipramine, doxepin, nortriptyline and reboxetine increased heart rate.
  • Fluvoxamine, mianserin, milnacipran, and mirtazapine increased weight gain
  • Paroxetine increased total cholesterol.
  • Fluoxetine increased blood pressure.

The author’s found that increases in blood pressure were worse if people had a higher weight at the start of antidepressant treatment. Increases in glucose were worse as people increased in age.

When people have high blood pressure, heart rate, total cholesterol, weight and/or blood sugar, this can increase the risk of heart disease, stroke and type 2 diabetes. However, it is important to note that the increases caused by antidepressants may not be big enough to be harmful for everyone. Their impact depends on a person’s health at the start of treatment and whether these changes are sustained. For example, if an individual was under weight, or was sufficiently below the threshold for being considered overweight, adding an extra 1kg may not make a difference. However, if this increase in 1kg continues over several months, the individual may become overweight and so would have an increased risk of serious long-term health problems.

Antidepressants have varying effects on physical health, with some causing clinically relevant changes in heart-related measures that may pose risks depending on baseline health and persistence.

Antidepressants have varying effects on physical health, with some causing clinically relevant changes in heart-related measures that may pose risks depending on baseline health and persistence.

Conclusions

The authors concluded that antidepressants differed considerably in their physical health side effects, particularly for side effects that increased the risk of conditions such as heart disease, stroke and type 2 diabetes.

They suggested that treatment guidelines should be updated to reflect these differences. However, they also stressed how the choice of antidepressant should be made on an individual basis, considering clinical need and individual preferences.

Antidepressants differ in physical health side effects, so treatment guidelines should reflect these risks while supporting individualised prescribing.

Antidepressants differ in physical health side effects, so treatment guidelines should reflect these risks while supporting individualised prescribing.

Strengths and limitations

The authors conducted a thorough search of all the appropriate databases containing information about clinical drug trials. Their use of the network meta-analysis method allowed them to compare multiple antidepressant medications, regardless of whether they were directly compared in the original research studies.

One limitation of this review is that not every antidepressant had information available for every physical health measurement. For example, while citalopram and escitalopram did not show evidence of harmful side effects, there were no trials for citalopram measuring the liver and kidney function markers – ALP and urea – and no trials for escitalopram measuring the blood electrolytes potassium or sodium.

The authors limited their search to only include RCTs. These are the gold standard way to evaluate the effects of medications. However, RCTs are typically short in duration, partly due to the high cost of running a trial. Therefore, a second limitation of this review was the short-term nature of the side effects measured. Some changes in physical health may take longer to occur and may increase further over time. This could mean the risk of serious long-term consequences, such as heart disease, are underestimated in this review.

Finally, RCTs may not always be representative of the real-world population, or applicable to all groups of people. For example, a number of the trials excluded people who already have physical health conditions. These individuals may be at higher risk of side effects due to already impaired health or interactions with other medications they are taking. Trials also often exclude older people, who are at increased risk of side effects, or pregnant women; where the risk of harm is unethical.

The review used robust methods to compare side effects of antidepressants, but limitations include missing data for some drugs, short duration of included trials, and underrepresentation of higher-risk groups.

The review used robust methods to compare side effects of antidepressants, but limitations include missing data for some drugs, short duration of included trials, and underrepresentation of higher-risk groups.

Implications for practice

This was the first systematic review to compare the physical health side effects of different antidepressant medications. This is a really important contribution to the evidence base for antidepressants, as treatment guidelines recommend consideration of side effects when choosing treatment (National Institute for Health and Care Excellence, 2022).

The choice of antidepressant should always be discussed with a medical practitioner. It is important to remember that everyone reacts differently to antidepressant medication, and we still don’t fully understand the reasons for this. However, this review provides important information that can help guide treatment decisions, particularly in people who may already be at increased risk of physical health problems.

The antidepressant medications that showed the greatest risk of physical health side effects are not typically prescribed as the first choice of antidepressant. Guidelines recommend starting treatment with a type of antidepressant called an “SSRI”. This includes citalopram and escitalopram, which had the least side effects in this review. Medications such as amitriptyline, duloxetine, desvenlafaxine and venlafaxine are usually only recommended when other antidepressants have failed to work. At this point, a discussion between patient and doctor should focus on the pros and cons of improving mental health symptoms (which can also negatively impact physical health) versus the risk of side effects.

Antidepressants with higher risk of physical health side effects can sometimes have a big impact on improving people’s mental health. In these situations, clinical teams can monitor physical health measurements (such as those in this review) more closely. Additional support could be offered to help individuals maintain a healthy lifestyle, which could counterbalance the risk of side effects such as weight gain or increased blood pressure.

Further research is required to understand the long-term physical health effects of antidepressant medications. Where this is not possible in drug trials, it could be possible by analysing real-world antidepressant use from medical records. This would also allow researchers to include people with physical long-term conditions, older people and pregnant women without risking harm to these more vulnerable groups. However, it can be tricky to separate the effect of the antidepressant medication on physical health from the detrimental impact of poor mental health itself.

Future RCTs should ensure they include a full range of physical health side effects in their evaluation of antidepressant medications. This would be beneficial for people with common mental disorders, clinical teams, and even pharmaceutical companies, to highlight the safest antidepressant medications available.

This review provides the first systematic comparison of physical health side effects across antidepressants, offering evidence to guide personalised treatment decisions, support updates to prescribing guidelines, and encourage further research into long-term risks and vulnerable populations.

This review provides the first systematic comparison of physical health side effects across antidepressants, offering evidence to guide personalised treatment decisions, support updates to prescribing guidelines, and encourage further research into long-term risks and vulnerable populations.

Statement of interests

Nothing to declare.

Links

Primary paper

Pillinger T, Arumuhan A, McCutcheon RA,… Cipriani A. et al. The effects of antidepressants on cardiometabolic and other physiological parameters: a systematic review and network meta-analysis. The Lancet. 2025. https://doi.org/10.1016/S0140-6736(25)01293-0

Other references

NHS Digital (2025). Adult Psychiatric Morbidity Survey: Survey of Mental Health and Wellbeing, England, 2023/4. https://digital.nhs.uk/data-and-information/publications/statistical/adult-psychiatric-morbidity-survey/survey-of-mental-health-and-wellbeing-england-2023-24

Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JPT, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JPA, Geddes JR. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018 Apr 7;391(10128):1357-1366. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext

Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019 Feb 23;393(10173):768-777. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31793-8/fulltext

An MH, Kim MG, Kim J, Chang S, Lee DY, Park RW. Public perception and changing attitudes toward antidepressants over a decade in social media: Lessons learned from online discussion using artificial intelligence. PLoS One. 2025 Sep 4;20(9):e0318464. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0318464

British National Formulary (2025). Antidepressant drugs. https://bnf.nice.org.uk/treatment-summaries/antidepressant-drugs/

National Institute for Health and Care Excellence (2022). Depression in adults: treatment and management. https://www.nice.org.uk/guidance/ng222

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