GLP-1 Agonists’ Potential in Neuropsychiatric Applications – Managing the Twin Co-morbidities of Depression and Obesity

Obesity and depression are not isolated diseases.

According to a large meta-analysis published in JAMA1, obese people are 55% more likely to develop depression, and people with depression are also significantly more likely to develop obesity.

In this context, GLP-1 receptor agonists (such as semaglutide), in addition to being rising stars in diabetes and obesity intervention, have also been recognised to have the potential to improve mental health.

Past controversies, present confidence

Of course, as many GPs may recall, these medications have had a chequered past.

Initially in 2023, the European Medicines Agency (EMA) and British regulators2 launched an investigation into semaglutide because some patients reported ‘mood swings and suicidal thoughts’.

However, in a preliminary conclusion released in 2024, the U.S. Food and Drug Administration (FDA)3 stated that ‘there is currently no evidence of a direct relationship between semaglutide and suicidal thoughts or behaviours.’

Another vindicating study, published in JAMA Psychiatry4 in May 2025 and involving 107,000 participants, found that compared with placebo, treatment with GLP1-RAs was not associated with increased risk of psychiatric adverse events.

The study states: ‘Furthermore, GLP1-RA treatment was associated with improvements in both physical and mental health–related quality of life, as well as reduced emotional eating behaviours and increased eating restraint.’

Possible mental health benefits of GLP-1 agonists

Medical News Today5 reports that people taking semaglutide were 45% less likely to be diagnosed with depression and 44% less likely to have anxiety compared to people not taking the drug. For tirzepatide, the reduced risk of depression was 65%.

Other benefits have also been found in the peer-reviewed medical journal Nature Medicine6, which states that semaglutide reduces the risk of addiction disorders (alcohol and tobacco), psychological disorders, epileptic seizures, and neurocognitive disorders (including Alzheimer’s disease).

In this study of 240,618 patients with obesity and 1,589,855 patients with type II diabetes:

Control drugs included non-GLP-1 weight loss drugs such as bupropion, orlistat, and topiramate.

The results showed that the risk of suicidal ideation in the semaglutide group was reduced by 73% (HR 0.27).
No suicide attempts occurred in the semaglutide group, while 14 occurred in the control group.

In people with a history of suicide, the recurrence rate of suicidal ideation in the semaglutide group was reduced by 56% (HR 0.44), and the proportion of anti-suicidal drug prescriptions was significantly reduced.
There was a reduction in addiction disorders (alcohol and tobacco) among participants in the semaglutide group.

The study was verified in a cohort of patients with type II diabetes (more than 1.58 million people), showing that semaglutide can also significantly reduce new and recurrent suicidal ideation, and the correlation persists in 1-year and 3-year long-term follow-up.

The connection between inflammation, obesity, and depression

It’s also theorised that semaglutide (GLP-1 RA) may have anti-inflammatory and antioxidant properties that can help reduce neuroinflammation.7

According to the research, obesity and depression are both caused by chronic inflammation. Depressed patients often have higher levels of cytokines in their bodies8, which may in turn increase obesity and a range of other inflammatory diseases such as diabetes, asthma and cancer. Inflammation is also thought to be involved in neurological diseases such as Alzheimer’s and Parkinson’s disease.

Are there risks or side effects associated with GLP-1 agonists?

Melbourne bariatric and laparoscopic surgeon Dr Jason Winnett says that whilst the medications have changed lives for many of his patients, they are not ‘a magic carpet ride’.

He says, ‘Rare side effects include gastroparesis, which can cause paralysis, usually temporary, but has resulted in 1800 lawsuits in the US as of May 2025.

‘More common side effects include putting on weight again after stopping the medication, and for people with severe obesity, surgery is generally a more affordable and more viable option in the long run.’

Dr Winnett advises that any side effects must be carefully considered and weighed up against the ‘side effects’ of not taking medications.

‘What people with obesity need to ask themselves is, what are the risks of not taking medications, or not having the surgery?’ Dr Winnett says. ‘Obesity has very clear links with cancer and sleep apnoea, and increases the risk of arthritis. After surgery, many of these risks drop significantly and Type II diabetes resolves permanently in most cases.’

The future of obesity treatment – the mind-body link

As science continues to uncover the surprising ripple effects of GLP-1 medications, these discoveries challenge us to rethink how we approach obesity – not just as a number on the scale, but as a condition deeply intertwined with the brain, behaviour, and emotional wellbeing. The future of treatment may not lie in choosing between body and mind, but in recognising that healing one often means healing both.

With extensive experience in both surgical and non-surgical obesity treatments, Dr Jason Winnett is a trusted expert in the evolving use of GLP-1 medications. If you’re a GP uncertain about prescribing these therapies, or if your patient may benefit from a more specialised assessment, consider referring them to Dr Winnett for expert guidance and personalised care.

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