The relationship between obesity and depression is complex. People with elevated weight have a higher risk of having or developing depression, and people with depression are more likely to have or develop obesity.
Likewise, there is a complex interplay between mental health and weight loss in people with obesity. While many people experience an improvement in mood with weight loss, others do not, and yet others may experience a deterioration in mood/mental health. In a recent long term retrospective study of people who have had bariatric surgery, the risk of suicide was 2.4 times higher in people who had had bariatric surgery compared to matched controls who hadn’t had surgery. There are many possible reasons for this finding. For example, it may be related to weight loss results not meeting a person’s expectations, or perhaps the weight loss didn’t lead to the hoped for improvements in quality of life. Substance abuse may also play a role after bariatric surgery.
Sometimes when people have weight loss success with any treatment modality, there can be unexpected negative consequences in their personal life. For example, a spousal relationship or friendships can change in a negative way, social circles may be negatively impacted, or a person may feel distressed by changes in body shape/skin/appearance (these are just a few of many possibilities). Some people may have a longstanding habit of turning to food as a source of joy or comfort; with changes in food choices, preferences, and/or reward response to food in the brain with various treatments, this could have a negative impact on mood when food is no longer providing that sense of joy or comfort (underscoring the importance of psychological counseling and support to find ways other than food to find joy and comfort).
As discussed in our 2022 Obesity Canada Pharmacotherapy (medications) chapter (disclosure: I am the lead author), most obesity medications are active in the brain. Therefore, it is important to evaluate their effect and safety on mental health parameters. There is also a prior track record of concern, the most dramatic of which was with rimonabant, a cannabinoid receptor antagonist approved in Europe in 2006 for obesity. In a large cardiovascular outcome trial, a signal for neuropsychiatric side effects was seen with rimonabant at a mean follow up of 14 months (32% vs 21% with placebo), and serious psychiatric side effects were seen in 2.5% of patients in the rimonabant group vs 1.3% with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. In a meta-analysis of randomized trials of rimonabant, patients given rimonabant had -4.7kg greater weight loss at one year compared to placebo. Those given rimonabant were 2.5 times more likely to stop treatment because of depressive mood disorders than those given placebo (clinicians: number need to harm =49). Given these findings, rimonabant was withdrawn from the worldwide market in 2008.
Given the higher risk of depression in people with obesity, and prior history of medications including rimonabant, mental health is rigorously monitored in clinical trials of weight loss medication.
Naltrexone/bupropion (trade name Contrave) actually contains an antidepressant medication (bupropion, trade name Wellbutrin). In the clinical trials of naltrexone/bupropion for obesity, participants reported significant improvements in quality of life vs placebo. No suicides nor suicide attempts were reported. Suicidal thoughts were reported in 1 out of 3239 patients (0.03%) treated with naltrexone/bupropion vs 3 out of 1515 patients (0.2%) with placebo. Clinical trials demonstrate an improvement in quality of life as early as week 8 of treatment. In the Canadian product monograph, as antidepressants can rarely (paradoxically) worsen mood/depression, it is recommended to rigourously monitor patients for suicidal ideation/behavior and emotional changes, and that consideration should be given to stopping treatment if this occurs.
Liraglutide (trade name Saxenda for weight management, Victoza for type 2 diabetes) has demonstrated neuropsychiatric safety and significant improvements in quality of life in obesity clinical trials.
Neuropsychiatric concerns have not been identified in the clinical trials of semaglutide (trade name Wegovy for weight management, Ozempic for type 2 diabetes). Obesity studies show significant improvements in quality of life.
Case reports of suicidal thoughts have subsequently emerged for both liraglutide and semaglutide. The GLP1 receptor agonist class of medications (including liraglutide and semaglutide) is now currently under investigation by health agencies around the world. In the Canadian product monographs for Wegovy and Saxenda, it is recommended to monitor patients for emergence or worsening of depression, suicidal thoughts/behavior, and/or any unusual changes in mood or behavior, and that medication should be stopped in patients who experience suicidal thoughts or behaviors.
Orlistat does not act in the brain (it works by reducing fat absorption from the gastrointestinal tract), so would not be expected to have any possible impact on mental health via direct mechanisms.
BOTTOM LINE: There is a complex relationship between obesity and mental health, as well as the impact of weight loss on mental health, with each individual’s journey being unique. While currently available obesity medications that act in the brain have demonstrated neuropsychiatric safety in clinical trials, postmarketing reports must be taken seriously, and we look forward to the review of GLP1 receptor agonists by global regulatory agencies in coming months.
Important: If you have concerns about your mood or feel in any danger of self harm, reach out to your health care provider, government support hotlines/services, or attend emergency care. In Canada, help for suicide crisis and prevention can be found here.
Disclaimer: I am/have been an investigator in clinical trials of liraglutide and semaglutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of liraglutide and semaglutide (Novo Nordisk) and naltrexone/bupropion (Bausch).
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