Have you heard the story of a breakthrough weight loss medicine called rimonabant?
As a once-a-day oral medicine, rimonabant was approved in Europe in 2006 based on randomized controlled trials demonstrating clinically significant weight loss1. It had all the signs of being the next blockbuster. Beyond the sustained weight loss results, for example, study participants also showed improvements in central adiposity (waist circumference), triglycerides, and HDL cholesterol. That means that people weren’t just getting thinner on rimonabant, they were getting healthier. Many participants even reported unexpected decreases in their cravings for sweets and desires for addictive substances such as nicotine.
One medicine with so many beneficial features. Released during nearly the same year, rimonabant looked to some like the pharmaceutical equivalent of the iPhone.
Somehow, almost overnight, it then all fell apart for rimonabant. By just 20082, rimonabant approval had been withdrawn (and never received FDA approval in the U.S.) due to psychiatric safety concerns. Clinical trials and meta-analyses reporting increases in depression, anxiety, and suicide led to the swift and stunning downfall of this once-heralded medicine.
Compounded by the equally sudden banning of the weight loss drug, phen-fen (phentermine-fenfluramine), in 1997 due to increases in cardiovascular risks, a mushroom cloud effect fell across the field of obesity medicine. More than a decade after the collapse of rimonabant, there remained no new promising pharmaceutical agents addressing obesity. This was despite continued rapid increases in weight and weight-related health conditions across the U.S. and Europe.
It wasn’t until 2021 when the FDA approved wegovy for the treatment of adults with overweight or obesity that the next breakthrough medicine for chronic weight management would become available.
Consider the parallels.
Like rimonabant before it, wegovy (called a “GLP-1 agonist” due to its ability to simulate the effects of a naturally occurring appetite hormone in the human body called glucagon-like peptide-1) shows:
- Clinically significant and sustained weight loss in adults in randomized controlled trials
- Beneficial effects on metabolic health parameters such as cholesterol, triglycerides, and cardiovascular function
- Surprising reductions in cravings for sweets, ultra-processed foods, and addictive substances such as nicotine and alcohol
Do these remarkable similarities suggest that GLP-1 agonists (for example, wegovy, zepbound) are likely to cause the same severe psychiatric side effects as rimonabant? What do we know about these medicines that we should be telling people who are interested in GLP-1 agonists for weight management but who have histories of depression, suicide, or other mental health conditions?
Why GLP-1 agonists may improve depression
Despite the above convergence in weight loss, metabolic health, and psychiatric symptom pattern changes, GLP-1 agonists work through very different mechanisms compared with rimonabant (rimonabant blocked cannabinoid-1 [CBD-1] receptors in the brain and other organs; this reduced pleasure from eating and consequent weight loss. But it also produced broader anhedonia and depression symptoms for some people).
The biological mechanisms behind how GLP-1 agonists function are likely to result in improved mental health for many people using them. Here is a summary of why:
- GLP-1 agonists are anti-inflammatory in the brain and body3. Chronic inflammation is one of the most recognized biological mechanisms involved in depression, including direct causal relationships observed in non-human animals4. Chronic inflammation—produced by factors such as excess body fat, insulin resistance, poor sleep, ultra-processed foods, environmental toxins and chemicals, and low levels of physical activity, among others—is ubiquitous in modernity and a likely contributor to increasing rates of mental illness in Westernized societies. Although not all depression is the result of chronic inflammation, treatments such as GLP-1 agonists that reduce systemic inflammation in the brain may produce mood and cognitive benefits in many people5.
- GLP-1 agonists reduce insulin resistance. A primary reason that GLP-1 medicines are showing benefits for seemingly different medical conditions such as diabetes, cardiovascular disease, sleep apnea, kidney disease, and even polycystic ovary syndrome6 is that all these conditions are caused or worsened by a process called insulin resistance (insulin is one of your most powerful metabolic hormones; when your body become insulin resistant, it cannot use insulin effectively resulting in problems across every major organ). Insulin resistance is also an important and underappreciated contributor to mental health conditions such as depression. For this reason, GLP-1 agonists may prove helpful in reducing depression symptoms for many people, perhaps especially those with overlapping metabolic health conditions such as those listed above.
- GLP-1 agonists decrease blood glucose variability. When you complete a physical exam with your doctor, you likely receive laboratory blood tests called a fasting blood sugar test and a hemoglobin A1c. Both tests are measures of how well your body is controlling the amount of “sugar” (glucose) in your blood and body. When these tests are high enough, a person may be diagnosed with diabetes. Although many people understand the basics about blood sugar for their health, far fewer know that blood sugar variability is also negatively associated with mood symptoms7. Reducing highs and lows in our blood sugar levels (even if you don’t have diabetes), therefore, is one way to improve our mood. The first use of GLP-1 medicines, before their weight loss benefits were recognized, was to improve blood sugar control among people with diabetes. Now that we also know from studies using continuous glucose monitors (CGMs) that improvements in blood glucose control can also decrease negative mood symptoms, this is another biological reason to expect that depression symptoms may improve for many people using GLP-1 medicines.
Summary
GLP-1 agonists such as wegovy and zepbound show many of the same promising early benefits as past medication failures such as rimonabant. However, unlike the adverse psychiatric outcomes observed with rimonabant, the biological mechanisms of action behind GLP-1 agonists suggest a different result. Based on these mechanisms, many people using GLP-1 medicines for medical conditions are likely to experience favorable changes in depression and depression symptoms.
Depression Essential Reads
Caution is nevertheless required, however. As we have observed from long-term studies of people receiving bariatric surgery—where long-term increases in suicidality have been observed despite early improvements in depressive symptoms8—monitoring mental health changes among GLP-1 agonist users and complementing their use as indicated with mental health treatments remains highly advisable.