The complicated connections between weight loss drugs and mental health

Mental illness can cause or worsen obesity, and obesity can cause or worsen mental illness. As an endocrinologist (Jody) and a psychiatrist (Karen), we know this connection better than most people, so we have long checked in with each other to help our mutual patients. Until recently, a quick curbside chat would do, asking, “Can I add bupropion if this patient is taking another antidepressant?” or, “What should I use next, if metformin is not helping with weight loss in a patient taking an atypical antipsychotic?”

With the rise of GLP-1s, our menu of treatment options increased, but so have questions about whether these medications can help patients’ mental health or hurt it. Patients now ask Jody: “Will Wegovy make my depression worse?” And they ask Karen: “Can I take Wegovy now that I’ve gained 50 pounds on the antipsychotic?”

While we wait for more data to clarify the relationship between GLP-1s and mental health, it is crucial for endocrinologists — who prescribe most of these drugs — and psychiatrists to work together to address the tangled connections between body weight and mental health. An endocrinologist needs a psychiatrist’s expertise from the top down, and a psychiatrist needs an endocrinologist’s expertise from the body up.

The best-known of the GLP-1s are semaglutide (Wegovy and Ozempic), liraglutide (Saxenda and Victoza), and dulaglutide (Trulicity). Tirzepatide (Zepbound and Mounjaro) is a newer molecule in the same family. These medications can be both highly effective and highly polarizing when taken for weight loss: They are FDA-approved for the long-term treatment of obesity, yet there are some who — wrongly — judge their use as “cheating” in the quest to lose weight.

Their effect on mental health remains unclear. Prescribing guidelines for several GLP-1s warn about risk of suicidal thoughts and self-injury, and the FDA Adverse Event Reporting System (FAERS) identified a “signal” that linked the GLP-1s and suicidality. However, a signal does not denote cause and effect, but rather calls for further investigation of the association between the medication and the reported side effect. The FDA has so far not identified a causal link between GLP-1s and suicidal thoughts or actions, and after evaluating all adverse events reported to FAERS for GLP-1s, a Canadian group concluded in an October 2023 paper that no causal link between GLP-1s and suicidality exists.

Figuring out whether the adverse effect is caused by the drug or by the underlying illness the drug is prescribed to treat can be thorny. Obesity itself can lead to depression and anxiety, which can sometimes lead to suicidal thoughts and actions. We also know that, despite their proven effectiveness overall, some people are non-responders to one or more GLP-1s. Expectations are always high at the start of treatment, so when disappointment and discouragement are piled on top of depression, the next step can be despair.

One more twist that you might not expect: We have observed that some super responders are not quite sure how to live in their body after losing, say, 100 pounds; a person with PTSD who has felt protected against harm from others by high body weight may feel vulnerable without that layer of protection. Without excess weight, some people feel exposed as never before.

Looking at the obesity/mental health connection from the other direction, the most common disorders, including depression, anxiety, and PTSD, can all affect eating behaviors, and many of the lifesaving medications to treat these disorders cause significant weight gain. People who are already stigmatized due to mental health diagnoses face double jeopardy when they also have obesity: Social isolation may worsen due to poor self-esteem and shame related to their weight. Just as using substances of abuse can be a way of self-medicating the symptoms of mental illness, so too can overeating, as the two share some of the same brain biology. As a general adult psychiatrist, Karen hears from her patients that bingeing has a dissociative aspect — numbing or distracting from painful feelings, thoughts, memories, and symptoms. The phrase “swallowing one’s feelings” comes to mind.

There is still so much we don’t know about the psychiatric effects of GLP-1s. Despite reports of suicidality to the FAERS, a very large cross-sectional study conducted by the National Institutes of Health and Case Western Reserve, published in January 2023, showed a lower risk for suicidal ideation in those taking semaglutide compared with non-GLP-1 pharmacotherapy for obesity or diabetes. In fact, there is now emerging data that GLP-1s may be neuroprotective by a variety of mechanisms, especially with respect to depression, substance use disorders, and cognitive function.

Additional observational data and interventional studies will help us understand the complex relationship between GLP-1s and mental health. In the meantime, conversations and close collaborations between doctors who treat the body and doctors who treat the mind will help patients. It is tough for busy internists to focus in on their patients’ psychiatric challenges, but physicians who specialize in the physical aspect of medical weight management need to understand what it takes to treat the mind: Patients with depression, anxiety, schizophrenia, bipolar disorder, and/or PTSD cannot stop or change their weight-promoting psychiatric medications without illness recurrence. Psychiatrists may try to treat their patients with weight-neutral medicines, but often the ones that turn out to be most effective cause a profound and difficult-to-treat increase in body weight. Psychiatrists then struggle to treat mental illness without causing or worsening medical illness.

Antipsychotics have the greatest capacity to cause weight gain, followed by many antidepressants and mood stabilizers. And some patients need to take all three types for symptom relief. People with mental illness die an average of 10 years younger than people without it — much more often from medical causes than from suicide. Antipsychotic medications in particular can cause metabolic syndrome (the five signs of which are excess abdominal weight, hypertriglyceridemia, low HDL cholesterol, elevated blood sugar, and high blood pressure), which increases a person’s risk for cardiac disease, stroke, and type 2 diabetes. There are new data indicating that the GLP-1s decrease the risk of heart attack and stroke in people with heart disease who have overweight or obesity.

Psychiatrists are learning that the GLP-1s are typically the only really effective medications for obesity in patients with mental health disorders. With guidance from their endocrinologist colleagues, some psychiatrists are starting to prescribe the GLP-1s to their patients. With weight loss comes a notable brightening of mood and lifting of anxiety. As people invariably start to feel better about themselves, we watch them get promoted at work, increase socialization, and improve relationships. Quality of life dramatically improves in many ways. These psychological effects, as well as their direct effects on the brain, may well account for the decrease in suicidality shown in the large study of GLP-1s.

The bottom line is that as GLP-1s produce weight loss, they simultaneously treat the depressive symptoms, shame, and low self-esteem that come from having been discriminated against. Though we may not yet have clear answers about the specific effects of GLP-1s on mental health, we know from the patients we share that the arrows connecting obesity and mental illness point in both directions. Given the high acuity and time constraints of our practices, it is easy to overlook these double arrows, but our patients, doubly stigmatized, need our combined areas of expertise to determine the best path forward.

Jody Dushay, M.D., MMSc, is an endocrinologist at the Beth Israel Deaconess Medical Center and assistant professor of medicine at Harvard Medical School. She is also the founder and director of Wellpowered, a comprehensive wellness and weight management program. Karen S. Greenberg, M.D., is a psychiatrist affiliated with the Beth Israel Deaconess Medical Center and instructor, part-time, at Harvard Medical School. She is also an alumna of the Harvard Medical School Center for Bioethics fellowship.

If you or someone you know may be considering suicide, contact the 988 Suicide & Crisis Lifeline: call or text 988 or chat 988lifeline.org. For TTY users: Use your preferred relay service or dial 711 then 988.