GLP-1 medications have changed the treatment of obesity and diabetes remarkably quickly. Semaglutide, tirzepatide, liraglutide, and newer medications are now used by millions of patients, which means psychiatric clinicians are increasingly encountering them on medication lists.
As the numbers continue to increase, I've started to notice something.
In a small number of patients taking GLP-1 medications, I've noticed what appears to be increased irritability, particularly early in treatment. A few patients have also seemed somewhat less animated or emotionally flat.
☕️ Have you seen this in your practice?
I cannot prove it based on current research, but the timing is suspicious. When millions of people take a medication, clinicians will inevitably see symptoms occurring at the same time that may have nothing to do with the drug.
But it made me curious enough to ask a more useful question:
Do GLP-1 medications cause depression?
The best available randomized evidence does not show that GLP-1 receptor agonists increase depression.
The largest and best-designed synthesis to date is a systematic review and meta-analysis of 80 randomized controlled trials involving 107,860 participants (Pierret et al., JAMA Psychiatry, 2025). Compared with placebo, GLP-1 receptor agonists were not associated with an increased risk of serious psychiatric adverse events (which included major depression, suicidality, and psychosis) or non serious psychiatric adverse events (anxiety and insomnia) and showed no difference in change in depressive symptom severity.
A frequently cited dataset comes from a post hoc psychiatric safety analysis of the STEP 1, 2, 3, and 5 semaglutide trials (Wadden et al., JAMA Internal Medicine, 2024). Researchers examined depressive symptoms using the PHQ-9 and suicidal thoughts and behaviors using the Columbia-Suicide Severity Rating Scale across several thousand participants. They did not find an increased risk of clinically significant depression or suicidal ideation with semaglutide 2.4 mg compared with placebo. PHQ-9 scores actually shifted slightly in favor of semaglutide, but the authors emphasized the difference was small and not clinically meaningful.
What do newer studies show?
A 2026 systematic review and meta-analysis of randomized trials (Hung et al., Human Psychopharmacology, 2026) examined GLP-1 receptor agonists and psychological outcomes. Twenty-five trials involving 17,751 participants evaluated psychological well-being, and 11 trials involving 1,961 participants evaluated depressive symptoms.
GLP-1 treatment was associated with a small but significant improvement in overall psychological well-being (standardized mean difference 0.374). For depressive symptoms specifically, there was no significant effect (standardized mean difference 0.079).
In other words, the accumulated randomized evidence does not currently support the idea that GLP-1 medications routinely worsen depression. If anything, some measures lean slightly in the opposite direction.
What about anxiety and suicidality?
These concerns received considerable regulatory attention as GLP-1 use expanded, prompting reviews by both the European Medicines Agency and the U.S. Food and Drug Administration.
The controlled evidence so far is reassuring. The 80-trial meta-analysis found no increased risk of psychiatric adverse events, and a 2026 meta-analysis of randomized trials found no increased risk across nine separate psychiatric outcomes, with no significant differences between individual agents (Han et al., Diabetes, Obesity and Metabolism, 2026). Regulators reached similar conclusions: the EMA stated that available evidence does not support a causal association between GLP-1 receptor agonists and suicidal or self-injurious thoughts and actions, and the FDA found no evidence that these medicines cause suicidal thoughts or actions—while noting a small risk could not be definitively excluded given the low number of events.
The picture from spontaneous-reporting (pharmacovigilance) databases is less uniform. A VigiBase disproportionality study (Nishida et al., Clinical Nutrition, 2025) found no overall increase in psychiatric reporting for GLP-1 receptor agonists as a class, but did detect significant signals for anxiety, depressed mood, and suicidality specifically with semaglutide, as well as eating-disorder signals across agents. A large retrospective cohort using the TriNetX database (Kornelius et al., Scientific Reports, 2024) similarly reported higher risks of depression, anxiety, and suicidal behavior. The most defensible summary is that a clear increased psychiatric risk has not been detected in controlled data, rather than that such a risk has been definitively excluded.
Why is psychiatry interested in GLP-1 drugs?
Because GLP-1 medications don't act exclusively on the gastrointestinal tract.
GLP-1 receptors and GLP-1 signaling are present in the central nervous system, including the hypothalamus, brainstem, hippocampus, and mesolimbic reward regions such as the ventral tegmental area and nucleus accumbens. These circuits are involved in appetite, motivation, reinforcement, and reward (Guo et al., Journal of Neuroscience, 2025; Giannakogeorgou and Roden, Alimentary Pharmacology and Therapeutics, 2024).
People taking GLP-1 medications frequently describe a dramatic reduction in "food noise." Cravings decrease. The drive to seek highly rewarding foods may diminish. A 2026 cross-sectional study of adults with obesity found that six-month GLP-1 users had significantly lower food-noise scores, cue responsivity, cravings, and food reward than pre-use controls (Rutigliani and Mattes, Physiology and Behavior, 2026).
This isn't simply a smaller stomach. There appears to be a neurological impact.
A systematic review of human studies found that GLP-1 receptor agonists consistently reduce energy intake and alter reward-related behavior, with decreased neurocortical activation in response to food cues, particularly high-calorie foods (Badulescu et al., Physiology and Behavior, 2024). Functional MRI studies show reduced activation in reward-related regions in response to anticipated palatable food (van Bloemendaal et al., Diabetes, Obesity and Metabolism, 2015).
Researchers are also actively investigating GLP-1 medications for substance-use disorders, because these same reward mechanisms may extend beyond food. Preclinical models consistently show reduced drug intake and craving, and early randomized trials suggest semaglutide reduces alcohol consumption in people with alcohol use disorder (Farokhnia and Leggio, JAMA Psychiatry, 2026; Völker et al., Frontiers in Pharmacology, 2025).
Irritability may be easy to miss
This brings me back to what I've noticed clinically.
If GLP-1 medications occasionally contribute to irritability, existing studies may not be well designed to detect it. Irritability is not a validated endpoint in the major GLP-1 trials, and where it appears at all, it is as a spontaneous-reporting term in pharma databases rather than a prospectively measured outcome.
Consider what the major psychiatric safety studies actually measure. The PHQ-9 asks about depressed mood, interest, sleep, energy, appetite, guilt, concentration, psychomotor changes, and suicidal thoughts. The C-SSRS captures suicidal ideation and behavior.
But a patient could score relatively well on a PHQ-9 and still tell you:
"I'm just more irritable since I started this medication."
Or:
"My spouse says I haven't seemed like myself."
What should PMHNPs watch for?
For now, the evidence alone does not support warning patients that GLP-1 medications commonly cause psychiatric symptoms. It does support asking questions, which is also consistent with the FDA-approved labeling, which advises monitoring for the emergence or worsening of depression and suicidal ideation.
☕️ When a patient taking a GLP-1 medication develops a change in mood or behavior, it is useful to establish the timeline:
When was the medication started, and was the dose recently increased?
When did the emotional change begin?
Did appetite and caloric intake fall dramatically?
Has sleep changed?
Is the patient experiencing nausea, dehydration, or episodes suggestive of hypoglycemia?
»Does the patient or family think the patient has changed since treatment began?
The bottom line
Current controlled research does not demonstrate that GLP-1 receptor agonists meaningfully increase the risk of depression, anxiety, or suicidal behavior.
At the same time, GLP-1 medications interact with brain systems involved in reward, motivation, appetite, and reinforcement. That makes their psychiatric effects scientifically interesting and potentially more complicated than whether someone develops major depression.
What we know considerably less about other experiences—irritability, apathy, emotional blunting, or changes in motivation. Those symptoms could turn out to be uncommon medication effects. They could be secondary to caloric restriction, weight loss, metabolic changes, or other consequences of treatment. Or future research may show no meaningful association at all.
For now, my observation remains exactly that: an observation.
☕️☕️ What have you seen amongst your clients, colleagues, friends or family?
Selected references
Badulescu, S., Tabassum, A., Le, G. H., et al. (2024). Glucagon-like peptide 1 agonist and effects on reward behaviour: A systematic review. Physiology & Behavior.
Chen, S. C., Wang, T. J., Chou, C. K., & Lee, C. (2026). Neuropsychiatric outcomes with tirzepatide, semaglutide, and other GLP-1 receptor agonists. Diabetes, Obesity & Metabolism.
Farokhnia, M., & Leggio, L. (2026). Prospects of GLP-1 therapies for addiction and mental health comorbidities—Quo vadis? JAMA Psychiatry.
Guo, J., Hayes, M. R., Leggio, L., Oru, E., & Rinaman, L. (2025). GLP-1 receptor agonists and research to treat overeating and substance use disorders. The Journal of Neuroscience.
Han, S., Yang, Y., Liu, Z., et al. (2026). Association of glucagon-like peptide-1 receptor agonist use with risk of psychiatric disorders: A systematic review and meta-analysis of randomised controlled trials. Diabetes, Obesity & Metabolism.
Healey, N. (2026). Is addiction the next frontier for GLP-1 receptor agonists? Nature Medicine.
Hung, T. H., Chen, C. R., Hsu, C. W., et al. (2026). Efficacy of glucagon-like peptide-1 receptor agonists for psychological well-being and depressive symptoms: A systematic review and meta-analysis of randomized controlled trials. Human Psychopharmacology.
Kornelius, E., Huang, J. Y., Lo, S. C., Huang, C. N., & Yang, Y. S. (2024). The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon-like peptide-1 receptor agonist therapy. Scientific Reports.
Nishida, K., Chrétien, B., Dolladille, C., et al. (2025). Psychiatric and psychological adverse effects associated with dulaglutide, semaglutide, and liraglutide: A VigiBase study. Clinical Nutrition.
Pierret, A. C. S., Mizuno, Y., Saunders, P., et al. (2025). Glucagon-like peptide 1 receptor agonists and mental health. JAMA Psychiatry.
Rutigliani, G., & Mattes, R. D. (2026). The effects of glucagon-like peptide-1 receptor agonists on chemosensory function and ingestive behavior. Physiology & Behavior.
Schifano, F., De Luca, M. A., Bonaccorso, S., et al. (2026). GLP-1 and dual GIP/GLP-1 receptor agonists' psychopharmacology and putative neuropsychiatric associated effects: A Bradford Hill–informed, systematic evaluation. Current Psychiatry Reports.
van Bloemendaal, L., Veltman, D. J., Ten Kulve, J. S., et al. (2015). Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diabetes, Obesity & Metabolism.