Depression: treatment and what peptide research shows

What depression is and how many people have it

Depression is a mood disorder, not passing sadness: according to the WHO, the person experiences depressed mood (feeling sad, irritable, empty) or loss of pleasure or interest in activities, most of the day, nearly every day, for at least two weeks¹. The WHO estimates that 5.2% of adults worldwide have it, about 322 million people, at 6.2% in women and 4.1% in men¹.

Its public health weight is large. In the Global Burden of Disease 2019, mental disorders accounted for 4.9% of all disability-adjusted life years (DALYs) worldwide and 14.6% of years lived with disability². The WHO itself notes that depression can lead to suicide¹.

Symptoms and how it is diagnosed

Beyond low mood or loss of interest, the WHO describes poor concentration, excessive guilt or low self-worth, hopelessness about the future, thoughts about dying or suicide, disrupted sleep, changes in appetite or weight, and feeling very tired¹. Diagnosis is clinical: it rests on the interview, duration and functional impact, and on ruling out other causes. Current guidelines, such as the CANMAT 2023 update, organize the process from assessment to treatment selection with a personalized, shared-decision approach³.

Peptides are not part of that diagnostic process or of the treatment guidelines. What follows describes existing research, not a therapeutic option.

Standard treatment today

According to the WHO, psychological treatments are the first treatments for depression; they can be combined with antidepressants in moderate and severe depression, and antidepressants are not needed for mild depression¹. The CANMAT 2023 guideline includes recommendations for psychological, pharmacological, lifestyle, complementary, digital health and neuromodulation treatments³.

The largest antidepressant comparison available included 522 trials with 116,477 participants: all antidepressants were more effective than placebo, with odds ratios from 1.37 (reboxetine) to 2.13 (amitriptyline)⁴. On acceptability, only agomelatine and fluoxetine were associated with fewer dropouts than placebo, and differences between drugs had wide intervals⁴.

A 2026 network meta-analysis of social functioning (94 trials, 23,874 participants) found that all active treatments outperformed control, that psychotherapy and pharmacotherapy did not differ at the end of treatment (SMD 0.10; 95% CI −0.05 to 0.25), and that the combination showed the largest effects versus placebo (SMD 0.75)⁵.

What peptide research has shown

No peptide has an approved indication for depression. These are the three agents asked about most, and what has been observed.

Intranasal oxytocin. A peptide hormone; its evidence in depression is limited to postpartum depression and small studies. In a double-blind, randomized, within-subject study of 45 mothers with postpartum depression symptoms (35 with a major depressive episode), oxytocin increased maternal positive regard for the child and self-reported positive affect, with no effects on maternal sensitivity, negative mood or physiological measures⁶. In another crossover study of 45 mothers, oxytocin shifted response bias from fear toward sadness and increased accuracy for sad infant faces, with no change in self-reported affect⁷. These are perception and affect outcomes in single sessions, not trials of depressive symptoms with follow-up. Context matters: in the largest intranasal oxytocin trial in childhood autism (290 participants, 24 weeks), the primary outcome did not differ from placebo (P = 0.61)⁸, and a 2016 statistical analysis concluded there is a high probability that many published findings with this route do not represent true effects⁹. More in Intranasal oxytocin: anatomy of a replication crisis.

GLP-1s (semaglutide, liraglutide, tirzepatide). They were not developed for depression; the clinical question is whether they affect mood. A 2024 cohort study using TriNetX records (240,618 patients with overweight or obesity) associated semaglutide with lower risk of incident suicidal ideation (HR 0.27) and recurrent suicidal ideation (HR 0.44; 95% CI 0.32–0.60) versus other anti-obesity drugs, with results replicated in 1,589,855 patients with type 2 diabetes¹⁴. It is an observational study with six months of follow-up, so it does not show causality. A meta-analysis of 25 randomized trials found no difference in suicidal behavior between GLP-1 and control (RR 0.84; 95% CI 0.54–1.32)¹⁵. A 2026 semaglutide meta-analysis that mixed trials, observational studies and pharmacovigilance estimated an RR of 1.25 for depression (95% CI 0.95–1.65; I² = 98%), not statistically significant, with certainty limited by heterogeneity¹⁶. Wider context in GLP-1 beyond weight.

Semax and Selank. Peptide analogs developed in Russia. Selank was compared with medazepam in 62 patients with generalized anxiety disorder and neurasthenia: anxiolytic effects were similar, with additional antiasthenic and psychostimulant effects with Selank; the study did not assess depression as a diagnosis and was published in Russian in 2008¹⁷. For Semax, an ACTH(4-10) analog, the data reviewed are from rats: it reduced anxiety-like behavior and normalized brain amines altered by neonatal fluvoxamine exposure¹⁸. No randomized trial of Semax or Selank in depression was identified. Review in Semax, Selank and DSIP: what the evidence shows.

• Intranasal oxytocin: small postpartum depression trials; effects on affect and perception; no trial with depressive symptoms as the primary outcome. Caution: weak replication in other fields⁶⁷⁸⁹.
• GLP-1s: not antidepressants; the evidence is about safety. Observational studies and trial meta-analyses show no higher suicide risk; the FDA asked to remove the warning in 2026¹³¹⁴¹⁵.
• Semax / Selank: one Russian anxiety trial (Selank) and animal data (Semax). Caution: scarce evidence of limited scope¹⁷¹⁸.

Safety: what regulators say about GLP-1s and mood

In January 2024 the FDA reported that its preliminary evaluation had not found evidence that these medicines cause suicidal thoughts or actions, although it could not rule out a small risk, and it asked clinicians to monitor for new or worsening depression or changes in behavior¹¹. In April 2024 the European Medicines Agency's safety committee (PRAC) concluded that the available evidence does not support a causal association between GLP-1 receptor agonists and suicidal and self-injurious thoughts and actions, and that no update to the product information was warranted¹².

On January 13, 2026, the FDA asked application holders to remove information on the risk of suicidal ideation and behavior from the labels of liraglutide (Saxenda), semaglutide (Wegovy) and tirzepatide (Zepbound), after a review that found no increased risk associated with use of these agonists¹³. Patients with depression who use these drugs for another indication still need individual clinical follow-up¹¹.

For oxytocin, Semax and Selank, the studies reviewed do not provide a safety profile in depression from which to draw conclusions; samples are small and follow-up is short⁶⁷¹⁷.

Frequently asked questions

Is any peptide approved for depression? Not according to the sources reviewed: treatment guidelines center on psychological therapies and antidepressants, and no peptide appears among the approved options¹³⁴.

Does oxytocin work for depression? It has not been shown. There are small postpartum depression studies showing effects on positive affect and recognition of infant emotions in a single session, with no effect on maternal sensitivity or physiological measures in one of them⁶⁷.

Do GLP-1s increase the risk of depression or suicide? The available evidence does not show an increase: the FDA found no higher risk in its 2026 review and the PRAC found no causal association in 2024¹²¹³. A meta-analysis of 25 trials also found no difference (RR 0.84)¹⁵.

Do GLP-1s reduce suicidal ideation? One cohort study associated them with lower risk (HR 0.27 for incident ideation), but it is observational and does not show causality¹⁴.

What is known about Semax and Selank in depression? Little: there is one Russian trial of Selank in generalized anxiety and neurasthenia, and rat data with Semax; no randomized trial in depression was identified¹⁷¹⁸.