PeptideJournal
Guides14 min read

Peptides for Depression Research Overview

Standard antidepressants work for many people. But roughly one-third of patients with major depressive disorder (MDD) never reach full remission with first-line medications like SSRIs [1]. Side effects — weight gain, sexual dysfunction, emotional blunting — push others to quit treatment altogether.

Standard antidepressants work for many people. But roughly one-third of patients with major depressive disorder (MDD) never reach full remission with first-line medications like SSRIs [1]. Side effects — weight gain, sexual dysfunction, emotional blunting — push others to quit treatment altogether. And the weeks-long delay before these drugs take effect leaves a gap that matters when someone is in crisis.

These shortcomings have pushed researchers toward a question that would have sounded strange a decade ago: can peptides treat depression?

The answer is not yet clinical. No peptide is FDA-approved for depression. But the preclinical and early clinical evidence is substantial enough to warrant attention. Neuropeptides regulate stress responses, social bonding, neurotransmitter balance, and the gut-brain axis — all systems that go wrong in depression. Targeting them offers a fundamentally different approach from the monoamine hypothesis that has dominated antidepressant development for 60 years.

Here is what the research actually shows.

Table of Contents

Why Peptides for Depression? The Scientific Rationale

Most antidepressants target monoamine neurotransmitters — serotonin, norepinephrine, dopamine. But monoamines are downstream signals. Depression involves disruptions in systems above them: the hypothalamic-pituitary-adrenal (HPA) axis, neuroplasticity pathways, inflammatory cascades, and gut-brain communication.

Neuropeptides operate across all of these systems. They act on specific receptor subtypes, which means peptide-based therapies could target the circuits that matter while leaving the rest of the brain alone [1]. The systems most implicated in depression include corticotropin-releasing hormone (CRH), which drives the stress response; neuropeptide Y (NPY), which counterbalances it; oxytocin, which regulates social bonding; and the serotonergic/dopaminergic modulators like Selank and Semax.

Selank: The Anxiolytic Peptide With Antidepressant Properties

Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) is a synthetic heptapeptide derived from tuftsin, an endogenous immune-modulating peptide. Developed at the Institute of Molecular Genetics of the Russian Academy of Sciences, Selank has been studied for anxiety and mood disorders for over two decades.

Mechanism of Action

Selank works primarily through the GABAergic system, increasing GABA release and reducing neuronal excitability. Researchers analyzed 84 neurotransmission genes in rat frontal cortex after Selank administration and found significant changes in 45 genes at one hour, many correlating positively with the effects of GABA itself [2]. Selank also modulates serotonin metabolism, affecting enzymes involved in serotonin synthesis and degradation — which may explain its antidepressant properties beyond simple anxiolysis.

Clinical Evidence

Clinical studies in patients with generalized anxiety disorder have shown that Selank's anxiolytic effect is comparable to low-dose benzodiazepines — without the sedation, dependence, or withdrawal that make benzodiazepines problematic for long-term use [3]. In chronic mild stress models (an established animal model for depression), Selank reduced elevated anxiety levels more effectively than diazepam alone. Combining Selank with diazepam produced the strongest effect, suggesting that Selank modulates benzodiazepine receptors allosterically [4].

The antidepressant, antistress, and anti-aggression effects observed in clinical settings make Selank particularly interesting for depression that presents with prominent anxiety — which is most depression, given the high comorbidity between the two conditions.

Limitations

Selank is not FDA-approved and has not been tested in large-scale Western clinical trials. Most clinical evidence comes from Russian research, and while the quality of individual studies is reasonable, independent replication in larger populations is needed.

Semax: BDNF, Dopamine, and Neuroplasticity

Semax is a synthetic analog of ACTH(4-10), the fragment of adrenocorticotropic hormone that affects the brain without stimulating the adrenal glands. It was developed alongside Selank and has been studied primarily for cognitive function and neuroprotection.

Why It Matters for Depression

Depression is increasingly understood as a disorder of neuroplasticity. Brain-derived neurotrophic factor (BDNF) drives neuroplasticity, and BDNF levels are consistently reduced in depressed patients. Most effective antidepressants — SSRIs, ketamine — raise BDNF levels, which may be their actual mechanism of action [5].

Semax increases BDNF expression and raises dopamine levels. This dual action addresses both the neuroplasticity deficit and the motivational symptoms (anhedonia, low drive) that SSRIs often miss.

Brain Imaging Evidence

Functional MRI in 52 healthy participants showed that Semax altered connections between the amygdala and temporal cortex, and increased activation in the default mode network [6] — precisely the circuits that show abnormal activity in depression.

Semax is approved in Russia for cognitive disorders and stroke recovery but has not undergone FDA-standard trials for depression. Its dual action on BDNF and dopamine makes it worth watching for depression subtypes characterized by low motivation and cognitive impairment.

Oxytocin: Adjunctive Therapy for Treatment-Resistant Depression

Oxytocin is best known as the "bonding hormone," but its mood role runs deeper. Oxytocin receptors are distributed throughout the limbic system, and oxytocin directly inhibits the HPA axis — the stress-response system that is chronically overactivated in depression [7].

Clinical Trial Evidence

Combined with antidepressants: In 14 patients with treatment-resistant depression unresponsive to escitalopram, adding 16 IU of intranasal oxytocin daily for four weeks produced significant reductions in depression scores (p<0.01), anxiety (p=0.04), and clinical severity (from 4.3 to 2.0) [8].

Combined with psychotherapy: A double-blind RCT tested 24 IU intranasal oxytocin before each of 16 therapy sessions for MDD. Oxytocin improved therapeutic alliance and produced greater symptom reductions than placebo. A meta-analysis found a large effect size (d = -1.58) for oxytocin-augmented psychotherapy [9].

Across subtypes: Oxytocin works best in MDD without comorbid borderline personality disorder, and shows promise for postpartum depression [10].

Limitations

A critical question remains unresolved: does enough intranasal oxytocin reach the brain to produce meaningful effects? Sample sizes remain small and results sometimes inconsistent. Oxytocin's value appears to be in amplifying other treatments, not as a standalone antidepressant.

BPC-157: The Gut-Brain Axis Connection

BPC-157 enters the depression conversation through the gut-brain axis — the bidirectional communication system between the gastrointestinal tract and the central nervous system. This is relevant because gut dysfunction is increasingly recognized as both a contributor to and consequence of depression.

Neurotransmitter Modulation

BPC-157 modulates the same neurotransmitter systems that go wrong in depression. A single dose alters serotonin synthesis rates across multiple brain regions — reducing synthesis in some areas while increasing it in others [11]. It also counteracts dopamine disruptions caused by amphetamines and neuroleptics, appearing to restore balance rather than simply pushing levels one direction. The peptide has shown antidepressant-like and anxiolytic effects in animal models through simultaneous central and peripheral actions [11].

Serotonin Syndrome Protection

BPC-157 may fully counteract serotonin syndrome in animal models [12] — a potentially fatal complication of antidepressant therapy. A peptide that modulates serotonin adaptively could theoretically provide a safety net for patients on serotonergic drugs.

Evidence Gap

All BPC-157 depression research is preclinical. No human trials have been conducted for any psychiatric indication. The pathways are promising, but clinical trials have not yet happened.

GLP-1 Receptor Agonists: Metabolic Drugs With Mood Effects

Semaglutide and other GLP-1 receptor agonists were developed for diabetes and obesity. Their potential effects on depression emerged as a secondary finding — and the picture is complicated.

Evidence for Antidepressant Effects

A systematic review and meta-analysis found that adults treated with GLP-1 receptor agonists showed significant reductions in depression scores compared to controls [13]. A 2025 analysis in Nature Mental Health compiled 278 preclinical and 96 clinical studies, finding consistent preclinical evidence for mood benefits [14]. The mechanisms are plausible: GLP-1 receptors sit in mood-regulating brain regions, and GLP-1 drugs reduce neuroinflammation and improve brain insulin signaling.

Evidence for Psychiatric Risk

Pharmacovigilance data tells a different story. A VigiBase study found significant signals for depressed mood (adjusted reporting odds ratio: 1.70) and suicidality (aROR: 1.45) with semaglutide [15]. A large cohort study found GLP-1 receptor agonist treatment associated with a 195% higher risk of major depression diagnosis [16].

Making Sense of Contradictions

Obesity and diabetes — the conditions GLP-1 drugs treat — are themselves risk factors for depression. Rapid weight loss can trigger mood changes. The honest answer: GLP-1 receptor agonists probably help some people's mood (especially those with metabolic depression) while worsening it in others. Identifying who benefits is the critical next step.

Neuropeptide Y: Stress Resilience in a Molecule

Neuropeptide Y (NPY) is the most abundant neuropeptide in the human brain. It acts as a natural counterbalance to stress — dampening the fear response, reducing anxiety, and promoting emotional resilience. People with higher NPY levels cope better with trauma. People with lower levels are more vulnerable to depression and PTSD [17].

Human Evidence

Postmortem brain studies of depressed suicide victims show significantly decreased NPY expression and protein levels in the prefrontal cortex and hippocampus, with compensatory upregulation of NPY receptors [18]. Genetic variants that produce higher NPY levels appear protective against depression even when environmental risk factors are present.

The First Clinical Trial for Depression

In the first controlled trial of NPY for MDD, 30 patients on stable antidepressant regimens received either 6.8 mg intranasal NPY or placebo. Effects were measured at baseline and at 1, 5, 24, and 48 hours post-administration. The intranasal NPY group showed reductions in depression severity on the Montgomery-Asberg Depression Rating Scale, building on a previous study that demonstrated intranasal NPY reduced PTSD symptoms [19].

Challenges

NPY faces the same delivery challenges as most neuropeptides: it does not cross the blood-brain barrier easily, has a short half-life in the body, and is expensive to manufacture. Intranasal delivery partially addresses the first problem, but developing stable, long-acting NPY analogs remains a pharmacological hurdle.

DSIP: Sleep, Stress, and Mood Regulation

DSIP (delta sleep-inducing peptide) was first isolated from rabbit brain blood in 1974. Its name describes its original discovery — it induces the slow-wave delta sleep that is restorative and often disrupted in depression.

Connection to Depression

DSIP levels in cerebrospinal fluid and plasma are altered in patients with major depression, with most studies finding lower concentrations than in healthy controls [20]. Since sleep disruption is both a symptom and a driver of depression, a peptide that normalizes sleep architecture could theoretically break this cycle.

In an open study of 7 patients with severe insomnia, a course of 10 DSIP injections normalized sleep in 6 of 7 patients for follow-up periods of 3-7 months. Daytime mood and performance improved alongside sleep quality [21]. DSIP also reduces cortisol levels when elevated and increases hypothalamic substance P — a neuropeptide involved in mood and anxiety regulation.

Limitations

DSIP research peaked in the 1980s and 1990s and has since declined. Clinical trial results for insomnia have been inconsistent. No receptor or precursor peptide has been identified, which limits understanding of how DSIP works. It remains far from clinical use for depression.

Other Neuropeptide Targets Under Investigation

Several additional neuropeptide systems are under active investigation for depression:

Substance P / NK1 receptor antagonists: Substance P levels are elevated in depression. NK1 receptor antagonists showed initial promise in clinical trials, though results have been mixed in larger studies [1].

Vasopressin V1B receptor antagonists: Depression with elevated plasma vasopressin correlates with anxiety and psychomotor retardation. Phase II trials are testing oral V1B antagonists in SSRI-resistant patients [1].

CRH receptor antagonists: Corticotropin-releasing hormone drives the HPA axis hyperactivation seen in depression. CRH receptor antagonists have been tested in clinical trials, though liver toxicity issues have slowed development.

Urocortin 3 analogs: Short synthetic analogs of urocortin 3 have shown antidepressant effects in animal models by inhibiting CRF-mediated stress responses [22].

For a broader look at peptides that address the anxiety component of depression, see our guide on best peptides for anxiety and stress. For cognitive symptoms that often accompany depression, see best peptides for cognitive enhancement.

Comparison Table: Peptides for Depression Research

PeptidePrimary MechanismEvidence LevelDelivery RouteKey AdvantageKey Limitation
SelankGABAergic modulation; serotonin regulationClinical studies (Russia)IntranasalAnxiolytic without sedation or dependenceLimited Western clinical data
SemaxBDNF upregulation; dopamine modulationPreclinical + early clinicalIntranasalTargets neuroplasticity and motivationNot tested specifically for depression in RCTs
OxytocinHPA axis inhibition; social bondingMultiple RCTs (small)IntranasalAmplifies psychotherapy and antidepressantsBrain penetration debated; small samples
BPC-157Serotonin/dopamine modulation; gut-brain axisPreclinical onlyOral/injectionMulti-system action; serotonin syndrome protectionNo human depression trials
SemaglutideNeuroinflammation reduction; metabolic improvementLarge observational + RCTsInjectionAlready FDA-approved for other conditionsContradictory psychiatric safety data
NPYStress resilience; anxiolytic1 controlled MDD trialIntranasalAddresses stress biology directlyShort half-life; delivery challenges
DSIPSleep normalization; cortisol reductionSmall clinical studiesInjectionTargets sleep-depression linkInconsistent results; declining research

Limitations and Practical Considerations

No peptide is approved for depression. Every peptide discussed here is either investigational, approved for other conditions, or available only as a research compound. Self-treating depression with unregulated peptides is not a substitute for evidence-based psychiatric care.

Depression is not one disease. The melancholic subtype (profound sadness, guilt, early-morning waking) may respond to different peptide approaches than the atypical subtype (oversleeping, overeating, rejection sensitivity) or the anxious subtype. Future research will likely match peptide therapies to depression subtypes.

Combination approaches look more promising than monotherapy. The strongest clinical signals — oxytocin with psychotherapy, Selank with diazepam, NPY added to existing antidepressants — involve peptides as adjuncts rather than replacements. This fits with what we know about depression biology: it involves multiple systems, and single-target approaches often fall short. For more on combining peptides, see our peptide stacking guide.

The gut-brain axis is worth watching. The connection between BPC-157, gut health, and mood regulation points toward an emerging understanding that depression may have gastrointestinal contributors that traditional psychiatry has overlooked. Food-derived peptides that modulate gut microbiota and BDNF signaling represent yet another avenue of research [23].

If you are struggling with depression, the most important step remains connecting with a qualified mental health professional. Peptide research offers hope for future treatments, but the treatments available today — therapy, medication, lifestyle interventions — remain the foundation of care.

FAQ

Which peptide has the most evidence for depression treatment? Intranasal oxytocin has the most human clinical trial data, with multiple randomized controlled trials showing it improves outcomes when combined with antidepressants or psychotherapy. However, sample sizes remain small and results are not always consistent.

Can Selank or Semax replace antidepressants? No evidence supports using either as a replacement. Selank shows anxiolytic effects comparable to low-dose benzodiazepines, and Semax raises BDNF and dopamine, but neither has been tested in large-scale depression trials. Both are more realistically positioned as potential adjuncts.

Does semaglutide help or hurt depression? Possibly both. Clinical trial data suggests mood improvements in people with metabolic conditions, but pharmacovigilance data shows increased depression and suicidality reports. If you are on a GLP-1 medication and notice mood changes, talk to your prescriber.

Is BPC-157 an antidepressant? In animal models, BPC-157 shows antidepressant-like effects through serotonin and dopamine modulation. No human studies have tested this. It would be inaccurate to call it an antidepressant at this stage.

How does neuropeptide Y differ from SSRIs? SSRIs increase serotonin availability. NPY directly counteracts the stress response by dampening HPA axis activation and reducing amygdala reactivity — addressing stress biology rather than monoamine chemistry. This makes it especially relevant for stress- or trauma-triggered depression.

Are peptide treatments for depression available now? Not as approved depression treatments. Intranasal oxytocin is used off-label in some clinical settings. Selank and Semax are available as research compounds in some countries. GLP-1 drugs are widely prescribed for metabolic conditions. None should be used for depression without medical supervision.

The Bottom Line

The peptide approach to depression represents something genuinely new: instead of flooding the brain with more serotonin or norepinephrine and hoping the downstream effects help, peptide therapies target the upstream systems — stress signaling, neuroplasticity, social bonding, gut-brain communication — where depression often originates.

The research is still early. Oxytocin leads with the most human data, showing consistent benefits as an adjunct to therapy and medication. Selank and Semax offer intriguing mechanisms that target GABA, BDNF, and dopamine through pathways current antidepressants miss. NPY addresses the stress resilience deficit that underpins much of depression. And BPC-157's gut-brain axis work hints at entirely new ways of thinking about mood disorders.

None of this is ready for the pharmacy shelf. But for the millions of people who do not get adequate relief from existing antidepressants, these peptides represent something worth tracking: a different set of biological tools aimed at different biological problems. The next five years of clinical trials will determine which of them makes the jump from promising research to practical treatment.

References

  1. Griebel, G., & Holsboer, F. (2012). "Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?" Nature Reviews Drug Discovery, 11(6), 462-478. PubMed

  2. Volkova, A., et al. (2016). "Selank Administration Affects the Expression of Some Genes Involved in GABAergic Neurotransmission." Frontiers in Pharmacology, 7, 31. PMC4757669

  3. Zozulia, A.A., et al. (2008). "Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia." Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova, 108(4), 38-48.

  4. Seredenin, S.B., et al. (2017). "Peptide Selank Enhances the Effect of Diazepam in Reducing Anxiety in Unpredictable Chronic Mild Stress Conditions in Rats." Bulletin of Experimental Biology and Medicine, 162(6), 756-760. PMC5322660

  5. Duman, R.S., & Monteggia, L.M. (2006). "A neurotrophic model for stress-related mood disorders." Biological Psychiatry, 59(12), 1116-1127.

  6. Lebedeva, I.S., et al. (2020). "Functional Connectomic Approach to Studying Selank and Semax Effects." Doklady Biological Sciences, 490(1), 9-11. PubMed

  7. Neumann, I.D., & Slattery, D.A. (2016). "Oxytocin in General Anxiety and Social Fear: A Translational Approach." Biological Psychiatry, 79(3), 213-221.

  8. Scantamburlo, G., et al. (2015). "Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: an open trial." Journal of Psychiatric Research, 61, 7-10. PubMed

  9. Perini, G., et al. (2024). "Could intranasal oxytocin enhance the effects of psychotherapy in individuals with mental disorders? A systematic review and meta-analysis." Psychotherapy and Psychosomatics. PubMed

  10. Kim, E.J., et al. (2025). "Effects of Intranasal Oxytocin Across Various Depressive Disorders." Psychiatry Investigation, 22(9), 964-974. PubMed

  11. Sikiric, P., et al. (2016). "Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications." Current Neuropharmacology, 14(8), 857-865. PMC5333585

  12. Sikiric, P., et al. (2021). "Pentadecapeptide BPC 157 and the central nervous system." Neural Regeneration Research, 17(3), 482-487. PMC8504390

  13. Pozzi, M., et al. (2023). "The Antidepressant Effects of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis." American Journal of Geriatric Psychiatry. PubMed

  14. De Giorgi, R., et al. (2025). "An analysis on the role of glucagon-like peptide-1 receptor agonists in cognitive and mental health disorders." Nature Mental Health. Link

  15. Martinotti, G., et al. (2025). "Psychiatric and psychological adverse effects associated with dulaglutide, semaglutide, and liraglutide: A vigibase study." Clinical Nutrition. Link

  16. Hossain, M., et al. (2024). "The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon like peptide-1 receptor agonist therapy." Scientific Reports, 14, 23919. Link

  17. Enman, N.M., et al. (2015). "Targeting the neuropeptide Y system in stress-related psychiatric disorders." Neurobiology of Stress, 1, 33-43. PMC4260418

  18. Sharma, A., et al. (2022). "Effect of depression and suicidal behavior on neuropeptide Y (NPY) and its receptors in the adult human brain: A postmortem study." Progress in Neuro-Psychopharmacology and Biological Psychiatry, 112, 110428. PMC8489679

  19. Murrough, J.W., et al. (2020). "Randomized Controlled Trial of Intranasal Neuropeptide Y in Patients With Major Depressive Disorder." International Journal of Neuropsychopharmacology, 23(12), 783-790. Link

  20. ScienceDirect. "Delta-Sleep-Inducing Peptide." Neuroscience Topics Overview. Link

  21. Schneider-Helmert, D. (1985). "A clinical trial with DSIP." European Neurology, 24(2), 144-148. PubMed

  22. Telegdy, G., et al. (2014). "Short analogs and mimetics of human urocortin 3 display antidepressant effects in vivo." Peptides, 62, 59-65. PubMed

  23. Chen, Y., et al. (2025). "The potential of food-derived peptides in alleviating depressed mood: Function, evaluation and mechanism." Food Research International. PubMed