ALTO-203

Overview

ALTO-203 is a histamine H3 receptor inverse agonist which is under development for the treatment of major depressive disorder with anhedonia. It was also under development for other psychiatric disorders and neurodegenerative disorders, but development for these indications was discontinued. The drug is taken orally. It has been found to increase dopamine release in the nucleus accumbens and produce antianhedonic-like effects in rodents, effects which another histamine H3 receptor inverse agonist, pitolisant, did not produce. ALTO-203 is under development by Alto Neuroscience. As of July 2025, it is in phase 2 clinical trials for major depressive disorder. In a phase 1 trial, ALTO-203 was reported to increase subjective positive mood to a similar degree as modafinil. On the other hand, the drug failed to meet its primary endpoint, a measure of mood and alertness, compared to placebo in a phase 2 trial.

ALTO-203
Clinical data
Other namesALTO203
Routes of
administration		Oral[1]
Drug classHistamine H3 receptor inverse agonist

ALTO-203 is a histamine H3 receptor inverse agonist which is under development for the treatment of major depressive disorder with anhedonia.[1][2][3][4][5] It was also under development for other psychiatric disorders and neurodegenerative disorders, but development for these indications was discontinued.[1] The drug is taken orally.[1] It has been found to increase dopamine release in the nucleus accumbens and produce antianhedonic-like effects in rodents, effects which another histamine H3 receptor inverse agonist, pitolisant, did not produce.[5] ALTO-203 is under development by Alto Neuroscience.[1][2] As of July 2025, it is in phase 2 clinical trials for major depressive disorder.[1][2] In a phase 1 trial, ALTO-203 was reported to increase subjective positive mood to a similar degree as modafinil.[6] On the other hand, the drug failed to meet its primary endpoint, a measure of mood and alertness, compared to placebo in a phase 2 trial.[7][8]

See also

References

  1. 1 2 3 4 5 6 "ALTO 203". AdisInsight. 7 July 2025. Retrieved 5 June 2026.
  2. 1 2 3 "Synapse". synapse.patsnap.com.
  3. ↑ Cooper N, Jordan J, Huys Q, Hajcak G, Avissar M, Powell J, et al. (December 2024). "Validation of assessments for reward processing, positive emotion, and anhedonia for use in a phase 2 study of a novel histamine H3 inverse agonist, ALTO-203, in major depression". Neuropsychopharmacology. 49: 505–506.
  4. ↑ Jordan J, Shen L, Ravindran A, Sundar G, Wang C, Etkin A, et al. (January 2026). "Prospective replication of an EEG biomarker for predicting changes in attention in ALTO-203, an H3 inverse agonist". Neuropsychopharmacology. 51 (Suppl 1).
  5. 1 2 Shen L, Guo Y, Ferreira da Silva M, Ravindran AS, Wang C, Savitz AJ, et al. (2025). ALTO-203, a Novel Histamine H3 Inverse Agonist, Increase Sucrose Preference in Dopamine-depleted Rats (PDF). Society of Biological Psychiatry's 2025 Meeting.
  6. ↑ Cooper NJ, Jordan JT, Huys QJ, Hajcak G, Avissar M, Powell J, et al. (2024). Effects of ALTO-203 on positive emotion and reward processing: methods and supporting data for an ongoing phase 2 proof-of-concept study (PDF). European College of Neuropsychopharmacology (ECNP) 2024.
  7. ↑ Taylor NP (26 June 2025). "Alto misses primary efficacy endpoint in phase 2 depression trial". Fierce Biotech. Retrieved 5 June 2026.
  8. ↑ Kuntz L (5 June 2026). "ALTO-203 Fails to Meet Primary Efficacy Endpoint in Phase 2 Major Depressive Disorder Trial". Psychiatric Times. Retrieved 5 June 2026.

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