ALTO-203 for Major Depressive Disorder and Anhedonia: Phase 2 Study Initiated


New phase 2 study initiated to determine the potential of ALTO-203 as an antidepressant in patients with major depressive disorder and anhedonia.



Alto Neuroscience has initiated its phase 2 double-blind, single- and multiple-dose study to determine the potential of ALTO-203 as an antidepressant in patients with major depressive disorder (MDD) and higher levels of anhedonia. The study will also assess the safety, tolerability, and pharmacokinetics of ALTO-203—a novel small molecule histamine H3 receptor inverse agonist, which has demonstrated positive emotional and cognitive effects in healthy participants after 1 dose.1

“This is the fifth phase 2 study we have initiated across our pipeline, a milestone that marks significant progress in our efforts to redefine mental health care through our Precision Psychiatry Platform,” said Jessica Powell, chief development officer of Alto Neuroscience. “In a phase 1 study, ALTO-203 demonstrated an acute increase in positive emotion relative to placebo and across several dosage levels. We look forward to completing this proof-of-concept study in patients as we believe this response may be an important attribute of an antidepressant to benefit patients with MDD and higher levels of anhedonia specifically.”

The study design includes a 2 study periods. In the first period, investigators use a randomized single-dose treatment to evaluate participant pharmacodynamic responses to ALTO-203 when compared with placebo, measured by an acute change in positive emotion assessed by the Bond-Lader Visual Analog Scale (BL-VAS) alertness and mood components. The BL-VAS was also used in a prior phase 1 study of ALTO-203. In the second period, investigators use a 28-day, multi-dose exposure design to assess the safety of ALTO-203 in participants with MDD. In this multi-dose period, exploratory and nonpowered objectives will measure changes in depression, anhedonia, and other clinical symptoms. Investigators will also measure change via cognition, electroencephalogram, and wearables.

Alto plans to enroll approximately 60 adult participants with MDD and evidence of anhedonia. Investigators will report this study’s topline data in early 2025.

Alto has another candidate for the treatment of MDD currently under study: ALTO-300. Investigators presented positive results from the 8-week phase 2a trial for ALTO-300 at the 62nd Annual Meeting of the American College of Neuropsychopharmacology (ACNP) that support ALTO-300’s potential as a novel treatment for MDD. In terms of safety, investigators examined possible biomarkers that could show the safety and efficacy of ALTO-300 as an adjunct treatment for individuals with MDD with poor antidepressant response. Additionally, ALTO-300 demonstrated a favorable safety and tolerability profile. There were no unexpected adverse effects. Alto also initiated a phase 2b study evaluating ALTO-300 in 200 patients with MDD. Results are expected in the first half of 2025.2

What treatment do you use in your clinical practice for anhedonia in patients with MDD? Are you excited about these novel, upcoming treatments? Let us know at!

If you want to read more on anhedonia, check out this article on navacaprant (NMRA-140): “Phase 3 Clinical Program Announced for Monotherapy Treatment for MDD.”


1. Alto Neuroscience announces initiation of phase 2 study of ALTO-203 in patients with major depressive disorder. BioSpace. News release. April 3, 2024.

2. Alto Neuroscience announces positive results from phase 2 study of ALTO-300 in major depressive disorder. News release. December 4, 2023. Accessed April 3, 2024.

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