ALTO-203 for Depression

No longer recruiting at 15 trial locations

Overseen By Alto Neuroscience

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Alto Neuroscience

Must not be taking: Antidepressants

Disqualifiers: Unstable medical condition, Bipolar, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ALTO-203, a potential antidepressant, for individuals with moderate major depressive disorder (MDD). It focuses on the treatment's effects on the body, as well as its safety and tolerability. Participants will receive different doses of ALTO-203 or a placebo (a harmless pill with no active drug) to assess its impact on symptoms like anhedonia (loss of interest or pleasure in daily activities). The trial includes single and multiple dose periods, during which participants will complete questionnaires and tasks to measure improvement. Those who have not recently taken antidepressants and can handle study procedures are suitable candidates for this trial. As a Phase 2 trial, the research aims to evaluate the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that participants are not taking antidepressants at the second screening visit, and some medications may be prohibited. It's best to discuss your current medications with the trial team to see if they are allowed.

Is there any evidence suggesting that ALTO-203 is likely to be safe for humans?

Research has shown that ALTO-203 was safe in past studies, with no unexpected side effects reported. Previous trials demonstrated that a single dose can improve mood and attention in healthy individuals. The treatment was well-tolerated, with no major safety concerns identified.

This trial is in Phase 2, indicating that ALTO-203's safety has already been studied in some participants. Although more research is needed to confirm these findings, current data suggests the treatment is generally safe for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Researchers are excited about ALTO-203 for depression because it offers a fresh approach compared to standard treatments like SSRIs and SNRIs, which primarily target serotonin and norepinephrine. ALTO-203 has a unique mechanism of action, potentially affecting different pathways in the brain that are not the primary focus of current medications. This could mean faster relief from depressive symptoms and benefits for patients who don't respond well to existing therapies. Additionally, it's administered orally, once daily, which is convenient and could improve patient adherence.

What evidence suggests that ALTO-203 might be an effective treatment for depression?

Research has shown that ALTO-203 has not yet significantly improved mood in people with major depressive disorder (MDD). In a previous study, ALTO-203 did not achieve its main goal of noticeably enhancing mood in MDD patients. However, the study found some positive effects on attention and alertness after just one dose. While ALTO-203 might not yet aid mood improvement, it could still offer other helpful effects under investigation. Participants in this trial will receive either ALTO-203 at different dosages or a placebo to further explore these potential effects. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with Major Depressive Disorder (MDD), particularly those experiencing anhedonia and depression. Participants will be involved in a study assessing the effects of a new treatment over single and multiple doses.

Inclusion Criteria

I experience a lack of pleasure in activities I once enjoyed.

Willing to comply with all study assessments and procedures

I have been diagnosed with moderate depression.

Exclusion Criteria

I have a health condition that is not stable.

Diagnosed bipolar disorder, psychotic disorder, or dementia

I am not taking any medications that are not allowed in the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Single-Dose Treatment

Participants receive single doses of ALTO-203 25 μg, 75 μg, and placebo to evaluate pharmacodynamic measures

1 day

Pre-Dose, 1.5 hours, 3 hours, and 5 hours on Day 1

Multi-Dose Treatment

Participants receive daily doses of ALTO-203 25 μg, 75 μg, or placebo for 28 days to assess safety, tolerability, and PK

28 days

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ALTO-203

Trial Overview The trial is testing ALTO-203 at two different strengths, 25 μg and 75 μg, against a placebo. It aims to understand how the drug works (pharmacodynamics), its safety, tolerability, and movement through the body (pharmacokinetics) over both single-dose and multi-dose periods.

How Is the Trial Designed?

Group I: ALTO-203 75 μg Experimental Treatment 1 Intervention

Drug: ALTO-203 75 μg Single-Dose Treatment Period: Single Dose, ALTO-203 75 μg Multi-Dose Treatment Period: ALTO-203 75 μg, administered orally, once daily for 28 days

Group II: ALTO-203 25 μg Experimental Treatment 1 Intervention

Drug: ALTO-203 25 μg Single-Dose Treatment Period: Single Dose, ALTO-203 25 μg Multi-Dose Treatment Period: ALTO-203 25 μg, administered orally, once daily for 28 days

Group III: Placebo Placebo Group 1 Intervention

Drug: Placebo Single-Dose Treatment Period: Single Dose, Placebo Multi-Dose Treatment Period: Placebo, administered orally, once daily for 28 days

Who Is Running the Clinical Trial?

Alto Neuroscience

Lead Sponsor

Trials

11

Recruited

1,300+

Published Research Related to This Trial

A study analyzing 720 cases of esketamine-related neurological adverse events (AEs) from 2019 to 2021 identified 21 safety signals, with sedation being the most concerning (ROR of 204.00), indicating potential long-term safety issues with esketamine.

The severity of neurological AEs was influenced by factors such as esketamine dosage and co-prescription with other medications, highlighting the need for careful monitoring and management of these risks in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. Guo, H., Wang, B., Yuan, S., et al.[2022]

In two large trials involving adults with major depressive disorder who did not respond adequately to standard antidepressants, adjunctive treatment with aripiprazole (2-20 mg/day) significantly improved depression scores compared to placebo, starting from 1-2 weeks into treatment.

Aripiprazole was generally well tolerated, with most side effects being mild to moderate, and it also led to higher rates of response and remission compared to placebo, indicating its efficacy as an adjunctive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aripiprazole: in major depressive disorder. Weber, J., Lyseng-Williamson, KA., Scott, LJ.[2021]

A review of 10 clinical trials on esketamine for resistant depression found that 90% of the trials had low-quality reporting of adverse events (AEs), indicating significant gaps in safety data.

The study revealed that 41.5% of serious AEs and 39% of non-serious AEs were not reported in published articles, particularly psychiatric and cardiovascular events, suggesting that the assessment of esketamine's risk-benefit balance may be inaccurate due to incomplete harm reporting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reporting of harms in clinical trials of esketamine in depression: a systematic review. Taillefer de Laportalière, T., Jullien, A., Yrondi, A., et al.[2023]

Ketamine shows promise as a treatment for treatment-resistant depression (TRD), but its use can lead to common adverse events, which are usually temporary.

A case of apnea during a slow sub-anesthetic infusion of ketamine highlights a rare but serious potential side effect, emphasizing the need for careful monitoring and management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., et al.[2021]

In a double-blind trial involving 90 patients with moderate to severe major depressive episodes, Org 3770 demonstrated significant efficacy compared to placebo, particularly in the first four weeks and at the end of the six-week treatment period.

Org 3770 was well-tolerated, with only minor side effects such as somnolence and increased appetite, indicating it is a safe option for treating major depressive disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind placebo-controlled study of Org 3770 in depressed outpatients. Claghorn, JL., Lesem, MD.[2019]

Esketamine nasal spray combined with a newly initiated oral antidepressant showed significant efficacy in treating treatment-resistant depression, with a number needed to treat (NNT) of 8 for response and 6 for remission after 4 weeks, indicating a strong potential benefit.

While there are some adverse effects associated with esketamine, such as dissociation and nausea, the likelihood to be helped (LHH) was favorable, showing that patients were three times more likely to achieve remission than to discontinue treatment due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed. Citrome, L., DiBernardo, A., Singh, J.[2021]

Nefazodone was found to be an effective treatment for major depression in Spanish-monolingual Hispanics, with a 63% response rate that aligns with previous studies on non-Hispanic subjects.

Despite similar efficacy and adverse effect rates to prior trials, a notably high dropout rate of 42% among participants suggests that factors beyond side effects may influence treatment adherence in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open trial of nefazodone among Hispanics with major depression: efficacy, tolerability, and adherence issues. Sánchez-Lacay, JA., Lewis-Fernández, R., Goetz, D., et al.[2021]

In a post-hoc analysis of 53 patients with major depressive disorder and suicidal ideation, intranasal esketamine showed a significant improvement in depression scores compared to placebo, with a mean difference of -3.8 on the MADRS scale by Day 2.

The safety profile of intranasal esketamine in the Asian subgroup was consistent with the overall ASPIRE I cohort, indicating no unexpected safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of esketamine nasal spray in addition to standard of care in patients with major depressive disorder who have active suicidal ideation with intent: A subgroup analysis of the Asian cohort of ASPIRE I (a randomized, double-blind, placebo-controlled study). Hong, JP., Malek, AZA., Li, CT., et al.[2023]

Esketamine nasal spray combined with an oral antidepressant significantly improves treatment outcomes for patients with treatment-resistant depression, with 5-21 more patients achieving remission and 14-17 more responding compared to those on a placebo during induction therapy.

In maintenance therapy, esketamine reduces the risk of relapse by 19-32 patients, while the incidence of serious adverse events remains low, indicating a favorable benefit-risk profile for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression. Katz, EG., Hough, D., Doherty, T., et al.[2021]

Nefazodone, an antidepressant, was effective in treating patients with moderate to severe depression, including those with melancholic features and recurrent episodes, based on a pooled analysis of four placebo-controlled studies involving 664 participants.

The studies showed that nefazodone improved depression symptoms significantly, as measured by the Hamilton Rating Scale for Depression and the Clinical Global Impressions scale, indicating its efficacy across clinically important subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nefazodone in the treatment of severe, melancholic, and recurrent depression. Marcus, RN., Mendels, J.[2018]

Citations

1. investors.altoneuroscience.com investors.altoneuroscience.com/news/news-details/2025/Alto-Neuroscience-Identifies-Biomarker-and-Reports-Positive-Pharmacodynamic-Results-from-Exploratory-Phase-2-Proof-of-Concept-Trial-of-ALTO-203/default.aspx

News Details The profile exhibited by ALTO-203 in the exploratory POC trial demonstrated clear effects on objective measures of attention and wakefulness, ...

2. psychiatrictimes.com psychiatrictimes.com/view/alto-203-fails-to-primary-efficacy-endpoint-in-phase-2-major-depressive-disorder-trial

ALTO-203 Fails to Meet Primary Efficacy Endpoint in Phase ... ALTO-203 failed to significantly improve mood in MDD patients, missing the primary efficacy endpoint in the phase 2 trial. Significant changes ...

3. clinicaltrialsarena.com clinicaltrialsarena.com/news/alto-trial-mdd-therapy/

Alto reports positive outcomes from Phase IIb trial of MDD ... Alto has reported positive outcomes from the interim analysis of its Phase IIb trial of oral ALTO-300, as an adjunctive treatment for MDD.

4. biospace.com biospace.com/drug-development/alto-digs-into-exploratory-outcomes-as-depression-drug-misses-phase-ii-endpoint

Alto Digs Into Exploratory Outcomes as Depression Drug ... Alto Neuroscience's investigational oral H3 receptor blocker ALTO-203 failed to significantly improve mood in patients with major depressive disorder.

5. fiercebiotech.com fiercebiotech.com/biotech/alto-misses-primary-efficacy-endpoint-phase-2-depression-trial-sings-cheerful-tune-anyway

Alto's phase 2 depression trial misses primary efficacy ... Alto reported significant improvements in alertness and mood five hours after a single dose of ALTO-203. The problem? Participants also improved ...

6. psychiatrictimes.com psychiatrictimes.com/view/alto-203-for-major-depressive-disorder-and-anhedonia-phase-2-study-initiated

ALTO-203 for Major Depressive Disorder and Anhedonia Additionally, ALTO-300 demonstrated a favorable safety and tolerability profile. There were no unexpected adverse effects. Alto also initiated a ...

7. ddw-online.com ddw-online.com/major-depressive-disorder-drug-progresses-to-phase-ii-trials-29250-202404/

Major depressive disorder drug progresses to Phase II trials To date, ALTO-203 has demonstrated positive emotional and cognitive effects in healthy participants after a single dose.

8. investors.altoneuroscience.com investors.altoneuroscience.com/news/news-details/2025/Alto-Neuroscience-Presents-New-Data-at-the-Society-of-Biological-Psychiatry-Annual-Meeting-Underscoring-Precision-Psychiatry-Approach/default.aspx

Alto Neuroscience Presents New Data at the Society of ... Key Takeaways: ALTO-203 (0.1 mg/kg) effectively reversed anhedonia-like behavior induced by dopamine depletion and demonstrated a significantly ...

9. ctv.veeva.com ctv.veeva.com/study/pd-pk-and-safety-of-alto-203-in-patients-with-mdd

PD, PK, and Safety of ALTO-203 in Patients With MDD The goal of this clinical trial is to determine the pharmacodynamic effects of ALTO-203 in patients with MDD in a randomized, placebo-controlled ...