Zelquistinel for Depression

Recruiting at 2 trial locations

Overseen By Kelly Kosko

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Gate Neurosciences, Inc

Must not be taking: Antidepressants, Antipsychotics, Mood stabilizers, others

Disqualifiers: Bipolar, Psychotic disorders, Substance abuse, others

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

1 Power Preferred Clinic 1 of this trial's clinic is considered top 20 on Power

Compensation: Varies

Number of Visits: 6

Duration: 6 weeks

164 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Yes, you will need to stop taking any current antidepressants, antipsychotics, mood stabilizers, sedatives, or stimulants at least 14 days before starting the trial. However, you can continue taking certain anxiety medications and sleep aids if you've been on a stable dose for at least 3 months and don't plan to change the dose during the trial.

What data supports the effectiveness of the drug Zelquistinel for depression?

Research shows that Zelquistinel, a new type of drug that affects certain brain receptors, can quickly and effectively reduce depression symptoms in animal studies. It works by enhancing brain activity related to mood improvement, similar to how other drugs like ketamine have shown rapid antidepressant effects. ^{1 2 3 4 5}

What safety data exists for Zelquistinel in humans?

The available research does not provide specific safety data for Zelquistinel in humans, as the study mentioned focuses on its effects in rodents. ^{2 6 7 8 9}

How is the drug Zelquistinel unique in treating depression?

Zelquistinel is unique because it is an orally available drug that acts as an allosteric modulator of NMDA receptors, which are involved in brain signaling. This mechanism allows it to produce rapid and sustained antidepressant effects by enhancing synaptic plasticity, setting it apart from traditional antidepressants that often take weeks to show effects. ^{1 2 10 11 12}

What is the purpose of this trial?

The goal of this clinical trial is to learn if GATE-251 works to treat depression in adults. It will also learn about the safety of GATE-251. The main questions it aims to answer are: Does GATE-251 reduce depression scores in participants compared to participants who take a placebo (a look-alike tablet that contains no GATE-251)? What medical problems are observed in participants who take GATE-251? Participants will take one tablet of GATE-251 or placebo every week for 6 weeks. Participants will visit the clinic every week of the 6 week period to have the severity of their depression evaluated.

Research Team

Ronald M Burch, MD, PhD

Principal Investigator

Gate Neurosciences

Eligibility Criteria

Adults aged 18-64 with Major Depressive Disorder, experiencing a depressive episode lasting between 3 weeks to 18 months. They must be moderately ill or worse and show significant distress or impaired functioning. Women must use birth control or be postmenopausal, and all participants need certain scores on depression and anxiety scales.

Inclusion Criteria

I am either male or female.

I am between 18 and 64 years old.

My current depressive episode has lasted between 3 weeks and 18 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive either GATE-251 or placebo once a week for 6 weeks

6 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GATE-251

Trial Overview The trial is testing GATE-251's effectiveness in treating depression compared to a placebo over six weeks. Participants will take one tablet weekly and have their depression severity assessed at each clinic visit during the study period.

Participant Groups

Group I: GATE-251 (zelquistinel) Experimental Treatment 1 Intervention

GATE-251 (zelquistinel) will be administered as a single 10 mg oral tablet one time each week for 6 weeks.

Group II: Placebo Placebo Group 1 Intervention

Placebo tablet identical in appearance to the experimental treatment tablet, administered as as a single oral tablet one time each week for 6 weeks.

Who Is Running the Clinical Trial?

Gate Neurosciences, Inc

Lead Sponsor

Trials

6

Recruited

850+

Worldwide Clinical Trials

Collaborator

Trials

70

Recruited

15,800+

Findings from Research

Ketamine, an NMDA receptor antagonist, has shown rapid and significant antidepressant effects in treatment-resistant depression (TRD), with an (S)-ketamine nasal spray now approved for use alongside oral antidepressants in the U.S. and Europe.

Despite its effectiveness, challenges such as maintaining response, potential side effects, and abuse risk remain, highlighting the need for further research to develop safer, next-generation rapid-acting antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine for depression. Jelen, LA., Stone, JM.[2021]

Zelquistinel, a novel NMDAR allosteric modulator, shows high oral bioavailability and produces rapid and sustained antidepressant-like effects in rodent models by enhancing synaptic plasticity.

The antidepressant effects of zelquistinel are linked to its ability to increase NMDAR function, as evidenced by improved performance in depression models and a favorable safety profile, with no negative impact on motor coordination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects. Burgdorf, JS., Zhang, XL., Stanton, PK., et al.[2023]

Zuranolone (30mg) showed significant benefits in treating major depressive disorder (MDD), with a number needed to treat (NNT) of 3-5 for response and remission by Day 15, indicating it is effective compared to placebo and standard antidepressants.

The analysis also revealed a negative number needed to harm (NNH), suggesting that zuranolone is associated with a lower risk of treatment discontinuation compared to SSRIs and SNRIs, highlighting its favorable benefit-to-risk profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Number Needed to Treat and Number Needed to Harm analysis of the zuranolone phase 2 clinical trial results in major depressive disorder. Arnaud, A., Suthoff, E., Stenson, K., et al.[2022]

In a study of 269 patients with treatment-resistant depression (TRD) using esketamine (ESK) intranasal spray, 61.3% completed the recommended induction phase, indicating good adherence to treatment.

Post-initiation of ESK, there was a trend of reduced mental health-related inpatient and emergency department costs, suggesting potential economic benefits alongside clinical outcomes for patients with TRD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment patterns, healthcare utilization, and costs of patients with treatment-resistant depression initiated on esketamine intranasal spray and covered by US commercial health plans. Joshi, K., Pilon, D., Shah, A., et al.[2023]

Intranasal esketamine significantly improved depression scores in patients with major depressive disorder (MDD), including treatment-resistant depression (TRD) and major depression with suicidal ideation (MDSI), starting from 2-4 hours after administration and maintaining effectiveness for up to 28 days, based on a meta-analysis of 8 randomized controlled trials involving 1,488 patients.

Esketamine was associated with a greater resolution of suicidal thoughts in patients with MDSI compared to placebo within the first few hours, although this effect did not persist at later time points. However, it also had a higher incidence of side effects, such as dissociation and increased blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis Wang, SM., Kim, NY., Na, HR., et al.[2021]

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 a phase 3 study involving 481 adults with major depressive disorder, vilazodone (40 mg/day) showed significant improvement in depression symptoms compared to placebo, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS).

Vilazodone was well tolerated, with common side effects including diarrhea and nausea, but it did not significantly affect sexual function or weight compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. Khan, A., Cutler, AJ., Kajdasz, DK., et al.[2022]

Edivoxetine, when used as an adjunctive treatment to SSRIs, showed a higher rate of treatment-emergent adverse events (TEAEs) compared to placebo, with 56.8% of patients reporting at least one TEAE, indicating a need for careful monitoring of side effects.

The safety profile of edivoxetine included significant increases in blood pressure and pulse rate, but no clinically significant changes in laboratory measures, suggesting that while it may enhance treatment efficacy, it also carries specific cardiovascular considerations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder. Martinez, JM., Ferguson, MB., Pangallo, BA., et al.[2020]

In a study involving 3,263 patients treated with vortioxetine for major depressive disorder in South Korea, the medication demonstrated a favorable safety profile, with only 17.13% reporting any adverse events, most of which were mild.

Vortioxetine was found to be effective, with significant improvements in depression symptoms observed in 1,918 patients after approximately 24 weeks, as indicated by various clinical and patient-reported measures, showing consistent efficacy across different age groups and sexes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of vortioxetine for major depressive disorder: Real-world evidence from a population-based study in South Korea. Moon, SW., Kim, JW., Kim, DH., et al.[2023]

Dopamine D3 receptors play a crucial role in motivation and reward-related behaviors, and their dysfunction is linked to symptoms of depression, such as anhedonia and loss of motivation.

Antidepressant treatments can reverse the down-regulation of dopamine D3 receptors caused by stress and depression, suggesting that enhancing dopaminergic neurotransmission through these receptors may contribute to the effectiveness of new antidepressant drugs currently in development, like aripiprazole and cariprazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Leggio, GM., Salomone, S., Bucolo, C., et al.[2022]

Buspirone, an azapirone anxiolytic, was studied in five placebo-controlled trials with 382 patients suffering from major depression and anxiety, showing significant improvements in both depressive and anxiety symptoms compared to placebo.

Patients with more severe depression symptoms responded better to buspirone, particularly at a commonly effective dose of 40 mg/day, indicating that azapirones may have important antidepressant properties through their action on the 5-HT1A receptor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. Robinson, DS., Rickels, K., Feighner, J., et al.[2021]

Gepirone, a serotonin receptor agonist, has been shown to be effective in treating major depression, outperforming placebo in two double-blind studies, with an established dose range of 5-30 mg/day.

In addition to its acute treatment efficacy over 8 weeks, gepirone also provided benefits in continuation therapy over 4 weeks for patients who initially responded well, particularly improving core depression symptoms as measured by the Hamilton Rating Scale.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gepirone in the treatment of major depression. Jenkins, SW., Robinson, DS., Fabre, LF., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Ketamine for depression. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Zelquistinel Is an Orally Bioavailable Novel NMDA Receptor Allosteric Modulator That Exhibits Rapid and Sustained Antidepressant-Like Effects. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Number Needed to Treat and Number Needed to Harm analysis of the zuranolone phase 2 clinical trial results in major depressive disorder. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Treatment patterns, healthcare utilization, and costs of patients with treatment-resistant depression initiated on esketamine intranasal spray and covered by US commercial health plans. [2023]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of vortioxetine for major depressive disorder: Real-world evidence from a population-based study in South Korea. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Gepirone in the treatment of major depression. [2019]