What is the mechanism of action of this treatment?

Common treatments for depression include selective serotonin reuptake inhibitors (SSRIs), which increase serotonin levels in the brain, and serotonin-norepinephrine reuptake inhibitors (SNRIs), which boost both serotonin and norepinephrine. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) also enhance neurotransmitter levels but with more side effects. These treatments aim to correct chemical imbalances in the brain that affect mood and behavior. Emerging treatments like XEN1101, a KCNQ2/3 potassium channel opener, represent a novel approach by modulating neuronal excitability, which may offer rapid and robust antidepressant effects. Understanding these mechanisms helps tailor treatments to individual needs, potentially improving efficacy and reducing side effects.

What side effects are associated with this type of intervention?

Common treatments for depression include SSRIs (e.g., fluoxetine, sertraline), which can cause side effects such as nausea, insomnia, sexual dysfunction, and weight gain. SNRIs (e.g., venlafaxine, duloxetine) may lead to similar side effects along with increased blood pressure. TCAs (e.g., amitriptyline, nortriptyline) often cause dry mouth, constipation, urinary retention, and sedation. Atypical antidepressants (e.g., bupropion, mirtazapine) can result in insomnia, dry mouth, and increased appetite. Ketamine, used for treatment-resistant depression, may cause dissociation, elevated blood pressure, and potential for abuse. These side effects are important to consider when evaluating new treatments like XEN1101, which targets KCNQ2/3 potassium channels.

What prior FDA approvals exist?

The FDA has approved several treatments for depression, including SSRIs (e.g., fluoxetine, sertraline), SNRIs (e.g., venlafaxine, duloxetine), and atypical antidepressants (e.g., bupropion, mirtazapine). More recently, treatments targeting different mechanisms, such as NMDA receptor antagonists like esketamine, have been approved for treatment-resistant depression. While there is limited information on FDA-approved treatments specifically targeting KCNQ2/3 potassium channels, the exploration of XEN1101 represents a novel approach in this area.

What other types of research exist?

Promising novel alternatives to XEN1101 for depression treatment include esketamine nasal spray, which has shown long-term safety and efficacy in treatment-resistant depression, and triple reuptake inhibitors, which are in development and aim to provide broader spectrum efficacy by targeting multiple neurotransmitter systems. Additionally, mGluR2/3 antagonists like LY341495 have demonstrated rapid and long-lasting antidepressant effects in preclinical models.

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XEN1101 for Depression

Phase 2

Waitlist Available

Led By James W Murrough, MD, PhD

Research Sponsored by James Murrough

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Men and women, age 18-65 years;

Are you willing to not take any other psychotropic medications during the trial?

Must not have

Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

Has a history of schizophrenia or other psychotic disorder, major depressive disorder with psychotic features, or bipolar I or II disorder.

Timeline

Screening 6 weeks

Treatment 8 weeks

Follow Up 4 weeks

Summary

This trial is testing XEN1101, a medication that opens specific brain cell channels, to help patients with mood disorders who may not respond well to typical treatments. It works by regulating brain cell activity to improve mood.

Who is the study for?

This trial is for men and women aged 18-65 with moderate to severe Major Depressive Disorder, as confirmed by a psychiatrist using the SCID-5-RV. Participants must not take other psychotropic meds during the study, have significant anhedonia (SHAPS score ≥20), and be able to follow study requirements. Exclusions include depression with peripartum onset, recent suicide attempts, swallowing issues, major neurocognitive disorders, or unstable medical conditions.

What is being tested?

The trial is testing XEN1101—a drug that targets specific brain potassium channels—as a potential new treatment for depression against a placebo. The goal is to see if XEN1101 can improve symptoms in those who haven't responded well to other treatments.

What are the potential side effects?

While side effects of XEN1101 are not detailed here, similar medications may cause changes in heart rhythm (QT prolongation), liver enzyme elevations, skin or eye pigment changes. Side effects often vary from person to person.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

You have a health condition that could affect your safety during the trial or the accuracy of the study results.

Select...

You have a history of severe mental illnesses such as schizophrenia, bipolar disorder or major depression with psychotic features.

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You have been diagnosed with depression during pregnancy or after giving birth.

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You have attempted suicide within the past two years.

Timeline

Screening ~ 6 weeks1 visit

Treatment ~ 8 weeks6 visits

Follow Up ~ 4 weeks1 visit

Screening ~ 6 weeks

Treatment ~ 8 weeks

Follow Up ~4 weeks

This trial's timeline: 6 weeks for screening, 8 weeks for treatment, and 4 weeks for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change in activation within the reward circuit by fMRI

Secondary study objectives

Change in Clinical Global Impression Scale

Change in Montgomery-Åsberg Depression Rating Scale Score

Change in Quick Inventory of Depressive Symptomatology, Self-Report [QIDS-SR] Score

+2 more

Trial Design

2Treatment groups

Active Control

Placebo Group

Group I: XEN1101Active Control1 Intervention

Subjects will take two 10 mg capsules of XEN1101 daily for 8 weeks for a total daily dose of 20 mg.

Group II: PlaceboPlacebo Group1 Intervention

Subjects will take a matching placebo daily for eight weeks.

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for depression include selective serotonin reuptake inhibitors (SSRIs), which increase serotonin levels in the brain, and serotonin-norepinephrine reuptake inhibitors (SNRIs), which boost both serotonin and norepinephrine. Tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) also enhance neurotransmitter levels but with more side effects. These treatments aim to correct chemical imbalances in the brain that affect mood and behavior. Emerging treatments like XEN1101, a KCNQ2/3 potassium channel opener, represent a novel approach by modulating neuronal excitability, which may offer rapid and robust antidepressant effects. Understanding these mechanisms helps tailor treatments to individual needs, potentially improving efficacy and reducing side effects.

Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants.Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond.Pharmacological approaches to the challenge of treatment-resistant depression.