What side effects are associated with this type of intervention?

Common treatments for depression, such as SSRIs and SNRIs, often have side effects including nausea, weight gain, sexual dysfunction, insomnia, and dry mouth. Treatments similar to nitrous oxide, like ketamine, can cause side effects such as dizziness, dissociation, increased blood pressure, nausea, and potential cognitive effects like disorientation and delirium. These side effects are generally mild to moderate in severity and tend to be short-lived.

What prior FDA approvals exist?

The FDA has approved several treatments for depression, including selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and sertraline, serotonin-norepinephrine reuptake inhibitors (SNRIs) like venlafaxine and duloxetine, and atypical antidepressants like bupropion and mirtazapine. Recently, there has been interest in NMDA receptor antagonists for treatment-resistant depression. Esketamine, an NMDA receptor antagonist, was approved by the FDA in 2019 for treatment-resistant depression, offering a novel mechanism of action compared to traditional antidepressants. This is similar to the investigational use of nitrous oxide, which also targets NMDA receptors.

What other types of research exist?

Promising novel alternatives to Nitrous Oxide for depression treatment in 2024 include ketamine and its derivatives, which also act as NMDA receptor antagonists. Other options include SSRIs, SNRIs, and second-generation antipsychotics (SGAs). Combining these pharmacological treatments with psychotherapy may also enhance treatment outcomes.

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Nitrous Oxide 99 % for Depression (SMILE Trial)

Phase 4

Waitlist Available

Research Sponsored by Unity Health Toronto

Eligibility Criteria Checklist

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

Must have

Experiencing moderate to severe depressive episode (HAMD > 17)

Failure of two trials of antidepressant therapy of adequate dose and duration during the current depressive episode

Must not have

Major Depressive Episode in people with Bipolar Disorder

Use of centrally acting medicinal products like opioid agonists, morphine derivatives, benzodiazepines, barbiturates, and alcohol

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 2 years

Awards & highlights

Pivotal Trial

No Placebo-Only Group

Drug Has Already Been Approved

Summary

This trial is testing nitrous oxide (laughing gas) for people with depression that hasn't improved with other treatments. The gas is inhaled and may quickly improve mood by affecting the brain. Nitrous oxide has been used for over a century in various medical fields for its pain-relieving and anesthetic properties, and recent studies suggest it may be effective for treatment-resistant depression.

Who is the study for?

Adults aged 18-65 with major depressive disorder who haven't improved after two antidepressant treatments can join. They must not be pregnant, breastfeeding, or have a history of certain mental health conditions like schizophrenia. Participants should agree to use effective contraception and maintain their current antidepressant regimen.

What is being tested?

The trial is testing if nitrous oxide gas can improve depression symptoms compared to an active placebo (oxygen + Midazolam). It's for those whose depression hasn't responded to standard treatments, with participants randomly assigned to either the study group or control group.

What are the potential side effects?

Possible side effects include reactions related to inhaling nitrous oxide such as headaches, nausea, dizziness, and fatigue. Midazolam may cause drowsiness, reduced alertness, respiratory issues and in rare cases paradoxical reactions like anxiety.

Eligibility Criteria

Inclusion Criteria

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

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I am experiencing a severe depressive episode.

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I have tried two different antidepressants without success during this depressive episode.

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I am between 18 and 65 years old.

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I have been diagnosed with a major depressive episode.

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I understand and can agree to the study's procedures and risks.

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I have been diagnosed with Major Depressive Disorder.

Exclusion Criteria

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

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I have experienced a major depressive episode while having bipolar disorder.

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I am not using opioids, sedatives, or consuming alcohol.

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I cannot receive nitrous oxide due to health reasons.

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I cannot take the placebo midazolam due to health reasons.

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I am not willing to keep taking my current antidepressants.

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I have undergone electroconvulsive therapy for my current depressive episode.

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I am currently receiving ketamine for my depression.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 2 years for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Adherence rate

Frequency of adverse events

Recruitment rate

Secondary study objectives

Montgomery-Åsberg Depression Rating Scale (MADRAS) Score 0-60 (Higher scores represent higher depression). Measure changes in symptoms of depression

Toronto Side Effects Scale (TSES) - 32 items (each item has a score 1-25; higher score means higher intensity). Measure adverse side effects from antidepressant treatment

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Drug Has Already Been Approved

The FDA has already approved this drug, and is just seeking more data.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Nitrous Oxide + saline solutionExperimental Treatment1 Intervention

Group II: Oxygen + MidazolamActive Control1 Intervention

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Nitrous Oxide 99 %

2021

Completed Phase 4

~40

0 / 13Eligibility 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 increase both serotonin and norepinephrine levels. Another emerging treatment involves NMDA receptor antagonists like ketamine and nitrous oxide. These drugs work by blocking NMDA receptors, which are involved in glutamate signaling, leading to rapid antidepressant effects. This mechanism is particularly important for treatment-resistant depression, as it offers a new pathway for relief when traditional treatments fail. Understanding these mechanisms helps patients and doctors make informed decisions about which treatment might be most effective based on the patient's specific condition and response to previous therapies.

Functional connectivity between prefrontal cortex and subgenual cingulate predicts antidepressant effects of ketamine.Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond.Pharmacological approaches to the challenge of treatment-resistant depression.