PEA vs. Placebo for Major Depression

NCT06063369 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: PEA-01
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Major Depression is often resistant to treatment, and all of the currently marketed anti-depressants can cause significant side effects and may precipitate mania. The aim of this proposal is to perform a proof-of-concept RCT testing Palmitoylethanolamide (PEA) as a treatment for unipolar or bipolar depression, randomizing 100 patients to 6-week treatment with PEA 1200 mg/d or matching placebo. There are several rationales for this study: (A) PEA acts at the peroxisome proliferator-activated receptor-alpha (PPAR-α), stimulating Allo biosynthesis. Allo is an endogenous, positive allosteric modulator of GABA-A receptors in glutamatergic neurons, including cortical and hippocampal pyramidal glutamatergic neurons and may be one of the endogenous regulators of depression and anxiety. (B) Sage Therapeutics has developed Allo which is FDA approved to treat post-partum depression, and is testing a molecular modification which can be administered orally for post-partum depression and unipolar depression, with mixed efficacy results. Pregnenolone, a precursor of neurosteroids, has also been reported to improve bipolar depression. Based on animal models, PEA increases Allo synthesis in areas of the brain thought to be involved in anxiety and depression. It may also favor the biosynthesis of sulfated forms of Allo and congeners that inhibit tonic rather than phasic NMDA-mediated excitatory neurotransmission. Showing that PEA-induced selective inhibition of tonic NMDA neurotransmission improves depression might enable development of steroid-based NMDA-inhibitor therapeutics. In addition, PEA-induced Allo upregulation potentiates GABA-A receptor-mediated inhibition. The NMDA and the GABAergic mechanisms may act in concert to improve behavioral outcomes. Since PEA increases Allo in the brain where it is endogenously formed, it might be more effective compared with exogenous administration, which is not site specific. There is evidence of a role of inflammation in depression; PEA has potent immunoregulatory and anti-inflammatory effects by directly activating PPAR-α, which has a protective role against neuroinflammation by inhibiting the signaling mediated by toll-like receptor 4.There is one published study which shows that PEA has an antidepressant effect in unipolar depression, 58 patients were randomized to receive 1200 mg/d of PEA or placebo added-on to citalopram, showing clinical improvements in patients receiving PEA.

Conditions

Bipolar Depression; Major Depressive Disorder

Outcome Measures

Primary Outcomes (1)

• Hamilton Depression Rating Scale (HAM-D)

  Depression Scale

  6 weeks trial

Secondary Outcomes (8)

• Clinical Global Impressions-Severity-Bipolar Scale or Clinical Global Impressions-Severity-Depression

  6 weeks trial

• Hamilton Anxiety Rating Scale (HAM-A)

  6 weeks trial

• Plasma measures including Allo and pregnanolone, their isomers, the sulfated congeners (pregnanolone sulphate and Allo sulphate)

  6 weeks trial

• DHEA

  6 weeks trial

• BDNF

  6 weeks trial

Study Arms (2)

Palmitoylethanolamide 1200 mg

EXPERIMENTAL

Dose: PEA 1200 mg given in 300 mg capsules (2 capsules twice daily) Route of administration: oral Duration and frequency: study medication will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: PEA Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.

Drug: Palmitoylethanolamide

Matching placebo

PLACEBO COMPARATOR

2 capsules twice daily identical to study arm. Route of administration: oral Duration and frequency: pills will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: placebo in identical capsules. Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.

Drug: Palmitoylethanolamide

Interventions

Palmitoylethanolamide DRUG

Dose: PEA 1200 mg given in 400 mg capsules (3 capsules per day) or Placebo Route of administration: oral Duration and frequency: study medication will be provided to patients in bottles every two weeks for the duration of the study (three dispensations). Formulation: PEA and placebo in identical capsules. Dosing scheme: Patients will be instructed to take two capsules twice daily for the 42 days of the study.

Also known as: PEA

Matching placebo; Palmitoylethanolamide 1200 mg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meet DSM V criteria for a Major Depressive Episode, with or without a diagnosis of Bipolar I or Bipolar II disorder.
• Between 18-65 years of age, male or female subjects of any race.
• Able to provide informed consent. All participant patients must have signed an informed consent document indicating they understand the purpose of the study and are willing to complying with the study procedures and restrictions.
• Have a MADRS above 20 and an YMRS \< 12.
• Inpatients or outpatients at the discretion of the investigator.
• Live with a caregiver or have a relative/close friend who is in contact with them at least twice a week via phone.

You may not qualify if:

• Diagnosis of schizophrenia or schizoaffective disorder
• Women of child-bearing potential who do not practice contraception.
• Women who are pregnant or breast-feeding.
• Psychotic symptoms during the 2 weeks preceding the baseline day.
• Failure of three or more antidepressant treatment trials.
• Unstable medical disease (malignancy, poorly controlled diabetes, or cardiomyopathy, serious pulmonary disease, kidney disease, impaired liver functioning. Particular attention should be given to exclude patients with ischemic heart disease).
• Has a clinically significant abnormal 12-lead electrocardiogram (ECG) at the Screening Visit, as determined by the Investigator.
• At significant risk of committing suicide, or in the opinion of the Investigator, currently is at imminent risk of suicide or harming others.
• Patients with a current DSM-V substance or alcohol dependence.
• Concurrent delirium, mental retardation, drug-induced psychosis.

Sponsors & Collaborators

• The Israeli Medical Center for Alzheimer's: lead

Study Sites (1)

State University of Medicine and Pharmacy " Nicolae Testemitsanu"

Chisinau, Moldova

RECRUITING

MeSH Terms

Conditions

Bipolar Disorder; Depressive Disorder, Major

Interventions

palmidrol

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders; Depressive Disorder

Central Study Contacts

Igor Nastas, Dr

CONTACT

+37367133770; igornastas@yahoo.com

Mark Prof Weiser, Professor

CONTACT

972-526666570; Mark.weiser@sheba.health.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-Blind
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head Psychiatrist

Model Details: Phase II - Randomized, double blind, placebo-controlled, parallel group clinical trial.

Study Record Dates

• First Submitted: March 23, 2023
• First Posted: October 2, 2023
• Study Start: December 21, 2022
• Primary Completion: December 21, 2023
• Study Completion: December 21, 2024
• Last Updated: October 2, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

MO (1)