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Study to Treat Major Depressive Disorder With a New Medication

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ClinicalTrials.gov Identifier: NCT03043560
Recruitment Status : Recruiting
First Posted : February 6, 2017
Last Update Posted : May 16, 2019
Sponsor:
Collaborators:
National Institute of Mental Health (NIMH)
Baylor College of Medicine
Information provided by (Responsible Party):
James Murrough, Icahn School of Medicine at Mount Sinai

Brief Summary:
This project is designed to examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a novel treatment target for mood disorders through the administration of the KCNQ-selective channel opener ezogabine (Potiga, GlaxoSmithKline; FDA-approved for the treatment of seizure disorders).

Condition or disease Intervention/treatment Phase
Depressive Disorder Anhedonia Drug: Ezogabine Drug: Placebos Phase 2

Detailed Description:

Depressive disorders are among the most disabling medical conditions worldwide and currently available treatments fall short of addressing this large public health burden. Dysfunction within the brain reward system is emerging as a core feature of depressive disorders, in particular related to deficits in motivation, interest, and response to pleasure (e.g., anhedonia: markedly diminished response to pleasure). Evidences from a series of preclinical studies from our group highlighted the KCNQ subtype of neuronal potassium (K+) channel as a novel target for the treatment of depressive disorders and our human pilot study showed a reduction in anhedonia and related symptoms, and an increased brain response to reward (as measured by functional magnetic resonance imaging [fMRI]) following treatment with ezogabine. Building on this data, the current project will assess reward circuit activity following treatment with ezogabine in depressed patients with a current depressive disorder (Major depressive disorder [MDD], persistent depressive disorder, other specified depressive disorder) and anhedonia (defined by a score ≥ 20 on the Snaith-Hamilton Pleasure Scale [SHAPS]), using fMRI to investigate the cortico-striatal circuit to reward.

This study represents the first part of the R61/R33 National Institutes of Health (NIH) founded project. A clear increase in reward circuit activation in at least one ezogabine treatment group compared to placebo, given acceptable tolerability, will constitute a "go" and the project will move to the next phase (R33), where we aim to examine the relationship between treatment, reward circuit activity, and behavioral and clinical outcomes in a larger, confirmatory efficacy trial of ezogabine for depression with anhedonia.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double blind
Primary Purpose: Other
Official Title: Developing Neuronal KCNQ Channel Modulators for Mood Disorders
Actual Study Start Date : September 25, 2017
Estimated Primary Completion Date : August 31, 2019
Estimated Study Completion Date : August 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Mood Disorders
Drug Information available for: Ezogabine

Arm Intervention/treatment
Experimental: Ezogabine
Participants will receive treatment with ezogabine up to 900mg/day.
Drug: Ezogabine
daily for 5 weeks
Other Name: Potiga

Placebo Comparator: Placebo
Participants will receive treatment with a matching placebo pill.
Drug: Placebos
placebo pill daily for 5 weeks




Primary Outcome Measures :
  1. Change in the cortico-striatal circuit response [ Time Frame: baseline and 5 weeks ]
    Change in the cortico-striatal circuit response to reward after at least one week treatment with the maximum dosage of ezogabine at baseline and after 5 weeks of treatment.


Secondary Outcome Measures :
  1. Snaith-Hamilton Pleasure Scale (SHAPS) [ Time Frame: 5 weeks ]
    14-item self-report questionnaire commonly used to assess anhedonia.

  2. Clinical Global Impression - Improvement (CGI-I0 [ Time Frame: 5 weeks ]
    A widely administered clinician rated global measure of the degree of improvement from the initial assessment in subject overall illness severity.

  3. Clinical Global Impression - Severity (CGI-S) [ Time Frame: 5 weeks ]
    Clinician rated global measure of subject overall illness severity.

  4. Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS) [ Time Frame: 5 weeks ]
    A measure specifically designed to assess hedonic capacity for social and interpersonal pleasure.

  5. Montgomery-Asberg Depression Rating Scale (MADRS) [ Time Frame: 5 weeks ]
    A 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms.

  6. World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) [ Time Frame: 5 weeks ]
    A 12-item generic assessment instrument that measures investigating the level of functioning in six domains: Cognition, Mobility, Self-care, Getting along, Life activities, and Participation.

  7. Temporal Experience of Pleasure Scale (TEPS) [ Time Frame: 5 weeks ]
    The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) components of anhedonia which consists of a series of statements that must be rated according to how accurate they are for the individual.

  8. Specific Loss of Interest and Pleasure Scale (SLIPS) [ Time Frame: 5 weeks ]
    The SLIPS is a recently developed and validated measure of anhedonia that is tailored to detect recent changes in anhedonia.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent obtained from subject and ability for subject to comply with the requirements of the study;
  • Men and women, age 18-65;
  • Participants must meet DSM-V criteria for current depressive disorder (major depressive disorder [MDD], persistent depressive disorder, other specified depressive disorder) as determined by a study psychiatrist and confirmed using the Structured Clinical Interview for DSM-V (SCID);
  • Clinically significant anhedonia as determined by a SHAPS score ≥ 20 at screening;
  • Current illness severity is at least moderate, defined as a score of ≥4 on the Clinical Global Impression-Severity (CGI-S) Scale;
  • If female of childbearing potential, must agree to use of a medically accepted form of contraception, or else agree to abstinence.

Exclusion Criteria:

  • A primary psychiatric diagnosis other than a depressive disorder as defined by DSM-V [co-morbid anxiety disorders (including agoraphobia, generalized anxiety disorder, social anxiety disorder and panic disorder) and Posttraumatic Stress Disorder (PTSD) are allowed] or major cognitive disorder;
  • Meets criteria for a substance or alcohol use disorder in the past 6 months;
  • Female participants who are pregnant, breastfeeding, or may become pregnant, or unwilling to practice birth control during participation in the study;
  • Positive urine toxicology screen for drugs of abuse at the time of screening;
  • Any unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease;
  • Clinically significant abnormalities of laboratory tests, physical examination, or ECG;
  • Prolonged QT Interval at screening, operationalized as a QTc of > 480 ms;
  • A history of retinal abnormalities (i.e., pigment changes, retinal dystrophy) or findings of retinal pathology on ophthalmological exam at baseline;
  • 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;
  • Use of any dis-allowed medication according to the study protocol;
  • Serious and imminent risk of self harm or violence as determined by the PI;
  • Extreme illness severity as defined by a GCI-S score >6;
  • Any contraindication to MRI including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more;
  • History of non-response to electroconvulsive therapy in the current depressive episode

    • Exceptions:

      1. Subjects with a positive urine drug screen for cannabinoids, barbiturates, opiates, amphetamines, or benzodiazepines may be allowed in the study provided that the drug was used for a documented, legitimate medical purpose and/or the use of such products may be discontinued (documented by a negative repeat test) prior to randomization;
      2. Medically appropriate episodic use (up to 3 days) of narcotic analgesics for acute medical indications is allowed (Discussion with PI required)

        • Potential participants will not be discontinued from medication for the purposes of this study. If a patient is taking a protocol dis-allowed medication at the time of screening, the patient may discontinue the medication under the supervision of the treating physician in the case that the patient is not benefiting from the medication or otherwise wishes to discontinue the medication. In no case will a dis-allowed medication be discontinued for the purpose of study participation if the patient is receiving clinical benefit from the medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03043560


Contacts
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Contact: Morgan Harnois 212-585-4619 morgan.harnois@mssm.edu
Contact: Sara Costi, MD 212-585-4637 sara.costi@mssm.edu

Locations
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United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Morgan Harnois    212-241-3089    morgan.harnois@mssm.edu   
Principal Investigator: James Murrough, MD, PhD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Tabish Iqbal    713-798-4095    tiqbal@bcm.edu   
Principal Investigator: SanJay Mathew, MD         
Sponsors and Collaborators
James Murrough
National Institute of Mental Health (NIMH)
Baylor College of Medicine
Investigators
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Principal Investigator: James Murrough, MD, PhD Icahn School of Medicine at Mount Sinai

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Responsible Party: James Murrough, Associate Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03043560     History of Changes
Other Study ID Numbers: GCO 16-0374
1R61MH111932-01 ( U.S. NIH Grant/Contract )
First Posted: February 6, 2017    Key Record Dates
Last Update Posted: May 16, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data from this study may be submitted to the National Database for Clinical Research Related to Mental Illness (NDCT). NDCT isa data repository run by the National Institute of Mental Health (NIMH) that allows researchers studying mental illness to collect and share deidentified information with each other. During and after the study, the researchers will send deidentified information about health and behavior and in some cases, genetic information, to NDCT. Other researchers nationwide can then file an application with the NIMH to obtain access to deidentified study data for research purposes.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by James Murrough, Icahn School of Medicine at Mount Sinai:
depression
anhedonia
reward

Additional relevant MeSH terms:
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Disease
Depressive Disorder
Depression
Anhedonia
Pathologic Processes
Mood Disorders
Mental Disorders
Behavioral Symptoms
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Ezogabine
Anticonvulsants
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action