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NMDA Antagonists in Bipolar Depression

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ClinicalTrials.gov Identifier: NCT01833897
Recruitment Status : Completed
First Posted : April 17, 2013
Results First Posted : June 1, 2016
Last Update Posted : June 1, 2016
Sponsor:
Information provided by (Responsible Party):
New York State Psychiatric Institute

Tracking Information
First Submitted Date  ICMJE April 12, 2013
First Posted Date  ICMJE April 17, 2013
Results First Submitted Date  ICMJE March 17, 2016
Results First Posted Date  ICMJE June 1, 2016
Last Update Posted Date June 1, 2016
Study Start Date  ICMJE March 2013
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2016)
Hamilton Depression Rating Scale (HAM-D) [ Time Frame: 8 weeks ]
Depression rating scale: Range 0-53, higher scores indicate worse depression. 0-7 = Normal 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression ≥ 23 = Very Severe Depression
Original Primary Outcome Measures  ICMJE
 (submitted: April 16, 2013)
Safety, tolerability and efficacy of ketamine and d-cycloserine [ Time Frame: 8 weeks ]
Vital signs will be closely monitored throughout ketamine infusion (60 min) and evaluation 2 consecutive days during phase. If responding, will begin 8 week treatment with d-cycloserine with weekly visits.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2016)
  • Loss of Motivated Behavior HAM-D Factor [ Time Frame: 8 weeks ]
    includes the total of four HAM-D items: (Item 7: Work and activities, Item 12. Somatic symptoms (appetite), Item 14. Genital symptoms (libido), and Item 16. Weight loss). Range 0-11, higher scores indicate worse symptoms
  • HAM-D Suicide Item [ Time Frame: 8 weeks ]
    Ham-D suicide item: range 0-4, higher scores indicate worse symptoms
  • Hamilton Anxiety Scale [ Time Frame: 8 weeks ]
    Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indi- cates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
  • Beck's Depression Inventory [ Time Frame: 8 weeks ]
    Range 0-63, with higher scores worse. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NMDA Antagonists in Bipolar Depression
Official Title  ICMJE NMDA Antagonists in Bipolar Depression
Brief Summary The purpose of this study is to test whether ketamine and D-cycloserine can be safely and effectively used for the treatment of depression. The investigators hypothesize that ketamine will serve as a rapid acting and safe antidepressant in patients with bipolar depression, and furthermore, that D-cycloserine will serve as an effective therapy following ketamine treatment.
Detailed Description Bipolar disorder affects 2% of the population in the United States and the depressive phase contributes disproportionally to morbidity and mortality. At present, few approved treatments for bipolar depression are available, and have primarily depended on manipulations of brain monoaminergic systems. In contrast, recent studies suggest that the N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonist, ketamine, may provide near-immediate relief for treatment resistant depression. Its utility during long-term treatment, however, is limited by its psychotomimetic potency and the need for repeated IV infusions. D-cycloserine (DCS) is an approved oral antibiotic for tuberculosis drug and a well-studied mixed agonist/antagonist at the NMDAR/glycine binding site. DCS showed preliminary evidence of efficacy in a pilot study. DCS would thus be practical from both a safety and route of administration perspective. The present study will explore the feasibility and safety of DCS for maintenance treatments, as measured by magnetic resonance spectroscopy (MRS).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Bipolar Disorder
Intervention  ICMJE
  • Drug: Standard of Care
    Quetiapine, olanzapine-fluoxetine, and lurasidone are approved treatments for bipolar depression. Quetiapine dosing will follow the product label(Anon), and will be titrated over the first 4 days to the target dose of 300 mg. Olanzapine-fluoxetine dosing will also follow standard guidelines. Lurasidone will be started at 20 mg, and titrated up to 60 mg daily as clinically indicated. Study physicians will use clinical judgment to choose between standard-of care treatments, and have the option to titrate standard-of-care within approved ranges, and to prescribe adjunctive benztropine and benzodiazepines if clinically indicated.
    Other Names:
    • Quetiapine
    • Olanzapine
    • fluoxetine
  • Drug: Ketamine
    Ketamine administration will be carried out according to the methods as described by previous studies. Subjects will receive ketamine hydrochloride (0.5 mg/kg) intravenously during 40 minutes. This dosage was selected based on previous trials of ketamine for the treatment of refractory depression and bipolar depression. Vital signs (blood pressure, heart rate) will be closely monitored throughout the time of infusion. Subjects will be evaluated for 2 consecutive days during this phase; i.e. treatment days (day 1) and rating days (day 2). Non-responders to ketamine will not proceed into the DCS phase. Response will be a 25% improvement on the Hamilton Depression Rating Scale (HDRS).
    Other Name: Ketamine Hydrochloride
  • Drug: D-cycloserine
    Immediately after the ketamine infusion, subjects will begin an eight-week treatment of DCS adjunctive to standard of care. DCS dosing will begin at 250 mg for three days→500mg (2 capsules)/day for 1 week → 750 mg (3 capsules)/day for 1 week → and 1000 mg (4 capsules)/day for the remainder of the study.
    Other Name: DCS
Study Arms  ICMJE Experimental: Ketamine and DCS treatment
Standard of Care: Subjects will receive treatment with either quetiapine, olanzapine-fluoxetine, or lurasidone. If after about 2 week, subjects are symptomatic, subjects will receive infusion of ketamine hydrochloride (0.5 mg/kg). After the ketamine phase, subject who show improvement will begin an 8-week treatment of oral D-cycloserine.
Interventions:
  • Drug: Standard of Care
  • Drug: Ketamine
  • Drug: D-cycloserine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 25, 2016)
8
Original Estimated Enrollment  ICMJE
 (submitted: April 16, 2013)
5
Actual Study Completion Date  ICMJE March 2016
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and female patients with Diagnostic and Statistical Manual, Version 4 (DSM-IV) diagnosis of bipolar disorder I or II, current major depressive episode without psychotic features, 18-60
  • Insufficient therapeutic response during the current episode
  • Medically stable for study participation
  • Judged clinically not to be at significant suicide or violence risk
  • Subject is off all psychotropic and other types of drugs likely to interact with glutamate for at least 14 days before starting the study. One exception is chloral hydrate or short acting benzodiazepines for distressing anxiety or insomnia (up to 72 hours prior to each MRI scan). In addition, subjects will be off antipsychotics for 1 month and off fluoxetine for 6 weeks prior to the study.
  • Subject is likely to be able to tolerate a medication washout. Only subjects who have failed their current medication regiment will be washed off medications.

Exclusion Criteria:

  • History of chronic psychosis or drug induced psychosis of any kind
  • Current DSM-IV diagnosis of drug abuse/dependence in the last six months. Subjects must have a negative drug screen at baseline.
  • Women will be excluded if they are pregnant lactating, or not either surgically-sterile or using appropriate methods of birth control. Women must agree to continue using applicable birth control throughout the trial. All women of child-bearing potential must have a negative urine pregnancy test
  • Taking any medication contraindicated with ketamine or DCS (ethionamide, isoniazid)
  • History of seizures, renal insufficiency or congestive heart failure
  • History of clinically significant violence
  • History of ketamine abuse/dependence or prior clinically significant adverse reaction to ketamine
  • Current alcohol abuse or dependence
  • Untreated hypertension
  • Clinically abnormal liver function tests (LFTs), thyroid, renal function or anemia
  • Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the body which may present a risk to the subject or interfere with the MR scan.
  • Medicinal patch, unless removed prior to the MR scan
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01833897
Other Study ID Numbers  ICMJE 6535
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party New York State Psychiatric Institute
Study Sponsor  ICMJE New York State Psychiatric Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Joshua T Kantrowitz, MD New York State Psychiatric Institute
PRS Account New York State Psychiatric Institute
Verification Date March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP