NMDA Antagonists in Bipolar Depression

Bipolar Disorder Clinical Trial

Official title:

NMDA Antagonists in Bipolar Depression

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01833897
• Other study ID #: 6535
• Status: Active, not recruiting
• Phase: Phase 4
• First received: April 12, 2013
• Last updated: September 28, 2015
• Start date: March 2013
• Est. completion date: December 2015

Study information

• Verified date: September 2015
• Source: New York State Psychiatric Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 30
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bipolar Disorder

Intervention

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.
• 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).
• 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.

Locations

Country	Name	City	State
United States	New York State Psychiatric Institute	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
New York State Psychiatric Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety, tolerability and efficacy of ketamine and d-cycloserine	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.	8 weeks	Yes
Secondary	Effect of ketamine and d-cycloserine on MRS.	We will pilot the effect of ketamine and d-cycloserine (DCS) on MRS.	8 weeks	No