NMDA Antagonists in Bipolar Depression

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01833897
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 36
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Standard of Care; Drug: Ketamine; Drug: D-cycloserine	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: NMDA Antagonists in Bipolar Depression
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

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.

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 Names: 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 Names: DCS

Outcome Measures

Primary Outcome Measures

1. Hamilton Depression Rating Scale (HAM-D) [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

Secondary Outcome Measures

1. Loss of Motivated Behavior HAM-D Factor [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

2. HAM-D Suicide Item [8 weeks]

   Ham-D suicide item: range 0-4, higher scores indicate worse symptoms

3. Hamilton Anxiety Scale [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.

4. Beck's Depression Inventory [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute

Investigators

• Principal Investigator: Joshua T Kantrowitz, MD, New York State Psychiatric Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT01833897
• Other Study ID Numbers: 6535
• First Posted: Apr 17, 2013
• Last Update Posted: Jun 1, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by New York State Psychiatric Institute: Bipolar Disorder
• Additional relevant MeSH terms: Bipolar Disorder; Cycloserine; Ketamine; Olanzapine; Quetiapine Fumarate; Fluoxetine

Study Results

Participant Flow

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Period Title: Overall Study
STARTED	8
COMPLETED	7
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37 (16)
Sex: Female, Male (Count of Participants)
Female	5 62.5%
Male	3 37.5%
Montgomery Asberg Depression Rating scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	29 (6)
Hamilton Depression Rating Scale (HAM-D) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	18.8 (6.7)
Hamilton Depression Rating Scale (HAM-D) suicide item (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.25 (0.9)
Loss of Motivated Behavior HAM-D Factor (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5 (1.6)
Hamilton Anxiety Rating Scale (HAM-A) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	12.6 (4.2)
Beck's depression inventory (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	31.4 (10.4)
Time of treatment resistance (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	3.3 (4)

Outcome Measures

1. Primary Outcome

Title	Hamilton Depression Rating Scale (HAM-D)
Description	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
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

bipolar depression

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Measure Participants	8
Mean (Standard Deviation) [units on a scale (final score)]	9.5 (7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine and DCS Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	F1,6.4=161.8,
	Method	linear mixed model
	Comments

2. Secondary Outcome

Title	Loss of Motivated Behavior HAM-D Factor
Description	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
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

bipolar depression

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Measure Participants	8
Mean (Standard Deviation) [units on a scale (final score)]	1.6 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine and DCS Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	HAM-D Suicide Item
Description	Ham-D suicide item: range 0-4, higher scores indicate worse symptoms
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Measure Participants	8
Mean (Standard Deviation) [units on a scale (final)]	0.3 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine and DCS Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Hamilton Anxiety Scale
Description	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.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Measure Participants	8
Mean (Standard Deviation) [units on a scale (final score)]	6.4 (5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine and DCS Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Beck's Depression Inventory
Description	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.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
Measure Participants	8
Mean (Standard Deviation) [units on a scale (final score)]	10.8 (9.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ketamine and DCS Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Arm/Group Title	Ketamine and DCS Treatment
Arm/Group Description	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.
All Cause Mortality
	Ketamine and DCS Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ketamine and DCS Treatment
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine and DCS Treatment
	Affected / at Risk (%)	# Events
Total	4/8 (50%)
Eye disorders
phosphenes	1/8 (12.5%)	1
Nervous system disorders
headache	2/8 (25%)	2
sedation	3/8 (37.5%)	3
Psychiatric disorders
hypomania	1/8 (12.5%)	1

Limitations/Caveats

Limitations include the small-sample and a non-placebo controlled, open-label design.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.