Research Study for Major Depressive Disorder: Investigation of Glutamate Medications

• Sponsor: Baylor College of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT00419003
• Collaborator: National Alliance for Research on Schizophrenia and Depression (Other), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 21
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This study is examining the safety and effectiveness of two medications, ketamine and riluzole, in treating patients with treatment resistant major depressive disorder. This study will also examine the effectiveness of an FDA approved drug called lamotrigine in decreasing the potential side effects associated with ketamine.

Condition or Disease	Intervention/Treatment	Phase
Major Depression	Drug: Lamotrigine; Drug: Ketamine; Drug: Riluzole	Phase 4

Detailed Description

This research proposal will investigate a glutamate-modulating agent, riluzole, in treatment-resistant patients who exhibit an acute, sustained response to a single dose of intravenous (IV) racemic ketamine. Fifty ketamine-responders will be randomized to riluzole or placebo in a 4-week, randomized, double-blind, continuation-phase study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Continuation Riluzole in the Prevention of Relapse Following Ketamine in Major Depression
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lamotrigine Pre-Treatment Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. 300 mg of lamotrigine 2 hrs prior to ketamine infusion. Responders were randomized to one of two continuation pharmacotherapy groups, receiving either two capsules of riluzole 50 mg each (100 mg/d) or matching pill placebo under double-blind conditions.	Drug: Lamotrigine; anticonvulsant medication; Other Names: lamictal ; Drug: Ketamine; subanesthetic dose of NMDAR antagonist; Other Names: ketalar ; Drug: Riluzole; glutamate release inhibitor; Other Names: rilutek
Placebo Comparator: Placebo Pre-Treatment 2 hours prior to ketamine infusion each patient received three capsules of placebo identical in size, weight, appearance, and taste to the lamotrigine tablets. Responders were randomized to one of two continuation pharmacotherapy groups, receiving either two capsules of riluzole 50 mg each (100 mg/d) or matching pill placebo under double-blind conditions.	Drug: Ketamine; subanesthetic dose of NMDAR antagonist; Other Names: ketalar ; Drug: Riluzole; glutamate release inhibitor; Other Names: rilutek

Outcome Measures

Primary Outcome Measures

1. Montgomery-Asberg Depression Rating Scale (MARDS) Score (Acute Response to IV Ketamine in Patients With Treatment Resistant Major Depression) [24 Hours]

   Montgomery-Asberg Depression Rating Scale, each of the ten items can be scored from 0 (absence of symptoms to 6 most severe) and has a total score range of 0-60. A lower score on a MADRS indicates a less severe depression. The primary outcome for the initial phase of the trial was the 24-h MADRS score, which included all 10 MADRS items.

Other Outcome Measures

1. Efficacy of Lamotrigine in Decreasing IV Ketamine Psychotomimetic Side Effects [24, 48, or 72-hrs]

   Response rate and side effect differences to IV ketamine infusion based on lamotrigine and placebo pretreatment groups

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients, 21- 70 years of age

2. Subjects have a history of at least one previous episode of depression prior to the current episode (recurrent major depressive disorder) or have chronic major depressive disorder (at least two years' duration)

3. Subjects have not responded to an adequate trial of one antidepressant in the current episode

Exclusion Criteria:

1. Female subjects who are either pregnant or nursing

2. Serious, unstable illnesses

3. Any previous use or treatment with ketamine, or riluzole

4. Past intolerance to lamotrigine, including drug rash

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mount Sinai School of Medicine	New York	New York	United States	10029

Sponsors and Collaborators

• Baylor College of Medicine
• National Alliance for Research on Schizophrenia and Depression
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Sanjay Mathew, MD, Baylor College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanjay Johan Mathew, MD, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00419003
• Other Study ID Numbers: 05-0850; 5M01RR000071-46
• First Posted: Jan 5, 2007
• Last Update Posted: Jul 31, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Depression; Depressive Disorder, Major; Lamotrigine; Ketamine; Riluzole

Study Results

Participant Flow

Recruitment Details	The intent-to-treat sample (n=26) was recruited from media/internet advertising (14), psychiatrist referral (8), or self-referral from the New York Mood Disorders Support Group (4). Patients had marked depressive severity, chronicity, and anxiety comorbidity, and were highly pharmacotherapy-resistant.
Pre-assignment Detail	2-wk psychotropic medication washout period (4 wk for fluoxetine)

Arm/Group Title	Lamotrigine Pre-Treatment (Phase I)/Riluzole (Phase II)	Placebo Pre-Treatment (Phase I)/Placebo (Phase II)
Arm/Group Description	Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth. All non responders were exited from the study. All responders (in both the lamotrigine and placebo pre-treatment groups were treated as one group and randomized into either treatment with riluzole or placebo for Phase II)	Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth. All non responders were exited from the study. All responders (in both the lamotrigine and placebo pre-treatment groups were treated as one group and randomized into either treatment with riluzole or placebo for Phase II)
Period Title: Phase I, Ketamine Infusion
STARTED	13	13
COMPLETED	7	7
NOT COMPLETED	6	6
Period Title: Phase I, Ketamine Infusion
STARTED	6	8
COMPLETED	5	8
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Lamotrigine Pre-Treatment	Placebo Pre-Treatment	Total
Arm/Group Description	Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth.	Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth.	Total of all reporting groups
Overall Participants	13	13	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.2 (11.8)	48.2 (11.8)	48.2 (11.8)
Sex: Female, Male (Count of Participants)
Female	5 38.5%	5 38.5%	10 38.5%
Male	8 61.5%	8 61.5%	16 61.5%
Region of Enrollment (participants) [Number]
United States	13 100%	13 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Montgomery-Asberg Depression Rating Scale (MARDS) Score (Acute Response to IV Ketamine in Patients With Treatment Resistant Major Depression)
Description	Montgomery-Asberg Depression Rating Scale, each of the ten items can be scored from 0 (absence of symptoms to 6 most severe) and has a total score range of 0-60. A lower score on a MADRS indicates a less severe depression. The primary outcome for the initial phase of the trial was the 24-h MADRS score, which included all 10 MADRS items.
Time Frame	24 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riluzole Group	Placebo
Arm/Group Description	Patients who responded (n=14) to the ketamine infusion (in either the lamotrigine or placebo pre-treatment groups) were randomized into phase II for treatment with either riluzole or placebo. One patient in the riluzole group was discontinued/withdrew consent before completing the study.	Patients who responded (n=14) to the ketamine infusion (in either the lamotrigine or placebo pre-treatment groups) were randomized into phase II for treatment with either riluzole or placebo.
Measure Participants	13	13
Mean (95% Confidence Interval) [scores on a scale]	24.4	22.0

2. Other Pre-specified Outcome

Title	Efficacy of Lamotrigine in Decreasing IV Ketamine Psychotomimetic Side Effects
Description	Response rate and side effect differences to IV ketamine infusion based on lamotrigine and placebo pretreatment groups
Time Frame	24, 48, or 72-hrs

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Riluzole Group		Placebo		Ketamine		Lamotrigine Pre-Treatment		Placebo Pre-Treatment
Arm/Group Description	Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth.		Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth.		IV infusion of 0.5 mg/kg of Ketamine Hydrochloride		Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth.		Patients who met enrolment criteria for phase 1 were randomly allocated to lamotrigine or placebo by a permuted block procedure consisting of blocks of two or four patients. The randomization list was created by a biostatistician with no patient contact. Following baseline ratings, 2 h prior to i.v. ketamine infusion, patients received 300 mg lamotrigine or placebo by mouth.
All Cause Mortality
	Riluzole Group		Placebo		Ketamine		Lamotrigine Pre-Treatment		Placebo Pre-Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Riluzole Group		Placebo		Ketamine		Lamotrigine Pre-Treatment		Placebo Pre-Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/8 (0%)		0/26 (0%)		0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Riluzole Group		Placebo		Ketamine		Lamotrigine Pre-Treatment		Placebo Pre-Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		5/8 (62.5%)		26/26 (100%)		5/13 (38.5%)		0/13 (0%)
Nervous system disorders
Headache	2/6 (33.3%)	6	0/8 (0%)	0	26/26 (100%)	26	5/13 (38.5%)	5	0/13 (0%)	0
Dizziness	1/6 (16.7%)	2	3/8 (37.5%)	3	26/26 (100%)	26	0/13 (0%)	26	0/13 (0%)	26
Fatigue	3/6 (50%)	3	2/8 (25%)	2	0/26 (0%)	2	5/13 (38.5%)	5	0/13 (0%)	5

Limitations/Caveats

The open-label administration of ketamine limits interpretation of phase 1 results. The sample size was too small to detect moderators and mediators of response. Third,lack of placebo-controlled efficacy data supporting riluzole's use in depression.

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.