Ketamine Plus Lithium in Treatment-Resistant Depression

• Sponsor: Icahn School of Medicine at Mount Sinai (Other)
• Overall Status: Completed
• CT.gov ID: NCT01880593
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arms: 2
• Duration (Months): 40
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to test the antidepressant effect of ketamine when given repeatedly over a period of 1 week, as well as the use of Lithium as a relapse-prevention strategy for patients with treatment-resistant depression (TRD) who respond to an initial series of ketamine infusions. Ketamine is a Food and Drug Administration approved anesthetic (a drug used to produce loss of consciousness before and during surgery). Ketamine is not approved for the treatment of major depressive disorder and is considered experimental in this study. An additional purpose of this study is to research the effects of ketamine on brain function.

You may qualify to take part in this research study because you have been diagnosed with major depressive disorder (MDD) and have not responded to past treatments.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: Lithium; Drug: Ketamine; Drug: Placebo	Phase 2

Detailed Description

Major Depressive Disorder (MDD) is a disabling medical illness and current monoaminergic treatments are slow to act and possess only limited efficacy. In this context, the discovery that the glutamate NMDA receptor antagonist ketamine is rapidly antidepressant (onset of action within hours) -- even in patients suffering from treatment-resistant depression (TRD) -- has ignited tremendous enthusiasm among clinicians, scientists and patients alike. A critical obstacle to the translation of this discovery into a novel treatment, however, is the limited duration of action following a course of ketamine (e.g. 1-2 weeks). The current project will address this important gap in medical knowledge by testing a rational neuropharmacological strategy designed to optimize and sustain the rapid antidepressant effects of ketamine. Driven by the recent characterization of the molecular mechanisms underpinning the antidepressant and neuroplasticity effects of ketamine, we will test the combination of ketamine plus lithium in patients with TRD using a randomized, double blind, placebo-controlled design. The primary aims of the project are (1) to test the efficacy of lithium-plus-ketamine compared to placebo-plus-ketamine as an antidepressant combination strategy in TRD and (2) to gather data on the safety and tolerability of the lithium-plus-ketamine.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Ketamine Plus Lithium as a Novel Pharmacotherapeutic Strategy in Treatment-Resistant Depression
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine and Lithium Subjects in this arm take 600-1200mg of Lithium pills at night for duration of the study	Drug: Lithium; Subjects in this arm take 600-1200mg of Lithium pills at night for duration of the study.; Other Names: Lithium Carbonate Immediate Release ; Drug: Ketamine
Placebo Comparator: Ketamine and Placebo Subjects in this arm take placebo pills at night for duration of the study.	Drug: Ketamine; Drug: Placebo; Subjects in this arm take placebo pills at night for duration of the study.

Outcome Measures

Primary Outcome Measures

1. MADRS-S Score [2 weeks after last ketamine infusion]

   The Montgomery Asberg Depression Rating Scale (MADRS-S) has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).

Secondary Outcome Measures

1. QIDS-SR Score [2 weeks after last ketamine infusion]

   Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) score - Each item is rated 0 (no depression) to 3 (severe depression), for a total score range of 0 (no depression) to 27 (severe depression).

2. CGI-S Score [2 weeks after last ketamine infusion]

   The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

3. HAM-A Score [2 weeks after last ketamine infusion]

   Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.

4. BSS Score [2 weeks after last ketamine infusion]

   BECK Scale for Suicidal Ideation (BSS) - 0-13 Minimal; 14-19 Mild; 20-28 Moderate; 29-63 Severe

5. CSSRS Score [2 weeks after last ketamine infusion]

   Columbia Suicide Severity Rating Scale (CSSRS) - Full range from 0 (low intensity suicidal ideation to 9 (high intensity suicidal ideation).

6. Patient Rated Inventory of Side Effects (PRISE) [2 weeks after last ketamine infusion]

   Number of Participants with PRISE

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female patients, 21-65 years of age;

• Female individuals who are not of childbearing potential (i.e., surgically sterile, postmenopausal for at least one year) or using a medically accepted reliable means of contraception. Women using oral contraceptive medication for birth control must also be using a barrier contraceptive. Women of childbearing potential must also have a negative serum B-HCG at screening and at pre-infusion;

• Participants must fulfill DSM-IV criteria for Major Depression without psychotic features, based on clinical assessment by a study psychiatrist and confirmed by a structured diagnostic interview, the Structured Clinical Interview for DSM-IV TR Axis I Disorders, Patient Edition (SCID-P);

• Participants must have a history of at least one previous episode of depression prior to the current episode (recurrent MDD) or have chronic MDD (of at least two years' duration);

• Participants have not responded to two or more adequate trials of an antidepressant as determined by Antidepressant Treatment History Form (ATHF) criteria (score >=3);

• Current Major Depressive Episode of at least moderate severity, defined as a QIDS-SR score ≥ 14 and a CGI-S score of ≥ 4;Current major depressive episode is of at least 4 weeks duration;

• Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document;

• Each participant must be able to identify a family member, physician, or friend who will participate in the Treatment Contract.

Exclusion Criteria:

• Lifetime history of psychotic features, diagnosis of schizophrenia or any other psychotic disorder, or diagnosis of bipolar disorder;

• Lifetime histories of autism, mental retardation, pervasive developmental disorders, or Tourette's syndrome;

• Current diagnosis of OCD or eating disorder (bulimia nervosa or anorexia nervosa);

• Subjects with DSM-IV drug or alcohol abuse/dependence within the preceding 2 years;

• Patients with schizotypal or antisocial personality disorder, or any clinically significant axis II disorder that would, in the investigator's judgment, preclude safe study participation;

• Patients judged clinically to be at serious and imminent suicidal or homicidal risk;

• Women who are either pregnant or nursing;

• Serious, unstable medical illnesses including hepatic, renal impairment, gastroenterologic (including gastro-esophageal reflux disease), respiratory (including obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics), cardiovascular (including ischemic heart disease and uncontrolled hypertension), endocrinologic, neurologic (including history of severe head injury), immunologic, or hematologic disease;

• Clinically significant abnormal findings of laboratory parameters, physical examination, or ECG;

• Patients who have a positive urine toxicology for illicit substances at screening and within 24 hours of the infusion;

• Patients with one or more seizures without a clear and resolved etiology;

• Treatment with an irreversible MAOI within 2 weeks prior to randomization or fluoxetine within 4 weeks prior to randomization;

• Treatment with other antidepressants within one week of randomization;

• Previous recreational use of PCP or ketamine;

• Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg) not controlled by diuretic or beta-blocker therapy alone or in combination;

• A blood pressure reading over 160/90 or two separate readings over 140/90 at screening or baseline visits;

• Renal impairment, as reflected by a BUN > 20 mg/dL and/or creatinin clearance of >1.3 mg/dL;

• Thyroid impairment, as reflected by a TSH > 4.2 mU/L;

• Cardiac disease, as reflected by an EKG that is abnormal and of concern for cardiac disease;

• Any anticipated change in medications that could affect fluid or salt balance, including the following antihypertensive agents: ACE inhibitor, loop diuretics, calcium channel blockers, thiazide diuretics, angiotensin II receptor blockers.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Icahn School of Medicine at Mount Sinai

Investigators

• Principal Investigator: James W Murrough, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mood and Anxiety Disorders Program

Publications

• Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS, Iosifescu DV. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013 Aug 15;74(4):250-6. doi: 10.1016/j.biopsych.2012.06.022. Epub 2012 Jul 27.

• Responsible Party: James Murrough, Assistant Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01880593
• Other Study ID Numbers: GCO 13-0365
• First Posted: Jun 19, 2013
• Last Update Posted: Jul 31, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by James Murrough, Assistant Professor, Icahn School of Medicine at Mount Sinai: Ketamine; glutamate; N-methyl-D-aspartate; depression; major depressive disorder; treatment resistant; antidepressant; lithium
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Ketamine; Lithium Carbonate

Study Results

Participant Flow

Recruitment Details	Recruitment from May 2013 through Sept 2016

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Period Title: Overall Study
STARTED	18	16
COMPLETED	10	10
NOT COMPLETED	8	6

Baseline Characteristics

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo	Total
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study	Total of all reporting groups
Overall Participants	18	16	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45 (12.65)	45.87 (10.94)	45.41 (11.70)
Sex: Female, Male (Count of Participants)
Female	9 50%	9 56.3%	18 52.9%
Male	9 50%	7 43.8%	16 47.1%
MADRS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	32.39 (3.87)	32.81 (5.61)	32.58 (4.69)
QIDS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	16.22 (4.33)	18.19 (3.082)	17.16 (4.32)
CGI-S (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.66 (.59)	5 (.52)	4.92 (.57)
BSS (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.89 (7.71)	7.56 (8.31)	7.24 (8.10)
HAM-A (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	18.78 (7.02)	20.31 (5.11)	19.5 (6.15)
CSSRS (lifetime) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.5 (2.7)	2.06 (2.02)	2.29 (2.28)

Outcome Measures

1. Primary Outcome

Title	MADRS-S Score
Description	The Montgomery Asberg Depression Rating Scale (MADRS-S) has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Mean (Standard Deviation) [units on a scale]	22.56 (11.22)	23 (12.6)

2. Secondary Outcome

Title	QIDS-SR Score
Description	Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) score - Each item is rated 0 (no depression) to 3 (severe depression), for a total score range of 0 (no depression) to 27 (severe depression).
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Mean (Standard Deviation) [units on a scale]	9.89 (6.04)	10.13 (6.47)

3. Secondary Outcome

Title	CGI-S Score
Description	The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Mean (Standard Deviation) [units on a scale]	3.83 (.86)	3.875 (1.36)

4. Secondary Outcome

Title	HAM-A Score
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 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Mean (Standard Deviation) [units on a scale]	13.5 (8.15)	11.13 (6.08)

5. Secondary Outcome

Title	BSS Score
Description	BECK Scale for Suicidal Ideation (BSS) - 0-13 Minimal; 14-19 Mild; 20-28 Moderate; 29-63 Severe
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Mean (Standard Deviation) [units on a scale]	4.94 (7.35)	2.69 (5.95)

6. Secondary Outcome

Title	CSSRS Score
Description	Columbia Suicide Severity Rating Scale (CSSRS) - Full range from 0 (low intensity suicidal ideation to 9 (high intensity suicidal ideation).
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Mean (Standard Deviation) [units on a scale]	.833 (2.12)	.44 (.89)

7. Secondary Outcome

Title	Patient Rated Inventory of Side Effects (PRISE)
Description	Number of Participants with PRISE
Time Frame	2 weeks after last ketamine infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine and Lithium	Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study	Placebo pills at night for duration of the study
Measure Participants	18	16
Count of Participants [Participants]	3 16.7%	2 12.5%

Adverse Events

Arm/Group Title	Ketamine and Lithium		Ketamine and Placebo
Arm/Group Description	600-1200mg of Lithium pills at night for duration of the study		Placebo pills at night for duration of the study
All Cause Mortality
	Ketamine and Lithium		Ketamine and Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/16 (0%)
Serious Adverse Events
	Ketamine and Lithium		Ketamine and Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine and Lithium		Ketamine and Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/18 (83.3%)		12/16 (75%)
Gastrointestinal disorders
Nausea	8/18 (44.4%)		4/16 (25%)
Dry Mouth	3/18 (16.7%)		0/16 (0%)
Diarrhea	9/18 (50%)		2/16 (12.5%)
Constipation	3/18 (16.7%)		0/16 (0%)
Vomiting	2/18 (11.1%)		0/16 (0%)
Abdominal Pain	3/18 (16.7%)		0/16 (0%)
General disorders
Fatigue	2/18 (11.1%)		0/16 (0%)
Chest Discomfort	0/18 (0%)		2/16 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/18 (11.1%)		0/16 (0%)
Nervous system disorders
Headache	8/18 (44.4%)		9/16 (56.3%)
Dizziness	2/18 (11.1%)		0/16 (0%)
Tinnitus	2/18 (11.1%)		0/16 (0%)
Tremor	2/18 (11.1%)		0/16 (0%)
Psychiatric disorders
Insomnia	2/18 (11.1%)		1/16 (6.3%)
Anxiety	0/18 (0%)		2/16 (12.5%)
Renal and urinary disorders
Pollakiuria	3/18 (16.7%)		1/16 (6.3%)
Polyuria	2/18 (11.1%)		0/16 (0%)
Skin and subcutaneous tissue disorders
Rash	3/18 (16.7%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.