A Pilot Study of Citicoline add-on Therapy in Patients With Bipolar Disorder or Major Depressive Disorder and Amphetamine Abuse or Dependence

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00377299
• Collaborator: Stanley Medical Research Institute (Other)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

Bipolar disorder (BD) is a common and severe psychiatric illness. Drug and alcohol abuse are very common in people with BD and other mood disorders and are associated with increased rates of hospitalization, violence towards self and others, medication non-adherence and cognitive impairment. However, few studies have investigated the treatment of dual-diagnosis patients as substance use is frequently an exclusion criterion in clinical trials of patients with BD. To address this need, we have developed a research program that explores the pharmacotherapy of people with BD and substance related-disorders. A potentially very interesting treatment for BD is citicoline. Some data suggest that this supplement may stabilize mood, decrease drug use and craving, and improve memory. We found promising results with citicoline in patients with BD and cocaine dependence. In recent years the use of amphetamine and methamphetamine has become an important public health concern. However, virtually no research has been conducted on the treatment of amphetamine abuse. We propose a double-blind placebo controlled prospective trial of citicoline in a group of 60 depressed outpatients with bipolar disorder, depressed phase or major depressive disorder and amphetamine abuse/dependence, to explore the safety and tolerability of citicoline, and its efficacy for mood symptoms, stimulant use and craving and its impact on cognition. Our goal is to determine which symptoms (e.g. mood, cognition, substance use) citicoline appears to be most effective and estimate effect sizes for future work.

Condition or Disease	Intervention/Treatment	Phase
Amphetamine Abuse; Amphetamine Dependence; Bipolar Disorder; Major Depressive Disorder	Drug: Citicoline; Drug: Placebo	N/A

Detailed Description

Sixty outpatients meeting the inclusion and exclusion criteria will be enrolled after completing an Institutional Review Board (IRB)-approved informed consent process. Baseline evaluation will include a medical and psychiatric history, structured clinical interview for Diagnostic and Statistical Manual (DSM-IV) (SCID), mood assessment with the Inventory of Depressive Symptomatology-Self Report (IDS-C), Young Mania Rating Scale (YMRS), and cognitive assessment with the Hopkins Auditory Verbal Learning Test (HVLT) (similar to the Rey Auditory Verbal Learning Test (RAVLT) but more alternative equivalent versions are available), Stroop and computer assessments including Sternberg Memory Task and the Running Memory Continuous Performance Test. Alternate but equivalent versions of all cognitive tests, except the Stroop, will be used to minimize practice effects with repeated administration. Days and amounts of amphetamine and other substance use will be assessed at each visit with urine drug screens, and through self-report using the timeline follow-back method. Amphetamine, and other drug, craving will be assessed with a visual analogue scales. Citicoline or placebo add-on therapy will be given beginning at one tablet (500mg)/day with an increase to two tablets 1000 mg/day at week 2, three tables 1500 mg/day at week 4 and four tablets 2000 mg/day at week 6.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Placebo-controlled Pilot Study of Citicoline add-on Therapy in Patients With Bipolar Disorder or Major Depressive Disorder and Amphetamine Abuse or Dependence
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Citicoline Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Drug: Citicoline; Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects. Citicoline or placebo (identical in appearance) add-on therapy was given beginning at one tablet (500mg/day) with an increase to two tablets (1000 mg/day) at week 2, three tablets (1500 mg/day) at week 4 and four tablets (2000 mg/day) at week 6. Doses were decreased, if needed, due to side effects.
Placebo Comparator: Placebo Placebo matching active medication.	Drug: Placebo; Placebo matching active medication in all other physical aspects

Outcome Measures

Primary Outcome Measures

1. Depression Symptoms [12 weeks]

   Inventory of Depressive Symptomatology-Clinician Rated (IDS-C), (a clinician-administered depression scale) is used to assess the severity of depressive symptoms.Scores can range from 0 to 84. The higher the score, the worse the depressive symptoms(worse outcome).

Secondary Outcome Measures

1. Amphetamine Craving [12 Weeks]

   Visual Analog Scale (VAS) assessing Methamphetamine craving with a 1-100 scale.Higher values on the VAS scale indicate a higher Methamphetamine craving(worse outcome).

2. Amphetamine Use [12 weeks]

   Participant reported days per 7-day week of methamphetamine use.

3. Hopkins Auditory Verbal Learning Test (HVLT) [12 weeks]

   The Hopkins Auditory Verbal Learning Test (HVLT) is a measure of cognition (memory/recall). Raw scores are derived for Total Recall, Delayed Recall, Retention (% retained), and a Recognition Discrimination Index. Raw scores are calculated into T-scores. T-scores are standardized scores on each dimension for each type. A score of 50 represents the mean. A difference of 10 from the mean indicates a difference of one standard deviation. Thus, a score of 60 is one standard deviation above the mean, while a score of 30 is two standard deviations below the mean.

4. Stroop Color Word Test [12 weeks]

   The Stroop Color Word Test measures the individual's ability to separate the word and color naming stimuli thus the ability to sort information from the environment and selectively react to this information. The scoring is a measure of time to complete 100 items and the numbers of items that can be completed. THe scores are converted into T-scores which have a mean of 50 and a standard deviation of 10.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Men and women ages 18-70 years

• Meeting criteria for a current major depressive episode (bipolar I,II, not otherwise specified (NOS)

, depressed phase) or major depressive disorder on the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders (SCID) with a duration of at least 4 weeks

• Meeting criteria for amphetamine abuse or dependence with use within 14 days prior to baseline

• No psychotropic medication changes within 14 days prior to study entry

Exclusion Criteria:

• Pregnant or nursing women

• Current citicoline therapy

• Active suicidal or homicidal ideation with plan and intent

• Dementia, mental retardation or other severe cognitive impairment that might interfere with the informed consent process

• Currently incarcerated at a prison or jail

• Severe or life threatening medical condition (e.g. terminal cancer, congestive heart failure)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Psychoneuroendocrine Research Program	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• Stanley Medical Research Institute

Investigators

• Principal Investigator: Sherwood Brown, M.D., Ph.D., University of Texas Southwestern Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT00377299
• Other Study ID Numbers: 052006-27
• First Posted: Sep 18, 2006
• Last Update Posted: Aug 8, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by University of Texas Southwestern Medical Center: Amphetamine Abuse; Amphetamine Dependence; Bipolar Disorder; Major Depressive Disorder; Citicoline
• Additional relevant MeSH terms: Disease; Amphetamine-Related Disorders; Depressive Disorder; Depression; Depressive Disorder, Major; Bipolar Disorder; Cytidine Diphosphate Choline

Study Results

Participant Flow

Recruitment Details	Sixty depressed outpatients with methamphetamine dependence were enrolled and randomized for 12 weeks of acute treatment after completing an IRB-approved written informed consent The study was conducted at the UT Southwestern Medical Center in Dallas. The first participant was enrolled on 10/11/06 and the final assessment was on 4/7/09.

Arm/Group Title	Citicoline	Placebo
Arm/Group Description	Citicoline add-on therapy was given beginning at one tablet(500mg/day) with an increase to two tablets(1000mg/day) at week 2, three tablets(1500mg/day)at week 4 and four tablets (2000mg/day) at week 6. Patients remained on 2000mg/day throughout the remaining weeks of the study (week 12). Doses were decreased, if needed, due to side effects.	Placebo identical in appearance to the medication was given beginning at one tablet with an increase to two tablets at week 2, three tablets at week 4 and four tablets at week 6. Patients remained on four tables throughout the remaining weeks of the study (week 12). Doses were decreased, if needed, due to side effects.
Period Title: Overall Study
STARTED	32	28
COMPLETED	13	4
NOT COMPLETED	19	24

Baseline Characteristics

Arm/Group Title	Citicoline	Placebo	Total
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Total of all reporting groups
Overall Participants	32	28	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.0 (9.6)	34.0 (7.4)	37.8 (9.3)
Sex: Female, Male (Count of Participants)
Female	17 53.1%	11 39.3%	28 46.7%
Male	15 46.9%	17 60.7%	32 53.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 3.6%	1 1.7%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	28 87.5%	20 71.4%	48 80%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 12.5%	7 25%	11 18.3%
Region of Enrollment (participants) [Number]
United States	32 100%	28 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Depression Symptoms
Description	Inventory of Depressive Symptomatology-Clinician Rated (IDS-C), (a clinician-administered depression scale) is used to assess the severity of depressive symptoms.Scores can range from 0 to 84. The higher the score, the worse the depressive symptoms(worse outcome).
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) group includes all who returned for at least one post baseline visit. Analysis uses Last Observation Carried Forward (LOCF) method.

Arm/Group Title	Citicoline	Placebo
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Placebo.
Measure Participants	28	20
Mean (Standard Error) [scores on a scale]	26.2 (2.5)	33.1 (3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citicoline, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	Significance was set at a p value of ≤ 0.05.
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Amphetamine Craving
Description	Visual Analog Scale (VAS) assessing Methamphetamine craving with a 1-100 scale.Higher values on the VAS scale indicate a higher Methamphetamine craving(worse outcome).
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

ITT includes those returning for at least one post baseline visit. LOCF used for end point data.

Arm/Group Title	Citicoline	Placebo
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Placebo.
Measure Participants	19	27
Mean (Standard Error) [scores on a scale]	31.9 (8.0)	44.1 (9.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citicoline, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance was set at a p value of ≤ 0.05.
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Amphetamine Use
Description	Participant reported days per 7-day week of methamphetamine use.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

ITT includes those returning for at least one post baseline visit. LOCF used for end point data.

Arm/Group Title	Citicoline	Placebo
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Placebo matching Citicoline.
Measure Participants	28	20
Mean (Standard Error) [days per week]	2.9 (0.6)	2.3 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citicoline, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance was set at a p value of ≤ 0.05.
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Hopkins Auditory Verbal Learning Test (HVLT)
Description	The Hopkins Auditory Verbal Learning Test (HVLT) is a measure of cognition (memory/recall). Raw scores are derived for Total Recall, Delayed Recall, Retention (% retained), and a Recognition Discrimination Index. Raw scores are calculated into T-scores. T-scores are standardized scores on each dimension for each type. A score of 50 represents the mean. A difference of 10 from the mean indicates a difference of one standard deviation. Thus, a score of 60 is one standard deviation above the mean, while a score of 30 is two standard deviations below the mean.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

ITT includes those returning for at least one post baseline visit. LOCF used for end point data.

Arm/Group Title	Citicoline	Placebo
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Placebo matching Citicoline.
Measure Participants	17	9
Mean (Standard Error) [T score]	38.5 (3.8)	47.5 (4.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citicoline, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance was set at a p value of ≤ 0.05.
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Stroop Color Word Test
Description	The Stroop Color Word Test measures the individual's ability to separate the word and color naming stimuli thus the ability to sort information from the environment and selectively react to this information. The scoring is a measure of time to complete 100 items and the numbers of items that can be completed. THe scores are converted into T-scores which have a mean of 50 and a standard deviation of 10.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Citicoline	Placebo
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.	Placebo.
Measure Participants	28	20
Mean (Standard Error) [T score]	56.2 (2.6)	54.3 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citicoline, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance was set at a p value of ≤ 0.05.
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	Citicoline		Placebo
Arm/Group Description	Citicoline is an over the counter supplement that may have neuroprotective properties and may have antidepressant effects.
All Cause Mortality
	Citicoline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Citicoline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/32 (3.1%)		4/28 (14.3%)
Injury, poisoning and procedural complications
Injuries Due to Car Accident	1/32 (3.1%)	1	0/28 (0%)	0
Drug Overdose	0/32 (0%)	0	1/28 (3.6%)	1
Car Accident	0/32 (0%)	0	1/28 (3.6%)	1
Psychiatric disorders
Drug Overdose / Suicidal Gesture	0/32 (0%)	0	1/28 (3.6%)	1
Psychiatric Hospitalization Involuntary	0/32 (0%)	0	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	Citicoline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/32 (6.3%)		0/28 (0%)
Infections and infestations
Tooth Abscess and Infection	1/32 (3.1%)	1	0/28 (0%)	0
Psychiatric disorders
Severe Panic Attack	1/32 (3.1%)	1	0/28 (0%)	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.