Journal of Affective Disorders 143 (2012) 257–260

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Brief report

A randomized, double-blind, placebo-controlled trial of citicoline for

bipolar and unipolar depression and methamphetamine dependence
E. Sherwood Brown n, Barry Gabrielson
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

a r t i c l e i n f o abstract

Article history: Background: Methamphetamine use disorders are common and severe problems. Persons with mood
Received 16 April 2012 disorders, particularly bipolar disorder, have high rates of substance use disorders. We previously
Accepted 1 May 2012 reported promising findings on drug use, memory and study retention in patients with a history of
Available online 11 September 2012
mania and cocaine dependence given the nutritional supplement citicoline. In the current proof-of-
Keywords: concept study, we examined citicoline in bipolar or unipolar depression and methamphetamine
Citicoline dependence.
Bipolar disorder Methods: Sixty adults with bipolar depression or major depressive disorder and methamphetamine
Depression dependence were randomized to citicoline (2000 mg/day) or placebo for 12 weeks. Mood was assessed
Cognition
using Inventory of Depressive Symptomatology-Clinician Version (IDS-C), and cognition with the Hopkins
Memory
Auditory Verbal Learning Test (HVLT). Drug use was assessed by urine drug screens.
Methamphetamine
Results: An ANCOVA of the intent-to-treat sample showed that those receiving citicoline (n¼ 28) had a
statistically significantly greater improvement in IDS-C scores than those receiving placebo (n¼ 20).
Survival in the study was significantly longer and completion rates significantly greater with citicoline than
placebo. No significant differences were observed in memory or methamphetamine use. Citicoline was well
tolerated.
Limitations: Sample heterogeneity and small sample size were limitations.
Conclusions: To our knowledge this is the first placebo-controlled trial in a dual diagnosis sample with
methamphetamine use disorders. Findings suggest that citicoline may have antidepressant properties in this
population. Greater treatment retention with citicoline is also noteworthy in a patient population with
substance dependence. Larger trials targeting depressive symptoms and treatment retention seem warranted.
& 2012 Elsevier B.V. All rights reserved.

1. Introduction
Dependence on amphetamines, particularly methampheta-
mine, is a major public health concern (Rawson et al., 2002). To
date, few clinical trials have been published on the pharma-
cotherapy of methamphetamine dependence. Limited available
data in this population suggest somewhat positive findings with
methylphenidate (Tiihonen et al., 2007), dexamphetamine (Longo
et al., 2010) and naltrexone (Jayaram-Lindstrom et al., 2008a;
Jayaram-Lindstrom et al., 2008b), and negative findings with
modafinil (Shearer et al., 2009), bupropion (Elkashef et al.,
2008) and ondansetron (Johnson et al., 2008).
Bipolar disorder and major depressive disorder have a prevalence
of substance use disorders (Regier et al., 1990). Mood disorders are
common in patients presenting with methamphetamine use dis-
orders (Glasner-Edwards et al., 2010). Methamphetamine use is
associated with cognitive impairment (Sofuoglu, 2010). Bipolar
n
Correspondence to: Department of Psychiatry, The University of Texas
Southwestern Medical Center, Dallas, 5323 Harry Hines Blvd., MC 8849, Dallas,
75390 8849 TX, USA. Tel.: þ 1 214 645 6950; fax: þ1 214 645 6951.
E-mail address: Sherwood.Brown@UTSouthwestern.edu (E.S. Brown).
disorder (Osuji and Cullum, 2005) and major depressive disorder
(McClintock et al., 2010) are also associated with poor cognition.
Therefore, an intervention that decreased drug use and improved
mood and cognition would be very useful in a patient population
with mood disorders and methamphetamine use. To our knowledge,
no placebo-controlled trials have been conducted in this dual
diagnosis population.
Citicoline is a naturally occurring compound sold as an over-the-
counter nutritional supplement in the United States and as a drug in
other countries (Adibhatla and Hatcher, 2005). Citicoline increases
phospholipid incorporation into membranes and enhances synthesis
of structural phospholipids (Adibhatla and Hatcher, 2005), as well as
increases norepinephrine, dopamine, serotonin and acetyl choline
levels in specific brain regions (Dixon et al., 1997; Petkov et al., 1990).
Citicoline may have neuroprotective and cognitive enhancing proper-
ties. A Cochrane review reported that citicoline was more effective
than placebo for cognitive impairment in vascular dementia
(Fioravanti and Yanagi, 2005). Citicoline was neuroprotective in
animal models of hypoxia (Clark et al., 1999). Cytidine (a citicoline
metabolite) had antidepressant effects in the forced swim test
(Carlezon et al., 2002). A small trial of citicoline in treatment
refractory depression (primarily bipolar depression) showed

0165-0327/$ - see front matter & 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jad.2012.05.006
258 E.S. Brown, B. Gabrielson / Journal of Affective Disorders 143 (2012) 257–260

promising results (Salvadorini et al., 1975) while another small trial
showed positive results with choline given to patients with mania
(Stoll et al., 1996). Citicoline may also decrease cocaine craving
(Renshaw et al., 1999).
We reported promising findings with citicoline in patients
with bipolar disorder and cocaine dependence (Brown et al.,
2007). As compared to placebo, citicoline was associated with a
significant reduction in cocaine-positive urines and improvement
in aspects of declarative memory. Improvement in depressive
symptoms and length of survival in the study favored citicoline
but were not statistically significant. The current trial is a proof-
of-concept study of citicoline in patients with current depression
(unipolar or bipolar) and methamphetamine dependence.
1.1. Patients and methods
Sixty depressed outpatients with methamphetamine dependence
were enrolled and randomized to citicoline or placebo, in a double-
blind fashion for 12 weeks of acute treatment after completing an
IRB-approved written informed consent process. Participants and all
staff members with patient contact were blinded to treatment group
assignment. Baseline evaluation included a medical and psychiatric
history, structured clinical interview for DSM-IV (SCID) (First et al.,
1995), mood assessment with the Inventory of Depressive Sympto-
last observation carried forward (LOCF) on continuous outcomes
were compared with ANCOVAs that used baseline scores of the
outcome being assessed, gender, mood disorder diagnosis (bipolar
and unipolar), age, baseline number of antidepressants used, and
grams of methamphetamine used as covariates. Urine drug screens
(þ / ) were compared using chi squares. Study survival was
assessed using a Kaplan–Meier survival analysis. Significance was
set at a p value of r0.05 for all comparisons.
2. Results
Of 60 participants, randomized 48 participants returned for at
least one post-baseline assessment and were used in the data
analysis (intent-to-treat sample). Demographic information about
the two treatment groups is provided in Table 1. The two groups
did not differ significantly on any baseline characteristic except
age, which was higher in the citicoline group and included as a
covariate on the data analysis. Baseline concomitant psychotropic
Table 1
Baseline demographic characteristics of citicoline and placebo groups.

matology-Clinician Rated (IDS-C) (Rush et al., 1996), and memory

Baseline characteristic Citicoline Placebo
with the Hopkins Auditory Verbal Learning Test (HVLT) (Brandt, (n¼28) (N¼ 20)
1991). Alternative versions (different words) were used on the HVLT
to minimize learning effects from repeated administration. Citicoline Mean age (SD) 41.6 (9.9) 34.0 (7.3)
Gender, N (%)
or placebo (identical in appearance) add-on therapy was given
Female 15 (53.6%) 7 (35.0%)
beginning at one tablet (500 mg/day) with an increase to two Male 13 (46.4%) 13 (65.0%)
tablets (1000 mg/day) at week 2, three tablets (1500 mg/day) at
Ethnicity, N (%)
week 4 and four tablets (2000 mg/day) at week 6. Doses were Caucasian 24 (85.7%) 13 (65.0%)
decreased, if needed, due to side effects. Concomitant medication African-American 0 (0%) 0 (0%)
changes were managed with a treatment algorithm. This approach Hispanic 3 (10.7%) 6 (30.0%)
was selected to prevent early discontinuation of any participant that Other 1 (3.6%) 1 (5.0%)
required an adjustment in a concomitant medication while provid- Income, N (%)
ing structure and consistency to the changes. Participants were less than $15,000 12 (42.9%) 5 (25.0%)
evaluated weekly for mood and drug use and at baseline and weeks $15,000–$34,999 5 (17.9%) 8 (40.0%)
$35,000–$79,999 8 (28.6%) 4 (20.0%)
4, 8 and 12 for the HVLT. Urine drug screens were obtained twice $80,000 and above 2 (7.1%) 1 (5.0%)
each week. Participants were paid for participation with both a flat Unreported/Missing 1 (3.6%) 2 (10.0%)
rate and a contingency management model (drawing for a chance to
Education, N (%)
win small prizes) for each of the urine samples they provided Did not complete high school 7 (25.0%) 6 (30.0%)
(whether positive or negative) between weekly assessments. High school graduate 6 (21.4%) 1 (5.0%)
Included were men and women aged 18–70 years meeting Some college 10 (35.7%) 9 (45.0%)
criteria for bipolar I, II or NOS disorders, currently depressed or College graduate or more 5 (17.9%) 4 (20.0%)

major depressive disorder (unipolar depression) with symptom Mood Diagnosis, N (%)
duration of at least 4 weeks, and amphetamine dependence with Bipolar I 5 (17.9%) 1 (5.0%)
Bipolar II 2(7.1%) 2 (10.0%)
methamphetamine use within 14 days prior to baseline. Exclusion
Bipolar NOS 4 (14.3%) 3 (15.0%)
criteria were psychotropic medication changes within 14 days prior Major depressive disorder 17 (60.4%) 14 (70.0%)
to study entry, pregnant or nursing, current citicoline therapy, active Mean body mass index (SD) 26.2 (9.1) 25.9 (5.1)
suicidal or homicidal ideation with plan and intent, or cognitive Mean days of methamphetamine use 8 (4.4) 6 (3.5)
impairment that might interfere with the informed consent process, (SD) (of last 14)
incarceration, and current severe or life threatening medical condi-
Mean grams methamphetamine used/day 0.25 (0.39) 0.28 (0.30)
tions. The study was registered at clinicaltrials.gov (NCT00377299). (SD)
Citicoline was purchased from Jarrow Formulas, Los Angeles,
Severity of depression based on IDS-C
California. Study medication was encapsulated and placebos were Mild 1 (3.6%) 1 (5.0%)
prepared by Abrams Royal Pharmacy, a Dallas pharmacy specializ- Moderate 10 (35.7%) 10 (50.0%)
ing in medication compounding. Severe 13 (46.4%) 7 (35.0%)
Very severe 4 (14.3%) 2 (10.0%)
Current psychiatric treatment 3 (10.7%) 1 (5.3%)
1.2. Statistical analysis
Administration route
Smoked 17 (60.7%) 15 (75%)
Baseline demographic characteristics were compared using inde-
Oral 3 (10.7%) 1 (5%)
pendent t-tests for continuous data and chi squares for discrete data Intravenous 4 (14.3%) 2 (10%)
(e.g. urine drug screens). Between-group differences in baseline to Multiple 4 (14.3%) 2 (10%)
exit change in the intent-to-treat sample (defined as those with at Mean years of methamphetamine use 15.7 (9.8) 9.1 (8.0)
least one post-baseline assessment on the outcome of interest) with
 E.S. Brown, B. Gabrielson / Journal of Affective Disorders 143 (2012) 257–260
medications (citicoline vs. placebo) included lithium (n¼1 each),
anticonvulsants (n¼3 vs. n¼1), antidepressants (n¼ 9 vs. n¼ 1),
antipsychotics (n ¼1 vs. n ¼0), sedatives, hypnotics or anxiolytics
(n¼ 1 each). During the trial two citicoline patients had concomi-
tant psychotropic additions and two had discontinuations while
two placebo patients had additions and none discontinuations.
Baseline to exit change in IDS-C scores was significantly
greater in the citicoline than placebo group (mean 7SE, baseline
38.8 71.5 citicoline, 37.8 72.3 placebo; exit 26.272.5 citicoline,
33.1 72.5 placebo; F(1.31)¼4.2, p ¼0.05). No significant differ-
ence was found on the HVLT.
Self-reported methamphetamine use decreased from baseline
to exit in both groups However, the ANCOVA revealed no
significant between-group differences in baseline to exit changes
in days/week or grams of methamphetamine use. The percentage
of amphetamine-positive urines was similar at baseline in each
group (60% in the citicoline group vs. 57% in the placebo group,
Pearson’s chi square p ¼0.84). At exit 64% on citicoline and 55% on
placebo had amphetamine-positive urines (p ¼0.23).
A Kaplan–Meier survival curve is presented in Fig. 1 illustrat-
ing longer survival in treatment in the citicoline group (log rank
test, p¼0.02). Completion rates were also higher for citicoline
(41%) than placebo (14%) (Pearson’s chi square, p ¼0.02). Reasons
for discontinuation were lost to follow-up (n¼19), moved out of
the area (n ¼2), entered inpatient drug rehabilitation, transporta-
tion problems (n¼1), and withdrawn due to adverse event (n ¼1)
in the placebo group. In the citicoline group, reasons for dis-
continuation were lost to follow-up (n ¼14), moved out of the
area (n¼ 1), entered inpatient drug rehabilitation (n ¼1), trans-
portation problems (n ¼1), stressors at home (n ¼1) and advice of
probation officer (n ¼1).
Citicoline was well tolerated. To our knowledge, no partici-
pants withdrew due to medication side effects and none required
a slower titration or could not tolerate the maximum dose. Side
effects reported in the study (citicoline vs. placebo) were diarrhea
(n¼ 2 vs. n¼1), insomnia (n ¼2 vs. n¼ 0), headache (n ¼0 vs.
n ¼2), decreased appetite (n ¼2 vs. n ¼1), increased sleep (n ¼1 vs.
n ¼0), nausea (n¼1 vs. n ¼0), constipation (n ¼2 vs. n ¼0),
decreased energy (n ¼0 vs. n ¼2), decreased concentration (n ¼0
Survival By Week
Cumulative Survival
Citicoline - - -
Placebo
Study Week
Fig. 1. Kaplan–Meier survival curve of cumulative survival in citicoline and
placebo groups.
259
vs. n ¼2), tinnitus (n ¼0 vs. n¼1), increased appetite (n ¼0 vs.
n¼ 2) and weight gain (n¼ 0 vs. n ¼1).
3. Discussion
This proof-of-concept study explored the impact of citicoline
on mood, drug use, memory, and study retention in a sample of
bipolar and unipolar depressed patients with methamphetamine
dependence. A significant between-group difference in change in
depressive symptoms, favoring citicoline, was observed. This
finding is consistent with a prior uncontrolled trial of citicoline
in treatment refractory depression (Salvadorini et al., 1975). In
our recent study of citicoline in patients with bipolar disorder and
cocaine dependence, improvement in depressive symptoms
numerically favored citicoline, but the findings did not reach
statistical significance (Brown et al., 2007). However, in the prior
study many of the participants were not depressed at baseline
limiting our ability to see changes in depressive symptoms.
Significant between-group differences in methamphetamine
use were not observed as assessed by either patient report or
urine drug screens. These findings differ from our prior report on
citicoline in bipolar disorder and cocaine dependence where
differences in frequency of positive urines at exit were observed.
This could be due to design differences. The prior study enrolled
patients with a brief period of self-reported abstinence while the
current study enrolled patients who reported active drug use. In
the current study mean years of methamphetamine use was
longer in the citicoline group. Thus, this group may have been
more refractory to treatment interventions. The findings could
also have been influenced by between-group differences in length
in treatment. Attrition was very high in the placebo group with
many participants dropping out within the first few weeks of
treatment. Other clinical trials for amphetamine abuse or depen-
dence of 8–12 weeks duration have reported low completion
rates ranging from 29 to 69% (Elkashef et al., 2008; Jayaram-
Lindstrom et al., 2008b; Johnson et al., 2008; Longo et al., 2010;
Roll et al., 2006; Shearer et al., 2009). Attrition is also typically
high in dual diagnosis studies (Nomamiukor and Brown, 2009).
Attrition could be a sign of relapse or increased drug use.
However, since many participants were lost to follow-up we do
not know whether drug use or other factors contributed to
attrition. Nonetheless, longer survival observed with citicoline
in the current report and in our prior trial in bipolar disorder and
cocaine use is a potentially clinically important finding.
Contrary to our report with citicoline in bipolar disorder and
cocaine dependence (Brown et al., 2007), significant between-
group differences were not observed in memory. Prior studies in
patients with neurological disorders (Adibhatla and Hatcher,
2005) and bipolar disorder and cociane dependence (Renshaw
et al., 1999) suggested improvement in cognition with citicoline.
The high rates of attrition along with cognitive assessment only
every 4 weeks may have limited our ability to observe changes in
cognition.
A limitation of the study is the sample heterogeneity with both
bipolar and unipolar depression included. The high attrition may
have limited our ability to see differences in cognition and
potentially other outcomes. However, reduced attrition with
citicoline was also a clinically meaningful outcome measure in a
patient population with drug use. Urine drug screens were only
obtained twice weekly. Thrice weekly monitoring might have
provided greater ability to detect differences in drug use. The
greater use of baseline antidepressants in the citicoline group is a
concern. This could either suggest that they were responding to
the antidepressant and not citicoline. However, antidepressants
were at stable doses at baseline. Alternatively, the antidepressant
260 E.S. Brown, B. Gabrielson / Journal of Affective Disorders 143 (2012) 257–260
use could suggest that the participants were relatively treatment
resistant at baseline, but responded to citicoline effects as an
augmenting agent.
In summary, citicoline was associated with an improvement in
depressive symptoms, and longer study survival than placebo,
with no differences in cognitive outcomes or drug use. Future
studies of citicoline in mood disorder populations should target
depressive symptoms.
Role of funding source
Funded by the Stanley Medical Research Institute.
Conflict of interest
Dr. Brown has research support from NIAAA, NIDA, NIMH, NHLBI, Stanley
Medical Research Institute, and Sunovion. Mr. Gabrielson has no disclosures to
report.
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