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
Article history:
Received16April2012
Accepted1May2012
Available online11September2012
Keywords:
Citicoline
Bipolar disorder
Depression
Cognition
Memory
Methamphetamine
a b s t r a c t
Background:Methamphetamine u disorders are common and vere problems.Persons with mood
disorders,particularly bipolar disorder,have high rates of substance u disorders.We previously
reported promisingfindings on drug u,memory and study retention in patients with a history of
mania and cocaine dependence given the nutritional supplement citicoline.In the current proof-of-
concept study,we examined citicoline in bipolar or unipolar depression and methamphetamine
dependence.
Methods:Sixty adults with bipolar depression or major depressive disorder and methamphetamine
火车的历史
dependence were randomized to citicoline(2000mg/day)or placebo for12weeks.Mood was assd
using Inventory of Depressive Symptomatology-Clinician Version(IDS-C),and cognition with the Hopkins
Auditory Verbal Learning Test(HVLT).Drug u was assd by urine drug screens.
Results:An ANCOVA of the intent-to-treat sample showed that tho receiving citicoline(n¼28)had a
statistically significantly greater improvement in IDS-C scores than tho receiving placebo(n¼20).
Survival in the study was significantly longer and completion rates significantly greater with citicoline than
placebo.No significant differences were obrved in memory or methamphetamine u.Citicoline was well
tolerated.
Limitations:Sample heterogeneity and small sample size were limitations.
Conclusions:To our knowledge this is thefirst placebo-controlled trial in a dual diagnosis sample with
methamphetamine u 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
梦见打老鼠是什么征兆substance dependence.Larger trials targeting depressive symptoms and treatment retention em warranted.
&2012Elvier B.V.All rights rerved.
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 positivefindings with
因为有你作文methylphenidate(Tiihonen et al.,2007),dexamphetamine(Longo
et al.,2010)and naltrexone(Jayaram-Lindstrom et al.,2008a;
Jayaram-Lindstrom et al.,2008b),and negativefindings with
modafinil(Shearer et al.,2009),bupropion(Elkashef et al.,
2008)and ondantron(Johnson et al.,2008).
Bipolar disorder and major depressive disorder have a prevalence
of substance u disorders(Regier et al.,1990).Mood disorders are
common in patients prenting with methamphetamine u dis-
orders(Glasner-Edwards et al.,2010).Methamphetamine u is
associated with cognitive impairment(Sofuoglu,2010).Bipolar
disorder(Osuji and Cullum,2005)and major depressive disorder
(McClintock et al.,2010)are also associated with poor cognition.
Therefore,an intervention that decread drug u and improved
mood and cognition would be very uful in a patient population
with mood disorders and methamphetamine u.To our knowledge,
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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 increas
phospholipid incorporation into membranes and enhances synthesis
of structural phospholipids(Adibhatla and Hatcher,2005),as well as
increas norepinephrine,dopamine,rotonin and acetyl choline
韩国犯罪电影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
Contents lists available at SciVer ScienceDirect
journal homepage:/locate/jad
Journal of Affective Disorders
0165-0327/$-e front matter&2012Elvier B.V.All rights rerved.
dx.doi/10.1016/j.jad.2012.05.006
n Correspondence to:Department of Psychiatry,The University of Texas
Southwestern Medical Center,Dallas,5323Harry Hines Blvd.,MC8849,Dallas,
753908849TX,USA.Tel.:þ12146456950;fax:þ12146456951.
E-mail address:Sherwood.Brown@UTSouthwestern.edu(E.S.Brown).
Journal of Affective Disorders143(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 decrea cocaine craving (Renshaw et al.,1999).
We reported promisingfindings 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 depresd outpatients with methamphetamine dependence were enrolled and randomized to citicoline or placebo,in a double-blind fashion for12weeks of acute treatment after completing an IRB-approved written informed connt process.Participants and all staff members with patient contact were blinded to treatment group assignment.Baline evaluation included a medical and psychiatric history,structured clinical interview for DSM-IV(SCID)(First et al., 1995),mood asssmen
t with the Inventory of Depressive Sympto-matology-Clinician Rated(IDS-C)(Rush et al.,1996),and memory with the Hopkins Auditory Verbal Learning Test(HVLT)(Brandt, 1991).Alternative versions(different words)were ud on the HVLT to minimize learning effects from repeated administration.Citicoline or placebo(identical in appearance)add-on therapy was given beginning at one tablet(500mg/day)with an increa to two tablets(1000mg/day)at week2,three tablets(1500mg/day)at week4and four tablets(2000mg/day)at week 6.Dos were decread,if needed,due to side effects.Concomitant medication changes were managed with a treatment algorithm.This approach was lected to prevent early discontinuation of any participant that required an adjustment in a concomitant medication while provid-ing structure and consistency to the changes.Participants were evaluated weekly for mood and drug u and at baline and weeks 4,8and12for the HVLT.Urine drug screens were obtained twice each week.Participants were paid for participation with both aflat rate and a contingency management model(drawing for a chance to win small prizes)for each of the urine samples they provided (whether positive or negative)between weekly asssments.
Included were men and women aged18–70years meeting criteria for bipolar I,II or NOS disorders,currently depresd or major depressive disorder(unipolar depression)with symptom durati
on of at least4weeks,and amphetamine dependence with methamphetamine u within14days prior to baline.Exclusion criteria were psychotropic medication changes within14days prior to study entry,pregnant or nursing,current citicoline therapy,active suicidal or homicidal ideation with plan and intent,or cognitive impairment that might interfere with the informed connt process, incarceration,and current vere or life threatening medical condi-tions.The study was registered v(NCT00377299).
Citicoline was purchad from Jarrow Formulas,Los Angeles, California.Study medication was encapsulated and placebos were prepared by Abrams Royal Pharmacy,a Dallas pharmacy specializ-ing in medication compounding.
1.2.Statistical analysis
Baline demographic characteristics were compared using inde-pendent t-tests for continuous data and chi squares for discrete data (e.g.urine drug screens).Between-group differences in baline to exit change in the intent-to-treat sample(defined as tho with at least one post-baline asssment on the outcome of interest)with last obrvation carried forward(LOCF)on continuous outcomes were compared with ANCOVAs that ud baline scores of the outcome being assd,
gender,mood disorder diagnosis(bipolar and unipolar),age,baline number of antidepressants ud,and grams of methamphetamine ud as covariates.Urine drug screens (þ/À)were compared using chi squares.Study survival was assd using a Kaplan–Meier survival analysis.Significance was t at a p value of r0.05for all comparisons.
2.Results
Of60participants,randomized48participants returned for at least one post-baline asssment and were ud in the data analysis(intent-to-treat sample).Demographic information about the two treatment groups is provided in Table1.The two groups did not differ significantly on any baline characteristic except age,which was higher in the citicoline group and included as a covariate on the data analysis.Baline concomitant psychotropic
Table1
Baline demographic characteristics of citicoline and placebo groups.
Baline characteristic Citicoline
(n¼28)
Placebo
(N¼20)
Mean age(SD)41.6(9.9)34.0(7.3) Gender,N(%)
Female15(53.6%)7(35.0%)
Male13(46.4%)13(65.0%) Ethnicity,N(%)
Caucasian24(85.7%)13(65.0%) African-American0(0%)0(0%)
Hispanic3(10.7%)6(30.0%)
Other1(3.6%)1(5.0%) Income,N(%)
less than$15,00012(42.9%)5(25.0%)
柠檬菊花茶$15,000–$34,9995(17.9%)8(40.0%)
$35,000–$79,9998(28.6%)4(20.0%)
$80,000and above2(7.1%)1(5.0%) Unreported/Missing1(3.6%)2(10.0%) Education,N(%)
Did not complete high school7(25.0%)6(30.0%)
High school graduate6(21.4%)1(5.0%)
Some college10(35.7%)9(45.0%) College graduate or more5(17.9%)4(20.0%)
Mood Diagnosis,N(%)
Bipolar I5(17.9%)1(5.0%)
Bipolar II2(7.1%)2(10.0%) Bipolar NOS4(14.3%)3(15.0%)
Major depressive disorder17(60.4%)14(70.0%) Mean body mass index(SD)26.2(9.1)25.9(5.1)
Mean days of methamphetamine u
(SD)(of last14)
8(4.4)6(3.5)
Mean grams methamphetamine ud/day
(SD)
0.25(0.39)0.28(0.30)
Severity of depression bad on IDS-C
Mild1(3.6%)1(5.0%) Moderate10(35.7%)10(50.0%) Severe13(46.4%)7(35.0%)
Very vere4(14.3%)2(10.0%) Current psychiatric treatment3(10.7%)1(5.3%) Administration route
Smoked17(60.7%)15(75%)
Oral3(10.7%)1(5%) Intravenous4(14.3%)2(10%)
Multiple4(14.3%)2(10%)
Mean years of methamphetamine u15.7(9.8)9.1(8.0)
E.S.Brown,B.Gabrielson/Journal of Affective Disorders143(2012)257–260 258
medications (citicoline vs.placebo)included lithium (n ¼1each),anticonvulsants (n ¼3vs.n ¼1),antidepressants (n ¼9vs.n ¼1),antipsychotics (n ¼1vs.n ¼0),datives,hypnotics or anxiolytics (n ¼1each).During the trial two citicoline patients had concomi-tant psychotropic additions and two had discontinuations while two placebo patients had additions and none discontinuations.
Baline to exit change in IDS-C scores was significantly greater in the citicoline than placebo group (mean 7SE,baline 38.871.5citicoline,37.872.3placebo;exit 26.272.5citicoline,33.172.5placebo;F(1.31)¼4.2,p ¼0.05).No significant differ-ence was found on the HVLT.篝火晚会
Self-reported methamphetamine u decread from baline to exit in both groups However,the ANCOVA revealed no significant between-group differences in baline to exit changes in days/week or grams of methamphetamine u.The percentage of amphetamine-positive urines was similar at baline 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 prented in Fig.1illustrat-ing longer survival in treatment in the citicoline group (log rank test,p ¼0.02).Completion rates were also higher for citicoline (41%)than pla
cebo (14%)(Pearson’s chi square,p ¼0.02).Reasons for discontinuation were lost to follow-up (n ¼19),moved out of the area (n ¼2),entered inpatient drug rehabilitation,transporta-tion problems (n ¼1),and withdrawn due to adver 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 (n ¼1),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 do.Side effects reported in the study (citicoline vs.placebo)were diarrhea (n ¼2vs.n ¼1),insomnia (n ¼2vs.n ¼0),headache (n ¼0vs.n ¼2),decread appetite (n ¼2vs.n ¼1),incread sleep (n ¼1vs.n ¼0),naua (n ¼1vs.n ¼0),constipation (n ¼2vs.n ¼0),decread energy (n ¼0vs.n ¼2),decread concentration (n ¼0
vs.n ¼2),tinnitus (n ¼0vs.n ¼1),incread appetite (n ¼0vs.n ¼2)and weight gain (n ¼0vs.n ¼1).
3.Discussion
This proof-of-concept study explored the impact of citicoline on mood,drug u,memory,and study re
tention in a sample of bipolar and unipolar depresd patients with methamphetamine dependence.A significant between-group difference in change in depressive symptoms,favoring citicoline,was obrved.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 depresd at baline limiting our ability to e changes in depressive symptoms.
Significant between-group differences in methamphetamine u were not obrved as assd by either patient report or urine drug screens.The findings differ from our prior report on citicoline in bipolar disorder and cocaine dependence where differences in frequency of positive urines at exit were obrved.This could be due to design differences.The prior study enrolled patients with a brief period of lf-reported abstinence while the current study enrolled patients who reported active drug u.In the current study mean years of methamphetamine u 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 hig
h in the placebo group with many participants dropping out within the first few weeks of treatment.Other clinical trials for amphetamine abu or depen-dence of 8–12weeks duration have reported low completion rates ranging from 29to 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 relap or incread drug u.However,since many participants were lost to follow-up we do not know whether drug u or other factors contributed to attrition.Nonetheless,longer survival obrved with citicoline in the current report and in our prior trial in bipolar disorder and cocaine u 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 obrved 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 asssment only every 4weeks may have limited our ability to obrve changes in cognition.
A limitation of the study is the sample heterogeneity with both bipolar and unipolar depression includ
ed.The high attrition may have limited our ability to e 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 u.Urine drug screens were only obtained twice weekly.Thrice weekly monitoring might have provided greater ability to detect differences in drug u.The greater u of baline 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 dos at baline.Alternatively,the antidepressant
Study Week
Survival By Week
Citicoline - - -Placebo
C u m u l a t i v e S u r v i v a l
Fig. 1.Kaplan–Meier survival curve of cumulative survival in citicoline and placebo groups.
E.S.Brown,B.Gabrielson /Journal of Affective Disorders 143(2012)257–260259
u could suggest that the participants were relatively treatment resistant at baline,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 u.Future studies of citicoline in mood disorder populations should target depressive symptoms.
Role of funding source
Funded by the Stanley Medical Rearch Institute.
Conflict of interest
Dr.Brown has rearch support from NIAAA,NIDA,NIMH,NHLBI,Stanley Medical Rearch Institute,and Sunovion.Mr.Gabrielson has no disclosures to report.
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