A Double-Blind, Placebo-Controlled Trial to Assess the Efficacy of Quetiapine Fumarate XR in Very Heavy-Drinking Alcohol-Dependent Patients

ArticleinAlcoholism Clinical and Experimental Research 36(3):406-16 · September 2011with49 Reads
Impact Factor: 3.21 · DOI: 10.1111/j.1530-0277.2011.01649.x · Source: PubMed
Abstract

Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients.

Full-text

Available from: Helen Pettinati
A Double-Blind, Placebo-Controlled Trial to Assess the
Efficacy of Quetiapine Fumarate XR in Very
Heavy-Drinking Alcohol-Dependent Patients
Raye Z. Litten, Joanne B. Fertig, Daniel E. Falk, Megan L. Ryan, Margaret E. Mattson,
Joseph F. Collins, Cristin Murtaugh, Domenic Ciraulo, Alan I. Green, Bankole Johnson,
Helen Pettinati, Robert Swift, Maryam Afshar, Mary F. Brunette, Nassima A.-D. Tiouririne,
Kyle Kampman, Robert Stout, and the NCIG 001 Study Group*
Background: Despite advances in developing medications to treat alcohol dependence, few such
medications have been approved by the Food and Drug Administration. Identified molecular
targets are encouraging and can lead to the development and testing of new compounds. Atypical
antipsychotic medications have been explored with varying results. Prior research suggests that
the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy
drinkers.
Methods: In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who
reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetia-
pine or placebo and Medical Management behavioral intervention. Patients were stratified on
gender, clinical site, and reduction in drinking prior to randomization.
Results: No differences between the quetiapine and placebo groups were detected in the pri-
mary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine signifi-
cantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking
outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking
prior to randomization had significantly better drinking outcomes during the maintenance phase
(p < 0.0001). No significant interactions, however, were observed between reducer status and
treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse
events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry
mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%),
and somnolence (34 vs. 9%).
Conclusions: This multisite clinical trial showed no efficacy for quetiapine compared with pla-
cebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients.
Key Words: Alcohol Dependence, Quetiapine, Seroquel
, Medications Development, Alcohol
Use Disorder.
A
LCOHOL USE DISORDER is a devastating complex
disease that affects 18 million Americans (de
Wit, 2010). Misuse of alcohol is responsible for a wide range
of medical, psychological, social, personal, and economic
problems. The cost to U.S. society is staggering at over
$235 billion annually (Rehm, 2009). Encouragin gly, advances
have been made in treatment approaches, especially with the
use of medications specifically targeting alcohol drinking.
Currently, there are four medications approved by the
Food and Drug Administration (FDA) for the treatment of
From the Division of Treatment and Recovery Research (RZL, JBF, DEF, MLR), National Institute on Alcohol Abuse and Alcoholism,
Bethesda, Maryland; Center for Behavioral Health Statistics and Quality (MEM), SAMHSA, Rockville, Maryland; Cooperative Studies Pro-
gram Coordinating Center (JFC, CM), VA Maryland Health Care System, Perry Point, Maryland; Boston University School of Medicine
(DC, MA), Boston, Massachusetts; Department of Psychiatry (AIG), Dartmouth Medical School (DHMC), Lebanon, New Hampshire;
Department of Psychiatric Medicine (BJ), University of Virginia, Charlottesville, Virginia; University of Pennsylvania Treatment Research
Center (HP, KK), Philadelphia, Pennsylvania; Center for Alcohol and Addiction Studies (RS), Brown University, Providence, Rhode Island;
Psychopharmacology Research Group (MFB), Dartmouth Medical School, Concord, New Hampshire; University of Virginia Center for Addic-
tion Research and Education (NA-DT), Richmond, Virginia; and Decision Sciences Institute PIRE (RS), Pawtucket, Rhode Island.
Received for publication March 28, 2011; accepted July 20, 2011.
Reprint requests: Daniel E. Falk, Division of Treatment and Recovery Research, National Institute on Alcohol Abuse and Alcoholism, 5635
Fishers Lane, Room 2040, Bethesda, MD 20892; Tel.: 301-443-0788; Fax: 301-443-8774; E-mail: falkde@mail.nih.gov
*See Appendix for authors in NCIG 001 Study Group.
Copyright 2011 by the Research Society on Alcoholism.
DOI: 10.1111/j.1530-0277.2011.01649.x
Alcoholism: Cl inical and Experimental Research Vol. 36, No. 3
March 2012
406 Alcohol Clin Exp Res, Vol 36, No 3, 2012: pp 406–416
Page 1
alcohol dependence: disulfiram (Antabuse
or Antabus
),
oral naltrexone (Revia
or Depade
), acamprosate (Camp-
ral
), and injectable naltrexone (Vivitrol
; Jo hnson, 2007;
Litten et al., 2005). Moreover, topiramate (Topamax
)has
recently been shown to be effective in treating alcohol depen-
dence in a multisite clinical trial (Johnson et al., 2007).
Although these medications demonstrate efficacy in clinical
trials, not all patients experience a benefit. Therefore, new
molecular targets are being identified, new drug compounds
are being tested, and new clinical trials are under way (see
http://www.ClinicalTrials.gov).
Over the past decade, several atypical antipsychotic medica-
tions have been explored to treat alcohol dependence. The
results, so far, have varied. Clozapine (Clozaril
or Fazaclo
)
has been reported to reduce alcohol use in people with schizo-
phrenia and co-occurring alcohol use disorder (Brunette
et al., 2006; Drake et al., 2000). Additionally, olanzapine
(Zyprexa
) appears to reduce the urge to drink in heavy social
drinkers after exposure to alcohol cues (Hutchinson et al.,
2001). In a 12-week pilot study, olanzapine reduced alcohol
craving and consumption in alcohol-dependent patients, par-
ticularly in those with the 7-repeat allele of the D4 receptor
gene (Hutchison et al., 2006). In co ntrast, Guardia and
colleagues (2004) found no differences in drinking outcomes
between olanzapine and placebo groups in alcohol-dependent
patients. Aripiprazole (Abilify
or Aripiprex
)appearsto
interact with alcohol, increasing the sedative effects and
decreasing the euphoric effects associated with it (Kranzler
et al., 2008). In addition, in a clinical laboratory setting,
aripiprazole appeared to decrease drinking in alcoholic
patients who were not seeking treatment (Voronin et al.,
2008). In a small clinical trial, aripiprazole seemed to be as
effective as naltrexone in treating alcohol-dependent patients
(Martinotti et al., 2009). However, in a multicenter trial,
alcohol-dependent patients had similar drinking outcomes
when treated with either aripiprazole or placebo (Anton et al.,
2008).
Quetiapine (Seroquel
) is another atypical antipsychotic
medication that has shown promise for the treatment for alco-
holism. Croissant and colleagues (2006) noted that 8 of 9
alcoholic patients treated with quetiapine for 2 to 7 months
reported having abstained from drinking during this period.
In addition, 2 retrospective studies reported a beneficial effect
from quetiapine. Sattar and colleagues (2004) followed 9 alco-
hol-dependent patients treated with quetiapine for 3 months
and observed increased days when they were abstinent from
drinking as well as decreases in depression, anxiety, and
insomnia. Monnelly and colleagues (2004) observed that
quetiapine-treated alcohol-dependent patients with disturbed
sleep had more days abstinent, took longer to relapse to
drinking, and were hospitalized less often during a 1-year
period than those who were not treated with quetiapine. In a
4-month open-label trial, Martinotti and colleagues (2008)
reported that quetiapine decreased alcohol intake, alcohol
craving, and psychiatric symptoms in alcoholic patients with
a concurrent Axis I disorder. Finally, Kampman and
colleagues (2007) conducted a pilot, 12-week, double-blind,
placebo-controlled trial of quetiapine for the treatment for
Type A and Type B alcoholism. In this trial, Type B alcoholics
were characterized by an earlier onset of problematic drink-
ing, more severe alcohol dependence, and greater psychopa-
thology and were more treatment resistant than the Type A
alcoholics. The Type B alcoholics treated with quetiapine
experienced more days abstinent, fewer heavy-drinking days,
and less alcohol craving than placebo-treated Type B alco-
holics. By contrast, there were no differences in drinking
outcomes between quetiapine and placebo among Type A
alcoholics.
Quetiapine is currently approved by the FDA for the treat-
ment for schizophrenia, bipolar disorder, and depression. The
preliminary results described above suggest that quetiapine
may be benefi cial as a treatmen t for alcohol dependency, par-
ticularly in a subpopulation of very heavy drinkers. This
study was conducted to assess the efficacy and safety of
quetiapine fumarate XR (extended-release) in very heavy-
drinking alcohol-dependent patients. A 3-month, multisite,
placebo-controlled, double-blind trial was conducted assess-
ing quetiapine’s effects on drinking outcomes, alcohol-related
consequences, quality of life, depression, anxiety, sleep, and
safety.
MATERIALS AND METHODS
Study Population
Randomized patients included 179 men and 45 women who were
diagnosed with alcohol dependence (Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition [DSM-IV]; American
Psychiatric Association 1994). Interested candidates responded by
telephone to advertisements at 5 academic centers in the United
States between December 2007 and May 2009. During the initial tele-
phone call screen, a brief set of standardized questions about drink-
ing was asked to preliminarily determine whether study drinking
criteria could be met and to ascertain the caller’s interest in study par-
ticipation. Individuals who reported levels of drinking consistent with
the study entry criteria were scheduled for an in-person screening
visit, during which they received information on the study and signed
an informed consent form (approved by each center’s Institutional
Review Board
1
) before beginning any study assessments. Addition-
ally, participants provided detailed baseline drinking histories, health
screens, and psychosocial assessments. The screening visit required
approximately 3.5 hours.
Key inclusion criteria included the following: (i) alcohol depen-
dence, determined by DSM-IV criteria; (ii) aged 18 to 64; (iii) drank
very heavily (10 or more drinks drinking day for men; 8 or more
drinks drinking day for women) at least 40% of the days during the
60-day interval (days 31 to 90) before the in-clinic screening visit,
with at least 1 day of very heavy drinking (10+ 8+) occurring
within the last 2 weeks before screening (a standard drink was 0.5 oz
of absolute alcohol, equivalent to 10 oz of beer, 4 oz of wine, or 1 oz
of 100-proof liquor; Miller et al., 1991); (iv) breath alcohol concen-
tration (BAC) equal to 0.00 at informed consent signing; and (v)
absolute neutrophil count of 1.5 · 10
9
lorgreater.
Key exclusion criteria included the following: (i) past-year depen-
dence on any psychoactive substances other than alcohol and
1
Each center also obtained a certificate of confidentiality issued by the
National Institute on Alcohol Abuse and Alcoholism.
QUETIAPINE FOR ALCOHOL DEPENDENCE 407
Page 2
nicotine, as defined by DSM-IV criteria; (ii) positive urine screen-
ing test for benzodiazepines, cocaine, opioids, amphetamines, or
methamphetamines; (iii) participation in a behavioral and or
pharmacological intervention research study of alcoholism treatment
within 3 months before signing the informed consent; (iv) inability
to be safely withdrawn from alcohol on an outpatient basis (e.g.,
Clinical Institute Withdrawal Assessment for Alcohol–revised
[CIWA-AR] score 10); (v) lifetime diagnosis (using DSM-IV crite-
ria) of panic disorder with or without agoraphobia, schizophrenia,
bipolar disorder, or other psychosis, or a past-year diagnosis of
major depression or eating disorde r; (vi) use of antidepressant medi-
cations within the last 30 days before randomization; and (vii) use of
anticonvulsants, hypnotics, antipsychotics, psychomotor stimulants,
or antianxiety agents in the last 14 days before randomization.
Additional exclusions addressed drug-specific safety precautions.
Assessments
Clinic assessments were made at screening, at baseline, and at the
beginning of weeks 2, 3, 4, 6, 8, 10, 12, and 13, while brief telephone
assessments were conducted at the beginning of weeks 5, 7, 9, and
11 (Table 1). A follow-up telephone interview to assess safety
and changes in drinking was conducted at week 17, approxi-
mately 4 weeks after the last in-clinic study visit. Patients were
not allowed to complete in-clinic assessments unless they had a BAC
of <0.02%.
Procedures
Patients who met eligibility criteria at the end of the screening visit
were randomly assigned, within 28 days and in a 1:1 ratio, to receive
either quetiapine or placebo. They were further stratified by clinical
site and then by using an adaptive randomization procedure
2
based
on 2 additional variables: reducer status (‘‘reducers’’ vs. ‘‘nonreduc-
ers’’) and gender. ‘‘Reducers’’ were defined as individuals who volun-
tarily reduced their average number of drinks per drinking day by at
least 50% before randomization.
3
Patients who self-initiated
withdrawal during the prerandomization period for which a
medically managed withdrawal was indicated were still eligible to be
placed in the ‘‘reducers’’ category for randomization purposes. The
rationale for stratifying by reducer status lies with the observation
that some of patients in alcohol clinical trials voluntarily reduce
drinking around the time they make thedecisiontoparticipateina
clinical trial, causing a rapid reduction in the average drinking level
of the total sample before treatment is even initiated (Epstein et al.,
2005). This prerandomization reduction in drinking has been linked
to treatment outcome (Epstein et al., 2005) and has been referred to
as participation reactivity. The reasons for its occurrence are not
understood but may include positive expectations on the part of the
subject or a response to the attention of the clinical staff and the ini-
tial assessments. This phenomenon introduces noise in the treatment
outcome. Given the small effect sizes typical of many alcohol treat-
ments, it can potentially make the detec tion of the ‘‘true’’ difference
between the treatment and placebo groups more difficult. Conse-
quently, reducer status was included both as a stratification variable
to ensure equal proportions among the treatment groups and also as
a covariate for primary and secondary drinking outcomes. Randomi-
zation was implemented via an interactive touch-tone randomization
system.
Study medication was dispensed to participants in a double-blind
manner for 3 months. Quetiapine fumarate extended-release (Sero-
quel XR
; AstraZeneca, Wilmington, DE) was supplied in 50- and
200-mg tablets by AstraZeneca with identical matching placebos.
During the first 2 weeks after randomization, the dose was titrated
up to a target dose of 400 mg d. This target dose was maintained
during weeks 3 through 11, followed by a final week 12 during which
the dose was tapered on a schedule as determined by the investigator.
Patients assigned to the placebo group received matched placebo on
the same schedule as the quetiapine group. Patients unable to tolerate
the 400 mg d target dose were allowed to continue in the study at a
lower dose, with 50 mg d as the lowest acceptable maintenance dose.
Participants who discontinued medication during the study were
allowedtoremaininthestudyandparticipateinstudyassessments.
The daily dose taken used to calculate drug compliance was derived
by corroborating the patient’s self-reported daily dose taken with the
number of pills removed from the weekly blister pack returned by
the patient at each clinic visit.
All participants received Medical Management (MM), a psychoso-
cial, medically based, minimally intensive intervention developed and
used in the COMBINE study (Pettinati et al., 2004). MM includes
assessment of medication side effects, subject education about exces-
sive drinking, abstinence advice, enhancement of adherence to the
study medication regimen, support for recovery, and encouragement
to attend mutual self-help groups such as Alcoholics Anonymous.
The first session was delivered at the randomization visit, with
subsequent sessions occurring at each in-person clinic visit thereafter,
for a total of 9 sessions. MM administrators were certified and
monitored throughout the study.
Analytical Plan and Statistical Methods
The primary efficacy outcome measure was weekly percentage
heavy-drinking days during study weeks 3 through 11. A grace per-
iod of the first 2 weeks was permitted for the titration of quetiapine
to the selected therapeutic target dose, while week 12 allowed for a
dose tapering of quetiapine. Secondary outcome measures included
other drinking measures (percentage days abstinent, drinks per
drinking day, drinks per day, percentage very heavy-drink ing days,
percentage subjects abstinent, and percentage subjects with no heavy-
drinking days) that were also assessed during weeks 3 through 11, as
well as alcohol-related consequences, craving, depression, anxiety,
poor sleep, and quality of life. Skewed variables were transformed as
follows: log transformations (percentage very heavy-drinking days,
Hamilton Anxiety Scale [HAM-A], Montgomery–Asberg Depression
Rating Scale [MADR], Daytime Somnolence Scale [DSS] score,
weight, alanine transaminase, aspartate transaminase, gamma-
glutamyl transpeptidase [GGT], triglycerides, and bilirubin), square-
root transformations (drinks per day, drinks per drinking day, Drinker
Inventory of Consequen ces [DrInC], Pittsburgh Sleep Quality Index
[PSQI], and eosinophils), and inverse transformations (CIWA score).
The primary and secondary efficacy outcome measure s were ana-
lyzed for a modified intention-to-treat (mITT) population that
included only patients who took at least 1 dose of medication
(n = 218). Continuous outcomes were analyzed using a repeated-
measures mixed model. A Toeplitz covariance matrix best fit the data
and was used to model the correlations between repeated measures
among participants. For descriptive purposes, least square means
(LSMEANs), standard errors (SEs), and 95% confidence intervals
(CIs) are presented for each treatment group and were derived from
unadjusted models with untransformed outcome variables and 2
predictors: week and treatment group. Corresponding Cohen’s d and
p-values were derived from adjusted models with appropriately
transformed outcome variab les and included the covariates gender,
2
The adaptive randomization procedure allocates treatment assignment based
on the assignments and prognostic variable levels for all previously random-
ized patients (Efron, 1971; Pocock, 1979; Pocock and Simon, 1975; Stout
et al., 1994).
3
Percentage reduction in drinks per drinking day = (average drinks drinking
day during the 31- to 90-day interval prior to the in-clinic screening ) average
drinks drinking day during the 7-day period prior to randomization) (average
drinks drinking day during the 31- to 90-day interval prior to the in-clinic
screening visit) · 100.
408
LITTEN ET AL.
Page 3
clinical center, reducer status, andbaselinevalueoftheoutcome.For
continuous outcomes assessed at a single time (e.g., SF-12 outcomes),
unadjusted means are presented on untransformed variables. Cohen’s
d and p-values were derived from general linear models (analyses of
covariance) with appropriately transformed outcome variables and
included the same covariate scheme as the repeated-measures models.
Single dichotomous drinking outcomes (i.e., abstinence and no heavy
drinking) were computed to reflect drinking across the entire mainte-
nance period (weeks 3 to 11). Prevalence rates are presented on un-
transformed variables. Odds ratios (ORs) and p-values were derived
from logistic regression models again with the same covariate
scheme. However, as there was no variability in the baseline equiva-
lents of these outcome variables, percentage days abstinent was used
as the covariate for the abstinence outcome, and percentage heavy-
drinking days was used as the covariate for the no heavy-drinking
outcome. All baseline drinking measures were computed during a 60-
day period (31- to 90-day interval before the first screening visit).
Outcomes for laboratory tests, safety measures, and vital signs were
analyzed using a similar approach as the primary and secondary out-
comes, except that adjusted models did not include reducer status.
To determine the effect of missing drinking data during treatment on
the analyses involving drinking outcomes, all models were rerun
where missing drinking data were imputed with the subject’s average
drinks per drinking day value during the prescreen period.
A series of exploratory subgroup analyses were conducted to
explore whether a differential treatment effect existed as a function of
subgroup status for the primary outcome, percentage heavy-drinking
days, and other measures of drinking. Subgroups included the
following: reducer status, Type B alcoholism, sleep quality, side
effects, and quantity of medication taken. Based on criteria approxi-
mating that used by Kampman and colleagues (2007), patients were
characterized as Type B alcoholics if they averaged 12 or more drinks
per drinking day in the 30- to 90-day period prior to screening if male
(female patients, 10 or more drinks per drinking day), and had either
of the following 2 criteria: (i) onset of alcohol dependenc e prior to
age 25 or (ii) a MADRS score 7 before entering the trial (at least
mild depressive symptoms). Sleep quality subgroups were created
using a baseline PSQI cutoff of 6 as indicative of poor sleep. The
‘‘side effects’’ subgroup was determined by the presence of at least 1
of the following adverse events occurring during treatment: dizziness,
dry mouth, dyspepsia, increased appetite, sedation, and somnolence.
Quantity of medication taken was computed as the total milligram
taken during the maintenance period (weeks 3 to 11) and was dichot-
omized using a 12,600-mg cutoff (i.e., 50% of 25,200 mg, the total
Table 1. Assessment Schedule
Assessment and sources Schedule (weeks)
a
Adverse events 1 & 2 (daily telephone), weekly after
Barnes Akathisia Rating Scale (BARS; Barnes, 1989) SCR, 2, 3, 6, 13
Breath alcohol concentration (BAC) SCR, BL, 2, 3, 4, 6, 8, 10, 12, 13
Blood chemistries
b
SCR, 4, 8, 12
Clinical Institute Withdrawal Assessment for Alcohol—Revised
(CIWR-AR; Sullivan et al., 1989)
SCR, BL, 1 & 2 (daily telephone), weekly after
Concomitant medications BL, 1 & 2 (daily telephone), weekly after
Daytime Somnolence Scale (DSS)
c
BL, 1 & 2 (daily telephone), weekly after
Drinker Inventory of Consequences (DrInC; Miller, 1995) BL, 6, 12
Electrocardiogram (ECG) SCR, 13
Fagerstrom test for nicotine dependence (Heatherton et al., 1991) BL, 6, 12
Family tree questionnaire (Mann et al., 1985)
d
BL
Hamilton Anxiety Scale (HAM-A; Guy, 1976) BL, 4, 6, 8, 10, 12
Height SCR
Hematology SCR, 4, 8, 12
Locator form SCR
Medical history SCR
Montgomery–Asberg Depression Rating Scale (MADRS; Montgomerty and Asberg, 1979) SCR, BL, 4, 6, 8, 10, 12
Penn Alcohol Craving Scale (PACS; Flannery et al., 1999) BL, 4, 6, 8, 10, 12
Physical exam SCR, 13
Pittsburgh Sleep Quality Index (PSQI; Buysee et al., 1989) BL, 4, 8, 12
Prior medications (past 30 days) SCR
Quality of Life Short Form 12 (SF-12; Szabo, 1996) BL, 12
Simpson-Angus Scale (SAS; Simpson and Angus, 1970)
e
SCR, 10, 13
Services utilization BL, 1, 2, 3, 4, 6, 8, 10, 12, 13
Structured Clinical Interview for the DSM-IV (SCID) Module E (First et al., 1996)
f
SCR
Suicidality monitoring 1 & 2 (daily telephone), 5, 7, 9, 11
Thoughts About Abstinence Scale (Hall et al., 1990; Marlatt et al., 1988) BL, 6, 12
Time-Line Follow-Back (Sobell and Sobell, 1992)
g
SCR, BL, 2, 3, 4, 6, 8, 10, 12, 13
Treatment compliance 2, 3, 4, 6, 8, 10, 12, 13
Urine drug screen SCR, BL, 4, 8, 12, 13
Urine pregnancy test SCR, BL, 4, 8, 12
Vital signs (blood pressure, heart rate, and respiration rate) and weight SCR, BL, 2, 3, 4, 6, 8, 10, 12, 13
a
All assessments were conducted in the clinic, except for weeks 5, 7, 9, 11 which were conducted via telephone. Where noted, daily telephone
calls were also used for some safety assessments during the first 2 weeks of titration.
b
Blood chemistries were assessed after >2 hours of fasting; repeated after >8 hours if blood glucose or triglycerides were elevated.
c
DSS was adapted from the Stanford Sleepiness Scale (Hoddes et al., 1973).
d
Family Tree Questionnaire assesses family history of alcohol problems.
e
SAS assesses neuroleptic-induced parkinsonism.
f
SCID Module E assesses alcohol dependence.
g
TLFB was used to assess daily drinking for the past 90 days at baseline and since the last assessment during treatment.
SCR, screening; BL, baseline.
QUETIAPINE FOR ALCOHOL DEPENDENCE 409
Page 4
possible amount of medication that could be taken during this
63-day period). LSMEANs and 95% CIs were estimated from unad-
justed mixed models on untransformed outcome variables (weeks 3
to 11). Treatment by subgroup interactions was tested for significance
via mixed models on appropriately transformed outcome variables
adjusted for gender, reducer statu s, center, and baseline value of the
outcome. For bivariate comparisons, treatment group differences
were tested for significance by t-tests for independent samples (for
normally distributed variables) or Wilcoxon rank-sum tests (for
skewed variables); prevalence rate differences were tested for signifi-
cance via chi-square or Fisher’s exact tests. For all statis tical tests,
p < 0.05 (2-tailed) is considered statistically significant. It was esti-
mated that a sample size of 230 patients was required to obtain 190
evaluable patients (95 per treatment group), yielding 80% power to
detect a treatment effect (Cohen’s d = 0.41) using a 2-tailed t-test at
a 0.05 significance level. Data were analyzed with SAS version 9.2
(SAS Institute, Inc., Cary, NC).
RESULTS
Baseline
A total of 416 patients were screened in the clinic. Of these,
192 were excluded for either not meeting eligibility criteria or
choosing not to participate. A total of 224 patients were
randomized, but only 218 patients actually took the first dose
of medication and returned to the clinic. Of these 218 patients
(the mITT population), 28% were ‘‘reducers’’—persons who
voluntarily reduced their average drinks per drinking day by
50% during the 7-day period before randomization, com-
paredwiththe31-to90-dayinterval before the first screening
visit. Patients in the quetiapine and placebo groups
had similar proportions of reducers (34.1% quetiapine vs.
24.8% placebo; p = 0.275) and all other values on baseline
characteristics (Table 2). Randomized patients were mostly
men, white, middle-aged , and employe d. On average, they
drank very heavily (approximately 76% of their days) and
thus greatly exceeded the minimum threshold for study entry
(40%). GGT was also elevated at levels consistent with heavy
drinking (Litten et al., 2010). Despite high levels of heavy
drinking, patients on average had low levels of depressive
symptoms (MADRS score = 5.3) and anxiety (HAM-A
score = 4.1), though their mental health functioning was
below normal (SF-12 mental health aggregate score = 45.7)
and sleep quality was somewhat compromised (PSQI
score = 7.1).
Overall compliance with study medication, defined as the
proportion of total prescribed medication taken during the
maintenance phase of the study (weeks 3 to 11), was 95.5%
and was similar between the treatment groups (96.1% for the
quetiapine group vs. 95.1% for the placebo group; p =
0.468). The average dose of medication taken was 350.7 mg
but was significantly lower in the quetiapine group compared
with the placebo group (327.7 vs. 370.4 mg, respectively;
p <0.001).
Research participation rate, defined as percentage of
patients with complete drinking data, was 83.5% overall and
did not differ significantly by treatment group (85.7% for the
quetiapine group vs. 81.4% for the placebo group; p =0.39).
Main Outcomes
Regardingtheprimaryefcacy outcome, percentage days
heavy drinking, there were no statistically significant differ-
ences between the unadjusted treatment group means during
any weeks of the study maintenance phase (weeks 3 to 11) for
either the placebo or the quetiapine group (all p >0.41;
Fig. 1). Fully adjusted mixed models further failed to show
significant differences between the groups on this outcome
(p = 0.68) and all of the 7 secondary drinking outcomes
during weeks 3 to 11, including percentage days abstinent
(p =0.86), drinks per day (p = 0.97), drinks per drinking
day (p = 0.92), percentage heavy-drinking days (p =0.68),
percentage very heavy-drinking days (p = 0.66), percentage
patients with no heavy-drinking days (p = 0.14), and percen-
tage patients abstinent (p = 0.77; Table 3). Results were
similar when models were repeated with missing data imputed
using baseline data (data not shown).
Treatment groups did not differ on a number of nondrink-
ing outcomes, including alcohol-related consequences (DrInC;
p = 0.42), alcohol craving (Penn Alcohol Craving Scale
[PACS]; p = 0.36), and anxiety (HAM-A; p =0.37).
Although depression, as measured by the MADRS, improved
in both groups overall, the quetiapine group showed greater
improvement during the course of the study (p = 0.01). Sleep
quality (PSQI) also improved in both groups overall and was
greater in the quetiapine-treated group (p = 0.009). The qual-
ity-of-life mental subscale (SF-12) improved from baseline in
both groups, but there was no difference between the 2 groups
(p = 0.45). There was no change in the physical subscale of
the SF-12 for either of the 2 groups during treatment
(p = 0.88). As expected, analysis of the DSS revealed a signif-
icant effect between treatment groups, with the quetiapine
group showing higher levels of daytime somnolence, especially
early in treatment (p < 0.0001).
Subgroup Analyses
Patients who reduced their drinking before randomization
had significantly better drinking outcomes during the
treatment maintenance phase on drinks per day, drinks per
drinking day, percentage days abstinent, and percentage
heavy-drinking days (all reducer main effects, p < 0.0001;
Fig. 2). There were, however, no significant interactions
between reducer status and treatment group. Four additional
subgroup analyses were performed on the primary outcome
measure percentage heavy-drinking days (Fig. 3). The quetia-
pine and placebo groups did not significantly differ as a
function of Type B status or sleep quality (PSQI score) at
baseline, or the presence of side effects or quantity of medica-
tion taken during treatment
4
(p-values for all treatment by
group interactions >0.05).
4
A follow-up analytic approach using Loess curves indicated no difference
between quetiapine and placebo groups on the primary outcome across the
entire continuous range of quantity of medication taken (data not shown).
410
LITTEN ET AL.
Page 5
Safety and Adverse Events
Analyses of 2 safety measures, the Barnes Akathisia Rating
Scale (BARS) and the Simpson-Angus Scale (SAS), revealed
no overall or treatment-related increases in motor movement
impairment or neuroleptic-induced Parkinsonian symptoms
over the course of the study (BARS, p = 0.49; SAS,
p =0.97).
Laboratory values were measured prerandomization and
throughout the trial. Over the course of the trial, patients tak-
ing quetiapine gained more weight than those on placebo (3
vs. 0.7 lbs; p = 0.006) and had larger increases in triglyce-
rides (26.4 vs. 6.5 mg dl, p = 0.02). Placebo patients had
greater reductions in cholesterol compared with quetiapine
patients ()9.8 vs. 0.1 mM, p = 0.001). Consistent with
observed decreases drinking during the trial, GGT decreased
in both groups; however, the decrease was greater in placebo
patients ()21 vs. )14 U l; p < 0.04). Glucose levels did not
significantly differ between the 2 groups (p = 0.65), nor did
any of the other laboratory measures assessed.
Treatment-emergent adverse events that were reported to
occur in at least 10% of study participants were dizziness, dry
mouth, dyspepsia, increased appetite, sedation, and somno-
lence; all were significantly more frequent in the quetiapine
group than in the placebo group (Table 4). Twelve unique
serious adverse events occurred during the maintenance phase
of the trial; 7 were for alcohol detoxification (quetiapine
group = 3 vs. placebo group = 4). The remainder included
Table 2. Baseline Characteristics of Participants (Modified Intention-to-Treat [mITT] Population)
Placebo (n = 113) Quetiapine (n = 105)
p-Value
a
n Mean OR% SD n Mean OR% SD
Demographics
Age 113 45.5 9.8 105 45.4 9.3 0.885
Male 87 77.0 88 83.8 0.206
Employed 84 74.3 73 69.5 0.429
Married 53 46.9 38 36.2 0.109
Education (>high school) 67 59.3 58 55.2 0.545
Race Ethnicity 0.200
White 88 77.9 91 86.7 0.091
Black 18 15.9 12 11.4 0.335
Hispanic 4 3.5 2 1.9 0.684
Other 3 2.7 0 0.0 0.248
Self-reported alcohol consumption
b
Drinks per day 113 12.9 4.5 105 14.4 6.3 0.105
Drinks per drinking day 113 14.4 5.0 105 16.1 7.0 0.111
Percentage days abstinent 113 9.3 14.4 105 9.6 15.6 0.889
Percentage heavy-drinking days 113 86.9 16.1 105 89.1 16.5 0.325
Percentage very heavy-drinking days (8+ 10+) 113 75.1 23.2 105 76.5 23.8 0.584
Other substance-related indicators
Gamma-glutamyl transpeptidase (GGT) (U L) 113 82.0 127.7 104 90.1 123.7 0.185
Drinker Inventory of Consequences (DrlnC) score (45-item) 113 39.7 19.1 105 41.5 21.4 0.758
Penn Alcohol Craving Scale (PACS) score 113 17.7 6.3 105 18.0 6.6 0.684
Age onset alcohol dependence 111 30.4 11.9 104 27.8 10.5 0.087
Age onset regular drinking 113 21.2 8.2 105 20.5 7.3 0.853
Type B alcoholism 42 37.2 34 32.4 0.459
Parental problematic drinking 68 60.2 57 54.3 0.380
Drinking goal: permanent abstinence
c
42 38.2 51 50.5 0.072
Current smoker
d
58 51.3 61 58.7 0.279
Marijuana use
e
15 13.3 19 18.1 0.327
Psychiatric characteristics
f
Montgomery–Asberg Depression Rating Scale (MADRS) score 113 5.8 5.7 105 4.8 6.5 0.093
Pittsburgh Sleep Quality Index (PSQI) score 108 7.1 3.6 101 7.0 4.0 0.575
Daytime Somnolence Scale (DSS) score 112 1.2 1.1 104 1.1 1.0 0.832
Hamilton Anxiety Scale (HAM-A) score 113 4.0 3.3 105 4.1 4.3 0.686
SF-12 Mental Aggregate score 113 45.9 10.9 105 45.4 11.7 0.803
SF-12 Physical Aggregate score 113 50.6 9.3 105 51.1 8.7 0.536
Clinical Institute Withdrawal Assessment of Alcohol (CIWA) score 111 1.7 1.9 102 2.2 2.5 0.285
a
Group mean differences are tested for significance by t-tests for independent samples or Wilcoxon rank-sum tests. Group prevalence rate
differences are tested for significance via chi-square or Fisher’s exact tests.
b
Reflects mean values during the 60-day period (days 31 to 90) before screening.
c
Denominator sample size is 110 for the placebo and 101 for the quetiapine group.
d
Denominator sample size for the quetiapine group is 104.
e
Marijuana use based on positive urine drug screen.
f
Scale range and interpretive values are as follows: MADRS: (0 to 60) 0 to 6 normal recovered; 7 to 19 mild depression; 20 to 34 moderate;
35 to 60 severe. PSQI: (0 to 21) 6 poor sleep quality. DSS: (0 to 4) 0 alert well-rested; 1 high-level functioning not peak, 2 awake not fully
responsive, 3 somewhat foggy, 4 very tired, fighting sleep. HAMA: (0 to 56) <14 normal; 14 to 17 mild anxiety; 18 to 24 mild–moderate; 35 to 30
moderate–severe. SF-12: (T to score 0 to 100) 50 normal functioning. CIWA: (0 to 70) 10 indicative of alcohol withdrawal.
QUETIAPINE FOR ALCOHOL DEPENDENCE 411
Page 6
suicidal ideation (quetiapine group), automobile accident
(quetiapine group), falling accident (quetiapine group),
preventricular contractions (placebo group), and behavioral
disturbance while intoxicated (placebo group).
DISCUSSION
Compelling reasons exist to study the efficacy and safety of
quetiapine as a treatment for alcohol-dependent patients.
Quetiapine binds to multiple targets, including serotonin
5-HT1A, 5-HT2A, dopamine D1 and D2, histamine H1, and
adrenergic a1anda2 receptors (AstraZeneca, 2010), which
have been shown to alter alcohol-seeking and drinking behav-
ior, primarily in animal models (Johnson, 2007; Litten et al.,
2005). Moreover, recent preliminary clinical results have sug-
gested that quetiapine reduces heavy drinking in alcohol-
dependent patients (Ray et al., 2010). Nonetheless, in this
multisite study, there was no effect on the primary outcome
measure percentage days heavy drinking. Similarly, there was
no difference between quetiapine and placebo groups in other
drinking outcome measures, including percentage days absti-
nent, drinks per drinking day, and drinks per day, as well as
the dichotomous measures—percentage of subjects with no
heavy-drinking days and percentage of subjects who are absti-
nent. Moreover, the negative result with the primary outcome
measure was not moderated by quantity of medication taken,
the presence of side effects, nor the presence of sleep distur-
bances. The negative findings in this study, in contrast to
promising earlier studies, demonstrate the complexity of
Table 3. Treatment Outcomes: Differences Between Placebo and Quetiapine
Drinking outcomes
Placebo Quetiapine
|d| p-Value
LSMEAN
a
SE 95% CI LSMEAN SE 95% CI
Drinks per day 4.4 0.41 3.6–5.2 4.3 0.43 3.5–5.2 0.00 0.972
Drinks per drinking day 6.3 0.45 5.4–7.1 6.2 0.47 5.3–7.1 0.01 0.924
Percentage heavy-drinking days 37.9 3.34 31.3–44.5 37.1 3.50 30.2–44.0 0.05 0.681
Percentage very heavy-drinking days (8+ 10+) 18.8 2.44 14.0–23.6 16.5 2.56 11.5–21.6 0.05 0.657
Percentage days abstinent 47.1 3.54 40.1–54.0 49.5 3.71 42.2–56.8 0.02 0.858
% n denom % n denom OR (95%CI)
b
p-Value
Percentage subjects abstinent 10.6 12 113 11.8 12 102 1.2 (0.5–3.0) 0.774
Percentage subjects with no heavy-drinking days 21.2 24 113 16.7 17 102 1.8 (0.8–3.9) 0.144
Nondrinking outcomes LSMEAN SE 95% CI LSMEAN SE 95% CI |d| p-Value
Montgomery–Asberg Depression
Rating Scale (MADRS) score
4.1 0.37 3.4–4.9 2.8 0.39 2.0–3.5 0.28 0.011
Pittsburgh Sleep Quality Index (PSQI) score 5.1 0.26 4.6–5.6 4.1 0.27 3.6–4.6 0.32 0.009
Daytime Somnolence Scale (DSS) score 0.6 0.06 0.5–0.7 0.9 0.06 0.8–1.0 0.39 0.000
Penn Alcohol Craving Scale (PACS) score 12.8 0.60 11.6–14.0 12.1 0.63 10.8–13.3 0.11 0.363
Drinker Inventory of Consequences (DrlnC) score 22.5 1.78 19.0–26.0 18.5 1.87 14.9–22.2 0.11 0.417
Hamilton Anxiety Scale (HAM-A) score 3.0 0.24 2.5–3.4 2.4 0.26 1.9–2.9 0.10 0.371
SF-12 Physical Aggregate score
c
50.6 0.93 48.8–52.4 51.0 0.82 49.3–52.6 0.02 0.877
SF-12 Mental Aggregate score
c
50.7 1.08 48.6–52.8 51.5 1.12 49.3–53.8 0.12 0.450
a
Unless otherwise noted, LSMEAN are based on the outcome variable (untransformed) and were obtained from a mixed model that includes
only study week and treatment group. Corresponding Cohen’s d and p-values are based on the outcome variable (appropriately transformed)
and were obtained from a mixed model that also includes the covariates gender, clinical center, reducer status, and the baseline value of the
outcome.
b
Odds ratios and corresponding p-values are derived from a logistic regression model that includes the covariates gender, clinical center, redu-
cer status, and baseline drinking. For the outcome percentage subjects abstinent, percentage days abstinent was used as the baseline drinking
covariate. For the outcome percentage subjects with no heavy-drinking days, percentage heavy-drinking days was used as the baseline drinking
covariate.
c
For the SF-12 outcomes, unadjusted means are presented on the untransformed variables. Corresponding Cohen’s d and p-values are based
on the outcome variables (appropriately transformed) and were obtained from a general Iinear model that includes the covariates gender, clinical
center, reducer status, and the baseline value of the outcome.
LSMEAN, least square means; SE, standard error; 95% CI, 95% confidence interval; |d|, absolute value of Cohen’s d; OR, odds ratio; n,
numerator sample size; denom, denominator sample size.
Number of Patients
0
10
20
30
40
50
60
70
Placebo 113 113 113 107 104 101 100 98 96 94 93 89
Quetiapine 105 102 101 100 96 95 96 94 93 92 90 89
123456789101112
Percentage Heavy Drinking Days
Study
Week
Placebo Quetiapine
Fig. 1. Percentage heavy-drinking days during treatment. Means are least
square means obtained from a mixed model that includes only study week
and treatment group. Error bars are 95% confidence intervals. All p > 0.41,
except week 1 (p = 0.05). Note: treatment * week interaction (p = 0.323).
412
LITTEN ET AL.
Page 7
biological mechanisms associated with alcohol addiction in
humans, as well as the need for adequately powered studies.
Quetiapine has been approved to treat depression in
bipolar patients and also has been shown to improve sleep
disturbances (Endicott et al., 2008; Robert et al., 2005). In
the current study, quetiapine also significantly reduced
depressive symptoms and improved sleep compared to
placebo, although both depression and sleep scores were near
Reducer Status * Treatment Group interaction: p=0.182
=0.131
p
:
n
oitcar
e
tnip
u
orGtn
em
taer
T*
su
ta
tSr
e
cud
e
R
Reducer Status * Treatment Group interaction: p=0.373
=0.363
p:
n
o
i
t
ca
re
tn
i
p
uorGtnemt
a
erT*s
ut
atS
r
ecude
R
1.3
2.1
5.4
5.4
0
2
4
6
8
10
Drinks per Day
Reducer—Placebo
Reducer—Quetiapine
Nonreducer—Placebo
Nonreducer—Quetiapine
10.7
14.3
46.8 47.9
0
20
40
60
80
100
Heavy-Drinking
Days
Reducer—Placebo Reducer—Quetiapine
Nonreducer—Placebo Nonreducer—Quetiapine
2.6
3.8
7.4 7.3
0
2
4
6
8
10
Drinks per Drinking Day
Reducer—Placebo
Reducer—Quetiapine
Nonreducer—Placebo
Nonreducer—Quetiapine
75.6
73.0
37.7
38.3
0
20
40
60
80
100
Percentage Percentage
Days Abstinent
Reducer—Placebo
Reducer—Quetiapine
Nonreducer—Placebo
Nonreducer—Quetiapine
Fig. 2. Drinking outcomes during treatment (weeks 3 to 11) by prerandomization reducer status. Means are least square means from unadjusted mixed
models on nontransformed outcome variables (weeks 3 to 11). Error bars are 95% confidence intervals. p-Values for main effects and interactions are from
mixed models on appropriately transformed outcome variables adjusted for gender, reducer status, center, and baseline value of the outcome. All main
effects for Reducer Status are significant (p < 0.0001).
p
noitcaretnIpuorG*tnem
t
aerT=0.964p
n
o
i
tc
a
re
t
n
I
pu
o
rG*
t
ne
m
t
a
er
T
pn
o
it
c
aret
n
Ipuo
r
G*tne
m
t
a
e
r
Tpno
i
tcaretnIpuorG
*t
n
emt
a
er
T
38.2
36.5
37.5
38.4
0
20
40
60
80
100
Percentage Heavy-Drinking Days
Percentage Heavy-Drinking Days
Placebo -
No
Quetiapine
-No
Placebo - Yes
Quetiapine - Yes
Type B Alcoholism
52.1
46.2
34.6
33.1
0
20
40
60
80
100
Placebo - <=12,600mg Quetiapine - <=12,600mg
Placebo
->12,600mg
Quetiapine - >12,600 mg
Quantity of Medication Taken
b
38.5
36.8
35.4
37.3
0
20
40
60
80
100
Percentage Heavy-Drinking Days
Placebo - No
Quetiapine - No
Placebo - Yes
Quetiapine - Yes
Side Effects
a
43.3
40.9
35.5
36.5
0
20
40
60
80
100
Percentage
Heavy-Drinking Days
Placebo - <=5 Quetiapine - <=5
Placebo - >5 Quetiapine - >5
Pittsburgh Sleep Quality Index Score
c
=0.936
=0.205
=0.829
Fig. 3. Additional subgroup analyses. Means are least square means from unadjusted mixed models on nontransformed outcome variables (weeks 3 to
11). Error bars are 95% confidence intervals. p-Values for interactions are from mixed models on appropriately transformed outcome variables adjusted for
gender, reducer status, center, and baseline value of the outcome.
a
The variable ‘‘side effects’’ was determined by the presence of at least 1 of the following
adverse events: dizziness, dry mouth, dyspepsia, increased appetite, sedation, and somnolence.
b
The cutoff, 12,600 mg, is 50% of 25,200 mg, the total
possible amount of medication that could be taken during the maintenance period (weeks 3 to 11).
c
A score of >5 is indicative of poor sleep quality.
QUETIAPINE FOR ALCOHOL DEPENDENCE 413
Page 8
normal in patients at baseline (Tables 2 and 3). This was simi-
lar to the results reported by Kampman and colleagues (2007)
in a study of quetiapine for alcohol-dependent patients. In
their study, depression and anxiety scores were also in the
normal range at baseline and during treatment, yet a signifi-
cant decrease in depression and anxiety was observed during
treatment. In other nondrinking outcomes, quetiapine failed
to improve anxiety, alcohol craving, quality of life, and alco-
hol-related consequences (Table 3).
So far, the alcohol medications that have shown effective-
ness do not work in all individuals, only in subgroups. A pre-
vious study by Kampman and colleagues (2007) suggested
that the immediate-release formulation of quetiapine may be
beneficial for Type B alcoholics. In that study, Type B partici-
pants exhibited very heavy drinking at baseline (average
20 drinks drinking day) and at least 1 of the following: early
onset of alcohol dependence, depression, or antisocial person-
ality disorder. Approximating this definition of Type B alco-
holism, we conducted a subgroup analysis, but found no
significant differential treatment effect for quetiapine above
placebo as a function of Type B status on the primary out-
come drinking measure. One reason for this lack of concor-
dance between the Kampman and colleagues’ (2007) study
and our study may be that our Type B definition did not
include antisocial personality disorder because these data
were available in our study. Another more likely reason may
have to do with study population differences between the 2
studies. For example, in the Kampman and colleagu es’ (2007)
study, 49% of study participants had a comorbid psychiatric
illness, including major depression, posttraumatic stress disor-
der, or other anxiety disorders. While quetiapine has been
shown to improve many symptoms of these disorders (Crois-
sant et al., 2006; Endicott et al., 2008; Martinotti et al., 2008;
Robert et al., 2005), our study recruited very heavy-drink ing
alcohol-dependent patients without serious psychiatric com-
orbidity, a design factor that may account for the treatment
effect differences between our study and that of Kampman
and colleagues (2007). Even though we excluded people with
major psychiatric disorders in our study, we expected that
patients with chronic very heavy levels of drinking at baseline
would also concurrently report elevated levels of anxiety,
depressive symptoms, and poor sleep. This hypothesis is
supported by recent theories of allostasis and addiction—that
long-term drinking results in a homeostatic dysregulation,
resultin g in negative emotion (e.g., dysphoria, depression, irri-
tability, and anxiety) and an elevation of the reward set point
(Koob, 2008; Koob and Le Moal, 2006). However, counter
to our assumptions, despite consuming very large amounts of
alcohol for an extended period of time, these study partici-
pants on average reported normal levels of levels of anxiety
and depression and only modest sleep disturbances at base-
line. It is likely that quetiapine’s efficacy in reducing drinking
observed in previous studies was attributable to the ameliora-
tion of psychiatric symptoms experienced by those patients.
Our failure to find an effect for quetiapine in this study may
be in part due to the high functionality and lack of psychiatric
symptoms of the study population. An argument can be made
that if depression, anxiety, and sleep disturbance mediate or
moderate the effects of quetiapine on drinking outcome,
larger treatment effects might potentially be found in a popu-
lation with higher pathology of these factors. We cannot
discount this possibility and recommend that future studies of
quetiapine test its efficacy in comorbid alcohol-dependent
populations.
During the past 20 years, the majority of patients recruited
for alcohol clinical trials have been required to be abstinent
for at least 3 to 4 days before randomization. However, in
several recent alcohol trials, patients were allowed or even
required to drink right up to randomization (Garbutt et al.,
2005; Johnson et al., 2007). Considerable discussion has
ensued among alcohol researchers as to whether a relapse pre-
vention study model, where prerandomization abstinence is
required, versus a more naturalistic cessation–initiation model
is more appropriate and optimally sensitive for proof-of-
concept testing of new medications. Each of these models has
different practical and theoretical merits. Abstinence or signif-
icant reduction in drinking before randomization appears to
influence treatment outcome. For example, Epstein and col-
leagues (2005) showed that patients who cut back on drinking
before treatment had better drinking outcomes. However, as
treatment outcome improves in the placebo group, it may
become more difficult to demonstrate a significant medication
treatment effect, as observed in depression and schizophrenia
studies (Kemp et al., 2010; Kirsch et al., 2008; Mallinckrodt
et al., 2010; Walsh et al., 2002). Epstein and colleagues (2005)
provided several explanations for this self-initiated reduction
in drinking prior to treatment. The reduction in drinking may
be prompted by merely (i) viewing an advertisement, (ii) dis-
cussingthedecisiontoseekhelpwithindividualsinthesame
social network, or (iii) the realization of the extent and sever-
ity of the drinking problem by acknowledging and discussing
one’s drinking with another individual (Epstein et al., 2005;
Sobell et al., 2003). In this study, we elected to allow patients
to regulate their own drinking before randomization. We then
evaluated analytically whether those patients who reduced
their drinking before randomization had better treatment
outcomes and whether prerandomization ‘‘reducer status’’
would increase the sensitivity to detect a treatment effect.
Table 4. Statistically Significant Adverse Events Occurring in 10% of the
Participants
Adverse event
Number (%) of participants
with adverse events
p-Value
a
Quetiapine Placebo
Dizziness 15 (14) 5 (4) 0.017
Dry mouth 34 (32) 10 (9) <.0001
Dyspepsia 14 (13) 2 (2) 0.001
Increased appetite 12 (11) 1 (1) 0.001
Sedation 16 (15) 3 (3) 0.001
Somnolence 36 (34) 10 (9) <.0001
a
Group prevalence rate differences are tested for significance via
chi-square or Fisher’s exact tests.
414
LITTEN ET AL.
Page 9
Approximately 30% of the patients reduced their drinks per
drinking day by at least 50% before starting study medica-
tion. These ‘‘reducers,’’ of whom 44% were abstinent 1 week
before randomization, had better treatment outcomes on all
drinking measures, including drinks per drinking day, percen-
tage days abstinence, drinks per day, and percentage heavy-
drinking days than the ‘‘nonreducers’’ (Fig. 2). Similar results
were also obtained when drinks per day and number of
heavy-drinking days were the endpoints used to define reduc-
ers and nonreducers (data not shown). Interestingly, however,
there was no reducer-by-treatment interaction, suggesting that
neither of the prerandomization drinking models had a clear
advantage in detecting a treatment effect.
At present, there is no single medication that decreases
alcohol use in all alcohol-dependent individuals. Although
disulfiram—a medication that causes aversive symptoms
when taken with alcohol—should have high efficacy among
patients who take the therapeutic dosage, disulfiram has had
limited success in treatment owing to poor compliance (Allen
and Litten, 1992; Jorgensen et al., 2011). Development of
more effective medications may, in part, require a better
understanding of brain circuits and mechanisms underpinning
alcohol addiction, as well as a more accurate delineation of its
subtypes. In essence, a more targeted approach may be
required to foster the creation of medications that will be truly
efficacious. For now, alcohol pharmacotherapy trials need to
focus on subpopulations that appear most likely to respond
to medication. In this study, we hypothesized and recruited
an alcohol-dependent population of very heavy drinkers as
the cohort who would most likely respond to quetiapine.
Even though the primary analyses were negative, further sec-
ondary analyses will be continued, exploring various sub-
groups that might benefit from quetiapine. For the present,
however, we cannot recommend the use of quetiapine as a
medication to treat alcohol-dependent individuals.
ACKNOWLEDGMENTS
This research was supported by the National Institute on
Alcohol Abuse and Alcoholism, National Institutes of
Health, Department of Health and Human Services. The Vet-
erans Affairs Cooperative Studies Program (VACSP), Perry
Point, MD, was the Coordinating Center; this research was
supported in part by the Investigator-Sponsored Study Pro-
gram of AstraZeneca.
APPENDIX
NCIG 001 Study Group
Boston University School of Medicine, Boston, MA:
Matthew J. Biondolillo, B.S., Laurie Sickles Colaneri, R.N.,
Eric G. Devine, Ph.D., Joseph Gugliotta, B.A., Clifford M.
Knapp, Ph.D., Megan A. Putnam, B.A., Courtney A. Rich-
ambault, B.A., Orfa Sarid-Segal, M.D., Chris C. Streeter,
M.D., and Megan E. Waters, B.A.
University of Pennsylvania Treatment Research Center,
Philadelphia, PA: Brenda Beitler, M.S., Janice Biddle,
M.S.N., Cynthia Clarke, Ph.D., Tiffany Sharkoski, B.A.,
Laura Sorensen, B.A., William D. Dundon, Ph.D., Kelly
Griffin-Farraday, B.A., Margo Hendrickson, M.S.S.,
Kathleen Kirchner, B.S., and Gail Kaempf, CRPN.
University of Virginia Center for Addiction Research and
Education, Richmond, VA: Eva Jenkins-Mendoza, B.S. and
CCRP and Sean Sembrowich, R.N.
Center for Alcohol and Addiction Studies, Brown Univer-
sity, Providence, RI: George Kenna, Ph.D., RPH and
Lorenzo Leggio, M.D., M.Sc.
Dartmouth Medical School, Lebanon, NH: Audrey Kern,
M.D., Christopher O’Keefe, M.S., and Shannon Rondeau,
R.N.
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    • "Quetiapine 400 mg daily for 6 weeks has shown positive results in drink reduction and impulsivity62 and, over 12 weeks, demonstrated reduced drinking in type B alcoholics (early onset, more severe) compared to type A alcoholics (late onset, less severe).63 Quetiapine may not be useful in very heavy drinkers64 or as an adjunct to naltrexone,65 but may be an option to reduce drinking in less heavy drinkers or type B alcoholics. "
    [Show abstract] [Hide abstract] ABSTRACT: Alcohol use disorders (AUD) continue to be a concerning health issue worldwide. Harmful alcohol use leads to 2.5 million deaths annually worldwide. Multiple options exist for the management of dependence on alcohol, not all of which are approved by drug-regulating agencies. Current practice in treating AUD does not reflect the diversity of pharmacologic options that have potential to provide benefit, and guidance for clinicians is limited. Few medications are approved for treatment of AUD, and these have exhibited small and/or inconsistent effects in broad patient populations with diverse drinking patterns. The need for continued research into the treatment of this disease is evident in order to provide patients with more specific and effective options. This review describes the neurobiological mechanisms of AUD that are amenable to treatment and drug therapies that target pathophysiological conditions of AUD to reduce drinking. In addition, current literature on pharmacologic (both approved and non-approved) treatment options for AUD offered in the United States and elsewhere are reviewed. The aim is to inform clinicians regarding the options for alcohol abuse treatment, keeping in mind that not all treatments are completely successful in reducing craving or heavy drinking or increasing abstinence.
    Full-text · Article · Jan 2014
    0Comments 7Citations
    • "Importantly, a large improvement in both 6-month trials was observed in the first 2 weeks between screening and the start of the treatment: in the Mann et al. study, 18% of the patients greatly reduced their alcohol consumption prior to treatment, whereas this was true for 33% of the patients in the Gual et al. study. This phenomenon has been reported previously (Epstein et al., 2005; Litten et al., 2012) and means that a substantial fraction of the patients was treated without a prospect of further improvement. Inclusion of these patients in the pre-specified efficacy analysis may have resulted in a substantial underestimation of the treatment effect. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of the study was to investigate the efficacy and safety of as-needed use of nalmefene 18 mg versus placebo in reducing alcohol consumption in patients who did not reduce their alcohol consumption after an initial assessment, i.e. the pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) at both screening and randomization from the two randomized controlled 6-month studies ESENSE 1 (NCT00811720) and ESENSE 2 (NCT00812461). Nalmefene 18 mg and placebo were taken on an as-needed basis. All the patients also received a motivational and adherence-enhancing intervention (BRENDA). The co-primary outcomes were number of heavy drinking days (HDDs) and mean total alcohol consumption (g/day) in Month 6 measured using the Timeline Follow-back method. Additionally, data on clinical improvement, liver function and safety were collected throughout the study. The pooled population consisted of 667 patients: placebo n = 332; nalmefene n = 335. There was a superior effect of nalmefene compared with placebo in reducing the number of HDDs [treatment difference: -3.2 days (95% CI: -4.8; -1.6); P < 0.0001] and total alcohol consumption [treatment difference: -14.3 g/day (-20.8; -7.8); P < 0.0001] at Month 6. Improvements in clinical status and liver parameters were greater in the nalmefene group compared with the placebo group. Adverse events and adverse events leading to dropout were more common with nalmefene than placebo. As-needed nalmefene was efficacious in reducing alcohol consumption in patients with at least a high drinking risk level at both screening and randomization, and the effect in this subgroup was larger than in the total population.
    Full-text · Article · Jul 2013 · Alcohol and Alcoholism
    0Comments 62Citations
    • "At randomisation, these patients consumed such a small amount of alcohol that there was little room for further improvement, irrespective of treatment. This is a phenomenon that has been observed in other alcohol treatment studies, including the recently published study by Mann et al. (2012), and can indeed have an impact on study outcome (Epstein et al., 2005; Litten et al., 2012). No doubt motivational factors (readiness to change), expectancy and natural course could explain why some patients selfinitiated a reduction in alcohol consumption immediately after they had been informed about the study and consented to participate and before they started on any treatment intervention. "
    [Show abstract] [Hide abstract] ABSTRACT: This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. Seven hundred and eighteen patients (placebo=360; nalmefene=358), ≥18 years of age, with a diagnosis of alcohol dependence, ≥6 heavy drinking days and an average alcohol consumption ≥WHO medium drinking risk level in the 4 weeks preceding screening, were randomised (1:1) to 24 weeks of as-needed placebo or nalmefene 18mg/day. The co-primary efficacy analyses showed a significantly superior effect of nalmefene compared to placebo in the change from baseline to month 6 in heavy drinking days (group difference: -1.7 days/month [95% CI -3.1; -0.4]; p=0.012) and a better but not significant effect in reducing total alcohol consumption (group difference: -5.0g/day last month [95% CI -10.6; 0.7]; p=0.088). A subgroup analysis showed that patients who did not reduce their drinking prior to randomisation benefitted more from nalmefene. Improvements in Clinical Global Impression and reductions in liver enzymes were greater in the nalmefene group than in the placebo group. Adverse events were more common with nalmefene; the incidence of adverse events leading to dropout was similar in both groups. This study provides evidence for the efficacy of nalmefene, which constitutes a new pharmacological treatment paradigm in terms of treatment goal (reduced drinking) and dosing regimen (as-needed), in alcohol dependent patients unable to reduce alcohol consumption on their own.
    Full-text · Article · Apr 2013 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
    A.   Gual A. Gual Y.   He Y. He L.   Torup L. Torup +17 more authors... W.   Van Den Brink W. Van Den Brink
    0Comments 51Citations
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