\m mi

BROWN
The Brown University
Psychopharmacology
THE PREMIER MONTHLY FORUM ABOUT THE USE OF PSYCHOTROPIC MEDICATIONS
VOLUME 19, MUMBER1
JANUARY 2008
ISSN 1068^5308
ONLINE ISSN 1556-7532
Editor:
Lawrence H. Price, M.D.
hliahts...
AHRO' s ANTIDEPRESSANT REVIEW
Our top story this month
examines the key findings from an
interesting metanalysis of 2nd-
generation antidepressants. The
AHRQ report found no predictors of
individual response and an almost
40% non-response rate to initial
treatment.
Also under review is a study
questioning whether aripiprazole
alone is an effective strategy for
maintenance treatment in patients
with bipolar 1 disorder.
Inside
SPECIAL REPORT 4
Long-term analysis confirms
value of combining medication,
cognitive behavioral therapy (CBTJ
NEWS NOTES 7,8
Suicidality during depression
treatment linked to genes
Health Canada approves
paliperidone
Topiramate helps weight loss
in women treated with olanzapine
CvsE REPORT 8
Disulfiram-Methylphenidate
interaction
FROM THE FDA 8
Published online Jn Wilev InlerScience
(www. I n ters c IB n c B. wi l ev. <: 0 m I
QOI: 1O.10O2/PU.200S9
j ' * * - AWILEt
inferScience'
Comparison of newer antidepressants
finds no individual-response predictors
nvestigators conducting a major mcla-
analysis of second-generation antide-
pressants found no reliable predictors of indi-
vidual responses to specific drugs. Because of
high non-response rates and a high incidence
of side effects, many patients try multiple an-
lidepressants before finding an effective med-
ication that they tolerate well.
Almost 2 out of 5 patients do not respond
to initial drug treatment. Future studies
should focus on making initial treatment
more effective, say the authors.
The study, conducted and published by the
Agency for Healthcare Research and Quality,
compared the effectiveness of 12 second-gen-
eration antidepressants, analyzing several key
clinical questions. "Comparative Effective-
ness of Second-Generation Antidepressants in
the Pharmacologic Treatment of Adult De-
pression." is Number 7 in AHRQ's Compara-
precis
Investigators conducted a meta-analysis of
187 studies of good or fair quality to deter-
mine the relative effectiveness of 12 second-
generation antidepressants
'The meta-anatysis yielded no predictors of
individual response to specific antidepres-
sants; almost 40% of patients do not respond
to initial treatment with antidepressants
> Future studies should explore making initial
treatments more effective
tive Effectiveness Review series.
The study was based on analysis of avail-
able evidence, and compared the following 12
second-generation antidepressants for efficacy
and side effects; bupropion. citalopram, dulox-
etine, escitalopram, fluoxetine, fluvoxamine,
niirtazapine, nefazodonc. paroxetine. sertra-
AHRQ, continued on page 6
BIPOLAR DISORDER
Is aripiprazole an effective maintenance
treatment option for bipolar disorder?
ong-term maintenance treatmeni with
aripiprazole monotherapy may offer
some benefits to patients with bipolar I disor-
der in delaying time to relapse. In a 100-
week, double-blind, placebo-controlled study,
researchers found that aripiprazole was well
tolerated and superior to placebo, particularly
in preventing and delaying time to manic re-
lapse. Although aripiprazole was no more ef-
fective than placebo in delaying time to de-
pressive relapse, the drug did not increase the
likelihood of recurring depression.
The research was conducted on behalf of
the Aripiprazole Study Group from March
BiPOL\R DISORDER, continued an page 2
nrecis
a
-*- ' A lOQ-week double-blind study found
aripiprazole to be well tolerated and superior
to placebo in preventing time to manic
relapse in patients with bipolar I disorder,
but no more effective than placebo in
preventing time to depressive relapse
' A relapse-prevention study of 66 patients
who were stabilized during 26 weeks of
double-blind treatment with aripiprazole or
placebo and then entered a 74-week double-
blind maintenance program
> A total of 12 patients (aripiprazole 7; placebo
5) completed 100 weeks of treatment with-
out relapse, limiting the generalizability of
the findings to a larger population
FREE PATIENT HANDOUT: ARIPIPRAZOLE (GENERIC) - ABILIFY (BRAND)
T H E B R O WN UNIVE RSIT Y PSYCHOPHARMACOLOGY UPDATE JANUARY 2008
The firiHvn t!"lvir^ily
Psychoptiarmacologv
BROWN
Psvchopharmacologv
Ul^DAT E
Editor:
Liiwrcncc H. Price,
M.D.. Professor.
Dciyurnmiil of
Psycliititry tiiid Hiiniiiri
Behavior. Brown
Medical School.
Director of ftcseutx it
and Clinical Director,
Butler Hospital. Providence, Rl.
Executive Managing Editor ....Karienne Stovel l
Associate Editor Sarah Meni l l
Associate Editor Diana Steimle
Medical Writer Brion P. McAlaniey. J.D.
Contributing Editor Gary Eiios
Production Editor Douglas Devaux
Executive Editor Isahcltc Cohen-DeAngcIis
Publisher Stie Lewis
Editorial Advisory Board:
Linda L. Carpenter. M.D.. Chief, Mood
Oisortler PrDi^ritm. Butler Hospital, Assi>ciaie
Professor t>f Psychiatry and Human Behavior,
Brown Medical School. Provideiiee, Rl: John
H. Kryst:tl. M.D.. Alhcri . Kent Professor
and De/iiiiy Chairman of Research.
Department of Psyciiiatry, Yale University
School of Medicine, New Haven. CT:
Christopher J. McDougle. M.D.. Albert E,
Sterne Professor and Chair, Department of
Psychiarry. Indiana University School of
Meilhine. liuiianapolis, IN.
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BIPOLAR DISORDER
continued frotn page 1
2000 to June 2003, with funding from
Bristol-Myers Squibb Company, and
Otuska Pharmaceutical Company Ltd,
According to the lead author Paul E.
Keck. M.D. and colleagues. "These are the
Ursl 2-ycar data in bipolar disorder since the
lithium studies of ihc 1970s, and this study
is the longest double-blind, placebo-con-
irolled study of an atypical agent in the treat-
ment of bipolar disorder." Keck is Professor
of Psychiatry, Pharmacology and Neuro-
science. Department of Psychiatry, Univer-
sity of Cincinnati College of Medicine.
Background
Bipolar disorder is the sixth leading
cause of disability worldwide. According
to Charles L. Bowden, M,D., Professor of
Psychiatry at the University of Texas
Health Science Center at San Antonio, "it
is important for practitioners in psychiatry
and in other medical llelds to recognize
that bipolar disorder is a lethal illness. The
age-corrected death rate from suieide in
bipolar disorder actually exceeds that in
some other chronic medical illnesses."'
The majority of bipolar patients can ex-
perience a lifetime of recurring episodes,
given the persistent nature of the disorder.
The risk of recurrence increases with each
episode, and the rate of recurrence can es-
calate to 49% within 2 years of a patient re-
covering from an initiai episode.
In view of the longitudinal course of
bipolar disorder and the need for effective
maintenance therapy, the current study was
designed to assess aripiprazole's tolerabili-
ty. safety, and effectiveness in preventing
recurrence of manic, depressive or mixed
episodes of bipolar disorder over a period
of two years. Aripiprazole is the first
dopamine agonist to be approved in the
United States for treating acute mania asso-
ciated with bipolar I disorder. Aripiprazole
and olanzapine are the only atypical an-
tipsychotics currently approved by the U.S.
Food and Drug Administration for mainte-
nance treatment of bipolar I disorder.
Study details
This relapse-prevention study enrolled
567 patients from 76 centers in Argentina,
Mexico, and the United States, who had
been diagnosed with DSM-IV bipolar I
disorder, and recently hospitalized and
treated for a manic or mixed episode. Par-
ticipants underwent a 6- to 18-week stabi-
lization period of open-label aripiprazole
15 or 30 mg/day.
Among the responders. 161 patients
were randomized to aripiprazole (N=78)
or placebo (N=83) for 26 weeks under
double-blind conditions.- At 26 weeks. 66
patients wbo were stabilized (i.e.. did not
experience a relapse) enrolled in further
double-blind treatment for 74 weeks, and
were randomized to aripiprazole (N=27)
or placebo (N=39).
Tbe same primary efllcacy cndpoint
was used during tbe initiai 26 weeks of
double-blind treatment and the 74-week
extension phase, i.e.. time to relapse due to
a manic, depressive or mixed episode. Re-
lapse was defined as a mood episode that
resulted in hospital admission and/or in-
crease or addition of a psychotropic med-
ication other than aripiprazole for manic
and/or depressive symptoms.
Secondary effieacy measures included
the mean change in total score from dou-
ble-blind randomization to endpoint on the
Young Mania Rating Scale (YMRS), the
Montgomery-Asberg Depression Rating
Scale (MADRS), the Clinical Global
Impressions-Bipolar Version (CGI-BP)
Severity of Illness scores, and the Positive
and Negative Syndrome Scale (PANSS)
total score and cognitive and hostility sub-
scale scores.
Tn evaluating safety and efficacy
measures, lust-observation-carried-forward
(LOCF) analyses were used witb com-
bined data from tbe initial 26-week trial
and the 74-week extension trial. The data
from participants in the 26-week: trial who
did not enter the maintenance program
were carried forward to week 100.
Results
The patients in this study were approx-
imately 40 years old, with more patients in
the aripiprazole group having mixed-type
mania than in the placebo group (38% vs
22%). During the 74-week maintenance
period, the trial was discontinued by the
sponsor when the prespecified number of
relapses had been attained (10 for placebo
and 14 for aripiprazole). A total of 12 pa-
tients completed the entire 100-week
study 5 out of 83 in tbe placebo group
and 7 out of 78 in the aripiprazole group.
The mean aripiprazole dose at the start
of maintenance treatment was 23.8 mg/day,
similar to the mean dose among patients
who completed KKl weeks of treatment
(23.6 mg/day; N=7). During the last 7 days
JANUARY 2008 THE BROWN UNIVERSITY PSYCHOPHARMACOLOGY UPDATE
of treatment, at whatever point in time that
occuned during the l(M)-week period, the
mean aripiprazole dose was 24.1 mg/day
(range 12.9-30 mg/day; N=77).
During the maintenance phase, 78% of
placebo patients (2i/27) and 62% of arip-
iprazole patients (24/39) received at least
one concomitant psychotropic drug, fn the
placebo group, the most commonly pre-
scribed medications were analgesics and
antipyretics (48%), anxiolytics (41%), and
anticholinergics (30%). In the aripiprazole
group. 31% of patients received either
anxiolytics or analgesics and antipyretics.
Relapse rates were relatively low in
both groups, suggesting that patients are
more likely to relapse into the same
episode as the index episode, write Keck
and colleagues. Patients treated with arip-
iprazole had a significantly Ionger time to
relapse into any mood episode compared
with placebo-treated patients (p=().Oll),
particularly in time to manic relapse
(p=0.()05). By week 100, 52% of placebo
patients (43/83) experienced a relapse for
any reason compared with 33% of arip-
iprazole patients (25/77) (p=0.02).
There were significantly fewer manic
relapses in patients who received aripipra-
zole compared with those who received
placebo (12% vs 28%; p<0.05), but there
was no significant advantage of aripipra-
zole over placebo in delaying time to de-
pressive relapse.
Other efficacy measures showed a
worsening in the placebo group in YMRS
total scores (LOCF) from baseline to end-
point compared with the aripiprazole group
(p=0,01). but no significant between-group
differences on MADRS scores (LOCF).
PANSS scores (LOCF) also favored arip-
iprazole, with reductions in hostility
(p=0.03) and improvements in cognitive
function (p=0.01) compared with placebo.
Overall scores favored aripiprazole on the
CGI-BP Severity of Illness scale (placebo
1.6 0.2 vs aripiprazole 1.0 0.2: p=0.01)
and on the Severity of Illness mania score
(placebo 1,1 0.2 vs aripiprazole 0.6 0.2;
p=0.02). There were no significant be-
tween-group differences on the CGI-BP
Severity of Illness depression scores.
Adverse events
Aripiprazole appeared to be well toler-
ated, with no significant differences in the
adverse event (AE) profile between initial
treatment and maintenance treatment. Pa-
continued on next page
Overview of approved pharmacologic treatments of bipolar disorder
Lithium (Eskalith) used as first-line therapy
for acute manic episodes nf bipolar disorder.
Since inlbrnialion regarding safely and
effectiveness of liihium in eliildren younger
Ihan 12 years is not available, its use in such
patients is not recommended.
Lwww.fda.gov/cder/foi/label/2(K)4/1686()slr
074.18152slr{)2()_eskalith^lbl.pdlJ
Atypical antipsychotics
Aripiprazole (Abilify) for acute and mainte-
nance treatment of manic and mixed
episodes of bipolar I disorder with or witboul
psycbotic fcalures; for treatment of agitation
associaled witb hipolar I disorder, manic or
mixed. Safely and elleetiveness in pediatrie
patients with bipolar mania or agitation asso-
ciated with bipolar mania have not been es-
tablished.
|pedibup;//packageinserts.bmsxom/pi/pi_abil
ify.pdii
Olanzapine (Zyprexa) as monotberapy for
treating acute mixed or manic episodes asso-
ciated with bipolar I disorder; as mainte-
nance monolherapy in paiienis who have re-
sponded for an average duration of 2 weeks;
as combination tberapy witb lithium or val-
proate for the shoii-tenn treatmeni of aeute
mixed or manie episodes associated with
bipolar I disorder. Safely and efficacy in pa-
tients younger tban 18 years bave not been
eslablisbed.
Lhttp://pi.lilly.eom/us/zyprexa-pi.pdf|
Combined olan/apine/fiiioxetinf (Sym-
byax) for depressive episodes associated
witb bipolar disorder: no established guide-
lines exist for the lengtb of lime patients witb
bipolar disorder experiencing a major depres-
sive episode should be treated with agents
eontaining aniidepressan! drugs. Safety and
efficacy of olanzapine and fluoxeline in com-
bination have not been established in patients
younger than 18 years.
tbltp://pi.!illy.eom/us/symbyax-pi.pdfl
Qut'tiapine (Seroquel) tor depressive
episodes assoeiated with bipolar disorder,
and (or manie episodes associaled wiih bipo-
lar I disorder as monotberapy or as adjunct
therapy to lithium or divalproex. Safely and
effectiveness in pedialric patients bave nol
been established.
[www.astra/eneea-us.com/pi/seroquel.pdf|
Risperidone (Rlsperdal) for short-ierm
treatment of acute manie or mixed episodes
associated witb bipolar I disorder in adulls.
to be used alone or in combination with litbi-
uni or valproate. and as monotberapy in chil-
dren and adoleseents (ages 10-17 years).
[www.risperdal.eom/risperdal/shared/pi/
risperdal.pdfl
Ziprasidone (Geodon) for acute manic or
mixed episodes assoeiated witb bipolar I dis-
order, witb or wiihout psyebolic features. Its
effectiveness lor prophylactic and longer-
term use in mania has not been systematical-
ly evaluated in controlled clinical trials. Safe-
ty and effectiveness in pediatrie patients have
not been established.
(www.pnzer.com/fi!es/products/uspi_
geodon.pdf)
Other antipsychotics
Cblorpromazine (Thorazine) for mania asso-
cialed with bipolar disorder.
lwww,fda.gov/(;der/foi/label/200l/l 1120s86
Ibl.pdf]
Anticonvulsants
Carbamazepine (Equetro) for acute manic
and mixed episodes associated with bipolar I
disorder. Safety and effectiveness in pedialrie
and adolescent patients have not been estab-
iished.
I www.equetro.com/Files/PDFs/Prescribing
Info.pdfj
Divalproex (or valproate) delayed-release
(Depakote) for manie episodes associaled
witb bipolar disorder. Safety and effective-
ness for long-term (>3 weeks) use in mania
have not been systematieally evaluated in
controlled, clinical trials. Safety and effec-
tiveness of Depakote in patients witb acute
mania younger tban !8 years have not been
established.
|www,rxabbott.com/pdf/depakote,pdfl
Divalproex (or valproate) F^^R (Depakote
ER) for acute manic or mixed episodes asso-
ciated with bipolar disorder, with or without
psyehotic features. Effectiveness of Depakote
ER for long-term use (>3 weeks) in mania
has not been systematieally evaluated in con-
irolled clinical trials.
I www.rxabbott.com/pdf/dep3.pdfi
Lamotrigine (Lamiital) maintenanee treat-
ment of bipolar 1 disorder to delay time to
oecurrencc of a mtwd episode (depression,
mania, hypomania. mixed episodes) in pa-
tients treated tor acute mood episodes with
siandard therapy. Effectiveness in aeute treat-
ment of mood episodes has not been c'-(ab-
Itshed, Safety and effectiveness m |>alients
younger tban 18 years with bipolar disorder
bave not been established,
lbttp://us,gsk.com/producls/assels/us_
lamiclai.pdrl.
T H E B R O W N UNI VE RSI T Y PSYCHOPHARMACOLOGY UPDATE J ANUARY 2008
continued from previous page
lienis in the placebo group experienced
higher rates of serious AEs compared with
the aripiprazole group (23% vs 12%). and
higher discontinuation rates due to AEs
(28% vs 16%), mainly due to worsening of
manic and depressive symptoms. The most
commonly reported serious AEs reported
hy patients in the placebo or aripiprazole
group were manic reaction (12% vs 8%),
and depression (5% vs 0%).
AEs that occurred in the aripiprazole
group with >5% incidence and at twice the
placebo rate were: tremor, akathisia. dry
mouth, hypertension, weight gain, vagini-
tis, abnormal thinking, pharyngitis, and flu
syndrome.
Clinically significant weight gain was
observed in both groups, with no between-
group differences in change from baseline
to week 100 in fasting and non-fasting glu-
cose, cholesterol (HDL. LDL). triglyc-
erides, or total cholesterol levels.
Clinical significance
The clinical significance of the study is
limited by the relatively small number of
patients who completed 26 weeks without
a relapse, and only 12 patients who com-
pleted 100 weeks of treatment. While such
a high attrition rate is not unusual in long-
term studies, the authors acknowledge that
il does make the findings difficult to gen-
eralize to a larger population of patients
wilh hipolar miinia. They also indicate thai
discontinuation of the trial once lhe prede-
fined number of relapses had been reached
prevented some patients from having the
opportunity to complete the study. Anoth-
er limitation was the use of a select sample
of participants who had been previously
stabilized prior to randomization and long-
term maintenance treatment, with data
from participants who did not enter the 74-
week maintenance period included in
LOCF efficacy and safety analyses.
Despite the weaknesses in the design of
this study, "they should not detract from
the evidence for efficacy of the approved
agents over other agents not approved for
maintaining efficacy in hipolar disorder,"
write Keck and colleagues. Although dival-
proex and atypical antipsychotics are used
in this indication, "there is a paucity of data
to support this use." Citing a 52-week, ran-
domized, double-blind study of 372 pa-
tients with bipolar mania. Keck and col-
leagues point out lhe lack of a significant
difference between divaiproex and placebo
in preventing time to any mood episode.'
Older antipsychotics. such as per-
phenazine, may also be unsuitable for long-
term treatment of bipolar disorder due to
tbe risks of prolactin elevation, extrapyra-
midal syndrome, and tardive dyskinesia.
While the small sample size of this
study limits its generalizability to a larger
population, the findings compare favorably
with those of other relapse prevention stud-
ies, some of which report higher relapse
rates with placebo or divalproex compared
with olanzapine. lithium, or lamotrigine.
The data presented in this study show
that aripiprazole monotherapy continued to
be effeclive over the course of 100 weeks,
providing additional evidence for aripipra-
zole's use as maintenance therapy for bipo-
lar I disorder, conclude the authors.
Nevertheless, the implications of long-
term Iherapy with regard to weight gain are
of particular concem, with increasing evi-
dence of a link between obesity and meta-
bolic disorders in bipolar disorder and
poorer functional outeome and clinical
measures. Clinicians need to consider addi-
tional metabolic measures when prescrib-
ing an antipsychotic, particularly in view ot
the heightened risk of life-threatening car-
diovascular events associated with hyper-
lipidemia. Weight gain and other metabolic
measures need to be monitored regularly,
write Keck and colleagues, noting ihat
clinically significant changes in this popu-
lation '"can be precursors to further poorer
overall outcomes."
Sludy supported by Bristoi-Myers Squibb Co. ami
by Olsuka Pharmaceutical Cl. Ud.
Keck PE Jr. Calabresc JR. Mclntyre RS. el al.:
Aripiprazole monotherapy tor maintenance iherapy
in bipolar I di.sorder: a 100-week, double-blind
sludy versus placebo. J Clin P.m-liititry 2007;
68(IO):i48O-149l. E-maii: paul.keck@uc.edu.
REFERENCES
1. Bowden CL, Calabrese JR. Goodwin FK. et al.:
Long-term use of mood siabilizers in bipolar dis-
order. J Clin P.syehiiitry Audiograph Scries 2(M)2:
5(6):i-l4.
2. Keck PE Jr. Calabrcse JR. McQuade RD. ct al.:
A randomized, double-blind, placebo-controlled
26-week trial of aripiprazole in recently tnanie
patients with bipolar 1 disorder. J Clin P.syihuiiiy
2006: 67(4):626-637.
3. Bowden CL. Calabrese JR. McElroy SL. el al.: A
randomized, placebo-controlled 12-month trial of
divalproex and lithium in Ircalmenl of outpatients
wilh bipolar I disorder. Divalproex Mainlenance
Study Group. Arch Gen Psychiatry 2000;
57(5):481-489.
SPECIAL REPORT: TREATMENT OF ADOLESCENT DEPRESSIO
Long-term analysis confirms value of combining
medication, cognitive behavioral therapy (CBT)
ombining lluoxetine treatment with
cognitive-behavioral therapy (CBT)
for adolescents with moderate to moderate-
ly severe levels of depression appears to re-
sult in better outcomes than either treatment
offered alone, suggest long-term results in
the Treatment for Adolescents With De-
pression Study (TADS). The long-term
analysis also indicates that using CBT in
conjunction with medication treatment ap-
peurs to offer a protective effect against sui-
cidal thoughts and behavior in adolescents.
The long-term effectiveness analysis.
which examined treatment response rates
at six-week intervals through a 36-week
period, also showed that fluoxetine treat-
ment performed better than CBT in the
early stages of treatment, with the results
from both the monotherapies and the com-
bined treatment converging in the later
stages of the study.
The finding regarding CBT's useful-
ness in mitigating suicidal ideation comes
at an important time as professionals and
policy-makers continue to wrestle with the
relative benefits and risks of using selective
serotonin reuptake inhibitor (SSRI) antide-
pressants to treat depression in young peo-
ple. The researchers stated in the journal
article that "patients treated with combina-
tion therapy show fewer psychiatric and
nonpsychiatric adverse events than patients
treated with fluoxetine alone."
TADS methods, results
Previous analyses under TADS, which
the National Institute of Mental Health
(NIMH) funded in 1999, showed that after
12 weeks of treatment, combination tbera-