June 2012
The Brown University Psychopharmacology Update 7
on SMMSE scores, with larger benefits ob-
served in those patients with moderate AD
(SMMSE score 10 to 13) than in those with
severe AD (SMMSE score 5 to 9).
On the secondary measure, patients
taking memantine vs. placebo memantine
had NPI scores that were lower (indicat-
ing fewer behavioral and psychological
symptoms) by an average of 4.0 points
(p=0.002), a smaller benefit than the mini-
mum clinically important difference. In
patients taking both memantine and donep-
ezil, the decrease in NPI score was greater
by 5.1 points (p=0.006), showing benefits
not seen on the primary outcome measures
in this combined medication group.
There were 188 serious adverse events
reported, but only six were judged “possi-
bly” related to the study drugs. There were
no differences in serious adverse events or
deaths between treatment groups.
Implications
Cognitive and functional improve-
ments associated with both donepezil and
memantine were small relative to the over-
News Notes
Maternal depression, antidepressants,
and pregnancy outcome
A large prospective cohort study found
no strongly increased risk of major malfor-
mations, including cardiovascular defects,
among infants exposed to antidepressants
during the first trimester of pregnancy. The
authors sought to examine whether first-
trimester exposure to antidepressants, spe-
cifically selective serotonin reuptake inhibi-
tors (SSRIs), was associated with increased
risk of congenital malformations, while
adjusting for maternal level of depres-
sion during pregnancy and other confound-
ing factors. The study examined data on
699 women (1.1% of 63,395 women from
the Norwegian Mother and Child Cohort
Study) who reported using antidepressants
during pregnancy, most frequently SSRIs
(0.9%). The women had completed two
self-administered questionnaires at gesta-
tional weeks 17 and 30 on medication use
and medical, sociodemographic, and psy-
chological factors. Researchers retrieved
data on pregnancy outcome from the Med-
ical Birth Registry of Norway. Results
showed that exposure to SSRIs during the
first trimester was not associated with in-
creased risk of congenital malformations
all size of the decline seen in all patients.
The cognitive benefit associated with con-
tinuing donepezil was equivalent to 32%,
and starting memantine was equivalent
to 20% of the total deterioration over 12
months compared to the group discon-
tinuing donepezil and receiving meman-
tine placebo. The functional benefits were
23% for continued donepezil and 11% for
memantine.
Howard said that the most surprising
aspect of these results was the size of the
benefits — particularly for cognition — as-
sociated with continuing donepezil in the
severely affected population. “These were
greater than we had expected: about twice
the magnitude in terms of MMSE score
than reported from an earlier independent
trial in mild to moderate AD,” he noted.
In terms of how the results might
impact a treatment plan, Howard recom-
mended not stopping treatment with a
cholinesterase inhibitor when a patient
has declined to the moderate to severe
stage of AD. “Stopping treatment had
been the advice of the Department of
in general (adjusted odds ratio [OR], 1.22;
95% confidence interval [CI], 0.81–1.84)
or cardiovascular malformations (adjusted
OR, 1.51; 95% CI, 0.67–3.43). Exposure
to antidepressants during pregnancy was
not associated with increased risk of pre-
term birth (adjusted OR, 1.21; 95% CI,
0.87–1.69) or low birth weight (adjusted
OR, 0.62; 95% CI, 0.33–1.16). The authors
conclude that these results do not suggest
a strongly increased risk of malformations,
preterm birth, or low birth weight follow-
ing prenatal exposure to antidepressants.
Without adjustments for level of maternal
depression and various sociodemographic
and lifestyle factors, antidepressant use
during pregnancy would wrongly have been
associated with an increased risk of preterm
birth. [Nordeng H, et al.: J Clin Psycho-
pharmacol 2012; 32(2):186–194.]
Lamotrigine augmentation of
SSRIs for treatment-resistant OCD
In a 16-week double-blind, random-
ized, placebo-controlled trial, researchers
explored the efficacy of lamotrigine add-
on pharmacotherapy in 33 outpatients with
treatment-resistant obsessive-compulsive
disorder (OCD) who were taking sero-
Health body charged with evaluating the
effectiveness of medicines in the United
Kingdom largely because until our trial
was published there wasn’t an evidence
base to show that continuing treatment had
benefits,” said Howard.
“We are following up all the trial
patients for a further three years to see
whether the results influence rates of
institutionalization in the treatment
groups,” Howard told The Update. “Both
donepezil and memantine will be avail-
able in cheap generic forms all around
the world very soon; several companies
are making combination tablets. It will be
interesting to see whether these get wide
take-up.” ▪
••••••••••••••••••••••••••••
*The study was funded by the U.K. Medical Re-
search Council and the Alzheimer’s Society. Pfizer-
Eisai and Lundbeck donated supplies of the drugs
and placebo.
Howard R, McShane R, Lindesay J, et al.: Donepe-
zil and memantine for moderate-to-severe Alzheim-
er’s disease. N Engl J Med 2012; 366(10):893–903.
E-mail: robert.j.howard@kcl.ac.uk.
tonin reuptake inhibitors (SRIs). Dosages
of SRIs had been stable for at least 2
months before the study and were left
unchanged throughout the study. Dur-
ing the study, no additional medications
were allowed. Researchers randomly as-
signed patients to receive, in a double-
blind design, lamotrigine 100 mg/day or
a placebo. The dose of lamotrigine was
increased from 25 mg/day to 100 mg/day
at week 4, in increments of 25 mg/week.
This dosage was maintained until the end
of the trial at week 16, with a maximum
dose of 100 mg per day. Results indi-
cate that lamotrigine added to stable SRI
treatment substantially improved obses-
sive-compulsive symptoms (Yale-Brown
Obsessive Compulsive Scale: obsessions,
p<0.0001; compulsions, p<0.0001; total
score, p<0.0001) and depressive symp-
toms (Hamilton Rating Scale for Depres-
sion total score, p<0.0001) in patients who
were resistant to SRI alone. Regarding
cognitive functions, improvement was ob-
served only in semantic fluency (p=0.004).
A mean 38.3% reduction in Y-BOCS total
score was observed at the end of 16 weeks
of adjunctive lamotrigine. The rate of
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