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August 15, 2002
In this issue: Editor's Note, Question of the Week, Clinical Updates,
Industry News and Featured Resource
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EDITOR'S NOTE
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As many as 50 percent of patients with
schizophrenia and other chronic medical conditions are non-adherent or
poorly adherent to their prescribed medication regimens, according to
some reports. Now, researchers have created a surgically implantable
long- term medication delivery device that may help improve compliance
rates.
Researcher Steven J. Siegel, M.D., of the University of Pennsylvania
school of Medicine, and colleagues, are currently investigating the
effectiveness of the new device in animal models. Siegel's most recent
research has been with a formulation of haloperidol (Haldol) using
biodegradable polymers. The implant is made of the polymer and drug,
which are intimately mixed. As the implant dissolves and the drug is
released, all components are metabolized and excreted.
Implanting the device would involve a small incision somewhere on the
body that wouldn't be obtrusive to the person. Once the incision is
made, a subcutaneous space is made using blunt forceps and the implant -
about the size of a quarter - is placed with perhaps a stitch to hold it
in place before the incision is closed. About six quarter-sized implants
would be needed to last a year.
According to researchers, this procedure, which is reversible, could
potentially be used for many medications, not only throughout psychiatry
but for any medicine that requires long-term administration. And, while
the research thus far has been limited to animal trials, the technology
will likely make its way to human trials in the near future.
MORE INFORMATION: To receive a free PDF copy of the article,
"Surgically implantable drug delivery systems may improve
compliance" from the August issue of The Brown University
Psychopharmacology Update, contact customer service at (800) 333-7771,
or e-mail your name and complete mailing address with your request to mailto:manissescs@manisses.com
.
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QUESTION OF THE WEEK
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A recently released survey by the American Medical Association (AMA)
found that the World Wide Web has had a major influence on the way
physicians practice medicine. The study, "2002 AMA Study on
Physicians' Use of the World Wide Web," is based on a survey of 977
physicians conducted between August and December 2001. It found that the
number of physicians' using the Internet is steadily increasing, with
two-thirds of online physicians reporting daily use of the Internet - an
increase of 24% since 1997.
How often do you or your staff use the Internet for
clinical and administrative work?
Send responses to mailto:kstovell@manisses.com
*Due to computer error, responses to the previous Question of the Week
were lost. Please feel free to resend your responses.
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CLINICAL UPDATES
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ANALYSIS FINDS VENLAFAXINE MORE EFFECTIVE THAN
SSRIs A team of researchers conducted a meta-analysis of 32 randomized
trials comparing venlafaxine (Effexor) with other antidepressants. They
found that venlafaxine was more effective than other antidepressants
generally and SSRIs specifically, but did not show a clear advantage
over tricyclic antidepressants (TCAs) or other antidepressants [trazodone
(Desyrel) and mirtazapine (Remeron)].
The researchers included all double-blind, randomized studies comparing
venlafaxine with an alternative antidepressant for treatment of
depression. The primary outcome was the mean depression severity measure
at the end of the trial, but response rate, remission rate and
tolerability were also examined. The final analysis included data from
5,562 patients, including 20 trials with SSRIs [fluoxetine (Prozac),
fluvoxamine (Luvox), paroxetine (Paxil) and sertraline (Zoloft)], nine
trials with TCAs [clomipramine (Anafranil), imipramine (Tofranil),
dothiepin (Prothiaden; not marketed in the US) and amitriptyline (Elavil)]
and three trials with trazodone or mirtazapine.
The overall effect size estimate was -0.14 (95% CI, -0.22 to -0.07),
favoring venlafaxine. The effect size estimate comparing venlafaxine to
SSRIs also favored venlafaxine at - .17
95% CI, -0.27 to -0.08). The effect size estimates for the TCAs
and for trazodone and mirtazapine were not significantly different from
venlafaxine. However, the researchers note that, while the results
appeared to be similar across the SSRIs, there were differences between
the TCA studies. Specifically, the effect size for
imipramine was significant at -0.38 (95% CI -0.57 to -0.19), but
other comparisons demonstrated no significant difference.
The authors estimate that venlafaxine has an advantage over other
antidepressants of approximately 1.2 points on the Hamilton Rating Scale
for Depression, and they suggest that this difference may be clinically
relevant. Additionally, they note that venlafaxine was as well-tolerated
(as assessed by dropout rates) as the other study medications, with the
exception of trazodone and mirtazapine. According to the researchers,
the most plausible mechanism for venlafaxine's increased efficacy is its
capacity to inhibit reuptake of norepinephrine as well as serotonin.
Smith D, Dempster C, Glanville J, et al.: Efficacy and tolerability of
venlafaxine compared with selective serotonin reuptake inhibitors
and other antidepressants: a meta-analysis. British Journal of
Psychiatry 2002; 180:396-404. Correspondence to: Dr. Freemantle,
Department of Primary Care and General Practice, University of
Birmingham, Edgbaston, Birmingham BI5 2TT; e-mail: mailto:N.Freemantle@bham.ac.uk
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TRIAL EXAMINES DESIPRAMINE FOR ADHD, TICS
A six-week, randomized, double-blind, placebo-controlled,
parallel-design trial comparing desipramine and placebo found that
treatment with desipramine was associated with clinically significant
reductions in tic and ADHD symptoms in children and adolescents with
chronic tic disorders and comorbid ADHD.
Forty-one patients (34 boys, 7 girls) aged five to 17 years who met the
DSM-IV criteria for combined-type ADHD and chronic motor tic disorder,
chronic vocal tic disorder, or Tourette disorder were randomized for six
weeks to desipramine, titrated weekly up to 3.5 mg/kg per day (N=21), or
placebo (N=20). Study medications were administered in divided doses.
Subjects were prohibited from taking any additional psychoactive
medications during the study period.
ADHD and tic symptoms were assessed weekly using a variety of measures,
including the Clinical Global Impressions (CGI) Scale, ADHD Rating
Scale, Yale Global Tic Severity Scale (YGTSS) and Children's Yale-Brown
Obsessive Compulsive Scale (CY-BOCS). EKGs, heart rate and blood
pressure were also taken weekly.
Desipramine (mean dose=3.4 mg/kg per day) significantly and robustly
reduced symptoms of ADHD and tics compared with placebo (p<0.001),
with the effects of drug treatment increasing with the duration of
treatment. End-point analysis revealed that 71 percent of patients (15
of 21) taking desipramine were ADHD responders compared with placebo
(0%), and 58 percent of patients (11 of 19) were tic responders while
taking the active drug compared with placebo (5%). Two patients taking
placebo withdrew from the study.
The most frequently reported adverse effect was
decreased appetite. Although decreased appetite was significantly more
common with desipramine (24%) than placebo (0%; p<0.02), the adverse
effect was not associated with weight loss. In addition, the researchers
report that heart rate was increased in subjects taking the active drug
compared with placebo (p<0.02).
The authors conclude that in their small sample, desipramine was well
tolerated and significantly improved ADHD and tic symptoms. However,
they note that questions remain about the safety of desipramine in
children, as there have been reports of sudden death in children with
ADHD who were treated with the drug.
Spencer T, Biederman J, Coffey B, et al.: A double-blind comparison of
desipramine and placebo in children and adolescents with chronic tic
disorder and comorbid attention-deficit/hyperactivity disorder. Archives
of General Psychiatry 2002; 59:649-656. Correspondence to: Dr. Spencer,
Pediatric Psychopharmacology Unit (ACC-725), Massachusetts General
Hospital, Fruit Street, Boston, MA 02114.
SERTRALINE APPEARS SAFE IN PATIENTS WITH MI OR UNSTABLE ANGINA
A controlled study evaluating the cardiovascular safety of sertraline
for recurrent depression in patients with recent myocardial infarction
(MI) or unstable angina has found that the drug is safe.
The randomized, double-blind, placebo-controlled
study, conducted in 40 outpatient cardiology centers and psychiatry
clinics in the United States, Europe, Canada and Australia, included 369
patients (mean age, 57.1 years) with major depressive disorder (MDD) who
had been hospitalized for MI (74%) or unstable angina (26%). Study
enrollment began in the spring of 1997 and follow-up ended in the spring
of 2001.
After a two-week, single-blind placebo lead-in, patients were randomized
for 24 weeks to sertraline in flexible dosages of 50 to 200 mg per day
(N=186) or placebo (N=183). The primary outcome (safety) measure of the
study was a change from baseline in left ventricular ejection fraction (LVEF).
The study found no statistically significant difference in LVEF between
patients in the sertraline group and those in the placebo group. There
were also no between-group differences found in secondary ECG
parameters, including blood pressure, heart rate and arrhythmias, QRS
duration, QTc interval and SDNN ("standard deviation of all normal
R-R intervals in a 24-hour ambulatory ECG recording").
The authors conclude, "We found no evidence of harm; sertraline was
indistinguishable from placebo across all surrogate measures of
cardiovascular safety."
Glassman AH, O'Connor CM, Califf RM, et al.: Sertraline treatment of
major depression in patients with acute MI or unstable angina.
Correspondence to: Dr. Glassman, Department of Clinical
Psychopharmacology, New York State Psychiatric Institute, 1051 Riverside
Drive, Unit 116, New York, NY 10032; e-mail: mailto:ahg1@columbia.edu
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INDUSTRY NEWS
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ESCITALOPRAM APPROVED BY FDA
Forest Laboratories announced August 15 that the FDA has approved
escitalopram (Lexapro) for the treatment of major depressive disorder.
Escitalopram is the single-isomer of the selective serotonin reuptake
> inhibitor (SSRI) antidepressant citalopram Celexa). Forest expects
escitalopram to be available in pharmacies by September 5th. "Lexapro
is a welcomed treatment option because it offers many patients relief
from depression symptoms quickly, with few side effects and a low risk
of drug interactions," said Jack M. Gorman, M.D., of the Department
of Psychiatry at the College of Physicians and Surgeons, Columbia
University. "APPROVABLE LETTER" FOR ATOMOXETINE Eli Lilly and
Company recently announced that the U.S. Food and Drug Administration
(FDA) has issued an "approvable letter" for atomoxetine (Strattera).
If approved, atomoxetine will be a new treatment for
attention-deficit/hyperactivity disorder (ADHD). Final approval of
atomoxetine is contingent on further labeling discussion and submission
of further data to the FDA. Lilly is planning on approval for
atomoxetine in the spring of 2003. The New Drug Application (NDA) for
atomoxetine was submitted in October of 2001 and included data from six
placebo-controlled trials of atomoxetine in children, adolescents and
adults. [Eli Lilly]
CLOZAPINE ALTERS apoD EXPRESSION
Antipsychotic drugs alter gene expression in nearly 70 genes, according
to research presented by Elizabeth Thomas, a researcher and faculty
member at Scripps Research Institute. Researchers compared gene
expression over time in mice injected with either the atypical
antipsychotic clozapine (Clozaril) or the conventional antipsychotic
haloperidol (Haldol). Thomas and colleagues found 69 genes that were
regulated in some way by one of the two drugs. Clozapine was found to
alter the expression of 25 genes, and haloperidol was found to alter the
expression of 22 genes, while both drugs affected 22 transcripts. In
particular, Thomas found that clozapine upregulated apolipopotein D (apoD)
after just five days, while haloperidol did not. Thomas also found apoD
to be present in disproportionate levels in the post-mortem brains of
patients with schizophrenia, even though most of the patients had been
treated with haloperidol. [BioMedNet]
ANTIINFLAMMATORY DRUGS NOT EFFECTIVE FOR AD
The use of nonsteriodal antiinflammatory drugs has no impact on
cognitive or behavioral function in patients with Alzheimer's disease
(AD), according to research presented at the 8th International
Conference on Alzheimer's Disease and Related Disorders. Researchers
randomized 351 patients with mild to moderate AD to receive 25 mg/day
rofecoxib (Vioxx), 200 mg twicedaily naproxen (Aleve), or placebo for 12
months. Most of the participants were also taking an
acetylcholinesterase inhibitor; vitamin E and low-dose aspirin were also
allowed. No differences were found between groups on the Alzheimer's
Disease Assessment Scale (ADAS-cog) or in activities of daily living (ADLs).
"The inflammatory hypothesis is an intriguing but unproven
strategy," noted lead researcher Paul Aisen, M.D., of Georgetown
University Medical Center." However, "there is insufficient
evidence to support recommendations to use antiinflammatory agents to
treat AD at this time."
[Reuters Health]
TRAMADOL PATENTED FOR OCD AND OTHER DISORDERS
The University of Cincinnati has received a patent for the use of the
painkiller tramadol (Ultram), for the treatment of obsessive-compulsive
disorder (OCD) and other disorders, such as eating disorders, body
dysmorphic disorder and Tourette's syndrome. The researchers began
investigation of tramadol after treating a patient with severe OCD and
Tourette's disorder. The patient experienced significant improvement
within 24 hours. "All the patients we have studied have had
anywhere from 25-65 percent relief from their symptoms," said
Nathan Shapira, M.D., a former resident of the UC Department of
Psychiatry. The drug is not yet approved by the FDA for use in treating
OCD and other disorders. [PR Newswire]
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