Psychiatric News April 1, 2005
Volume 40 Number 7
© 2005 American Psychiatric Association
p. 30
Med Check
Jim Rosack
Regulatory and Legal Briefs
- Aripiprazole gained FDA approval last month for
"maintaining efficacy" in patients with bipolar I disorder who
have experienced a recent manic or mixed episode. The next-generation
antipsychotic has already been approved for treatment of schizophrenia and
acute mania. Clinical data demonstrated that the drug significantly delayed
time to relapse. The approval was based on a double-blind, randomized,
controlled trial in which 161 patients who had been stabilized on aripiprazole
for at least six weeks were followed to monitor relapse to either mania or
depression. Of those who experienced a relapse during follow-up, patients
taking the drug relapsed significantly later than those taking placebo. In
addition, fewer patients taking aripiprazole relapsed, compared with patients
on placebo. Commonly observed adverse events in all aripiprazole clinical
trials include akathisia, constipation, and accidental injury. Headache,
agitation, anxiety, nervousness, insomnia, nausea, somnolence,
light-headedness, and vomiting have also been observed.
- Escitalopram has received a "nonapprovable"
letter from the FDA for treatment of panic disorder. The March 1 letter was
the second thumbs down the agency has given to the use of the highly selective
SSRI for that indication. In August 2004 the agency issued its first
nonapprovable letter, citing "issues related to methods and statistical
analysis performed" for the two clinical trials Forest Labs had
submitted. The company had filed a response to that initial determination, and
the second nonapprovable letter reflects the agency's unfavorable review of
the company's response. Forest said in a prepared statement that it "is
currently reviewing the FDA's response to determine the appropriate
action." Escitalopram carries indications for major depression and
generalized anxiety disorder.
- Duloxetine will not be approved for the treatment of stress
urinary incontinence (SUI) in the U.S. Eli Lilly and Co. and Boehringer
Ingelheim jointly announced Lilly's withdrawal of its application for approval
for the treatment of SUI. The serotonin-norepinephrine dual reuptake inhibitor
was approved last year by the U.S. and the European Commission for the
treatment of major depression and approved in the U.S. for the treatment of
diabetic peripheral neuropathic
pain.
A company statement noted the decision was based on discussions with the
FDA in which the agency made it clear that it was "not prepared at this
time to grant approval" for the SUI indication, based on the patient
data submitted. However, it is not clear whether the agency's concerns related
to efficacy or safety. Lilly and Boehringer noted they will explore all
options and that clinical trials with SUI patients would continue. Duloxetine
is marketed as Yentreve in 27 countries for the treatment of SUI.
Separately, the two companies announced that the Committee for Medicinal
Products for Human Use of the European Medicines Agency had issued a positive
opinion recommending the approval of duloxetine for the treatment of diabetic
peripheral neuropathic pain. If the European Commission accepts the
recommendation for approval, the drug would be approved for all three
indications—depression, SUI and DPNP—in the 25 European Union
countries.
- GlaxoSmithKline's paroxetine–controlled release may
be difficult to come by in the next few months. Unsatisfied with the company's
efforts to alleviate long-standing manufacturing concerns involving the
controlled-release SSRI, the FDA and the Department of Justice ordered U.S.
marshals to seize thousands of bottles of the drug from three GSK facilities,
two in Puerto Rico and one in Knoxville, Tenn. An FDA talk paper said the
manufacturing problem allowed Paxil CR tablets to split apart, "and
patients could receive a portion of the tablet that lacks any active
ingredient, or alternatively that contains active ingredient that does not
have the intended controlled-release effect."
Research Briefs
- Methylphenidate may be linked to an increased risk of
cytogenetic abnormalities in children at commonly used doses. In a small study
of 12 children (average age 8.2 years) treated with therapeutic doses
(20mg/day to 54mg/day) of methylphenidate, researchers examined three
cytogenetic endpoints in peripheral blood lymphocytes, obtained before and
three months after initiation of drug therapy. In all 12 children, treatment
was associated with significantly increased frequencies of chromosome
aberrations (three-fold increase), sister chromatid exchanges (4.3-fold
increase), and micronuclei (2.4-fold increase).
Although no association between methylphenidate and increased cancer has
been noted in the nearly 50 years the drug has been marketed, the study's
authors said the findings "warrant further investigations... especially
in view of the well-documented relationship between elevated frequencies of
chromosome abnormalities and increased cancer risk." They acknowledged,
however, that one small study is not a reason to stop treatment in children
who are otherwise responding well.
Cancer Lett 2005. The article can be accessed online ahead of
print at
<www.sciencedirect.com/science/journal/03043835>
by clicking on "Articles in Press" and then entering the term
"methylphenidate" in the "Quick Search" box.
- Ziprasidone is not associated with the adverse metabolic
changes or weight gain observed in some patients taking olanzapine. A
retrospective chart review of 191 patients showed no significant differences
in QTc interval in patients taking either antipsychotic drug. Significant
weight gain was observed in olanzapine-treated patients, while those taking
ziprasidone experienced weight loss. Adverse changes were seen in total
cholesterol, triglycerides, and hemoglobin (Hb)A1C in patients taking
olanzapine compared with favorable changes in total cholesterol, low-density
lipoprotein, high-density lipoprotein, and HbA1C in patients taking
ziprasidone.
Int Clin Psychopharmacol 2005; 20:105-112
- Risperidone can significantly and persistently improve
symptoms of tardive dyskinesia (TD) associated with typical antipsychotics. A
new study followed 40 patients with chronic schizophrenia and severe TD who
were switched to risperidone therapy for 48 weeks. The average total Abnormal
Involuntary Movement Scale (AIMS) score decreased from 15.7 at baseline to
10.6 at week 48 with an average dose of risperidone of 3.6 mg a day.
Twenty-three patients (57.5 percent) were responders, with a greater than 50
percent reduction in their AIMS scores and an average AIMS score decrease of
8.0 points. Significant improvement in TD symptoms was seen as early as week
eight and persisted through week 48.
Int Clin Psychopharmacol 2005; 20:79-85
- Fluoxetine appears to have limited efficacy in treating
dysthymia in elderly patients. A randomized, double-blind, placebo-controlled
trial of 90 patients (aged 60 and older) revealed that scores on the Hamilton
Depression Rating Scale (Ham-D) and the Cornell Dysthymia Rating Scale (CDRS)
showed a treatment-by-time effect that favored fluoxetine over placebo.
However, the percentage change in Ham-D scores was not significantly different
between those on fluoxetine and those on placebo. Percentage changes in CDRS
scores were significantly better in those on active drug compared with
placebo; however, response rates were not significantly different (27.3
percent response for fluoxetine versus 19.6 percent for placebo).
Am J Geriatr Psychiatry 2005; 13:59-68
Industry Briefs
- Shire Pharmaceuticals Group and New River Pharmaceuticals Inc. announced an
agreement for the global commercialization of New River's NRP104, a novel
compound developed for the treatment of ADHD. NRP104 is a prodrug of
amphetamine—that is, it is an amphetamine conjugated to a specific amino
acid. By conjugating the pair, NRP104 is intended to provide better overdose
protection and reduced potential for addiction, compared with currently
marketed stimulants. A preliminary review by the U.S. Drug Enforcement
Administration last year indicated that.the agency did not consider NRP104 to
be an amphetamine, and thus it is not subject to controlled-substance
scheduling.
Under their agreement, the two companies will collaborate on the continued
phase III development, manufacturing, and eventual marketing of the drug in
the United States. Shire has a license to develop and commercialize the
product in the rest of the world. 
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