PART I -Atypical Antipsychotic Drugs and Hyperglycemia
Letters To the Editor:
Hyperglycemia has been associated with the atypical antipsychotic
agents clozapine and olanzapine, and a recent case report described diabetic ketoacidosis associated with
olanzapine in a pediatric patient. To gain further insight into the association between hyperglycemia and these 2 drugs in
the pediatric population, we queried the US Food and Drug Administration (FDA) MedWatch drug surveillance system to identify
cases occurring in patients younger than 19 years.
Olanzapine-Associated Cases (Olanzapine (Zyprexa)
January 1996 and May 2001, the FDA received 9 spontaneous-adverse-event reports of hyperglycemia in adolescents who were aged
13 to 18 years (4 males and 5 females) and received olanzapine in daily doses of 10 to 20 mg. Seven presented with newly diagnosed
hyperglycemia and 2 had exacerbation of preexisting diabetes.
Presentation occurred within 1 week of drug initiation for 2 patients and within 6 months for 6 others. Glycemic
control improved in 4 patients after olanzapine was discontinued or the dose decreased. In 1 patient, however, hyperglycemia
recurred in the absence of islet cell antibodies 6 months after the patient switched to risperidone and venlafaxine.
The most common concomitant drugs included benztropine, sertraline, tegretol, and valproate. In this group, there was 1 death
from necrotizing pancreatitis.
Clozapine-Associated Cases (Clozapine (Clozaril)
1993 and March 2001, the FDA received 11 reports of hyperglycemia in adolescents who were aged 13 to 18 years (7 males and
4 females) and received clozapine in daily doses from 100 to 1000 mg. Eight had newly diagnosed hyperglyecemia, 2 experienced
exacerbation of preexisting diabetes, and the diabetes status of 1 was unknown.
Presentation occurred within 6 weeks of drug initiation for 5 patients and within 6 months for 5 others. Clozapine was
discontinued or the dose decreased in 6 patients. Three experienced improved glycemic control. One patient presented with
profound hyperglyemia (1300 mg/dL) and pancreatitis with elevated lipase levels 34 days after clozapine treatment was initiated.
Clonazepam was the sole concomitant medication.
Diabetes is relatively uncommon in children.
The National Health Assessment and Nutrition Survey found less than 1 incident case per 1000 yearly for the population aged
0 to 24 years. A 1983 study found an incidence rate of 13.5 per 100,000 yearly for those younger than 20 years. Crude
estimates of exposure to atypical antipsychotics can be calculated according to the total numbers of US prescriptions, mean
prescription length, and fraction of patients aged 0 to 18 years through 2000, yielding approximately 4200 patient-years for
clozapine and 97 000 patient-years for olanzapine.
Assuming no underreporting, these data suggest that the
risk for hyperglycemia with clozapine is approximately 10-fold higher than background.
The incidence of hyperglycemia with olanzapine appears similar to the background rate, assuming that
all cases were reported to the FDA.
Given that underreporting is typical of these voluntary adverse-event systems, the number of cases may be larger. The
mechanism for hyperglycemia remains unknown.
Among these 20 patients, 2 also had pancreatitis
suggests a causal association with the antipsychotic agents. Pancreatitis is uncommon in children in the absence of trauma,
anatomic anomalies, heritable metabolic disorders, and exposure to toxins or drugs. Although valproate has been associated
with pancreatitis, only 1 patient of the 2 patients in our series had been treated with this drug. These 2 cases of pancreatitis
were identified by our search for hyperglycemia and so may not represent all cases of pancreatitis.Atypical
antipsychotic agents continue to have a role in treating pediatric psychotic disorders, although they are not currently labeled
for pediatric use. Until systematic studies of the various agents are conducted to determine relative and absolute risk, physicians
should consider monitoring patients for hyperglycemia.
Elizabeth Koller, MD and Saul Malozowski, MD,
PhD Center for Drug Evaluation and Review Food and Drug Administration Rockville, Md
P. Murali Doraiswamy, MD Departments
of Psychiatry and Medicine Duke University Medical Center Durham, NC
Can J Psychiatry 2001 Oct;46(8):741-5
Atypical antipsychotic use in treating adolescents and
young adults with developmental disabilities.
Friedlander R, Lazar S, Klancnik J.
University of British
Columbia, Vancouver, British Columbia.
study the usage, efficacy, and side effects patterns of atypical neuroleptics (atypicals) in adolescents and young adults
with developmental disabilities (DDs) (mental retardation).
We undertook a chart review
of adolescents and young adults (under age 25 years) seen by our specialized mental health team.
Risperidone and olanzapine were by far the most frequently prescribed atypicals. Robust clinical effects
were noted for both psychotic and nonpsychotic disorders. Most patients tolerated atypicals well, although a significant minority did experience neuroleptic induced movement disorders (NIMDs), particularly
dystonias and dyskinesias.
SSRI Antidepressants in Youth-Amotivational Syndrome
This article discusses recent findings on SSRI meds Fluoxtine
and Paroxetine (Paxil) potentially causing reversible frontal lobe syndrome in adolescents. This is reported
as a "rare" side effect.
Frontal lobe syndrome makes the patient apathetic, lose initiative, ie indifferent.
(Note: this report suggests some adults develop this syndrome too with these drugs)
Parents of any adolescents on either
of these 2 drugs who have been experiencing problems with apathy, attitudes of indifference, loss of initiative, etc.
that they had not been experiencing before taking the drug may want to consult with their neurologists. This would apply
to any adults who have experienced this too.
An Unprofessional Opinion
The Brown University Child and Adolescent Psychopharmacology Update
Amotivational Syndrome Linked With SSRI
Use in Youth for the First Time
[Brown Univ Child and Adol Psychopharm 3(10):1,
6-8, 2001 by Manisses Communications
E. Jane Garland, M.D., clinical associate professor of psychiatry and Elizabeth A. Baerg, M.D., clinical
assistant professor of psychiatry at the University of British Columbia's Children's Hospital in Vancouver, Canada,
report on five patients with dose-dependent, reversible frontal
(amotivational) syndrome characterized by delayed onset after treatment with fluoxetineand paroxetine, two selective serotonin
reuptake inhibitors (SSRIs) commonly prescribed to treat adolescent depression.
A frontal lobe syndrome
characterized by apathy, indifference, loss of initiative and/or disinhibition has developed in some adults during SSRI therapy
but has not been previously reported in the pediatric population (Hoehn-Saric et al. 1990). In each case the patient had a
significant change in behavior, which included becoming indifferent toward work performance, exhibiting impulsive and
disinhibited behavior, or developing poor concentration and forgetful behavior (Hoehn-Saric et al. 1991).
a frontal lobe syndrome may be rare, it is important to consider, as its symptoms could be easily misinterpreted. Apathy
and indifference could be mistakenly attributed to depressive symptoms or sedation; impaired judgment and disinhibition could
be attributed to hypomania -induced behavior.
According to Garland, delayed onset is a consistent feature in both adult
and child cases, although there is presently little understanding behind the late onset of symptoms.
is that it only becomes evident as the primary condition remits and function returns. However, the common pattern is a period
of 3-4 weeks or a month of good functioning before it is evident. Another hypothesis is that there is some neurochemical adaptation
occurring, perhaps involving the dopaminergic system, or even the complex network of serotonin receptor subtypes," says Garland.
website for cases)
"Clearly, it is important to weigh the
risks and benefits [of treatment with SSRIs] carefully with children and families," Garland says. "A good
measure is overall function in various dimensions of life. A young person who is apathetic may be easier to parent in some
ways, but the negative effects on academic and social functioning with peers needs to be considered. This takes ongoing monitoring
and negotiation, and input of various observers, including teachers."
Garland concludes, "These case reports remind
us that intermediate term side effects, such as the more common sexual side effects and less common amotivational syndrome,
require awareness on the part of the treating physician, and specific inquiry as patients may not bring them up spontaneously."
case reports also draw attention to the complex neurochemical effects of medications which overall have a relatively benign
profile of side-effects.what this means for longer-term use, over several years, is less clear. While these medications clearly
improve symptoms and quality of life
tremendously, we need to keep an open mind and clinical awareness for new patterns
of unexpected effects."
References - See resource website
- the Mental Health Medication site says safety and effectiveness in patients below the age of 18 have not been established
for this drug. It also warns about neurologic side affects, many which mimic HD symptoms
Paroxetin (Paxil)- Again the safety and
effectiveness of paroxetine in children under 18 years of age have not been established. This one appears to have a lower
incidence of neurological symptoms based on tests however the "rare" incidences of the nervous system cover antisocial behavoir,
abnormal gait, dystonia, etc.
Both report a common side affect is somnolence/drowsiness.
All drugs, as well as the condition for which they are prescribed, for 54 common disorders such as depression, bi-polar
can be found at http://www.mentalhealth.com/