From pfpc@istar.ca Tue Jun 13 08:50:19 2000
Date: Fri, 2 Jun 2000 14:50:35 -0800

Subject: PFPC BRIEF:"Prozac death"

Hi all,

Item of interest:

Sallee FR, DeVane CL, Ferrell RE - "Fluoxetine-related death in a child
with cytochrome P-450 2D6
genetic deficiency" J Child Adolesc Psychopharmacol 10(1):27-34  (2000)

ABSTRACT:

The clinical course of a 9-year-old diagnosed with attention-deficit
hyperactivity disorder, obsessive-compulsive disorder, and Tourette's
disorder and treated with a combination of methylphenidate, clonidine, and
fluoxetine is described. The patient experienced over a 10-month period,
signs and symptoms suggestive of metabolic toxicity marked by bouts of
gastrointestinal distress, low-grade fever, incoordination, and
disorientation. Generalized seizures were observed, and the patient lapsed
into status epilepticus followed by cardiac arrest and subsequently
expired. At autopsy, blood, brain, and other tissue concentrations of
fluoxetine and norfluoxetine were several-fold higher than expected based
on literature reports for overdose situations. The medical examiner's
report indicated death caused by fluoxetine toxicity. As the child's
adoptive parents controlled medication access, they were investigated by
social welfare agencies. Further genetic testing of autopsy tissue revealed
the presence of a gene defect at the cytochrome P450 CYP2D locus, which
results in poor metabolism of fluoxetine. As a result of this and other
evidence, the investigation of the adoptive parents was terminated. This is
the first report of a fluoxetine-related death in a child with a confirmed
genetic polymorphism of the CYP2D6 gene that results in
impaired drug metabolism. Issues relevant to child and adolescent
psychopharmacology arising from this case are discussed.
------------------------------------

Fluoxetine normally inhibits cytochrome P450.  Prolonged inhibition of P450
leads to thyroid hormone reduction. Thyroid hormones modulate the levels of
P450 in the liver, where the majority of thyroid hormone synthesis occurs.
(T4 ->T3) .

A recent Canadian study by Urichuk et al (2000) of the University of
Alberta in Edmonton showed that levels of p-trifluoromethylphenol (a
metabolite of fluoxetine)  was 10-fold higher in the liver of rats than in
brain.

Further, studies by David Thompson [Monsanto...published in
"Chemico-Biological Interactions"  126(1):1-14 (2000)] on
4-trifluoromethylphenol in rat liver slices showed intracellular
glutathione levels decreased and fluoride ion levels increased in a time
and concentration-dependent manner.

Glutathione is important as a co-factor for the enzyme glutathione
peroxidase which is a selenium-containing enzyme ESSENTIAL for T4 to T3
synthesis in the liver.

In 1991, Guan in China  found glutathione peroxidase to be useful as
diagnostic function discriminant of mild and severe chronic fluorosis in
blood biochemistry.

Best to all,

Andreas  Schuld
Parents of Fluoride Poisoned Children
Vancouver, BC, Canada
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