Fluoxetine Overdose: A Case Report*

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triptyline, doxepin, and imipramine in patients with unipolar depression, although it may be less effective than tricyclic anti- depressants in relieving sleepĀ ...

Journal of Analytical Toxicology, Vol. 13, September/October 1989

case Reportl

Fluoxetine Overdose:A Case Report* T i m o t h y P. Rohrig and Richard W. P r o u t y Office of the Chief Medical Examiner, Oklahoma City, Oklahoma, 73117

l Abstract A fatality due to the ingestion of fluoxetine and ethanol is reported. Quantitation of the drug and its active normetabolite was accomplished by gas chromatography with a flame ionization detector. Identification of the compounds was performed by gas chromatography/mass spectrometry. Tissue distribution of fluoxetine and norfluoxetine, as well as analytical details, is presented,

Introduction Fluoxetine hydrochloride (Prozac, Dista) is a relatively new antidepressant, which is structurally unrelated to tricyclic, tetracyclic, or other available antidepressant drugs (l) (Figure l). The therapeutic efficacy of fluoxetine is comparable to amitriptyline, doxepin, and imipramine in patients with unipolar depression, although it may be less effective than tricyclic antidepressants in relieving sleep disorders in depressed patients (2). The antidepressant activity of fluoxetine is attributed to its selective inhibition of presynaptic serotonin reuptake in the central nervous system (2). In addition to its use as an antidepressant, fluoxetine has been shown to be an effective anorexic in nondepressed patients (3) and preliminary data suggest its usefulness in the treatment of bulimia nervosa (4). Therapeutic dosing of fluoxetine causes signficantly fewer anticholinergic side effects (2,5) and appears not to cause the cardiovascular side effects seen in therapy with tricyclic antidepressants (2,6). Fluoxetine undergoes hepatic metabolism to norfluoxetine and other metabolites (2). Norfluoxetine is at least equipotent and may be as much as l0 times more potent than fluoxetine, based on the inhibition of serotonin uptake and pharmacoelectroencephalographic alterations in man (7). Following a single oral 40-mg dose, peak plasma concentrations of fluoxetine range from 15 to 55 ng/mL (1). Chronic therapeutic dosing of fluoxetine results in serum concentrations of fluoxetine ranging from 47 to 469 ng/mL and norfluoxetine concentrations ranging from 52 to 446 n g / m L (8).

9 Presented at the meeting of the Southwestern Association of Toxicologists, Inc., Shreveport, Louisiana, November 12, 1988.

Fluoxetine overdose has been associated with agitation, vomiting, and seizures. Two deaths have been reported following ingestion of multiple drugs including fluoxetine (1). This report describes the postmortem toxicologic findings in a fatality resulting from the ingestion of fluoxetine and ethanol.

Case History A 28-year-old white female was found dead near her bed. The decedent had a history of brain damage and physical disability secondary to a motor vehicle accident which occurred four years earlier. The decedent was prescribed Prozac (fluoxetine) two weeks prior to her death for depression related to her physical disabilities. The decedent also had prescriptions for Xanax (alprazolam) and ibuprofen. It was further alleged that the decedent had access to methamphetamine and cocaine. On the day of her death, the decedent was visited by a friend, during which time each had a drink. The decedent called her mother later that afternoon and stated she did not feel well. The mother noted the decedent's voice was slurred at that time. The body was found later that evening.

Materials and M e t h o d s Reagents Fluoxetine hydrochloride and norfluoxetine hydrochloride were generous gifts from Lilly Research Laboratories. Alphaprodine hydrochloride was obtained from Hoffman-La Roche. All other reagents were of analytical grade and were purchased from Fisher Scientific or Baxter. Analytical procedures Blood and urine were screened for basic drugs using a modified Foerester and Mason procedure (9) with alphaprodine as the internal standard. The extract was initially analyzed on a Hewlett-Packard 5890 gas chromatograph equipped with 15-m J&W DB-5 megabore column and a nitrogen-phosphorus detector. The column operating conditions were 130 to 300~ at 10~ with a final hold of 5 min. The second chromatographic system employed a 15-m J&W DB-1 narrowbore column

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Journal of Analytical Toxicology, Vol. 13, September/October 1989

F3C-~ > -O-CH-(CH2)2-NH' CH3 /

at 180~ The chromatographic performance of fluoxetine and norfluoxetine under the prescribed conditions for quantitation is illustrated in Figure 2. The peak height ratio of each analyte to internal standard was compared to a calibration curve prepared from spiked whole blood controls.

Results

F3C- ~ \ i ~

-O-CH- ( CH2 ) 2 ~NH 2

/

Figure 1. Structures of fluoxetine and norfluoxetine.

Fluoxetine and norfluoxetine were easily detected and separated in both gas chromatographic systems. The relative retention times of fluoxetine and norfluoxetine to alphaprodine on the DB-5 megabore column were 1.08 and 1.05, respectively. The hydrocarbon retention indices on the DB-1 narrowbore column were 1844 and 1815, respectively. The mass spectra of fluoxetine and norfluoxetine are presented in Figure 3. A qualitative urine drug screen was positive for fluoxetine, norfluoxetine, and chlorpheniramine. A qualitative blood drug screen revealed the presence of fluoxetine, norfluoxetine, and chlorpheniramine. The heart blood concentration of chlorpheniramine was less than 0.1 mg/L. All other common acidic, basic, and neutral drugs were negative in the blood and urine. The heart blood ethanol concentration was 0.22 g~ The concentrations of fluoxetine and norfluoxetine in the postmortem specimens are presented in Table 1.

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