Amoxapine (Asendin | Lederle Laboratories) is an antidepres- sant of the dibenzoxazepine class. It is indicated for the relief of symptoms of depression in ...
Journal of Analytical Toxicology, Vol. 10, September/October 1986
CASE REPORT
Amoxapine Overdose: Report of Two Cases Timothy P. Rohrig
Kansas Bureau of Investigation, Toxicology Laboratory, Topeka, Kansas 66612 Ronald C. Backer
Office of the Chief Medical Examiner, South Charleston, West Virginia 25303
Abstract Two deaths are described Involving amoxaplne. Toxicological analysis in Case 1 revealed an amoxaplne blood concentration of 5.7 iAg/mL, and in Case 2, a concentration of 3.2 p,g/mL. Qualitative analysis of other body fluids were performed.
found unresponsive in a Veteran's Administration dormitory. Resuscitation was attempted with no success. The decedent had been severely depressed and had threatened suicide. He was being treated with amoxapine (Asendin) and apparently had been hoarding some of his medication. Asendin, cocaine, and marijuana were found at the scene.
Reagents and Methods Reagents
Introduction Amoxapine (Asendin| Lederle Laboratories) is an antidepressant of the dibenzoxazepine class. It is indicated for the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions (1). Its therapeutic and toxic effects are similar to those of the tricyclic antidepressants. The drug is available in tablets of 25 to 150 mg for oral administration and the recommended daily dose ranges from 200 to 300 mg, with occasional 400-mg doses (I). Relatively few cases of death due to amoxapine have been reported (2-5). In this report, the findings in two fatal cases involving amoxapine are described.
Case Histories Case 1 A 48-year-old white female was found lying in bed with apparent seizures and difficult breathing. An ambulance was called to the residence and the patient was transferred to a community hospital. At the hospital, an intravenous line was established and 5 mg of diazepam was administered. The patient was then transferred to a regional hospital; en route, the patient went into cardiac arrest. Resuscitation was attempted with no success. The decedent had been depressed since the death of her daughter about one year ago. She was being treated with amoxapine (Asendin).
Case 2 A 41-year-old white male, known to be a drug abuser, was
Amoxapine was obtained from Alltech-Applied Science. The 8-hydroxyamoxapine was obtained from Lederle Laboratories, and the n-docosane was purchased from Sigma Chemical Company. All other reagents were of analytical grade and were purchased from Fisher Scientific.
Analytical Procedures A 15-mL aliquot of an 8.3% sulfuric acid solution was added to 10 mL of bile. This mixture was then placed in a pressure cooker (250~ for 20 min. The hot mixture was then filtered, and its pH was neutralized with 50% sodium hydroxide/solid sodium bicarbonate and adjusted to pH 9 with a carbonate/bicarbonate buffer. The buffered hydrolysate was then adsorbed onto an Extrelut column (EM Science). The column was then eluted with dichloromethane:isopropanol (9:1). The organic eluant was evaporated to dryness, reconstituted in chloroform:methanol (1:1), and spotted on a 20-cm • 20-cm silica plate. The developing solvent was ethyl acetate:methanol:concentrated ammonium hydroxide (85:10:5). The plate was sprayed sequentially with ninhydrin, diphenylcarbazone, mercuric nitrate, sulfuric acid, and iodoplatinate. The urine was screened for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and phencyclidine, using enzyme immunoassay (Syva d.a.u.) according to the manufacturer's instructions. The stomach contents were diluted (1:!0) and analyzed using the Toxi-Lab A system (Analytical Systems) according to the manufacturer's instructions. Sodium bicarbonate was added to 5 mL of blood to bring the pH to 8. The mixture was extracted with 25 mL of n-butyl chloride:ethyl ether (3:1). The organic phase (20 mL) was extracted with 2N hydrochloric acid (4 mL) and an aliquot of the acid
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Journal of AnalyticalToxicology,Vol. 10, September/October 1986 (3 mL) was adjusted with 50% sodium hydroxide to pH 13. The aqueous phase was neutralized with 2N hydrochloric acid and adjusted to pH 9 with a carbonate/bicarbonate buffer. The aqueous phase was then extracted with I00 IxL of chloroform containing n-docosane. The chloroform extract was analyzed with a gas chromatograph (Perkin-Elmer 3920) equipped with a 3% OV-17 on GasChrom Q, 100/120 mesh, 3-ft glass column (200~ for 8 min and then increased 8~ to 260~ with a final hold of 16 min) and a flame ionization detector. The chloroform extracts (Case 2) were also subjected to gas chromatography/mass spectrometry (GC/MS). A Finnigan model 5500 gas chromatograph/mass spectrometer with an electron impact source was used. It was equipped with a 15-m DB-5 capillary column; the temperature program was 2 min at 50~ 10~ to 260~ and then held at 260~ for 7 min. The quadrapole mass spectrometer was operated at approximately 5 • 10 --" torr with a beam current of 75inV. The electron energy was 70eV.
Discussion Amoxapine is a relatively new antidepressant, closely related to loxapine. Its therapeutic and toxic effects are quite similar to those of the tricyclic antidepressants. There have been a limited number of reported fatalities due to amoxapine intoxication, most being associated with alcohol and/or other drugs (2-5). The blood amoxapine concentration in these cases ranged from 0.89 to 11.5 I.Lg/mL. Two suicidal deaths are reported in this paper. These deaths were solely due to acute amoxapine intoxication. The blood amoxapine concentrations were 5.7 and 3.2 Ixg/mL. These blood concentrations are consistent with the previously reported lethal levels, and are significantly higher than concentrations found in patients on chronic therapy (5, 6). Amoxapine is metabolized to 8-hydroxyamoxapine and 7-hydroxyamoxapine. Amoxapine and its metabolites were detected in the decedents' bodily excretory fluids, however, the metabolites were not detected in the blood.
Results Case 1
The qualitative drug screen of the bile hydrolysate revealed the presence of amoxapine and two spots consistent with 8-hydroxyamoxapine and 7-hydroxyamoxapine, all other common acidic, basic, and neutral drugs were negative. Blood ethanol was negative. The qualitative drug screen of the gastric contents revealed the presence of amoxapine; all other basic drugs were negative. The amoxapine concentration in the blood was 5.7 I-~g/mL. The metabolites, 8-hydroxyamoxapine and 7-hydroxyamoxapine were not detected in the blood specimen. In consideration of the circumstances surrounding the death, the available clinical information, and the findings noted upon postmortem examination, the manner of death was classified as suicide due to amoxapine intoxication. Case 2
The qualitative drug screen of the urine was negative for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, and phencyclidine. Blood ethanol was negative. A qualitative drug screen of the blood was negative for all basic drugs, except amoxapine. The amoxapine concentration in the blood was 3.2 ~g/mL. The metabolites, 8-hydroxyamoxapine and 7-hydroxyamoxapine, were not detected in the blood specimen. The mass spectrum of the major peak from the chloroform extract was identical to that of amoxapine. It had a base peak of 245 and the characteristic ions of 164, 193, 228,257, 269, 283, and 313. In consideration of the circumstances surrounding the death, the available clinical information, and the findings noted upon postmortem examination, the manner of death was classified as suicide due to amoxapine intoxication.
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Acknowledgements The authors are grateful to M. Park (West Virginia Medical Examiner's Office) for her technical assistance, and also would like to thank K. Orr (Kansas Bureau of Investigation) for her assistance in the preparation of this manuscript.
References 1. Physician's Desk Reference, 39th Edition. Medical Economics Co., 1985, pp. 1088-89. 2. C.L. Winek, W.W. Wahba, and L. Rozin. Amoxapine fatalities: Three case studies. Forensic ScL Int. 26:33-38 (1984). 3. J.J. Tasset and A.J. Pesce. Amoxapine in human overdose. J. Anal ToxicoL 8:124-28 (1984). 4. P. Sedgwick, V.R. Spiehler, and D.R. Lowe. Toxicological findings in amoxapine overdose. J. AnaL Toxicol. 6:82-84 (1982). 5. R.C. Baselt. Disposition of Toxic Drugs and Chemicals in Man, 2nd Edition. Biomedical Publications, Davis, CA, 1982. 6. W.E. Boutelle. Clinical response and blood levels in the treatment of depression with a new antidepressant drug, Amoxapine. Neuropharmacology 19:1229-31 (1980).
Manuscript received April 25, 1986; revision received June 17, 1986.
