Investigation of a Fatality Due to Trazodone Poisoning: Case Report ...

Journal of Analytical Toxicology,Vol. 29, May/June2005

]CaseReport

Investigation of a Fatality Due to Trazodone Poisoning: Case Report and Literature Review Maria A. Martinez TM, Salom6 Ballesteros2, Carolina Siinchez de la Torre 1, and Elena Almarza 1 1Chemistry Department, 2Spanish Poison Control Center, National Institute of Toxicology and Forensic Sciences, Ministry of Justice, C/ Luis Cabrera 9, 28002 Madrid, Spain

Abstract

Introduction

Trazodone is an antidepressant agent used in Spain since 1975. There are few documented reports of fatalities solely attributed to trazodone and none in which the main metabolite is analyzed. A fatal case of self-poisoning following oral ingestion is reported along with a description of the validated analytical methods involved, a discussion of poisoning characteristics, and a review of reports describing trazodone overdose cases with analytical results. The deceased was an 86-year-old man with cancer, who suffered depression. He went to see his doctor in a primary health care unit and told him he had just taken an unknown amount of tablets of Deprax | to commit suicide. The doctor induced emesis as a first emergency measure. His death occurred before arriving to the hospital, and he left a suicide note nearby. Systematic toxicological analysis of postmortem blood used routinely in our laboratory revealed the presence of trazodone 4.9 mg/L and m-chlorophenyl-piperazine (m-CPP) 0.6 rag/L, its active and major metabolite. In addition, metamizol 19.6 mg/L and 4-methyl-amino-antlpyrine (4-MAA) 40.7 rag/L, its active metabolite, were also found in blood. All drugs and metabolites involved in the case were detected using gas chromatography-nitrogen-phosphorus detection (GC-NPD) and confirmed using gas chromatography-mass spectrometry (GC-MS) mode total ion chromatogram. An additional high-performance liquid chromatography-diode array detection (HPLC-DAD) screening also obtained the same results. Quantitation of trazodone together with its metabolite in blood was carried out using GC-NPD, while quantitation of metamizol was performed using HPLC-DAD. Limits of detection for trazodone and m-CPP were 33 and 11 pg/L, respectively, absolute recoveries were more than 86% and 75%, respectively, intra-assay precisions less than 4%, interassay precisions less than 5%, and linearity up to 2.0 mg/L. Limit of detection for metamizol was 1117 pg/L, absolute recovery more than 84%, intra-assay precision less than 8%, interassay precision less than 12%, and linearity up to 48 mg/L. Based on the autopsy findings, patient history, toxicology results, and previously reported trazodone intoxications, the forensic pathologists ruled that the cause of death was due to an overdose of trazodone, and the manner of death was listed as suicide. *Author to whom correspondence should be addressed. E-mail: [email protected].

262

Trazodone is a triazolopyridine antidepressant drug used since 1975 in Spain. The drug has been available in 25-, 50-, and 100-mg tablets and as 50-mg ampoules as the hydrochloride salt under the name Deprax. The usual oral dosage for adults is up to 400 mg daily for severe depression and up to 75 mg daily in elderly people (1,2). Trazodone undergoes oxidative cleavage, yielding rnchlorophenyl-piperazine (m-CPP) (Figure 1). Following a single 150-rag oral dose of trazodone given to young volunteers, plasma concentrations of trazodone and its active metabolite (m-CPP), were 2.1 mg/L and 0.01 mg/L, respectively, after 2--4 h (3). The plasma concentration of trazodone is predictable after an initial dose of trazodone (4). This may be useful in establishing the adequate dose in susceptible patients (5) as there are wide interindividual variations (6). In elderly patients, steady-state plasma concentrations are higher because of a lower clearance (0.24--4.89 rag/L). Geriatric patients may not tolerate a single dose, and a divided dose should be considered (7,8). Trazodone possesses antidepressant, anxiolytic, and hypnotic activities. It has an antagonistic activity at the 5-HT2Apostsynaptic receptor and some selective inhibition of reuptake of serotonin. Meanwhile, m-CPP has an agonistic effect for various 5-HT receptor subtypes and contributes to the potent serotoninergic agonist properties of the drug (9,10). Although the structure of trazodone superficially appears to be similar to the cyclic antidepressants, it is less cardiotoxic than other cyclic antidepressants (11,12). Trazodone also has a high therapeutic index in the elderly (13). As a result, it has been recommended in patients with preexisting arterial hypotension, cardiac failure, and after myocardial infarction. HowN~

N--CH2--CFI:--CH2--N O

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I I-m-CHLOROPHENYLPIPERAZINE

Figure 1. Chemical structuresof trazodone and its main active metabolite.

Reproduction(photocopying)of editorialcontentof thisjournalis prohibitedwithoutpublisher'spermission.

Journal of Analytical Toxicology, Vol. 29, May/June 2005

ever, there are reported cases of side effectssuch as hypotension, eosinophilic pneumonia, serotonin syndrome, coma, seizures due to hyponatremia, and cardiorespiratory arrest (14-21). Metamizol, or dipyrone, is a pyrazolone nonsteroidal-anti-inflammatory agent with potent analgesic and antipyretic effects. It is widely used in several European countries including Spain since 1967 in daily doses as high as 4 g (1,2). Metamizol is associated with agranulocytosis, aplastic anemia, hypotension, and drowsiness among other adverse effects. It is nonenzymatically hydrolyzed in the intestinal tract to 4-methylaminoantipyrine (4-MAA),an active metabolite that is further metabolized in the liver (22). To date, few fatalities due exclusively to trazodone ingestion have been reported (23-27). The purpose of this paper is to report a fatal case of trazodone self-poisoning in an elderly man along with a discussion of poisoning characteristics, analytical procedures, and a review of previous reports of trazodone intoxications with analytical data. The simultaneous determination of the drugs involved in the case was performed using Bond Elut Certify columns, a mixed solid-phase extraction (SPE) procedure, and the combination of gas chromatography-nitrogen-phosphorus detection (GC-NPD) for screening analysis and gas chromatography-mass spectrometry (GC-MS) mode total ion chromatogram (TIC) for confirmation of the obtained results. An additional high-performance liquid chromatography-diode-array detection (HPLC-DAD) screening to complete the previous analysis also obtained the same results. GC-NPD was used for quantitation of trazodone and m-CPP, and HPLC-DADwas used for quantitation of metamizol and 4-MAA.

Case History The deceased was an 86-year-old man with cancer who suffered depression over the death of his wife. He went to see his doctor, a general practitioner, and told him he had just taken an unknown amount of Deprax tablets to commit suicide. The exact moment of the ingestion was unknown. The doctor induced emesis as a first emergency measure. The man began vomiting and suffered a cardiorespiratory arrest before arrival at the hospital. Cardiopulmonary rescue was attempted without success. A search of the circumstances surrounding the case showed that the deceased had left a suicide note in his house. He had been under treatment with amiloride/hydrochlorotiazide. Autopsy findings showed a cachectic body with generalized visceral congestion and no specific changes except coal worker's pneumoconiosis. Based on the autopsy findings, patient history, toxicology results, and previously reported trazodone intoxications, the forensic pathologists ruled that the cause of death was due to an overdose of trazodone, and the manner of death was listed as suicide. Heart blood was submitted for toxicological analysis.

Experimental Materials Trazodone, m-CPP, mepivacaine, the internal standard (IS), and prazepam, the chromatographic standard, were purchased

from Sigma Aldrich (Buch, Switzerland). Metamizoi was kindly provided by Boehringer Ingelheim Espafia (Barcelona, Spain) and 4-MAAwas unavailable. Individual stock solutions were prepared by dissolving 10 mg of each pure compound in 10 mL of methanol. These stock solutions were stored in glass tubes and maintained at -27~ Appropriate dilution with methanol yielded the working solutions containing all compounds involved in the study. The IS solution was prepared by diluting the stock solution of mepivacaine with deionized water to 16 mg/L. All chemicals (Merck, Darmstadt, Germany) and solvents (Scharlau, Barcelona, Spain) were of analytical grade. Phosphate buffer (0.1M, pH 6.0), 0.01M acetic acid, acetone/ dichloromethane (1:1), and dichloromethane/isopropanol/ammonia (78:14:8) were used for the SPE extraction procedure. Bond Elut Certify columns (130 mg of sorbent mass, 3 mL of column reservoir volume) and a VAC-ELUTSPS 24 vacuum manifold system for the manual mixed-mode bonded silica SPE were purchased from Varian Sample Preparation Products (Harbor City, CA). A P-Selecta sonication bath and a P-Selecta Centronic S centrifuge were both obtained from Selecta (Barcelona, Spain). A pool of citrated human whole blood samples was provided by Comunidad de Madrid Blood Bank (Madrid, Spain) and verified to be drug-free. No interferences were found for the studied compounds and the samples were kept frozen at -27~ until used.

Apparatus Three different chromatographic systems were used. GC-NPD analysis was performed with an HP 5890 series II apparatus linked to an HP 3396A integrator (Hewlett-Packard, Avondale, PA) with a 25-m (0.20-ram i.d., 0.11-pro film thickness) Ultra-1 HP cross-linked methylsilicone column. The GC conditions were as follows: helium carrier gas (column head pressure of 195 kPa), split mode (splitting ratio 1:20), injector temperature 280~ oven temperature programmed from 180~ (initial time I rain) to 300~ (final time 3 rain) at 10~ and detector temperature 300~ The chromatographic time was 16 rain. Insert liners silanized with dimethyldichlorosilane/toluene (5:100) and packed with Supelco silanized glass wool (from Supelco Park, Bellefonte, PA) were used. GC-MS analysis was performed with an HP 5971 mass-selective detector controlled by an HP G-1034 C ChemStation (Hewlett-Packard, Avondale, PA). The GC and column were as described. The MS conditions were as follows: full scan (m/z 35--650) mode, electron impact (EI) ionization with a 70 eV energy, and transfer line and ion-source temperatures were both maintained at 280~ The presence of all the detected drugs were confirmed using identical chromatographic conditions. HPLC-DADwas performed with an HP 1100 controlled by an HP G-2170AA and an HP G-2180AA ChemStation (HewlettPackard, Avondale, PA). The endcapped reversed-phase chromatography column was a Lychrospher ODS 5-pro (250 x 4.0mm i.d.). The mobile phase was a 50raM pH 3.0 phosphate buffer/acetonitrile mixture (90:10v/v) in gradient elution mode, and the flow rate was 1.0 mL/min at 42~ The chromatographic time was 28 rain, and the detection wavelength range was 210--400 nm.

263


Extraction All blood calibrators, controls, blank, and case blood specimens (including an appropriate dilution, 1:3 with deionized water) were prepared following a procedure based in our previously published work (28). The extraction was performed on a VAC-ELUTSPS 24 vacuum manifold system. To each 2.5 mL of sample, 7.5 mL of 0.1M phosphate buffer (pH 6.0) and 125 IJL ofa mepivacaine aqueous solution of 16 mg/L as IS were added, sonicated for 5 rain and centrifuged at 4000 rpm for 10 rain, then 8 mL of the supernatant, equivalent to 2 mL of whole blood, were used for further extraction. The columns were preconditioned with 1 mL methanol, followedby 1 mL 0.1M phosphate buffer (pH 6.0) under light vacuum, approximately 2 in. Hg, to avoid the columns becoming dry before the application of the sample. Then the samples of pretreated whole blood were applied onto the columns and drawn through completely at a flow rate of approximately 1.5 mL/min. The columns were washed with 2 mL deionized water. The columns were acidified by passing through 0.5 mL of 0.01M acetic acid. Then the columns were dried under full vacuum (15 in. Hg) for 4 rain. Methanol (601JL)was added, and the columns were dried under full vacuum for 1 rain. After the column outlets were wiped with tissue, the labeled evaporation tubes recently rinsed with methanol, in order to avoid retention of polar drugs in the walls of the glass tubes, were placed into the manifold basin. To each column, first 3.5 mL of acetone/dichloromethane (1:1) was added, and then 3 mL of dichloromethane/isopropanol/ammonia(78:14:8). The eluents were pulled through completely at a flow rate of 0.8 mUmin and 0.5 mL/min, respectively,and the combined eluates were evaporated at 50~ under a nitrogen stream. The extraction residues were reconstituted with 200 I2L of methanolic solution of chromatographic standard and prazepam (5 rag/L) to check the stability of the NPD chromatographic system. Then 2 ~L were injected first for GC-NPD screening analysis and later for a full scan GC-MS analysis for confirmation of analyte identity using identical chromatographic conditions. An HPLC-DADanalysis (10 I2L)was used to complete the screening analysis and for quantitation of metamizol and 4-MAAbecause these drugs are partially decomposed in the heated injection port of the GC.

Validation study Trazodone and m-CPP were added to human whole blood (50 mL) to achieve 0.1, 0.5, and 2 mg/L, while metamizol was added to achieve concentrations of 6, 24, and 48 mg/L, respectively. The spiked blood was sonicated for 15 min at room temperature, and then submitted to the extraction procedure and quantitations described. Calibration curves were prepared with five methanolic standard solutions of the drugs. The concentrations for trazodone and m-CPP were 0.5, I, 5, 15, and 30 mg/L, while the concentrations for metamizol were i0, 50, 100, 200, and, 500 rag/L, respectively. The concentration of mepivacaine (IS) was fixed at 8 mg/L. Analytes to IS area ratios were measured, respectively, and the calibration curves were generated from least-squares linear regression. The regression lines were used to calculate the absolute recoveries (n = 6) of the studied compounds from 264

spiked blood at six concentration levels. The intra-assay precision was assessed at three concentration levels by the extraction and analysis on the same day of six spiked blood samples for each level.The interassay precision was assessed by analyzing (on two different days) a set of nine spiked blood samples for each level. The limits of detection and quantitation were determined as the lowest concentration giving a response of three times and ten times, respectively,the average of the base line noise defined from six control samples. The linearity of the method for trazodone and m-CPP was checked by preparing six replicates of the calibration curves at three different concentrations, ranging from 0.1 to 2 rag/L, (from 6 to 48 mg/L for metamizol), by addition of known amounts of each drug to human whole blood.

Results and Discussion Assay characteristics A comprehensive toxicological screening was performed on the deceased's heart blood. This included ethanol and other volatiles (methanol, acetone, n-propanol, and isopropanol) analysis by headspace GC-FID. The results obtained ruled out the presence of these volatiles. Modifiedimmunoassay screening of the blood sample performed on a Hitachi 902 Automatic Analyzer (Tokyo, Japan) using Cedia | reagents (Microgenics, Fremont, CA)was negative for propoxyphene, cocaine and benzoylecgonine, methadone, opiates, cannabinoids, benzodiazepines, amphetamine and related compounds, barbiturates, and tricyclic antidepressants. Acidic-neutral and basic drug screening of the deceased blood was carried out using GC-NPD and completed with HPLC-DAD.The analysis of the extracts revealed the presence of trazodone 4.9 rag/L, and m-CPP 0.6 mg/L. In addition, metamizo119.6 mg/L and 4-MAA40.7 mg/L were also found in blood. All drugs and metabolites involved in the case were detected using GC-NPD and confirmed using GC-MS mode TIC. An additional HPLC-DAD screening also obtained the same results. Quantitation of trazodone and its metabolite in blood was carried out using GC-NPD, whereas for quantitation of metamizol and 4-MAA, HPLC-DAD was required because these drugs are partially decomposed in the heated injection port of the GC. Quantitation of 4-MAAwas performed using metamizol as reference standard due to the unavailability of 4-MAAin the market, the structural similarity of the compounds, and the wide therapeutic concentration range for metamizol (7). These quantitations were performed using whole blood calibration curves in the range of 0.1-2 mg/L for trazodone and m-CPP, and in the range of 6-48 mg/L for metamizol and 4-MAA. Figure 2 shows the GC-NPD chromatogram of the deceased's blood. Figures 3 and 4 show the GC-MS of analyte peaks eluting at 2.76 rain (peak No. 1) and 14.07 rain (peak No. 7) and the resulting match of the computerized library searches, respectively. Analytical validation data of each drug are listed in Table I. The method is precise, sensitive, and reliable for the studied analytes. Good linearity and excellent recoveries were obtained.


The proposed analytical method is used routinely in our laboratory and allows the simultaneous determination of a wide variety of drugs with a limit of detection of less than 0.1 mg/L (signal-to-noise ratio ---3) (28-30). GC-NPD has excellent sensitivity for the detection of traces of drugs with minimum interferences and can be combined with GC-MS for confirmation of analyte identities. It can also be combined with HPLC-UVdetection for drugs not detected by GC-NPD or drugs that display thermal instability or poor chromatographic properties. Furthermore, the use of the Bond Etut Certify columns allows, with a single sample extract, the analysis of the acidic-neutral and basic eluates to achieve the most comprehensive drug screening. The review of the literature regarding analytical procedures for the simultaneous determination of trazodone and m-CPP revealed that most of them used HPLC-DAD as a detection technique and were focused only on these two compounds (31-34). Furthermore, most of them have been limited to relatively clean biological samples such as plasma or serum (31-33). Only one of these publications described an SPE extraction procedure for detection of trazodone and m-CPP, but the biological sample was plasma (33), whereas whole blood is most frequently encountered in postmortem cases. Until now, as far as we know, our work is the first to report the simultaneous determination of trazodone and m-CPP in whole blood as part of a systematic toxicological analysis using a mixed SPE extraction procedure with validated analytical data. Polsonings

characteristics

A suicide case due to trazodone is reported here. The deceased was an 86-year-old man under trazodone therapy for his reactive depression. Trazodone may fail to suppress suicidal

2

ideation, at least early in therapy, and this fact accounts for voluntary ingestion of massive doses by depressed patients (35). Similar to other authors, our Poison Control Center (PCC) recorded that 70% of trazodone overdoses were suicide attempts (36). The mean quantity of trazodone ingested was 2 g, which is equivalent to 25 times the recommended daily dose in the elderly. However, the most commonly reported symptoms were mild: drowsiness, dizziness, hypotension, and bradycardia. In fact, fatalities are rarely attributed solely to trazodone, while deaths have been reported in cases of concurrent ingestion of other central nervous system depressants (23,26,27). Trazodone serum levels may be difficult to obtain quick enough to be useful in the acute management as hospitals may not be equipped to run the procedures routinely. Therefore there is a paucity of data in the literature on trazodone and mCPP concentrations in overdose. Review of literature revealed only 10 manuscripts of trazodone intoxication with no co-ingested compound (24,37-42). Results are reported in Table II. Nonfatal overdose blood concentrations of trazodone included cases of people aged 18-63 years, who intentionally ingested trazodone and exhibited mild signs of toxicity; in these cases, serum trazodone concentrations were as high as 30 mg/L (24,38-40). Lethal trazodone blood concentrations in mixed overdoses have ranged between 9 and 32 mg/L (21,23,26,27). However, only two fatalities were solely attributed to trazodone and were compared to our case (41,42) (Table II). In the first case, the patient was a 63-year-old female with a history of congestive heart failure, diabetes mellitus, and mild renal insufficiency, who ingested 3-4.5 g of trazodone. On presentation to the hospital 10 h later, she was lethargic with sinus bradycardia and prolonged corrected Q-T interval. She had a cardiac

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Figure 3. GC-MS of analyte eluting at 2.76 rain (peak no. 1) (A) and mCPP from data system reference library (B).

265

Journal of Analytical Toxicology,Vo[. 29, May/June2005

circulatory insufficiency due to the arrhythmias and a serotonin syndrome (42). Our case is the lowest fatal trazodone concentration in a death caused exclusivelyby this drug currently reported in the literature. This emphasizes the fact that toxic and fatal ranges are dynamic concepts that should be updated (43). We have obtained an m-CPP/trazodone ratio of 0.12 showing a certain metabolism of trazodone beforedeath. Trazodoneexhibits postmortem redistribution, the heart-femoral blood concentration ratio for the drug was between 1.5 and 1.7 (25,27). Unfortunately, a peripheral blood sample was not collected during autopsy, but concentrations may have been lower. Furthermore, in suicide attempts, time of ingestion is often uncertain. If elapsed time between ingestion and death were long, the levels of trazodone would have been even lower. Because of the number of mechanisms of toxicity associated with trazodone, its specific role in fatalities is often difficult to determine. At highly elevated concentrations, central nervous system depression is a likely mechanism of death but at lower concentrations other mechanisms need to be considered. As the number of trazodone-treatedpatients increasedannually around the world, the reports of cardiovascular complications in patients with no prior cardiovasculardisease have also increased (44-51). Dangerous hypotension in elderly patient after the commencementof therapy has been described, possibly associated to antihypertensive treatment and could be involved in our case (48). The autopsy findings, as expected, were unremarkable. The lack of immediate medical attention could also contributed to the fatal course. One other mechanism contributing to death could be a vagal response during emesis. Any possible interactions with other drugs, which could complicate the patient's physical status, should be taken into account. Only metamizol and its main metabolite at therapeutic concentrations were found in the present case (7). Adverse pharmacokinetic drug interactions are unlikely because trazodone is a substrate of CYP3A4,which converted it to m-CPP (52), and metamizol is mainly metabolized by CYP2A1.

arrest 12 h after admission. The inciting rhythm was recognized as torsade de pointes. The patient suffered complications including coma, renal failure, and cardiac instability and died 20 days after admission. Serum trazodone levelat hospital admission was 5.6 mg/L (41). In the second case, 25.4 mg/L of trazodone was measured in the serum several hours after the ingestion. The 40-year-oldman was admitted with Glasgow coma 3 and asystolia. Life threatening arrhythmias were thereafter observed including recurrent torsade de pointes, ventricular fibrillation, and a complete auriculoventricular block. Fluvoxamine was also taken but without any documented overdose, and the death was attributed to a prolonged Scan 952 (14.925 min): J~IgOI06.D

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Table I. Summary of Validation Data of Trazodone, m-CPP,and Metamizol from Fortified Whole Blood Samples Intra-assay Precision

Interassay Precision

Linearity

Limit of Detection

Limit of Quantitation

(n = 6)

RSD* (%) (n = 6)

RSD (%) (n = 9)

r2 (n = 6)

(pg/[) (n = 6)

(pg/t) (n = 6)

Quantitation Technique

0.1 0.5 2

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2 4 3

2 4 3

0.999

33

109

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0.999

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36

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86 87 84

8 7 7

9 12 12

0.999

1117

3686

Level of Fortification

Percent Recovery

Compound

(mg/L)

Trazodone

m-CPP

Metamizol

6 24 48

* RSD:Relativestandarddeviation.

266

HPLC-DAD


Table II. Review of Reported Cases of Trazodone Overdose Without Any Other Drug with Toxic| Interactions: Case Reports are Confirmed by Analytical Measurement of Trazodone Estimated Age (years)/ Amount Gender Ingested(g)

Matrix

TrazodoneLevels (mg/L)

86/male 63/female

Unknown 3-4.5

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4.9 at unknown interval 5.6 at 10 h postingestion

48/female 40/male

2-4 Unknown

Unknown Serum

15 at unknown interval 25.4 at aproximately 12 h

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2 Not specified 2.5 1 2.5-5 4-8 0.6-6.4

Serum Serum Serum Serum Serum Serum Serum

1.5 at 22 h postingestion 2.1 at unknown interval 7.7 at unknown interval 8 at unknown interval 19 at unknown interval 25.7 at aproximately 4 h 3.3-30 at unknown interval

ClinicalSigns,Symptoms, andComplications Cardiorespiratoryarrest Torsadesde pointes, cardiac arrestand complications of it Drowning in her bathtub Arrthymias.Multiple organ failure probably associatedwith a serotonin syndrome Drowsiness, nausea No physical effects Alert and orientated Unconscious (fell downstairs) Drowsy, slurred speech Mild hypotension, lethargia Not specified

Conclusions The present method for the analysis of trazodone and rnCPP, its active and major metabolite, combined SPE and GC-NPD for screening analysis/quantitation and GC-MS for confirmation of the obtained results. Satisfactory analytical validation data were obtained for recovery,precision, linearity, and sensitivity. Regarding poisoning characteristics, the complete reviewof the literature disclosed only two deaths due to trazodone alone in which levels are measured. In our case, trazodone was found in the death of an elderly man who took trazodone for suicidal purposes. A role for trazodone can be invoked after several considerations were made. Certain factors such as individual susceptibility and advanced age could have accounted for the fatality,and we could not disregard this possibility. Our work providesbaseline information regarding overdose and fatalitieswith data of concentrations of trazodone and m-CPP with validated analytical techniques.

6.

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References 1. Consejo General de Colegios Oficiales de Farmac~uticos. Cat~logo Especialidades Farmac~uticas, 2003 Plus. Einsa, Madrid, Spain, 2003, pp 1980. 2. K. Paffitt. Martindale. The Complete Drug Reference, 32nd ed, Pharmaceutical Press,London, U.K., 1999, pp 35 and pp 308-310. 3. S. Caccia, M.H. Fong, S. Garattini, and M.G. Zanini. Plasma concentrations of trazodone and 1-(3-chlorophenyl)piperazine in man after a single oral dose of trazodone. J. Pharm. Pharmacol. 34: 605-606 (1982). 4. K. Otani, K. Mihara, N. Yasui, M. Ishida, T. Kondo, N. Tokinaga, T. Ohkubo, T. Osanai, K. Sugawara, and S. Kaneko. Plasma concentrations of trazodone and rn-chlorophenylpiperazine at steady state can be predicted from those after an initial dose of trazodone. Prog. Neuropsychopharmacol. Biol. Psychiatry 21:239-244 (1997). 5. K. Mihara, N. Yasui-Furukori, T. Kondo, M. Ishida, S. On|

12. 13. 14. 15. 16. 17. 18.

or Toxic|

Status

Reference

Postmortem

Martinezet al.

Postmortem Postmortem

Augensteinet al. (41) Demorest(37)

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