Fatal Multiple Drug Intoxication Following Acute Sertraline Use

Abstract

A 53-year-old Caucasian male victim of suicide was suspected of overdose with sertraline and alprazolam after death-scene
investigation. The concentration of sertraline, a selective serotonin reuptake inhibitor, was determined by a gas chromatograph
with mass selective detection. The concentration of alprazolam, a triazolobenzodiazepine, was determined by high-performance
liquid chromatography. The sertraline concentration was reported at 1.0 mg/L in peripheral blood, which is greater than previously
reported in other postmortem cases in which death was attributed to a multiple drug overdose. The N-desmethylsertraline concentration was reported at 0.2 mg/L in peripheral blood, which is far less than in other postmortem
cases and suggests acute intoxication in this case. The alprazolam concentration was reported at 33 µg/L in heart blood, which
is within the therapeutic range. The cause of death was multiple drug intoxication following acute use of sertraline, the
manner of death was suicide, and the mechanism of death is an unexplained drug interaction and/or toxicity.

Full text

Journal of Analytical Toxicology, Vol. 22, October 1998
Case
Report
I
Fatal Multiple Drug Intoxication Following
Acute Sertraline Use
D.A. Milner, M. Hall, G.G. Davis, R.M. Brissie, and C.A. Robinson*
University of Alabama at Birmingham, Department of Pathology, Division of Forensic Pathology, Birmingham, Alabama
[ Abstract I
A
53-year-old Caucasian
male victim
of suicide was suspected of
overdose with sertraline and alprazolam after death-scene
investigation. The concentration of sertraline,
a selective
serotonin
reuptake inhibitor, was determined by a gas chromatograph
with
mass selective detection. The concentration of alprazolam,
a
triazolobenzodiazepine,
was determined by
high-performance liquid
chromatography. The sertraline concentration was reported at
1.0 mg/L in peripheral blood, which is
greater than previously
reported in other postmortem cases in
which death was attributed to
a multiple drug overdose.
The N-desmethylsertraline concentration
was reported at 0.2
m8/I. in peripheral blood, which is far less than
in other postmortem
cases and suggests acute intoxication in this
case. The alprazolam concentration was reported at 33
pg/L in
heart
blood, which is within
the therapeutic range. The cause of death was
multiple
drug intoxication following acute use of sertraline, the
manner of death was suicide, and the mechanism of death is an
unexplained drug interaction and/or
toxicity.
Introduction
Sertraline (Zoloft | ([1S-cis]-4-[3,4-dichlorophenyl]-l,2,3,4-
tetrahydro-N-methyl-l-naphthalenamine hydrochloride) is a
selective serotonin reuptake inhibitor (SSRI) structurally unre-
lated to fluoxetine and paroxetine (1). The drug is commonly pre-
scribed for depression, panic disorders, and obsessive-compulsive
behavior and does not induce euphoria or demonstrate depen-
dency (2). The drug functions in the same manner as other SSRIs
at neural synapses through the 5-HT receptors but with fewer side
effects because of its decreased affinity for cholinergic, adrenergic,
and GABA receptors (3). Sertraline does inhibit the reuptake of
dopamine, suggesting it may have abuse potential, although less
than a benzodiazepine (2). It is metabolized by first-pass kinetics to
its nearly inactive metabolite, N-desmethylsertraline (4). The
usual dose is 50- to 100-rag tablets in a single oral dose per day, not
exceeding 200 mg (1).
Alprazolam (Xanax| -
zolo [4,3-a][1,4] benzodiazepine) is a triazolobenzodiazepine
related to diazepam and is commonly prescribed for the manage-
ment of anxiety disorder with short-term effects on depression.
*Author to whom correspondence should be addressed.
The effects of benzodiazepines result from an increased frequency
of GABA receptor chloride channels opening in central nervous
system (CNS) inhibitory neurons (5). The drugs elicit pronounced
CNS inhibition, ranging from mild neurologic disturbance to hyp-
nosis. The usual dose of alprazolam is 0.25 to 2 mg in a single oral
dose per day or as indicated for anxiety (6).
Fatal cases of alprazolam toxicity have been reported with the
postmortem blood concentrations ranging from 122 to 390 lag/L
(7). The increased toxicity of benzodiazepines in conjunction with
alcohol and other drugs is well documented. Recent studies have
shown SSRIs to impair the clearance of alprazolam by inhibiting
Cytochmme P450-3A4, but fatal cases of co-administration have
not been reported (8,9). One case of fatal multi-drug intoxication
involving sertraline with the maximum concentrations in periph-
eral blood being 0.64 mg/L of sertraline, a concentration 3.4 times
greater than the maximum therapeutic concentration reported in
clinical trials, and 0.58 mg/L of diphenhydramine, a therapeutic
concentration, is reported (10). Although no cases of fatal overdose
with only sertraline have been reported, symptoms of non-fatal
sertraline-only overdoses include somnolence, nausea, vomiting,
tachycardia, ECG changes, anxiety, and dilated pupils with the
amounts ingested ranging from 500 to 6000 mg (1).
We discuss a fatality in which sertraline and alprazolam were
suspected in a suicide. Sertraline and N-desmethylsertraline were
identified by gas chromatography-mass spectrometry (GC-MS)
and quantitated from heart blood, peripheral blood, liver tissue,
antemortem gastric contents, and postmortem gastric contents.
Alprazolam was identified by high-performance liquid chromatog-
raphy (HPLC) and quantitated in heart blood, liver tissue, ante-
mortem gastric contents, and postmortem gastric contents.
Case History
A 53-year-old male with a history of suicidal threats was found
unresponsive in his home. Empty bottles of Zoloft and Xanax were
found along with suicide notes. He was transported to a medical
facility but, after unsuccessful resuscitation by medical staff, was
pronounced dead 1 h and 23 min later. Gastric suction was per-
formed in the resuscitation attempt.
Autopsy findings were unremarkable and showed no evidence of
violence or anatomic cause of death. No tablet fragments were
found in the antemortem gastric contents or in the stomach at
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autopsy. Neither the number of tablets consumed nor the time
elapsed between ingestion and death could be determined from
the available evidence.
The antemortem gastric sample was obtained from the medical
staff. Postmortem samples submitted for toxicological analysis
included urine, heart blood, peripheral blood, vitreous, bile, brain
and liver tissue, and postmortem gastric contents. Toxicological
analysis included screening for ethanol, drugs of abuse, and alka-
line drugs.
Materials and Methods
Urine was screened for the presence of drugs of abuse on the
Syva EMIT Plus Analyzer using EMIT reagents and calibrators
according to the manufacturer's instructions (Syva, Palo Alto, CA).
Volatile analysis was performed on blood with a headspace pro-
cedure (11), using n-propanol as the internal standard. The
column was a 6-ft Porapak-S at a temperature of 180~ Instru-
mentation was Shimadzu (Kojoto, Japan) GC-14A.
All reagents for alkaline drug extraction and GC-MS analysis
were supplied through Baxter (McGaw Park, IL). The GC--MS was a
Hewlett-Packard (Palo Alto, CA) 5890 series II GC with Hewlett-
Packard 5971 mass selective detector equipped with a 12.5-m x 0.2-
mm HP-I methyl silicone column. The column temperature was
programmed from 70 to 280~ at 20~ Helium carrier gas
flow was 1 mUmin. A total ion scan was performed. Mepivicaine
was used as the internal standard. Multipoint calibration curves
(0.2-1.0 rag/L) for sertraline and N-desmethylsertraline were used
for quantitation and confirmation of the compounds.
All reagents for HPLC were supplied through Bio-Rad (Her-
cules, CA) (12). HPLC was preformed with a Shimadzu LC-6A
(Kyoto, Japan) system. A UV detector was used at 242 nm and
Journal of Analytical Toxicology, Vol. 22, October 1998
0.001 AUFS. Fludiazepam was used as the internal standard. A
standard curve of alprazolam concentrations in blood ranging
from 20 to 200 IJg/L with corresponding alprazolangfludiazepam
peak ratios was used for quantitation.
Sample preparation
The heart and peripheral blood were extracted for GC-MS,
HPLC and volatile analysis. A liver homogenate was prepared with
water (final concentration, 0.2 g/mL) prior to extraction on both
systems. The gastric contents were diluted 1:99 and used for
extraction on both systems. Urine was screened directly.
Sertraline extraction and analysis
A 5-mL portion of each sample as prepared above was extracted
with n-butyl chloride (adjusted to a pH of greater than 9 with
ammonium hydroxide) using a modification of the procedure
described by Forester et al. (13,14). The butyl chloride was then
rotated with 1N HC1, centrifuged, aspirated, and discarded. The
samples were alkalinized with ammonium hydroxide and re-
extracted into chloroform. The chloroform bead was then injected
into the GC-MS. A total ion chmrnatogram was obtained. The
identity of compounds was confirmed by comparison with a previ-
ously established standard for each drug. Specific ions visualized
by MS denoting sertraline, N-desrnethylsertraline, and mepivi-
caine (274,119, and 98, respectively) were extracted from the total
chromatograrn for each compound. The areas for each peak desig-
nated by the selected ions were calculated by integration for all
three compounds. Quantitation used the area ratio of each com-
pound peak to the internal standard peak with comparison to the
calibration curve.
Alprazolam extraction and analysis
Portions (2 mL) of the prepared samples were extracted using
the method previously described by Hall et al. (15). Each sample
Table
!. The Concentrations of Sertraline, N-Desmethylsertraline, and
Alprazolam
Gastric Contents
Blood AM PM
Compound Heart Peripheral Liver
TV* (189
mL)
TV (125
mL)
Method
Sertraline 3.0 mg/L 1.0 mg/L 17.4 mg/kg 33.0 mg/1-V 16.0 mg/1Y GC-MS
N-Desmethylsertraline 1.2 mg/L 0.2 mg/L 0.4 mg/kg 0.1 mg/1-V ND GC-MS
Alprazolam 33.0 lag/L NA 92.0 pg/kg 143.0 tJg/lV 78.0 pg/TV HPLC
* Abbreviations: TV. total volume; AM, antemortem; PM, postmortem; NO, none detected; NA, not analyzed.
Table 11. Summary of Reported
Post
Mortem Concentrations of Sertraline and N-Desmethylsertraline
Author # of Cases Heart blood Peripheral blood Outcomes
Logan et al. (10) 3 0.44-0.83 mg/L (S) 0.61-0.64 rng/L (S)
1.30-1.52 mg/!_ (D) 1.54-1.55 mg/L (D)
Levine et al. (3) 7 0.23-0.46 mg/L (S) 0.23--0.82 mg/L (S)
0.08-0.99 mg/L (D) 0.17-1.8 mg/L (D)
* Abbreviations: S. sertraline and D, N-desmethylsertraline.
* Drugs reported include sertraline and diphenhydramine only.
* Drugs reported include sertraline, lidocaine, doxylamine, dextromethorphan, metoprolol, and verapamil.
2 deaths, non-drug related;
1 death, multidrug intoxication.
6 deaths non-drug related;
1 death, rnultidrug intoxication.
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Journal of Analytical Toxicology, Vol. 22, October 1998
was combined with 4 mL of acetone and thoroughly mixed
(vortex mixed 30 s, allowed to stand 10 s, vortex mixed 30 s). The
sample was centrifuged, and 3 mL was transferred to a clean tube.
Under helium at 70~ the supernatant was removed. Recon-
stitution of the filtrate was performed with the addition of 1 mL
of 0.1M phosphate buffer at pH 6.4, sonication, and vortex mixing.
Each 1-mL extract was then carried through a solid-phase extrac-
tion column (Bio-Rad) as described by Mazher et al. (12). The
samples were injected into the HPLC, and a chromatogram was
obtained. The identity of the compounds was confirmed by com-
parison with established standards for each drug. Quantitation
used the ratio of the area from the chromatogram of the alpra-
zolam peak to fludiazepam peak with respect to the standard
curve.
Results
The urine was positive for benzodiazepines. Urine screening for
barbiturates, opiates, amphetamines, propoxyphene, and cocaine
and blood screening for volatiles were negative.
Analysis of the samples by GC--MS indicated the presence of ser-
traline and N-desmethylsertraline with no other pharmaceuticals
or drugs of abuse identified. ,a~alysis of the samples by HPLC indi-
cated the presence of alprazolam with no other pharmaceuticals or
drugs of abuse identified.
Sertraline was identified in all samples analyzed. N-Desmethyl-
sertraline was identified in 4 of 5 samples. Alprazolam was identi-
fied in 4 of 5 samples.
The concentrations and sample types are summarized in Table I.
Discussion
Adverse effects associated with antidepressants have been a
major focus of study in an effort to produce drugs that relieve
patients' symptoms without addictive tendencies or harmful side
effects. For this reason, new drugs with fewer side effects are being
developed to replace older drugs with well-documented adverse
reactions. Sertraline, one of the newer SSRI antidepressants now
replacing the bicyclics, tricyclics, and tetracyclics, has few
reported side effects, less non-specific receptor interaction, and
little abuse potential (2,3).
Minimizing the number of medications a patient requires while
maximizing efficacy in order to reduce the possibility of adverse
pharmaceutical interactions is an important consideration in any
patient. CNS inhibitors have additive effects with well-docu-
mented cases of coma and death reported for a variety of combina-
tions. In addition, the benzodiazepine class of anxiolytic CNS
inhibitors in combination with other drugs and alcohol has been
reported to induce coma and death.
In the current context, the alprazolam concentrations in blood
and its distribution in gastric and tissue samples do not demon-
strate levels indicating overdose or significant toxicity. These levels
are consistent with therapeutic use and this is further supported
with the positive urine screen (6,16). This does not suggest that
the alprazolam can be considered to be acting in a vacuum as ser-
traline and metabolites are also present.
The sertraline concentration in the heart blood was three times
greater than in the peripheral blood and is most likely due to post-
mortem redistribution. The peripheral blood concentration of ser-
traline that we found is five times greater than in the clinical trial
(17). Using a previously reported blood concentration factor of
0.23 ng/mL per milligram of drug ingested and the proportional
administered dose toachieved concentration relationship, we esti-
mate greater than 5000 mg of drug was ingested (17). The avail-
able antemortem and postmortem gastric samples demonstrate
total drug amounts that suggest the bulk of adsorption from the
stomach and transfer of stomach contents to the intestinal tract
had already occurred prior to treatment and death.
In two previous studies (3,10), findings from cases in which ser-
traline had been ingested were reported. Heart blood and periph-
eral blood findings from these studies are summarized in Table II.
In consideration of both of these series of cases, there were a total
of two deaths from this group which were directly attributable to
drug intoxication. In both cases, death was ruled due to multiple
drug intoxication, involving one and five other drugs, respectively,
in combination with sertraline and its rnetabolite. In the other
eight cases from this series, the sertraline and N-desrnethylsertra-
line drug findings were incidental to the cause of death. It is inter-
esting to note in both of these studies, the N-desrnethlysertraline
metabolite values in either peripheral or heart blood samples gen-
erally ranged higher than that of the parent compound.
The most significant finding in our case is the small concentra-
tion of N-desmethylsertraline in all samples. A high ratio of
N-desmethylsertraline to sertraline concentration would be an
expected finding in a patient on a therapeutic regimen because of
the first-pass metabolism and elimination half-life of the drug. In
our case, the extremely high concentration of sertraline with the
extremely low concentration of metabolite in the heart and
peripheral blood suggests death acutely followed ingestion in a
patient not on a daily regimen. Additionally, the relative distribu-
tion ratio between the liver and the peripheral blood sertra-
line concentration approached 20 to 1, whereas that for the
N-desmethlysertraline was 2 to 1.
The reported cause of death in this case was multiple drug intox-
ication following an acute use of sertraline. The manner of death,
considering the case history and the death scene along with the
toxicological evidence, was determined to be suicide. The exact
mechanism of death remains unexplained.
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