European Neuropsychopharmacology (2013) 23, 13641372

www.elsevier.com/locate/euroneuro

REVIEW

Intoxications with the monoamine oxidase

inhibitor tranylcypromine: An analysis of
fatal and non-fatal events
Maximilian Gahrn, Carlos Schnfeldt-Lecuona, Markus A. Klle,
Roland W. Freudenmann
Department of Psychiatry and Psychotherapy III, University Hospital of Ulm, Leimgrubenweg 12-14,
89075 Ulm, Germany
Received 15 November 2012; received in revised form 25 February 2013; accepted 28 May 2013

KEYWORDS

Abstract

Antidepressants;
Major depression;
Psychopharmacology;
Adverse events;
Suicide;
Toxicology

Tranylcypromine (TCP) is a non-selective and irreversible monoamine oxidase inhibitor and an

effective agent in the treatment of major depression. It features a complex pharmacologic
prole and overdoses might induce severe intoxications. To identify typical clinical presentations of TCP-intoxications, range of associated TCP-dosages and possible differences between
fatal and non-fatal intoxications a systematic review of all previously published cases of TCPintoxications was conducted. We detected n =20 reports of TCP-intoxications in the literature
(fatalities n= 10). Mean age was 36.7 years (median 37); the majority of patients were female
(60%). Frequent ndings in patients with TCP-intoxications were disturbance of consciousness/
cognitive dysfunction (90%), cardio-vascular symptoms (55%), hyperthermia (50%), respiratory
distress (45%), delirium (45%), muscular rigidity (30%) and renal failure (20%). Suicidal intent
was present in n =18 (90%) patients. First clinical symptoms related to TCP-intoxication
developed on average in less than 1 day. The average dosage related to TCP-intoxication was
677 mg. The highest survived TCP-dosage was 4000 mg and the lowest fatal dosage was 170 mg.
Patients with fatal intoxications were on average older (40.5 vs. 32.8 years) and developed a
more rapid onset of symptoms (0.2 vs. 0.8 days). Death occurred after a mean time of 0.6 days;
symptom relief in patients with non-fatal intoxications developed on average after 3.2 days.
Considering the large dose spectrum between survived and lethal TCP-dosages individual
susceptibility factors might play a role regarding the severity of clinical symptoms independently of the ingested dosage.
& 2013 Elsevier B.V. and ECNP. All rights reserved.

Corresponding author. Tel.: +49 731 50061552; fax: +49 731 50061412.
E-mail address: maximilian.gahr@uni-ulm.de (M. Gahr).

0924-977X/$ - see front matter & 2013 Elsevier B.V. and ECNP. All rights reserved.
http://dx.doi.org/10.1016/j.euroneuro.2013.05.009

Intoxications with the monoamine oxidase inhibitor tranylcypromine

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Contents
1.
2.
3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Experimental procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Background of TCP-intoxications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Course-specic parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4. TCP-dosages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5. Fatal vs. non fatal-intoxications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6. Treatment of TCP-intoxications, presence of TCP-abuse/-dependence . . . . . . . . . . . . . . . . . . . . . .
4. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Pharmacodynamic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Clinical presentationdelirium and serotonin syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Hemorrhages and thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. TCP-dosages, suicidal intent and fatalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Role of the funding source. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Appendix A.
Supporting information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Introduction

Monoamine oxidase inhibitors (MAOIs) have been relegated

to a second line treatment in clinical practice (Adli et al.,
2002) due to their potentially lethal dietary and drug
interactions (Frieling and Bleich, 2006). However, they are
effective in the treatment of major depression (Parker
et al., 2001), especially atypical (Pae et al., 2009;
Stewart and Thase, 2007) and treatment-resistant forms
(Amsterdam and Shults, 2005). MAOIs act by a covalent
binding to the active center of monoamine oxidases (MAO)
(Baker et al., 1992), that are important enzymes in the
neurotransmitter metabolism with two isoforms in the
human MAO system designated as MAO-A and MAO-B (Shih
and Chen, 2004). While MAO-A preponderantly metabolizes
serotonin, melatonin and norepinephrine, MAO-B preferentially breaks down phenylethylamine and benzylamine,
whereas dopamine and tyramine are metabolized by both
isoforms (Billett, 2004; Kalgutkar et al., 2001). Several
adverse events associated with MAOI-treatment result from
irreversibility (regarding the binding of the drug to the MAO
enzyme) and nonselectivity (referring to the tendency to
bind to both isoenzymes).
Tranylcypromine (TCP) constitutes the prototype of a
non-selective and irreversible MAOI and is an important
antidepressant in the treatment of therapy-refractory
depression (Adli et al., 2008; McGrath et al., 2006) that is
still frequently used in psychiatry (Adli et al., 2008; Nardi
et al., 2012; Quante and Zeugmann, 2012; van Haelst et al.,
2012). In the STARnD trial (sequenced treatment alternatives to relieve depression), TCP was reported to be as
efcacious as, but not superior to venlafaxine plus mirtazapine (McGrath et al., 2006). Phenelzine and isocarboxazid
are two more irreversible and non-selective MAOIs that

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feature efcacy in the treatment of therapy-refractory

depression (Birkenhger et al., 2004; Levkovitz et al.,
2011). However, their use in the treatment of major
depression is limited compared to TCP (Vieta and Colom,
2011; Vieta et al., 2010). In addition, TCP is the only
irreversible and non-selective MAOI that is approved in the
USA as well as in Europe for the treatment of major
depressive disorder (Levkovitz et al., 2011; Vieta et al.,
2010).
Chemically, TCP is a racemic (7)-trans-phenylcyclopropylamine and has structural similiarity to amphetamine
(Baker et al., 1992). The MAO inhibitory effects rather
depend on the (+)- than the ()-enantiomer (Tuomisto and
Smith, 1986; Tuomisto et al., 1973). Both enantiomers,
mainly ()-TCP, also have presynaptic amphetamine-like
effects such as monoamine reuptake inhibition and release
(Tuomisto and Smith, 1986; Tuomisto et al., 1973). All these
actions may explain TCP's antidepressant properties (Baker
et al., 1992; Frieling and Bleich, 2006).
TCP was introduced as an antidepressant in the early
1960s, but soon became notorious for an association with
headaches, hypertension, cerebral hemorrhage and death in
those on the drug who ate ripe cheese, later prompting the
term cheese reaction, as rst described by Blackwell in
1963 (Asatoor et al., 1963; Beavan, 1964; Bethune et al.,
1963; Blackwell, 1963; Cuthill et al., 1964; Graham, 1964).
The substance was withdrawn from the market in 1964 until
the discovery that fooddrug interactions caused these
fatalities, i.e. the incompatibility of TCP and a diet rich in
tyramine. In the further course, TCP was re-launched as a
second-line antidepressant with the well-established dietary warnings in order to avoid tyramine-rich food and
beverages under treatment with TCP. In summary, TCP is a
MAOI with a good benetrisk ratio in the treatment of

1366

M. Gahr et al.

major depression (Adli et al., 2008). However, treatment

with TCP requires to bear in mind that it features a
potential of relevant food and drug interactions.
By contrast, much less appraised are TCP's chemical
similiarity to amphetamines and amphetamine-like presynaptic actions (Tuomisto and Smith, 1986; Tuomisto et al.,
1973) as well as the risk of abuse, dependence and withdrawal syndromes of different severity after abrupt discontinuation of even normal TCP-dosages (Abdi and Fishman,
1996; Absher and Black, 1988; Baumbacher and Hansen,
1992; Eyer et al., 2008; Le Gassicke, 1963; Le Gassicke
et al., 1965).
Moreover, TCP, as other antidepressants, might induce
severe intoxications when taken in daily dosages that
exceed the manufacturer's recommendations (according to
the prescribing information of Jatrosom N and Parnate
the maximum daily TCP-dosage should not exceed 60 mg).
Taking into account that suicide attempts by intoxication
with antidepressants may frequently occur in patients with
major depression (Leon et al., 2011; Mandour, 2012) the
prescription of antidepressants with a potential of relevant
food and drug interactions represents a risk in this patient
population. Nevertheless, second-line antidepressants such
as TCP might be occasionally indispensable in patients with
e.g. therapy-refractory depression. Regarding intoxications
with TCP, literature merely provides anecdotal reports and
lack of systematic approaches that would have a direct
impact on the further safety evaluation and risk assessment
of TCP. In addition, being familiar with possible clinical
symptoms related to TCP-intoxications can help physicians
to come up with a fast and accurate diagnosis in patients
with TCP-associated intoxications.
The aim of the present article was to perform a systematic selective review of previously published cases of TCPintoxications in order to identify
(i) possible clinical presentations of TCP-intoxications,
(ii) background/circumstances of TCP-intoxications (suicidal intent/accidental),
(iii) course-specic parameters of TCP-intoxications
(latency until the development of rst symptoms
related to TCP-intoxication after ingestion of TCP;
duration of TCP-intoxications),
(iv) range of underlying TCP-dosages (highest survived and
lowest lethal TCP-dosages), and
(v) possible differences regarding fatal vs. non-fatal
intoxications.

2.

Experimental procedures

A systematic review was conducted. The entire Medline and Scopus

database were searched using the search term tranylcypromine.
If titles and abstracts suggested a possible correspondence with the
inclusion criteria (see below), the articles were obtained and
further checked. The main inclusion criterion was the description
of intoxication with TCP by means of case reports or reviews of the
literature. Only cases that described intoxications exclusively
related to TCP were included. Cases of intoxications due to TCP
plus X and cases suspicious of (additional) food interaction were
excluded (a total of n=4 case reports). A separate assessment of

the plausibility of the reported intoxications was not performed.

Identied articles were cross-checked for relevant publications that
were not indexed in Medline or Scopus. Data extracted from the
included case reports were age, sex, psychiatric diagnosis/target
symptoms of treatment with TCP, prescribed TCP-dosage and TCPdosage related to intoxication, duration of treatment with prescribed TCP-dosage, background/circumstances of TCP-intoxication
(presence of suicidal intent/accidental ingestion etc.), time until
the development of symptoms related to TCP-intoxication, clinical
presentation of TCP-intoxication, duration of clinical symptoms
until death/symptom relief, presence of thrombocytopenia, elevated creatine kinase concentrations or transaminases and evidence of abuse of or dependence on TCP. Time until development of
symptoms was assessed in days (integers 1, 2, 3, etc.). 0 was
assigned when it was reported that rst symptoms had developed
within the rst 24 h after the intake of TCP. In the second step
fatalities and non-fatalities were compared with regard to particular parameters (patient characteristics, duration of treatment
with prescribed TCP-dosages, TCP-dosages related to intoxication,
presence of suicidal intent, time until development of symptoms
related to TCP-intoxication, duration of clinical symptoms until
death/symptom relief). Data were analyzed descriptively (mean
values, median, and mean standard deviation (MSD)).

3.

Results

In June 2012 we retrieved 2036 MEDLINE hits according to

the search term. We identied 18 publications that reported
20 intoxications related to TCP (Bacon, 1962; Bell and Scaff,
1963; Boniface, 1991; Chatterjee and Tosyali, 1995;
Fischbach, 1968; Grifths, 1973; Iwersen and Schmoldt, 1996;
Jacobziner and Raybin, 1963; Maccaig and Edmondson,
1965; Mackell et al., 1979; Marra et al., 1965; Matter
et al., 1965; Mawdsley, 1968; Midwinter, 1962; Pennings et al.,
1997; Robertson, 1972; Thorp et al., 1997; Youdim et al.,
1979). The mean age of the entire patient population
was 37 years (range 172, median age = 37, MSD717.4),
and majority of patients were female (n= 12, 60%). There
was one female infant (age 20 months) that accidentally
ingested 50 mg TCP. There were 10 (50%) fatal intoxications.
We could identify one patient (5%) who was described to
abuse TCP (Chatterjee and Tosyali, 1995). Information
regarding abuse of or dependence on TCP was missing in
11 patients (55%) for details (e.g. frequency of psychiatric
diagnoses) see Table 1.

3.1.

Clinical presentation

Frequent ndings in patients with TCP-intoxications were

disturbance of consciousness/cognitive dysfunction (90%),
cardio-vascular symptoms (55%), hyperthermia (50%), respiratory distress (45%), delirium (45%), muscular rigidity (30%)
and renal failure (20%). For details see Table 2.

3.2.

Background of TCP-intoxications

Suicidal intent was reported in 18 (90%). Other settings

were accidental overdose in the context of TCP-dependence
(Chatterjee and Tosyali, 1995) and accidental ingestion of
TCP by an infant (Midwinter, 1962). TCP was prescribed for
the treatment of a psychiatric disorder in 17 patients (85%).

Intoxications with the monoamine oxidase inhibitor tranylcypromine

Table 1 Patient characteristics, psychiatric diagnoses,

prescribed/actually taken TCP-dosages, duration of
treatment with TCP, presence of suicidal intent (entire
population).
Patients with TCP-intoxication
(n =20)
Patient characteristics
Mean age [years] 37 (range 172, median 37,
MSD717.4)
Sex
F: n =12/60%; M: n =8/40%
Psychiatric diagnosis/target symptoms of TCP treatment
[n/%]a
Depression
12/60%
Depression plus X 2/10%
Other
3/15%
No underlying
1/5%
diagnosis
Mean TCP dosages [mg]
48.3 (range 10100, median 40,
Prescribedb
MSD740.7)
677.1 (range 504000, median 400,
Related to
MSD7918.1)
intoxicationc
3.7 (range 024, median 0,
Duration of
treatment with MSD78.9)
prescribed TCPdosaged [weeks]
Presence of suicidal 18/90%
intente
Abbreviations/legend: F=female; M=male; MSD=mean
standard deviation; TCP=tranylcypromine; X =anxiety disorder and/or any personality disorder and/or any substance
use disorder.
a
Missing data in n=2 (10%).
b
Missing data in n=13 (65%).
c
Missing data in n=3 (15%).
d
Missing data in n=13 (65%).
e
Missing data in n=0.

3.3.

Course-specic parameters

First clinical symptoms related to TCP-intoxication developed on average in less than 1 day (0.5 days, range 07
days). Mean duration of clinical symptoms until symptom
relief/death was 1.9 days (range 08 days) (for details see
Tables 1 and 2).

3.4.

TCP-dosages

Mean prescribed TCP-dosage was 48.3 mg (range 10100 mg)

and the average dosage related to TCP-intoxication was
677.1 mg (range 504000 mg). The highest survived TCPdosage was 4000 mg (Pennings et al., 1997) and the lowest
fatal dosage was 170 mg (Bell and Scaff, 1963). The lowest
dosage associated with TCP-intoxication was 50 mg
(Midwinter, 1962) (in an infant) and 140 mg (in an adult)
(Fischbach, 1968). We identied n= 2 cases with prescribed

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Table 2 Time until development, clinical phenomenology and duration of TCP-intoxication.

Patients with TCPintoxication (n=20)
Mean time until development of 0.5 (range 07, median
clinical symptoms related to 0, MSD71.6)
TCP-intoxication [days]a
Frequency of symptoms related to TCP-intoxication
(multiple selection) [n/%]b
Hemorrhages
1/5%
Elevated liver enzymes
1/5%
Elevated creatine kinase
2/10%
levels
Nystagm
2/10%
Epileptic seizures
2/10%
Profuse sweating
2/10%
Thrombocytopenia
3/15%
Renal failure
4/20%
Muscular rigidity
6/30%
Delirium
9/45%
Respiratory distress
9/45%
Hyperthermia
10/50%
11/55%
Cardio-vascular systemc
Disturbance of consciousness/ 18/90%
cognitive dysfunction
1.9 (range 08, median
Mean duration of clinical
1, MSD72.3)
symptoms until death/
symptom relief [days]d
Abbreviations/legend: MSD=mean standard deviation;
TCP=tranylcypromine.
a
Missing data in n=0.
b
Missing data in n=3 (15%) (in these cases solely death was
reported).
c
Cardiac arrhythmias/cardiac arrest/hypotonia, brady-/
tachycardia.
d
Missing data in n=2 (10%).

dosages beyond the approved maximum of 60 mg (90 and

100 mg) (Chatterjee and Tosyali, 1995; Pennings et al.,
1997) (for details see Tables 1 and 2).

3.5.

Fatal vs. non fatal-intoxications

Patients with fatal intoxications (n = 10) were on average

older (41 vs. 33 years) and developed a more rapid onset of
symptoms (0.2 vs. 0.8 days). Death occurred after a mean
time of 0.6 days, while symptom relief in patients with nonfatal intoxications developed on average after 3.2 days. The
differences regarding the TCP-dosage related to intoxications (mean TCP-dosage of 483.8 mg in fatal intoxications
vs. 848.9 mg in non-fatal intoxications) result from one
single case of ingestion of a 4000 mg TCP-dosage (Pennings
et al., 1997) in the group of non-fatal intoxications. There
were no remarkable differences regarding the clinical
presentation between both groups. Further details can be
found in Table 3.

1368

M. Gahr et al.

Table 3

Comparison of fatal vs. non-fatal intoxications.

Fatal intoxications (n =10)

Non-fatal intoxications (n=10)

Patient characteristics
Mean age [years] 40.5 (range 1772, median 39, MSD719.3)
Sex
F: n=7/70%; M: n =3/30%
Duration of treatment
with prescribed
TCP-dosage [weeks]
Mean TCP-dosage
related to
intoxication [mg]
Presence of suicidal
intent
Mean time until
development of
symptoms related
to TCP-intoxication
[days]e
Mean duration of
clinical symptoms
until death/
symptom relief
[days]

0.4 (range 02, median 0, MSD70.9)a

32.8 (range 150, median 35.5, MSD715.4)

F: n= 5/50%; M: n =5/50%
12 (range 024, median 12.0, MSD716.9)b

483.8 (range 170850, median 425, MSD7274.3)c 848.9 (range 504000, median 400, MSD71244.7)d

10/100%

8/80.0%

0.2 (range 01, median 0, MSD70.4)

0.8 (range 07, median 0, MSD72.2)

0.6 (range 01, median 1, MSD70.5)f

3.2 (range 18, median 3, MSD72.6)g

Abbreviations/Legend: F=female; M=male; MSD=mean standard deviation; TCP=tranycylpromine.

a
Missing data in n=4 (40%).
b
Missing data in n=8 (80%).
c
Missing data n=2 (20%).
d
Missing data in n=1 (10%).
e
Missing data in n=0.
f
Missing data in n=10% (10%).
g
Missing data in n=1 (10%).

3.6. Treatment of TCP-intoxications, presence of

TCP-abuse/-dependence
In general, these parameters were presented mostly incomplete and with varying accurateness. Therefore they were
not assessed systematically. For details see the online
supplementary data.

4.
4.1.

Discussion

are called trace amines (Baker et al., 1992). These trace

amines facilitate effects on release and re-uptake of catecholamines and 5-HT (Baker et al., 1992; Baker et al., 1977;
Raiteri et al., 1977) and also feature neuromodulatory effects
via direct acting on catecholamine and 5-HT-receptors (Baker
et al., 1992; Jones, 1982, 1983; Paterson and Boulton, 1988;
Paterson et al., 1990). These actions together with TCP's
presynaptic amphetamine-like properties (Smith, 1980;
Tuomisto and Smith, 1986; Tuomisto et al., 1973) may explain
TCP's antidepressant properties (Baker et al., 1992; Frieling
and Bleich, 2006).

Pharmacodynamic considerations

Covalent binding of TCP to the MAO's active center reduces

the synaptic degradation of serotonin (5-HT), melatonin
and norepinephrine (through blocking of MAO-A), 2phenylethylamine and benzylamine (through blocking of
MAO-B) as well as dopamine and m- and p-tyramine (through
blocking of MAO-A and B), resulting in increased synaptic
availability of these agents (Baker et al., 1992; Billett, 2004;
Kalgutkar et al., 2001). In addition, pharmacologic inhibition
of MAOs results in an elevation of further brain amines such as
octopamine and tryptamine (Boulton and Juorio, 1982; Philips
and Boulton, 1979). Due to their low brain concentration in
comparison to norepinephrine, 5-HT or dopamine 2-phenylethylamine, m- and p-tyramine, octopamine and tryptamine

4.2. Clinical presentationdelirium and serotonin

syndrome
Currently, four core features dene delirium: a disturbance
of consciousness, a disturbance of cognition, limited course
and external causation (Blazer and van Nieuwenhuizen,
2012). However, other symptoms as psychotic features or
sleep disturbances might occur as well and may dominate
the clinical picture (Blazer and van Nieuwenhuizen, 2012).
According to this diagnostic concept delirium was
reported in n= 9 patients (45.0%) rendering delirium as
the most frequent clinical syndrome in the analyzed cohort.
No features typical for delirium related to TCP-intoxication
could be identied.

Intoxications with the monoamine oxidase inhibitor tranylcypromine

TCP-intoxications usually lead to abrupt discontinuation
of TCP-treatment. Thus, the symptoms immediately after
ingestion of the TCP-overdose might be due to elevated TCP
serum levels while the following clinical course might be
rather the consequence of TCP-discontinuation, especially
in patients with previous abuse of or dependence on TCP or
long-term TCP-treatment. At least in n = 1 patient of our
analysis the clinical course can be explained plausibly by an
intoxication followed by thus triggered TCP-withdrawal
delirium (Chatterjee and Tosyali, 1995). The sympathomimetic component of TCP on presynaptic receptors was
suggested to one possible mechanisms that could explain
the development of delirium subsequent to abrupt removal
of TCP (Dilsaver, 1990). Sudden termination of TCP treatment thus results in a decrease of norepinephrine and
dopamine in the synaptic cleft, rendering patients susceptible to the development of delirium (Dilsaver, 1988, 1990).
However, delirium not only occurs after discontinuation of
TCP, but also in the course of TCP-intoxications. In this
context, delirium might be an element of TCP-related
serotonin syndrome (Boyer and Shannon, 2005). There are
reports of TCP-related serotonin-syndrome related to additional serotonergic medication or inappropriate dietary
conditions (tyramine-rich food) (Brubacher et al., 1996;
Degner et al., 2010). Typical clinical features of serotonin
syndrome are increased heart rate, myoclonus, hyperthermia, muscular rigidity, rhabdomyolysis, overresponsive
reexes, cognitive disturbances, seizure, shock and in some
cases death (Boyer and Shannon, 2005). Several characteristics of serotonin syndrome were found frequently in our
population, especially regarding cognitive dysfunction,
hyperthermia, cardio-vascular symptoms, muscular rigidity
and renal failure. Though the majority of the symptoms
observed in the evaluated sample of TCP-intoxications are
unspecic there might be an overlap between some TCPintoxications and serotonin syndrome, at least with regard
to the clinical phenotype. However, the ndings of this
article do not allow to draw any conclusions concerning a
possible link between TCP-intoxications and serotonin
syndrome, particularly because important features of
the serotonin syndrome such as myoclonus and tremor
(Boyer and Shannon, 2005) were not reported in the
analyzed cases.

4.3.

Hemorrhages and thrombocytopenia

Though disseminated intravascular coagulation might occur

as a possible nding of severe serotonin syndrome (Boyer
and Shannon, 2005) hemorrhages in the course of TCPintoxications can be an effect independent of serotonin
syndrome. The occurrence of TCP-related thrombocytopenia was already reported in several previous case reports of
chronic TCP-overdose (Briggs et al., 1990; Chatterjee and
Tosyali, 1995; Davids et al., 2000). We observed thrombocytopenia in n= 3 (15%) and hemorrhages in n= 1 (5%) cases
of the entire cohort. The patient with the hemorrhages
(multiple subcutaneous bleedings) belonged to the three
patients with thrombocytopenia. Taking into account missing data regarding thrombocytopenia in n= 13 (65%) of the
entire cohort, the true prevalence of thrombocytopenia in
the analyzed cohort might have been higher. The underlying

1369

pathomechanisms of TCP-related thrombocytopenia are not

yet conclusively resolved. However, thrombocytopenia
could be the consequence of sympathomimetic effects
secondary to discontinuation of TCP resulting in enhanced
sequestration or pooling of platelets in the spleen (Szelnyi
and Albrecht, 1998). Moreover, thrombocytopenia might be
due to the long-term inhibition of MAO in platelets, that, in
turn, may reduce their life-span (Szelnyi and Albrecht,
1998). These considerations imply that TCP-related thrombocytopenia could be an effect of TCP-discontinuation as
well as directly substance-induced, especially by addressing
our detected case reports of patients featuring signicant
thrombocytopenia related to TCP-overdoses (Chatterjee
and Tosyali, 1995; Mawdsley, 1968; Pennings et al., 1997).
Thus, subcutaneous bleedings and thrombocytopenia can
have diagnostic value in the context of TCP-intoxication.

4.4.

TCP-dosages, suicidal intent and fatalities

The large spectrum of dosages between the highest survived

and the lowest lethal TCP-dosage in two single cases (4000
vs. 170 mg) suggests that beside the ingested TCP-dosage
also individual susceptibility factors might play a crucial
role for the clinical outcome of TCP-intoxications. However,
both observed dosages relate to single cases and are outliers
within the retrieved data. Thus they do not represent the
analyzed groups. Considering the difference between mean
survived and lethal dosages (484 vs. 849 mg) the connection
between ingested TCP-dosage and clinical effect is more
plausible. Factors that inuence serotonergic neurotransmission such as dietary conditions or serotonergic comedication were not described in detail in the analyzed
publications. The presence of such conditions in particular
cases could explain the observed spectrum of dosages in the
two outliers. Notably, we detected two cases with medically
prescribed TCP-dosages beyond the approved maximum of
60 mg (90 and 100 mg) (Chatterjee and Tosyali, 1995;
Pennings et al., 1997).
As expected the majority of intoxications were performed with suicidal intent (90%). According to the manufacturer's recommendation TCP should thus be administered
only in daily dosages up to 60 mg and close follow-up in
depressed patients with suicidal ideation.
Interestingly, fatal intoxications exclusively occurred
during the rst 2 weeks after initialization of TCP, while
all subjects who were on TCP for a longer time survived the
TCP-intoxication although the mean TCP-dosage related to
the intoxication was higher in the cohort of non-fatal
intoxications. This nding might be due to a particular
susceptibility of the human organism to toxic effects of TCP
during initialization of TCP. Furthermore it might indicate
that adaption phenomena could increase the tolerability
towards toxic effects of TCP after several weeks of
treatment.

4.5.

Limitations

Limitations of our analysis are generally based on the small

sample size. Thus, a statistically reasonable comparison
between fatal and non-fatal intoxications was not possible,
especially regarding the parameters of particular interest as

1370

M. Gahr et al.

mean TCP-dosages or time until development of rst

symptoms. Therefore, outliers are particularly skewing
mean values of the results of each group, especially
considering the time until development of rst symptoms
of 7 days reported by Chatterjee et al. (Chatterjee and
Tosyali, 1995), and the two outliers regarding the highest
survived (Pennings et al., 1997) and lowest lethal dosage
(Bell and Scaff, 1963). Another aspect resulting from
presentation of the cases from different medical perspectives (toxicology, pharmacology, forensic medicine, and
psychiatry) is the heterogeneous description of the parameters of interest that were pre-set for our analysis. It is
possible that in single cases the reported clinical symptoms
do not reect the true clinical phenomenology. Thus, the
frequencies of symptoms such as hemorrhages, thrombocytopenia or elevated creatine kinase concentrations might
actually have been higher than our analysis revealed.
Another limitation concerns the fact that it is ultimately
not possible to completely rule out the involvement of other
agents, namely food and drug interaction, within the
analyzed sample of TCP-intoxications. Especially regarding
the cohort of fatal intoxications anamnestic exploration of
the patient in terms of additionally ingested agents or
problematic food was not possible, although the exclusive
causation of the intoxication by TCP was explicitly stated in
all analyzed publications.

5.

Conclusions

Frequent ndings observed in the assessed sample of

patients with TCP-intoxications were confusion, cognitive
dysfunction, hyperthermia, muscular rigidity, cardiovascular symptoms, and occasionally death. Though we did
not identify high frequencies of hemorrhages or thrombocytopenia, theoretically these features might be present in
patients with TCP-intoxications and thus provide diagnostical value. Comparing fatal and non-fatal intoxications,
patients with fatal intoxications were older and demonstrated a faster onset of clinical symptoms related to TCPintoxication. Considering the large dose spectrum between
survived and lethal TCP-dosages in single outliers of the
analyzed data, individual susceptibility factors might play a
role regarding the severity of clinical symptoms independently of the ingested dosage.

Role of the funding source

No funding for this study was provided regarding study
design, collection, analysis and interpretation of data, the
writing of the text and the decision to submit this paper for
publication.

Contributors
Maximilian Gahr wrote the rst draft of the manuscript and
developed the study design. Roland W. Freudenmann, Markus A.
Klle and Carlos Schnfeldt-Lecuona collected and interpreted the
data. All authors contributed to and have approved the nal
manuscript.

Conicts of interest
All authors declare that they have no conicts of interest.

Acknowledgments
No acknowledgments.

Appendix A.

Supporting information

Supplementary data associated with this article can be

found in the online version at http://dx.doi.org/10.1016/
j.euroneuro.2013.05.009.

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