ADVERSE DRUG REACTION
Hypersensitivity syndrome caused by amitriptyline
administration
Haralampos J Milionis, Antigone Skopelitou, Moses S Elisaf
Abstract
Adverse cutaneous manifestations are
among the most common side eVects
associated with psychotropic drugs. Skin
reactions due to amitriptyline (a tricyclic
antidepressant agent) include rashes and
hypersensitivity reactions (for example,
urticaria and photosensitivity) as well as
hyperpigmentation. Hypersensitivity syn-
drome is a specific severe idiosyncratic
reaction causing skin, liver, joint, and
haematological abnormalities, which usu-
ally resolve after the discontinuation of
the implicated drug. A case of a 24 year old
woman who experienced hypersensitivity
syndrome three weeks after the initiation
of amitriptyline is reported.
(Postgrad Med J 2000;76:361–363)
Keywords: tricyclic antidepressant drugs; amitriptyline;
adverse cutaneous reactions; hypersensitivity syndrome
Psychotropic agents, such as mood stabilising
drugs, antidepressants and antianxiety drugs,
have been in widespread use since mid-1950s.
Among the most common side eVects associ-
ated with their use are those involving the skin.
1
It is estimated that skin reactions caused by
psychotropic drugs are twice as frequent as
those caused by most other drugs.
1
Amitriptyl-
ine is a tricyclic antidepressant agent pre-
scribed for the management of depressive
illness, particularly when sedation is required.
Adverse cutaneous manifestations related to
amitriptyline include rashes and hypersensitiv-
ity reactions (for example, urticaria and
photosensitivity).
1
Hypersensitivity syndrome is a specific
severe idiosyncratic reaction causing skin, liver,
joint, and haematological disturbances. Cer-
tain drugs have been incriminated.
2
We report
the case of a 24 year old woman who
experienced hypersensitivity syndrome three
weeks after the initiation of amitriptyline.
Case report
A 24 year old woman was referred to the emer-
gency department because of erythroderma
and fever. She was receiving amitr iptyline 25
mg orally twice daily because of mild depres-
sion for three weeks when she noticed a pruritic
morbilliform rash on the trunk. Her past medi-
cal history was unremarkable.
On admission she was anxious and febrile
(38.3°C), blood pressure was 110/65 mm Hg,
pulse rate 125 beats/min, and respiration rate
was 23 breaths/min. On physical examination,
generalised erythroderma with mild scaling (fig
1) was evident. There was also cervical
lymphadenopathy, but no hepatomegaly or
splenomegaly.
The electrocardiogram showed sinus tachy-
cardia; a chest radiog raph was nor mal. Com-
plete blood count showed: packed cell volume
0.45, white blood cell count 29 × 10
9
/l, with
neutrophils 40%, lymphocytes 30%, mono-
cytes 5%, and eosinophils 25% (absolute
number of eosinophils 7.25 × 10
9
/l). The plate-
let count was 210 × 10
9
/l; erythrocyte sedimen-
tation rate 10 mm/hour; and C reactive protein
12 mg/l. Serum aspartate aminotransferase was
87 U/l (normal range 0–40 U/l) and alanine
aminotransferase 103 U/l (normal range 0–40
U/l). Other laboratory investigations gave
results within normal limits. Serological tests
for syphilis, cytomegalovirus, Epstein-Barr
virus, hepatitis A, B, and C, HIV, human T cell
leukaemia virus (HTLV)-I, and HTLV-II were
negative. Urinalysis as well as urine and blood
cultures were also negative.
An ultrasound of the abdomen and an
echocardiogram showed no abnormalities.
A bone marrow specimen showed a normal
erythroid cell line, normal megakaryocytes,
and a remarkable increase of eosinophils in the
Figure 1 Erythroderma after three weeks of amitriptyline
initiation (reproduced with the patient’s permission).
Postgrad Med J 2000;76:361–363 361
Department of
Internal Medicine,
Medical School,
University of Ioannina,
GR 451 10 Ioannina,
Greece
H J Milionis
A Skopelitou
M S Elisaf
Correspondence to:
Dr Elisaf (e-mail:
Submitted 14 June 1999
Accepted 8 October 1999
myeloid cell line. The myeloid to erythroid cell
line ratio was 5:1.
Skin biopsy disclosed sites of basal cell layer
hydropic degeneration and the presence of
melanin within macrophages in the upper der-
mis (pigmentary incontinence). A moderate
inflammatory eosinophilic infiltration was
found perivascularly and round skin append-
ages (fig 2). These findings were consistent
with a drug induced eruption.
Amitriptyline was discontinued. Pred-
nisolone 25 mg daily was administered intrave-
nously for seven days, tapered over the follow-
ing week. Five days after amitriptyline
withdrawal, the patient was afebrile. The rash
became exfoliating with generalised scaling
from the head downwards. An emollient euser-
ine cream was applied. A month later, skin
lesions and blood tests normalised.
Discussion
Amitriptyline administration has been associ-
ated with skin rashes and hypersensitivity reac-
tions, such as urticaria and photosensitivity as
well as hyperpigmentation.
1
The rapidly pro-
gressive pigmentation has been attributed to
the synergistic eVect of amitriptyline and
minocycline, potentiating the functional dis-
ruption in cellular activity that leads to
hyperpigmentation.
3
Hypersensitivity syndrome refers to a spe-
cific severe idiosyncratic reaction. The syn-
drome typically includes skin rash and fever,
often with hepatitis, arthralgias, lymphaden-
opathy, or haematological disorders (mainly
eosinophilia and atypical lymphocytosis).
2
Hy-
persensitivity syndrome develops two to six
weeks after a drug is initiated, a period that is
significantly longer than that seen with other
drug associated skin reactions.
2
For example,
Stevens-Johnson syndrome or drug induced
vasculitis usually appear one to three weeks
after a drug’s first dose.
24
Because of its
relatively late onset, slow evolution, and clinical
similarities with many infections (principally
viral), the diagnosis of hypersensitivity syn-
drome may be delayed. Certain drugs, such as
antiepileptic agents (phenytoin, car-
bamazepine, and phenobarbital), allopurinol,
gold salts, dapsone, and sulphonamides have
been reported to be associated with hypersen-
sitivity syndrome.
256
Hypersensitivity syn-
drome due to either antiepileptics or sulphona-
mides are clinically indistinguishable.
2
In
addition to exfoliating dermatitis, atypical lym-
phoid hyperplasia, pseudolymphoma, hepati-
tis, interstitial nephritis, and haematological
abnormalities (eosinophilia and
mononucleosis-like atypical lymphocytosis)
have been described in relation with phenytoin
and carbamazepine treatment.
26
Like replicating viruses (for example
Epstein-Barr vir us), drugs such as phenytoin,
carbamazepine and sulfamethoxazole, stimu-
late major T cell subgroups, while drug
specific T cell clones (mainly CD4+ and
CD8+) may be generated.
7
Fur thermore, drug
specific T cells secrete in vitro remarkably high
amounts of interleukin-5, which is mainly
involved in the maturation of eosinophils.
7
Since amitriptyline shares a common tr icyclic
nucleus with carbamazepine, the aforemen-
tioned immunological mechanisms may be
implicated in the pathogenesis of hypersensi-
tivity syndrome. It is also of interest that a
genetically determined inability to detoxify the
toxic arene oxide metabolic products of
anticonvulsants, including carbamazepine, has
been documented in many (but not all) hyper-
sensitivity syndrome patients.
28
Cells from
family members of aVected patients show an
increased in vitro sensitivity to these toxic
metabolites.
8
Drug withdrawal usually leads to total
recovery, although rash and hepatitis may per-
sist for weeks.
2
However, in patients receiving
antidepressants, abnormal liver function tests
in isolation represent a significant problem to
the clinician. These disturbances fall into two
categories: predicted dose related (for example
suicidal overdose) and dose independent idio-
syncratic (immune mediated) drug reactions.
9
The latter is usually the case with antidepres-
sive agents. Clinical manifestations vary widely
from minor elevations of aminotransferases to
acute severe hepatitis.
9
Corticosteroids have
been widely advocated in the management of
hypersensitivity syndrome, despite the lack of
controlled studies.
10
Although erythema multiforme, ang ioneu-
rotic oedema, and hyperpigmentation have
been rarely described in patients treated with
amitriptyline,
13
to the best of our knowledge,
hypersensitivity syndrome related to am-
itriptyline administration has not as yet been
reported. Moreover, neither the manufacturer
(Dambergis-Tropon) nor the committee of
adverse drug eVects of the National Drug
Organisation are at present aware of reports of
such a side eVect.
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2 Roujeau JC, Stern RS. Severe adverse cutaneous reactions
to drugs. N Engl J Med 1994;331:1272–85.
Figure 2 Skin biopsy: a site of “pigmentary incontinence” and mild eosinophilic
infiltration (haematoxylin and eosin × 40) consistent with the diagnosis of drug induced
eruption.
362 Milionis, Skopelitou, Elisaf
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Hypersensitivity syndrome caused by amitriptyline administration 363
