Abstract Yawning, frequent in daily
life, is accepted as a complex arousal reflex.
Excessive yawning may be due to neurological,
psychiatric, infectious, gastrointestinal or
metabolic diseases. This reflex has also been
associated with different selective serotonin
reuptake inhibitors. We report a female patient,
with excessive yawning, who was on selective
serotonin reuptake inhibitor treatment with the
diagnosis of generalised anxiety disorder. She
was then found to have endometrial carcinoma.
Her complaints of palpitation, shortness of
breath and loss of energy might be explained by
a psychiatric disease and/or anaemia. Previous
anaemic periods and partial response of her
psychiatric symptoms during last 3 years alerted
us to think about an organic cause.
Investigations for chronic disease anaemia
resulted in diagnosis of endometrial carcinoma.
This case is a good example showing misdiagnosis
caused by medical stigmatisation.
Introduction
Yawning, frequent in daily life, is accepted
as a complex arousal reflex located in the
reticular brainstem with both peripheral and
central arches. Although its mechanisms and
functional role are still quite a mystery to
science, animal experiments have shown the
involvement of several neurotransmitters
(dopamine, acetylcholine, adrenocorticotropic
hormone, oxytocine, serotonin, neuropeptides,
hypocretin and sexual hormones) in its
generation and modulation (Alóe, 1994;
Daquin, et al., 2001).
Excessive yawning is defined as a
compulsive, repetitive action that is not
triggered by appropriate stimuli such as fatigue
or boredom. It may be due to neurological,
psychiatric, infectious, gastrointestinal or
metabolic diseases. However, drugs such as
serotonin reuptake inhibitors (SSRI) may also
cause excessive yawning (Beale and Murphree,
2000; Gutierrez-Alvarez, 2007; Sommet, et al.,
2007). In this study, we report a female
patient, with excessive yawning, who was on SSRI
treatment with the diagnosis of generalised
anxiety disorder (GAD), and she was then found
to have endometrial carcinoma.
Case report
A 68-year-old woman was admitted to
Psychiatry Department of Uludag University
Medical Faculty with the complaints of yawning,
restlessness, irritability, tension, loss of
energy, hand tremor, palpitation and shortness
of breath. Her complaints leading to her
hospitalisation started when she was 20-year
old. She had 8 (including the recent one)
relapses with the same complaints that were
always triggered by different stress factors and
responded well to treatment with different
antidepressants prescribed by different
psychiatrists. Between every two relapses, she
was in full remission without any need for
medication except for the last 3 years.
During the last 3 years, she received low
doses of various antipsychotics, different
anxiolytics, carbamazepine and antidepressants
like venlafaxine, mirtazapine, trazodone,
nefazodone, tianeptine sodium and chlomipramine.
Full remission was not accomplished even though
different treatment strategies were tried.
Patient received the diagnosis of GAD, as
determined on the basis of the Diagnostic and
Statistical Manual of Mental Disorders, fourth
edition, Text Revision (DSM-IV-TR) (American
Psychiatric Association, 2000). She was put on
intravenous diazepam (because of her intensive
and severe anxiety) and biperidene chlorhydrate
treatment (because of cog wheel rigidity on her
wrists as a consequence of 0.5 mg/day
haloperidol use) for a week. On the 8th day of
her hospitalisation, her treatment was switched
to citalopram 20 mg/day, lorazepam 3 mg/day and
biperidene 4 mg/day. On the 14th day, dosage of
citalopram was increased to 40 mg/day because
her anxiety continued, and biperidene was
discontinued because of disappearance of
rigidity.
On the 20th day of her hospitalisation,
because her anxiety did not respond to lorazepam
administration, lorazepam was replaced by
clonazepam 6 mg/day. Her medical history
included anaemia that was corrected with iron
supplementation 2 years ago and hospitalisation
because of her psychiatric problems. Her general
physical and neurological examinations were
normal except her pale appearance. Complete
blood count showed anaemia with haemoglobin (Hb)
of 9.2 g/dL (12.20&endash;18.10). She was
referred to Haematology Department for
consultation. Blood picture repeated because of
Haematology Department's suggestion showed Hb
9.11 g/dL (12.20&endash;18.10), MCV 61 fL
(80&endash;97), MCH 19.5 pg (27&endash;31.20),
MCHC 32 g/dL (31.8&endash;35.4), white blood
cell count 9.8 * 109 L-1 with 65%
polymorphonuclear leucocytes, 26% lymphocytes,
7% monocytes, 1% eosinophiles and 1% band
leukocyte differentiation and a platelet count
of 358 * 109 L-1. Reticulocyte count was 2%.
Erythrocyte sedimentation rate was 33 mm/h
(2&endash;10 mm/h). Biochemistry tests were
normal except for low total protein (6.2 g/dL).
Iron level was low (33 ?g/dL; 150&endash;450),
ferritine level was high (436 ng/mL;
5&endash;148), iron binding capacity (332 ?g/dL;
15&endash;450), vitamin B12 (453 pg/mL;
211&endash;911) and folic acid levels (6.5
ng/mL; 5&endash;20), Hb electrophoresis (HbA1:
96.2%, HbA2: 3.8%) and tumour markers (CA125:
9.0 U/mL, CA19&endash;9: 18.0 U/mL, CA15.3: 25.0
U/mL, ?-fetoprotein: 1.0 IU/mL, carcinoembrionic
antigen: 3.4 ng/mL) were within normal
limits.
Peripheral blood smear showed hypochromia,
micrositosis, anisositosis, polichromasia and
basophilic punctuation. Chronic disease anaemia
was diagnosed and diagnostic work-up included
abdominopelvic and transvaginal ultrasound
examinations, which showed a 45 * 30 mm solid,
heterogeous hypoechoic lesion within the
endometrial cavity. She was referred to
Obstetrics and Gynaecology Department for
consultation. Biopsy taken was compatible with
grade 2 endometrial adenocarsinoma. On the 57th
day of her hospitalisation, she was admitted to
Obstetrics and Gynaecology Department. A total
abdominal hysterectomy with bilateral
salpingo-oophorectomy and omentectomy was done.
She received six courses of
vincristine/doxorubicin/ paclitaxel
chemotherapy. After 4 years of surgery, she is
alive with no evidence of endometrial carcinoma
or anxiety symptoms and yawning.
Discussion
Yawning has been related to different SSRIs
(Beale and Murphree, 2000; Daquin, et al., 2001;
Gutierrez-Alvarez, 2007; Sommet, et al., 2007).
Occurrence of yawning largely varies from 30 min
to several months after drug introduction and
remits following SSRI discontinuation or dose
reduction. At first sight, possible explanations
of intensive and severe yawning in our patient
seemed to be related to either presence of
anxiety and depression (Daquin, et al., 2001) or
SSRI use.
Previous history of disappearance of yawning
upon resolution of depression and anxiety with
SSRI treatment guided us to think that only SSRI
use would not explain that pathological yawning.
That is why we insisted on SSRI treatment. Most
prominent symptoms of our patient during her
hospitalisation were treatment resistant anxiety
and yawning. This last clinical picture seemed
to be different from her other episodes because
sufficient dose of SSRI and high doses of
anxiolytic did not suppress her anxiety. We
started to search for an other cause especially
an organic (because anaemia might explain
palpitation, shortness of breath and loss of
energy) one.
Presence of anaemia in her blood picture
resulted in consulting the patient with a
haematologist who found that this anaemia was
resulting from a chronic disease. In our case,
further investigations for chronic disease
anaemia resulted in diagnosis of endometrial
carcinoma. In the 1960s, Ashley Montagu centred
the aim of yawning on the reversal of brain
hypoxia or hypoxemia. Although Dr Provine, in
1987, showed that giving people additional
oxygen did not decrease yawning, and decreasing
the amount of carbon dioxide in a subject's
environment also did not prevent yawning
(Provine, et al., 1987), we think underlying
anaemia causing chronic hypoxia may be
responsible for our patient's severe yawning and
treatment resistant anxiety. Disappearance of
symptoms following correction of anaemia after
oncological intervention supports our idea.
Another explanation of excessive yawning in
our patient may be due to association of
oxytocin (OT) with both yawning and endometrial
carcinoma. OT, the hypothalamic peptide secreted
by the neurohypophysis, acts on target cells
binding to specific G-protein-coupled receptors
(OTRs). The OTR gene has in fact been described
in human non-pregnant endometrial, human primary
breast carcinomas, human primary neuroblastomas
and astrocytomas. OT is suspected to have
regulatory effect on endometrial tumour growth.
(Cassoni, et al., 2000; Daquin, et al., 2001).
Although we do not have OT level for our
patient, her excessive yawning may be linked to
production with OT, which was possibly expressed
in her endometrial carcinoma cells. Two years
previous to her hospitalisation, our patient had
the diagnosis of anaemia that was not thought as
a cause of her signs and symptoms.
Because she had similar problems for 20
years, organic pathology was not thoroughly
searched. Repeated anaemic periods and partial
response of her psychiatric symptoms during last
3 years should have alerted physicians to think
about other masquerading causes. A person with
psychiatric problems unfortunately becomes
stigmatised. Every sign and symptom of that
person can be ascribed to his psychiatric
disease leading to delay in diagnosis of the
underlying problem. Organic pathology must be
excluded before attributing them to a person's
psychiatric disease. It should be kept in mind
that human being is a biopsychosocial entity,
and biological, psychological and social factors
altogether play a significant role in human
functioning in the context of disease or
illness. The biopsychosocial model presumes that
it is important to handle the three together. As
in our case, we must consider that a patient's
repetitive complaints may have different
etiologies. Medical stigmatisation of our
patient led to delay in diagnosis of malignancy
as real reason of her anaemia because her
complaints were attributed to her psychiatric
disease.
References
Alóe, F
(1994) Yawning. Arq Neuropsiquiatr 52:
273&endash;276.
American Psychiatric Association (2000)
Diagnostic and Statistical Manual of Mental
Disorders, fourth ed, Text Revision. Washington,
DC: American Psychiatric Association.
Beale, MD, Murphree,
TM (2000) Excessive yawning and SSRI
therapy. Int J Neuropsychopharmacol 3:
275&endash;276.
Cassoni, P, Fulcheri, E, Carcangiu, ML,
Stella, A, Deaglio, S, Bussolati, G (2000)
Oxytocin receptors in human adenocarcinomas of
the endometrial: presence and biological
significance. J Pathol 190: 470&endash;477.
