mise à jour du
9 juin 2008
J Psychopharmacol
Pathological yawning in a patient with anxiety
and chronic disease anaemia
Taskapilioglu O, Akkaya C, Sarandol A, Kirli S.
Neurology Department, Uludag University Medical Faculty, Bursa, Turkey


Bâillements et dépression - Yawning and depression
Le bâillement: de la physiologie à la iatrogénie
Yawning: from physiology to iatrogenic effect
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.
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.
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.
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