mise à jour du 6 décembre 2001 Unusual side effects of clomipramine associated with yawning D McLean, RG Forsythe, IA Kapkin Department of psychiatry, St John Regional Hospital, New Brunswick, Canada Canadian Journal of Psychiatry Vol 28 november 1983 Harrison W, Stewart J, McGrath PJ, Quitkin F Unusual side effects of clomipramine associated with yawning Sustained yawning as a side effect of imipramine Goldberg RL Bâillements et dépression - Yawning and depression Le bâillement: de la physiologie à la iatrogénie Yawning: from physiology to iatrogenic effect Case 1 : A married woman in her late twenties presented with a three month history of depression. Psychiatrie assessment led to a diagnosis of a unipolar depressive illness, arising in an anancastic personality. She was treated as an out-patient, with clomipramine 100 mg per 24 hours. Complete symptom remission occurred within ten days. At that point, however, the patient questioned how long she would be "allowed" to take the medication. She sheepishly admitted that she hoped to take the medication on a long terrn basis, not so much because of the symptom relief that she had experienced, but rather because she had noted that since taking the medication, every time she yawned she had an orgasm. She found she was able to experience orgasm hy deliberate yawning. With discontinuation of the medication several weeks later, this phenomena disappeared. Case 2 : A married male in his mid-twenties presented with symptoms of depression of three or four months duration. Psychiatric assessment established a diagnosis of unipolar depressive illness, occurring in a passive-aggressive personality. Treatment with clomipramine, 75 mg per 24 hours, on an out-patient basis produced complete symptorn relief within fourteen days. However, the patient was particularly ambivalent about continuing the medication, because he had noted a frequent intense urge to yawn without tiredness and that on many occasions when he yawned, he experienced orgasm, with ejaculation. He denied increased libidinal drive or related fantasy. Although he found this both awkward and embarrassing, he elected to continue the medication because of the therapeutic benefit he obtained. The awkwardness and embarrassment was overcorne by continuously wearing a condom. With discontinuation of the medication several weeks later, the phenomenon disappeared. Case 3 : A single woman in her carly forties was seen in consultation at the Department of Urology of a Regional General Hospital, where she was admitted originally with presenting complaints of renal calculus. Following proper treatment she was observed displaving depressive symptornatology for approximately four months. A psychiatric consultation established the diagnosis of a unipolar depressive illness, occurring in an obsessive-compulsive personality. Following transfer to the psychiatric unit, treatment with clomipramine 100 mg per 24 hours began and produced complete symptom relief within twelve days. At the beginning of her third week of her hospitalization, the patient began to complain of, what she termed "yawningspells" during which she experienced "unresistable sexual urges." In view of the environmental limitations and despite her occasional masturbatory relief, she found these peculiar symptoms niost difficult to tolerate and requested the psychiatrist to discontinue this medication, since she had observed that her sensations began shortly after the prescription of the medication. Discontinuation led to remission of these symptoms Case 4 : A rnarried man in his early thirties presented with symptoms of depression that lasted eighteen months. Psychiatric assessment led to a diagnosis of a pathological grief reaction, occurring in a passive-aggressive personality. An outpatient treatment regime of psychotherapy and clomipramine 50 mg per 24 hours, was initiated. The patient subsequently reported that he had stopped taking clomipramine after seven days because he had noted that every time he yawned he experienced such as intense sense of exhaustion and weakness, that he had to lie down for 10 to 15 minutes after each yawn, until the sensation subsided. This phenomenon disappeared within 48 hours after discontinuing the medication. Discussion : These reported side effects have been discovered coincidentally during routine side-effect queries. However, no placebo-replacement or challenge by clomipramine following discontinuation has been attempted. The authors are unable to explain the origins of these peculiar phenomena, coinciding with the administration of clomipramine. These cases are being reported not only for the benefit of readers who might wish to explore the origins of these occurrences, but also because of the clinical implications for patient compliance. The authors suspect that these side effects may not have been reported previously (particularly the phenomenon of orgasm) because of patientunwillingless to reveal the experience. It is suggested that all patients receiving this medication should routinely be queried about their experiences with orgasm in order to more clearly establish the frequency of this phenomenon. References Cooper-Smartt J D. A technique for surveying side-effects of tricyclic drugs with reference to reported sexual effects. J Int Med 1973; 1: 473-6. NiningerJE. Inhibition of ejaculation by amitriptyline. Am J Psychiatrv 1978; 135: 750-1. Yassa R. Sexual disorders in the course of clomipramine treatment: a report of three cases. Can J Psychiatry 1982, 27(2): 148-9. Résumé : Bien que l'on connaisse dans la littérature médicale certains cas de diminution de la puissance sexuelle comme effet secondaire des antidépresseurs (1-3), les auteurs ne connaissent aucun cas où l'on rapporte une augmentation de la capacité sexuelle du type décrit dans le présent article, ni d'instances où des effets secondaires de ce genre ont été associés au bâillement. Les auteurs font état d'effets secondaires inhabituels associés au bâillement, dans le but d'éveiller l'attention des cliniciens en ce qui touche les effets secondaires possibles des antidépresseurs; ces effets peuvent rendre les patients moins disposés à prendre ce genre de médicaments lorsque ceux-ci leur sont prescrits. Unusual Side Effects of Clomipramine Associated with Yawning W Harrison, J Stewart, P McGrath, F Quitkin Canadian J of Psychiatry 1984; vol 29, n°6; p546 McLean, Forsythe, and Kapkin (November 1983 issue) described an interesting and unusual sexual side effect observed in several patients treated with clomipramine, namely, repetitive yawning associated with spontaneous orgasm. The authors stated that they were unable to explain the mechanism for this peculiar phenomenon. We would like to suggest the following explanation for the reported side effect. Injection of ACTH-like peptides into the cerebrospinal fluid of mammals, including primates, has been shown to induce a syndrome of frequent repetition of stretching and yawing movements called the "stretching yawning syndrome" (SYS) (1). When these peptides are injected into hypothalamic areas the frequency of the reaction isincreased (2). Injection of ACTH-like peptides into the CSF of animals has also been shown to result in recurrent episodes of spontaneous penile erection and ejaculation (3).The SYS and sexual response have a similar time onset. Studies of the structure of the peptide responsible for these effects suggest that it is the esopeptide Gll-Hist-Phel-Arginyl-tryl-Glycine and that it is synthesized in the hypothalamus (3). This peptide sequence is contained in the corticotropin releasing factor (CRF) molecule. Hypothalamic release of CRF is regulated by serotonin (4). We propose that the increase in brain serotonin levels resulting from clomipramine's effect on serotonin re-uptake may stimulate released of hypothalamic CRF. The CRF relaesed has the potential to activate neural circuits responsible for the previously described behavior patterns, i.c., yawning and spontaneous sexual response. Drs Mc Lean, Forsythe and Kaplin reply We wish to express our thanks to Drs Harrison, Stewart, McGrath and Quitkin for their most interesting comments on our observation of unusual side effects of Clomipramine. Initially during the composition stage of our paper, in our literature review, we had noted the existence of a simillar stretching-yawning behaviour (SYB) and spontaneous orgasm in opium withdrawal (1). This parallel observation between Clomipramine side effects and opium withdrawal momentarily tempted us to speculate on a possibility of endorphine connection. However, we decided to leave the explanation to future careful explorations. Reference Mark S. Gold, A. Carter Pottash, Donald R. Sweeney, Herbert D. Kleber. Opiate withdrawal using clonidine (A safe effective and rapid monopiate treatment.) J AMA 1980; 243(4): 343-6.