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mise à jour du
6 juin 2002
J Clin Psychopharmacol
Repeated observations of yawning, clitoral engorgement, and orgasm associated with Fluoxetine administration
Jack G. Modell
University of Michigan School of Medicine, Ann Arbor, Michigan, USA
Bâillements et dépression - Yawning and depression
Le bâillement: de la physiologie à la iatrogénie
Yawning: from physiology to iatrogenic effect
Fluoxetine, a bicyclic propylamine antidepressant, is a potent and highly selective inhibitor of the presynaptic reuptake of serotonin and has been reported to have fewer troublesome effects than the tricyclic antidepressants. I report a case in which this agent appeared to induce repeatedly the side effects of yawning in the absence of drowsiness and multiple orgasms associated with clitoral engorgement in the absence of voluntary sexual stimulation. Yawning is listed as a frequently occurring side effect of fluoxetine in the product literature; however, no reports of spontaneously occurring orgasms or clitoral engorgement in association with fluoxetine administration were found.

The patient was a bright, 30-year-old woman who presented for treatment of a major depressive episode in December, 1987. The depression was of moderate severity, melancholic type, with seasonal pattern, and without psychotic features (DSMIII-R criteria). She was free of active medical and gynecologie problems, and had no history of sexual dysfunction. No medications, other than the prescribed antidepressants, were taken during the following periods of observation.

Depressive symptoms responded well to an initial trial of nortriptyline, and the patient remained symptom-free for the following 3 months on doses of 75- 100 mg daily. The medication produced neither yawning nor sexual side effects. The patient did, however, suffer a 30% increase in weight above her previous ideal body weight during the 3 months on nortriptyline, and she therefore requested a change in medication to an agent less prone to induce weight gain.

Nortriptyline was discontinued, and after a 2-week drug-free period, fluoxetine (Prozac) was prescribed at a starting dosage of 20 mg orally every morning, followed by a dosage increase after 1 week to 40 mg every morning. The lower dosage produced no side effects. Within 2 days following the dosage increase, however, the patient noted the onset of frequent yawning, without sensations of drowsiness, and "several, little-tingly orgasms, for no apparent reason." Orgasms were further described as occurring in a typical slow-crescendo, rapid-decrescendo intensity of sensation, and preceded by clitoral engorgement (non-painful) associated with the physical sensation of sexual arousal. Both the yawning and orgasms returned each morning following medication ingestion, continued for several hours, and disappeared by mid-afternoon. The patient reduced the dosage to 20 mg every morning after 1 week of these symptoms, complaining that the yawning was interfering with normal activity; both the yawning and the sexual feelings disappeared within 1 day of the dosage decrease. The yawning was spontaneously reported by the patient at follow-up 4 weeks after the onset of the symptom; the sexual symptoms were elicited upon asking whether she had experienced any unusual sexual sensations while taking the medication. No other side effects were reported.

Interested in understanding these unusual reactions further, the patient agreed to perform a prospective trial of increasing fluoxetine dosage in an attempt to determine whether there might be a true causal relationship between the medication and these side effects. The patient kept notes during these trials, with special attention to the timing of side effects in relation to medication ingestion and to each other; and to the frequency, intensity, and association of side effects with other symptoms. Orgasms were scaled in intensity from 1 - 10, with 1 signifying very mild, just detectable, and 10 signifying extremely intense, overwhelming.

Having been on fluoxetine 20 mg every morning for the previous 2 weeks, the patient took 40 mg the following morning. Sixty minutes later, she began yawning at an approximate rate of four yawns/minute, and again, the yawning was not associated with drowsiness. The yawning gradually decreased in frequency and intensity over the following 30 minutes, and then disappeared. Five minutes after the yawning began, the patient experienced a feeling of sexual arousal and fullness in the genital region, associated with clitoral engorgement (verified visually by the patient). Three minutes later, she experienced an orgasm of intensity level 5, followed by seven spontaneous orgams over the next 45 minutes that gradually decreased in intensity until they disappeared. Orgasms persisted for 5 minutes following the cessation of yawning, and the two symptoms did not appear to the patient to be causally linked. The patient then stopped the medication entirely because she developed a sinus infection, and did not want this to confound the outcome of the study. She remained off the fluoxetine for the next 2 weeks, and had neither side effects nor return of depressive symptoms during this period.

The patient then abruptly resumed 40 mg of fluoxetine taken orally every morning, and remained on this dose for the next 7 days. Responses to medication over this week were as follows. Day 1 (also first day of menses): From 55 to 110 minutes following ingestion, the patient experienced 24 separate orgasms, intensity 1-3. Yawning commenced at the same time as the orgasms, but ceased after 15 minutes of approximately two yawns/minute. Day 2: Yawning, 1-4/minute, began 50 minutes after medication ingestion, and continued throughout the day and evening. There were no sexual sensations. Days 3-7: Yawning began 60 mintues after ingestion, persisted about 4 hours on day 3, and gradually waned in frequency and duration over this 4-day period; there were no sexual sensations. On the eighth day following resumption of fluoxetine, the patient increased the dosage to 60 mg (single dose) in the morning. Sixty minutes later, the sexual arousal and clitoral engorgement returned, and was followed by 13 orgasms over the next 50 minutes, with gradually decreasing intensity from a level of 5 to 1. Yawning began 5 minutes after the onset of the orgasms, and persisted at a rate of about 2/minute for 20 minutes before disappearing. The saine pattern and frequency of symptoms occurred after 60 mg fluoxetine on the ninth day. On the 10th day, the patient experienced minimal yawning and no orgasms after taking 60 mg of fluoxetine. She then stopped taking the medication, and she bas had no further unusual yawning or sexual sensations during the 7 months since its discontinuation. All orgasms experienced by this patient were preceded by at least a few minutes of sexual arousal and clitoral engorgement. No increased libidinal drive or sexual fantasy preceded the onset of sexual symptoms. Clitoral engorgement was present for up to several hours each day, but it was never painful. Vaginal lubrication did not occur during feelings of sexual excitation. Neither the frequency of masturbation nor intercourse appeared to alter the nature or frequency of the sexual symptoms. Yawning occurred despite adequate sleep and feeling well rested. Consistent with the variable temporal association between the yawning and sexual sensations, the patient found no direct relationship between these symptoms. Depressive symptoms remained in remission throughout treatment with fluoxetine and did not return until September, 5 months after fluoxetine discontinuation; the patient is, however, usually free of depression during the suminer months.

This report illustrates an apparent causal relationship - occurring on four separate occasions in one patient - between the administration of fluoxetine, and involuntary yawning, clitoral engorgement, and multiple spontaneous orgasms. A very similar coincidental occurrence of yawning and multiple orgasms early in the course of drug treatment has been reported with the tricyclic antidepressant clomipramine. Clomipramine shares with fluoxetine the potent inhibition of presynaptic serotonin reuptake as a mechanism of action, although clomipramine treatment also inhibits norepinephrine reuptake. Trazodone, a triazolopyridine antidepressant with mixed serotonergie agonist and antagonist activity, bas caused sustained penile erections - possibly related mechanistically to the clitoral engorgement observed in this case.

Yawning may be induced in experimental animals by administration of serotonergic or cholinergic agonists, and may be inhibited by dopamine agonists: a reciprocal balance of serotonergic activation, dopaminergic inhibition, and cholinergic activation appears to be involved in the phenomenon.The neurochernistry of the sexual response is somewhat more complicated, and involves complex interrelationships among various neurotransmitter system. Serotonergie systems have been implicated in the regulation of sexual response, although data are conflicting as to whether the role of serotonin is primarily inhibitory, excitatory, or possibly mixed according to the receptor subtype stimulated. Interestingly, the symptom dyad of yawning and penile erection has been induced in rats by administration of a dopamine agonist, but no reports were found in which both sexual arousal and yawning were induced by a purely serotonergie agent.

As serotonin agonism is the one element common to the acute administration of fluoxetine, clomipramine, and trazodone, as well as to the neurochernical regulation of yawning and sexual arousal, it seems likely that the side effects, observed in this patient occurred secondary to acute increases in central serotonergie neuronal activity. The yaning of symptoms on an established dosage of fluoxetine, and their reappearance upon dosage increase, are consistent with this mechanism, of action.

It was the yawning and not the clitoral engorgement or sexual sensations that most disturbed this patient; the initial presence of the sexual side effects was not spontaneously reported by the patient and might have been missed had she not been specifically questioned about unusual sexual symptoms in association with the yawning. Also, although clitoral engorgement was never painful in this patient, mechanistic similarities between clitoral and penile engorgement provide that a similar neuropharmacologic action of this drug in the male might, induce priapism. A better understanding of the associations between serotonin, yawning, and sexual stimulation; and of the relevance these associations may have to the pathophysiology of depression, may be possible as further experience with the potent serotonergic psychopharmacologic agents is acquired.


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Donald F. Klein, New York State Psychiatric Institute New York
J Clin Psychopharmacol 1989; vol 9; n°5; p384
Modell, reports a case of an apparent causal relationship between fluoxetine and involuntary yawning, clitoral engorgement, and multiple spontaneous orgasms that occurred on four separate occasions in one female patient. He suggests that these effects occurred secondary to acute increases in central serotonergic neuronal activity.
An alternative mechanism is brought to mind by the fact that yawning and spontaneous orgasms are a common feature of opiate withdrawal. Therefore, fluoxetine in this patient may be causing a process analogous to endogenous opiate withdrawal. A fairly large clinical experience with fluoxetine indicates that for most patients it is sexually inactive, wehereas for some it is a sexual and orgiastic depressant. Therefore, the patient with spontaneous orgasms and yawning must be manifesting some idiosyncratic aspect of her biology rather than simply responding to a common central serotonergic effect. That there is some relationship between opiate response and serotonin physiology has been widely discussed.
Wikler A. Opiate addiction: psychological and neurophysiological aspects in relation to clinical problems. Springfield, Il.: Charles C.Thomas, 1953.
Reply from Dr. Modell
I wish to thank Dr. Klein for pointing out that the yawning and spontaneous orgasms during fluoxetine administration reported by my patient are also observed during opiate withdrawal, and for suggesting as an alternative interpretation that fluoxetine in this patient may have caused a process analogous to endogenous opiate withdrawal. Of note, this patient had no other signs or symptoms that are commonly observed during opiate withdrawal. Dr. Klein's conclusion, however that because fluoxetine more commonly does not affect, or suppresses, sexual function, "the patient with spontaneous orgasms and yawning [therefore] must be manifesting some idiosyncratic aspect of her biology rather than simply responding to a common central serotonergic effect"---does not necessarily follow.
For the many reasons discussed in my letter, I believe that serotonergic mechanisms probably were directly involved; additionally the neurophysiologic relationships between serotonergic and opiate systems pointed out by Dr Klein might make possible that an interaction between these systems might have led to the observed side effects. I maintain that further experience,with the potent serotonergic psychotropic agents, as well as a more complete understanding of the complexities of the serotonergic systems of the brain, will be necessary before such definitive conclusions regarding the mechanisms of actions of these agents can be made.