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.
References
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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.
