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- mise à jour
du
- 10 avril
2025
- Therapie
- 2025 March
15
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- Unexpected
haloperidol-induced yawning while neuroleptic
switch, paradoxical reaction or dopaminergic
supersensitivity? A case report
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- Jacques Hamarda, François
Montastruc,
- Dalil Boulefaab, Julie Haybrarda, Julien Lia
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- Introduction
- Yawning is a complex stereotyped behavior
whose physiology is still poorly understood. It
can occur in various physiological situations
such as hunger, drowsiness as well as in various
pathological situations (neurological,
psychiatric or infectious diseases). Yawning is
characterized by an opening of the mouth, which
is accompanied by a long inspiration, with a
brief interruption of ventilation and followed
by a short expiration [1]. Many
neurotransmitters are involved in the yawning
process such as dopamine or serotonin. Sev- eral
drugs have been described as responsible for the
onset of excessive and disabling yawning,
including some psy- chotropic drugs
(antidepressants or dopaminergic agonists)
[1].
- We report here the case of a 28-year-old
female patient with a chronic psychotic disorder
initially treated with extended-release
zuclopenthixol who experienced intrusive yawning
when switching to haloperidol. This adverse drug
reaction seems a pharmacological paradox given
the anti- dopaminergic properties of haloperidol
in a context where other etiologies have been
eliminated. It should be noted that this adverse
drug reaction subsided after haloperidol dosage
stabilization.
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- Case report
- The 28-year-old female patient was admitted
in a psy- chiatric department during a psychotic
episode. She had previously presented an acute
psychotic episode a year ago, requiring
inpatient care for several months and the
introduction of drug treatment with amisulpride
800 mg/d, paroxetine 20 mg/d and lorazepam 1
mg/d. She had no somatic medical history, no
family history of somatic or psy- chiatric
disorders.
- The patient was admitted to the psychiatric
emergency unit for a recrudescence of psychotic
symptoms after sev- eral weeks of
discontinuation of medication. On admission, she
presented with major psychic disorganization,
acoustic and verbal hallucinations, distrust,
and persecutory feel- ing towards care. Because
she refused any oral treatment, zuclopenthixol
with semi-prolonged action at 100 mg, an
injection every 72 h was initiated. A relay by
zuclopenthixol with prolonged action at 200 mg
every 2 weeks was carried out one month after
the beginning of the inpatient care. This drug
treatment allowed a significant clinical
improvement with a regression of persecutory and
hallucinatory symp- toms but a persistence of
some delirious symptoms. It was therefore
decided to switch the zuclopenthixol to per os
haloperidol. Haloperidol was introduced as part
of a cross- over switch at 1 mg a day, then very
gradually increased to 4 mg on 3 weeks.
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- Two weeks after haloperidol introduction,
while the dosage of this drug was 2 mg/d, the
patient started to present invasive yawning,
objectified during the medical interviews
(20&emdash;30 per hours), which she described as
dis- abling. The patient did not experience
sedation, and the yawning appeared continuous
throughout the day. The neu- rological
examination was unremarkable, and the patient
had no jaw pain or signs of dislocation. It
should be noted that there were no other
treatments introduced or sus- pended that could
be suspected of causing this adverse drug
reaction. The patient complained of yawning for
several days, which progressively regressed
until it completely dis- appeared 4 days after
having reached the target dosage of haloperidol
(i.e. 4 mg/d).
- This case was reported on December 24, 2024
to the regional pharmacovigilance center in
Toulouse at number 2024002352 [2].
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- Discussion
- Drug-induced yawning is a rare and usually
not serious adverse drug reaction. Several
psychotropic drugs have been found to be
potential providers of invasive yawning. A
pharmacovigilance study conducted on the French
pharma- covigilance database by Sommet et al.
found 28 cases of yawning reported between 1985
and 2004 in France. The study found 38 suspected
drugs, including several serotonergic drugs
(serotoninergic reuptake
inhibitors&emdash;SRIs), dopaminergic agonists,
benzodiazepines and opioids. It should be noted
that only one case involving a neurolep- tic
drug was described, which was zuclopenthixol
[3]. Yawning induced by drugs may
nevertheless have major functional consequences.
Indeed, a few serious cases of jaw dislocation
as well as vascular accidents have been reported
in the literature in connection with excessive
yawning [4].
- The neurophysiology of yawning is complex
and not entirely elucidated. One of the major
cerebral structure participating in yawning is
the paraventricular nucleus (PVN) of the
hypothalamus, also referred to as the yawn- ing
center of the brain [1,5]. Several
neurotransmitters are involved in this
phenomenon. Acetylcholine is the last effector
at the muscle level and might be triggered
through 3 distinct pathways. The most studied
pathway seems to be that of oxytocin neurons,
which can be acti- vated by dopamine, glutamate,
nitric oxide and oxytocin or conversely
inhibited by gamma aminobutyric acid (GABA) or
µ-opioids. Other pathways, independent of
the first, could involve serotonergic pathways
or the adrenocorti- cotropic
hormone/alpha-melanocyte stimulating hormone
(ACTH/_ MSH) pair whose final effector remains
acetyl- cholin.
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- Neuroleptics, with dopaminergic antagonist
activity, are known to inhibit yawning
[6], notably haloperidol (antag- onist
of D2 and D3 receptors) [7]. Some
findings suggest that the induction of yawning
is mediated by the selec- tive activation of D3
receptors whereas the inhibition of yawning is
mediated by the concomitant inhibition of D2
receptors [6]. Thus, this case report
raises several ques- tions about the nature and
pharmacological mechanisms of this disorder. It
is conceivable that this adverse drug reaction
is related to a paradoxical effect of haloperi-
dol, by antagonism of presynaptic dopamine
receptors, thus inhibiting the negative feedback
of dopaminergic neurons. Another hypothesis can
be a dopaminergic supersensitivity reaction.
Indeed, during prolonged exposure to a dopamin-
ergic antagonist, an up-regulation of dopamine
receptors can occur, manifested by an increase
in the density of receptors as well as the
emergence of ''supersensitive'' receptors
[8]. Stopping the dopaminergic
antagonist drug can then cause a withdrawal
phenomenon due to the pres- ence of these
''supersensitive'' receptors [8,9].
Thus, in our case, it could be that the
reduction in dopaminergic- antagonism coverage
imposed by the change of neuroleptic drug could
have transiently increased dopaminergic trans-
mission. This phenomenon could be responsible
for the appearance of the adverse drug reaction
observed until haloperidol stabilization and
thus reaching saturation of dopaminergic
receptors. All the more so as the clinical
examination does not point to a neurological or
psycholog- ical differential diagnosis. One
hypothesis would be that neuroleptic coverage
would make it possible to avoid this
supersensitivity phenomenon and thus prevent the
appear- ance of such yawning. From a
pharmacokinetic point of view, it is likely that
neuroleptic withdrawal may have provoked a
paradoxical reaction, hence the importance of
cross-switching two different antipsychotics as
indicated in the recommendations for good
practice. As the half-life of zuclopenthixol is
20 hours, the chronology of the appear- ance of
yawning, although surprising, remains plausible
[10,11].
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- Conclusion
- To the best of our knowledge, this is the
first case report- ing yawning due to a
neuroleptic drug switch. This rare and atypical
clinical situation occurred during a drug
treatment change. If the involvement of
haloperidol is probable due to chronological
arguments, this case allows us to question the
underlying pharmacological mechanism and to warn
clini- cians about the possible appearance of
this adverse drug reaction after change or
initiation of neuroleptics
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