its effect is mediated via interactions with several receptors in the central nervous system and results from a combination of antidopaminergic , anticholinergic , antihistaminic , and weak antiadrenergic actions .
the therapeutic effects of chlorpromazine are frequently accompanied by unwanted side effects that include sedation , autonomic , endocrine , and neurological effects . to date
tinnitus is a common adverse reaction ( adr ) to several drugs and may occur during long - term therapies or after a single drug administration .
even though not life threatening , tinnitus may be discomforting ; it may also be irreversible despite drug withdrawal .
to date , over 130 drugs have been described to be potentially ototoxic , among which the most common inducers of tinnitus are aminoglycosides and other antimicrobials .
we report on a suspect adr to chlorpromazine that occurred in a 12-year - old boy , affected by severe generalized anxiety disorder .
he received initially a benzodiazepine therapy , which was switched to chlorpromazine ( 6.25 mg / day orally ) because of the absence of a significant clinical response .
ten days after treatment with chlorpromazine , the patient experienced an enhanced sensitivity to sounds accompanied by perception of noises of the buzzing or ringing type .
information about the patient 's medical history did not report conditions that may have predisposed to the onset of the disturbance manifested .
moreover , the patient was in overall good health and had never suffered from hearing disorders . in view of the medical history ,
the inability to discontinue therapy with chlorpromazine resulted in an objective worsening of the patient 's symptoms , which are still present to date .
the naranjo adr probability scale identified the relationship between the patient 's development of adr and the drug as  possible . 
this is the first report on a case of tinnitus related to the administration of chlorpromazine .
chlorpromazine is an antagonist of several dopamine cochlear receptors that play an important role in the sensory process by modulating afferent auditory nerve activity .
dopamine , released from the terminals of lateral olivocochlear efferent fibers , is protective against acoustic trauma , hypoxia , and ototoxicity . in this context
, the dopamine antagonist activity of chlorpromazine may result in a higher risk of ototoxicity .
it controls the cochlear blood flow , acting on the precapillary sphincters and increasing the microcirculatory flow .
clinical evidence indicates that h1 histamine agonists are effective in reducing tinnitus via improving vestibular compensation of the microcirculation .
chlorpromazine antagonism on h1-receptors may thus play a role in counteracting the vessel modulatory effect of histamine and by this means have contributed to tinnitus development in our patient .
acetylcholine is the major neurotransmitter in the olivocochlear efferent pathway , which is a feedback control system to the inner ear comprising a medial olivocochlear pathway projecting to outer hair cells and a lateral olivocochlear pathway projecting to dendrites of cochlear nerve fibres . in this context , the anticholinergic effects of chlorpromazine may have inhibited efferent signalling via the 9/10 nicotinic acetylcholine receptor complex in the outer hair cells which is known to be protective against acoustic injury .
another action of chlorpromazine that may have contributed to generate tinnitus in our patient is its antagonism of serotonergic receptors .
serotonin is one of the neurotransmitters acting on the auditory pathways ; in particular it is involved in sound detection , location , and interpretation .
serotonin is currently believed to be one of the most important neurotransmitter involved in the perception of tinnitus .
indeed , serotonin reuptake inhibitor drugs reduce the intensity of tinnitus acting directly on nerve conduction of the auditory stimulus , particularly in the central auditory pathways . in this scenario , it is thus conceivable that antagonism at serotonin receptor levels caused by chlorpromazine causes auditory disorders leading to tinnitus .
finally , a role for an action of chlorpromazine on gamma amino butyric acid ( gaba ) can not be excluded .
gaba inhibits auditory system and systemic administration of a gaba transaminase inhibitor improves tinnitus by suppressing hyperactivity in the auditory system .
the neurotransmitter serotonin , involved in a large variety of physiological functions , behaves as a neuromodulator by strengthening the gaba system .
chlorpromazine , by decreasing the availability of serotonin , may lead to decreased gabaergic activity and this action may have contributed to tinnitus development .
we can not establish which among the actions of chlorpromazine described above has been predominant in the tinnitus - inducing action we observed , and the most likely possibility is that tinnitus resulted from a synergism among these different actions .
a predisposition of the patient to develop tinnitus following chlorpromazine can not also be ruled out .
receptors for serotonin , histamine , dopamine , and gaba are polymorphic and the presence of specific single nucleotide polymorphisms that acted as predisposing factors may be present in this specific patient .
in addition chlorpromazine is substrate of cytochrome p4502d6 ( cyp2d6 ) , a highly polymorphic isoform of cytochrome .
genetically determined functional variations of this cytochrome may be present in the patient and may also have contributed to the onset of tinnitus .
to our knowledge , this is the first report on the development of tinnitus following chlorpromazine administration .
although there is no information on dechallenge and rechallenge , the inability to discontinue therapy with chlorpromazine resulted in an objective worsening of the patient 's symptoms .
this clinical case is of great clinical interest as chlorpromazine is not currently included among potentially ototoxic drugs ; paradoxically phenothiazines can be prescribed to alleviate symptoms related to disorders of the vestibular system .
 chlorpromazine is a well - known antipsychotic agent that binds with a variety of receptors in the central nervous system . to date 
 , chlorpromazine has never been associated with onset of hearing disorders and tinnitus . 
 we report on an unexpected suspect adverse reaction to chlorpromazine that occurred in a 12-year - old boy , affected by severe generalized anxiety disorder . 
 after treatment with chlorpromazine , the patient experienced an enhanced sensitivity to sounds accompanied by perception of noises of the buzzing or ringing type . 
 this clinical case is of great clinical interest as chlorpromazine is not currently included among potentially ototoxic drugs . 