Aripiprazole and Unexpected Salivation: A Case of Drug-Induced Sialorrhea Refractory to Anticholinergics

Introduction

Sialorrhea, characterized by excessive drooling due to an inability to control saliva can significantly impact an individual’s quality of life by affecting their physical health, emotional well-being, and daily functioning. Sialorrhea can arise from various factors including inflammation, gastroesophageal reflux disease, and neurological conditions such as Parkinson’s Disease. ¹ Among these, drug-induced sialorrhea is a known potential adverse reaction that can occur from antipsychotics, antidepressants, and other psychotropic drugs. Antipsychotic-induced sialorrhea pathophysiology is non-specific with agonism of muscarinic receptors (M1 and M3) and antagonism of alpha-2 adrenergic receptors are described as the most common mechanisms.^2,3 Aripiprazole, a second-generation or atypical antipsychotic, is used to treat various conditions including schizophrenia and bipolar I disorder. In a large EudraVigilance analysis, aripiprazole was associated with salivary hypersecretion (286 cases) indicating a notable reporting signal for aripiprazole-induced sialorrhea. ⁴ There have been previous case reports of aripiprazole-induced sialorrhea which resolved with anticholinergic treatments including diphenhydramine, ⁵ trihexyphenidyl ⁶ and amitriptyline. ⁷ We report a patient case of aripiprazole-induced sialorrhea responsive to treatment with alpha-2 adrenergic agonism after failing multiple anticholinergic therapies.

Discussion

The autonomic nervous system contributes to sialorrhea, with the parasympathetic pathway affecting cholinergic systems and the sympathetic pathway affecting adrenergic systems. These pathways stimulate salivary production through muscarinic and alpha receptors, respectively. ⁸ There are two mechanisms in which sialorrhea can occur, through inability to clear secretions or through overproduction of saliva. The overproduction of saliva can be attributed to the agonism of both M1 and M3 acetylcholine muscarinic receptors as well as antagonism of the alpha 2-adrenergic receptors.^2,3 Salivary production is carried out by acinar cells. Acinar cells are divided into serous and mucous types, with serous cells secreting enzyme-rich saliva for digestion and mucous cells for oral lubrication. Myoepithelial cells surround the acinar cells and assist with contraction to help release saliva into the ducts. ⁸

Aripiprazole is an atypical antipsychotic with a broad pharmacological profile. It functions as a potent partial agonist at the serotonin 5-HT1A receptor and dopamine D2 receptors while displaying limited antagonistic activity at the alpha adrenergic, H1 histamine, and 5-HT2A serotonin receptors. Additionally, it acts as an inverse agonist at the 5-HT2B receptor and a partial agonist at the 5-HT2A, 5-HT2C, 5-HT7, D3, and D4 receptors.^9,10 Aripiprazole exhibits moderate affinity for antagonizing both alpha-1 and alpha-2 adrenergic receptors but this blockade rarely results in notable adverse effects. Dexmedetomidine and clonidine are potent alpha-2 adrenergic agonists with a high binding affinity to these receptors. The addition of selective alpha-2 adrenergic agonism would occupy alpha receptor sites over aripiprazole and counteract adverse effects that aripiprazole may have been exerting. ¹¹ Although sialorrhea is rare among antipsychotics other than clozapine, several treatment options are available including trihexyphenidyl, clonidine, benztropine, atropine, and diphenhydramine. ¹² These agents commonly target receptors associated with sialorrhea by blocking muscarinic and histaminic receptors or acting as adrenergic agonists to counteract any antagonism within the adrenergic system. Attempts to treat our patient’s sialorrhea with anticholinergic medications, including scopolamine patches, atropine sublingual drops, and oral glycopyrrolate were ineffective. After the initiation of dexmedetomidine, subjective improvements in secretion volume and suctioning frequency were reported suggesting a sympathetic-driven sialorrhea refractory to anticholinergics.

There are several mechanisms that may have contributed to the patient’s refractory sialorrhea. Aripiprazole has intrinsic activity at dopamine receptors estimated to be around 25% which means that its ability to antagonize dopamine receptors is limited to about 75%. ¹⁰ This partial agonist effect allows dopamine receptors to have some level of activation but does not produce the full effects of dopamine agonists. Since dopamine can modulate cholinergic activity by influencing the release and action of acetylcholine, we hypothesized that this partial activation of dopamine receptors can lead to only partial or limited cholinergic activity. This could explain why anticholinergic medications which target muscarinic receptors directly did not effectively resolve sialorrhea in this case. Instead, it suggests that a different mechanism such as an influence on the alpha-adrenergic pathway could be contributing to sialorrhea.

The active metabolite of aripiprazole, dehydroaripiprazole, has a long half-life of approximately 94 h. It can take about 15-18 days (5-6 half-lives) for the drug to be fully eliminated from the body once steady-state levels are reached. ¹⁰ The patient was started on aripiprazole 20 mg daily two months prior to admission with no information on whether a titration was provided. Considering this, it is plausible that the high dose and prolonged presence of the drug contributed to the persistence of sialorrhea even after discontinuation. Considering the patient’s 24-day hospital stay, it is likely that some improvement in sialorrhea could have occurred naturally as the drug was gradually cleared from the system. However, the significant and rapid reduction in secretions observed immediately after the initiation of dexmedetomidine, an alpha-2 adrenergic agonist, suggests that this medication played a key role in managing the symptoms. This observation led to the consideration of clonidine, another alpha-2 adrenergic agonist, which was subsequently introduced and resulted in a gradual improvement in sialorrhea eventually facilitating the patient’s discharge. The Naranjo Adverse Drug Reaction Probability Scale was utilized to evaluate the potential link between aripiprazole and the patient’s sialorrhea. This case was deemed a possible dose-dependent adverse drug reaction based on a score of 4. Factors include temporal association with aripiprazole, symptom improvement after discontinuation, objective evidence, and offset by potential alternative causes. This case is limited by several factors including the lack of an objective measurement of sialorrhea (Drooling Severity and Frequency Scale) and an incomplete psychiatric medication history making it difficult to fully characterize the severity and potential contributors to the patient’s symptoms. Additional limitations include not assessing an alternative glycopyrrolate formulation to address its poor oral bioavailability and not implementing a scheduled atropine regimen. These limitations may prevent us from conclusively determining whether anticholinergic agents were ineffective in controlling sialorrhea. Despite the rarity of sialorrhea with aripiprazole use, this case highlights the importance of considering antipsychotic-induced sialorrhea when other causes have been ruled out.

Conclusion

While aripiprazole has minimal antagonistic properties at the adrenergic receptor, it is still possible that it could contribute to the occurrence of sialorrhea in certain cases. Although aripiprazole is primarily known for its partial agonism at dopamine D2, serotonin 5-HT1A, and 5HT2A receptors, its potential to contribute to sialorrhea should not be entirely disregarded. In cases of antipsychotic-induced sialorrhea, discontinuation or dose reduction of the offending drug should be considered the first-line approach to minimize symptoms. If sialorrhea persists, the prompt administration of anticholinergic agents such as glycopyrrolate, scopolamine, or atropine is appropriate for management. However, if sialorrhea is refractory to these treatments, addressing alpha-adrenergic antagonism may also be necessary depending on the causative agent. Clinicians should be vigilant about the risk of antipsychotic-induced sialorrhea and consider appropriate treatment adjustments to minimize its occurrence to improve patient outcomes.

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