How do you dose ophthalmic atropine for sialorrhea secondary to recently started aripiprazole?

How do you dose ophthalmic atropine for sialorrhea secondary to recently started aripiprazole?

Comment by InpharmD Researcher

While a comprehensive literature search did not reveal aripiprazole-induced sialorrhea treated with ophthalmic atropine, one randomized trial reported successful administration of two drops of atropine sulfate 1% (600 mcg) sublingually in reducing salivary secretion rate in patients with clozapine-induced hypersalivation. Available case reports primarily use oral trihexyphenidyl or diphenhydramine to resolve frequent drooling associated with aripiprazole.

Background

A 2019 systematic review evaluated the sublingual use of atropine as a potential treatment for clozapine-induced sialorrhea (CIS). The majority of literature included in this review consisted of case reports, with only one randomized controlled trial. Four case reports described either complete resolution or immediate improvement in CIS after receiving atropine 1% sublingually. Doses used in these case studies included two drops twice daily and one to two drops once daily. Case studies of sialorrhea not associated with clozapine were also included. One of these case reports of a severe head trauma patient described a 50% reduction in secretion, intraoral, and oropharyngeal accumulation of saliva. Another case report described the beneficial effects of one drop of 0.5% atropine sublingually (0.25 mg every six hours). [1]

An open-label trial including 25 children with cerebral palsy found that 0.5% atropine administered three times/day (six-hour intervals) resulted in significant improvement. Two pilot studies also showed a significant reduction in salivation. The lone randomized, controlled, cross-over trial included 22 patients receiving two drops or 0.5 mg of atropine every six hours for drooling not related to clozapine, which failed to prove the effectiveness compared to a placebo. Xerostomia was mentioned in some case reports as a potential side effect. The review authors concluded that atropine appears to be safe and effective for CIS treatment; however, large-scale randomized trials with systematic evaluation of symptoms were required to confirm the systemic absorption of atropine. [1]

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

How do you dose ophthalmic atropine for sialorrhea secondary to recently started aripiprazole?

Level of evidence

X - No data Read more→

Please see Tables 1-6 for your response.

The Effect of Sublingual Atropine Sulfate on Clozapine-Induced Hypersalivation: A Multicentre, Randomised Placebo-Controlled Trial
Design	Randomized, multicenter, double-blind, placebo-controlled trial N= 21
Objective	To measure the effect and safety of sublingual (SL) atropine sulfate when used for the treatment of nocturnal clozapine-induced hypersalivation (CIH) and clozapine-induced drooling (CID)
Study Groups	Chloramphenicol 0.5% SL drops (placebo; n= 11) Atropine sulfate 1% SL drops 600 μg (n= 10)
Inclusion Criteria	Clozapine-treated hospitalized patients at participating psychiatry centers, age ≥ 18, hypersalivation or drooling after starting clozapine assessed by physician
Exclusion Criteria	Known allergy to atropine or chloramphenicol, contraindication to study medication, failure to follow study instructions
Methods	Participants were randomized to receive either 600 μg sublingual atropine sulfate 1% drops or placebo (chloramphenicol 0.5% eye drops). Baseline saliva rate secretion was measured 1 hour after dinner. Cotton rolls and saliva pads were placed under the tongue and below the lower lip for 1 minute to dry out the mouth; pre-weighted cotton rolls and saliva pads were then placed in the mouth for 5 minutes, after which they were re-weighed. Two drops of SL atropine were administered, and after 2 hours, the cotton rolls and saliva pads procedure at 1 and 5 minutes was repeated to measure the post-medication saliva rate. Food, flavored drinks, and gum were not allowed 1 hour prior to saliva collection and 30 minutes after administering the atropine. A version of the Sialorrhea Clinical Scale for PD was used to assess the severity of hypersalivation and drooling and response to atropine. A Sleep-Time Sialorrhea Assessment was used to assess the impact of CIH and CID on participants' sleep on the night of the study in comparison to the previous night. The questionnaire also assessed saliva throughout the night based on pillow wetness. Vital signs were measured prior to administration of the intervention and for 120 minutes after in 30-minute intervals.
Duration	August 2017-March 2019
Outcome Measures	Primary Outcome: salivary secretion rate Secondary Outcomes: participants' satisfaction with atropine treatment and effects of atropine on vital signs (blood pressure [BP], pulse rate)
Baseline Characteristics		Atropine (n=10)	Placebo (n=11)
	Age, years	41 ± 12.4	36 ± 10.8
	Male	6 (60%)	7 (64%)
	Total saliva secretion over 5 min, grams	3.07 ± 1.05	2.57 ± 1.74
	Total drooling screening score	3.8 ± 2.39	4.4 ± 2.20
	Clozapine dose, mg/day	285 ± 122.0	380 ± 162.7
	Clozapine plasma level	385.3 ± 204.2	447.1 ± 253.6
	Current cigarette smokers	6 (60%)	4 (36%)
	CIH onset after initiation of clozapine First week Second week Third week Fourth week > Four weeks Unknown	5 (50%) 0 3 (30%) 0 1 (10%) 1 (10%)	6 (54.5%) 0 0 0 2 (18.2%) 3 (27.3%)
Results	Endpoint	Atropine (n= 10)	Placebo (n= 11)	Difference in percentage change (95% confidence interval)	p-value
	Salivation secretion rate change Rolls Pads Total	-37.47% -26.09% -34.45%	48.03% 29.28% 22.75%	- 85.50 (-157.58 to -13.42) - 55.37 (-131.45 to 20.72) - 57.21 (-104.30 to -10.11)	0.023 0.144 0.020
	Patients' satisfaction Hypersalivation score decreased Drooling score decreased Pillow wetness less or dry Positive effect on sleep	(n= 6) 3 (50%) 3 (50%) 4 (66%) 4 (66%)	(n= 4) 3 (50%) 2 (33%) 2 (33%) 2 (33%)
	Vital signs Sitting systolic BP at 90 minutes Sitting systolic BP at 120 minutes Sitting diastolic BP at 30 minutes Sitting diastolic BP at 120 minutes Standing systolic BP at 60 minutes Standing systolic BP at 120 minutes Standing diastolic BP at 60 minutes Standing diastolic BP at 120 minutes Standing pulse at 60 minutes			Not significant 6.27% (1.44 to 11.11) -8.5% (-13.77 to -3.24) Not significant Not significant Not significant 8.6 (2.33 to 14.81) Not significant -5.8 (-9.54 to -2.15)	- 0.011 0.002 - - - 0.007 - 0.002
Adverse Events	Common Adverse Events: N/A
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions	The present study finds that a small dose of sublingual atropine drops reduces the rate of saliva secretion significantly better than placebo. A paradoxical increase in saliva secretion was recorded in only one participant in the atropine group. A reduction in sitting diastolic blood pressure was recorded in patients treated with sublingual atropine. No difference could be found between the saliva secretion changes measured through cotton rolls compared with saliva pads.
InpharmD Researcher Critique	Although the study found statistically significant results, the sample size was small and may have limited the generalizability of the results. Future studies using radiolabelled atropine and ultrasonography would help to examine correlations between local atropine absorption and distribution to the salivary glands. This present study was also an overnight study; studies extended throughout several nights would help to determine the long-term effect of atropine.

References:

Mubaslat O, Lambert T. The effect of sublingual atropine sulfate on clozapine-induced hypersalivation: a multicentre, randomised placebo-controlled trial. Psychopharmacology (Berl). 2020;237(10):2905-2915. doi:10.1007/s00213-020-05627-4

Quetiapine-Induced Hypersalivation
Design	Caes report
Case presentation	A 36-year-old woman of Korean descent with a 16-year history of schizoaffective disorder was admitted to the adult psychiatric medical care unit with a relapse of mania with psychosis. Her symptoms included elated mood, grandiose delusions of being a Power Ranger, disorganized behavior, and decreased need for sleep, which had been managed with clozapine without noticeable side effects except for increased sedation. During the current hospitalization, the patient refused to take clozapine and received risperidone instead. Within a few days of initiation, the patient developed extrapyramidal symptoms with rigidity, dystonia, and slurring of speech, leading to discontinuation of the risperidone. Three days afterward, quetiapine 25 mg BID was commenced, but patient developed increased salivation within one day, which was worsened with further dose titration to quetiapine 50 mg BID. The patient was drooling most of the day, and all of her clothing was wet. As a trial of benztropine (1 mg PO BID) and atropine eye drops (0.1%) sublingually failed to reduce the hypersalivation, quetiapine was stopped, and 1 day after, hypersalivation resolved. Given the temporal relationship between the administration and discontinuation of quetiapine and the onset and cessation of the patient's hypersalivation, it is possible that the hypersalivation was induced by the quetiapine.
Study Author Conclusions	Quetiapine and clozapine both share blocking affinity at α₂-adrenergic receptors, whereas only clozapine has agonist properties at the M₄ receptor. We thus propose that α₂-adrenergic blockade is the mechanism for quetiapine-induced hypersalivation. Further study is needed to draw definite conclusions regarding this proposed relationship.

References:

Allen S, Hoffer Z, Mathews M. Quetiapine-induced hypersalivation. Prim Care Companion J Clin Psychiatry. 2007;9(3):233. doi:10.4088/pcc.v09n0311a

Aripiprazole-induced sialorrhea
Design	Case report
Case presentation	A 27-year-old single male from the eastern part of India was diagnosed with bipolar affective disorder and was experiencing a current episode of mania with mood-congruent psychotic symptoms. He was given valproate sodium tablet 1 g/day. Due to his persistent psychotic symptoms (grandiose and persecutory delusions), aripiprazole tablet 10 mg/day was initiated, leading to symptomatic improvements. However, the patient started to develop sialorrhea 3 months into aripiprazole treatment and would feel an excess of saliva in his mouth almost throughout the day. Frequent drooling was noticeable, especially during the night and after waking up in the morning from sleep, invariably the side of his chin would be wet with saliva. Additionally, a wet spot of around 8 cm in diameter of soaked saliva would be observed over his pillow daily. To control the drooling, the patient would continuously swallow his saliva to save himself from embarrassment. There was no associated sign suggestive of extrapyramidal syndrome. The decision was made to initiate trihexyphenidyl tablet 2 mg/day, and patient responded to it within a week. A significant reduction in drooling was noticed, and he no longer woke up with a wet chin or soaked pillow.
Study Author Conclusions	In the presented case, the most likely mechanism for hypersalivation is through central α2-adrenergic antagonism, similar to that reported with quetiapine and risperidone. Trihexyphenidyl was effective in controlling hypersalivation by reestablishing the balance between adrenergic and cholinergic levels through muscarinic receptor blockade. Aripiprazole may rarely produce troublesome sialorrhea, which responds to low doses of anticholinergics.

References:

Praharaj SK, Jana AK, Sinha VK. Aripiprazole-induced sialorrhea. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(2):384-385. doi:10.1016/j.pnpbp.2008.12.016

Insights into the pathophysiology of aripiprazole-induced sialorrhoea: A case report
Design	Case report
Case presentation	A 35-year-old married Hindu lady presented with an acute onset of suspiciousness, fearfulness, and sleep disturbances, and she reported persecutory and referential ideas and probable delusions for a week, likely related to a financial stressor. Based on the symptoms and Brief Psychiatric Rating Scale (BPRS) score of 44, the patient was diagnosed with Acute and Transient Psychotic Disorder (ATPD), with moderate level of illness and polymorphic type. The patient was initiated on risperidone 2 mg/day for a week in the outpatient setting, which led to reduced psychotic symptoms (BPRS= 30) but induced mild tremors of outstretched hands. Thus, the patient received trihexyphenidyl 2 mg/day for suspected extrapyramidal symptoms (EPS). While her psychotic symptoms continued to improve (BPRS=22) after 2 weeks, she started to experience galactorrhoea without EPS, which was deemed to be associated with risperidone after ruling out other causes. As such, the decision was made to stop trihexyphenidyl and cross-tapered risperidone with aripiprazole tablet 10 mg/day. There were no signs and symptoms of galactorrhea or EPS after the switch, but she now complained of excessive drooling of saliva from her mouth. It was throughout the day but more at night while sleeping. In the mornings, her pillow would be soaked with saliva (approximately 5–10 cm diameter of saliva-soaked patch). Assessment of drooling with the Drooling Severity Scale (DSS) showed moderate severity, and the patient had to swallow frequently throughout the day to control her symptoms. The otolaryngologist consultation did not reveal any abnormality, and trihexyphenidyl 2 mg/day was added back while maintaining aripiprazole at the same dosage. By the subsequent follow-up after a week, her sialorrhoea had complete improvement. There was no EPS, galactorrhoea, or psychotic symptoms.
Study Author Conclusions	Researchers consider sialorrhoea to be related to aripiprazole and galactorrhoea to be related to risperidone due to temporal association, clinical features, and laboratory investigations. Naranjo Adverse Drug Reaction Probability Scale (NADRPS) for galactorrhoea was +6, and sialorrhoea was +5. The authors contemplate that aripiprazole-induced sialorrhoea may be due to an imbalance of adrenergic and muscarinic pathways, and this can be successfully treated with trihexyphenidyl. They also raise an important question of whether these adverse effects in the same patient show a general sensitivity towards antipsychotic-related adverse effects.

References:

Nayok SB, Maurya R, Akshatha H S D, Malleshwara Thimmaiah S. Insights into the pathophysiology of aripiprazole induced sialorrhoea: A case report. Schizophr Res. 2021;228:227-228. doi:10.1016/j.schres.2020.12.019

Aripiprazole-Induced Sialorrhea Responsive to Diphenhydramine Treatment
Design	Case report
Case presentation	A 14-year-old boy with diagnoses of moderate intellectual disability and cerebral palsy was admitted to the child and adolescent psychiatry outpatient clinic by his parents with complaints of self-injurious behaviors, irritability, aggression, and hyperactivity. His disruptive behaviors were managed with risperidone 0.25 mg BID, but the medication was subsequently discontinued by his mother due to severe sedation. Aripiprazole 2.5 mg/day was then initiated and increased to 5 mg/day in the 2nd week. While his mother reported significant improvement in his disruptive behaviors at the next clinic visit in 4 weeks, sialorrhea was observed, leading to drooling most of the day. His clothing was becoming soaked with saliva during the daytime and his pillow during sleep. According to his mother’s report, his sialorrhea began when the dose of aripiprazole was increased to 5 mg/day. His physical examination showed normal gait, no muscular rigidity, and no symptoms of esophageal dysfunction. Considering the benefits of reducing his descriptive behaviors, the provider decided to add diphenhydramine 12.5 mg BID to the treatment, and his sialorrhea resolved significantly within 1 week.
Study Author Conclusions	Authors presented a patient who experienced sialorrhea during aripiprazole treatment and remitted after diphenhydramine treatment. Based on the temporal relationship between administration of aripiprazole and the onset of sialorrhea, it is possible that the sialorrhea was associated with aripiprazole. To our knowledge, this is the first report of a pediatric patient with aripiprazole-induced sialorrhea that was remitted with diphenhydramine administration. Clinicians should be aware that aripiprazole may induce sialorrhea, and should monitor their patients for this potentially troublesome adverse effect. Diphenhydramine may be a therapeutic option for patients having sialorrhea when treated with aripiprazole.

References:

Kılınç S, Hergüner A, Hergüner S. Aripiprazole-Induced Sialorrhea Responsive to Diphenhydramine Treatment. J Child Adolesc Psychopharmacol. 2016;26(8):767-768. doi:10.1089/cap.2015.0133

Paliperidone-Associated Sialorrhea
Design	Case report
Case presentation	A 56-year-old Black male with schizoaffective disorder, intellectual disability, hypertension, hypothyroidism, hyperlipidemia, and diabetes mellitus type 2 was admitted to an acute psychiatric facility with a 1-week history of altered mental status, minimal oral intake, increased rigidity, and sialorrhea. His current medications included paliperidone, palmitate 234 mg every 4 weeks, paliperidone 6 mg daily, and benztropine 1 mg daily. The patient was readmitted 18 days after a 2-week stay in the facility, with disorganization, worsening behavioral problems, word-salad, clang associations, auditory hallucinations, delusions, coarse tremor (bilateral, left greater than right), sialorrhea, and sparse oral intake. The patient reported not missing any doses of paliperidone palmitate, but the patient was intermittently adhering to oral paliperidone. Lorazepam, initially started for catatonia as well as rigidity, mutism, and decreased oral intake, was discontinued after 3 days due to inefficacy. For the patient's sialorrhea, atropine 1% ophthalmic drops sublingually at a dose of 2 drops every 3 hours while awake was reported to be effective. Benztropine was increased 1 mg by mouth twice daily to treat tremors and sialorrhea. Additionally, a 9-hydroxyrisperidone (paliperidone) level was drawn before the next monthly dose and showed a supratherapeutic level of 133.4 ng/mL (reference range, 20 to 60 ng/mL). For this reason, in addition to ongoing psychiatric symptoms, a decision was made to discontinue the long-acting injection of paliperidone and cross-taper the oral paliperidone to aripiprazole 5 mg daily plus divalproex extended-release 1,000 mg nightly. Oral aripiprazole was titrated up to a dose of 30 mg daily, but due to continued mania symptoms, was reduced to 15 mg daily while quetiapine 100 mg nightly was added and subsequently titrated to a total daily dose of 600 mg. Atropine drops were discontinued after 5 days, and benztropine was discontinued after 12 days. However, the patient's sialorrhea returned 2 and a half weeks after discontinuing the atropine drops and 5 days after discontinuing benztropine. Oral olanzapine was also given for breakthrough agitation on 3 consecutive days before sialorrhea recurrence. Atropine drops at a dose of 1 drop sublingually three times daily were reinitiated with subsequent improvement. The patient remained on atropine drops until discharge after a 40-day stay with improvement in clinical status. During the most recent follow-up, the patient was noted to be well-maintained on divalproex, quetiapine, and aripiprazole with no reported sialorrhea.
Study Author Conclusions	The presented patient experienced sialorrhea, likely as a result of supratherapeutic paliperidone levels, possibly secondary to the high dose in combination with decreased renal function. Although commonly associated with clozapine or first-generation antipsychotics, there have been reports of paliperidone causing this adverse effect within adverse event databases, as well as in a few case reports. Although the precise mechanism of paliperidone-associated sialorrhea is unknown, proposed mechanisms include α adrenergic, neurokinin 1, and dopaminergic receptor upregulation and supersensitivity. Further studies on antipsychotic-associated sialorrhea are warranted. It is important for clinicians to be aware of the possibility of sialorrhea caused by paliperidone and other second-generation antipsychotics, especially given the increased frequency of their use for a variety of psychiatric disorders.

References:

Burk BG, Donaldson V, Jackson CW, Cates ME, Birur B. Paliperidone-Associated Sialorrhea: A Case Report With Review of Current Literature. J Clin Psychopharmacol. 2022;42(5):480-484. doi:10.1097/JCP.0000000000001588