Acute Extrapyramidal Side Effects Associated With the Combined Use of Low Doses of Haloperidol and Clarithromycin

Extrapyramidal side effects (EPS) are one of the major side effects that may frequently occur in the use of antipsychotics. EPS may cause distress and worsen the psychopathological condition. In this paper, we report a case of a 12-year-old boy with tic disorders who developed EPS after using haloperidol and clarithromycin combined.


Introduction
Antipsychotic medications are generally used in children and adolescents for bipolar disorder, depression, schizophrenia, anxiety disorders, and tic disorders.Like other drugs, antipsychotic agents may have both beneficial and adverse effects at the optimum dose used for treatment [1].One of the most important adverse effects of antipsychotic medications is extrapyramidal side effects (EPS) such as dystonia, akathisia, parkinsonism, or tardive dyskinesia [2,3].In this paper, we report the occurrence of acute EPS with haloperidol and clarithromycin use in a boy with tic disorders.

Discussion
We reported a case who developed acute EPS after using low doses of haloperidol and clarithromycin combined and relieved after biperiden injection.The occurrence of EPS in the use of only these two drugs may indicate that EPS develops due to combined use.Also, the patient did not have any medical illnesses, trauma, or history of previous EPS.
When antipsychotics block dopamine (D2) receptors, dopamine cannot prevent acetylcholine release in the nigrostriatal region.This may lead to overactivity of acetylcholine in the basal ganglia which may cause EPS [4].Dystonia, also seen in our case, is a type of EPS with sustained or intermittent involuntary muscle action.Especially in children and young adults, dystonia may occur in 25-40% of patients using firstgeneration antipsychotics (FGA) like haloperidol, chlorpromazine, or zuclopenthixol.Acute dystonia usually occurs between 24 and 48 hours of oral FGA use [5].
Haloperidol is a D2 receptor antagonist that can be used in child and adolescent psychiatry practice for a variety of clinical conditions, such as psychosis, mood disorders, or tic disorders [4].It is metabolized in the liver primarily by cytochrome P450 3A enzyme (CYP3A4) and is subsequently cleared mainly by glucuronidation [6].Clarithromycin is a macrolide antibacterial agent widely used in the treatment of respiratory tract infections and inhibits CYP3A in the liver [7].In this context, a drug interaction between haloperidol and clarithromycin via CYP3A may cause increased serum levels of haloperidol and overall antipsychotic effects.Increased antipsychotic activity with this drug-drug interaction may be related to the emergence of EPS in our case.
The use of anticholinergic medications may reduce acetylcholine overactivity resulting from D2 receptor blockade.Therefore, administration of an anticholinergic like diphenhydramine, biperiden, or benztropine may reduce EPS caused by antipsychotics [4].In emergencies, as shown in our case, studies have suggested that intramuscular anticholinergic injection may resolve EPS within 30 minutes [8].