Funding/financial disclosures. The author has no conflicts of interest relevant to the content of this letter. No funding was received for the preparation of this letter.

Innov Clin Neurosci. 2023;20(4–6):9–10.

Dear Editor:

Aripiprazole is one of the most widely prescribed atypical antipsychotics, and its use in children and adolescents has become common. Aripiprazole has shown efficacy in children and adolescents with schizophrenia, bipolar disorder, Tourette syndrome, and behavioral disorders associated with autism and has the advantage of fewer metabolic and motor side effects than other medications.1 However, we recently reported an adolescent female patient who suffered from a certain type of extrapyramidal symptoms (EPS) called aripiprazole-induced open bite.2 The patient, a 27-year-old female, was treated for depression with aripiprazole and developed open bite. The four main causes of open bite are thumb or pacifier sucking, tongue protrusion, temporomandibular joint disorder, and skeletal problems, but the patient had an unexplained malocclusion without these causes. Her open bite developed in association with the timing of aripiprazole medication and tended to worsen with increasing aripiprazole dosage and improve with decreasing dosage. 

Open bite is a type of malocclusion in which the upper and lower teeth do not touch when the mouth is completely closed, leaving a gap between them, and is treated jointly by orthodontics and psychosomatic dentistry (Figure 1).3,4 If open bite is not treated, it can result in speech disorders, such as lisp, increased wear of the back teeth, and physical complaints, such as stiff shoulders and headaches.5 Open bite is often based on dental abnormalities, but can also be caused by tension in the masseter muscle due to antipsychotic drugs, such as haloperidol, even in the absence of dental abnormalities.6 

Aripiprazole, even at low doses, can cause open bite as a symptom of EPS in adolescent patients. In a meta-analysis of aripiprazole treatment in 2,114 pediatric patients in 41 studies, the incidence of EPS was 17.1 percent (95% confidence interval [CI]: 0.128–0.223), and in a subgroup analysis of placebo-controlled studies, the risk of EPS with aripiprazole was significantly higher versus placebo with an odds ratio of 3.85 (95% CI: 2.37–6.28 ).7 Aripiprazole-induced EPS in children and adolescents has been observed at nonnegligible levels. In an experiment with juvenile rats, aripiprazole administration increased D2 receptor expression and sustained amphetamine-induced behavioral changes, indicating that aripiprazole functions as a robust D2 blocker in the developing brain and is likely to cause EPS in children.8

Although the exact mechanism by which aripiprazole causes EPS is unknown, I believe that aripiprazole reduces intracellular dopamine signaling at the molecular level. When the receptor and ligand interact, the conformation of the receptor changes. When the agonist attaches to the receptor, the receptor takes on the agonist’s conformation and intracellular signaling is initiated. The dopamine D2 receptor is a G protein-coupled receptor (GPCR). When agonists bind to the dopamine D2 receptor, a conformational change in the alpha-subunit (Gα) occurs, causing guanosine diphosphate (GDP) to be released and guanosine triphosphate (GTP) to bind instead, becoming the active form and transmitting dopamine signaling. Although studied with cariprazine, D2 partial agonists dissociate less Gα than dopamine, resulting in weaker dopamine signaling.9 At the same time, GPCRs are phosphorylated and β-arrestins attach, resulting in β-arrestin signaling. GPCRs are then coated with clathrin and translocated into the cytoplasm, where internalization leads to desensitization.10 Desensitization is a phenomenon in which intracellular signaling by agonists is attenuated from the initial response. Binding of partial agonists to D2 receptors results in weaker signaling than dopamine both in the G protein pathway and internalization of D2 receptors in the β-arrestin pathway. Consequently, when partial agonists act on D2 receptors, they reduce dopamine signaling at the molecular level more than dopamine, depending on the degree of action of these intracellular systems (Figure 2). 

 In clinical practice, aripiprazole’s potential to induce EPS in pediatric and adolescent patients has been ignored due to its favorable side effect profile.1 In children and adolescents, the brain is still developing, so the phenotype of EPS may also appear unexpectedly in the form of an open bite. Aripiprazole administration in children and adolescents should be closely monitored for the appearance of all types of EPS.

References

  1. Coustals N, Ménard ML, Cohen D. Aripiprazole in children and adolescents. J Child Adolesc Psychopharmacol. 2021;31(1):4–32.
  2. Sumi S, Nagamine T, Sumi K, et al. Case report: open bite as an extrapyramidal side effect with aripiprazole, a dopamine partial agonist. Front Psychiatry. 2022;13:976387. 
  3. Feres MF, Abreu LG, Insabralde NM, et al. Effectiveness of the open bite treatment in growing children and adolescents. A systematic review. Eur J Orthod. 2016;38(3):237–250.
  4. Suga T, Nagamine T, Tu TTH, et al. Orthognathic surgery for patients with neurodevelopmental disorders requires careful decision-making by a multidisciplinary team. Innov Clin Neurosci. 2022;19(4–6):9–10.
  5. Kulkarni GV, Lau D. A single appliance for the correction of digit-sucking, tongue-thrust, and posterior cross bite. Pediatr Dent. 2010:32(1):61–63.
  6. Nakamura H. A case of the drug induced open bite in a patient with schizophrenia. J Jpn Soc Dentist Med Compromised Patient. 2007;16:149–154. 
  7. Bernagie C, Danckaerts M, Wampers M, De Hert M. Aripiprazole and acute extrapyramidal symptoms in children and adolescents: a meta-analysis. CNS Drugs. 2016;30(9):807–818.
  8. Varela FA, Der-Ghazarian T, Lee RJ, et al. Repeated aripiprazole treatment causes dopamine D2 receptor up-regulation and dopamine supersensitivity in young rats. J Psychopharmacol. 2014;28(4):376–386.
  9. Shen Y, McCorvy JD, Martini ML, et al. D2 Dopamine receptor G protein-biased partial agonists based on cariprazine. J Med Chem. 2019;62(9):4755–4771.
  10. Chen X, Sassano MF, Zheng L, et al. Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists. J Med Chem. 2012;55(16):7141–7153.

With regards,

Takahiko Nagamine, MD, PhD

Dr. Nagamine is with Sunlight Brain Research Center in Hofu, Japan, and Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University in Tokyo, Japan.