Rabbit syndrome (RS) is a relatively rare extrapyramidal symptom characterized by fine, rapid, rhythmic movements along the vertical axis of the mouth, typically without involvement of the tongue [1]. It is commonly associated with prolonged exposure to antipsychotic medications, particularly first-generation antipsychotics. However, emerging evidence suggests that newer antipsycho-tics [2] may also be implicated in RS. With the advent of long-acting injectable antipsychotics (LAIs), an increasing number of patients are receiving these formulations for the management of schizophrenia or bipolar disorder, aiming to enhance medication adherence and treatment outcomes. Additionally, LAIs are purported to offer comparable efficacy with reduced side effects compared to their oral counterparts. Herein, we present a case of RS observed in a patient diagnosed with bipolar I disorder receiving Abilify Maintena, along with an updated review of RS associated with newer generation antipsychotics.

A 53-year-old man diagnosed with bipolar I disorder according to the Diagnostic and Statistical Manual, 5th edition criteria, experienced the onset of a manic episode characterized by irritability and grandiose delusions at age 44 years. Over the subsequent years, he was readmitted to the psychiatric acute ward multiple times due to behavioral disturbances associated with mania. Various treatments were attempted, including antipsychotics such as zotepine, sulpiride, and quetiapine, along with lithium. The patient experienced extrapyramidal symptoms (EPS) such as hand tremors and constricted facial expression. However, due to poor adherence and lack of family support, aripiprazole Maintena 400 mg was initiated during his final compulsory admission in September 2021. Following discharge, he maintained mood stability with monthly injections of Abilify Maintena 400 mg and oral lithium at a dosage of 600−900 mg/day during outpatient clinic follow-ups. Approximately 7 months later, in April 2022, He developed stuttering, bradykinesia, mask-like facial expression, lower lip tremors, akathisia, which were partially relieved by the administration of trihexyphenidyl at a dosage of 2−4 mg/day. Due to mask mandates during the coronavirus disease pandemic, perioral tardive dyskinesia was suspected but not definitively diagnosed. Upon removing his mask, involuntary fine, rhythmic, and vertical movements of his lips were observed, along with resting tremors in his hands, particularly in the left hand. There was no involvement of his tongue. The diagnosis of RS was favored. He appeared psychomotor retarded with restricted facial expressions and slowed movements but without apparent limb rigidity. Trihexyphenidyl dosage was titrated up to 6 mg/day to alleviate the patient’s discomfort, yielding only marginal improvement. Attempts to taper Abilify Maintena dosage from 400 mg to 300 mg were met with resistance from his daughter, who expressed concerns about his previous episodes of severe violent and destructive behavior during manic episodes. Laboratory examinations, including thyroid function and lithium levels, were within normal ranges. Presently, he continues to receive monthly injections of Abilify Maintena 400 mg alongside oral lithium at 600 mg/day and trihexyphenidyl at 6 mg/day. Involuntary lip movements persist, mildly affecting activities such as eating and drinking.

To the best of our knowledge, this is the first reported case associating RS with Abilify Maintena in the literature. RS, initially described by Villeneuve [1] in 1972, is a rare adverse event of extrapyramidal syndrome associated with typical antipsychotics, with a prevalence rate ranging from 1.5 to 4.4% [3,4]. Although current evidence indicates a lower risk of EPS with second-generation antipsychotics compared to first-generation ones, there remains a potential risk of RS associated with newer agents, including the latest serotonin-dopamine activity modulators such as aripiprazole. As of now, only three cases of aripiprazole-induced RS have been reported. The first case involved a 29-year-old female with schizophreniform disorder who developed RS six weeks into aripiprazole monotherapy at a dosage of 10 mg/day. Complete recovery from RS was achieved with intravenous administration of promethazine (50 mg) followed by tapering aripiprazole to 5 mg/day and adding trihexyphenidyl at 4 mg/day. In the second case, a 35-year-old female experiencing her first episode of psychosis developed RS after three months of treatment with aripiprazole at a dosage of 15 mg/day. Reduction of aripiprazole to 10 mg/day and prescription of biperiden at 4 mg/day led to improvement in RS symptoms, with no recurrence after one month of maintenance on aripiprazole at 10 mg/day. The final case involved a 45-year-old woman with not otherwise specified psychotic disorder who developed RS at the end of the third month of aripiprazole treatment, with the latest dosage being 10 mg/day. RS symptoms significantly improved five days after initiating biperiden at 3 mg/day and resolved completely after three weeks. Notably, RS reappeared two days after discontinuing biperiden, prompting the decision to completely discontinue aripiprazole. The patient’s RS symptoms were fully resolved by the end of the first week after stopping aripiprazole. For the first reported case of RS induced by LAIs, Albayrak et al. [5] described the initial instance wherein a patient receiving long-acting risperidone at a dosage of 25 mg via bimonthly injections developed RS after the fourth injection (during the second month of treatment). Regarding other newer antipsychotics associated with RS, Catena Dell’Osso et al. [2] provided a limited review update up to 2007. Herein, we augment their findings with additional recent cases identified through a search of the PubMed database, which are presented in Table 1 [5-16].

The mechanism underlying RS remains unclear but is likely related to a hypercholinergic state resulting from blockade of dopaminergic neurons in the extrapyramidal system [17]. Alternatively, it may resemble tardive dyskinesia, indicating cholinergic hypofunction due to denervation-type dopaminergic hypersensitivity in the basal ganglia [18]. Additionally, RS has been reported to improve upon switching antipsychotics to olanzapine [19] and quetiapine [20], which exhibit high anticholinergic effects, suggesting a role in reducing RS. In general, RS may result from an imbalance of cholinergic and dopaminergic function in the basal ganglia.

Aripiprazole is a unique antipsychotic agent with a novel pharmacological mechanism, acting as a partial agonist on dopamine D2 and D3 receptors and serotonin 5HT1a receptors while antagonizing 5HT2a receptors [21]. Study has shown very high occupancy of striatal D2 receptors with aripiprazole, significantly correlated with plasma drug concentrations, even at the lowest dose of 10 mg, leading to 85% D2 occupancy [22]. Increased likelihood of EPS has been observed with D2 occupancy exceeding 78%, even with atypical antipsychotics [23]. Like lurasidone [6], aripiprazole also exhibits relatively low anticholinergic activity, which may contribute to the risk of developing RS.

Our reported case exhibited typical rapid, fine, rhythmic movements of the peri-oral muscles along a vertical axis, resembling the chewing actions of a rabbit, which manifested 7 months after initiation of Abilify Maintena. Notably, unlike tardive dyskinesia, the tongue was not involved. The doses of oral aripiprazole implicated in the previously mentioned three cases of RS ranged from 10 to 15 mg/day. It appears dose-dependent, as RS resolved following tapering of aripiprazole dosage. The equivalent oral dose of aripiprazole in our patient receiving Abilify Maintena 400 mg monthly is 20 mg/day [24]. This suggests that the higher daily dose in our case is more likely to precipitate RS. This extended duration contrasts with previous cases involving oral aripiprazole, where symptoms appeared within 1.5 to 3 months of initiation. This discrepancy may be attributed to the prolonged time required for steady-state concentrations of long-acting injectable Abilify Maintena to be achieved, as the mean elimination half-life of aripiprazole is 46.5 days for a dosage of 400 mg, with steady-state concentrations typically reached by the fourth injection [25]. However, administration of anticholinergic drugs appeared less effective in our case. Moreover, our case presented several risk factors associated with treatment-emergent movement disorders, including middle age, affective disorder diagnosis, greater total drug exposure, pre-existing parkinsonism [26,27], and concomitant use of lithium [28]. To address this movement disorder, the next step is to consider tapering the dosage of Abilify Maintena to assess whether RS diminishes or disappears. Efforts will be made to persuade the patient and her daughter to proceed with this approach.

In conclusion, newer generation antipsychotics have become the mainstay of therapy in managing patients with psychosis or mood disorders, owing to their efficacy and safety profile. However, the emergence of cumulative, undesired, unexpected, and potentially life-threatening adverse effects, including uncommon ones like RS, has become apparent. Previous reports suggest that tapering the dosage or adding anticholinergic agents are commonly employed strategies. The newer LAIs have demonstrated superior efficacy and safety profiles compared to their oral counterparts in treating patients with schizophrenia or bipolar affective disorder, leading to a significant increase in their global utilization over the past decade. Our case serves as a reminder to clinicians and nurses of the potential occurrence of RS, albeit rare, when administering Abilify Maintena.

None.

No potential conflict of interest relevant to this article was reported.

Conceptualization: Ming-Han Hsieh, Shang-Chien Huang. Data acquisition: Ming-Han Hsieh. Formal analysis: Ming-Han Hsieh. Supervision: Ming-Han Hsieh. Writing—original draft: Ming-Han Hsieh. Writing—review & editing: Ming-Han Hsieh.