Restless revelations - Unveiling Uncommon Occurrence of Cariprazine-Induced Akathisia

Dear Editor,

A 45-years-old female, with no family history of psychiatric illness, was diagnosed with Schizophrenia in 2012. She reported to a private hospital for relapse of symptoms in Apr 2023. Her symptoms were predominantly negative symptoms and she reported sedation with earlier medication. She was started on Cap. Cariprazine 3 mg/day by the treating psychiatrist. Within two weeks of starting the medication, she presented to our outpatient department (OPD) with a history of severe restlessness, inability to sit still, and sleep disturbances lasting five days.

General and systemic examinations revealed physical restlessness with no focal neurological deficit. Mental Status Examination showed her to be restless, frequently shifting positions while sitting and moving her legs. Her speech was relevant and coherent, and she had an anxious mood and affect. There was no evidence of formal thought disorder, delusion, depressive cognitions, or suicidal ideation. She was preoccupied with her subjective sense of restlessness, but there were no perceptual disturbances. She had partial insight. Her score on the Barnes Akathisia Rating Scale was 3 (marked akathisia). On the basis of clinical history, temporal association of onset of symptom after starting of Cap. Cariprazine, and Clinical examination, a provisional diagnosis of drug-induced akathisia was made. Her medications was optimized by reducing the dosage of Cap Cariprazine to 1.5 mg/day, and Tab. Propranolol TR 40 mg/day was added.[1] Progressive improvement in her symptoms was observed over a period of one week. Her restlessness reduced with improvement in sleep. After one week, her score on the Barnes Akathisia Rating Scale was 2 (Mild akathisia). She was discharged and followed- up in the OPD fortnightly. At present, she is asymptomatic and maintaining well on the same dosages.

Cariprazine is a third-generation atypical antipsychotic which is Food and Drug Administration (FDA) approved for the treatment of schizophrenia and the acute treatment of manic, depressive, or mixed episodes associated with Bipolar I disorder. Its mechanism of action involves partial agonism at D2/D3 receptors with a predominant affiliation towards D3 receptors. It acts to inhibit overstimulated D2/D3 dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. It has high selectivity towards D3 receptors located in the ventral striatum, and is implicated in reduced motor side effects. It also acts on serotonin 5-HT1A receptors and antagonizes serotonin 5-HT2A receptors.[2] It has unique pharmacology that supports well-defined efficacy advantages, as well as a favorable safety and tolerability profile. However, it can rarely cause extrapyramidal symptoms, including akathisia, as highlighted in this case report.

Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness and an objective finding of inability to sit still, often resulting from antipsychotic medications. Traditionally, an imbalance between the dopaminergic and serotonergic/noradrenergic systems has been considered the basis for akathisia. More recently, D2/D3 receptor occupancy in the ventral striatum has been linked to the pathogenesis of akathisias. Additionally, new pathophysiological mechanisms involving neuroinflammation, blood-brain barrier damage, and impaired neurogenesis have been implicated in the development of akathisia.[3]

Cariprazine’s partial agonism at D2 receptors may contribute to dopaminergic imbalance, leading to akathisia. Our case is one of the few reported instances of cariprazine-induced akathisia, underscoring its rarity and the importance of monitoring. Early detection and management can significantly improve patient outcomes. Effective strategies include dose adjustment, switching to another antipsychotic, and the use of adjunctive medications like beta-blockers (e.g. propranolol), benzodiazepines, or anticholinergics. It is important to warn patients about this potential side effect and to educate them that if they experience increased suicidal thoughts, they should stop the medication and then contact their clinician immediately.[4]

Authors’ contributions

Both authors contributed to conceptualizing, writing. Editing and approving the manuscript.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.