Case of aripiprazole long-acting-related akathisia successfully managed with carvedilol: A case report.

Abstract

Treating antipsychotic-induced akathisia is challenging.1 The use of the beta-blocker propranolol is useful,2 but data on other beta-blockers, such as carvedilol (CAR), are not available. CAR blocks cardiac beta2-adrenoceptors more than beta1-adrenoceptors, and has an additional alpha1-blocking effect exerting anti-oxidant actions.3 We report a patient with akathisia related to aripiprazole long-acting (ARI-LAI) treated with CAR. Mrs A. is a 27-year-old woman affected by schizophrenia since she was aged 22 years. In the past, she took risperidone up to 6 mg/day and olanzapine 10 mg/day without effect. Her family history was positive for schizophrenia (mother) and negative for akathisia. She come to our observation in February 2019 due to constant restless movement of the legs, inability to remain seated for a long time, and internal sensation of restlessness, lasting for 4 months. She was administered aripiprazole long-acting 400 mg once monthly (after testing with aripiprazole 15 mg/day for a week before injection without adverse effects) with efficacy (Positive and Negative Syndrome Scale: positive 17, negative 18 and general 68 when we saw her the first time). Mrs A. told us, “…this injection was the only drug that makes me feel better; I don't want to suspend it!” Her other therapy was alprazolam 1.5 mg/day. According to the Barnes Akathisia Rating Scale (BARS), her global score was 4 (marked). On the Naranjo Adverse Drug Reaction Scale, the probability of associating this adverse reaction with ARI-LAI was 7 (probable). She had no medical problems, and laboratory examinations were negative. In the past, she was prescribed propranolol 40 mg/day without benefit. All considered, we decided to introduce in therapy CAR 25 mg/day after a discussion of its risk–benefits with a cardiologist and the patient accepted. After 1 week, the patient felt slightly better. After the another 2 weeks of improvement, the BARS global score fell to 2. We decided to continue with CAR 25 mg/day, repeating ARI-LAI. After 3 weeks, the BARS global score was 1. In the follow-up visits every 2 weeks, no signs of akathisia were observed or reported (absent on BARS-Global Clinical Assessment of Akathisia (GCAAS)). The last visit was in September 2020, and BARS-GCAAS was zero without adverse effects. The patient provided written informed consent for the off-label use and the publication of this manuscript. This is the first case of CAR treatment of ARI-LAI-related akathisia. CAR was effective at low dosages (25 mg/day), and a component of “serendipity” was present, as we prescribed CAR after a cardiologist consultation. CAR inhibition on beta1 and beta2 receptors might explain the response seen. Aripiprazole causes akathisia as a side-effect, through the partial agonism at 5-HT1A receptors.4 Typically, akathisia is generally considered a consequence of an imbalance between dopaminergic and serotonergic/noradrenergic neurotransmitter systems.2, 5 The therapeutic action of beta-blockers on akathisia is linked to their activity in blocking noradrenergic/serotonergic input into the dopaminergic pathways.6 However, drugs with marked postsynaptic serotonin 5-HT2a receptor antagonism showed efficacy in treating akathisia.7 Murnane et al. evaluated CAR interactions with 5-HT2A receptors both in vitro and in vivo.8 In vitro experiments confirmed that CAR had a high affinity for 5-HT2A receptors. In vivo experiments proved that CAR enhances the ethanol-caused loss of the rectifying reflex and reversed operant responding in mice. Both effects were reduced by pretreatment with the 5-HT2A receptor antagonist M100907. Thus, CAR interacts with serotonin 2A receptors both in vitro and in vivo in an atypical manner, antagonizing serotonin-mediated signaling.8 A recent meta-analysis reported a positive effect of drugs with antagonistic properties at the 5-HT2A receptor on antipsychotic-induced akathisia.9 This atypical action of CAR on the 5-HT2A receptor might explain the excellent response seen in our case. Besides aripiprazole, it is also possible to hypothesize that the typical antagonism action on 5-HT2A of CAR might be usefu,l even in other antipsychotic-induced akathisia, as seen for mirtazapine, a 5-HT2A antagonist drug.10 In the present case, we did not consider an ARI-LAI dose reduction based on the current clinical response, the previous failed treatments, and the fact the 300 mg might often not be suitable for severe patients. In conclusion, CAR is safe and useful, but further studies are required. The authors have no conflicts of interest to declare.