Akathisia is a common side effect of antipsychotic treatment. It is usually considered a movement or extrapyramidal disorder, with motor signs and sensory disturbance (eg, restlessness, the need to move) as the defining characteristics of the condition⁴. The reported prevalence of akathisia with second-generation antipsychotics varies widely, but it may be quite high depending on the drug^5,6. Risk factors for drug-related akathisia include higher medication dose or rapid dose increase, as akathisia seems to be dose-dependent. The initial recommendation for treatment is dose reduction, which can help reduce a patient’s discomfort and improve adherence. Several medications, including beta-blockers (eg, propranolol and metoprolol) and anticholinergic drugs (eg, biperiden, trihexyphenidyl, and benztropine) are useful for improving symptoms⁴.

Extrapyramidal symptoms, primarily akathisia, were frequently reported treatment-emergent adverse events with cariprazine treatment^2,3. The akathisia events reported here are based on pooled data from 4 short-term, 6-week studies (RGH-MD-03 [NCT00404573], RGH-MD-16 [NCT00694707], RGH-MD-04 [NCT01104766], RGH-MD-05 [NCT01104779])³ and 2 long-term, 48-week open-label safety studies (RGH-MD-17 [NCT00839852], RGH-MD-11 [NCT01104792])², respectively.

In the pooled data set of 2048 cariprazine-treated patients (including in addition to the above 1 long-term, 26-week study in patients with negative symptoms of schizophrenia (RGH-188-005 [EudraCT2012-005485-36]), and 1 long-term, (up to 92-weeks) maintenance of effect study (RGH-MD-06 [NCT01412060]), in the approved dose-range of 1.5-6 mg/d and 683 placebo treated patients, the rate of akathisia was 14.6% for cariprazine and 3.4% for placebo⁷. Most cases were mild to moderate in intensity, and rarely lead to study discontinuation¹. The low discontinuation rates potentially mean that akathisia is an event that can be well managed in the clinic^2,3.

The first occurrence of akathisia was generally reported within the first 6 weeks of treatment and showed a dose dependency⁷ , meaning that the likelihood of akathisia with low doses of cariprazine was less (1.5 mg: 7.8%, 3 mg: 15.7%, 4.5 mg: 9.1%, 6 mg: 18.0%)⁷.
The majority of patients used anti EPS medication to manage symptoms of akathisia/restlessness^2,3; propranolol along with diphenhydramine, benztropine or equivalent were used most frequently^2,3.
The mean duration of akathisia was 24 days for cariprazine-treated and 29 days for placebo treated patients in the short term studies³.

Failure to correctly identify akathisia and increasing severity of akathisia has been linked to the emergence and/or worsening of suicidal ideation, aggression, and violence⁸. It is important to note that no relationship between akathisia and suicidal tendency was observed in the cariprazine schizophrenia program.
None of the patients who died due to completed suicide (0.3%) during the cariprazine clinical development program had high akathisia scores. The safe use of the product in the context of early detection and mitigation of treatment emergent akathisia /restlessness, and prevention of suicide should be assured by individualized dosing regimen with close monitoring during the initiation of the treatment and lowest effective maintenance doses⁷.