Akathisia and Newer Second‐Generation Antipsychotic Drugs: A Review of Current Evidence

Abstract

Akathisia continues to present a significant challenge in clinical practice. As a class, so-called atypical, or second-generation, antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and are commonly used to treat mood disorders. These medications have traditionally been distinguished from first-generation antipsychotics by their lowered risk of extrapyramidal side effects (EPS) such as dystonia, dyskinesia, akathisia, and pseudoparkinsonism. However, the occurrence of EPS, particularly akathisia, has been demonstrated to some degree in all commercially available SGAs. This review examines the incidence of akathisia in nine newer SGAs in patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We performed a search of PubMed, ClinicalTrials.gov, Cochrane Central Register, and Google Scholar, as well as manufacturer websites and product labeling for published and unpublished clinical trials, meta-analyses, and systematic reviews. Studies evaluating adult patients with schizophrenia, bipolar disorder, or MDD were eligible for inclusion. Data on treatment-emergent akathisia rates were gathered from each study, and potential dose-response relationships were explored. A total of 177 studies were included in this review, comprising 58,069 patients across 414 treatment arms. Compared with placebo with a composite 3.7% incidence of akathisia, individual SGAs produced akathisia at total composite rates ranging from 2.9-13.0% across the included studies. High doses of an SGA were generally associated with an increased risk of akathisia. Clinicians should consider the risk of akathisia when choosing a treatment option and monitor for akathisia in patients beginning therapy with an SGA or following a dose increase of the SGA. KEY WORDS akathisia, antipsychotics, bipolar disorder, major depressive disorder, schizophrenia. (Pharmacotherapy 2020;40(6):565-574)

Safety and Effectiveness of Lurasidone in Patients with Schizophrenia: A 12-Week, Open-Label Extension Study

“…30,31 In addition to schizophrenia and nasopharyngitis, akathisia and nausea were also among the more common adverse events during the current 12-week extension study, though occurring at a low overall incidence (akathisia at 6.6% of patients was the most common TEAE). Although study designs differ, the incidence of akathisia for some antipsychotic drugs in patients with schizophrenia has been reported 32 to be 3-13% across various studies, and the current result is also within that range. The lack of noticeable effects on weight, BMI, metabolic parameters, prolactin, and ECG parameters in the current study is consistent with previous safety findings, 30,31 and the double-blind study that preceded the extension study reported here.…”

Safety and Tolerability of Cariprazine in Patients with Schizophrenia: A Pooled Analysis of Eight Phase II/III Studies

“…[11][12][13][14] Akathisia is one of the most frequently occurring movement disorders associated with antipsychotic agents, although the propensity for its occurrence differs by pharmacologic profile and receptorbinding affinities; all antipsychotics may cause some degree of akathisia, with lower rates generally noted for second-generation agents versus first-generation agents. 15 Cariprazine is a dopamine D 3 /D 2 receptor partial agonist that is approved by the European Medicines Agency (EMA) and by the United States (US) Food and Drug Administration (FDA) for the treatment of schizophrenia (1.5-6 mg/d); it is additionally approved in the US for manic and mixed episodes associated with bipolar I disorder (3-6 mg/d), and for bipolar depression (1.5 or 3 mg/d). 16 Cariprazine differs from all other atypical antipsychotics in having a greater affinity for the D 3 receptor than does dopamine itself, thereby exhibiting a functional D 3 partial agonism in the human brain 17 that other antipsychotics, such as aripiprazole, risperidone, and olanzapine, fail to exhibit.…”

Dopamine-receptor blocking agent-associated akathisia: a summary of current understanding and proposal for a rational approach to treatment

“… 55 – 58 The relative “EPS advantage” of second-generation agents is touted as producing multiple clinical benefits, 59 , 60 but movement side effects can still occur in second-generation agents despite lower D 2 receptor occupancy. 5 , 24 , 34 , 61 , 62 …”

“…[55][56][57][58] The relative "EPS advantage" of second-generation agents is touted as producing multiple clinical benefits, 59,60 but movement side effects can still occur in secondgeneration agents despite lower D 2 receptor occupancy. 5,24,34,61,62 The risk of akathisia, for instance, may be comparable or even greater in second-generation agents. 52 Akathisia does not correspond well with other types of EPS in terms of symptom severity and treatments, suggesting that there are other important mechanisms underlying its development.…”