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

Abstract

Dopamine-receptor blocking agent-associated akathisia (DRBA-A) is an adverse effect that can significantly limit the use of these important medications for the treatment of a variety of psychiatric diseases, yet there is no unifying theory regarding its pathophysiology. This knowledge gap limits clinicians’ ability to effectively manage DRBA-A and mitigate negative outcomes in an already vulnerable patient population. Based on a review of the current literature on the subject, it is hypothesized that dopaminergic and noradrenergic signaling is perturbed in DRBA-A. Accordingly, it is proposed that the optimal agent to manage this extrapyramidal symptom should increase dopamine signaling in the affected areas of the brain and counteract compensatory noradrenergic signaling via antagonism of adrenergic or serotonergic receptors.

A systematic review of the prognostic value of motor abnormalities on clinical outcome in psychosis

“…However, the evidence for the prognostic value of akathisia and dystonia in this review was weak and inconclusive. These MAs may be more specifically drug-induced, as they are directly related to the dopamine D2 affinity of antipsychotic agents (Loonen and Ivanova, 2021;Musco et al, 2020). Therefore, akathisia and dystonia may be considered as treatment-induced phenomena rather than "genuine" MAs that are directly linked to the pathophysiology of psychosis.…”

Neuropsychiatric Consequences of Lipophilic Beta-Blockers

“…Akathisia is a clinical syndrome characterized by the feeling of inner discomfort and an imperative need for movement [ 84 ]. Acute akathisia most often occurs as a side effect of drugs, such as neuroleptics, selective serotonin reuptake inhibitors, or calcium channel blockers.…”

The role of lumateperone in the treatment of schizophrenia

“…18 In contrast to first-generation antipsychotics, second-generation antipsychotics provide superior treatment for negative symptoms, cognition, mood, and aggression 19 and reduced risks of movement disorders. 20 The hallmark of currently available atypical antipsychotic medications, high levels of occupancy of striatal dopamine D 2 receptors, produces Parkinsonism, akathisia, 16 and other extrapyramidal symptoms. 21 Another issue with current antipsychotic drugs is the high affinity for off-target receptors such as serotonin 5-HT 2c, muscarinic, histamine H 1 , and adrenergic α-1 A receptors, as well as excessive antagonism of dopamine receptors.…”

“…21 Another issue with current antipsychotic drugs is the high affinity for off-target receptors such as serotonin 5-HT 2c, muscarinic, histamine H 1 , and adrenergic α-1 A receptors, as well as excessive antagonism of dopamine receptors. Targeting of these receptors has caused serious side effects such as akathisia, 16 weight gain, dyslipidemia, hyperglycemia, type II diabetes, and cardiac conduction issues. 21 The clinical actions of antipsychotics result from their pharmacokinetic properties.…”

“…[10][11][12][13][14][15] Antipsychotics Antipsychotics, dopamine D 2 receptor blocking drugs, constitute a major therapeutic tool for the treatment of schizophrenia. However, Parkinsonism, akathisia, 16 and other movement disorders are common adverse effects of traditional (first-generation) antipsychotics. 17 Newer atypical (second-generation) antipsychotics modulate neurotransmission of 5-hydroxytryptamine (serotonin) and dopamine by acting as both serotonin 5-HT 2A receptor antagonists and dopamine D 2 receptor antagonists to treat both positive and negative symptoms of schizophrenia.…”