Antipsychotic efficacy: Relationship to optimal D₂-receptor occupancy

Abstract

Clinically important differences exist between antipsychotic agents and formulations in terms of safety and tolerability. Features of the biochemical interaction between the antipsychotic and the D2-receptor may underlie these differences. This article reviews current information on the relationship between antipsychotic receptor occupancy and clinical response. A literature search was performed using the keywords 'antipsychotic or neuroleptic', 'receptor' and 'occupancy' and 'dopamine' and 'D2' supplemented by the authors' knowledge of the literature. Imaging and clinical data have generally supported the hypotheses that optimal D2-receptor occupancy in the striatum lies in a 'therapeutic window' between approximately 65 and approximately 80%, however, pharmacokinetic and pharmacodynamic properties of a drug should also be taken into account to fully evaluate its therapeutic effects. Additional research, perhaps in preclinical models, is needed to establish D2-receptor occupancy in various regions of the brain and the optimal duration of D2-receptor blockade in order to maximise efficacy and tolerability profiles of atypical antipsychotics and thereby improve treatment outcomes for patients with schizophrenia.

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

“…Dopamine D 2 receptor antagonism or partial agonism is the fundamental mechanism of action of current antipsychotics (Kapur and Mamo, 2003;Kapur et al, 1996;Nordstrom et al, 1993;Pani et al, 2007). D 2 receptors are predominantly expressed in indirect pathway medium spiny neurons (MSNs) in the striatum and are coupled with an inhibitory G protein (G i ) that impedes the enzyme activity of adenylate cyclase.…”

Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice

“…Although the receptor pharmacology underlying the action of conventional and atypical antipsychotics is different, D2 receptor antagonism is a primary target of these drugs [6]. Thus, testing antipsychotic drugs in D2R À/À mice could provide some valuable insight into D2 receptor interactions for these drugs.…”

“…Because this weight gain is associated with other health complications such as obesity and metabolic syndromes, it is important to understand why these antipsychotics cause these unwanted effects. Antipsychotics bind to multiple neurotransmitter receptors and may work through different receptor pharmacology [5,6]. Typical antipsychotics are high-affinity dopamine D2 receptor (D2R) antagonists, which includes D2, D3, and D4 receptors, while atypical antipsychotics are antagonists of both serotonin type 2A (5-HT2A) and D2R, with additional affinities for other serotonin and dopamine receptor subtypes as well as histamine, muscarinic, and adrenergic receptors [5,7].…”

Tedavide Hızlı Salınımlı ve Uzatılmış Salınımlı Formülasyonların Farkları

“…Bu da, sedasyon ve hipotansiyon gibi istenmeyen etkileri azaltmakta ve ketiapin XR ile yavaş doz arttırma gereğini ortadan kaldırmaktadır. Kontrollü salınım etken maddenin ve metabolitlerinin plazmaya ve hedef organa ulaşımında daha yavaş bir akış ve reseptörlerde daha stabil bir tutunma meydana getirmektedir (33).…”