Pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure.

Pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure. Behav Brain Res. 2021 Jan 27;:113144 Authors: Chestnykh DA, Amato D, Kornhuber J, Müller CP Abstract Schizophrenia is a multi-dimensional disorder with a complex and mostly unknown etiology, leading to a severe decline in life quality. Antipsychotic drugs (APDs) remain beneficial interventions in the treatment of the disorder, but vary significantly in binding profile, clinical effects and adverse reactions. The present review summarizes the main principles of APD mechanisms of action with a particular focus on recent findings in APD accumulation and its role in the therapeutic efficacy and treatment failure. High and low doses of APDs were shown to be effective in different dimensions of antipsychotic-like behaviour in rodent models. Efficacy of the APDs correlates with high dopamine D2 receptor occupancy, which occurs quickly after drug administration. However, onset and peak of action are delayed up to several days or weeks. APD accumulation via acidic trapping in synaptic vesicles is considered to underlie the time course of APD action. Use-dependent exocytosis, co-release with dopamine and serotonin and inhibition of ion channels impact on the neuronal transmission and determine effects of APDs. Disruption in accumulating properties leads to diminished APD effects. In addition, long-term APD administration at therapeutic ...
Source: Behavioural Brain Research - Category: Neurology Authors: Tags: Behav Brain Res Source Type: research