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

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 doses leads to treatment failure both in animal models and in humans. APD failure was associated with treatment induced neuroadaptations, including a decline in extracellular dopamine levels, dopamine transporter upregulation, and altered neuronal firing. However, enhanced synaptic vesicle release has also been reported. APD loss of efficacy may be reversed through inhibition of the dopamine transporter or switching the administration regimen from continuous to intermittent. Thus, manipulating the accumulation properties of APDs, changes in the administration regimen and doses, or co-administration with dopamine transporter inhibitors may be considered to yield benefits in the development of new effective strategies in the treatment of schizophrenia.