Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention

Abstract

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

Abordajes y tratamientos contemporáneos para la esquizofrenia: Diagnóstico e Intervención Psiquiátrica

“…Aunque estas características a menudo aumentar o disminuir en paralelo, ese no es siempre el caso. Otras medidas cuantitativas piden al paciente considere tanto la frecuencia como la gravedad de los síntomas, lo que también puede dificultar la determinación de los hallazgos (Gomes & Grace, 2021).…”

Perineuronal nets as regulators of parvalbumin interneuron function: Factors implicated in their formation and degradation

“…Adapted from Reichelt et al 3 many pyramidal neurons. 22 This modulation results in an E/I balance that essentially pertains to a stable global neuronal activity predominantly achieved in the brain through a coordinated equilibrium between excitatory and inhibitory inputs. 23 A proper E/I balance is crucial for precise temporal control over the information flowing through neurons and synchronized activity in certain neural circuits.…”

“…They are also enriched with K v 3.1 channels, a class of voltage‐gated potassium channels that contribute to their fast‐spiking activity 21 . PV interneurons synapse onto the cell body and/or initial segments of axons of glutamatergic pyramidal neurons, modulating their activity through a cellular network capable of synchronizing the excitatory state of many pyramidal neurons 22 . This modulation results in an E/I balance that essentially pertains to a stable global neuronal activity predominantly achieved in the brain through a coordinated equilibrium between excitatory and inhibitory inputs 23 .…”

Two Cases of Schizophrenia Treated with Individualized Homoeopathy

“…Negative symptoms include blunting of effect, anhedonia, and social withdrawal. Cognitive symptoms are related to deficits in main cognitive domains such as working memory, attention, verbal learning, and problem-solving [9].…”