Abstract
The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia.
Highlights
Schizophrenia is a chronic multifactorial neuropsychiatric disorder with an incidence of 0.7–1% [1]
It is noteworthy to mention a clinical research paper in which Woodward and colleagues discovered an association between a single nucleotide polymorphism (SNP), the val108/158met, within the gene encoding for catechol-O-methyltransferase (COMT), which is an enzyme involved in the control of prefrontal cortex (PFC) DA neurotransmission, and the cognitive improvement induced by clozapine
They discovered that the viral-mediated silencing of D2 receptor (D2R) in the medial PFC (mPFC) of dysbindin heterozygous mice abolished the beneficial effect of risperidone on cognitive dysfunctions relevant for schizophrenia
Summary
Schizophrenia is a chronic multifactorial neuropsychiatric disorder with an incidence of 0.7–1% [1]. Regarding cognitive impairments associated with schizophrenia (CIAS), no pharmacological treatments have been approved so far by any regulatory agencies worldwide [7,8] This has produced considerable interest mostly because CIAS have been reported as the main cause of functional disability and poor quality of life [9]. Multiple lines of evidence suggest that the cognitive improvement exerted by old and new SGAs still depends on dopaminergic mechanisms, and it is unclear whether the efficacy of SGAs is linked to serotoninergic mechanisms [15] In this respect, the dopamine D2 receptor (D2R) and D1, D3, and D4 receptors (D1R, D3R, D4R) have been investigated for their possible contribution in the SGAs-induced cognitive improvement. Among these previously overlooked dopamine receptors, the D3R appears to be highly involved in the cognitive improvement produced by some SGAs and currently represents one the most attractive target for future drug development or repositioning in the context of CIAS pharmacotherapy
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