Background: Risk factors represented by genetic, environmental or social stress induce severe
psychiatric disorders such as depression, schizophrenia or severe neurodegenerative processes.
Antipsychotics are required for the pharmacological treatments of these disorders, but their molecular mechanisms and
especially those involved in protecting the nervous system, are still unclear. The latest strategies in the neuroscience field
consider as very important the discovery of new applications, such as promoting neurite growth by antipsychotics that are
already clinically-approved. Objective: We reviewed in silico and in vivo studies that addressed aspects of the molecular
mechanisms by which antipsychotics induce a decrease of psychotic symptoms while promoting neurite growth. Method:
We presented the biological activities of psychiatric drugs evaluated by QSAR models based on 2D and 3D- dependent
and independent molecules alignment. These are correlated with common pharmaceutical descriptors and also with new
components of QSAR models such as the contributions of membrane ions to the antagonism of these drugs at membrane
receptors. We also presented in vivo studies that by using a chemical genetic approach, piperazine antipsychotics, paliperidone,
amisulpride and also aripiprazole as promoters of neurite outgrowth have been identified. Results: 2-
trifluoromethyl-phenothiazine dihydrochloride and 2-trifluoromethyl-phenothiazine hydrochloride derivatives exhibited a
weak influence on frequency of necrotic effect on lymphocytes in culture in comparison with fluphenazine. Conclusion:
Based on the idea that an increasingly attractive strategy in pharmaceutical science is to discover new applications for already
clinically approved drugs, we are confident that future studies will predict similarities or differences in neurite outgrowth
promotion capabilities of new antipsychotics.
Keywords: Antipsychotics, nD-QSAR, neurite growth, neuroprotective promoters, psychosis drugs, schizophrenia.
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