Background: The pharmacological treatment of schizophrenia is currently based on the
employment of antipsychotic medications showing an antagonism of dopaminergic and serotoninergic
inhibitors. 20-40% of patients are drug-resistant or residually symptomatic in the long-term antipsychotic
treatment, and new strategies are needed for improving their functional and cognitive
Methods: This systematic review has summarized evidences from the literature regarding the newer
pharmacological targets proposed for the treatment of psychosis. We included 128 peer-reviewed
articles and 5 other relevant sources published from 2002 to 2020 on PubMed EMBASE,
The Cochrane Library, and Google Scholar.
Results: The possible role of glutamate and its receptors as targets of the antipsychotic mechanism
of action has been described. Glutamatergic neurotransmission and NMDA receptors hypofunction
are involved in the neurobiological explanatory model of psychosis and possibly targeted for the
successful treatment of cognitive and residual symptoms. Results show an efficacy of D-cycloserine
(antagonist at the Glycine site of the NMDA-R) in the treatment of negative symptoms of
schizophrenia as well as Memantine (NMDA- Receptor antagonist) for cognition and psychopathology.
The putative antipsychotic effect of cannabidiol on positive symptoms and cognition will also
be discussed. The action on serotoninergic and GABAergic receptors will be considered as a new
pharmacological target, with a possible efficacy of Vabicaserin on symptoms of psychosis. Mynocicline
has shown to induce improvements in cognitive symptoms in schizophrenia, as well as Erythropoietin.
Oxytocin has been reported to have an antipsychotic-like effect; moreover, COX-2 inhibitors
lead to a reduction in positive symptoms of psychosis, specifically in the first episode of illness.
Conclusion: This narrative report suggests a promising role of new agents in the treatment of Schizophrenia;
however, more research is needed to approve their clinical employment.