Background: Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some
patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine.
Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on
therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score.
Objectives: The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant
forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic
or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby
social functioning and quality of life.
Results: The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic
drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of
patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated
only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with
cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions
were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic
drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such
as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic
receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in
preclinical and clinical trials.
Conclusion: In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know
whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total
score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy.
In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses
can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing