Update on novel antipsychotics and pharmacological strategies for treatment-resistant schizophrenia.

The search for therapy against TRS, beyond clozapine or in addition to clozapine, has emerged over time, capturing mainly three types of strategies: 1. Add-on of a second-generation antipsychotic (i.e. amisulpride); 2. Add-on of a second antipsychotic with significantly different receptor profile compared to the older ones (e.g. aripiprazole and cariprazine); 3. Novel strategies beyond dopamine D2/D3 receptor occupancy (e.g. xanomeline + trospium, TAAR1-agonists, sodium benzoate, and D-amino acids). More high-quality clinical trials applying the current operationalized criteria for TRS and clozapine-resistance are required to evaluate the efficacy of alternative and add-on treatments.