Evidence indicates that adding an AAP to clozapine may be associated with a small to modest improvement in symptom control in patients not adequately responding to optimized monotherapy with clozapine. Also, based on the most commonly studied add-on AAP (risperidone), dual therapy with clozapine may be associated with increased risk of elevated prolactin levels as shown in the included studies. Concerning the clinical impact of using higher doses of an AAP, evidence is limited. Most of the evidence from well conducted systematic reviews and RCTs is derived from subanalyses and post-hoc analyses. These suggest that escalating doses of certain AAPs to the upper limit of the usual recommended dosing range may help controlling psychotic symptoms in certain patient subgroups, such as in patients with more severe baseline symptoms or with treatment resistant disease. Combination therapy with two AAPs may occur in the treatment of schizophrenia. Based on the evidence reviewed, clozapine and risperidone may be the most commonly combined AAPs in dual therapy. The use of high doses of AAPs also may occur, and may be limited to patients with treatment-resistant disease.