Pharmacological treatment is the gold standard in delusional disorder (DD), moreover the second generation antipsychotics (SGA) are widely used in the treatment of DD, in spite of this, none SGA is authorized for the treatment of DD.

To evaluate the evidence available for pharmacological treatment in adults with DD. Especially, that concerning SGA.

A systematic review on pharmacological treatment of DD was conducted. We selected the best evidence available. Then, we analysed them critically, assessing its biases and quality, finally performed a narrative and quantitative synthesis.

The quality of the evidence was very low. There were not randomized clinical trials. n = 385, 177 SGA. Antipsychotics achieved a good response in a 33.6% of the patients. First generation antipsychotics (FGA) did show superiority compared to SGA (39% good response vs. 28%, respectively. P ≤ 0.02). We could not find data about superiority of any drug over other. Pimozide, traditionally considered the most effective drug, did not confirm to be a superior treatment compared to others. Reasons for superiority of FGA were analyzed. The role of another treatments were testimonial, but antidepressants can be a promising treatment.

There is no evidence to make strong recommendations, although antipsychotics in general appear to be an effective treatment for DD. Superiority of FGA against SGA was shown. We need to develop clinical trials in DD and SGA, since their better tolerance profile might be the best candidates to do.

The authors have not supplied their declaration of competing interest.