Several antipsychotics and antidepressants have been associated with electrocardiogram alterations, the most clinically relevant of which is the heart rate-corrected QT interval (QT_c) prolongation, a risk factor for sudden cardiac death. Genetic variants influence drug-induced QT_c prolongation and can provide valuable information for precision medicine. The effect of genetic variants on QT_c prolongation as well as the possible interaction between polymorphisms and risk medications in determining QT_c prolongation were investigated. Medications were classified according to their known risk of inducing QT_c prolongation (high-to-moderate, low, and no risk). QT_c duration and risk of QT_c &#x3e; median value were investigated in a sample of 77 patients with mood or psychotic disorders being treated with antidepressants and antipsychotics, and who had at least 1 ECG recording. A secondary analysis considered QT_c percentage change in patients (<i>n</i> = 25) with 2 ECG recordings. Single-nucleotide polymorphisms previously associated with QT_c prolongation during treatment with psychotropic medications were investigated. No association survived after multiple-testing correction. The best results for modulation of QT_c duration were identified for rs10808071 (the <i>ABCB1</i> gene, nominal <i>p</i> = 0.007) when at least 1 medication with a moderate-to-high risk was prescribed, and for rs12029454 (the <i>NOS1AP</i> gene) in patients taking at least 1 medication with a cardiovascular risk (nominal <i>p</i> = 0.008). In the secondary analysis, rs2072413 (the <i>KCNH2</i> gene) was the top finding for the modulation of QT_c percentage change (nominal <i>p</i> = 0.001) when 1 drug with a moderate-to-high risk was added compared to baseline. Despite the limited power of this study, our results suggest that <i>ABCB1</i>, <i>NOS1AP</i>, and <i>KCNH2</i> may play a role in QT_c duration/prolongation during treatment with psychotropic drugs.