Mitochondrial pathology has been implicated in the pathogenesis of psychotic disorders. A few studies have proposed reduced leukocyte mitochondrial DNA (mtDNA) copy number in schizophrenia and bipolar disorder type I, compared to healthy controls. However, it is unknown if mtDNA copy number alteration is driven by psychosis, comorbidity or treatment. Whole blood mtDNA copy number was determined in 594 psychosis patients and corrected for platelet to leukocyte count ratio (mtDNAcnres). The dependence of mtDNAcnres on clinical profile, metabolic comorbidity and antipsychotic drug exposure was assessed. mtDNAcnres was reduced with age (β = -0.210, p < 0.001), use of clozapine (β = -0.110,p = 0.012) and risperidone (β = -0.109,p = 0.014), dependent on prescribed dosage (p = 0.006 and p = 0.026, respectively), and the proportion of life on treatment (p = 0.006). Clozapine (p = 0.0005) and risperidone (p = 0.0126) had a reducing effect on the mtDNA copy number also in stem cell-derived human neurons in vitro at therapeutic plasma levels. For patients not on these drugs, psychosis severity had an effect (β = -0.129, p = 0.017), similar to age (β = -0.159, p = 0.003) and LDL (β = -0.119, p = 0.029) on whole blood mtDNAcnres. Further research is required to determine if mtDNAcnres reflects any psychosis-intrinsic mitochondrial changes.