Mitochondrial DNA copy number is significantly increased in bipolar disorder patients and is correlated with long-term lithium treatment.

Mitochondrial dysfunctions have been reported in bipolar disorder (BD), but their role in the etiopathogenesis of BD as well as their implications in modulating response to pharmacological treatments with psychotropic medications have been scarcely explored. Mitochondrial DNA copy number (mtDNA-cn) has been linked to mitochondria functioning, and, despite some degree of inconsistence, previous findings showed that BD patients present significant differences in mtDNA-cn compared to healthy controls. Here we measured mtDNA-cn in a sample of 89 patients with BD and 78 healthy controls (HC). Patients in the BD sample were treated either with lithium (n = 47) and characterized as responders (n = 22) or non-responders (n = 25), or with other mood stabilizers (n = 42). BD patients had larger mtDNA-cn compared to HC (adjusted model: F2=9.832; p = 0.000095; contribution of diagnosis F1= 10.798; p = 0.001). When the BD sample was stratified for treatment exposure, mtDNA-cn was lower in patients treated with lithium compared to those treated with other mood stabilizers (adjusted model: F4=23.770, p = 7.0929E-13; contribution of treatment: F1=54.300, p = 1.55E-10). Moreover mtDNA-cn was higher in patients treated with other mood stabilizers compared to controls and Li-treated BD patients (F3=28.125, p = 1.36E-14; contribution of groups F2=36.156, p = 1.25E-13). Finally, there was no difference in mtDNA-cn levels in lithium responders compared to non-responders and neither between the two diagnostic groups (BD type 1 and 2). Our findings suggest that BD may be associated with mitochondrial dysfunctions, and that exposure to lithium but not to other mood stabilizers may restore these abnormalities, though this does not appear correlated with the clinical efficacy of lithium.