Vitamin D3 and zinc supplements augment the antimanic efficacy of lithium and olanzapine treatments in an animal model of mania.

Objective: Bipolar disorder (BD) is a challenging psychiatric disorder and a complex disease. The associated reduction in serum vitamin D3 (VitD3) levels in BD patients and the contribution of zinc (Zn) to the treatment, along with the severe side effects of lithium (Li) treatment, were encouraging to assess the efficacy of different correlated combinations of therapeutic/nutraceutical treatments such as olanzapine (Oln), VitD3, and Zn against Li. Methods: Mania was induced in C57BL/6 mice by administering methylphenidate (MPH) for 14 consecutive days. On the 8th day of MPH injection, different treatment regimens were administered, Li, Oln, VitD3/Zn, VitD3/Zn/Oln, VitD3 + Zn + Oln + Li50mg/kg (C50), and VitD3 + Zn + Oln + Li100mg/kg (C100). Both VitD3 (850 IU/kg) and Zn (180 mg/kg) were supplied with food for 2 weeks before starting the induction of mania, which continued until the end of MPH administration. Behavioral, brain oxidative stress, thyroid hormones, VitD3, Zn, GsK-3ß, and Bcl2 levels, as well as brain histopathological alterations, were assessed. Results: Manic mice exhibited alterations in all tested parameters, and the histopathological examination of the cortex and hippocampus confirmed these results. The VitD3/Zn/Oln, C50, and C100 treatment regimens reversed most of the behavioral and pathophysiological alterations; however, the C50 treatment regimen was the most efficient. Conclusions: This study emphasizes the importance of combining different antimanic medications like Li and Oln with nutraceutical supplements to increase their antimanic efficacy, reduce their adverse effects, and, ideally, improve the BD patient's quality of life.

Decreased global methylation in patients with bipolar disorder who respond to lithium.

Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mM). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness.