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

ABSTRACT

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), VitD_3, 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 + Li_50mg/kg (C50), and VitD₃+ Zn + Oln + Li_100mg/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-3β, 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.

KEYWORDS:

• Bipolar disorder
• mania
• glycogen synthesis kinase
• oxidative stress
• lithium
• olanzapine
• Vitamin D
• Zinc

Acknowledgments

This research is neither funded by governmental or private institutions nor received any grants.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Limitation

This study investigated the efficacy of different combinations of therapeutic/nutraceuticals treatments in an animal model of mania induced by methylphendate administration. Manic mice exhibited behavioral and pathophysiological alterations. The combination treatment regimens of VitD₃/Zn/Oln, C50, and C100 were able to reserve most of the alterations, with C50 regimen being the most efficient. The study highlights the importance of combining different antimanic medications with nutraceutical supplements to increase their efficacy and reduce adverse effects. Even though the study is only preliminary, it is regarded as an original approach. The study was unfunded, which prevented us from examining more advanced behavioral and neurochemical/pathophysiological parameters, gender differences, varying dose levels of combination nutraceuticals/therapeutic regimens, and long-term research to examine their precise mechanisms on mania, potential interactions, and side effects. These are some limitations to be aware of.

Ethics approval

The research was approved by Institutional Ethics Committee and followed the recommendations of the proper care and use of laboratory animals.

Data availability statement

The datasets generated and/or analyzed during the current study will be available upon reasonable request.

Author contributions

Aya A. S. Huzayyin, contributed to conceptualization, methodology, formal analysis, investigation, resources, data curation, visualization and wrote the original manuscript. Michael K. Ibrahim, contributed to software, formal analysis, investigation, visualization, and reviewing/editing of the manuscript. Nahed M. A. Hassanein contributed to the conceptualization, visualization, supervision, and reviewing/editing of the manuscript. Helmy M. S. Ahmed contributed as a supervisor and reviewed/edited the manuscript. All authors read and approved the final manuscript.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Notes on contributors

Aya A. S. Huzayyin

Aya A. S. Huzayyin, M.Sc. of Pharmaceutical Sciences in Pharmacology & Toxicology/Central Administration of Drug Control/Egyptian Drug Authority (EDA), Giza, Egypt.

Michael K. Ibrahim

Michael K. Ibrahim, Ph.D. Pharmacology and Toxicology/Preclinical Studies unit manager/Central Administration of Biological and Innovative Products and clinical studies/Egyptian Drug Authority (EDA), Giza, Egypt.

Nahed M. A. Hassanein

Nahed M. A. Hassanein, Professor of Physiology/Developmental Pharmacology and Acute Toxicity Department/National Organization for Drug Control and Research (NODCAR), Giza, Egypt.

Helmy M. S. Ahmed

Helmy M. S. Ahmed, Professor of Pharmacology and Toxicology/Department of Pharmacology and Toxicology/Faculty of Pharmacy-Cairo University, Cairo, Egypt.