Dr. Analía Bortolozzi, researcher in the IDIBAPS Systems Neuropharmacology group, and Dr. Eduard Vieta, head of the Psychiatry and Psychology Service at the Clínic Barcelona and the IDIBAPS Bipolar and Depressive Disorders group, participated in this review, published in the journal Pharmacological Reviews and selected as a cover article.
This review coincides with the 75th anniversary of the first publication of the use of lithium for the treatment of bipolar disorder (John Cade, The Medical Journal of Australia, 1949) and with the 75th anniversary of the journal, Pharmacological Reviews.
Bipolar Disorder affects the mechanisms that regulate mood and presents as recurrent episodes ranging from mania to depression. One of the main problems is that it takes 5 to 10 years to be detected, because it is often mistaken for depression. “Although there is no cure, proper monitoring and treatment allow most patients to lead a normal life in the work, social and family spheres”, explains Eduard Vieta.
Lithium has been the standard treatment for bipolar disorder for over six decades. It is effective in preventing manic and depressive episodes, as well as in reducing suicidal behaviour. “However, its mechanism of action in mood stabilization remains unknown”, says Analía Bortolozzi.
Analysing lithium’s mechanism of action
This review provides a comprehensive analysis of current knowledge and current hypotheses on the various mechanisms related to the effects of lithium. These findings are based on research using cellular models and animal models of neurodegenerative and psychiatric disorders.
Recent studies have provided evidence for the importance of glycogen synthase kinase-3 (GSK3) as a crucial mechanism. This enzyme is involved in a wide range of cellular processes, including neuroprotection, antioxidant action and neuroplasticity. Inhibition of GSK3 by lithium appears to be a key factor in its ability to stabilize mood and provide neuroprotective effects.
Research also suggests that lithium may interact with the expression of microRNAs, which are small RNA fragments that regulate gene expression. These microRNAs are involved in the regulation of key processes in the brain, including synaptic plasticity and neuroprotection. The modulation of microRNAs by lithium could be another mechanism through which lithium exerts its therapeutic effects.
In addition, several studies show that lithium induces modifications in synaptic plasticity that may play a key role in its clinical efficacy. Synaptic plasticity is the brain’s ability to reorganize itself by forming new neural connections. This process is essential for memory, learning and adaptation to new experiences.
There are translational studies that suggest that lithium may have applications in the treatment of various brain disorders, such as Alzheimer’s disease, Parkinson’s disease and stroke, among others. “These findings significantly broaden the therapeutic profile of lithium”, says Analía Bortolozzi.
Clinical Implications and Future Research
The convergence of evidence between preclinical and clinical models supports the idea that lithium exerts regulatory effects on several brain cellular pathways crucial for neuroplasticity and neuroprotection. These include the neurotrophic response, endoplasmic reticulum regulation, autophagy, oxidative stress, mitochondrial function, and inflammation. The wide range of responses it influences suggests that the effects of lithium may be mediated by the inhibition of GSK3 and IMPase, another key brain enzyme.
These findings provide important clues for developing predictive models of response to lithium treatment and for identifying new biological targets. “This could allow for the personalization of lithium treatment, increasing its efficacy and reducing the side effects”, concludes Eduard Vieta.
Study reference:
Bortolozzi A, Fico G, Berk M, Solmi M, Fornaro M, Quevedo J, Zarate CA Jr, Kessing LV, Vieta E, Carvalho AF. New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview. Pharmacol Rev. 2024 May 2;76(3):323-357. doi: 10.1124/pharmrev.120.000007. PMID: 38697859; PMCID: PMC11068842.
