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Therapeutic potential of mood stabilizers lithium and valproic acid:Beyond bipolar disorder
Open accessAbstract
The mood stabilizers lithium and valproic acid (VPA) are traditionally used to treat bipolar disorder (BD), a severe mental illness arising from complex interactions between genes and environment that drive deficits in cellular plasticity and resiliency. The therapeutic potential of these drugs in other central nervous system diseases is also gaining support. This article reviews the various mechanisms of action of lithium and VPA gleaned from cellular and animal models of neurologic, neurodegenerative, and neuropsychiatric disorders. Clinical evidence is included when available to provide a comprehensive perspective of the field and to acknowledge some of the limitations of these treatments. First, the review describes how action at these drugs' primary targets--glycogen synthase kinase-3 for lithium and histone deacetylases for VPA--induces the transcription and expression of neurotrophic, angiogenic, and neuroprotective proteins. Cell survival signaling cascades, oxidative stress pathways, and protein quality control mechanisms may further underlie lithium and VPA's beneficial actions. The ability of cotreatment to augment neuroprotection and enhance stem cell homing and migration is also discussed, as are microRNAs as new therapeutic targets. Finally, preclinical findings have shown that the neuroprotective benefits of these agents facilitate anti-inflammation, angiogenesis, neurogenesis, blood-brain barrier integrity, and disease-specific neuroprotection. These mechanisms can be compared with dysregulated disease mechanisms to suggest core cellular and molecular disturbances identifiable by specific risk biomarkers. Future clinical endeavors are warranted to determine the therapeutic potential of lithium and VPA across the spectrum of central nervous system diseases, with particular emphasis on a personalized medicine approach toward treating these disorders.
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“Psychotropic medicines may have an anti-inflammatory effect, signified by the fact that 1st episode mania group has a greater level of inflammation in comparison to bipolar mania.”
From Comparison of NLR (neutrophil/lymphocyte ratio) and PLR (platelet/lymphocyte ratio) as inflammatory markers in 1st episode mania and bipolar mania: A preliminary study (2023) · cites this paper as [12]
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In the citing paper
“Lithium and valproate in bipolar disorder are thought to be partly responsible for therapeutic effects via their anti-inflammatory properties.”
From Comparison of NLR (neutrophil/lymphocyte ratio) and PLR (platelet/lymphocyte ratio) as inflammatory markers in 1st episode mania and bipolar mania: A preliminary study (2023) · cites this paper as [12]
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“Different psychotropic medications may affect the inflammatory state via different mechanisms.[12,13]”
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“Lithium and valproate can affect microglial inactivation along with the reduction of overexposed proinflammatory cytokines, nitric oxide synthase, and COX-2.[12]”
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Metadata
- Authors
- Chiu, C.-T., Wang, Z., Hunsberger, J. G., & Chuang, D.-M.
- Affiliations
- National Institutes of Health (US)
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 65
- Issue
- 1
- Pages
- 105-142
- ISSN
- 0031-6997 (ISSN-L)
- PMC
- PMC3565922
- OpenAlex
- W2098378665
- Semantic Scholar
- 6456393e5aa0c08efe167d1c5f7431d6ee18dae1
- Cited by
- 404
- References
- 580
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 14 · 2023: 20 · 2022: 19 · 2021: 39 · 2020: 31 · 2019: 29 · 2018: 27 · 2017: 33 · 2016: 53 · 2015: 42 · 2014: 45 · 2013: 13
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Institute of Mental Health
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- lithium, valproic acid, mood stabilizers, bipolar disorder, glycogen synthase kinase-3, histone deacetylase, neuroprotection, neurotrophic factors, angiogenesis, oxidative stress, protein quality control, stem cell homing, microRNA, neuroinflammation, blood-brain barrier, neurogenesis, anti-inflammation, personalized medicine, risk biomarkers, neurodegenerative diseases, neuropsychiatric disorders
- MeSH terms
- Animals, Bipolar Disorder, Central Nervous System Diseases, Humans, Valproic Acid, Lithium Compounds, Antimanic Agents, Neuroprotective Agents
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