The Neuroprotective Effects of Lithium

February 14, 2020
David N. Osser, MD
Volume 37, Issue 2

Do you need help persuading patients to try lithium?

Do you need help persuading patients to try lithium? A major but often underemphasized benefit of lithium is its unique neuroprotective effects. Bipolar disorder seems to be a condition characterized by gradual progressive shrinkage in some areas of cortical gray matter as well as some tracks of white matter. These losses are associated with increased neurocognitive impairment. However, in patients who have been treated with long-term lithium, there is better preservation of white matter structural integrity.1 Reduction of gray matter volume in bipolar patients has been shown to be arrested, or even reversed to some degree, by lithium. No other mood stabilizers have this effect. Some ambivalent patients have been persuaded to accept lithium after reading the article by Giakoumatos and colleagues.1

At the microcellular level (in rats), lithium is protective against neuronal apoptosis (destruction) and glutamate-induced cytotoxicity, and it promotes dendritic length and number in the hippocampus.2 The preservation of cognitive function in humans with bipolar disorder seems to occur through the brain-derived neurotrophic factor (BDNF) system: lithium markedly increases secretion of BDNF from cortical and hippocampal neurons and upregulates intracellular production of relevant proteins.3

The evidence for lithium’s neuroprotection even extends to the prevention, treatment, or slowing of mild cognitive impairment, Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis in non-bipolar patients.4 Even low-dose lithium has been found in preliminary studies to slow the progression of Alzheimer disease.

Given this information, it should not be surprising that the benefits of lithium treatment seem to exist for patients across the life span.5 However, there is no reason to wait: the long-term benefits seem greatest when lithium is started early in the course of the illness,6 perhaps because some of the brain structural losses may be irreversible. These mechanisms of lithium action also help explain the evidence that of all medication regimens used for bipolar treatment, lithium is the medication most likely to be maintained as a monotherapy over time. This has been demonstrated in surveys of bipolar patients receiving maintenance treatment in the US and in two European studies.7


Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, MA.


1. Giakoumatos CI, Nanda P, Mathew IT, et al. Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder. J Psychiatr Res. 2015;61:180-187.

2. Nunes MA, Schowe NM, Monteiro-Silva KC, et al. Chronic microdose lithium treatment prevented memory loss and neurohistopathological changes in a transgenic mouse model of Alzheimer disease. PLoS One. 2015;10, e0142267.

3. De-Paula VJ, Gattaz WF, Forlenza OV. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor in cortical and hippocampal neurons at subtherapeutic concentrations. Bipolar Disord. 2016;18:692-695.

4. Forlenza OV, De-Paula VJ, Diniz BS. Neuroprotective effects of lithium: implications for the treatment of Alzheimer disease and related neurodegenerative disorders. ACS Chem Neurosci. 2014;5:443-450.

5. Young RC, Mulsant BH, Sajatovic M, et al. GERI-BD: A randomized double-blind controlled trial of lithium and divalproex in the treatment of mania in older patients with bipolar disorder. Am J Psychiatry. 2017;174:1086-1093.

6. Kessing LF, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry. 2014;205:214-220.

7. Hayes JF, Marston L, Walters K, et al. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15:53-58. 

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