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Lithium’s Neuroprotective Effects

Lithium’s Neuroprotective Effects

Lithium, used to treat affective disorders for more than a half-century, has neurotrophic and neuroprotective properties that may help preserve cognitive function in patients with bipolar disorder and possibly in those with Alzheimer disease. At the American Psychiatric Association’s annual meeting in San Francisco, Ariel Gildengers, MD, Associate Professor of Psychiatry at the University of Pittsburgh, told scientific session participants that “more than 75 studies and more than 5 reviews have established an association between bipolar disorder and cognitive dysfunction.”

Specifically, Gildengers described a large meta-analysis of individual patient data across 31 studies of cognitive impairment in bipolar disorder by Bourne and colleagues.1 The researchers found evidence of significant cognitive impairment in patients with bipolar disorder, even during periods of euthymia. They concluded that the impairments “seem unrelated to drug treatment.”

Dysfunction is present in executive function, verbal memory, and information processing, and the deficits are apparent in first-degree relatives, said Gildengers, who spoke during the Advances in Geriatric Psychopharmacology session. There are studies of identical twins who are discordant for bipolar disorder.2 The twin without the illness has a similar pattern of cognitive deficits, although not as severe, but “there is something genetically present.”

The two most common findings in patients with bipolar disorder are enlarged ventricles and increased white matter hyperintensities (WMHs), Gildengers said. While acknowledging that enlarged ventricles are present in patients with schizophrenia and that WMHs are present in aging adults, he said their prevalence is higher than expected in individuals with bipolar disorder.

Bipolar disorder is “not simply a disease of the brain,” but it is rather “a multisystem disorder,” according to Gildengers. Some of the biological mechanisms include altered mitochondrial function, dysregulated dopaminergic/glutamatergic systems, and inflammation.

“The good news is that some of the medications, such as lithium, quetiapine (Seroquel), and valproate (Depakote, Depakene), have very positive effects on some of the things that may be deranged in bipolar disorder, such as abnormalities of brain-derived neurotrophic factor (BDNF) and the protein Bcl-2,” Gildengers said. “Lithium enhances BDNF and Bcl-2. These are neuroprotective factors that may lead to neuronal health. Lithium may also reduce oxidative stress.”

More recently, there has been significant interest in lithium’s ability to inhibit glycogen synthase kinase-3 (GSK-3). Increased activity or overexpression of GSK-3 is associated with an increase in tau hyperphosphorylation and alterations in amyloid-β processing related to the formation of neurofibrillary tangles and plaques, which are the hallmarks of Alzheimer disease. “What I’m suggesting here is that lithium may be a treatment for Alzheimer disease,” Gildengers said.

A significant research question is whether the incidence of dementia and of the pathological markers of Alzheimer disease are lower in older patients with bipolar disorder who have been taking lithium for a very long time than in those with bipolar disorder who have been taking other medications.


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