Lithium’s Neuroprotective Effects

[[{"type":"media","view_mode":"media_crop","fid":"17324","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_6001640685529","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"909","media_crop_rotate":"0","media_crop_scale_h":"129","media_crop_scale_w":"160","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]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.

In 2007, Nunes and colleagues³ published a report of a cross-sectional study that examined lithium and the risk of Alzheimer disease in elderly patients (60 years and older) with bipolar disorder. The researchers found that the prevalence of dementia was lower in the patients who were receiving continuous lithium treatment than in those who were not.

Case registry studies have also found a lower risk of Alzheimer disease in bipolar patients after long-term lithium use, according to Gildengers. He described the work of Kessing and colleagues⁴ that linked registry data on prescribed lithium in all patients discharged from a psychiatric health care service with a diagnosis of mania or bipolar disorder and subsequent diagnoses of dementia. Continued treatment with lithium was associated with a reduced rate of dementia in patients with bipolar disorder in contrast to continued treatment with anticonvulsants, antidepressants, or antipsychotics.

Certainly, there is the concern that having bipolar disorder may increase the patient’s risk for dementia, but among individuals with bipolar disorder who took lithium continuously, their rate for having dementia returned to that of the general population, Gildengers said.

In their research, Nunes and colleagues found that among older patients with bipolar disorder, the prevalence of dementia was 19%-almost 3 times that expected in the elderly Brazilian population. But in their study, the prevalence of Alzheimer disease was increased only in patients who had not received recent continuous lithium treatment (33%). Conversely, the prevalence of Alzheimer disease in the continuous lithium group (5%) was similar to that reported in the elderly general population in Brazil.

Gildengers’ study

Gildengers also presented preliminary data from his ongoing study of the effects of long-term lithium treatment in older adults with bipolar disorder. He and his colleagues are comparing patients with bipolar disorder (50 years or older) who have been taking lithium for 10 or more years with patients with bipolar disorder who had minimal or no exposure to lith-ium and also with mentally healthy controls matched for age, education, and medical burden.

Gildengers’ team has been studying older patients with bipolar disorder for the past decade and has been giving them repeated cognitive assessments and brain scans. The team is looking at cognitive function assessed across multiple domains (eg, language, memory, information processing speed, executive function, visuospatial ability, and attention) and at neuroimaging measures of brain health, specifically WMH burden, and fractional anisotropy (a measure of brain integrity). Comparing the patients with bipolar disor-der with controls, Gildengers’ team found that those with bipolar disorder have “much higher markers of inflammation,” lower total gray matter, and lower brain integrity values.

Gildengers said that those with bipolar disorder who have had lithium treatment for a decade or more have “significantly lower amounts of white matter hyperintensity burden than those with minimal or no exposure. They look like the controls.”

Lithium for Alzheimer disease

Some studies have explored lithium’s effects on mild cognitive impairment (MCI) (mild neurocognitive disorder) and Alzheimer disease; the results have been mixed. For instance, Hampel and associates⁵ tested the effects of short-term (10 weeks) lithium treatment in patients with mild Alzheimer disease. The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau and GSK-3 activity in lymphocytes. No treatment effect on GSK-3 activity or CSF-based biomarker concentrations was observed.

In a small, open-label study to investigate the feasibility and tolerability of lithium for Alzheimer disease, Macdonald and colleagues⁶ gave low-dose lithium to 22 patients with Alzheimer disease for up to a year. Discontinuation rates were high, but reports of adverse effects on the primary outcome scale did not differ between those who discontinued therapy and those who remained in the study. There were no differences in deaths, dropouts, or changes in the Mini Mental State Examination (MMSE) between patients who received lithium and the comparison group.

Conversely, in a single-center, randomized, double-blind, placebo-controlled study, Forlenza and colleagues⁷ sought to assess the potential neuroprotective effects of longterm low-dose lithium treatment in patients with amnestic MCI. Participants with amnestic MCI were randomized to receive lithium (0.25 to 0.5 mmol/L) (n = 24) or placebo(n = 21) in a 12-month trial. Lithium treatment was associated with a significant decrease in CSF concentrations of phosphorylated tau and better performance on the cognitive subscale of the Alzheimer Disease Assessment Scale and on attention tasks.

“The number of patients who progressed from amnestic MCI to Alzheimer disease was higher in the placebo group, which is suggestive evidence that lithium may be helpful against Alzheimer disease,” Gildengers said.

A more recent clinical trial conducted by Nunes and colleagues⁸ explored the use of microdose (300 µg/d) lithium administered to patients with Alzheimer disease for 15 months. In the evaluation phase, the treated group showed no decreased performance on the MMSE, yet the control group showed lower MMSE scores. Significant differences between the lithium-treated and control groups were observed starting at 3 months after treatment initiation. Their findings suggest that microdose lithium treatment is efficacious in preventing cognitive loss, which reinforces its therapeutic potential to treat Alzheimer disease.

In a recent review of lithium and the evidence regarding its neuroprotective properties and possible use in neurodegenerative diseases, Diniz and colleagues⁹ concluded that “current evidence points to a potential role of lithium as a drug with disease modifying properties in Alzheimer disease.” But they warned “it is very important to emphasize that the risk-benefit ratio of using lithium for neuroprotection is still very unclear and lithium should not yet be used for neuroprotection in older adults.” Additional clinical trials are necessary to establish efficacy, optimal dose regimen, and duration of drug use to attain optimal clinical benefit.

Carl Salzman, MD, Professor of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center and Massachusetts Mental Health Center in Boston and a discussant in the Advances in Geriatric Psychopharmacology session, also urged caution. “Lithium had been slipping into American obscurity in the past 10 years, but it is making a welldeserved comeback as a therapeutic substance that may have numerous uses. Not only is it the best mood stabilizer, but . . . it may have protective effects on the central nervous system. These effects could be clinically relevant and could provide the foundation for new research into molecular changes occurring in late life that may be associated with cognitive and other dysfunction.” Lithium may increase mitochondrial activity; may decrease oxidative stress; may suppress GSK-3; may increase levels of BDNF, which is food for neurons; and may even increase cortical gray matter.

“That’s all terrific. But in real life, lithium is hard to use in the elderly. It is highly toxic. Blood levels, in general, need to be quite low for therapeutic effect,” he warned. Lithium is difficult to use in older adults because of drug interactions and lithium’s effects on the kidney and thyroid. Also, the toxicity of lithium in older adults is mostly neurocognitive, which “may interfere with our diagnostic assessment of whether the patient is getting worse neurocognitively or whether the patient is experiencing a lithium side effect.” Moreover, compliance is very difficult in older adults, which makes most clinicians reluctant to use lithium as a mood stabilizer for that age-group.

Summing up, Gildengers told Psychiatric Times that while the growing evidence base for the positive effects of lithium on brain health is compelling, the evidence remains preliminary. “More carefully controlled, prospective clinical trials are needed before we can definitely say that lithium can protect or mitigate against the effects of neurodegenerative illnesses, such as Alzheimer disease.”

References:

1. Bourne C, Aydemir O, Balanzá-Martínez V, et al. Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis. Acta Psychiatr Scand. 2013 Apr 26; [Epub ahead of print].

2. Gourovitch ML, Torrey EF, Gold JM, et al. Neuropsychological performance of monozygotic twins discordant for bipolar disorder. Biol Psychiatry. 1999;45:639-646.

3. Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007;190:359-360.

4. Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? Bipolar Disord. 2010;12:87-94.

5. Hampel H, Ewers M, Bürger K, et al. Lithium trial in Alzheimer’s disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009;70:922-931.

6. Macdonald A, Briggs K, Poppe M, et al. A feasibility and tolerability study of lithium in Alzheimer’s disease. Int J Geriatr Psychiatry. 2008;23:704-711.

7. Forlenza OV, Diniz BS, Radanovic M, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-356.

8. Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 2013;10:104-107.

9. Diniz BS, Machado-Vieira R, Forlenza OV. Lithium and neuroprotection: translational evidence and implications for the treatment of neuropsychiatric disorders. Neuropsychiatr Dis Treat. 2013;9:493-500.