Brigham Researchers Take a Closer Look at Lithium’s Effects on the Brain

Close up of a pile of pink lithium tablets with "223" imprinted on one side

Lithium has been used as a treatment for bipolar disorder for decades, but very little is known about its mechanism of action in the brain. While many newer drugs have been developed to treat the condition, lithium remains a mainstay for the treatment of bipolar disorder and other psychiatric illnesses in psychiatry’s toolbox.

Investigators at Brigham and Women’s Hospital are now using brain imaging and laboratory research to examine precisely how lithium affects the brain at the molecular, neuronal, and brain-circuit levels. They are also studying how it may actually increase the growth of certain areas of the brain and influence the organ at a structural level.

“Lithium has been shown to be very effective at treating bipolar disorder and reducing the incidence of suicide in certain populations,” says Amit Anand, MD, a psychiatrist at the Brigham. “At the same time, it’s very interesting because it’s a chemical element. Most medications belong to a class made up of similar drugs, but there is really nothing else like lithium.”

Correlating Gene Expression and Brain Changes

In a study published in Translational Psychiatry in April 2020, Dr. Anand and colleagues collected MRI scans and blood samples from 21 people with bipolar disorder before lithium treatment and at two and eight weeks after treatment. As a control, they also collected matched samples from 16 healthy, untreated individuals.

The research showed that after eight weeks of lithium treatment, the subjects had significant increases in gray matter fraction, global cortical thickness, and the thickness of frontal and parietal cortices. Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures.

Additionally, several genes showed significant expression changes; nine out of 14 pathways that were identified as being affected by lithium correlated significantly with the structural changes that were observed. These findings corresponded with lab research showing that lithium can boost the growth of neurons and suggest that lithium may also be useful in treating other diseases such as neurodegenerative disorders.

“Lithium goes inside neurons and has a direct effect on DNA and gene expression, particularly on neurotropic genes that help the growth of neurons,” Dr. Anand says. “We can correlate those changes with what we see happening on brain scans. This gives us more power to identify the changes in those genes, which would help in the development of other novel treatments for bipolar disorder and other psychiatric illnesses for which lithium has been found to be useful.”

Expanding Efforts to Find Drugs for Depression

Dr. Anand and his colleagues are now launching a new study to get a closer look at these effects. The National Institutes of Health has funded a larger trial that will include not only structural and functional brain scans, but also analysis of blood samples to look for changes in gene expression. Patients with bipolar disorder who are not currently taking any medications are eligible to participate. The patients will be treated with lithium and followed for six months.

“We’re using the Brigham’s 7-Tesla scanner, which is the strongest scanner approved by the U.S. Food and Drug Administration for use in human subjects and is very sensitive at picking up signals from the brain,” Dr. Anand says. “We plan to use resting-state brain connectivity and diffusion tensor imaging to look at the white matter fibers in the brain to see the changes after short- and long-term lithium treatment.”

In the future, the team plans to do similar kinds of studies looking at how other drugs, such as ketamine, affect brain structure in people who are being treated for treatment-resistant depression.

“There’s also a lot of interest in using psychedelics and MDMA to treat depression,” Dr. Anand says. “It’s important to establish experimental paradigms to do this kind of translational research and develop a deeper understanding of how these treatments work.”

Leave a Reply