NIH Grant Fuels Study of Mechanisms Behind Lithium’s Bipolar Benefits

Cleveland Clinic researchers have received a $3.7 million National Institutes of Health R01 grant to investigate the effects of lithium on the brains of patients with bipolar disorder. The element’s mood-stabilizing qualities have been recognized for decades, but its exact mechanisms of action are poorly understood.

“Lithium is one of the most specific and effective treatments we have for bipolar disorder, but no one knows how it works,” says psychiatrist Amit Anand, MD, who is leading the study. “This research will address important knowledge gaps by exploring changes in the brain and at the molecular level in patients on lithium therapy.”

Dr. Anand is Vice Chair for Research in Cleveland Clinic’s Center for Behavioral Health and directs the Mood and Emotional Disorders Across the Life Span (MEDALS) program in the Department of Psychiatry and Psychology.

Study design

The five-year study will recruit 90 patients diagnosed with bipolar II disorder (depressed type) who are not on medications. Participants will be studied with MRI and blood testing at baseline and after two, eight and 26 weeks of lithium monotherapy. In addition, 30 closely matched healthy controls will undergo the same testing, but without treatment. Preliminary results are expected to be available in about three years.

The investigations are multifold:

• Brain imaging will be conducted with 7 tesla (7T) MRI using Cleveland Clinic’s ultra-high-resolution 7T scanner, which dramatically increases the sensitivity of imaging compared with conventional scanning. Subjects will undergo resting-state functional MRI (a sample image is at the top of this post), which detects areas of brain activity when a subject has not been told to think about anything specific, and diffusion-weighted structural imaging, which reveals brain anatomy in great detail.
• Gene expression changes will be assessed by analyzing RNA from peripheral blood lymphocytes. Unlike DNA, which is constant in an individual throughout life, RNA analysis reveals which genes are being transcribed in a cell at a given time. Such gene expression profiling (see image below) provides a window into cellular activity and may reveal interesting contrasts between patients and healthy controls. This work will build on a study of lithium gene expression effects that Dr. Anand published last year (Mol Neuropsychiatry. 2016;2:115-123).
• The effects of lithium on imaging and gene expression will be further correlated with improvements in depression and mood stability over the six months of therapy.

A gene expression microarray of the type to be used in the new study.

Exploring brain networks

Dr. Anand is a leader in the field of advanced neuroimaging in bipolar disorder. He is especially interested in characterizing the neural networks or “connectomes” between different regions of the brain rather than focusing on possible abnormalities in discrete areas. The functional and structural MRI scans obtained in this study will be analyzed using graph theory metrics and independent component analysis, sophisticated mathematical techniques for revealing hidden factors underlying apparently random signals. They are anticipated to provide important insights into how mood elevation and stabilization affect brain networks.

A newly published Cleveland Clinic study led by Dr. Anand (J Affect Disord. 2018;225:4-12) found that clinical improvement during lithium therapy in patients with bipolar disorder correlated with changes in the brain’s amygdala-ventromedial prefrontal cortex. This study had fewer test subjects than the new study, observed the effects of lithium therapy for only eight weeks and evaluated only resting-state functional connectivity. “Our initial study led to interesting results despite its limited scope,” Dr. Anand notes. “We are eager to confirm and expand our findings with this larger and more extensive investigation of both short- and longer-term effects of lithium therapy, using the most sophisticated imaging and cellular analysis techniques available.”

Lithium therapy — a balancing act

Beside its very specific effects for treatment of bipolar disorder, lithium’s benefits have recently been touted in the popular and scientific press, with some experts even suggesting that lithium should perhaps be added to drinking water to provide public health benefits (JAMA Psychiatry. 2017;74:983-984). Several studies have shown that high levels of naturally occurring lithium in drinking water are associated with reduced suicide rates as well as a lower risk of dementia.

The problem with lithium, Dr. Anand explains, is that too much of it can lead to lithium toxicity, which, if not treated, can evolve from gastrointestinal symptoms to confusion, seizures and coma. Therefore, lithium treatment should always be administered under the care of a physician.

Lithium also interacts with multiple drugs and foods that can either enhance or diminish its effects. Frequent lithium monitoring is required to ensure that blood levels stay in the therapeutic range.

Dr. Anand expects that a better understanding of the effects of lithium will enable development of safer drugs with similar benefits but without the associated toxicities. “This new study provides a novel paradigm to investigate the effects of lithium and other psychotropic drugs,” he says. “Our ultimate goal is to discover biomarkers that can be used for treatment monitoring and drug development.”