The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis

The scientific paper by Machado-Vieira et al., titled The Role of Lithium in the Treatment of Bipolar Disorder: Convergent Evidence for Neurotrophic Effects as a Unifying Hypothesis, explores lithium’s multifaceted role in managing bipolar disorder (BD). As a cornerstone treatment for over 60 years, lithium not only stabilizes mood but also protects and supports brain health through its neurotrophic effects. The authors discuss how lithium reverses brain atrophy associated with BD, enhances neurotrophic factors like brain-derived neurotrophic factor (BDNF), and modulates critical enzymes such as glycogen synthase kinase-3 (GSK-3). By examining molecular pathways, clinical data, and neuroimaging findings, the study presents lithium as a unique therapeutic agent capable of addressing both the symptoms and underlying pathophysiology of BD.

This study brings together data from human and animal research to explore how lithium supports brain health in people with bipolar disorder (BD) . Researchers used neuroimaging tools like MRI to measure brain structure changes, and they analyzed molecular and cellular pathways affected by lithium. The study highlights key processes, such as lithium’s ability to block harmful enzymes like glycogen synthase kinase-3 (GSK-3) and its role in increasing neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Combining biochemical findings and real-world patient outcomes, the study comprehensively examines how lithium works.

For over six decades, lithium has been the foundation of treatment for BD. It reduces the frequency and intensity of mood episodes and has a unique ability to lower suicide risk. Lithium is not just a mood stabilizer; it also strengthens and protects brain cells. The study notes that “enhancing neuroprotection, which directly involves neurotrophic effects, is a therapeutic strategy intended to slow or halt the progression of neuronal loss.” These benefits suggest that lithium may prevent some of the long-term damage associated with BD.

BD causes stress and damage to brain cells , particularly in areas like the hippocampus, prefrontal cortex, and amygdala, which control emotions and decision-making. Unlike typical neurodegenerative diseases, BD involves subtle changes in brain structure rather than complete degeneration. For instance, “MRI studies consistently show decreased gray matter volume in neural areas regulating cognitive and emotional processing.” However, lithium can reverse some of these changes by promoting cell survival and increasing brain volume in critical regions.

• Lithium increases gray matter volume in regions essential for emotional regulation and memory. The study highlights that “total hippocampal volume was significantly greater in lithium-treated patients with BD compared with healthy controls (by 10%) and unmedicated patients (by 14%).”
• It promotes the production of BDNF, a protein critical for neuron repair and growth. Chronic lithium treatment was shown to increase BDNF levels in the hippocampus and frontal cortex, which are often impaired in BD.

• Lithium blocks GSK-3, a key enzyme that triggers cell death and disrupts neuronal function. By inhibiting GSK-3, lithium activates survival pathways and enhances cellular stability. As noted in the study, “lithium inhibits GSK-3 with an enzyme inhibition constant (Ki) of 1–2 mM, which corresponds to its therapeutic serum range.”
• It reduces oxidative stress and stabilizes calcium levels in neurons, preventing processes like apoptosis (cell death) that are often heightened in BD.

Lithium regulates pathways like the phosphoinositol (PI) cycle, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK), which influence cell signaling and mood regulation. The study notes that “lithium alters signaling pathways that also directly regulate neurotrophic effects,” making it highly effective for managing mood disorders.

The study suggests that lithium’s neurotrophic effects could inspire new drugs that are safer and more effective. While lithium works well for about 50% of patients, it has a narrow therapeutic range and potential side effects, such as thyroid and kidney problems. The authors emphasize that “the search for biological predictors of better lithium response has begun,” which could lead to personalized treatments for BD.

Lithium shows promise for treating other brain conditions. In Alzheimer’s disease models, it reduces the buildup of harmful plaques and improves memory. Lithium delays the onset of symptoms for ALS and extends lifespan in animal studies. The study highlights that “lithium’s ability to regulate Bcl-2 and reduce oxidative stress makes it a potential treatment for other neurodegenerative disorders.” These findings suggest that lithium’s benefits could extend far beyond mood stabilization.

This scientific study underscores lithium’s dual role as a mood stabilizer and brain protector. By enhancing neurotrophic factors like BDNF, reducing oxidative stress, and reversing neuronal damage, lithium provides powerful benefits for people with bipolar disorder. Its mechanisms also offer hope for treating other neurodegenerative diseases, like Alzheimer’s and ALS. As researchers uncover more about how lithium works, its potential to improve mental and neurological health continues to grow. Whether managing BD or exploring cutting-edge neuroscience, lithium remains a cornerstone of modern brain therapy.