Why Lithium Remains the Gold Standard Treatment for Bipolar Disorder

Today, lithium is widely associated with smartphones, batteries and electric cars. Historically, however, its medical importance came from its role as a mood stabilizer.

Lithium was first used to treat bipolar disorder in 1949. Despite decades of research and drug development, this simple treatment remains the gold standard for bipolar disorder. Why has lithium remained so effective for one of the most complex mental illnesses?

What is bipolar disorder?

According to Rebecca Strawbridge, a senior lecturer in psychological medicine at King’s College London, the simplicity of lithium may help address the complexity of bipolar disorder—a lifelong condition that affects about 100,000 people in the context described and approximately 36 million people worldwide.

Bipolar disorder is a mood disorder involving persistent changes in mood and energy. Depending on the type and course of the illness, a person may experience episodes of mania, hypomania and depression either individually or sequentially.

“Experiencing mania itself is sufficient to warrant a diagnosis of bipolar disorder,” said Dr. David Cousins.

During mania, people can become extremely energetic, motivated and impulsive. They may take significant risks or engage in pleasurable but potentially harmful behavior. Treating this state is challenging because medication must also account for the risk of depression and future mood episodes.

Why treating bipolar disorder is difficult

Managing bipolar disorder requires balancing two opposing mood states. A treatment that helps one state can sometimes worsen the other.

For example, using an antidepressant without an antimanic medication can trigger mania or destabilize the illness, Cousins explained.

Antidepressants, antipsychotics and mood-stabilizing anticonvulsants are often prescribed in combination to manage bipolar symptoms. However, relatively few medications have an overall effect on both mania and depression. Once a person is stable, doctors must also work to prevent the destructive cycle from returning.

How lithium helps prevent mania, depression and relapse

Unlike many other treatments, lithium can help address both major poles of bipolar disorder: mania and depression. Its most important overall benefit may be relapse prevention—helping stop either type of episode from returning.

Psychiatrists typically prescribe lithium as lithium carbonate tablets or lithium citrate liquid. These forms separate in the body into lithium ions and their corresponding counterions, carbonate or citrate. This simple, active form is part of what gives lithium its broad mood-stabilizing effects, Strawbridge said.

“It’s often considered the gold standard for bipolar disorder. It’s effective for both depression and mania, but its main benefit overall is relapse prevention, stopping either of these two symptoms from coming back.”

How lithium works in the brain

Lithium is a small ion that can resemble sodium. Because of this, it may pass into brain cells in ways that many other medications cannot, according to Strawbridge.

Lithium can diffuse throughout the brain and the rest of the body. Once inside the body, it interacts with many cellular processes, although researchers still do not fully understand the mechanisms behind its beneficial effects.

Victoria Wing, a clinical lecturer at Newcastle University’s National Institute for Health Research and CNTW NHS Foundation Trust, said that lithium affects monoamine systems and neurotransmitters involved in emotion and reward. These include dopamine and serotonin, which may be underactive or overactive depending on the type of bipolar episode.

Lithium ions also block an enzyme called glycogen synthase kinase 3. This enzyme has a range of effects, including regulating gene activity, circadian rhythms, inflammation and cell survival.

“Lithium also aids in autophagy, the removal of debris and toxins within cells, has antioxidant properties, and promotes mitochondrial function, which is important for cellular energy processes,” Wing said.

What are the risks and side effects of lithium?

Lithium is not effective for everyone. About one-third of people experience a large benefit, another third experience an intermediate effect, and nearly one-third do not respond to the drug.

Identifying likely responders as early as possible is important because bipolar disorder is cyclical. It can take years to determine whether lithium is preventing long-term relapse, Cousins said.

Lithium also has a narrow therapeutic range. This means there is only a small margin between a dose that is effective and one that can become toxic to the kidneys and thyroid. Some people taking lithium report side effects such as increased urination or slight tremors. Medical monitoring is therefore an important part of treatment.

As with any medication, lithium has risks, and alternatives also have potential side effects. When prescribed and monitored carefully, however, lithium can have a transformative effect on patients.

“I have met many patients through patient engagement groups who have told me how effective lithium has been for them and how it has saved their lives,” Wing said. “We know it works, but can we fine-tune how it’s used so more people can benefit from it?”

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