Why does lithium work against bipolar disorder?

In modern times we tend to think of lithium as powering smartphones and cars, yet its historical fame comes from its role as a mood stabilizer.

Lithium was first used as a treatment for bipolar disorder in 1949. Yet despite decades of research and drug development, this simple medication remains the gold standard for treating one of the most complex psychiatric conditions. But why?

According to Becci Strawbridge, a senior lecturer in psychological medicine at King’s College London, lithium’s simplicity could be what helps it cut through the complexity of bipolar disorder, a lifelong disorder that affects about 36 million people worldwide.

Clinically, bipolar disorder is defined as a mood disorder characterized by specific, lasting changes to a person’s mood and energy levels. Depending on the type of bipolar disorder, individuals can experience manic, hypomanic and depressive episodes — either individually, or in sequence.

However, “experiencing mania itself is sufficient to have a diagnosis of bipolar [disorder],” said Dr. David Cousins, a clinical senior lecturer and honorary consultant psychiatrist at Newcastle University in the U.K. “It’s probably easiest to think of that as the opposite of depression — people become elevated in mood, extremely energized, driven, motivated, and engage in hedonistic behavior with lots of risk taking,” he said. “It’s a highly detrimental, highly damaging, highly disruptive state.”

Treating an illness that operates at such extremes is a difficult balance to strike, with any intervention to treat one emotional state needing to factor in how it could impact the other. “For example, if you gave somebody antidepressants without an antimanic drug, you might either trigger mania or destabilize the illness,” Cousins explained.

A combination of antidepressants, antipsychotics, and mood-stabilizing anticonvulsants are often prescribed in combination to juggle these highly variable symptoms. “There are really very few medications that have an overall effect against both poles,” Strawbridge said. Once stabilized, the challenge then becomes preventing relapse back into this destructive cycle.

Lithium, by contrast, does not suffer from these limitations, Strawbridge added.

“It’s often considered the gold standard for bipolar disorder; it’s helpful for the depression and for the mania, but its main benefit overall is in preventing relapse, so stopping either of those two types of episodes from coming back.”

Psychiatrists usually prescribe lithium as either lithium carbonate tablets or a lithium citrate liquid, both of which dissociate inside the body into lithium ions and their corresponding counterion (either carbonate or citrate). This simple active form is part of what gives lithium its powerful, broad-ranging mood-stabilizing effect, Strawbridge said.

“Because lithium is quite a simple ion, it’s able to disguise itself as sodium, and that means it can slip inside of brain cells, whereas most medications act on the surface of cells,” she explained.

Lithium’s simple form enables it to spread throughout the brain and rest of the body. Once inside, it interacts with many cellular processes, but doctors still don’t really understand the underlying mechanism behind its beneficial effects.

“We know that the monoamine system and the neurotransmitters in the brain that are involved in reward emotions and cognition are disrupted,” Victoria Wing, a clinical lecturer at the National Institute for Health and Care Research at Newcastle University and CNTW NHS Foundation Trust, told Live Science. Included in this disruption is the regulation of crucial mood molecules, such as dopamine and serotonin, which may be underactive or overactive depending on the nature of the bipolar episode.

The same small lithium ion also blocks an enzyme called glycogen synthase kinase 3. This enzyme has wide-ranging downstream effects, such as controlling gene activity, regulating the body’s circadian rhythms and managing inflammation and cell survival.

“Lithium can also help with autophagy, which is the clearance of debris and toxins in cells, and it has antioxidant effects and boosts mitochondrial function, which are important for cell energy processes,” Wing said.

However, despite its manifold therapeutic benefits, lithium does have some drawbacks. While around one-third of people experience profound benefits from the drug, another close third only experience intermediate effects, and the final rough third don’t respond at all.

This means it’s vital to identify which patients respond well to the drug as early as possible, especially because the cyclic nature of the condition means it can take years to ascertain whether lithium is effective in preventing relapses in the long-term, said Cousins. The drug also has a narrow therapeutic window, which means it has a small margin of safety between doses that are high enough to be effective and those that are toxic to the kidneys and thyroid. Some patients who undergo lithium treatment also report having to urinate more frequently or experiencing slight tremors.

As with any medication, some side effects are unavoidable. The alternatives to lithium also carry their own risks. But if carefully and correctly managed, lithium medications can have a transformative impact for patients.

“I’ve met a lot of patients through patient involvement groups that have told me how effective and lifesaving lithium has been for them,” Wing said. “We know it works, but can we fine-tune the use even better so more people can benefit from it?”

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