Lithium in the Management of Bipolar Mania: A Comeback Worth Seeing

Clinical practice guidelines agree: Lithium remains the gold standard for treating mania in patients with bipolar disorder. Yet as evidenced by recent data, clinical practice reality does not agree, said Stephen Stahl, M.D., Ph.D., a clinical professor of psychiatry and neuroscience at the University of California, Riverside. People with bipolar disorder are increasingly being prescribed antipsychotics in place of lithium.

Current prescription trends show that the power of promotion trumps the power of evidence, Stahl said at the start of today’s Annual Meeting session on the benefits and potential side effects of lithium. Over 90 minutes, he and co-presenter Jonathan Meyer, M.D., a voluntary clinical professor of psychiatry at the University of California, San Diego, made their case that lithium is an undervalued gem that deserves a therapeutic revival.

Stahl told the attendees that several myths have led to lithium’s decline. While the myths primarily paint lithium as a drug that poses health risks and requires complicated patient management, it is also thought of as ineffective because it’s old.

But while newer atypical antipsychotics can improve mania symptoms, they don’t treat underlying aspects of the disorder, thus leaving a risk of emergent psychosis, impulsivity, or mood instability. Stahl said this phenomenon was aptly described by Danish psychiatrist and lithium pioneer Mogens Schou, M.D., as follows: “An experienced patient, who during previous manias had first tried a neuroleptic and then lithium, reported that during treatment with the former he felt as if the gas pedal and the brake were pressed down at the same time. With lithium it was as if the ignition had been switched off.”

Observational studies have borne this out, Stahl continued. Among patients taking monotherapy for bipolar disorder, those on antipsychotics have higher rates of treatment failure than those on lithium.

What about valproate? While it is roughly comparable to lithium in efficacy for mania, this drug poses significant neurodevelopmental risks that should make it a nonstarter — for both women and men. Stahl said the link between valproate use during pregnancy and congenital birth defects and other problems has been well established, and this past January, the European Medicines Agency warned that use of valproate in men within three months of conception may increase the risk of neurodevelopmental problems in their children.

Stahl added that the U.K. has likewise become more cautious; in 2023, new valproate prescriptions were prohibited for men and women under 55 years unless no other options are available.

Lithium may pose some health risks as well, especially for the kidneys, Meyer acknowledged during his portion of the talk. However, kidney problems are typically related to underlying risk factors like diabetes or hypertension that are common in bipolar patients rather than to the medication. Meyer cited retrospective data from Denmark indicating that bipolar patients taking lithium or anticonvulsants like valproate have similar risk levels of chronic kidney disease.

Meyer said most concerns related to lithium toxicity can be alleviated by following two simple commandments:

• Thou shall give patients lithium once a day, at bedtime.


• Blood levels of lithium shall not go above 1.0 mEq/L for outpatients.

Meyer said the practice of prescribing lithium twice daily is an artifact of the 1950s and 1960s. Given lithium’s half-life of around 12 to 24 hours, a bedtime dosing schedule is sufficient to maintain therapeutic levels in the brain while ensuring more accurate blood readings. If nausea (a common side effect) is an issue, patients can initiate lithium with twice-daily half-doses for a week or so, Meyer said. Another option is to use a sustained-release lithium capsule that dissolves in the gut over several hours. Once a patient is established, maintaining a dose of 0.6-0.8 mEq/L minimizes toxicity complications.

To keep kidneys healthy, Meyer said that patients and clinicians should just be aware that a key channel for ion transport in the kidneys is more selective for lithium over molecules like sodium, so they should maintain good electrolyte levels. “If patients get dehydrated, they should drink electrolyte solutions and not just water,” he said. One of the first signs of potential kidney trouble is polyuria, and he said identifying that requires psychiatrists ask their patients about side effects.

“I always ask my patients about three potential lithium side effects that are difficult to observe,” Meyer told attendees. “Is your hair thinning? Do you have any rashes? Are you peeing too much?” If patients report urinary issues, a clinician can confirm potential renal issues with a blood test to calculate the kidney’s filtration rate or ask patients to provide a morning urine sample to determine if their urine is concentrated enough.

The good news is polyuria is easily treated if identified early, Meyer continued. The diuretic amiloride blocks the lithium-sensitive ion channel and can quickly reverse the urinary problem. ■

(Image: Getty Images/iStock/LumiNola)