Lithium for Bipolar Mania: The Forgotten Gold Standard

Clinical practice guidelines agree: Lithium remains the gold standard for treating mania in patients with bipolar disorder. So noted Stephen Stahl, M.D., Ph.D., a clinical professor of psychiatry and neuroscience at the University of California, Riverside, at the start of his Annual Meeting presentation. Yet as evidenced by recent data, lithium has become underused in bipolar management in favor of antipsychotics.

Over the 90-minute session, Stahl and co-presenter Jonathan Meyer, M.D., a voluntary clinical professor of psychiatry at the University of California, San Diego, made a compelling case that lithium is an undervalued gem that deserves a therapeutic revival.

Stahl told the attendees that several myths have led to lithium’s prescriptive downfall. Among those is the belief that lithium is an old drug that is seldom effective. The truth is that lithium provides more robust mood stabilization than antipsychotics. While some features of mania will improve in patients taking antipsychotics, other aspects related to impulsivity or mood instability can persist.

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. For example, among patients taking just one medication to manage mania following a hospitalization, those on antipsychotics or the anticonvulsant valproate had higher rates of treatment failure than those on lithium.

On top of the robust symptom improvements, lithium has also been associated with reduced suicidality and improved cognitive function in patients—benefits unique to this bipolar medication, Stahl noted.

Lithium does pose some health risks, especially risks to the kidneys, Meyer acknowledged. However, kidney problems are typically related to underlying risk factors like diabetes or hypertension that are common in bipolar patients, and not the medication. Meyer cited some retrospective data from Denmark that found bipolar patients taking lithium or 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, 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 on lithium, 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 does prefer lithium over molecules like sodium, so they should maintain good electrolyte levels. “If they 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 Meyer said identifying that requires psychiatrists to do something difficult—talk to their patient.

“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 do report urinary issues, a clinician can confirm potential renal issues with a blood test to calculate the kidney’s filtration rate or ask a patient to provide a morning urine sample to examine how concentrated it is.

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. Meyer added that the other two common side effects he asks about—hair thinning and skin problems like acne—can also be treated with over-the-counter products (minoxidil and benzoyl peroxide cleaners, respectively).

Meyer agreed that other medication options for bipolar disorder like antipsychotics have clinical evidence supporting their efficacy. “These medications are better than placebo; but I don’t want my patients to do better than placebo,” he said. “I want them to get well.” ■