The management of mood-stabilizing drugs for patients with renal and/or hepatic disease is similar to a teeter-totter: a balancing act for psychiatric pharmacists, experts said at the AAPP 2025 Annual Meeting, in Salt Lake City.

Psychiatric pharmacists must juggle the doses of these medications—which are prescribed for bipolar disorder, mania and hypomania, and recurrent, severe depression—so that they are effective in aiding mental health, while not causing or worsening liver and/or kidney disease, said Shadi Doroudgar, PharmD, a professor in the Clinical and Social Pharmaceutical Sciences Department at Touro University California College of Pharmacy, in Vallejo, and the lead clinical psychiatric pharmacist at the Pathways to Wellness medical group, in Oakland. Even determining drug doses for patients with healthy livers and kidneys is challenging, as this depends on a patient’s symptoms and clinical history. The process is made trickier by the fact that liver dysfunction and acute kidney injury can cause pharmacokinetic changes in drug absorption, metabolism and excretion, she noted.

Dr. Doroudgar emphasized the importance of fully informing patients about the risks and benefits of taking mood stabilizers. The lowest possible dose should be prescribed; diligent monitoring is required to ensure safety and efficacy; and frequent dosing modifications may be needed. When a mood-stabilizing medication must be used in patients with organ dysfunction, doses need to be limited and organ function monitored frequently.

Lithium Pharmacokinetics and Kidney Impact

Of all mood stabilizers, lithium is considered the “gold standard” in the treatment of bipolar disorder. But it also can cause nephrotoxicity, especially with long-term use. A study in the United Kingdom found that, compared with those prescribed lithium, patients with bipolar disorder who received other drugs experienced lower rates of stage 3 or more severe chronic kidney disease (valproic acid hazard ratio [HR], 0.56; P<0.001; olanzapine HR, 0.57; P<0.001; quetiapine HR, 0.62; P<0.001) (PLoS Med 2016;13[8]:e1002058). The risk for chronic kidney disease also is 30% higher in lithium-treated patients than the average population (Int J Bipolar Disord 2017;5:27 and 2021;9:1). Acute renal failure with lithium intoxication can cause minor tubular changes and/or acute tubular necrosis; recurrent lithium intoxication is believed to promote progressive lithium nephropathy (World Psychiatry 2015;14[2]:119-136).

“Between 13.9% [and] 55% of lithium-treated patients will show progressive renal impairment, reflecting progression to end-stage renal disease during long-term use,” Dr. Doroudgar said. “As a result, periodic monitoring of renal function is essential, even in patients who have been on a stable dose for a very long time.”

She noted that the length of treatment positively correlates with reduced estimated glomerular filtration rate. “End-stage renal failure starts appearing in some patients after continuous treatment of more than 15 to 20 years. [These patients] tend to be age 50 and older [and] have had prior episodes of lithium toxicity, and a high cumulative dose of lithium over their lifetime,” Dr. Doroudgar said. “Although there is not a cutoff for this dose, lithium may need to be discontinued due to progressive renal insufficiency” (BMC Med 2015;13:12 and 2013;11:33).

Factoring in Liver Dysfunction

Liver disease can alter the way that the body absorbs, distributes, metabolizes and excretes psychotropic drugs. It is imperative to monitor patients who receive mood stabilizers and develop acute liver failure or who have chronic liver failure.

Hepatotoxicity caused by psychotropic agents, especially mood stabilizers, is uncommon with standard doses, Dr. Doroudgar emphasized. But because carbamazepine and valproic acid are associated with the highest incidences of hepatotoxicity, she said, they should not be prescribed to patients with preexisting liver disease. Also, the risk for drug-induced liver injury can increase with concomitant administration of multiple hepatotoxic medications.

Clinically apparent hepatotoxicity from carbamazepine is uncommon, but tends to develop within one to eight weeks after starting the drug. Symptoms can be mild, such as a drug rash with eosinophilia developing, or abrupt, with onset of symptoms that are similar to acute hepatitis. Such symptoms may include fever, rash, facial edema, lymphadenopathy, elevations in white blood cell count, and eosinophila or atypical lymphocytosis, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

“Patients may not recognize symptoms of a drug reaction because they are associated with many illnesses or conditions,” Dr. Doroudgar said. “In addition to being informed about the risks associated with a drug, pharmacists need to counsel patients to recognize signs and symptoms of liver dysfunction.”

Carbamazepine-induced hepatotoxicity without immunoallergic features may occur six to 12 months after therapy starts. Whether early or late, once the drug is halted, toxicity resolves and the liver improves within a week. However, Dr. Doroudgar advised that due to the risk for rapid and more severe recurrence, carbamazepine therapy should not be resumed.

Valproic acid produces both therapeutic and toxic metabolites. Liver enzyme elevation occurs when a patient commences this drug regimen. But because rare cases of acute liver failure can occur, it is important to monitor the patient, especially during the early weeks of treatment. Liver tests should be performed before therapy and at frequent intervals, she noted.

“Pharmacists face many key considerations for patients using mood-stabilizing meds in kidney and liver disease,” Dr. Doroudgar concluded. “These include accounting for pharmacokinetic changes in chronic kidney and liver disease, assessing patient-specific factors that are necessary in medication decision-making in the presence of end-organ damage, dosing for safe and effective med use, and tailoring the med regimen based on patient-specific criteria.”

Every Patient a Unique Puzzle

How often pharmacists see patients with kidney or liver disease “will vary based on practice setting and subspecialty, such as inpatient psych, outpatient psych, inpatient medicine and outpatient medicine,” observed Stephanie D. Nichols, PharmD, a professor of pharmacy practice at the University of New England School of Pharmacy, in Portland, Maine, and an adjunct assistant clinical professor of psychiatry at Tufts University School of Medicine, in Boston, who was not involved with the presentation. “Pharmacists who work in acute care medical hospitals are likely to have a very high percentage of patients with acute kidney disease, a moderate percentage of patients with chronic kidney disease, and a moderate percentage of patients with acute and/or chronic liver disease, sometimes as a result of medical poisoning.”

She noted that pharmacists dose lithium more cautiously now than previously, but many patients with a history of lithium nephrotoxicity require lifelong dialysis and/or renal transplant. Dr. Nichols recommended that patients who take lithium should be warned about the risks for lithium toxicity and kidney damage when taking nonsteroidal anti-inflammatory drugs such as ibuprofen without monitoring and supervision.

“Managing these patients does require skill and expertise,” Dr. Nichols said. “In addition to kidney and/or liver disease, we need to consider co-occurring conditions involving organs other than the brain for patients with psychiatric conditions, such as cardiovascular conditions or autoimmune disease.

“Each patient is like an interesting jigsaw puzzle,” she continued. “I envision that by putting the pieces together of their situation, and the medication pharmacology and pharmacokinetics, and considering each part logically, I can use my unique skills as a psychiatric pharmacist.”

Regina Evans, PharmD, a pharmacy clinical specialist at Lee Health, a regional health system headquartered in Fort Myers, Fla., estimated that about one-third of her patients with psychiatric disorders admitted to Lee Memorial Hospital have either acute/chronic kidney or liver dysfunctions. Dr. Evans, who was not involved with the AAPP session, added that liver dysfunction is a particular area of concern for her.

“Liver function is much more difficult to estimate, and dosing recommendations for many of the classic mood stabilizers just state, ‘don’t use in liver dysfunction,’” Dr. Evans said. “When you add in the challenge of varying patient responses to the different agents, options become limited for patients with liver disease.”

Her advice: Be aware that managing acute changes in liver and renal function often involves day-to-day monitoring, as these conditions can resolve.

Order appropriate levels (free vs. bound drug) for drugs that have monitorable levels, and communicate the meaning of these levels to the prescriber to avoid misunderstandings.

If liver or renal function changes become chronic, you may have to rely on studies, case reports and increased monitoring to find a good therapeutic option for your patients.

The sources reported no relevant financial disclosures.