Serum Lithium Algorithm Predicts Affective Episode Recurrence in Bipolar Patients

Fran Lowry

June 22, 2010

June 22, 2010 (Boca Raton, Florida) — Measuring the coefficient of variation (CV) in the ratio between the level of lithium in the serum and the dose of lithium (L/D ratio) that has actually been prescribed provides an index that can predict a recurrent affective episode in patients with bipolar disorder.

In new research presented here at the New Clinical Drug Evaluation Unit 50th Anniversary Meeting, patients who had unstable L/D ratios were more likely to experience an affective episode relapse than patients with stable ratios, Ellen Frank, PhD, from the University of Pittsburgh School of Medicine in Pennsylvania, said in a poster session.

Lithium remains a cornerstone in the treatment of bipolar disorder even after 5 decades of clinical use. Still, a substantial proportion of patients do not respond adequately to maintenance therapy with lithium. Being able to identify those patients is an important goal, she said.

"This was a long-term maintenance study of patients with bipolar disorder. Our goal in the maintenance phase of the study was to have pretty much all of the patients on consistently therapeutic levels of lithium or lithium plus one other drug," Dr. Frank told Medscape Medical News.

In a 2-year treatment program, the researchers measured lithium levels in 111 patients who had recovered from their index episode and who were receiving maintenance lithium therapy to prevent a recurrent affective episode.

The CV for the L/D ratio was calculated from 8 sequential monthly blood samples that directly preceded any of the 3 study outcomes, which were date of recurrence, dropout, or completion of the 2-year maintenance program, Dr. Frank explained.

Forty-five patients completed 2 years of successful maintenance treatment with lithium, 46 patients experienced a recurrent affective episode, and 20 patients dropped out.

The Pittsburgh team found that the CV of the L/D ratio (mean ± SD) was higher among patients who had recurrent affective episodes (23.1 ± 14.0) compared with those who completed the maintenance program without recurrences (18.2 ± 10.9) or with those who dropped out (16.8 ± 7.4; P = .026).

Within the recurrence group, the CV of the L/D ratio was higher among the 29 patients whose episodes occurred after 20 or more weeks of maintenance treatment (26.4 ± 16.1) compared with 17 patients with recurrences before 20 weeks (17.5 ± 6.7; P = .014), Dr. Frank told meeting attendees.

In contrast, mean serum lithium levels were similar in all outcome groups and did not differ by time to recurrence. The mean ± SD serum level was 0.81 ± 0.15 among patients who experienced recurrence, 0.82 ± 0.16 in those who completed 2 years without recurrence, and 0.80 ± 0.13 in those who terminated the program early (P = .86).

"If you just look at mean serum level over the 2 years of the maintenance phase, or however long the patient was in the trial, you don't really see any difference between people who recurred, people who completed, and people who terminated early, suggesting that there was something really important about looking at variability in the lithium level, rather than just the mean," Dr. Frank told Medscape Medical News.

She added that high variability in the L/D ratio could reflect nonadherence to the prescribed dose, or it could reflect something going on biologically within the patient.

"For example, if we have a patient who is a marathoner and he has got wild variation in his body fluid levels as a result of training for a marathon, that could affect his dose level ratio even though he is being 100% adherent. Also, we do see patients who develop difficulties with kidney function over many years of lithium treatment, so if you happen to be in that window where kidney function is beginning to become less reliable, the level to dose ratio could reflect that."

"I think this study is very important," Mark Hyman Rapaport, MD, chairman and professor of psychiatry and behavioral neurosciences, the Polier Endowed Chair in Schizophrenia and Related Disorders, and vice chair, psychiatry, at the University of California at Los Angeles School of Medicine, told Medscape Medical News.

"What these data show is that there is a simple and easy way to begin to look at the issues around adherence in bipolar disorder, and that by using an inexpensive test, one could potentially design interventions that would facilitate people to be adherent because you could then engage the patient in a collaboration."

Dr. Rapaport suggested that showing patients the results of their tests would open up a dialogue. "The physician could say 'we are seeing that there is more variance here. We need to deal with this because we know that if this continues, you're much more likely to have a relapse'. So I think this is a great idea. I was really enthusiastic seeing that."

Dr. Frank and Dr. Rapaport have disclosed no relevant financial relationships.

New Clinical Drug Evaluation Unit (NCDEU) 50th Anniversary Meeting: Abstract 1, Session II. Presented June 16, 2010.


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