In a 6-month study, the use of adjunctive moderately dosed lithium to optimized treatment in patients with bipolar disorder was well tolerated yet did not lead to improved outcomes or decreased suicidality. However, use of adjunctive lithium resulted in a significant reduction in the use of second-generation antipsychotics.

Those are key findings from the Bipolar Trials Network Lithium Treatment Moderate Dose Study, a randomized trial that compared the use of lithium plus optimized treatment with optimized treatment alone.
Doug Brunk/Elsevier Global Medical News

Dr. Michael Thase

“Currently, only about one-third of bipolar patients take lithium,” Dr. Michael E. Thase said during a psychopharmacology conference sponsored by the Nevada Psychiatric Association. “And outpatients uncommonly take lithium in higher, well-established doses. Today it’s more commonly used in moderate doses in combination with newer generation therapies. However, the value of lower dose, combination strategies has not been well-studied.”

For the outpatient study, known as the Lithium treatment – moderate dose use study, or LiTMUS, and led by Dr. Andrew A. Nierenberg at the Massachusetts General Hospital, investigators at six clinical sites enrolled 283 patients with bipolar I or bipolar II disorder with a Clinical Global Impressions-Bipolar Scale (CGI-BP-S) score of 3 or greater to assess whether lithium, in moderate doses, “could be a useful platform upon which other newer treatments could be evaluated,” said Dr. Thase, professor of psychiatry at the University of Pennsylvania, Philadelphia.

“We were working in partnership with colleagues at the National Institute of Mental Health to do this study in a real-world, relevant way, meaning that it must be inclusive so that people with common comorbidities needed to be in the study, that it needed to be administered in an open way so that the results would be generalizable,” said Dr. Thase, who also pointed out that there was no placebo control group.

The investigators compared lithium plus optimized treatment or optimized treatment without lithium. Patients in the lithium arm were started on 300 mg b.i.d. and sustained on 600 mg/day for 8 weeks, adjusted as needed thereafter. The Texas Implementation of Medication Algorithms for bipolar disorder informed care.

The two main outcomes assessed at 6 months were the CGI-BP-S and the number of Necessary Clinical Adjustments (NCAs), a measure of how difficult treatment was to implement. “This takes into account how many times you had to change the treatment in response to side effects or in response to the treatment not working,” Dr. Thase explained. “The higher the NCA count, the stormier the treatment course.”

A secondary measure was side effect burden as measured by the Frequency and Intensity of Side Effects Ratings, “which provides composite ratings of tolerability rather than focusing on specific side effects,” he said. “These were completed at each study visit by the treating psychiatrist.”

Dr. Thase reported that 84% of patients completed the 6 months of treatment. The attrition rate was not significantly different among those who received lithium, compared with those who did not receive the drug. The modal dose of lithium was 600 mg/day, and the average lithium levels ranged between 0.5-0.6 mEq/L.

Patients who received lithium did not have better outcomes compared with those who did not in terms of overall change in the CGI-BP-S (–1.5 vs. –1.2, respectively). “The average level of improvement for all of our patients was only about a 30% reduction in symptom burden,” Dr. Thase said. “Thus, despite using guideline-based treatment algorithms, more patients remained ill than got better.”

No statistically significant differences were found between groups in terms of depression and manic symptom severity based on the CGI-BP-S, the Quick Inventory of Depressive Symptoms Score, the Quality of Life Enjoyment and Satisfaction Questionnaire Score, and the Modified Scale for Suicidal Ideation Score.

One significant difference in the study was noted at week 2, when patients who received adjunctive lithium required fewer NCAs, compared with those who did not receive the drug. “Keep in mind, however, that the lithium dose was set at 300 b.i.d. for the first 8 weeks, so unless you were deviating from the protocol you couldn’t adjust the lithium dose,” Dr. Thase said. “As a result, the fact that there are fewer adjustments of lithium in the first few weeks of treatment is determined by the [study] protocol. Across the whole 6 months there were no fewer necessary clinical adjustments in the lithium-treated group than in those who received optimized treatment without lithium.”

Another significant finding was that patients who received lithium carried a slightly greater side effect burden during the initial 2 months of treatment (P less than .05), “but it was not different after that time period,” he said. “The intensity of side effects was also greater in the lithium group during the first two months but was not different [than the optimized treatment without lithium group] after that time period.”

There were no serious adverse events specifically related to lithium therapy, but two events (one case of dehydration and one case of acute renal failure) involved medical considerations related to lithium therapy.

The only significant difference in medication use between the two groups pertained to second-generation antipsychotics. Patients who received adjunctive lithium were 15-20% less likely to receive a second-generation antipsychotic (SGA) over the course of the study. “Put another way, if you don’t use lithium in your practice, you are going to be 15-20% more likely to be prescribing SGAs,” Dr. Thase noted.

He acknowledged certain limitations of LiTMUS, including the study’s silence on “the utility of higher doses of lithium or the merits of lithium at higher doses in patients taking simpler psychopharmacology regimens.”

While LiTMUS found that the use of lithium as an adjunct “did not improve the simplicity of the treatment regiment, it didn’t increase it, either,” Dr. Thase said. “So if you know doctors who say ‘I don’t use lithium because it’s too complicated,’ remind them that we did not find lithium complicated in this study.

“In fact … lithium was associated with a clinically meaningful reduction in the use of SGAs, “which means that using it lead to less patient exposure to the newer generation antipsychotics.

Dr. Thase disclosed that he has received research funding from the Agency for Healthcare Research and Quality, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, the National Institute of Mental Health, Otsuka Pharmaceuticals, and Sepracor. He also has received honoraria or is on the scientific board of several pharmaceutical companies.