HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.
That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.
Dr. Andrew A. Nierenberg
By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.
"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.
"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."
Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.
‘Rules of engagement’
The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.
The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.
"But they could get anything else that they needed," Dr. Nierenberg said.
At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.
This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.
‘Similar’ results
Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.
For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."
The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.