Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.
There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.
Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).
Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.
"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.
Adverse effects, predictors of response
Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.
Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.
The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).
Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).
To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).
"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."
Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.
Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.