Frequently Asked Questions

Yes. In EMBOLDEN I, quetiapine monotherapy at both 300 mg/day and 600 mg/day improved depressive symptoms significantly more than placebo over 8 weeks in adults with bipolar depression. Mean change in MADRS total score at week 8 was -15.4 with quetiapine 300 mg/day and -16.1 with quetiapine 600 mg/day, compared with -11.8 with placebo (P<.001 for both quetiapine doses vs placebo).

Significant benefit with both quetiapine doses was seen from week 1 and was maintained through week 8. Quetiapine also significantly improved response and remission rates, HDRS scores, CGI-BP measures, and HARS scores versus placebo.

No. Lithium did not differ significantly from placebo on the primary efficacy outcome in this 8-week study of acute bipolar depression. Mean MADRS total score change at week 8 was -13.6 with lithium versus -11.8 with placebo (P=.123).

Lithium also did not show significant improvement versus placebo on MADRS response or remission rates, HDRS total score, CGI-BP measures, HARS scores, SDS, or MOS-Cog. In a post hoc subgroup with median serum lithium concentrations ≥0.8 mEq/L, improvement in MADRS total score still did not differ significantly from placebo at week 8 (difference of -2.76 points; P=.128).

Quetiapine generally showed stronger acute antidepressant effects than lithium in this trial. Quetiapine 600 mg/day was significantly more effective than lithium on the primary outcome, with a week 8 MADRS difference of -2.49 points (P=.013).

At week 8, both quetiapine doses were also significantly better than lithium on HDRS total score: difference -1.62 for quetiapine 300 mg/day (P=.047) and -1.81 for quetiapine 600 mg/day (P=.026). Both quetiapine doses were more effective than lithium on HARS at week 8, and quetiapine 600 mg/day was significantly better than lithium on several individual MADRS items, including apparent sadness, reported sadness, reduced sleep, and inability to feel.

Quetiapine separated from placebo by week 1 on both depressive and anxiety symptom measures. In the intent-to-treat population, both quetiapine 300 mg/day and 600 mg/day were significantly better than placebo for MADRS total score starting at week 1 and continuing through week 8.

Both doses also showed significant improvement versus placebo on HARS from week 1 through week 8. This study therefore found early symptom improvement with quetiapine during acute treatment of bipolar depression.

At week 8, response and remission rates were significantly higher with quetiapine than with placebo, but not with lithium.

• Response rates: 68.6% with quetiapine 300 mg/day, 69.6% with quetiapine 600 mg/day, 62.5% with lithium, and 55.8% with placebo.
• Quetiapine response was significant versus placebo: P<.05 for 300 mg/day and P<.01 for 600 mg/day. Lithium was not significant versus placebo (P=.279).
• Remission rates: 69.8% with quetiapine 300 mg/day, 70.3% with quetiapine 600 mg/day, 62.5% with lithium, and 55.0% with placebo.
• Both quetiapine doses were significant versus placebo for remission (P<.01), while lithium was not (P=.228).
• Number needed to treat was 8 and 7 for response and 7 and 7 for remission with quetiapine 300 mg/day and 600 mg/day, respectively; for lithium, NNT was 15 for response and 13 for remission.

Yes. Both quetiapine doses significantly improved anxiety symptoms, and quetiapine also showed benefits on functioning measures. HARS scores improved significantly with quetiapine 300 mg/day and 600 mg/day versus placebo from week 1 through week 8, while lithium showed only numerical improvement.

At week 8, quetiapine 600 mg/day significantly improved Sheehan Disability Scale total score (P<.01) and MOS-Cog total score (P=.01) versus placebo. Quetiapine 300 mg/day significantly improved SDS total score (P<.05), while lithium showed only numerical, statistically nonsignificant improvement on SDS and MOS-Cog.

The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine, and nausea with lithium. Most adverse events across treatment groups were mild to moderate in severity.

Discontinuation due to adverse events occurred in 10.4% of patients on quetiapine 300 mg/day, 13.9% on quetiapine 600 mg/day, 8.8% on lithium, and 8.4% on placebo. Serious adverse events were infrequent and similarly distributed across groups: 3.8% with quetiapine 300 mg/day, 2.6% with quetiapine 600 mg/day, 2.2% with lithium, and 2.3% with placebo.

In this study, treatment-emergent mania and suicidal ideation were uncommon across all groups. Treatment-emergent mania occurred in 4.2% of patients on quetiapine 300 mg/day, 2.2% on quetiapine 600 mg/day, 2.2% on lithium, and 0.8% on placebo.

Treatment-emergent suicidal ideation occurred in 1.9% with quetiapine 300 mg/day, 1.1% with quetiapine 600 mg/day, 0.7% with lithium, and 2.3% with placebo. No suicides occurred during the acute treatment phase, but patients at current serious suicidal risk were excluded, so the study cannot provide conclusive evidence about treatment effects in currently suicidal patients.

EMBOLDEN I was an 8-week, multicenter, randomized, double-blind, placebo-controlled trial of monotherapy for acute bipolar depression. The study randomly assigned 802 adults with DSM-IV bipolar I or II disorder and a current major depressive episode to quetiapine 300 mg/day (n=265), quetiapine 600 mg/day (n=268), lithium 600-1,800 mg/day (n=136), or placebo (n=133).

The primary endpoint was change in MADRS total score at week 8. Because the trial was randomized, double-blind, and placebo-controlled, it was designed to compare short-term efficacy and tolerability under controlled conditions; however, the article reports only the acute 8-week phase.

A key limitation is that lithium exposure may have been relatively low for some patients, although even protocol-based and higher-level subgroup analyses still did not show significant benefit over placebo. In the intent-to-treat population, the mean median daily lithium dose was 981 mg and the mean median serum concentration was 0.61 mEq/L, which was at the lower end of the target range.

Only 64.4% of patients in the lithium group achieved median serum concentrations in the target range of 0.6 to 1.2 mEq/L, and 34.9% had median serum concentrations below 0.6 mEq/L. The authors note that some patients may have withdrawn before the first sampling time point or may not have had enough opportunity for dose adjustment, but lithium remained nonsignificant versus placebo in the per-protocol analysis and in the subgroup with median serum lithium concentrations ≥0.8 mEq/L.