Clinical Summary: A Double-Blind, Placebo-Controlled Study of Quetiapine and Lithium Monotherapy in Adults in the Acute Phase of Bipolar Depression (EMBOLDEN I)
Acute bipolar depression drives much of the morbidity and disability in bipolar disorder, yet first-line treatment choices still often include agents with limited direct evidence for antidepressant efficacy. This trial matters because it directly compares quetiapine monotherapy, lithium monotherapy, and placebo in adults with bipolar depression and shows which option produced measurable symptom relief over 8 weeks.
Key Findings
- Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d, -16.1 for quetiapine 600 mg/d, -13.6 for lithium, and -11.8 for placebo (P < .001 for both quetiapine doses, P = .123 for lithium, vs placebo).
- At end point (week 8), response rates were 68.6% for quetiapine 300 mg/d and 69.6% for quetiapine 600 mg/d versus 55.8% for placebo, with NNTs of 8 and 7, respectively; lithium response was 62.5% (P = .279 vs placebo; NNT = 15).
- At end point (week 8), remission rates were 69.8% for quetiapine 300 mg/d and 70.3% for quetiapine 600 mg/d versus 55.0% for placebo (P < .01 both doses), while lithium remission was 62.5% (P = .228 vs placebo); the corresponding NNTs were 7, 7, and 13 for quetiapine 300 mg/d, quetiapine 600 mg/d, and lithium, respectively.
- Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 (difference of -2.49 points at week 8, P = .013); at week 8, both doses were also significantly better than lithium on HDRS total score (difference, -1.62; P = .047 for quetiapine 300 mg/d; difference, -1.81; P = .026 for quetiapine 600 mg/d).
- Discontinuation due to adverse events was 10.4% with quetiapine 300 mg/d, 13.9% with quetiapine 600 mg/d, 8.8% with lithium, and 8.4% with placebo; treatment-emergent mania was 4.2%, 2.2%, 2.2%, and 0.8%, respectively, and treatment-emergent suicidal ideation was 1.9%, 1.1%, 0.7%, and 2.3%, respectively.
For acute bipolar depression, quetiapine monotherapy at 300 mg/d or 600 mg/d improved depressive symptoms, response, and remission over placebo within 8 weeks, while lithium did not separate from placebo on the primary efficacy measure. When choosing monotherapy for short-term bipolar depression, quetiapine has stronger acute efficacy data than lithium in this study.
Practice Implications
- Consider quetiapine monotherapy when rapid antidepressant benefit is a priority, since both quetiapine doses were significantly better than placebo from week 1 through week 8 on MADRS and HARS.
- Do not assume lithium monotherapy will provide acute antidepressant efficacy in bipolar depression on the basis of this trial; lithium showed a week 8 MADRS change of -13.6 versus -11.8 for placebo (P = .123).
- Discuss dose tradeoffs with patients: quetiapine 600 mg/d showed some advantages over lithium, including a MADRS difference of -2.49 points at week 8 (P = .013), but had the highest discontinuation due to adverse events at 13.9%.
- Monitor tolerability and mood polarity during treatment, especially somnolence, dry mouth, and dizziness with quetiapine, nausea with lithium, and treatment-emergent mania rates of 4.2% with quetiapine 300 mg/d, 2.2% with quetiapine 600 mg/d, 2.2% with lithium, and 0.8% with placebo.
