1 Boring Old Man

^{Joe: I was looking over some of those trials we buried. Seroquel is kind of a lightweight in spite of all our hype, isn’t it?}

 

Extended Release Quetiapine Fumarate Monotherapy for Major Depressive Disorder:

Results of a Double-Blind, Randomized, Placebo-Controlled Study
by Richard Weisler, J. Mark Joyce, Lora McGill, Arthur Lazarus, Johan Szamosi, and Hans Eriksson
CNS Spectrums 2009;14(6):299-313

^{Introduction: Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy was evaluated in major depressive disorder (MDD).}

^{Method: This was an 8-week (6-week randomized-phase; 2-week drug-discontinuation/tapering phase), double-blind, parallel-group, placebo-controlled study. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) total score randomization-to-Week 6 change. Other assessments included the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and adverse events (AEs).}

^{Results: 723 patients were randomized: 182, 178, 179, and 184 to quetiapine XR 50, 150, 300 mg/day, and placebo, respectively. At Week 6, significant reductions occurred in MADRS score with quetiapine XR 50 mg/day (–13.56; P<.05), 150 mg/day (–14.50; P<.01) and 300 mg/day (–14.18; P<.01) versus placebo (–11.07); at Day 4, reductions for quetiapine XR (titrated to 50 or 150 mg/day according to dose group) versus placebo (–2.9) were: –4.7 (P<.01), –5.2 (P<.001), and –5.1 (P<.001), respectively. At endpoint, MADRS response (≥50% reduction in score) was 42.7% (P<.01), 51.2% (P<.001), and 44.9% (P≤.001) for quetiapine XR 50, 150, and 300 mg/day, respectively; 30.3% for placebo. Overall, quetiapine XR 150 mg/day provided consistently more positive secondary efficacy results than 50 mg/day and 300 mg/day versus placebo. The most common AEs in quetiapine XR-treated patients were dry mouth, sedation, somnolence, headache, and dizziness.}

^{Conclusion: In patients with MDD, quetiapine XR monotherapy (50/150/300 mg/day) is effective in reducing depressive symptoms, with improvement from Day 4 onwards. Safety and tolerability were consistent with the known profile of quetiapine.}

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^{Faculty Affiliations: Dr. Weisler is Adjunct Professor of Psychiatry in the Department of Psychiatry at the University of North Carolina, Chapel Hill, and Adjunct Associate Professor of Psychiatry at Duke University, in Durham, North Carolina. Dr. Joyce is Principal Investigator at CNS Healthcare in Jacksonville, FL. and Dr. McGill is Lead Principal Investigator at CNS Healthcare in Memphis. Dr. Lazarus, Mr. Szamosi, and Dr. Eriksson are employees of AstraZeneca.}

^{Funding/Support: The study (Moonstone; D1448C00001) was funded by AstraZeneca. The study was registered at ClinicalTrials.gov (identifier number NCT00320268).}

^{Acknowledgments: The authors would like to thank Jocelyn Woodcock, MPhil, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca…}

• an academically affiliated, AstraZenica affiliated lead author
• a Clinical Trials Company that organizes and conducts the study
• a Medical Writing Company that… well does something
• AstraZeneca staff in a variety of capacities
• AstraZeneca funding for the project

Looking over a number of these clinical trials, I found them annoying. Using this one as an example, the primary outcome scale was the Montgomery-Åsberg Depression Rating Scale [MADRS]. There’s obviously a difference between placebo and the medication [though the dose doesn’t seem to matter very much]. But there’s a lot of number manipulation involved in the graph. There were many drop-outs [~50%], but unlike the studies in the initial approval, we can’t see them. And the "modified intention-to-treat [MITT] [all patients assigned to randomized treatment who took study medication and who had a MADRS assessment at randomization and ≥1 valid MADRS assessment after randomization]" is a mouthful and a half. Then they used that LOCF [last observation carried forward] method to fill in for missing data. Put all that together and there’s no way to see the primary data. Just looking at the graph itself, it looks like just being in their study is really good for Major Depressive Disorder, and that adding a bit of Seroquel [in any dose] gives you a slight boost. We know from looking at these graphs before that if we’re given the full data, we can evaluate them more precisely, but the information just isn’t here. I don’t doubt that there is a statistical difference, but I question if what I see here is relevant – and there’s absolutely no way to find the answer. They included the more familiar Hamilton Depression Scale [HAM-D] values as a secondary outcome measure: