Data from: Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

Objectives: To reanalyse SmithKline Beecham’s Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine. Design: Double blind randomised placebo controlled trial. Setting: 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998. Participants: 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality. Interventions: Participants were randomised to eight weeks double blind treatment with paroxetine (20-40 mg), imipramine (200-300 mg), or placebo. Main outcome measures: The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified. Results: The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group. Conclusions: Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

研究目的：本次研究旨在重新分析史克必成公司的329研究（该研究由Keller等人于2001年发表），该研究的原始主要目的为比较帕罗西汀、丙米嗪与安慰剂治疗单相重性抑郁障碍青少年的疗效与安全性。本次在恢复隐匿与废弃试验（Restoring Invisible and Abandoned Trials, RIAT）倡议下开展的再分析，旨在探究获取并重新分析随机对照试验的完整数据集是否会对循证医学产生具有临床意义的影响。研究设计：双盲随机安慰剂对照试验。研究地点：1994年4月20日至1998年2月15日期间，北美12所学术精神病学中心。研究对象：275名病程至少8周的青少年重性抑郁障碍患者。排除标准包括多种共病精神与躯体疾病及自杀倾向。干预措施：受试者被随机分配接受8周双盲治疗，方案为帕罗西汀（20~40mg）、丙米嗪（200~300mg）或安慰剂。主要结局指标：预先设定的主要疗效变量为8周急性治疗阶段基线至终点的汉密尔顿抑郁量表（Hamilton Depression Scale, HAM-D）总分变化，以及急性治疗终点时的应答者比例（HAM-D评分≤8分或较基线HAM-D评分降低≥50%）。预先设定的次要结局包括：K-SADS-L抑郁项目评分自基线至终点的变化、临床总体印象量表评分、自主功能检查表评分、自我感知概况量表评分、疾病影响量表评分；应答预测因素；以及维持阶段复发的患者数量。不良事件主要采用描述性统计方法进行比较，未预先指定编码字典。研究结果：帕罗西汀与丙米嗪的疗效在任何预先设定的主要或次要疗效结局中，均未表现出统计学或临床意义上优于安慰剂的差异。帕罗西汀组、丙米嗪组与安慰剂组的HAM-D评分分别降低10.7（最小二乘均数）（95%置信区间9.1~12.3）、9.0（7.4~10.5）与9.1（7.5~10.7）分（P=0.20）。帕罗西汀组出现具有临床意义的不良事件增加，包括自杀意念与行为及其他严重不良事件，丙米嗪组则出现心血管问题。研究结论：帕罗西汀与高剂量丙米嗪均未对青少年重性抑郁障碍表现出明确疗效，且两种药物均会增加不良事件风险。获取试验原始数据对临床实践与研究均具有重要意义，包括不应将已发表的疗效与安全性结论视为权威结论。本次对329研究的再分析表明，公开试验原始数据与研究方案对于提升证据基础的严谨性至关重要。