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Reanalysis of Study 329: efficacy and harms of paroxetine and imipramine in adolescents

How difficult it is to get the truth about questionable drugs

The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.

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.

Jon Jueridini and colleagues have reanalysed SmithKline Beecham’ infamous 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.

Their analysis finds that neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.

Antidepressant use in pregnancy linked to increased risk of congenital and cardiac malformations

This systematic review found that the overall risk of major birth defects remains low

image of antidepressant-and-woman — The question of whether paroxetine can cause birth defects has been under discussion since 2005 The strengths of this study are that it was a systematic review, so should have included any relevant research, and that the researchers analysed the data in different ways to look for potential biases or factors that could have skewed the results. *i finally started taking my anti-depressant again*.

Abstract

The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis, British Journal of Clinical Pharmacology, DOI: 10.1111/bcp.12849, Jan 2016.

Aims
The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design, and reference category.

Method
A systematic review of studies published between 1966 and November 2015 was conducted using EMBASE and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations, and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models.

Results
Twenty-three studies were included. Compared to non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n=15 studies); major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n=18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n=8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n=4 studies), and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n=4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed.

Conclusions
Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population.

Study 329 Lessons: published conclusions about drugs efficacy and safety should not be read as authoritative

Study 329 reanalysis illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base

study-329 poster — Unpublished and misreported studies make it difficult to determine the true value of a treatment. RIAT stands for “restoring invisible and abandoned trials.

2015 (2nd) Study Abstract

The RIAT re-analysis marks a new chapter in the story of Study 329, showing the remarkable power of open data. But it also shows how much our current systems are failing patients and the public. It should not have taken 14 years to get to this point. It shows that we need regulation, and perhaps legislation, to ensure that the results of all clinical trials are made publicly available and that individual patient data are available for legitimate independent third party scrutiny.

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.

AntiDepressants and Pregnancy: Class-Action Suit highlights expectant Mothers rising use of SSRIs

The controversy surrounding antidepressants and pregnancy

” Last December, the Supreme Court of British Columbia set a bold precedent: it green-lit the first class action suit in Canada alleging that an antidepressant taken by a woman during pregnancy caused a birth defect in her child. Faith Gibson of Surrey, B.C., named “representative plaintiff,” had been prescribed Paxil, a selective serotonin reuptake inhibitor (SSRI), in December 2002. Her daughter, Meah Bartram, was born in September 2005 with a hole in her heart. The defect was repaired months later, but Meah remains a “sickly” child, prone to infection. Two weeks after her birth, Health Canada and Paxil’s manufacturer, GlaxoSmithKline Inc. (GSK), issued an advisory stating that paroxetine (Paxil’s generic name) taken in the first trimester may pose “an increased risk” of cardiovascular defects. ”

Read The controversy surrounding antidepressants and pregnancy
by Anne Kingston, April 20, 2013

Tag: paroxetine

Reanalysis of Study 329: efficacy and harms of paroxetine and imipramine in adolescents

More on Study 329 from The BMJ

More on Study 329 from Dr David Healy’s blog

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