Efficacy of Paroxetine (Paxil) in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial Case Study presented by: carlo carandang, MD MCDA 5520, November 27, 2017

Paroxetine Study- Background (circa 2001) To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression 1988- Prozac- dawn of SSRI blockbuster drugs (multi-billion dollars) Push to find new indications for SSRIs, given their profitability I chose this study, as this study was eventually debunked for misleading statistical analysis Big Pharma and Psychiatry: SSRIs were lucrative for both sides Big Pharma overseas and sponsors the majority of the studies submitted to FDA for approval Perfect Storm of bias and greed affecting the scientific process

Justification For Selecting This Study I chose this study as it shows how statistical analysis can be gravely affected by human intervention due to bias and the pressures of: Financial gain Academic fame Pressure on researchers to produce positive studies (“publish or perish”) Pressure on journals to only produce positive studies, and not publish negative ones For business statistics, this study emphasizes how important integrity and sound methodology are to statistical analysis and not participating in cherry-picking variables based on best response for financial gain and recognition

Paroxetine Study: Demographics 275 adolescents (12-18, males and females) with major depression began 8 weeks of double- blind paroxetine (20–40 mg), imipramine (gradual upward titration to 200–300 mg), or placebo 10 centers in the United States and 2 in Canada 425 subjects were screened, and 275 were randomly assigned to one of the treatment arms Study and investigators funded by GSK (GlaxoSmithKline) Keller et al., 2001

Paroxetine Study: Outcome Measures 2 primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score ≤8 or ≥50% reduction in baseline HAM-D) and change from baseline HAM-D score Secondary outcome measures: HAM-D depressed mood item depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L) Clinical Global Impression (CGI) improvement scores of 1 or 2 nine-item depression subscale of K-SADS-L mean CGI improvement scores

Paroxetine Study: Statistical Methods Power Analysis: a sample size of 90 patients per arm was required to provide approximately 80% power to detect an effect size of 0.4 between an active regimen and placebo with an α level of 5% (two-tailed) Continuous variables, such as changes from baseline to endpoint in the HAM-D total score, CGI improvement scale, and K-SADS-L, were analyzed by a two-factor analysis of variance using the general linear model procedure of the Statistical Analysis System (SAS) Categorical variables, such as percentage of subjects responding to treatment, were analyzed with logistic analysis implemented in the categorical modeling procedure (CATMOD) of the SAS Pairwise comparisons between each active treatment and placebo were two-tailed and performed at an α level of .05. Data are reported as least square means (±SD or SE)

Paroxetine Study: Results A total of 190 subjects (69% of 275) completed the 8- week study Premature withdrawal rates were 24% for placebo, 28% for paroxetine (p = .60 versus placebo), and 40% for imipramine (p = .02 versus placebo) Significant for primary outcome variable of HAM-D < 8 Problem: in the completers, much less than the power analysis requirement of 90 for each treatment arm This may have consequences in the outcome variables, as study is underpowered

Paroxetine Study: Results High placebo response Paroxetine does not really separate from placebo Not significant for primary outcome variable of HAM-D > 50% decrease from baseline

Paroxetine Study: Weaknesses High placebo response (actually, why not just give placebo for depression?) Underpowered High drop-out rate (most due to side effects) One of the primary outcome variables (HAM-D < 8) was not significant (could be from being underpowered, or could be from lack of treatment effect) Emphasis on secondary outcome variables when presenting the results (amateurish) So one of the primary outcome variables is significant, but most likely not clinically significant (low effect size) Not enough to say statistically significant…need to calculate and report effect size (Big Pharma probably suppressed this)

Paroxetine Study Retracted- Reanalysis A recent reanalysis of a 2001 paroxetine (Paxil) study has put into serious doubt the whole field of psychiatry and how it conducts clinical trials (Le Noury et al., 2015; Keller et al., 2001) The reanalysis showed that Paxil (paroxetine) is not effective for adolescents with depression and also found that there was an increase in harm on Paxil compared to a placebo, including suicidal ideations and behaviors and other serious side effects (Le Noury et al., 2015) These findings are in stark contrast to the original 2001 Paxil study 329, which published its findings in the leading journal for child and adolescent psychiatrists, that Paxil was both safe and effective for adolescent depression (Keller et al., 2001)