I don't know why I decided to do this today. Maybe because I'm finally finished writing my Carlat article, and I also finished some other writing I needed to do. Or maybe it had to do with reading Ben Goldacre's most recent post on Bad Science, Public Accounts Committee issues damning report on clinical trial results being withheld. But I decided to look up the actual Paxil Study 329.
I mean, the infamous Paxil Study 329, the one that got GSK fined 3.3 billion dollars.
Quick review. It's paxil in adolescents, ages 12 to almost 19, in the acute phase, at least 8 weeks, of a unipolar major depressive episode, as defined by DSM III-R, with a HAM-D score >12. The study took place between April 20, 1994 and May 7, 1997 (for the acute phase), and February 15, 1998 (for the continuation phase). Subjects were randomized to paxil 20-40mg, imipramine 50-300mg, and placebo. Primary outcome measures were change from baseline on the HAM-D total score, and proportion of responders with a 50% reduction in the total HAM-D or a score of < 8. There were also secondary measures, and adverse events were evaluated and followed.
The analyses of these measures support that paroxetine is beneficial in treating
adolescents with major depression, but the support is derived mainly from the
secondary measures. In the protocol defined primary endpoints, the placebo
response was large and the magnitude of the benefit of paroxetine response over placebo was modest and did not achieve statistical significance (boldface mine).
And the adverse events?
The nature and incidence of adverse events reported for the paroxetine group were
similar to that reported for adult depressed patients receiving paroxetine in
controlled trials of comparable duration and as described in the Paxil U.S.
prescribing information. Two exceptions to the profile seen in adults include tooth disorder and hostility. The latter term includes aggressiveness and conduct disorders. These exceptions may be related to the age of the study population. As
in the adult, adverse events were more likely to occur during the initial weeks of
treatment. Analysis by age suggests that events associated with the nervous
system (dizziness, sleep problems, and conduct disorders) were more likely to
occur in the younger subset (<15 yrs.).
There were no deaths during the trial. Serious adverse events occurred in 18
patients, 11 in the paroxetine group, 5 in the imipramine group, and 2 in the
placebo group. One of the paroxetine patients experienced migraine headache
during down titration after completing 8 weeks of treatment. For the remaining
patients the events were psychiatric in nature and included worsening depression,
suicidal ideation/gestures, and conduct disturbances (hostility). In the imipramine
group, one patient developed a maculopapular rash, one had dyspnea associated
with chest pain, one reported auditory hallucinations, and two were reported to
have serious conduct disturbances (hostility). In the placebo group, the two
serious events were worsening depression. (boldface mine)
The wording is a little funny. My reading is that 11 paxil subjects had adverse events. One of these had migraines. the other 10 had worsening depression, suicidal ideation/gestures, and/or "hostility". There were a total of 93 paxil subjects, so roughly 11% of these became more depressed, suicidal, and/or hostile. That's vs. 2/95 (2%) of imipramine subjects, and 2/87 (2%) of placebo subjects. And since none of the placebo subjects experienced either hostility or suicidality, it kinda looks like those might be related to the active meds.
Immediately following the paragraph above, there's this table:
Notice that the description in the table, "emotional lability", does not match that in the prose, "worsening depression and suicidal ideation/gestures".
And where did I get this information?
BRL-029060/RSD-100TW9/1/CPMS-329 Report Synopsis, from gsk.com.
I wasn't able to track down the actual study. I'm guessing what I did find came out during legal proceedings.
But the bottom line is, in the adolescents studied, paxil showed no benefit over placebo, and caused suicidality, worsening depression, and hostility in a hefty percentage.
How did this get past the powers that be, and what DON'T we know about other meds?