Summing Up 2015

Here we are at the end of the year. A lot has happened in the world of psychiatry in 2015.

Collaborative Care is alive and scoring a 0 on the PHQ-9. The Clozaril REMS deadline was extended. Tom Insel left NIMH for Google. Mandatory E-prescribing was postponed until this coming March. EHRs continue to disappoint. Meds long past patent have had their prices jacked up 5000%. The FDA is looking to appoint a new head, and Robert Califf, a cardiologist with strong ties to the pharmaceutical industry has been nominated (See NY Times and David Healy).

On the upside, Dinah at Shrink Rap came up with a brilliant way for people to access psychiatric care in Maryland. I hope this approach is replicated more broadly.

I was perusing my posts from this past year, and I made a list of some of the major topics, and their respective posts, both general and personal:

Maintenance of Certification

I studied for:
The Montillation of MOC
Percentages

And passed:
Done
There and Back Again
Framed
Signed, Sealed, Delivered
Switching the Labels

my board recertification exam.

And I was certified by the NBPAS, as well:
Another Board

The ABPN refused to make any significant changes to MOC, especially Part IV:
I Really Should be Studying, But...
An MOC Step?
Follow the Money

Although the Part IV Feedback modules are now optional.

And I developed my own Psychoanalytic PIP Module:
Fascinating
Here Goes Nothin'
A Monkey's Uncle

The best part about all of this is that I've written enough MOC posts that I now misspell "Maintenance" only about 5% of the time.


Affordable Care Act (ACA)

The ACA has kicked in:
Out of Network Benefits in NY

And pushed me over the edge into the realm of blog ads:
Adding Ads and the ACA


Psychoanalysis

I terminated my analysis:
Termination
Blessings

And wrote some other posts about psychoanalytic evidence and topics:
Analytic Evidence
AA Brill
The Blank Screen
Narcissism, Part I
Narcissism, Part 2


Jeffrey Lieberman

His book, Shrinks was published:
"Shrinks" Review: Introduction
Shrinks: The Untold Story of Jeffrey Lieberman's Oedipal Victory over Papa Freud
Shrinks Links, Etc.

And a torrent of posts followed, culminating in the one about his fiasco of a presentation at the White Institute:
Lieberman Speaks


Addyi

The FDA approved a drug that could hurt you but can't help you:
They Caved

That was immediately sold for $1Billion:
Addyi-dendum

And then the FDA and Valeant pawned off responsibility onto the doctors who prescribe it, and the pharmacies that fill the prescriptions:
Addyi REMS-A Shanda


Paxil 329

Finally, and perhaps most importantly, the restored version of Paxil Study 329 was published, with disturbing conclusions:
329


Do I have a favorite post from the year? Not really. The Lieberman posts, especially the reviews and the one about his talk at White took the most out of me. But in terms of content, I think the Analytic Evidence and 329 posts are the most important.

On to pastures greener.

329

You've probably seen it already, but if you haven't, please read it:

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

It's been eagerly anticipated, and everyone pretty much guessed what the conclusions would be, but it's finally official. The data from Study 329 show that paxil improved depression in adolescents no more than placebo (same for imipramine).

More importantly, from my perspective, since there are always some outliers who respond to meds others don't, are the adverse events. The re-analysis showed a lot more harm than the original. Paxil had a lot more psychiatric adverse events, such as suicidal behavior, and imipramine a lot more cardiovascular events.

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.

The reasons for the discrepancies are interesting. It seems like the difference in efficacy results was related to the fact that the original authors deviated from protocol, so that the same data give different results:

The marked difference between the efficacy outcomes as reported by us and those reported by SKB results from the fact that our analysis kept faith with the protocol’s methods and its designation of primary and secondary outcome variables.

The authors/sponsors departed from their study protocol in the CSR itself by performing pairwise comparisons of two of the three groups when the omnibus ANOVA showed no significance in either the continuous or dichotomous variables. They also reported four other variables as significant that had not been mentioned in the protocol or its amendments, without any acknowledgment that these measures were introduced post hoc. This contravened provision II of appendix B of the Study 329 protocol (“Administrative Matters”), according to which any change to the study protocol was required to be filed as an amendment/modification.

The difference in adverse events had to do with how the events were coded. The original article used a now obsolete and unavailable coding system, and the language in the Case Study Reports (CSR's) was often translated to something innocuous. I particularly liked one table which showed the ways that adverse events could be inaccurately reported:

As for GSK's reaction, the NY Times included this quote from the original authors:

Dr. Keller and his co-authors strongly disputed the reassessment of their work. In a joint statement, he and his team said they incorporated secondary measures before knowing which patients were taking Paxil and which were not — not afterward, as the new analysis claims, for some of the measures. “In summary, to describe our trial as ‘misreported’ is pejorative and wrong,” they conclude.


The authors of the new study, Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, and Elia Abi-Jaoude, had their work cut out for them:

This RIAT exercise proved to be extremely demanding of resources. We have logged over 250 000 words of email correspondence among the team over two years. The single screen remote desktop interface (that we called the “periscope”) proved to be an enormous challenge. The efficacy analysis required that multiple spreadsheet tables were open simultane- ously, with much copying, pasting, and cross check- ing, and the space was highly restrictive. Gaining access to the case report forms required extensive correspondence with GSK.12 Although GSK ultimately provided case report forms, they were even harder to manage, given that we could see only one page at a time. It required about a thousand hours to examine only a third of the case report forms. Being unable to print them was a considerable handicap. There were no means to prepare packets for multiple independent coders, to decrease bias; to make annotations or use margin comments; or to sort and collate the adverse event reports. Our experience highlights that hard copies as well as electronic copies are crucial for an enterprise like this. 

I think they deserve huge thanks.

So check out the study. And also check out Study329.org for the whole history, as well as multiple posts by authors Mickey Nardo at 1boringoldman.com and David Healy at Davidhealy.org and Rxisk.org.

A Quick 329

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 result:

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?

Adverse Experiences:
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[1] 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?