1 Boring Old Man

"Will this drug help me?" "… hurt me?" "… do nothing?" "What if I don’t take it?" Questions asked as if there’s an answer. But in every case the answer is in the form of likelihoods, not certainties. Each question has "how much?" tacked on – "how much might it help me?" "… hurt me?" Sometimes the answer depends on who you are – male/female? black/white? young/old? One can go on and on with things that might affect the answer, and still only end up with a risk benefit estimate, not the simple answer you want to hear. With interventions that have been around for a while, the doctor and sometimes even the patients have the benefit of long usage that makes things a lot easier. But every new treatment has a beginning with no clinical experience to fall back on. What then? So to the Clinical Trials.

In the laboratory, you can take two groups of genetically identical animals living under the same conditions and give one group a medication and the other something inert, then compare the results. We humans are much harder. We’re not genetic clones. We live in a wide variety of ways and places. We’re a fickle lot – sometimes we don’t consistently take the medication; sometimes we miss appointments; sometimes we drop out of studies altogether. And then there’s this placebo effect thing. For reasons known and unknown, just being in a study itself often makes us significantly better, a particularly common finding in psychiatric drug trials. Thus any Clinical Trial comes out of the gate with built in variabilities and confounding factors, no matter what is being tested. Then there’s time. Most trials are short compared to the projected drug use. So a Clinical Trial is only a rough starting point at best, picking up on harms and judging efficacies in a closely attended but brief setting – an abnormal setting.

I never paid too much attention to Clinical Trials. I think I even thought the FDA did them [that’s how little attention I paid!]. New drugs that mattered didn’t come along that often, and I [we] learned about them from other sources. I remember coming into Psychiatry from Internal Medicine, and being awed by how much we talked about them. There were only a few classes with not that many member drugs in each class. That was nothing, compared to where I came from. But "Why did you pick this-azine instead of that-azine?" was a frequent question, so I got into the swing of things and learned the standard lines about what seemed minor differences. By the time the "new" drugs showed up [SSRIs, SRNIs, Atypicals, Mood Stabilizers(?), etc], I was a practicing psychotherapist and mostly kept up out of habit, with lite usage. So Randomized Clinical Trials and drug approval processes are an acquired interest.

Actually, people like me who didn’t pay attention were part of our current problems. We relied on the academic community to keep us up to date about medications with journal articles and review articles. We took our required Continuing Medical Education [C.M.E.] Courses and went to our professional organizations’ meetings. And we didn’t really notice that things were slowly changing, that the firewall between the commercial medical enterprises and academic medicine had eroded a little more with every passing year. Medicine is traditionally a self-regulating profession, and we fell down on the job. So now we’re in the position of trying to reclaim things we just took for granted, and the commercially funded Randomized Clinical Trial [RTC] is right in the center of the problem.

I’ve had the opportunity to be on a RIAT team that has spent a couple of years immersed in looking back on a single Randomized Clinical Trial [RCT] that began recruitment 21 years ago, was published 14 years ago, and is now a classic – not as a breakthrough, but rather becoming a paradigm for what needs our attention. It was the SmithKline Beecham trial of Paxil® in depressed adolescents known as Study 329. Our reanalysis will be published shortly [see A Milestone in the Battle for Truth in Drug Safety]:

Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial

by MARTIN B. KELLER, M.D., NEAL D. RYAN, M.D., MICHAEL STROBER, PH.D., RACHEL G. KLEIN, PH.D., STAN P. KUTCHER, M.D., BORIS BIRMAHER, M.D., OWEN R. HAGINO, M.D., HAROLD KOPLEWICZ, M.D., GABRIELLE A. CARLSON, M.D., GREGORY N. CLARKE, PH.D., GRAHAM J. EMSLIE, M.D., DAVID FEINBERG, M.D., BARBARA GELLER, M.D., VIVEK KUSUMAKAR, M.D., GEORGE PAPATHEODOROU, M.D., WILLIAM H. SACK, M.D., MICHAEL SWEENEY, PH.D., KAREN DINEEN WAGNER, M.D., PH.D., ELIZABETH B. WELLER, M.D., NANCY C. WINTERS, M.D., ROSEMARY OAKES, M.S., AND JAMES P. MCCAFFERTY, B.S.

Journal of the American Academy of Child and Adolescent Psychiatry, 2001, 40(7):762–772.

[full text on-line]

Objective: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression.

Method: After a 7 to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine [20–40 mg], imipramine [gradual upward titration to 200–300 mg], or placebo. The two 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. Other depression-related variables were [1] HAM-D depressed mood item; [2] depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version [K-SADS-L]; [3] Clinical Global Impression [CGI] improvement scores of 1 or 2; [4] nine-item depression subscale of K-SADS-L; and [5] mean CGI improvement scores.

Results: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score <8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects.

Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.