Normal Limits

"Chance is the very guide of life"

"In practical medicine the facts are far too few for them to enter into the calculus of probabilities... in applied medicine we are always concerned with the individual" -- S. D. Poisson

March 29, 2006

STAR*D: landmark study in psychiatry

The Orion Nebula [M42] by NASA via Flickr

The results of Sequenced Treatment Alteratives to Relieve Depression (STAR*D), a landmark study in psychiatry, are beginning to be published. Beyond the important questions it answers, STAR*D is remarkable for:

  1. Large sample size: about 4,000 patients are recruited, a mammoth study by the standards of psychiatry literature

  2. Broad inclusion criterion: any patient presenting for care with nonpsychotic major depressive disorder (defined using the HAM-D scale) for whom his/her clinician deems outpatient anti-depressant therpay would be appropriate. Most anti-depressant trials advertise for patients, which would arguably select for a qualitatively different patient population.

  3. Participation of primary care physicians: in addition to psychiatrists in outpatient psych clinics, PCPs were managing these patients in their daily practice. Titration of anti-depressant dosages were based on validated psychometric instruments (for example see the HRS-D and QIDS-C form used by the STAR*D researchers)

  4. Use of depression remission as endpoint: this is closer to the goals of treatment in clinicial practice. Quantitative abatement of depressive symptoms--the outcome measure of most previous anti-depressant trials--may be maningful and significant but its clinical value is difficult to assess.

Simply, by virtue of its design, STAR*D has ecological validity and clinicians can incorporate with confidence the findings of STAR*D studies.

What are these findings? So far, they have found:

  1. About 30 percent of patients showed remission when placed on Celexa. Predictors of remission include high levels of education, employment status, Caucasian race, and few psychiatric and medical co-morbidities. (Trivedi et al 2006, American Journal of Psychiatry 163, 28)

  2. Of the patients who showed no sufficient response to Celexa and who immediately switch to another anti-depressant (either Wellbutrin, Effexor, or Zoloft), about 1 in 3 patients will show remission within 14 weeks. The magnitude of the effect is about the same regardless of the class of medication switched to. That is, switching to Zoloft--another SSRI like Celexa--was as effective as switching to either Wellbutrin or Effexor (Rush et al 2006, NEJM 354, 1231).

  3. Of patients who showed no sufficient response to Celexa and whose medication regimen were immediately augmented with Wellbutrin or BuSpar, about 30 percent showed remission. (Trivedi et al 2006, NEJM 354, 1243)

STAR*D is a result of the NIMH's push for "practical clinical trials", trials that by design answer practical questions of great clinical value.

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: Joseph j7uy5 said...

Nice post. It is good to see some attention to studies that are designed from the start to have practical clinical application. Unfortunately, those two particular papers leave unanswered one of the most interesting questions: in the event of a lack of remission, is it better to add, or to switch?

Although the outcomes suggest that the results are comparable with either strategy, the studies were not designed specifically to answer that question.

Of course, no study will answer all questions. Plus, I am sure that the STAR*D data set will result in many more publications.

Ming-Chih said...

yes, although by 14 weeks augmentation has about 50% remission rate and switching has about 30%, this difference is almost certainly not significant as only few subjects are left in each group by that point.

(begin speculation)
To me, the most striking findings of the 2 NEJM papers (on augmenting and on switching) were the 2 time-to-remission survival curves.

First of all, the Wellbutrin and BuSpar curves in the augmentation study and the Wellbutrin, Effexor, or Zoloft curves in the switching study look *almost identical*. They take on similar values across the entire duration of observation and trace out the same shapes.

Secondly, these curves look too neat: they look almost as if each week a constant proportion of those still depressed spontaneously show remission. Whereas a previously untreated person with depression is not expected to show response to SSRIs until say 4 weeks after starting treatment, here in both the switching and the augmentation studies, response was immediate. Celexa has a half-life of 36 hours, taking about 6 days to wash out of the body. Hence response at week 0 was not surprising. But remission for the rest of the patients started promptly at 2 weeks and beyond.

I'm unfamiliar with the clinical time course of response to SSRIs, and to me these graphs are quite surprising. Perhaps they reveal something about the nature of the brain's response to SSRIs?
(end speculation)


: Joseph j7uy5 said...

I am not an expert on research design, but to my way of thinking, there is only one way to address the question of which is better: add or switch? That would be to do a single study, and randomize those who do not attain remission into three groups: placebo, add, or switch. All patients would start out taking two pills per day: one active, one placebo. After randomization, one group would keep taking the original active drug and the placebo, one group would get a different active drug and placebo, and the final group would get two active drugs. Obviously, it would have to be a very large study to have adequate statistical power.

Regarding the time course to achieve remission, it is one of the peculiarities of psychiatric research that remission and response curves tend to be nearly identical. I do think it is reasonable to assume that the similarities of the curves implies something about the way the brain works. Almost certainly, the drugs provoke some response in the brain, that response takes a certain amount of time, and it is the response (not a direct action of the drug) that is therapeutic.

Ming-Chih said...

you are right. I was at first under the impression that the majority of STAR*D patients were randomized across augmentation and switching, such that the survival curves are roughly comparable.

Looking over Figure 1 of Rush et al again, this was not the case. Of the 1439 patients eligible, 583 chose switch only and 430 augmentation only. Only 105 patients (rows 5, 7, and 8) were actually randomized across both augmentation and switching strategies.

The design you proposed had a placebo group, which STAR*D doesn't. We were told at a psychiatry lecture that a 2005 study compared the magnitude of placebo effects in different psychiatric disorders. Near the bottom are OCD and MDD with psychotic features. At the top was MDD without psychotic features, the main inclusion criteron of STAR*D. So any effect observed in STAR*D could be attributed, in part or in whole, to placebo effect.

And STAR*D was doubly non-blinded so both physicians and patients knew exactly which med and what dose.

But IMHO STAR*D remains an important study that should change many physicians' practices.

it is one of the peculiarities of psychiatric research that remission and response curves tend to be nearly identical.

This is intersting. Do you mind showing me some more examples next time you see them? I have been thinking about predominance of Cox proportional hazards model in clinical research and the violations of the proportional hazards assumption. These violations can sometimes be painfully obvious by looking at the shapes of the survival curves. (I guess this explains my obsessiong with comparing the 2 survival figures)