by Thomas R. Insel and Philip S. Wang
Psychiatric Services 2009. 60(11):1466-1467.
For us, STAR∗D demonstrates that treatment for depression may be less effective than advertised. After 14 weeks of citalopram (average dosage of 41.8 mg per day), 28% to 33% of participants experienced remission. A total of 50% achieved remission after a subsequent switch to or augmentation with another antidepressant. An additional 13% to 14% experienced remission after additional trials with other antidepressants or augmenting strategies. At the end of 12 months, with up to four treatment steps, roughly 70% of participants were in remission. These results are positive, especially for a population with moderate to severe depressive symptoms and substantial comorbidity. However, most placebo controlled trials report response rates of roughly 30% among depressed persons in placebo groups. It should be noted that remission rates in such placebo groups are lower than 30%. In addition, depressive episodes frequently last from six to 12 months, suggesting that some episodes among STAR∗D participants could have been self-limiting even without treatment. Furthermore, many STAR∗D participants who achieved remission subsequently relapsed. In the absence of a placebo control group, one could argue that the results of STAR∗D demonstrate weak, transient effects of antidepressant treatment.Nevertheless, let’s assume that the results are due to medication effects and not placebo effects or nonspecific influences. Should we accept 28% remission rates after 14 weeks as success? Is a 70% remission rate at one year sufficient? How high should we set our goals for this disabling and often deadly disease? For us, the results of STAR∗D suggest that important goals remain out of reach…
Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report
by Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M.
Am J Psychiatry. 2006 Nov;163(11):1905-17.AbstractOBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of <or=5 on the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)) (equivalent to <or=7 on the 17-item Hamilton Rating Scale for Depression [HRSD(17)]) defined remission; a QIDS-SR(16) total score of >or=11 (HRSD(17)>or=14) defined relapse.RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps.CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.
Ed Pigott’s takes a ‘very close read’ [Efficacy and Effectiveness of Antidepressants: Current Status of Research, blog, the appearance of conflict of interest…]. But you don’t have to get that close to see how far off Insel’s version is. Rush et al say, "After two treatment steps, it appears that over 50% of patients will achieve remission if they stay in treatment [i.e., 36.8% step 1 plus 30.6% of the remaining 63.2% of patients]. Thereafter, the chances of subsequent remission are much lower. The theoretical cumulative remission rate after four acute treatment steps was 67%." That’s a guesstimate of the worst kind because it leaves out the huge drop-out rates and the relapses in STAR*D. They could not definitively prove breaking 10%. So Insel’s article is based on a fable of the STAR*D authors, not the reality of the study.
The fragment of Insel’s article may seems like a critical reading – mentioning the placebo effect and saying that we need to do better. But he mistates the results even more blatantly than the STAR*D team [70% instead of 67%]. And I expect Insel’s motive in saying that we need to do better has to do with justifying further NIMH research into depression. Insel took the reported result of STAR*D at face value instead of gasping aloud at the poor quality of the work like the rest of us. I guess if you’ve just paid $35 M for a study, you cheerlead it no matter what.
But my real complaint about Insel is more about what’s missing. In spite of an impressive 38 page Strategic Plan with the loftiest of goals, he strikes me as a really good speaker with nothing to say. Like his cronies, he’s a breakthrough freak [breakthrough freaks…], always swinging to knock it out of the park. He seems to be about more treatments, faster development. He can’t seem to get enough of "Translational Science" – rapidly moving things from the bench to the bedside, as they say. But I don’t hear much focus on the bench. It’s more about the "moving" than anything else. To wit, in that article at the top of this post, he says:
Depression is the largest source of medical disability for Americans between 15 and 44 years of age. The National Comorbidity Survey Replication reported an annual prevalence of 6.6%, with half of the cases classified as "severe" or "very severe". Although more people are receiving treatment for mental disorders such as depression, there is no evidence that either the morbidity or mortality of these disorders has substantially changed in the past two decades…
But perhaps most of all, STAR*D reminds us that we have a long way to go in the treatment of this common, disabling illness. In 2007 in the United States more prescriptions were written for antidepressants than for any other class of medication, at a cost of nearly $12 billion. Research needs to move beyond simply investigating the comparative effectiveness of current medications to pursuing the development of better treatments that will reduce the burden of illness from depression…