Insel’s decade…

Posted on Tuesday 31 May 2011

The STAR∗D Trial: Revealing the Need for Better Treatments
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…
In the ‘college’ where I sometimes taught, the comparative literature professors often use the term – ‘close read.’ What they meant was a kind of critical reading that I’d not known before. I was frequently in awe of their ability to extract meanings from texts that weren’t apparent to we mortals until shown – then they were obvious. Because of the volumes of medical papers in my multiple training programs, I had become a ‘scanner.’ So I tried to take their example to heart and began to read less – more ‘closely.’ I’m not so good at it as many, but I improved. At least I can tell when it hasn’t occurred. In this case it’s easy to be definite. Tom Insel’s version of STAR*D is not a ‘close read.’

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.
OBJECTIVE: 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.

Another recent example from Insel’s NIMH had to do with Mahukar Trivedi’s failed IMPACTS study [algorithmic psychiatry – the fall…]. That study collected grant money for five years to the tune of $3.5 M, but was never even done [and, by the way, Trivedi's CO-MED adventure didn't turn out so well either]. And yet, Trivedi is now the holder of a big NIMH grant [the race for biomarkers…]. With a string of marginal outings at best [STAR*D, IMPACTS, COMED], he is now the P.I. for yet another fat NIMH grant [focusing on a line item from Insel's strategic NIMH plan - personalized medicine]:
    In general, traditional intervention research has focused on comparing how groups of individuals receiving an experimental intervention fare against a comparison group that does not receive that intervention. This approach has given us information about treatments for selected groups of people but not necessarily about how to choose the best treatment for a specific individual. We need personalized medicine: tailoring pharmacological, behavioral, and other forms of treatment to the needs of each individual. A new generation of clinical trials is needed to gather a wider array of data and examine the kinds of questions that can be used for personalized decision-making in medicine.
Insel’s NIMH seems to be a network of insiders like Mahukar Trivedi who are recurrently funded, independent of their work product. And I expect that right now, Insel’s pal Charlie Nemeroff would already be back on the NIMH rolls if Insel’s tête-à-tête with Nemeroff and Goldschmidt hadn’t come to light [who is not telling the truth? yes…]. And speaking of Nemeroff and the conflict of interest problem with Emory’s NIMH grant, Insel says,
    Public trust will ultimately depend on finding better treatments, but this goal can only be reached if psychiatry finds a way for academic investigators to interact with industry without real or perceived financial conflicts of interest. New NIH regulations will increase clarity and rigorous NIMH oversight can ensure better management, but academic leaders and their professional societies will need to transform what has become a culture of influence. The greatest threat to an era of improved public health stemming from the productive and ethically sound relationship among academia, industry, and practice is a defiant embrace of the status quo, in which psychiatrists are seen as a leading source of the problem rather than as leaders in finding the solution for financial conflicts of interest.
but he fails to mention that it happened under his own nose, un-noticed until Grassley and Thacker came along and found it.

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…
and he ends with:
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…
He’s talking about a study that compares and contrasts messing around with ten existing drugs [STAR*D] and he says we have to move beyond such comparisons. What’s next? CO-MED, trying two existing drugs at the same time. And after that? IMPACTS, computerized algorithms using existing drugs. Coming soon? Looking into the genetics of the responses to existing drugs. I know he can’t be expected to know exactly what comes next, but I’d like to hear a plan, a vision of some sort. Or maybe even an idea about why the $12 B spent on pills hasn’t achieved much in 20 years – the golden age of evidence-based medicine that he praises at other times. His articles are monotonously like this one – start by lamenting the burden of illness, then a commentary on the topic du jour, then exhortations that we need to do better. The commenting is usually at face value, as in the STAR*D study. But there’s never a sense that he’s gotten his teeth into whatever he’s commenting about or that he’s got a plan. We need more than a well-spoken commentator to run the NIMH. I guess I don’t get the sense that he’s leading. I see him as following. And the people he’s chosen to follow don’t seem to be going anywhere. He’s correct that we need something different – but his Directorship is actually the first thing that ought to be changed…
    Bernard Carroll
    June 2, 2011 | 2:26 AM

    It used to be that Directors of NIMH, as well as their staffers, understood that they are stewards of scientific resources – that their job was to get the money out the door to institutions and working scientists, and to administer fairly the grants review process. They never pretended themselves to be the driving engine of scientific progress. They left that work to the real scientists in the Intramural Program and in academia. The last 30 years, however, saw the growth of a bureaucracy of policy wonks inside NIMH who presumed to set research agendas. These policy makers could make no claim to original scientific achievements. I have vivid memories of some of these functionaries bragging about their ‘portfolios’ of supported research. It was just a short step from there to Road Maps, RFAs (Requests for Applications), Strategic Plans, Consensus Conferences, and other instances of hubris and chutzpah aimed at hijacking the research agenda.

    That’s how we got STAR*D and CO-MED and IMPACT and the Emory-GlaxoSmithKline-NIMH Depression Research Initiative. The last of these was headed up by Charles Nemeroff. Now it is directed by Helen Mayberg, who has no track record in psychopharmacology and who is not even a psychiatrist. Former NIMH Director Steven Hyman set the ball rolling with approval of STAR*D and the Emory-GSK project. Current NIMH Director Thomas Insel signed off on the plan for Mayberg to take over the Emory-GSK program. Insel has displayed no appetite to rein in these wasteful and distracting projects. I cannot disagree with your call for Insel’s replacement, especially in view of his role in the events surrounding Nemeroff’s move to Miami.

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