Dual medications for depression increases costs, side effects with no benefit to patients
UT Southwestern Medical Center
May 2, 2011Taking two medications for depression does not hasten recovery from the condition that affects 19 million Americans each year, researchers at UT Southwestern Medical Center have found in a national study.“Clinicians should not rush to prescribe combinations of antidepressant medications as first-line treatment for patients with major depressive disorder,” said Dr. Madhukar H. Trivedi, professor of psychiatry and chief of the division of mood disorders at UT Southwestern and principal investigator of the study, which is available online today and is scheduled for publication in an upcoming issue of the American Journal of Psychiatry. “The clinical implications are very clear – the extra cost and burden of two medications is not worthwhile as a first treatment step,” he said…
After 12 weeks of treatment, remission and response rates were similar across the three groups: 39 percent, 39 percent and 38 percent, respectively, for remission, and about 52 percent in all three groups for response. After seven months of treatment, remission and response rates across the three groups remained similar, but side effects were more frequent in the third group.
Only about 33 percent of depressed patients go into remission in the first 12 weeks of treatment with antidepressant medication, as Dr. Trivedi and colleagues previously reported from the Sequenced Treatment Alternatives to Relieve Depression, or STAR*D, study. STAR*D was the largest study ever undertaken on the treatment of major depressive disorder and is considered a benchmark in the field of depression research. That six-year, $33 million study initially included more than 4,000 patients from sites across the country. Dr. Trivedi was a co-principal investigator of STAR*D.
The next step, Dr. Trivedi said, is to study biological markers of depression to see if researchers can predict response to antidepressant medication and, thus, improve overall outcomes…
International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol.
by Williams LM, Rush AJ, Koslow SH, Wisniewski SR, Cooper NJ, Nemeroff CB, Schatzberg AF, Gordon E.
Trials. 2011 Jan 5;12:4.
Williams, Koslow, Cooper, and Gordon from Brain Resource; Rush and Wisniewski from STAR*D, Nemeroff and Schatzberg – the bosses. What happened to Madhukar Trivedi? Did he make someone angry? He’s always been there before. So when Stephany of Soulful Sepulcher forwarded this piece from UT Southwestern, and I read about what came next [to study biological markers of depression to see if researchers can predict response to antidepressant medication], I went looking at the NIMH, and there he was – Madhukar Trivedi – going it on his own [funded at $2,080,159]:
| Project Number: | 1U01MH092221-01 | Contact Principal Investigator: | TRIVEDI, MADHUKAR H |
| Title: | ESTABLISHING MODERATORS/BIOSIGNATURES OF ANTIDEPRESSANT RESPONSE- CLINICAL CARE | Awardee Organization: | UNIVERSITY OF TEXAS SW MED CTR/DALLAS |
| Abstract Text: | |||
| DESCRIPTION (provided by applicant): The timely selection of the best treatment for patients with depression is critical to the goal of improving remission rates. Due to the biological heterogeneity and variable symptom presentation of depression, it is unlikely that a single clinical or biological marker can guide treatment selection. Rather, a biosignature developed from a systematic exploration of a group of clinical and biological markers is more likely to be successful. Two types of biosignatures are needed to achieve improved outcomes: 1) biosignatures to maximize the selection of optimal treatment for individual patients at the beginning of treatment (moderators) and 2) biosignatures to identify indicators of eventual outcomes early in treatment (mediators). This approach has great potential to personalize treatment and maximize the number of patients who can be treated to full remission with a given treatment. We propose a comparative effectiveness trial of three mechanistically distinct treatments for MDD (citalopram, bupropion, and cognitive behavioral therapy) in which we will assess a comprehensive array of carefully selected clinical (i.e. anxious depression, early life trauma, & gender) and biological (i.e. genetic, neuroimaging, serum, epigenetic & qEEG) moderators and mediators of outcome. Using innovative statistical approaches the identified moderators and mediators will then be used to develop a differential depression treatment response index (DTRI). The proposed study is a randomized two-stage trial (Stagel:12 wks; Stage2: 12 wks) design with 675 MDD patients (with a history of one adequate trial of an SSRI except citalopram) assigned to one of three treatment conditions (n=225 each). This two stage approach is similar to a Sequential Multiple Assignment Randomized Trial (SMART) design. This application brings together researchers with extensive experience in conducting large clinical trials and experts at the forefront ofthe neurobiology of depression, including: clinical trials (Trivedi, Fava, Schatzberg,Nierenberg, Shelton, Gaynes, Hollon), genetics (Smoller, Binder, McMahan, Perils), neuroimaging (Phillips, Sheline, Etkin, Pizzagalli, Buckner), qEEG (losifescu, Ellenbogen), neurotrophins/cytokines (Duman, Sanacora, Turck, Shelton), clinical predictors (Shelton, Hollon, Trivedi, Fava, Nierenberg, Goodman, Yehuda), neuroendocrine markers (Holsboer, Schatzberg, Shelton, Yehuda), epigenetics (Nestler, Yehuda),and cognitive behavior therapy (Hollon, Manber, Arnow). This team will also be guided by internationally known biomarker scientists (Holsboer, Schatzberg, Krystal, Charney, Goodman), as well as a highly qualified group of biostatisticians (Kraemer, Wisniewski, Schoenfeld). PUBLIC HEALTH RELEVANCE : This study will examine multiple carefully selected clinical and biological markers, using both existing state of-the-art technologies as well as pioneering, innovative approaches. Evaluation of the usefulness of these markers in a trial with three different treatments will assist in generating a depression treatment response index (DTRI). The DTRI will help clinicians match treatments to patients with MDD, resulting in timely selection of treatments best suited for individual patients. Results from this study could significantly improve the treatment of patients with MDD. | |||
Did I say going it on his own? My mistake:
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clinical trials (Trivedi, Fava, Schatzberg, Nierenberg, Shelton, Gaynes, Hollon),
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genetics (Smoller, Binder, McMahan, Perils),
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neuroimaging (Phillips, Sheline, Etkin, Pizzagalli, Buckner),
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qEEG (losifescu, Ellenbogen),
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neurotrophins/cytokines (Duman, Sanacora, Turck, Shelton),
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clinical predictors (Shelton, Hollon, Trivedi, Fava, Nierenberg, Goodman, Yehuda),
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neuroendocrine markers (Holsboer, Schatzberg, Shelton, Yehuda),
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epigenetics (Nestler, Yehuda)
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cognitive behavior therapy (Hollon, Manber, Arnow)
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biomarker scientists (Holsboer, Schatzberg, Krystal, Charney, Goodman)
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biostatisticians (Kraemer, Wisniewski, Schoenfeld)
Really impressive stuff. 39 to 50% response/remission rate, and NO placebo arm, which, if included in the study design, would have resulted in . . . drum roll please . . . 39 to 50% response/remission rate. And the explanation? Why we just need biomarkers!!! I have a simpler explanation: Maybe we just have shitty drugs that don’t really work as well as the marketing departments of the drug companies told us they did. Remember the good old days of “80 to 90%” of patients taking SSRI’s remit? Then it dropped to 70 to 75%. Then 50%. Then less than 40% And down and down we go. Except in cases of melancholic depression, they don’t even achieve separation from placebos anymore. Biological psychiatrists need to go back to the drawing board and re-think their models. They need new drugs.
They also need to quit meeting their enrolment quotas with symptomatic volunteers who come out of the woodwork in response to advertising.
And the general population believes the FDA is watching out for safety in medicine approval! There is no watchdog possibilities with these KOLs running the psychiatry movement! $$$ UGH as always a big
btw the NIH project reporter tool you used is outstanding! Just search for Joseph Biederman and Charles Schulz and its a reminder of how entrenched these KOLs are, and they are using gov $$$ to boot
Is there any research literature on the efficacy of antidepressants in samples of REALLY, REALLY depressed patients (e.g. people hospitalized and being treated on a psychiatric unit) versus the “worried well” who volunteer for drug studies (cf. Dr. Carroll’s comment)?
Tom, here would be a good place to start – with the 1959 controlled trial of imipramine in U.K.
A CONTROLLED TRIAL OF IMIPRAMINE IN TREATMENT OF DEPRESSIVE STATES. J. R. B. BALL and L. G. KILOH.
British Medical Journal 1959; Nov 21;2(5159):1052-5
These were real patients in a real outpatient clinical referral stream in a real treatment setting. Imipramine worked… no doubt about it. Today’s mavens might carp about issues like no structured severity measures (the Hamilton scale was not yet invented) but the efficacy signal was unmistakeable. One especially revealing offhand comment in the paper is “It has certainly been obvious in this department that since the introduction of iproniazid and imipramine the amount of in-patient and out-patient E.C.T. given has fallen sharply.” That’s called ecological validity.
I was wondering the same thing re effective antidepressants for those in dire straights…what abt the trycylic immipramine triggering psychosis in people? this happened to my daughter who was given that for bed wetting prevention ( i had no idea it was what it is)..i know other ppl who cannot tolerate due to that….so…a patient is given Imipramine for severe depression and goes psychotic as a result and the patient is then dx bipolar or SZ, what then? they receive a boatload of pills and dx’s and what if the Imipramine was just removed….?
I know this is a quandary for doctors as well as patients!
Look into Johnson and Johnson biomarkers… http://www.msnbc.msn.com/id/23337532/?GT1=10856 Dr. Alexander Niculescu http://projects.propublica.org/docdollars/search?term=Alexander+Niculescu&state%5Bid%5D=
http://www.genomeweb.com/sequencing/merck-gsk-jj-embrace-targeted-sequencing-drug-development-and-biomarker-studies
http://clinicaltrials.gov/ct2/show/NCT00951483?term=biomarkers+depression&rank=1
Just when we think Seroquel wasn’t being talked about enough in the depression and biomarkers convo!
one more
http://clinicaltrials.gov/ct2/show/NCT01185977?term=biomarkers+depression&rank=5
Prozac and the biomarkers talks
They’re coming out of the woodwork! The Seroquel one is the most bizarre…
Mickey, I saw Trivedi speak at the APA meeting today (unfortunately, I don’t think I’ll be able to attend Nemeroff’s personalized medicine symposium on Wednesday – going snorkeling instead!). He described his next project, the EMBRAC study, which looks like a very extensive (and expensive) study to evaluate a broad range of neurophysiological, behavioral, and genetic markers (actually all the speakers are calling them “bio-signatures”) to predict beforehand which antidepressant or combination is/are best for a given patient. He raced through the slide very quickly, though, so I couldn’t take notes. I also can’t find anything about it online. But it’s on the way. Be ready for it.