1 Boring Old Man

I have repeatedly teased about Dr. Trivedi’s difficulty finishing tasks. His IMPACTS study was never completed. In STAR*D, they never published their primary efficacy results. CO-MED came in way late and was decidedly negative. TMAP landed in a courtroom. But in EMBARC, his new genetics study, he didn’t even finish his web-site.

^{NIMH RePORTER: 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 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.&}

^{clinicaltrials.gov: The current study is designed to identify biomarkers for the prediction of differential treatment outcomes between the SSRI antidepressant citalopram [CIT] and placebo [PBO] in a randomized trial for patients with MDD. In addition, a second stage will collect data to explore moderators and mediators of treatment outcomes between pharmacologically distinct active treatment arms: citalopram [CIT], a serotonergic antidepressant or bupropion [BUP], a nonserotonergic antidepressant… In the first stage, patients will receive an 8−week course of treatment in one of the two study arms. As part of the Sequential Multiple Assignment Randomized Trial [SMART] design patients that have not achieved response at the end of 8 weeks to their stage one treatment, defined by < 50% improvement on the Clinical Global Improvement scale [CGI], will be switched to Stage 2 treatment [8 weeks]. Patients who have achieved satisfactory response [>= 50% improvement on the CGI] will be continued on treatment for an additional 8 weeks.}

Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study
American Journal of Psychiatry
^{by A. John Rush, M.D., Madhukar H. Trivedi, M.D., Jonathan W. Stewart, M.D., Andrew A. Nierenberg, M.D., Maurizio Fava, M.D., Benji T. Kurian, M.D., Diane Warden, Ph.D., David W. Morris, Ph.D., James F. Luther, M.A., Mustafa M. Husain, M.D., Ian A. Cook, M.D., Richard C. Shelton, M.D., Ira M. Lesser, M.D., Susan G. Kornstein, M.D., and Stephen R. Wisniewski, Ph.D.}
May 2, 2011

^{Objective: Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment.
Method: The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (upto 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care.The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology-Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition.
Results: Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%–52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%–46.6%), response rates (57.4%–59.4%), and most secondary outcomes were not significantly different.
Conclusions: Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events.}

I’m assuming that Citalopram [Celexa] and Escitalopram [Lexapro] are bioequivalent drugs. So, if there were two populations [Citalopram Responders and Bupropion Responders], in CO-MED there would’ve been a greater response to Escitalopram+Bupropion than to Escitalopram+Placebo. It didn’t happen.