Psychiatric Research and the Targeted Treatment of Depression

New psychiatric research seeks biomarkers to guide the targeted treatment of depression

 Richard J. Metzner, M.D.

Clinical Professor  
Semel Institute for Neuroscience and Human Behavior at UCLA 
On May 19, 2013 a symposium was held at the APA annual meeting in San Francisco to present data from the International  Study to Predict Optimized Treatment for Depression (iSPOT-D). The study is the first large-scale project seeking biomarkers that might help match antidepressants to patients. We applaud this effort and are glad to see mainstream psychiatric research finally moving in the direction that many clinicians have been advocating for years.
For those old enough to have been practicing psychiatry when imipramine was the "gold standard," tracking the evidence base of psychopharmacology for clinical relevance has sometimes felt like watching the universe for signs of sentient life. In the beginning, the short-lived serotonin and norepinephrine hypotheses of depression fueled the hope that antidepressants (ADs) would be matched to patients based on their mechanisms of action. That never happened. Perhaps the first-generation ADs weren't sufficiently selective for that purpose (although there was that optimistic moment when it seemed that atypical and melancholic depressions might respond differentially to MAOIs and TCAs). The fact is that during the six decades of their availability, ADs have been prescribed with minimal guidance from psychiatric research. For example, when the more selective SSRIs, SNDIs and NDRIs began appearing in the late 1980's, not one head-to-head study was done to compare their benefits as first-line treatments for people with different presenting symptoms such as apathy or agitation. Instead, the standard clinical trial compared an AD versus a placebo in totally heterogeneous depressed populations. Considering the annual billions of dollars lost to depressive disorders, this deficiency would seem utterly inexplicable except for the fact that most AD research has been funded by pharmaceutical companies seeking to prove the universal benefit of each product tested. The result is an evidence base that provides no guidelines for matching ADs to depressed patients. Experienced clinicians have learned to do that on their own with a fair amount of success. We have seen remission rates above 60% among the prescribers we've followed who are using our measurement-based algorithm. Unfortunately, some academicians seem to equate absence of definitive studies with proof of irrelevance. I will never forget the APA meeting a few years ago at which a prominent university researcher told a roomful of psychiatrists that they should stop prescribing different ADs based on patient symptoms, because to do so wasn't "evidence-based practice."
Getting back to iSPOT-D, according to one of its investigators, the cost of the study was twenty million dollars. The sponsor is a private Australian company called Brain Research, Inc., whose stated goal is "to develop a tool that can be easily used by physicians and health care professionals to ensure that those suffering from depression receive the right medication first go." Whether they have what it takes to accomplish this task remains to be seen, but it is a worthy goal and a welcome start.
The study randomly assigns patients to receive either escitalopram, sertraline or venlafaxine within assigned dosage ranges, which are adjusted by prescribers. Why those three ADs, two of which are SSRIs and none of which is an NDRI? According to Dr. Radu Saveanu, one of the study leaders, they were chosen because of their popularity with prescribers internationally. It may seem odd that a major scientific project would pick its biomarker targets on the basis of popularity rather than pharmacological diversity, but if the product being developed is a "tool that can be easily used by physicians...," perhaps it's logical to make it as relevant to current practice as possible. I agree, however, with the first question asked about this study from a member of the APA audience: "Where is bupropion?"
As for the other methods and results: Patients take a battery of emotional, cognitive, genetic and brain imaging tests at the outset and after eight weeks. The researchers then look for patterns that might enable them to associate specific biomarkers with a greater likelihood of remission on one of the three ADs. The initial conclusion based on the first 1,008 patients was that the iSPOT-D methodology is effective although not yet ready for prime time. One group of test results they found offered some guidance in identifying sertraline responders, primarily on the basis of psychomotor functioning and information processing speed. Since sertraline is the most dopaminergic of the non-NDRIs, it is possible that iSPOT-D is uncovering biomarkers that will be relevant to the use of bupropion and other pharmacological activators as well.
By identifying neurophysiological, biochemical and genetic factors that can guide the selective use of antidepressants, iSPOT-D may further validate the concept of targeted treatment of depression, which we introduced at the May 2000 APA meeting in Chicago. Clinicians who have been using the Targeted Treatment of Depression Inventory (TTDI) online since 2005 and the Clinaptica Depression Consultant on iPad since 2012 to match ADs to patients, will no doubt appreciate the new research supporting methods that have been working in their offices for some time. We look forward to hearing more from iSPOT-D, and hope that other such studies will soon follow.



APA = American Psychiatric Association

iSPOT-D = International Study to Predict Optimized Treatment for Depression

AD = antidepressant

MAOI = Monoamine oxidase inhibitor

TCA = Tricyclic antidepressant

SSRI = Selective serotonin reuptake inhibitor

NDRI = Norepinephrine dopamine reuptake inhibitor

SNRI = Serotonin norepinephrine reuptake inhibitor



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