1 Boring Old Man

Ten or 20 years from now, we will be sending our patients to the laboratory to characterize them in terms of genetic polymorphisms and/or to an imaging laboratory. Then based on those findings, and on the clinical presentation of the patient, we will be able to do what we can’t do right now, which is to answer the question—of all the treatments that are effective for depression, what is the best one for this particular patient?… This is where the future of psychiatry is going. The task before us is very large because each of these subtypes of depression is biologically distinct and will have different predictors of treatment response. But there is no doubt that what we will be able to do is end this interminable trial-and-error method that all of us are stuck with treating depressed patients._[link]

Is the variable response of depressed people to medications because each subtype of depression is biologically distinct? Do different medications have a therapeutic effect in a specific group of people? Is depression genetic? Is depression biologic? Is depression even an entity? Is the variability in drug response genetic? Is the variability in drug response even biologic? At this moment, is there any solid evidence that any of these  assumptions are true? And personalized medicine in psychiatry has even overrun the banks of the genetic river so the search for biomarkers for depression or drug response now encompasses a wide range of measurable parameters – many far from the genetic shores.

In spite of the fact that the answers to those questions are in the range of doubtful to maybe, there’s an infrastructure being constructed to handle the projected need for such testing – the testing that will free us from the bondage of this interminable trial-and-error method that all of us are stuck with treating depressed patients. Companies like Brain Resources or PsychoGenics have tooled up to measure these proposed but yet undiscovered biomarkers in the days when we will be sending our patients to the laboratory to characterize them in terms of genetic polymorphisms and/or to an imaging laboratory. In the meantime, these companies are selling their services to pharmaceutical companies for research into new drugs to fill this soon-to-be-discovered future need – gearing up to create a new pipeline for the drug trade.

Like the towns that sprung up outside the walls of a medieval castle, these new companies join the clinical research industry in a support/safety symbiosis with the powerful Lords of Pharmacy. Why would such an expensive infrastructure be developing in preparation for the possibilities of such a speculative science? supported by such a large cohort of prominent scientists? financed by the Pharmaceutical elite? Aren’t they getting the cart before the horse? These are questions we probably can answer.

We are approaching the phase of paradigm exhaustion for the antidepressants. It’s a time when the former exciting new scientific paradigm’s warts begin to show as it ages and is overused. Supporters or people who profit from the aging idea are always the last to know that it’s time for the paradigm to find its own place of limited usefulness instead of being the solution for all things for all times I came into rheumatology on the tail-end of the steroid "craze." If you’re a person with severe rheumatoid arthritis and someone puts you on one of the corticosteroids, it’s a miraculous "cure" [for a while]. By the time I came along, using steroids was a sin of the first magnitude because of the long term consequences of the medications. But there were still plenty of patients around who virtually begged to be put back on steroids, or took them on the sly, because of the relief they offered – fully knowing the drastic consequences. It was to be years before alternatives became available.

Psychiatry has been through waves of such cycles because of the often desperate nature of the conditions: fever therapy, psychosurgery, insulin coma therapy, electroconvulsive therapy. Each was a "breakthrough" that was over-utilized, then falling into disrepute, and then disappearing. Only ECT in a modified form stood the test of time and found a place of circumscribed usefullness. Similarly, the first generation neuroleptics were "miracle drugs" until they weren’t as it became apparent that tardive dyskinesia lurked in the future with long term use. The same cycle repeated for the Atypical Antipsychotics and their metabolic syndrome. In every case, the "enthusiasts" hung on to the bitter end – denying the obvious down-sides of the drugs until they became impossible to ignore. Neuroleptics, Lithium, Tricyclics, SSRIs, anticonvulsants as "mood stabilizers" – these drugs have created a generation of psychiatrists who have come into prominence in the age of psychopharmacology, holding the psychotherapists of the former age in contempt. The same was true for the psychotherapists and psychoanalysts of that earlier age who saw the psychosurgeons and ECT doctors in the same light.

Right now, it’s hard for the antidepressant biologists to accept that their drugs are probably not the answer to depression. It’s even harder for the pharmaceutical companies to accept. They’ve raked in a fortune with their SSRI, SNRIs, Atypicals, – all "blockbusters." Even today, over one in twenty adults are on their medications. So as the patents run out, and the flow of new versions dry up, it’s only natural for them to look for the next big idea. Enter stage left – personalized medicine. What they know is that people [consumers] will go for that idea. What they also know is that general physicians and prescribing psychiatrists will go for it too. Send a person for a lab test and it comes back saying – give this medication. It’s guaranteed success, just like the SSRIs were in recent times. Clinical Trials become easier. You don’t have to succeed in everybody, just some segment that you can identify. They can just hear the pot of gold jingling at the end of this rainbow.

If it were true, there’s nothing wrong with this scenario. The problem is that this product has already gone to market, and there’s nothing to sell. It’s a futures market at best – a speculative futures market. And in this case, it’s riding a borrowed medical paradigm that has a low probability of fitting – probably none at the level of that speech. We know from their past behavior what’s going to happen. They’re going to do everything in their power to make it fit. It’s already happening. My last post [personalized medicine: a conclusion in search of an argument…] was about an early shot – a sow’s ear sold as a silk purse. Even though it was a disreputable study, it was used in that speech at the top of this post as a confirming example at last year’s APA meeting._[link]

^{Patients who had a better clinical outcome were characterized by a decrease in the amplitude of the Auditory Oddball N1 at baseline. The ‘Met/Met’ variant of the COMT gene was the best genetic predictor of treatment outcome. Impaired verbal memory performance was the best cognitive predictor. Raised frontal Theta power was the best EEG predictor of change in HAM-D scores. A tentative integrative model showed that a combination of N1 amplitude at Pz and verbal memory performance accounted for the largest part of the explained variance. These markers may serve as new biomarkers suitable for the prediction of antidepressant treatment outcome.}