Sean X. Luo M.D., Ph.D.

Hooked on Patterns

The End of the Road

Some Modest Proposals on Treatment Resistant Depression

Posted Sep 09, 2014

In my last blog post, I talked about “precision medicine” and finding out if a particular antidepressant medication is going to make you achieve remission. I talked about that at the end of the big study sponsored by the National Institutes of Mental Health, STAR*D, about 50% of the patients achieve remission—their symptoms have improved to such a degree that they no longer qualify for a diagnosis of major depressive disorder. Another 30-40% of patients achieve what is called a “response”, which means that their symptoms improved quite significantly, though not quite enough to meet the threshold for remission.

That leaves us with another 10%.

Lifetime prevalence of depression in the US is about 20%. 10% of 20% is about 2%. 2% of people in the US have what we call Treatment Resistant Depression, which is a nasty condition that we have very few treatments for. The main remaining options are (1) Electroconvulsive Therapy (ECT) (2) Transcranial Magnetic Stimulation (TMS), which is expensive and not particularly effective (3) Ketamine infusion (4) Deep Brain Stimulation (DBS) (5) intensive psychotherapy of some kind.

The most effective treatment and one that has the most empirical support is ECT, which has a response rate of up to 80%, although in patients with “real” Treatment Resistant Depression, the response rate even for ECT tends to be lower—and of course ECT has its well-known undesirable effects. DBS was a technique pioneered by Helen Mayberg, who has had tremendous press coverage and got many people very excited. Here is the problem: although there are a few dramatic cases, it turns out that it doesn’t work for everyone and that the responses often do not sustain itself. The very much anticipated BROADEN trial from St. Jude’s Medical failed early this year in a whimper. For further coverage see here.

“At NYU, Mayberg admitted that she has to wonder why her implant studies show better results than the BROADEN trial apparently did. “Do my patients want to please me?” she asked.”

Large, double blind, randomized controlled trial is our best defense against hype. Perhaps Mayberg was being slightly glib--not as facile with psychodynamics as a neurologist, she probably didn’t see the pretty obvious transference-countertransference slipping through that comment. Those of us who often treat these patients see a lot of co-morbid personality disorders, and many psychodynamic theories posit depression as some kind of “resistance”, and the dramatic response can be a manifestation of “narcissism” to please a famous researcher in a cutting-edge clinical trial. This is of course all conjecture. The enemies of the psychodynamics theory in my head can and will immediately come back and retort, “how could you blame the victim for what is clearly a brain disease!”

Here is where “precision medicine” should come in.

What is and isn’t a “brain disease” isn’t well defined and this “debate”, just like the debate over efficacy of antidepressants, is trivial. Here is what we know and can define and measure: DBS works for some people. Some patients have genuine “resistance” or have “subconscious primary gain”. Every investigator thinks he/she is right because he/she only sees that small number of patients, and some of these patients get better with whatever treatment they received in the study that they got into. What should be obvious to everyone is that Treatment Resistant Depression is highly heterogeneous, but what is being sold is that a specific treatment works for everyone. The reality is messy: some people might do better with DBS; others might need confrontations from a therapist in a treatment like Transference Focused Psychotherapy. Some of these patients might even just remit without any of these treatments.

Is that possible? I looked for it in a cursory search: it turns out there are very few quality longitudinal studies on Treatment Resistant Depression [1]. The largest naturalistic study, following Treatment Resistant Depression patients through 2 years [2] (no DBS or any fancy psychotherapy) reports this shocker: at the end of 24-months, 20% of these patients achieve a “response” and 10% achieve a remission. 

It seems that patients who have Treatment Resistant Depression come in and out of depression just like the other patients. They just come out of it less frequently, and for not as long, and their symptoms more severe. These patients don’t just always stay depressed, as we might assume. Treatment Resistant Depression is not just heterogeneous for different patients; it’s also heterogeneous in time for the same patient!

We don’t know very much about this condition, and given the relative high prevalence (twice as common as bipolar and schizophrenia) it’s really a travesty. I propose to create a national de-identified registry so that all Treatment Resistant Depression patients, defined by some clear NIMH established criteria, are reportable and tracked in time and in space. We gather large, quality longitudinal data on these patients and use machine learning to figure out which of them get better and which of them do not, and who got better with ECT, and who went and had a ketamine infusion. Will you, my reader, be willing to write this grant?


[1] Fekaddu A et. al, 2009 What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies, J. Affective Disorders, 116: 4-11

[2] Dunner DL et. al 2006 Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression, Journal of Clinical Psychiatry 67: 688-695

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