Thinking Creatively About Treatment-Resistant Depression: Q&A with J. Alexander Bodkin, MD

treatment resistant depressionTCPR: The term “treatment-resistant depression” is sort of thrown around a bit. I’m sure that there are various formal or informal definitions of it, but how do you think about it?

Dr. Bodkin: The formal definition basically requires 2 failures of distinctly different antidepressants at robust doses for adequate duration. But personally, I think it is important to look at the type of depression before you start talking about whether or not it is treatment resistant. In other words, not just does your patient meet the criteria for depression, but what does the depression look like?

TCPR: How do you think about depression?

Dr. Bodkin: In my opinion, depressive illness is a final common pathway for a number of different brain problems. There are a whole range of ways to have 5 out of the 9 DSM symptoms. Some of them are highly genetic; some of them are less genetic; some of them seem not to be genetic at all; some of them seem to have to do with literal brain injury; some of them have to do with—shall we say—psychological injury, and many of these versions of depression overlap.

TCPR: What are some of the useful large categories of types of depression?

Dr. Bodkin: I ask myself the following questions as I’m evaluating and treating patients: 1. Does this patient have a bipolar illness? If so, that calls, at least to some extent, for a significantly distinct treatment approach. 2. Does this patient have melancholia? This is a clear acute-onset medical-looking depressive illness with loss of capacity for any emotional experience at all, reward or otherwise. We see this a relatively small percentage of the time in its pure form, but melancholia is an illness that has one set of best interventions. 3. Does this patient have a major depression with atypical features? What I mean by this is the capacity to be brought back to an emotionally normal or an undepressed state, at least briefly, by things in life going the right way. A patient might have a wonderful couple of days until a disappointment happens or a perceived affront, rejection, or failure. This is called mood reactivity and it is a requirement as far as a DSM diagnosis. About 15% of patients have atypical features (Seemüller F et al, J Affect Disord 2008;108(3):271–278).

TCPR: What’s the best treatment approach for depression with atypical features?

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Dr. Bodkin: These are the patients who also tend to respond better to the monoamine oxidase inhibitors (MAOIs). But these medications are rarely used. In fact, one of the reasons I think we have this troublesome population of so-called treatment-resistant depressives is because by and large, nobody gets tried on MAOIs. And you can’t really be said to be treatment resistant until you’ve been on the standard available treatments.

TCPR: Can you expand upon this?

Dr. Bodkin: Sure. I think that the enormous overgrowth of the treatment resistant category has to do with the hesitancy in using the MAO inhibitors or tricyclics due to their side effects. Tricyclics, in particular, are great uptake inhibitors that cover not only serotonin and norepinephrine, but they are also to some extent antiadrenergic and anticholinergic. We are learning more about how tricyclics may have downstream effects on both the opioid (Onali J et al, Pharmacol Exp Ther 2010;332(1):255–265) and dopamine (Menza M et al, Neurology 2009;72(10):886–892) pathways. The pure serotonin uptake-inhibiting drugs really only take one feature of these wonderful old dirty drugs and therefore are less effective for certain types of depression. In the STAR*D trial, only 28% of people adequately treated with an SSRI achieved remission (Trivedi MH et al, Am J Psychiatry 2006;163(1):28–40). That’s a low rate of remission, and yet SSRIs remain the standard of care. My colleague and I did a review on the extensive published evidence for markedly greater efficacy of the TCAs relative to SSRIs (Bodkin JA and Goren JL, Psychiatric Times 2007; 24(11):20–32). The 2 most famous studies that we looked at were the Danish comparisons of clomipramine with citalopram (Psychopharmacology (Berl) 1986;90(1):131–138), and with paroxetine (J Affect Disord 1990;18(4):289–299). In our 2007 review, we also reviewed published evidence of the superior efficacy of MAOIs compared to SSRIs in 2 subgroups of depression patients: those with atypical features and those showing treatment resistance.

Thinking Creatively About Treatment-Resistant Depression: Q&A with J. Alexander Bodkin, MD

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This article was published in print April 2016 in Volume:Issue 14:4.


APA Reference
Psychiatry Report, T. (2017). Thinking Creatively About Treatment-Resistant Depression: Q&A with J. Alexander Bodkin, MD. Psych Central. Retrieved on June 27, 2019, from


Scientifically Reviewed
Last updated: 14 Aug 2017
Last reviewed: By John M. Grohol, Psy.D. on 14 Aug 2017
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