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

TCPR: Of course SSRIs are quite safe, which may be a reason why standard practice is to start with them.

Dr. Bodkin: This is a standard practice, and I do not think that it is sound. Multiple SSRI trials can be a terrible waste of valuable time for patients who are suffering. In general, the SSRIs are most effective in anxiety disorders. I choose SSRIs first for patients with somatic symptoms of panic, or sometimes for patients with a more generalized anxiety, people who are clearly stewing, worrying, ruminating, fretting, and anticipating problems. SSRIs are somewhat less effective in depressive disorders with prominent anxiety. Now, in patients with psychomotor retardation, deep apathy, anergia, lassitude, loss of drive, if you can ameliorate the anxiety component, these symptoms will get somewhat better in some patients, but you will really not achieve remission.

TCPR: So what do you do in this case?

Dr. Bodkin: If there is a partial response, generally the typical next step is to try to enhance that rather than stop the drug and begin with something else. If the prominent residual symptoms has to do with, let’s say, insomnia or persistent loss of appetite, then you would add something that might ameliorate that, for example, mirtazapine. But if the problem is actually most prominently anergia, bupropion is very helpful (Bodkin J et al, J Clin Psychiatry 1997;58(4):137–145). Similarly, bupropion can help patients with a loss of sexual drive, whether from the depression itself or from an SSRI. Atypical antipsychotics have a place, and they can be remarkably helpful in treating what I call the “turbulent distress” experience, which can be anxiety, or anger, or both. Published evidence in this realm has focused primarily on quetiapine, which has been shown robustly effective in generalized anxiety disorder, a condition featuring “turbulent distress,” both as an SSRI adjunct (Simon NM et al, Psychopharmacology (Berl) 2008;197(4);675–681) and as monotherapy ( Of course, people often gain weight on atypical antidepressants; they can develop Type 2 diabetes and experience other problems, so these drugs should not be prescribed without caution. But used appropriately they are often a sensible component of treatment.

TCPR: What about patients who may be in need of a more stimulant-like medicine?

Dr. Bodkin: You can always try psychostimulants like amphetamine or methylphenidate, but doctors are often uncomfortable prescribing them, and patients can be uncomfortable receiving them. There are some alternatives. For patients whose depression is characterized by lethargy, apathy, dragging of the feet, etc. there is the partial agonist strategy of aripiprazole (Abilify) or brexpiprazole (Rexulti). In addition, sometimes pramipexole (Mirapex) is remarkably helpful if you have a patient who ideally should have been started on an MAOI but instead is taking an SNRI and is still lethargic. Pramipexole is a direct dopamine agonist used for Parkinson’s and for restless leg syndrome. It’s sort of a stimulant-like drug without the stimulant-like problems of potential abuse and tolerance.

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.
~ J. Alexander Bodkin, MD

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TCPR: What sort of side effects should I be warning my patient about when I’m using pramipexole?

Dr. Bodkin: Both hypotension and nausea are potential problems, and sometimes people paradoxically get quite sedated. In older patients, especially those who have some degree of dementia, there can be a side effect of impulsivity or excessive initiative. It’s also inconvenient. It’s a t.i.d. drug, occasionally a b.i.d. drug, so dosage has to be titrated with great care.

TCPR: So there are a lot of options out there. It can get confusing. Can you help us with our decision-making?

Dr. Bodkin: I often look at symptoms in terms of a very simple bifurcation: the distress factor vs. the drive factor (Watson D and Tellegen AJ, Pers and Soc Psychol 1988;54(6):1063–1070). The distress factor has to do with anxiety, irritability, rage, panic, etc. These symptoms call for anxiolytic medications—SSRIs, benzodiazepines, many of the atypical antipsychotics. The drive factor has to do with initiative, interest, and energy level. If there is too much of those, we call it hypomania, but patients need at least an average amount of initiative, interest, and gratification from the pursuit of things that are interesting. Diminished drive leads me to reach for dopaminergic interventions, and to a lesser extent to noradrenergic interventions. As we discussed, these include stimulants, bupropion, aripiprazole, pramipexole, but also MAOIs, which among other things inhibit metabolism of dopamine.

TCPR: That is very interesting. Thank you for your time, Dr. Bodkin.

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.

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APA Reference
Psychiatry Report, T. (2017). Thinking Creatively About Treatment-Resistant Depression: Q&A with J. Alexander Bodkin, MD. Psych Central. Retrieved on October 27, 2020, from


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