This is a very useful piece that should stimulate a good deal of re-thinking on the topic of treatment-resistant depression (TRD). I agree with essentially all the points in the article, but would add an important consideration: undiagnosed bipolarity. Having carried out hundreds of psychopharmacology consultations with the referral question of "TRD", I soon learned, over the course of more than twenty years, that a large percentage of these patients had undiagnosed bipolar spectrum disorders.
Antidepressant treatment almost invariably failed, and created what I came to call ARAD: antidepressant-related agitation and dysphoria. NB: this was not an actual "switch" into hypomania or mania, by DSM criteria. Patients would typically complain of feeling "antsy", irritable, and unable to sleep, while taking antidepressants. Changing to a mood stabilizer--especially lithium--very often produced a marked improvement in their clinical symptoms and course of illness. All this prompted me to develop--with the collaboration of my colleague, Dr. Nassir Ghaemi,--the Bipolar Spectrum Diagnostic Scale (BSDS). This patient-completed form helps uncover more subtle forms of bipolarity, including BP II Disorder. The scale is widely available without charge on the internet, and has been shown, in several multi-cultural studies, to possess reasonably good sensitivity and specificity [see references, below].
Undiagnosed bipolar illness remains, in my view, one of the chief "drivers" of so-called treatment-resistant depression.
Ronald W. Pies, MD
Nassir Ghaemi S, Miller CJ, Berv DA, Klugman J, Rosenquist KJ, Pies RW. Sensitivity and specificity of a new bipolar spectrum diagnostic scale. J Affect Disord. 2005 Feb;84(2-3):273-7. doi: 10.1016/S0165-0327(03)00196-4. PMID: 15708426.
Vázquez GH, Romero E, Fabregues F, Pies R, Ghaemi N, Mota-Castillo M. Screening for bipolar disorders in Spanish-speaking populations: sensitivity and specificity of the Bipolar Spectrum Diagnostic Scale-Spanish Version. Compr Psychiatry. 2010 Sep-Oct;51(5):552-6. doi: 10.1016/j.comppsych.2010.02.007. Epub 2010 Apr 1. PMID: 20728015.
Using the WHIPLASHED Mnemonic to Distinguish Unipolar from Bipolar Depression
Very much appreciate your work and perspective, Dr. Pies. I use the BSDS scale frequently and find that many “treatment resistant depression” patients show bipolarity by that scale. At the same time, I don’t see striking improvement in the majority of these patients with mood stabilizers (including lithium). “Unrecognized bipolarity” may be as much an oversimplification as “treatment resistant depression.”
Hi, Dr. Weiss--Many thanks for the kind comment, and I'm happy to hear that you find the BSDS useful! I do understand your observation that many of those identified as having "unrecognized bipolarity" do not show "striking improvement" with mood stabilizers. I suppose my description of "marked improvement" is a notch down from "striking." What I did see was a cessation of the ARAD symptoms I described above, once the patient was taken off the antidepressant--and this, in itself, was often a relief to the patient, especially those whose sleep was disturbed by the antidepressant. But as we know, most people with bipolar disorder spend most of their time in the depressed phase. That is to say, " Depression represents the predominant abnormal mood state for treated outpatients with bipolar I and II disorder..." [1]. And bipolar depression can be stubborn and long-lived--even with mood stabilizers (of which, lithium is still my "go-to" base therapy).
I think we would agree that we need better and more robust treatments for bipolar depression--but getting the patient off their antidepressant, in my view, is still a good first step. Thanks again for writing!
Best regards,
Ron
1. Kupka RW, Altshuler LL, Nolen WA, Suppes T, Luckenbaugh DA, Leverich GS, Frye MA, Keck PE Jr, McElroy SL, Grunze H, Post RM. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord. 2007 Aug;9(5):531-5. doi: 10.1111/j.1399-5618.2007.00467.x. PMID: 17680925
If someone gets better whilst taking an antidepressant, but their recovery isn't due to the antidepressant, or to any other treatment in fact, and they also wouldn't have responded to another antidepressant - is their depression properly described as treatment resistant or not?
Well, we are not in a position to definitively say for any particular individual whether the recovery is because of the treatment or because of natural history, so the question doesn’t arise. (Sometimes we can guess where the patient can link the improvement to a phenomenological change, eg, but it’s not definitive). So self-limiting-but-theoretically-non-responsive-to-treatment depressions kinda get lumped into the responder category.
This is a very useful piece that should stimulate a good deal of re-thinking on the topic of treatment-resistant depression (TRD). I agree with essentially all the points in the article, but would add an important consideration: undiagnosed bipolarity. Having carried out hundreds of psychopharmacology consultations with the referral question of "TRD", I soon learned, over the course of more than twenty years, that a large percentage of these patients had undiagnosed bipolar spectrum disorders.
Antidepressant treatment almost invariably failed, and created what I came to call ARAD: antidepressant-related agitation and dysphoria. NB: this was not an actual "switch" into hypomania or mania, by DSM criteria. Patients would typically complain of feeling "antsy", irritable, and unable to sleep, while taking antidepressants. Changing to a mood stabilizer--especially lithium--very often produced a marked improvement in their clinical symptoms and course of illness. All this prompted me to develop--with the collaboration of my colleague, Dr. Nassir Ghaemi,--the Bipolar Spectrum Diagnostic Scale (BSDS). This patient-completed form helps uncover more subtle forms of bipolarity, including BP II Disorder. The scale is widely available without charge on the internet, and has been shown, in several multi-cultural studies, to possess reasonably good sensitivity and specificity [see references, below].
Undiagnosed bipolar illness remains, in my view, one of the chief "drivers" of so-called treatment-resistant depression.
Ronald W. Pies, MD
Nassir Ghaemi S, Miller CJ, Berv DA, Klugman J, Rosenquist KJ, Pies RW. Sensitivity and specificity of a new bipolar spectrum diagnostic scale. J Affect Disord. 2005 Feb;84(2-3):273-7. doi: 10.1016/S0165-0327(03)00196-4. PMID: 15708426.
Vázquez GH, Romero E, Fabregues F, Pies R, Ghaemi N, Mota-Castillo M. Screening for bipolar disorders in Spanish-speaking populations: sensitivity and specificity of the Bipolar Spectrum Diagnostic Scale-Spanish Version. Compr Psychiatry. 2010 Sep-Oct;51(5):552-6. doi: 10.1016/j.comppsych.2010.02.007. Epub 2010 Apr 1. PMID: 20728015.
Using the WHIPLASHED Mnemonic to Distinguish Unipolar from Bipolar Depression
https://womensmentalhealth.org/posts/whiplashed/
Very much appreciate your work and perspective, Dr. Pies. I use the BSDS scale frequently and find that many “treatment resistant depression” patients show bipolarity by that scale. At the same time, I don’t see striking improvement in the majority of these patients with mood stabilizers (including lithium). “Unrecognized bipolarity” may be as much an oversimplification as “treatment resistant depression.”
Hi, Dr. Weiss--Many thanks for the kind comment, and I'm happy to hear that you find the BSDS useful! I do understand your observation that many of those identified as having "unrecognized bipolarity" do not show "striking improvement" with mood stabilizers. I suppose my description of "marked improvement" is a notch down from "striking." What I did see was a cessation of the ARAD symptoms I described above, once the patient was taken off the antidepressant--and this, in itself, was often a relief to the patient, especially those whose sleep was disturbed by the antidepressant. But as we know, most people with bipolar disorder spend most of their time in the depressed phase. That is to say, " Depression represents the predominant abnormal mood state for treated outpatients with bipolar I and II disorder..." [1]. And bipolar depression can be stubborn and long-lived--even with mood stabilizers (of which, lithium is still my "go-to" base therapy).
I think we would agree that we need better and more robust treatments for bipolar depression--but getting the patient off their antidepressant, in my view, is still a good first step. Thanks again for writing!
Best regards,
Ron
1. Kupka RW, Altshuler LL, Nolen WA, Suppes T, Luckenbaugh DA, Leverich GS, Frye MA, Keck PE Jr, McElroy SL, Grunze H, Post RM. Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disord. 2007 Aug;9(5):531-5. doi: 10.1111/j.1399-5618.2007.00467.x. PMID: 17680925
I agree, undiagnosed bipolarity is a huge factor. Thanks for bringing it up!
If someone gets better whilst taking an antidepressant, but their recovery isn't due to the antidepressant, or to any other treatment in fact, and they also wouldn't have responded to another antidepressant - is their depression properly described as treatment resistant or not?
Well, we are not in a position to definitively say for any particular individual whether the recovery is because of the treatment or because of natural history, so the question doesn’t arise. (Sometimes we can guess where the patient can link the improvement to a phenomenological change, eg, but it’s not definitive). So self-limiting-but-theoretically-non-responsive-to-treatment depressions kinda get lumped into the responder category.
‘A highly parochial mindset.’ Well put!