Table of Contents

Volume 2, Issue 1                                                                                        January, 2016

Special Article:

“Treatment-resistant” depression
A Galenic fallacy

"All who drink of this remedy recover in a short time, except those whom it does not help, who all die.  Therefore it is obvious that it fails only in incurable cases.” 


“Treatment-resistance” as a concept

It’s well-known that “treatment-resistant” depression (TRD) is a major problem in clinical psychiatry.  It’s also widely accepted that there is no illness in which 100.00% of patients respond to appropriate treatments.  In other words, even when a disease is correctly diagnosed, and effective treatments are proven to exist, it is never the case that every single person who has that disease will always respond to effective  treatments. 

In this sense, there always can be treatment-resistance in any illness.  

But, in most illnesses, if the disease is correctly diagnosed, and the treatments are proven effective, a minority of cases should be treatment-resistant.  By definition, if an effective treatment exists, it will be effective for the majority of cases.  

TRD is a different story: One could argue, based on our best studies, that the majority of patients who are diagnosed these days with “major depressive disorder” (MDD), and treated with the class of agents that are proven effective for that treatment (“antidepressants,” or monoamine agonists) are treatment-resistant.  

How can that be?  If the diagnosis is right, and treatments are proven effective, why are a majority treatment-resistant?

This brings us to the alternative hypothesis:  It might not be that the illness is resistant to otherwise correct treatments; it could be that the treating clinician is resistant to changing incorrect treatments for an incorrect diagnosis.  

This is where Galen comes in. 

Blaming the illness

The quote from Galen that starts this article states the conceptual assumption underlying TRD.  The unstated belief, usually completely unconscious to clinicians, is that the MDD diagnosis is correct, and the drugs are just weak.  In fact, it could be that the MDD diagnosis is weak, and the drugs are just fine, seeming ineffective because they are being used for the wrong disease. 

We’ve always known that misdiagnosis is one possibility in TRD, but this possibility is not taken seriously in most cases.  It is listed as one among a dozen reasons for TRD in most cases, and it is given 1/12 the emphasis of other reasons, such as medication noncompliance, substance abuse, poor therapeutic alliance, and such. 

PL thinks that misdiagnosis should be seen as by far the most important cause of TRD, and that we should begin by making Galen’s assumption, which many clinicians hold, conscious, and analyzing it, so that we can stop thinking that way.

“The unstated belief is that the MDD diagnosis is correct, and the drugs are just weak.” 

Galenic assumptions

Galen’s fallacy is obvious: This illness should respond to this kind of treatment; if it doesn’t, then the patients were incurable, or, to use modern terms, “treatment-resistant.”  The clear assumptions are:

a) the illness is correctly diagnosed.

b) the treatments work for that illness. 

In TRD, PL holds that both assumptions often are false.  Frequently, TRD is present because the “MDD” diagnosis is mistaken.  Also, even when MDD is correct using DSM definitions, TRD often is present simply because “antidepressants” are less effective than often presumed for MDD.  These two points require a discussion of the misdiagnosis literature and a critical analysis of the classic STAR*D study.


In the long list of causes of TRD, misdiagnosis usually is one of many.  But some research  suggests that one-third to one-half of all cases of TRD reflect misdiagnosis, a frequency that is much greater than the many other individual causes that often are raised.  Thus, when TRD is observed, misdiagnosis should be examined carefully and seen as the most likely factor above other possible causes.  In other words, other possibilities should not receive the same priority as misdiagnosis, which needs to be ruled out carefully before other possibilities are considered.  

Among the other conditions which are misdiagnosed as MDD, the most common is bipolar illness, especially the type II subtype. Hypomanic, and sometimes manic, episodes are missed in clinical histories, often because patients lack insight into those symptoms and do not report them to clinicians, sometimes because clinicians do not ask about or recognize those manic/hypomanic episodes.  

When bipolar illness is misdiagnosed as MDD, TRD can result because monoamine agonists have been shown to be ineffective in bipolar illness, in meta-analyses and multiple randomized clinical trials (RCTs), as opposed to MDD, where monoamine agonists have been shown to be effective over placebo (at least acutely).  

Hence TRD is not TRD when it represents misdiagnosis.  It is not that the depression is “refractory” to treatments, it is refractory to the wrong treatments. Such patients respond well to a number of dopamine blockers and mood stabilizers, which are proven effective in bipolar depression. 

“Antidepressant” efficacy in MDD

The STAR*D study was a NIMH-sponsored study published in the last decade, reviewed in detail in the Classic Article of the Month.  As described there, a key finding of that study (although not one accepted by many of the researchers involved with it) was that monoamine agonists are not as effective as often presumed.  

Specifically, as noted below, only about 1/3 of patients responded to the whole panoply of monoamine agonists with long-term response.  This is much less than the 60-80% efficacy range that many of us often cited before STAR*D.  One special observation of concern was that about one-half of patients who responded acutely for a current depressive episode would still relapse within a year, despite staying on the same medication which improved their acute depression.  In other words, monoamine agonists seemed much more effective short-term than long-term, acutely than in maintenance prevention.  

Hence, the fact that many patients with MDD should get better temporarily, but then relapse despite staying on monoamine agonists, is not an unusual observation.  This happens in about one-half of patients.  Another quarter of patients never seem to respond to any monoamine agonist at all, even short-term.  

“TRD is not TRD when it represents misdiagnosis.” 

TRD reassessed

Now we can return to the Galenic assumptions.  It seems that about one-third of cases of TRD conservatively can be stated to reflect misdiagnosed bipolar illness. Another one-half of cases reflect the inherent low long-term efficacy rate of monoamine agonists in MDD. The remainder of patients, a small group of 20% or so of subjects, may be truly refractory for other reasons, most commonly medication noncompliance or concurrent substance abuse or concurrent borderline personality or concurrent psychotic symptoms.  

The two biggest factors, though, which explain the vast majority of cases, are misdiagnosed bipolar illness and the limited long-term efficacy of so-called “antidepressants.” 

In the case of misdiagnosis, patients can improve with a change in treatment strategy toward mood stabilizers and/or dopamine blockers. 

In the case of low long-term antidepressant efficacy, a larger clinical question is raised about whether and how long such agents should be used.  This question has not been asked and answered sufficiently, in the opinion of PL, in the scientific literature on depressive illnesses. 

“The two biggest factors…are misdiagnosed bipolar illness and the limited long-term efficacy of so-called ‘antidepressants.’” 

The PL Bottom Line

  • TRD blames the illness instead of the drugs.  
  • The largest class of causes for TRD is misdiagnosis, especially for bipolar depression.  
  • The second largest class of causes for TRD is an inherent low efficacy of “antidepressants” for long-term maintenance prevention of MDD.   
  • In the case of misdiagnosis, treatment should shift to mood stabilizers and/or dopamine blockers.  
  • In the case of low maintenance efficacy in MDD, given STAR*D results, TRD is the rule rather than the exception in antidepressant treatment of MDD.  

PL Reflection

The prime object of the physician in the whole art of medicine should be to cure that which is diseased....Whenever the illness is too strong for the available remedies, the physician surely must not expect that it can be overcome by medicine.  To attempt futile treatment is to display an ignorance that is allied to madness. 


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