Treatment Resistant Depression — A Collective Failure of Imagination [REPOST]
This was originally published on Psychiatry at the Margins on Sep 24, 2023. I am reposting it with some minor edits for the benefit of new as well as old readers.
“What cannot be cured by medicaments is cured by the knife, what the knife cannot cure is cured with the searing iron, and whatever this cannot cure must be considered incurable.” Hippocrates
“We have had an ever-growing population of patients whose illness is seemingly refractory to standard therapies… The interest in newer somatic treatments in part reflects a sense of near desperation in treating this group of patients, many of whom may actually not be particularly responsive to somatic therapy… The assumption has been that we need more effective somatic treatments, but that may not be entirely correct.” Alan Schatzberg, 2020, American Journal of Psychiatry
“We posit that, in practice, a failure to respond is often the result of having administered wholly inappropriate treatment; that which is unsuitable because of a paradigm failure… it is not uncommon for patients to end up being treated for a disorder that they do not quite have, with treatments that do not have proven efficacy for their specific symptomatology… By defining TRD in this way, we are cementing the idea that it is an exceptional form of depression and not questioning whether the patient may have been misdiagnosed or may have a subtype of depression for which the benefit of antidepressants has not been demonstrated.” Gin Malhi, et al., 2019, British Journal of Psychiatry
“Unfortunately, there is another major problem with research on TRD: the almost complete absence of psychological treatments. In one systematic overview, a total of 148 different definitions of TRD were collected from the literature. All definitions included at least one failed treatment with antidepressants, but only six definitions (4%) included one failed treatment with psychotherapy. This is remarkable…” Pim Cuijpers, 2023, World Psychiatry
“Show me a patient diagnosed with treatment resistant depression, and the likelihood is that I will show you someone whose underlying personality dynamics were never understood or addressed in psychotherapy. And it can’t be done in 8-12 sessions, because engrained psychological patterns that develop over a lifetime do not change in a matter of weeks.” Jonathan Shedler, 2020, Conversations in Critical Psychiatry
“Insofar as a major goal of any treatment is to diminish suffering, clinicians must consider the physical and emotional burden that patients incur when they submit to multiple ineffective treatments.” Joseph F. Goldberg, 2018, Journal of Clinical Psychiatry
The concept of “treatment-resistant depression” (TRD), as we currently understand and use the term, reflects a highly parochial mindset. The assumptions embedded in the concept point towards a clinical world in which initial treatment with antidepressants is the norm and further pharmacological treatment is the default option; other treatment modalities, especially psychotherapy, are an afterthought; diagnostic heterogeneity runs rampant; symptom clusters are poorly validated; and no one quite knows how to prioritize treatment of comorbid diagnoses. It is only in such a world that it even becomes reasonable to think, “Oh no, this patient has failed to respond to two trials of antidepressants! They must have some exceptional form of depression. What do we do now?!” A clinical state of affairs centered around the concept of TRD is an impoverished one, where clinicians are expected to follow treatment algorithms on autopilot, with minimal self-reflection and a lack of awareness of the contradictions that sustain this model of care.
When patients don’t adequately respond to standard antidepressant medications, there will be patients for whom the next best step is further pharmacotherapy with various augmentation agents or pharmacological alternatives that are now available, but this should also be an opportunity to consider the following questions:
Do I have the right diagnosis or formulation? (In particular, have I considered undiagnosed bipolarity and personality psychopathology?)
Is depression in this case better understood as a problem secondary to, or linked to, a comorbid condition (PTSD, ADHD, substance use disorder, eating disorder, autism, etc.) whose treatment should be prioritized?
Does the state of depression exist in the context of long-standing personality dynamics that powerfully sustain it and ensure its repetition?
What medical comorbidities are present, and what is their relationship to the state of depression?
Have I considered undiagnosed medical conditions such as hormonal disorders or nutritional deficiencies in the differential?
What is the relationship between the state of depression and the interpersonal and social world in which the patient lives? Is the depressed state a signal, similar to pain, of something dysfunctional in their lives — a relationship, a job, a stubborn pursuit of a hopeless goal — and would persist until relevant changes are made?
How well connected is the patient to sources of meaning in their lives?
Pharmacokinetic considerations: does the patient metabolize medications in an unusual way?
Does the patient have an ecophenotype characterized by childhood abuse?
Have I taken into account lifestyle and metabolic factors, such as diet and physical activity?
Have I successfully developed a therapeutic relationship with the patient? Has the patient had adequate opportunities to share their story the way they want to? Do they perceive that their concerns are being taken seriously?
How does the patient conceptualize their problem? What do they understand to be possible solutions? Does the story they tell about their problems have any bearing on the course of the illness?
Was first-line treatment with antidepressants appropriate to begin with? Have I considered the full range of interventions?
Is treatment with antidepressants worsening dysphoria, irritability, or anxiety?
And in situations where we truly are at the end of the care we can offer, how can we embrace “the here-and-now reality of existing treatment limitations” without abandoning care or withholding the therapeutic relationship?
“To paraphrase Winnicott, a “good enough” psychopharmacology often means coming to terms with the reality of imperfection. It serves no one’s interests to pretend that psychiatric problems hold an immunity from that reality in ways that are somehow different from other chronic nonpsychiatric medical conditions.” (Goldberg, 2018)
P.S. There is an unfortunate dynamic in certain clinical contexts where consideration of, say, personality dynamics or lifestyle factors becomes an excuse to withhold pharmacological treatment that the patient prefers. I obviously don’t condone that. As I have written previously, “a liberatory psychopharmacology should reject all forms of moralizing about medication use and shouldn’t shame people for using them, or not using them.” I’m frequently surprised by how some people use clinical recommendations that are otherwise perfectly reasonable to justify therapeutic abuse or neglect. The human factor in healthcare is a double-edged sword. We color everything with our messy motivations.
See also:
I am a master’s level therapist. I love your thoughts here. I feel an internal crisis when I hear TRD in consult groups occasionally. We can be so self-focused instead of client-focused, i.e. preferring our reaction to a client, shaped in the lineage of our specific training, over a curious stance that favors ecology. Your exploratory questions feel right on. They feel both theoretical and right on the ground. I also read the article about Dr Ray Osheroff. I imagined if I was working with him at the onset, one of the things I would say is “Can you take a sabbatical, right now, get on a plane, and fly to Europe to be in proximity to your children for a bit, and learn to be close to them in a way you haven’t before?” Then go through the mechanics of the “what’s and why’s” of the “no, I couldn’t possibly!” that I predict would be said back to me. And we would find a way through together to something that likely feels impossible but is actually just nonconforming. Perhaps would be a useful intervention, perhaps not. Lots of good imaginings sparked by this post. Thanks.
Hi Dr. Aftab: Thank you for posting this. I am hesitant to go too far back in a writer's archives, since commenting on older posts seems to invite very few, if any, responses or further discussion. I am reposting similar comments I made earlier with edits appropriate for here.
I am assuming, maybe incorrectly, that the P.S. part of the post is speaking directly to my wanting to be clear about certain aspects of one of your recent posts. I think you made it clear in the PS section for sure.
I think this post hits all the right notes. I went back and read your earlier post on Treatment Related Suicidality. I will comment on it there, and copy to notes so that it may be noticed, since it was a much older post. From my first scan of it, it looks like it significantly speaks to the right concerns, mostly because you are clearly able to formulate the right questions, among other things. In addition, it would unforgivable of me not to say "Your analysis and writing is easily in the top five of any writing by a psychiatrist that I have ever read."
My conclusions as noted below come from over 15 years of an intense dive into diagnosing and treating ADHD in adults who were trying to figure out what the heck was going on with them. A large majority of them were unevaluated for, or even apprised of, ADHD when put on SSRIs for panic, anxiety, agoraphobia, OCD, and depression, among other things.
My early observations led me to doing 3 hour evaluations of new clients, utilizing my own diagnostic evaluation checklists and insisting that new clients bring along someone who would be willing to corroborate or clarify the self reporting of the person being evaluated (a child, sibling, parent, good friend or several members of a family). I have an observational and recorded database that includes more than 300 clients. I also used a standardized method for testing working memory at baseline and during treatment, which consisted of what the literature says is the most useful, cost-effective way to assess working memory capacity -- a reverse digit span protocol.
From all of my observations, research and reading, it seems that working memory at baseline (meaning non-threat scenario) is a valid proxy for understanding what I would call the main vulnerability indicator for possible manifestation of ADHD characteristics. I use the term "free roaming dopamine" to stand for "tonic dopamine," as opposed to synaptic or phasic dopamine. Although phasic may contribute a bit to working memory capabilities, the literature is more than clear about the connection between "tonic" and working memory operations.
Threat scenarios increase tonic dopamine, and, thus, you could say "threats treat poor working memory," and thus, treats the major variable in the manifestation of ADHD characteristics. A large part of my 2013 book discusses my findings related to the "upside" of the ADHD brainset – threat response capabilities. Non-ADHDers (good working memory) aren't so good at threat response due to tonic dopamine quickly accelerating to above optimal, which degrades working memory (the upside-down U shaped curve), among other non-helpful actions.
My data showed that 90% of about 35 TRD diagnosed patients fit or did fit the criteria for the diagnosis of ADHD, but had not been evaluated or diagnosed for ADHD. Twelve of those had received a course of treatment that included a series of increasing dosages of an SSRI, then an "augmentation" medication (usually olanzepine, but also aripiprazole) and then ECT. They clearly fit the criteria for ADHD, but had never been evaluated, or even apprised of the possibility.
A similar set of percentages of undiagnosed ADHD was also found to be true with respect to patients who had been diagnosed with panic and anxiety disorders. Much larger percentages existed for undiagnosed ADHD in OCD, hoarding, AUD, SUD, binge drinking or eating, bulemia, tobacco use disorder, fibromyalgia, etc. In my book, I set out a table showing 25 different disorder types which have been studied for the co-existence of, or the missed diagnosis, of ADHD.
My experience and ongoing studies of the best ways to assess and treat adult ADHD clearly shows TRD and other "sickening" effects of missed diagnosis and mistreatment of such undiagnosed ADHD with SSRIs happens all of the time.
There are few published studies about the prevalence of undiagnosed and untreated ADHD among diagnosed anxiety disorders (including panic disorders and PTSD in a couple of studies) is around 38%. Interestingly, that is close to the same percentage of undiagnosed ADHD found in a more recent TRD study.
Biases are so programmed that docs learn to find ways around even attempting an evaluation which could lead to first line treatment with a so-called "stimulant." Clearly, the influence of what constitutes first line treatment for ADHD, a "stimulant," is a huge obstacle to considering the diagnosis. I call it "comfort-zone prescribing." Being diagnosed with ADHD carries almost no stigma these days. It has been normalized to the extent that it is now "okay." However, the first line treatments have been demonized and carry more stigma than the diagnosis, by far.
You have covered that issue in this post.
The language needs to change before docs will ever get scientific about ADHD and its treatment, rather than engage in emotional responses based on repeated misinformation based on even more biased statements from past, outdated, science. Such a nomenclature using "stimulant" (a side effect) is tantamount to categorizing ibuprofen as a "kidney damage pill."
Until the terminology changes to, let's say, "dopamine enhancers" or "norepinephrine enhancers" or "combined DA/NE enhancers," the clearly almost unalterable highly-programmed response to the term "stimulant" will rule. Not to mention how calling a category of medications "stimulant" is great advertising for encouraging diversion. I mean, come on….
Enough data exists, but clearly more studies are needed on the downside of SSRIs that decrease dopamine dependent working memory functionality. The studies exist. The observations are huge. And, why is it not being studied more intensely?
Suboptimal working memory at baseline (non-threat scenarios) is the common denominator to 90% of the downside characteristics of what we currently call ADHD.
Decreasing working memory below an already low baseline dopamine dependent working memory with an SSRI will create the perfect storm for an ongoing depression with ever more cognitive downsides as the SSRIs and antipsychotics continue the downward spiral, until? Until the patient with the undiagnosed ADHD finally receives a dopamine enhancer (TMS, ECT, ketamine).
This same perfect storm can increase suicidality in those undiagnosed for ADHD presenting as anxiety or depressive disorders. By depressing working memory and other cognitive corollaries with SSRIs, what do you get? Less able to think twice, more forgetful, distracted, more impulsive, impatient, frustrated, fuzzy, less fearful (more risk capable), in addition to likely feeling weird and sickly, not to mention the resulting loss of hope.
I am hoping that you will read my book to get most of the full story. It is still ahead of its time. I will bet good money that you will find it more than a little interesting.
Thank you again for your excellent work and best wishes. Hope we can continue to discuss.