Treatment Resistant Depression — A Collective Failure of Imagination
“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, and I have nothing against that — it’s an important line of treatment — but this should also be an opportunity to consider…
Do I have the right diagnosis or formulation?
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 a change is needed?
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?
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?
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.
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