Comment
Reconceptualising treatment-resistant depression as
difficult-to-treat depression
Although the label of treatment-resistant depression
has been used for decades, there are no consensually
agreed or formalised diagnostic criteria for this term. The
concept itself poses problems, because it misleadingly
implies that treatments for depression are generally
highly effective, just as antibiotics are for bacterial
infections. Yet for most patients with depression, both
pharmacological and psychological treatments have
only modest or moderate effectiveness.1
Beside semantic imprecision, the concept of treatment-
resistant depression is impaired by substantial diagnostic
ambiguity, such as whether resistance should be used to
label failure to achieve remission of symptoms, or rather,
the failure to respond to treatment. There is no consensus
about how many treatments should be tried before
diagnosing treatment-resistant depression, or whether
these treatments should come from distinct categories
(eg, pharmacological, physical, psychotherapeutic) or
drug classes (eg, SSRIs). A recent systematic review
identified as many as 155 definitions of treatment-
resistant depression, with the required number of failed
treatments ranging from one to more than five.2 Around
half of the definitions referred to two failed treatments,
but with considerable variability concerning drug class,
treatment length, and timing. Diagnostic variability has
substantial implications for the approval of new therapies.
For example, in the pivotal trials supporting the US Food
and Drug Administration’s approval of esketamine,
treatment resistance was defined as the absence of
clinically meaningful improvement, operationalised as
symptom reduction of less than 25% after treatment
with at least two different antidepressant drugs,
without requiring these drugs to be of different classes.
Consequently, 22% of all patients in the short-term trials
had failed to respond to only one drug class.3
Conceptual problems and diagnostic imprecision about
treatment-resistant depression motivated develop­ment
of a consensus statement by an international group of
experts, who recommended the reconceptualisation
of treatment-resistant depression as difficult-to-treat
depression, defined as “Depression that continues to
cause significant burden despite usual treatment efforts”.4
Rethinking treatment-resistant depression is important
www.thelancet.com/psychiatry Published online October 13, 2020 https://doi.org/10.1016/S2215-0366(20)30416-8 1
and the new label is, on the surface, appealing. Clinicians Lancet Psychiatry 2020
can often identify patients with depression who have Published Online
October 13, 2020
difficult-to-treat symptoms, and frequently cycle these https://doi.org/10.1016/
patients through numerous (usually pharmacological) S2215-0366(20)30416-8
treatments, without improve­ment in symptomatology.
However, we are concerned that difficult-to-treat
depression could be a case of diagnosis creep5 (ie,
the broadening of disease definitions), in this case
by lowering diagnostic thresholds. Diagnosis creep
magnifies the need for treatment by expanding the pool
of potential patients. Difficult-to-treat depression does
not adequately address, and will likely exacerbate, the
problems associated with the label treatment-resistant
depression. The consensus statement proposing this
reconceptualisation was not based on a systematic
review or any formal process (eg, the Delphi technique).
It is unclear how the clinical guidelines used to inform
the development of the consensus statement were
selected. An assessment model was proposed on the
basis of a list of prognostic factors relating to patient,
disorder, and treatment characteristics, but it is unclear
how these will be combined to reach a diagnosis.
The diagnostic criteria for difficult-to-treat depression
are broader and even more susceptible to subjective
interpretations than the criteria for treatment-
resistant depression, making it unlikely that clinicians
and investigators will implement them rigorously or
consistently. Sponsors could easily take advantage of
such loose criteria when designing pivotal trials for new
drug applications. Allowing vague diagnostic criteria to
be used for controversial conditions creates unnecessary
challenges when regulators have to review costly
therapies with discernable risks and uncertain benefits
(eg, esketamine for treatment-resistant depression).6
Additionally, the new diagnostic category threatens
to erode the threshold above which riskier and more
expensive treatments are offered to patients. This new
category will increase and diversify the range of patients
ostensibly eligible for esketamine or vagus nerve
stimulation, two therapeutic options for treatment-
resistant depression.6 The promise of larger markets with
expanding disease definitions is an important financial
incentive for the industry.7 Examples abound of industry
 Comment
manipulating ill-defined and heterogeneous conditions
to market them as pressing public health issues that
warrant immediate attention.8 Concerningly, the
consensus panel advocating difficult-to-treat depression
was funded by the manufacturer of vagus nerve
stimulation, the first treatment specifically approved for
treatment-resistant depression, and almost half of the
panel members had a financial relationship with that
company.
The label of treatment-resistant depression has
numerous problems that are unlikely to be fixed by
another, broader, and more porous, diagnostic label.
Instead, a way forward is a better understanding of
why treatment success remains low for some patients.
For example, for persistent depressive disorder, which
overlaps with treatment-resistant depression in
about 40% of patients, reasons for treatment failure
include treatment delays, inadequate dose or duration,
low compliance, and low motivation to change (eg,
patients view their depression as an immutable part
of their personality).9 Most definitions of treatment-
resistant depression do not include psychotherapy as
a treatment,2 which implies that some patients might
be prematurely classified as having treatment-resistant
symptoms.
Although modifying disease definitions can be
beneficial for both clinicians and patients, there is always
the potential for overdiagnosis and overtreatment,
particularly when expert panels do not rigorously and
2 www.thelancet.com/psychiatry Published online October 13, 2020 https://doi.org/10.1016/S2215-0366(20)30416-8
systematically assess the potential for patient harm10
and have commercial ties with industry. These issues are
particularly important for invasive treatments that have
potentially serious adverse effects.
We declare no competing interests.
Lisa Cosgrove, Florian Naudet, Göran Högberg,
Allen F Shaughnessy, *Ioana A Cristea
ioana.cristea@unipv.it
Department of Counseling Psychology, University of Massachusetts-Boston,
Boston, MA, USA (LC); University of Rennes 1, Rennes, France (FN); Clinical
Investigation Centre (INSERM 1414), Rennes University Hospital, Rennes, France
(FN); Memory Reconsolidation Therapy, Stockholm, Sweden (GH); Tufts
University School of Medicine, Malden, MA, USA (AFS); Cambridge Health
Alliance, Malden, MA, USA (AFS); and Department of Brain and Behavioral
Sciences, University of Pavia, 27100 Pavia, Italy (IAC)
1 Cuijpers P. The challenges of improving treatments for depression. JAMA
2018; 320: 2529–30.
2 Brown S, Rittenbach K, Cheung S, McKean G, MacMaster FP, Clement F.
Current and common definitions of treatment-resistant depression:
findings from a systematic review and qualitative interviews.
Can J Psychiatry 2019; 64: 380–87.
3 Turner EH. Esketamine for treatment-resistant depression: seven
concerns about efficacy and FDA approval. Lancet Psychiatry 2019;
6: 977–79.
4 McAllister-Williams RH, Arango C, Blier P, et al. The identification,
assessment and management of difficult-to-treat depression:
an international consensus statement. J Affect Disord 2020; 267: 264–82.
5 Moynihan R. Caution! Diagnosis creep. Aust Prescr 2016; 39: 30–31.
6 Cristea IA, Naudet F. US Food and Drug Administration approval of
esketamine and brexanolone. Lancet Psychiatry 2019; 6: 975–77.
7 Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017
ACC/AHA guidelines and in the real world. JAMA 2018; 319: 115–16.
8 Cosgrove L, Shaughnessy AF, Shaneyfelt T. When is a guideline not a
guideline? The devil is in the details. BMJ Evid Based Med 2018; 23: 33–36.
9 Schramm E, Klein DN, Elsaesser M, Furukawa TA, Domschke K. Review of
dysthymia and persistent depressive disorder: history, correlates,
and clinical implications. Lancet Psychiatry 2020; 7: 801–12.
10 Doust J, Vandvik PO, Qaseem A, et al. Guidance for modifying the definition
of diseases: a checklist. JAMA Intern Med 2017; 177: 1020–25.