Review Paper

Definition, Assessment, and Staging of

Treatment–Resistant Refractory Major Depression:
A Review of Current Concepts and Methods

Marcelo T Berlim, MD, MSc1, Gustavo Turecki, MD, PhD2

Objective: Up to 15% of depression patients eventually present with treatment-resistant or

refractory depression (TRD), a condition that causes significant social and economic
burdens. Our paper aims to summarize the current medical literature on the conceptual and
methodologic issues involved in the definition, assessment, and staging of TRD.
Method: We reviewed the recently published medical literature to identify papers that
specifically discuss TRD. For this, we searched MEDLINE, EMBASE, and PsycINFO for
potentially relevant English-language articles published between January 1996 and June
2006.
Results: Recent methodologic and conceptual advances have contributed to the
achievement of an acceptable level of theoretical consensus on the general meaning of
TRD. Accordingly, depression is usually considered resistant or refractory when at least 2
trials with antidepressants from different pharmacologic classes (adequate in terms of
dosage, duration, and compliance) fail to produce a significant clinical improvement.
Regarding diagnostic assessments, an accurate and systematic evaluation should be made
to elicit the potential role of several contributing factors, such as medical and psychiatric
comorbidity.
Conclusion: Recently, 3 staging methods for TRD have been described, but they currently
require extensive empirical support. Future research on TRD should include prospective
studies addressing the validity of the proposed criteria, the impact of depression comorbid
with other psychiatric disorders and (or) physical conditions, and the possible predictors of
treatment outcome. There is an important and clear need for studies that empirically test
current definitions, assessment strategies, and staging methods of TRD.
(Can J Psychiatry 2007;52:46–54)
Information on funding and support and author affiliations appears at the end of the article.

Clinical Implications

· In its broadest sense, TRD characterizes a significant number of patients in therapy.

· Depression is usually considered resistant or refractory when at least 2 appropriate trials of
antidepressants from different pharmacologic classes fail to produce significant improvements.
· Accurate and systematic clinical evaluations are fundamental to elicit the potential role of
several contributing factors to TRD.

Limitations

· The characterization and definition of TRD are inconsistent in the specialized literature.
· There is a lack of definitive, consensual, standardized operational criteria for TRD.
· There is a lack of prospective studies addressing the validity of the proposed criteria for TRD.

46 W La Revue canadienne de psychiatrie, vol 52, no 1, janvier 2007

 Definition, Assessment, and Staging of Treatment–Resistant Refractory Major Depression: A Review of Current Concepts and Methods
Key Words: treatment-resistant depression, definition,
assessment
lthough the therapeutic armamentarium available for cli-
A nicians treating MDD patients has expanded substan-
tially over the last decades, TRD in its broadest sense still
characterizes a significant number of patients in therapy.1,2
About one-third of patients treated for major depression do
not respond satisfactorily to the first antidepressant pre-
scribed.3,4 There are many individuals (up to 15% of patients)
for whom multiple interventions will be unhelpful and who
will have significant depression despite aggressive pharmaco-
logic and psychotherapeutic approaches.1–3
Although TRD appears to be relatively common in clinical
practice, the inconsistent way in which it has been character-
ized and defined has been a major problem and has limited
systematic research.2 There are no definitive consensual stan-
dardized operational criteria for TRD, and one can find more
than 10 disparate definitions while searching the specialized
literature.1,4 This confused context may explain, at least in
part, why assisting treatment-resistant or treatment-refractory
depression patients still remains a daunting task even when
one applies the currently available evidence-based systematic
algorithms.
This paper aims to summarize the current conceptual and
methodologic issues regarding the definition, assessment, and
staging of TRD in adult patients.
Literature Search and Review
We performed a systematic review of the recent literature to
identify papers specifically discussing TRD. The selection
process involved 3 steps. First, we searched the MEDLINE,
PsycINFO, and EMBASE databases for potentially relevant
English-language articles published between January 1996
and June 2006. For the search, we used a combination of the
following title words: resistant, refractor*, difficult, intracta-
ble, antidepress*,”and depress*. Second, we retrieved rele-
vant articles (judged on the basis of the title and abstract) for
more detailed evaluation. Articles were included if they
focused on conceptual and methodologic aspects of
treatment-resistant or treatment-refractory unipolar major
Abbreviations used in this article
BD bipolar disorder
MAOI monoamine oxidase inhibitor
MDD major depressive disorder
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
TRD treatment-resistant depression
The Canadian Journal of Psychiatry, Vol 52, No 1, January 2007 W
depression, if they were published in peer-reviewed journals,
and if they were written in English. Third, we hand-searched
the bibliographies of relevant articles and of mood disorder
textbooks for additional references. In total, we retrieved
327 full electronic references, 16 of which met our selection
criteria.5–20
Defining Resistance to Treatment in Unipolar
Depression
Central Issues
Although various definitions have been suggested and loosely
used in the literature, TRD is broadly defined as the occur-
rence of an insufficient clinical response following adequate
antidepressant therapy (in terms of dosage, duration, and
compliance) among patients diagnosed with major depres-
sion.6,15,16 However, the required number of adequately deliv-
ered trials and when these trials should be considered
indicative of treatment resistance (that is, in the current epi-
sode only or in previous episodes also) remains debatable.8,17
During the last decades, several authors developed different
criteria for considering the categorical presence of TRD,
including a failure to respond to adequate dosages of a single
TCA (for example, amytriptilyne), an MAOI (for example,
phenelzine) trial for a minimum of 4 weeks, a single adequate
antidepressant treatment, 3 or more adequate trials of treat-
ment (one of which must have been a TCA), 5 or more ade-
quate treatments, at least one trial of electroconvulsive
therapy, or a single trial of the newer heterocyclic
antidepressants.1,2,5,6,8,10
Unfortunately, none of these classifications have been sys-
tematically examined, verified for reliability, or validated for
prospective predictive utility, and therefore, it is currently dif-
ficult to select criteria from among these different approaches
to defining TRD.10 Nevertheless, there is a general sense that
a patient has clinically significant treatment resistance if a cur-
rent episode of depression has not benefited from at least 2
adequate trials of different classes of antidepressants.7,14,17,18
There are, however, at least 2 methodologic issues related to
this definition: first, it assumes that nonresponse to 2 agents of
different classes is more difficult to treat than nonresponse to
2 agents of the same class; second, it postulates that a switch
within one class is less effective than switch to a different
class.16 It is significant that neither supposition has been
entirely supported by current the literature (for more detailed
discussion, see Fava16). Despite these limitations, this defini-
tion of the categorical presence of TRD is the one that is cur-
rently most accepted .
Regardless of the specific criteria, narrow definitions of TRD
result in the selection of homogenous groups of absolute
nonresponders that are suitable for biological investigations
and research on clinical characteristics and predictive
47
Review Paper
factors.10 In contrast, broader definitions of resistance apply
more appropriately to the clinical reality of daily practice and
allow consideration of a range of resistance severity.2
Related Issues
The Spectrum of Treatment-Resistant Depression. There is
variety among research groups as to whether TRD is a specific
subtype of depression or whether it is a nebulous residual cat-
egory.19 However, there is an emerging consensus that TRD is
usually best understood not as an all-or-none phenomenon but
as one that occurs along a continuum ranging from partial
response to complete treatment resistance.2,10,11
Relative Compared With Absolute Resistance. Some authors
have proposed that the definition of TRD should be divided
into 2 categories: absolute and relative.21 Absolute resistance
to antidepressants was then defined as an inadequate response
to a trial of medication given over an extended period of time
(for example, 8 weeks) with a confirmed daily dosage compli-
ance of the maximum nontoxic dosage.8,10 This definition
takes no account of the number of previous forms of treatment
received and thus may be practical in a clinical context as
patients are classified as nonresponders to a specific anti-
depressant therapy.14 Relative resistance, on the other hand,
was referred to as a failure to respond to a less than adequate
(in terms of dosage and duration) antidepressant trial.2,6 How-
ever, the latter definition is spurious because a patient’s
depression should be considered resistant or refractory to
treatment only when an adequate intervention has been
administered.
Chronic, Refractory, and Difficult-to-Treat Depressions. An
important distinction should be made between the terms resis-
tant, chronic, refractory, and difficult-to-treat depressions
because they are often used synonymously to describe a fail-
ure to respond to an unspecified number of adequate trials
involving one or more courses of specific antidepressant treat-
ment. Such terminology often causes confusion and leads to
the inclusion of a highly heterogeneous population within
TRD samples.5,10
A chronic specifier implies a major depressive episode con-
tinuously sustained for at least 2 years during which therapy
has not necessarily been tried.2 Conversely, difficult-to-treat
depression includes not only cases that inherently do not
respond to optimally delivered treatments (that is, TRD) but
also depression treated under circumstances precluding the
optimal delivery of potentially effective approaches (such as
the use of subtherapeutic dosages, noncompliance, or intoler-
able side effects17). Thus difficult to treat depression may or
may not actually include TRD. Finally, to some authors, the
term refractory suggests a greater (although usually not
clearly specified) degree of resistance.10,11 The distinction
between resistant and refractory seems to be arbitrary because
48
these are somewhat overlapping constructs. Semantically,
refractory and resistant appear to be synonymous.22 There-
fore, in principle they could be used interchangeably,
although it seems that the term resistant has been applied more
frequently in the literature.
Symptom Threshold Required for Treatment-Resistant
Depression. Although there is no definitive consensus regard-
ing the degree of symptom severity that should be required to
qualify the presence of TRD, it has been argued that it is nec-
essary for patients to present with sufficient baseline symptom
severity to provide a metric to detect a treatment effect.17
Overall severity need not be as high as is typically suggested
for trials of antidepressant treatment because even mild-to-
moderate depressions carry reduced daily function as well as a
worse prognosis than that faced by remitted patients. Accord-
ingly, it has been suggested that a score of at least 16 on the
17-item Hamilton Depression Rating Scale is sufficient con-
firmation of TRD.17
Previous Psychotherapeutic Treatments. Because the utility
of some psychotherapies (interpersonal, cognitive, and
behavioural) for patients with resistant depression has been
recently shown, one can argue that the prevailing view of what
constitutes an adequate antidepressant therapy appears some-
what narrow and pharmacocentric.5–16
Nevertheless, some authors (for example, Rush et al17) have
argued that it is not essential for trials of medication for TRD
to require that psychotherapy be proven ineffective. If, on the
other hand, the interest is focused on the next best treatment
for patients not responding to psychotherapy, it would be
appropriate for resistance to one or more prior trials of psy-
chotherapy to be carefully documented.
Assessment of Contributors to
Treatment-Refractory Depression
Several clinical, biological, and sociodemographic variables
have been studied in relation to response and (or) resistance to
antidepressant therapy. Nevertheless, this literature yields
largely unreliable results, owing especially to methodologic
variability and the heterogeneity of depression itself (for more
detailed discussion, see Fava16; Berman and collaborators6;
and Kornstein and Schneider12).
Depression Subtypes
The recognition of depression subtypes (particularly melan-
cholic, psychotic, atypical, and seasonal) is an important ele-
ment in the evaluation and management of TRD because
individuals with different subtypes of depression may
respond in somewhat different ways to the available thera-
pies.14,15 Additionally, resistance to treatment may also be
related to misdiagnosis of a unipolar MDD in patients with
declared or undeclared BD. Patients with BD present in the
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 Definition, Assessment, and Staging of Treatment–Resistant Refractory Major Depression: A Review of Current Concepts and Methods
depressive phase 2 to 3 times more often than they do in the
manic state24 and it is estimated that BD I is undetected in
35% to 45% of patients.25 It is important to evaluate patients
with TRD specifically for a history of manic or hypomanic
episodes to rule out bipolar spectrum disorders.
Psychiatric Comorbidity
Many studies have reported the association between the pres-
ence of comorbid psychiatric disorders (especially anxiety,
alcohol or substance use, and personality disorders) and
TRD.2,12,15 These comorbid disorders are often missed or are
suboptimally treated, and they can confound both the evalua-
tion and the management of depression.26 The implication for
treatment is to address these conditions simultaneously, if
possible, to avoid consolidating treatment resistance (for
more information see1,2,6,13).
Sociodemographic Factors
There is little evidence to support the idea that female sex is a
risk factor for TRD15, although recent evidence does suggest
that women may be less responsive than men to TCAs and
may respond preferentially to SSRIs or MAOIs.12 Further, in
terms of age at onset, both ends of the spectrum have been
described as risk factors for TRD.12
Clinical Factors
Some studies have shown that a positive family history of
affective disorders is associated with early onset of depression
and with chronicity, both of which have been linked to
TRD.5,6 Moreover, chronic forms of depression have been
associated with poorer outcome in some, but not all, studies5,12
and the delay in initiating treatments was found to be a main
predictor of chronicity and nonresponse.10 Regarding the
intensity of depression, it seems that mild and markedly
severe presentations may be more refractory to somatic treat-
ments.6,12 Finally, recent life event stressors and early child-
hood loss do not seem to be associated with poor long-term or
acute treatment outcome.5,6
Biological Markers
Despite significant research, there has not been substantial
conclusive evidence of the significance or validity of biologi-
cal markers (for example, the dexamethasone suppression
test, monoamine markers, and sleep characteristics) in pre-
dicting response to treatment of individuals suffering from
depression.2,5,6,15
Comorbid Medical Illness
Organic factors may contribute to affective illness in as many
as 50% of patients.1,16 In a patient with a suspected TRD, it is
crucial to rule out the presence of underlying medical dis-
orders, especially from an endocrinologic origin
(hypothyroidism1,2). Other examples of medical conditions
The Canadian Journal of Psychiatry, Vol 52, No 1, January 2007 W
that may contribute to TRD include Cushing’s syndrome,
neurological disorders (both cortical and subcortical), pancre-
atic carcinoma, connective tissue disorders, vitamin deficien-
cies, and certain viral infections. 2,6 Several types of
medications, such as immunosuppressants, steroids and seda-
tives, may also precipitate or contribute to resistance.3
A diagnosis of secondary depression is usually associated
with a significant likelihood of chronicity, despite adequate
treatments.1,4,10 Aggressive antidepressant therapy may need
to accompany adequate medical management.6
Evaluating the Adequacy of Antidepressant
Treatments
There is strong evidence that up to 60% of depression patients
initially classified as suffering from TRD fall into the category
of pseudo-TRD.6,16 Community-based surveys have revealed
that less than 50% of patients actually receive either an ade-
quate dosage or duration of antidepressants,8,14 and this figure
does not account for the high noncompliance rate for taking
medications as prescribed.2,10 This is especially problematic
in light of recent studies showing a therapeutic decrement
whereby patients who have not responded to one antidepres-
sant have a 20% lower chance of responding to the next
antidepressant.11
One of the clinician’s fundamental tasks is to review the ade-
quacy of treatment to date.12 In particular, an adequate trial of
antidepressant treatment must occur at each level of treatment
resistance.14 An adequate therapy typically consists of one or
more trials with antidepressants that have established efficacy
in MDD and that are prescribed in at least standard dosages
(that is, dosages that have shown efficacy in randomized tri-
als) for a duration long enough to produce significant thera-
peutic effects.12,16–18
Adequacy in Terms of Dosage
Underdosing of antidepressants has historically been one of
the main causes of nonresponse to treatment,1,14 and the rec-
ommended adequate dosages have increased from 150 mg
daily to between 250 and 300 mg daily of imipramine or its
equivalent.2 The maximum tolerated dosage according to dos-
age recommendations should be used (although for some
anitdepressants, such as fluoxetine, there is a less clear need to
reach maximal dosages before considering nonresponse4,6).
Given that there is an estimated thirtyfold range of drug
metabolism among individuals taking such medications
(resulting, for example, from differences in drug handling and
factors such as age, sex, weight, and physical condition), it is
not uncommon that at least some patients who fail to respond
to treatment may do so as a result of less than optimal plasma
drug concentrations.4,8 For instance, up to 50% of patients
treated with moderate dosages of imipramine (200 mg to
49
Review Paper
225 mg daily) will present with subtherapeutic plasma
levels.6–14
It is also important to evaluate the concomitant use of meta-
bolic inducers that may be associated with relative reductions
in antidepressant blood levels16 as well as to consider that
some patients may be rapid or fast metabolizers. In such cases,
dosage adjustments may produce a significant treatment
improvement.27
For some antidepressants (imipramine, desipramine, and
nortriptyline) drug efficacy may be correlated with the pres-
ence of adequate antidepressant plasma levels.27 The problem
with some newer antidepressants (for instance, SSRIs) is that
some studies to date have suggested that increasing the dosage
of an SSRI may not increase the probability of response but
may increase both side effects burden and treatment costs.14
Nonresponse in the absence of any side effect is a useful guide
to raising the possibility of less than adequate antidepressant
blood levels, and its measurement may be indicated in these
circumstances.1,6,7
Finally, medication intolerance may be another important
cause of underdosing because discontinuation rates owing to
intolerable side effects range from about 10% to 25%.6 In
clinical practice, patients experiencing difficulty tolerating
standard dosages of medication may often (and wrongly) be
left on subtherapeutic dosages. Many of the side effects even-
tually abate, and if not, they may become better tolerated,
especially after the onset of clinical improvement.
Adequacy in Terms of Duration
Pressures of the clinical setting commonly lead practitioners
to change pharmacologic strategies too early. Shifting regi-
mens and incorrectly drawing the conclusion that a given
medication is ineffective may also be considered a cause of
nonresponse and (or) pseudo-TRD.1,8
Most definitions of adequate treatment length are derived
from the conventions of industry-sponsored drug trials. How-
ever, the optimal duration of antidepressant drug treatment
necessary for TRD patients may be considerably longer than
the 6-week duration used in these studies. It has been sug-
gested that prolonged trials of treatment, lasting more than 10
weeks, may lead to a therapeutic response in certain resistant
or refractory cases.1,6,17 Further, in elderly patients with
depression, 12 weeks or more may be necessary for a satisfac-
tory clinical improvement.4,13 Finally, most TCAs and SSRIs
have a half-life of 20 to 58 hours, which results in steady-state
plasma concentrations being achieved on average only 5 to 12
days after beginning any given dosage. The exception is
fluoxetine, which has an average half-life of about 150 hours.
This may account for continued evolution of treatment over an
extended period of time.14
50
There is a current lack of compelling evidence to support the
advantage of prolonged trials over 6 to 8 weeks, compared
with other treatment strategies.2,14 Of interest, it has been
shown that minimal response after 4 weeks of antidepressant
use predicts poorer outcome at 8 weeks.16
Adequacy in Terms of Patient Compliance
Another important step toward the assessment of TRD con-
cerns the level of treatment nonadherence5 because it has been
estimated that nonadherence may account for as many as 20%
of cases considered resistant or refractory.15 Many reasons for
patient noncompliance have been suggested, including a
breakdown in the patient–doctor relationship, inadequate
psychoeducation, and intolerable side effects.14 The actual
prevalence of noncompliance may be underestimated and dif-
ficult to assess.6 Thus a collateral history from past records or
from the patient’s companion may be useful to assist in the
evaluation of adherence.12
Few studies to date have adequately assessed adherence in
depression patients, even though good compliance in and of
itself is strongly associated with a positive response.8,15 Fur-
ther work in this area is urgently needed.
Adequacy in Terms of Treatment Outcome
What constitutes inadequate response to treatment of depres-
sion has been the subject of considerable debate, but most
experts would probably argue that it is the failure to achieve
remission.18,28 The recently completed National Institute of
Mental Health–sponsored study, Sequenced Treatment Alter-
natives to Relieve Depression, used this criterion to define
antidepressant treatment success.29
Given the protracted and disabling nature of some cases of
TRD, one may argue that even a 30% to 40% reduction in
baseline symptom severity would probably provide a clini-
cally meaningful benefit.7 Not achieving remission despite
adequate treatment usually results in the presence of residual
depressive symptoms (for example, insomnia, fatigue, psy-
chic or somatic anxiety, and excessive reactivity to social
stress) that have consistently been shown to be associated
with poorer outcomes, increased risk of relapse, and impaired
social functioning.8,12,28,30
Despite its being a worthwhile treatment goal, only 25% to
50% of patients in clinical trials achieve remission30; thus,
some authors have suggested that it would be more practical to
use either lack of response or the persistence of clinically sig-
nificant levels of depressive symptoms—rather than the lack
of remission—of a previous trial to define resistance.17
Instruments Used to Assess Adequacy of Previous
Antidepressant Treatment(s)
The literature provides the clinician with 3 main instruments
to assess treatment resistance in depression. While 2 of them
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 Definition, Assessment, and Staging of Treatment–Resistant Refractory Major Depression: A Review of Current Concepts and Methods

Table 1 Thase and Rush Staging Methoda

Stage 0: Any medication trials, to date, judged to be inadequate
Stage I: Failure of at least 1 adequate trial of 1 major class of antidepressants
Stage II: Failure of at least 2 adequate trials of at least 2 distinctly different classes of
antidepressants
Stage III: Stage II resistance plus failure of an adequate trial of a TCA
Stage IV: Stage III resistance plus failure of an adequate trial of an MAOI
Stage V: Stage IV resistance plus a course of bilateral electroconvulsive therapy
a
Adapted from Thase and Rush32

are clinician-rated (the Antidepressant Treatment History
Form13; and the Harvard Antidepressant Treatment His-
tory31), one is self-rated (the Massachusetts General Hospital
Antidepressant Treatment Response Questionnaire16). Of
these instruments, only the Antidepressant Treatment History
Form has been empirically validated with prospective treat-
ment outcome reports.13–16
Staging Treatment-Refractory Depression
The classification of TRD in stages has been recently pro-
posed where increasing resistance is equated with an
increased failure to respond to antidepressant strategies.10,16
The rationale behind this approach is the clinical impression
that the greater the degree of treatment resistance, the lower
the probability of response to any new treatment.17
This perspective has yet to be empirically tested, and it is
important to keep in mind that all classifications of TRD are
not diagnoses per se. Moreover, any staging system based on
administered treatments has the limitation of being dependent
on the available therapeutic options as they evolve over time,
rather than being based on the underlying neurobiology of
TRD.2,8 Despite these limitations, staging systems do have
merit and are promising approaches to guide treatment selec-
tion and ultimately help predict long-term illness course.1,11
Below we summarize the 3 existing staging models for TRD.
Thase and Rush Staging Method
Thase and Rush32 first proposed a model of staging 5 levels of
resistance. In this model, patients are staged according to the
number and classes of antidepressants that have failed to pro-
duce a response, with staging moving from more common
( TCA s an d S S RI s ) to les s co mmo n ( MA O I s o r
electroconvulsive therapy) treatments (see Table 1).
include the fact that the degree of intensity of each trial in
terms of dosing and (or) duration is not accounted for. Further,
it assumes that nonresponse to 2 agents of different classes is
more difficult to treat than nonresponse to 2 agents of the same
class. It also indirectly assumes that switching antidepressants
within the same class is less effective than switching to an
antidepressants in a different class. Although this may be the
case with TCAs, switching between SSRIs appears to be
sometimes associated with a favourable clinical response.16
There is also an implicit hierarchy of antidepressants, in
which MAOIs are considered superior to TCAs and SSRIs,
and TCAs are considered more effective than SSRIs. This
hierarchy has not been supported by metaanalyses of antide-
pressant clinical trials. The Thase and Rush Staging Method
does not consider the role of augmentation or combination
strategies.16
The European Staging Method
According to the European approach, TRD is defined as a fail-
ure to respond to 2 adequate trials of different antidepressants
given in adequate dosages for a period of 6 to 8 weeks10 (see
Table 2). This is in contrast to the Thase and Rush Staging
Method, which refers to resistance as the failure of at least one
adequate trial. Thus, for the European Staging Method, after
the first trial patients are classified as nonresponders to the
antidepressants prescribed (TCA, SSRI, MAOI). Staging of
TRD would then correspond to the number of the following
failed adequate medication trials. Additionally, the European
Staging Method proposed the existence of a condition called
chronic resistant depression, which was defined as a resistant
or refractory depressive episode lasting more than 1 year,
despite adequate interventions.

This approach could be a very useful tool in the classification With reference to the European criteria, one must consider the
of TRD, although its predictive value with respect to treat- possibility that the duration of adequate trials and the distinc-
ment outcome has not yet been systematically assessed.14 tion between TRD and chronic resistant depression were arbi-
Additional limitations of the Thase and Rush Staging Method trarily chosen.

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Review Paper
Table 2 The European Staging Methoda
A. Nonresponder to:
TCA
Serotonin reuptake inhibitor
MAOI
SNRIb
Electroconvulsive therapy
Other antidepressant(s)
No response to one adequate antidepressant trial
Duration of trial: 6–8 weeks
B. TRD
Resistance to 2 or more adequate antidepressant trials
Duration of trial(s):
TRD 1: 12–16 weeks
TRD 2: 18–24 weeks
TRD 3: 24–32 weeks
TRD 4: 30–40 weeks
TRD 5: 36 weeks–1 year
C. Chronic resistant depression
Resistance to several antidepressant trials, including
augmentation strategy
Duration of trial(s): at least 12 months
a
Adapted from Souery et al10
b
Dual serotonin-noradrenaline reuptake inhibitors (for example,
venlafaxine)
Massachusetts General Hospital Staging Method
Given the above-mentioned concerns about the Thase and
Rush Staging Method, a group from the Massachusetts Gen-
eral Hospital proposed a slightly different approach (see
Table 3) that considers both the number of failed trials and the
intensity or optimization of each trial but that does not make
assumptions regarding a hierarchy of antidepressant classes.
This method generates a continuous variable reflecting the
degree of resistance in depression.16
While such a staging approach has merit for producing an
apparently more sound classification, the reliability of data is
still limited by the accuracy of patient recall and medical
records. Further, the scores attributed to each different treat-
ment approach appear somewhat arbitrary, and it is not clear,
for example, why augmentation increases the overall resis-
tance score by 0.5 points and electroconvulsive therapy by 3
points; that is, these crude values do not seem to be empiri-
cally validated, but rather, arbitrarily chosen.
Recently, Petersen and colleagues20 published the first effort
to empirically test the Massachusetts General Hospital Stag-
ing Method and the Thase and Rush Staging Method. For this
52
Table 3 Massachusetts General Hospital Staging
Methoda
1. No response to each adequate (at least 6 weeks of an
adequate dosage of an antidepressant) trial of a marketed
antidepressant generates an overall score of resistance
(1 point per trial)
2. Optimization of dose, optimization of duration, and
augmentation or combination of each trial (based on the
Massachusetts General Hospital or Antidepressant
Treatment Response Questionnaire) increase the overall
score (0.5 point per trial per optimization or strategy).
3. Electroconvulsive therapy increases the overall score by 3
points.
a
Adapted from Fava16
purpose, they evaluated both approaches as predictors of
remission status in a sample of 115 outpatients with current
major depressive episode. Their results suggested that the 2
models are highly correlated, but with the use of multivariate
analysis, the Massachusetts General Hospital Staging Method
demonstrated significantly greater ability to predict
nonremission status than did the Thase and Rush Staging
Method. This study had several limitations, including the rela-
tively small sample size, the use of chart review methodology,
and the probable nongeneralizability of the findings to other
populations.
Conclusion
Despite the numerous options available for the treatment of
depression, many patients do not achieve a satisfactory
improvement with adequate dosages of antidepressants given
for sufficient durations and are eventually classified as pre-
senting with TRD. Generally, these patients are highly
demanding for their families and often require major involve-
ment of health care services.
Despite its significant impact, there is still some degree of
controversy regarding a suitable and definitive description of
TRD. Nonetheless, the key parameters that define TRD have
been described and include the accurate diagnosis of the cur-
rent major depressive episode and of the presence of other
psychiatric or medical comorbidity, as well as the assessment
of response to previous and current treatments (with special
reference to their number and adequacy in terms of dosage,
duration, and patient compliance).
In summary, future research on TRD should include prospec-
tive studies addressing, among other issues, the validity of the
proposed criteria, the naturalistic course of resistance through
the longer term, the impact of depression comorbid with other
psychiatric disorders and (or) physical conditions, the exis-
tence of possible predictors of treatment outcome, and
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 Definition, Assessment, and Staging of Treatment–Resistant Refractory Major Depression: A Review of Current Concepts and Methods
innovative management strategies. Undoubtedly, a better
understanding of TRD and the many facets of its etiology, as
well as the availability of new and effective therapies, will
decrease the morbidity and mortality of TRD and minimize
the confusion and therapeutic nihilism for both clinicians and
patients.
Funding and Support
This review paper received no funding and no support.
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Manuscript received June 2006, revised, and accepted September 2006.
1
Clinical and Research Fellow, Depressive Disorders Program, Douglas
Hospital Research Centre, McGill University, Montréal, Québec; McGill
Group for Suicide Studies, Douglas Hospital Research Centre, McGill
University, Montréal, Québec.
2
Head, Depressive Disorders Program, Douglas Hospital Research Centre,
McGill University, Montréal, Québec; Coordinator, McGill Group for
Suicide Studies, Douglas Hospital Research Centre, McGill University,
Montréal, Québec.
Address for correspondence: G Turecki, 6875 LaSalle Blvd, Douglas
Hospital Research Centre, Frank B Common Pavilion, Room F-3125,
Montréal, Québec, H4H 1R3; gustavo.turecki@douglas.mcgill.ca
53
Review Paper

Résumé : Définition, évaluation et stadification de la dépression majeure résistante

ou réfractaire au traitement : un examen des méthodes et concepts actuels
Objectif : Jusqu’à 15 % des patients déprimés présentent éventuellement une dépression résistante
ou réfractaire au traitement (DRT), une affection qui impose des fardeaux sociaux et économiques
significatifs. Notre article vise à résumer la documentation médicale actuelle qui aborde les
questions conceptuelles et méthodologiques de la définition, de l’évaluation et de la stadification de
la DRT.
Méthode : Nous avons effectué une revue de la documentation médicale récemment publiée pour
repérer les articles qui traitent spécifiquement de la DRT. À cette fin, nous avons recherché dans
MEDLINE, EMBASE et PsycINFO des articles potentiellement pertinents publiés en anglais, entre
janvier 1996 et juin 2006.
Résultats : Les récents progrès méthodologiques et conceptuels ont contribué à l’atteinte d’un
niveau acceptable de consensus théorique sur la signification générale de la DRT. Conformément, la
dépression est habituellement considérée résistante ou réfractaire quand au moins 2 essais
d’antidépresseurs de différentes classes pharmacologiques (adéquats quant au dosage, à la durée et à
l’observance) ne réussissent pas à produire une amélioration clinique significative. En ce qui
concerne les évaluations diagnostiques, il faudrait faire une évaluation précise et systématique pour
déceler le rôle potentiel de plusieurs facteurs contributifs, comme la comorbidité médicale et
psychiatrique, Enfin, 3 méthodes de stadification de la DRT ont récemment été décrites, mais il leur
faut présentement un fort appui empirique.
Conclusion : La recherche future sur la DRT doit comprendre des études prospectives abordant la
validité des critères proposés, les répercussions de la dépression comorbide doublée d’autres
troubles psychiatriques et /ou d’affections physiques, et les prédicteurs possibles du résultat du
traitement. Il y a un important besoin défini d’études pour vérifier empiriquement les définitions,
stratégies d’évaluation et méthodes de stadification actuelles de la DRT.

54 W La Revue canadienne de psychiatrie, vol 52, no 1, janvier 2007