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Patient Preference and Adherence 2012:6 369–388
Patient Preference and Adherence
Treatment-resistant depression: therapeutic
trends, challenges, and future directions
Khalid Saad Al-Harbi
Medical College, King Saud Bin
Abdulaziz University for Health
Sciences, King Abdulaziz Medical City,
Riyadh, Kingdom of Saudi Arabia
Correspondence: Khalid Saad Al-Harbi
Medical College, King Saud Bin Abdulaziz
University for Health Sciences,
King Abdulaziz Medical City,
Riyadh, Kingdom of Saudi Arabia
Tel +966 1252 0088
Email ks-alharbi@hotmail.com
Background: Patients with major depression respond to antidepressant treatment, but 10%–30%
of them do not improve or show a partial response coupled with functional impairment, poor
quality of life, suicide ideation and attempts, self-injurious behavior, and a high relapse rate.
The aim of this paper is to review the therapeutic options for treating resistant major depressive
disorder, as well as evaluating further therapeutic options.
Methods: In addition to Google Scholar and Quertle searches, a PubMed search using key words
was conducted, and relevant articles published in English peer-reviewed journals (1990–2011)
were retrieved. Only those papers that directly addressed treatment options for treatment-resistant
depression were retained for extensive review.
Results: Treatment-resistant depression, a complex clinical problem caused by multiple risk
factors, is targeted by integrated therapeutic strategies, which include optimization of medica-
tions, a combination of antidepressants, switching of antidepressants, and augmentation with
non-antidepressants, psychosocial and cultural therapies, and somatic therapies including elec-
troconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy,
deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation. As
a corollary, more than a third of patients with treatment-resistant depression tend to achieve
remission and the rest continue to suffer from residual symptoms. The latter group of patients
needs further study to identify the most effective therapeutic modalities. Newer biomarker-based
antidepressants and other drugs, together with non-drug strategies, are on the horizon to address
further the multiple complex issues of treatment-resistant depression.
Conclusion: Treatment-resistant depression continues to challenge mental health care provid-
ers, and further relevant research involving newer drugs is warranted to improve the quality of
life of patients with the disorder.
Keywords: treatment-resistant depression, antidepressants, biomarkers, therapeutic options,
somatic therapies
Introduction
Major depression is a common debilitating disorder affecting 10%–15% of the
population per year. Despite advances in the understanding of the psychopharmacology
and biomarkers of major depression and the introduction of several novel classes of
antidepressants, only 60%–70% of patients with depression respond to antidepressant
therapy. Of those who do not respond, 10%–30% exhibit treatment-resistant symptoms
coupled with difficulties in social and occupational function, decline of physical health,
suicidal thoughts, and increased health care utilization. Treatment-resistant depres-
sion represents a dilemma for health care providers. Major depression with a poor or
unsatisfactory response to two adequate (optimal dosage and duration) trials of two
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different classes of antidepressants has been proposed as an
operational definition of treatment-resistant depression.
1–4
It is reported that at any one time 14 million people suffer
from depression, and only 50% of them receive some form
of treatment. Up to 70% of people who have depression
show substantial improvement as measured by commonly
used rating scales, such as the Hamilton Rating Scale for
Depression (HRSD),
5,6
but they require additional psycho-
social interventions for achieving complete remission. It is
estimated that 10%–30% of patients with major depression
do not respond to typical antidepressant medications,
7
and
this group of patients needs trials of a variety of treatment
strategies. For this purpose, it is particularly important to
determine the adequacy and outcome of prior treatment trials
by using the Antidepressant Treatment History Form that
helps to exclude “pseudoresistance” cases.
8
Complete remis-
sion is achieved in 70%–90% of patients with depression,
leaving 10%–30% refractory to treatment, and managed by
a variety of therapeutic modalities. Unfortunately, approxi-
mately 30% of patients with treatment-resistant depression
do not respond to any treatment.
9,10
According to the findings from the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) study,
50%–66% of patients with depression do not recover fully
on an antidepressant medication and one-third of patients
do have a remission of their depressive symptoms.
11,12
It is obvious that use of a variety of treatment approaches
versus only an antidepressant makes the outcome variable
in patients with major depression. Notably, the results of
mega STAR*D studies open windows into the effective-
ness or ineffectiveness of antidepressant medications among
patients seeking treatment in real-world settings, including in
primary health care
13,14
and help clinicians to make treatment
decisions in patients with treatment-resistant depression.
The prevalence of both treatment-resistant depression and
non-treatment-resistant depression would impressively be
variable across time attributed to methodological issues, defi-
nition of treatment-resistant depression, and the therapeutic
options used, including neurostimulation therapies.
Treatment-resistant depression defies true definition
9
(Table 1), but mental health experts agree that it should
only be diagnosed in patients who have not been helped
by two or more antidepressant treatment trials of adequate
dose and duration. To add difficulty to the definition of
treatment-resistant depression, treatment response and suc-
cess has different meanings across multiple research settings.
By and large, treatment-resistant depression evades universal
definition and meaning, and poses a number of diagnostic
Table 1 Suggested terminology for treatment-resistant
depression
9
Treatment
non-response
A response that is poor enough with signicant
residual symptoms that a change in the treatment
plan is called for (eg, failure to evidence at least a
50% reduction in the HRSD score
Treatment
response
A response that is good enough that a change in
the treatment plan is not usually called for
(eg, at least a 50% reduction in HRSD score)
Remission Attainment of a virtually asymptomatic status
(eg, HRSD 7) for at least 2 consecutive weeks
Recovery Remission for 6 consecutive months
Relative treatment
resistance
Non-response to an adequate dose of a
potentially effective medication for an adequate
length of time
Absolute treatment
resistance
Failure to respond to a maximal trial of a single
treatment for an extended period of time
(eg, imipramine at 300 mg/day for 6 weeks)
Treatment-refractory
depression
Treatment non-response (ie, persistence of
signicant depressive symptoms) despite at least
two treatment trials with drugs from different
pharmacological classes, each used in an
adequate dose for an adequate time period
Adequate dose An oral dose that is close to the manufacturers’
recommended maximal dose. Adequate dose
may be smaller for elderly patients
Adequate length
of treatment
At least 4 consecutive weeks of treatment,
during which the patient has had an adequate
dose for at least 3 weeks
Medication
intolerance
Inability to achieve or maintain an adequate
therapeutic dose of an antidepressant drug due
to idiosyncratic reactions or side effects
9
Abbreviation: HRSD, Hamilton Rating Scale for Depression.
and therapeutic challenges to mental health experts. The aim
of this paper is to review the therapeutic options for treating
resistant major depressive disorder, as well as evaluating
further therapeutic interventions.
Search methods
In addition to Google Scholar and Quertle websites, literature
searches were also conducted using PubMed for the years
1990–2011 and entering the keywords “treatment-resistant
depression”, “treatment-refractory depression”, “partial
response depression”, and “nonresponsive depression”.
These words were combined with tricyclic antidepressants
(TCA), selective serotonin reuptake inhibitors (SSRI),
serotonin norepinephrine reuptake inhibitors (SNRI),
and atypical antipsychotics, somatic therapies, such as
electroconvulsive therapy (ECT), vagus nerve stimulation
(VNS), deep brain stimulation (DBS), repetitive transcranial
magnetic stimulation (rTMS), magnetic seizure therapy,
transcranial direct current stimulation (tDCS), and
psychotherapy for a second round of computer searching.
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Patient Preference and Adherence 2012:6
Another round of searching included a combination
of keywords, ie, “treatment-resistant depression with
augmentation strategies”, “combined antidepressants”,
“switching approaches”, “names of individual antidepressant
medications”, and “nonpharmacological interventions”. As a
corollary, relevant articles published in English peer-reviewed
journals were retrieved. Only those papers including original
studies, clinical trials, systematic reviews, and meta-analyses,
which directly addressed treatment-resistant depression, were
retained for extensive review and inclusion in this study.
Some exceptions were made with regard to small case series,
and related mainly to somatic therapies.
Therapeutic trials: pros and cons
Well designed clinical trials provide strong evidence-based
data for antidepressant therapy for treatment-resistant depres-
sion, but there are many difficulties in interpreting their
results. There is no absolutely correct dosage for a specific
antidepressant, because dosage requirements vary with age,
gender, weight, physical health, concomitant medication
usage, and tolerance. Confirmation of treatment adequacy by
serial plasma drug levels is not the rule in clinical practice,
and valid plasma level-response relationships are limited
to only a subgroup of TCA and lithium,
9
and are now
extended to certain newer antidepressants. In a study that
examined the relationship between plasma antidepressant
concentration and both clinical response and adverse effects
in treatment-resistant depressed adolescents, 334 participants
with major depression who had not responded to an SSRI
were randomized to one of four treatments, ie, switch to
another SSRI (fluoxetine, citalopram, or paroxetine), switch
to venlafaxine, switch to SSRI + cognitive behavior therapy,
or switch to venlafaxine + cognitive behavior therapy.
Adolescents who did not improve by 6 weeks had their
dose increased. Plasma concentrations of medication and
metabolites were measured at 6 weeks in 244 participants
and at 12 weeks in 204 participants.
Adolescents treated with citalopram whose plasma con-
centration was equal to or greater than the geometric mean
showed a higher response rate compared with those having
less than the geometric mean, with parallel but nonsignificant
findings for fluoxetine. A dose increase of citalopram or fluox-
etine at week 6 was most likely to result in a response when it
led to a change in concentration from less than the geometric
mean at 6 weeks to the geometric mean or greater at week 12.
Plasma levels of paroxetine, venlafaxine, or O-desmethylven-
lafaxine were not related to clinical response. Exposure was
associated with more cardiovascular and dermatologic side
effects in those receiving venlafaxine. It was concluded that
the antidepressant concentration may be useful in optimiz-
ing treatment for depressed adolescents receiving fluoxetine
or citalopram.
15
With respect to psychotherapy, adequacy of
treatment may depend on the number of sessions, the expertise
of the practitioner, the therapist’s adherence to a particular
form of therapy, and also interaction within the patient-
therapist dyad. The efficacy of ECT trials may be gauged by
the total number of treatments, the use of bilateral electrode
placement, and verification of seizure occurrence and its
timing by electroencephalographic monitoring. Therefore,
treatment resistance is linked to a certainty about the adequacy
of a specific treatment trial.
16–19
Researchers have categorized treatment-resistant
depression in accordance with antidepressant trials as: stage 0,
has not had a single adequate trial of medication; stage 1,
failure of an adequate trial of one class of an antidepressant,
ie, monotherapy; stage 2, failure of adequate trials of
two distinctly different classes, ie, an SSRI and TCA, as
two monotherapy trials; stage 3, stage 2 plus failure to
respond to one augmentation strategy, ie, lithium or thyroid
augmentation of one of the monotherapies; stage 4, stage 3
plus a failure on a second augmentation strategy in terms
of monoamine oxidase inhibitors; and stage 5, stage 4 plus
failure of an adequate course of ECT.
9
There are other staging
methods for treatment-resistant depression, including the
Antidepressant Treatment History Form, the Thase and Rush
model, the European Staging model, the Massachusetts
General Hospital Staging model, and the Maudsley Staging
model, with variable predictive validity and reliability.
20
These staging methods help researchers and clinicians to
understand the severity and chronicity of treatment-resistant
depression and plan trial interventions accordingly.
Patient concerns
Treatment-resistant depression is a difficult condition to
treat. Patients with the disorder should interactively share
their inner experiences with the treating expert and be able
to ask freely any questions related to risk factors underlying
treatment-resistant depression, better treatment options,
lifestyle changes, costs and insurance coverage, a proper
medication schedule, duration of treatment, severity of side
effect, suicidal thoughts and attempts, non-suicidal self-
injurious behaviors, and intolerance issues. Other related
issues to be discussed with patients having treatment-
resistant depression are adherence to treatment, impact
of medical comorbidities such as heart disease, cancer,
thyroid disease, anemia, and eating disorders, interactions
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Treatment-resistant depression
Patient Preference and Adherence 2012:6
between antidepressants and other medications including
herbal supplements, manifestations of impending relapse,
and genetic vulnerability. Mental health experts should also
address in nontechnical language patients’ concerns about
somatic therapies, including ECT, VNS, tDCS, rTMS,
magnetic seizure therapy, and DBS.
12,19
Patients with treatment-resistant depression should
know about the predictors of good and bad outcomes of
treatment. In a UK study that aimed to assess the impact
of post-treatment clinical states on longer-term outcome
recruited 118 patients with treatment-resistant depression
who received specialist inpatient treatment and were followed
up for a median of 3 years. Longitudinal outcome, dichoto-
mized into good and poor, was used as the primary outcome
and functional measures were used as secondary outcomes.
Among the 118 treated patients, 40 (34%) entered clinical
remission, 36 (31%) entered partial remission, and 42 (37%)
remained in a depressive episode at discharge. At follow-up,
35% had a longitudinally defined poor outcome. According
to this study, post-treatment clinical status was the main
predictor of both poor and good outcome. Nearly 50% of
patients achieved post-discharge recovery, and subsequently
had a longer-term outcome comparable with that of patients
discharged in remission. Patients who remained in an episode
post-treatment were more symptomatically and functionally
impaired. In summary, post-treatment clinical states are
a useful guide for clinicians in projecting the longer-term
outcome for patients with treatment-resistant depression. The
persistence of residual or syndromal symptoms predicts a
poorer longer-term outcome, whereas treatment to remission
is associated with better outcomes.
21
In another study of young adolescents with SSRI-resistant
depression, suicide attempts and nonsuicidal self-injuries
were found to have clinical and prognostic significance.
This research further called for preventive and therapeutic
strategies for treatment-resistant depression and its associated
adverse behavioral complications.
22
Patients with treatment-
resistant depression also need to be familiar with issues
related to weight gain.
23
Like patients with depression and
general medical conditions,
24
patients with treatment-resistant
depression also have cost concerns associated with variable
outcomes and poor adherence to treatment or combined
therapies. Patients with depression who respond/remit on
antidepressant treatment bear less cost than those who have
persistent depression.
25,26
By and large, treatment-resistant
depression is associated with extensive use of depression-
specific and general medical services, which poses a sub-
stantial economic burden, together with work loss costs.
27,28
In a related context, a randomized, controlled trial evaluated
the incremental cost-effectiveness over 24 weeks of combined
cognitive behavior therapy plus a switch to a different
antidepressant medication versus a medication switch only
in adolescents who continued to have depression despite
adequate initial treatment with an SSRI. Participants were
randomly assigned to switch to a different medication
only or to switch to a different medication plus cognitive
behavior therapy. Clinical outcomes were depression-free
days, depression-improvement days, and quality-adjusted
life-years based on depression-free days. It was revealed that
combined treatment had a higher net benefit for subgroups
of youth without a history of substance abuse, with lower
levels of hopelessness, and with comorbid conditions. For
youth with SSRI-resistant depression, combined treatment
decreases the number of days with depression and was more
costly. It was concluded that, depending on a decision-maker’s
willingness to pay, combined therapy may be cost-effective,
particularly for some subgroups.
29
Risk factors
There is no one reason for treatment-resistant depression.
Depression is a heterogeneous disorder, as reflected by treat-
ment heterogeneity and variable nonresponse rates,
30
and the
latter could be due to patient age and gender. Elderly patients
may be somewhat less treatment-responsive than those at
midlife. Conversely, younger women may benefit less from
TCA than men or women treated with monoamine oxidase
inhibitors.
9
Individuals with fewer interpersonal or economic
resources, minority status, lower function and quality of
life, and chronic depression may also be less responsive
to antidepressant treatment. Furthermore, a higher level of
objective stress, poorer social support and family networks,
and/or a greater risk of noncompliance also contribute
to treatment-resistant depression.
9,31,32
However, for most
patients with treatment-resistant depression, it is probably
a combination of different risk factors (Table 2) which are
as follows: not staying on prescribed antidepressants long
enough, ie, for 6–12 weeks when they have their full effect;
skipping doses, in terms of poor adherence (blood sample
analysis for measuring drug levels is an option for confirming
or excluding such a possibility); unpleasant side effects of
prescribed psychiatric and non-psychiatric drugs; drug–drug
interactions in particular antidepressants and medical
treatments; the wrong medicine or the wrong dose for the
individual in question; genetic disposition in terms of fast
or slow metabolizers of antidepressants; medical comorbid
conditions, such as hypothyroidism and anemia, which also
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contribute to depression by several mechanisms and each
needs a separate treatment approach, and ignoring either
of them would result in treatment failure and nihilism; and
eating disorders, alcohol, and other substance-use disorders,
which tend to worsen the depression or might be the main
underlying cause of depression.
9,32
Furthermore, break-
through episodes can also occur among patients partially or
fully improved that may contribute to the resistant nature of
depression.
33
In addition, misdiagnosis of depression also
leads to treatment-resistant depression.
34
Misdiagnosis also
includes failure to identify the actual subtype of depres-
sion, such as atypical, psychotic, bipolar, or melancholic
depression, that has an impact on treatment selection and
outcome and may require concurrent pharmacotherapy,
such as an antipsychotic or augmentation psychotherapy.
9
Some evidence also indicates a poorer response to TCA in
atypical depression, bipolar depression, psychotic depression,
and depression associated with significant Axis I, Axis II, or
Axis III comorbidity.
31
Further, major depressive disorder that
remains unrecognized and untreated may become treatment-
resistant depression.
35
Another symptomatic correlate of treatment resistance
is the global severity of depression. A naturalistic study
revealed that most patients with a substantial degree of
treatment resistance continue to have significant symptoms
and functional disability when receiving their usual
treatment.
36
Finally, the adverse effects of medication and
poor compliance determined by poverty and low education
may be additional obstacles to successful treatment of
depression.
19,37,38
According to the World Health Organization
International Classification of Functioning, Disability and
Health, that includes psychiatric disorders,
39
including
major depression and treatment-resistant depression,
the participation level of patients with depression is an
important treatment component that may influence their
outcomes and correspondingly might contribute to treatment-
resistant depression. Interestingly, based on the perceived
relative therapeutic efficacy of available treatment options,
depression may also be seen as a secondary compliance
risk factor for treatment-resistant depression. In a recent
review, risk factors for treatment-resistant depression in
adolescents were identified to be the severity of depression,
level of hopelessness and suicidal ideation, psychiatric
and medical comorbidities, environmental factors such as
family conflict, maternal depression, and history of physical
and sexual abuse, as well as pharmacokinetics and other
biomarkers.
40,41
In another study, a team of researchers reported that
genetic polymorphisms in the transcription factor, cyclic ade-
nosine monophosphate response element binding (CREB1),
could be associated with treatment resistance in patients
with depression.
42
Also, based on an experimental animal
study,
43
researchers reported discovering a mutant gene on
chromosome 12 that codes for tryptophan hydroxylase-2.
This enzyme helps in the biosynthesis of serotonin, and is
produced 80% less than normal by individuals with major
or treatment-resistant depression who have this mutant gene,
which was also identified in normal individuals (3/219),
but much less often than in patients with severe depression
(9/87).
44
The implication of this study is that genetic test-
ing, if developed, could identify patients with depression
who would or would not respond satisfactorily to one of the
antidepressants, eg, a TCA, SSRI, or SNRI.
Table 2 Risk factors for treatment-resistant depression
Risk factors Remarks
Not staying on a
medicine long enough
Antidepressants can take as long as 6–8
weeks before they fully take effect
Skipping doses Take depression medicine exactly as
prescribed to know it is working effectively
Unpleasant side effects Consult doctor for emerging side effects of
antidepressants because he/she may offer
some help including informing that side
effects tend to decrease over time
Drug interactions Some medicines do not work well
with antidepressants and in some cases
interactions with dangerous consequences
may occur
Wrong medicine
or wrong dose
Antidepressant drugs work very differently
in different people and nding the right
medicine, at the right dose, takes trial
and error
Genes Researchers have found a gene that
interferes in the synthesis of tryptophan,
a substrate for serotonin synthesis,
deciency of which contributes to
treatment resistance
Co-occurring medical
conditions
Medical conditions like heart disease,
cancer, or thyroid problems, and eating
disorders can contribute to depression,
and need to be treated simultaneously
Co-occurring psychiatric
conditions
Co-occurring Axis I and Axis II diagnosis
needs concurrent treatment
Alcohol or drug abuse Depression may pre- or post-cede
substance abuse that need proper
treatment as well
Wrong diagnosis Some people are simply misdiagnosed with
treatment-resistant depression and need
comprehensive reassessment
Poverty and low
education
As environmental effect sizes in affected
individuals with treatment-resistant
depression may negatively interfere with
compliance
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In summary, depressive illness-related factors, personal
characteristics, medication variables, and psychosocial
stresses collectively contribute to the development of
treatment-resistant depression, and are associated with a
considerable disease burden.
45
Therapeutic options
There are five main strategies (Table 3) used to overcome a
partial response or lack of response to antidepressant therapy,
ie, optimization, switching, combination, augmentation, and
somatic therapies.
46
Because there is no standard treatment
approach, mental health experts offer the aforesaid strategies
based on re-evaluation of patients with treatment-resistant
depression. The patient with depression not responding to
antidepressant monotherapy requires a highly individualized
treatment plan and, accordingly, some people will respond
to a specific treatment, while others do not. Finding the
right approach to treat depression can take a lot of effort
and time.
29,30
Therefore, the following principles need to
be followed to manage patients with treatment-resistant
depression: ensure accurate diagnosis, including subtype
of depression; assess comorbid psychiatric and medical
conditions; evaluate psychosocial stressors, as well as social
and family support; ensure adequate dose and duration of
treatment; monitor and treat adverse events; educate the
patient regarding depression and antidepressants; ensure
compliance; and aim for remission. The five approaches are
now described briefly.
Optimization of antidepressants
The two core features of this strategy are to optimize dosage
and duration of antidepressant therapy for patients who have
experienced only partial improvement. The advantages of this
strategy are to capitalize on the natural history of episodic
depression which remits over time and to counteract the
tendency of some patients to discontinue the antidepressant
prematurely. Furthermore, it helps to distinguish a true
enduring antidepressant response from a more transient
placebo response. Specifically, placebo responders have a
greater likelihood of relapse between weeks 6 and 12 than
patients who have responded to active antidepressants.
9,32
An adequate trial of antidepressant therapy has been defined
by some clinicians as a minimum of 6 weeks.
7
If the patient
exhibits a partial response during this initial period, another
4–6 weeks of treatment should be added. Thus, a total of
10–12 weeks may be required in some cases to elicit a full
response to antidepressant therapy.
47
Irrational prescribing
of antidepressant medications with regard to dosage and
duration is a common cause of treatment failure
9,47
and
is common in clinical practice. In a study conducted in a
managed care environment, only 11% of patients requiring
antidepressant therapy received either an adequate dosage
or duration of therapy.
48
This irrational prescribing trend is
particularly common in elderly patients,
49
and is especially
problematic in low-income and middle-income countries.
The older literature suggests that routine prescription of
maximal doses of TCA, monoamine oxidase inhibitors, and
second-generation antidepressants is associated with a greater
likelihood of response than more modest doses in patients
with treatment-resistant depression.
9
Notably, administration
Table 3 Management strategies for treatment-resistant depression
Therapeutic strategies
and options
Remarks
Optimization
of antidepressants
Maximize dose for adequate time
and check serum levels of prescribed
antidepressant if supported by evidence-
based data
Switching
of antidepressants
Changing from one ineffective
antidepressant to similar or different
class of antidepressant; SSRI/SNRI to
TCA, MAOI, and atypical antipsychotics
with antidepressant properties
Combination
of antidepressants
Adding another antidepressant from
different classes, eg, TCA + MAOI,
SSRI + TCA, SSRI + atypical
antidepressant, SSRI + buspirone, etc
Augmentation
strategies
Adding a second agent that is not
an antidepressant but may enhance
the antidepressant effect of the
drug in question, eg, lithium, thyroid
hormones, pindolol, psychostimulants,
atypical antipsychotics, sex hormones,
anticonvulsants/mood stabilizers, and
dopamine agonists
Somatic therapies ECT, VNS, rTMS, MST, DBS, and TDCS
Integrated approach Use of antidepressants together with
other modes of treatment, which
include psychotherapy, risk management
strategies, CAM therapies, and life style
changes such as exercise and school
vacation
Adjunctive approach Use of a treatment to manage the side
effects of antidepressants and also to
increase its efcacy
Neurosurgical
interventions
Isolated, severe cases of treatment-
resistant depression
Continuing research In genetic, biomarkers, and animal models
for drug development
Abbreviations: CAM, complementary and alternative medicine; TDCS, transcranial
direct current stimulation; ECT, electroconvulsive therapy; VNS, vagus nerve
stimulation; rTMS, repetitive transcranial magnetic stimulation, DBS, deep brain
stimulation; MST, magnetic seizure therapy; TCA, tricyclic antidepressant; MAOI,
monoamine oxidase inhibitors; SSRI, selective serotonin reuptake inhibitor; SNRI,
serotonin-norepinephrine reuptake inhibitor.
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Patient Preference and Adherence 2012:6
of higher doses of first-generation and second-generation
antidepressants in patients with treatment-resistant depres-
sion requires monitoring of blood levels to track the clinical
response and to avoid adverse effects.
Switching strategies
The switching approach mainly involves discontinuing an
ineffective antidepressant and starting a new antidepressant
from a similar or different class in patients with treatment-
resistant depression. Earlier studies found response rates
of only 10%–30% for TCA in patients with a past history
of lack of response to TCA.
9
A trial course of nortriptyline
guided by plasma levels similarly suggested a 30% response
in patients with a prior history of TCA failure.
50
Conversely,
better response rates of up to 70% have been reported when
patients are switched to an alternative class of antidepressant,
including the second-generation heterocyclic antidepres-
sants and SSRI/SNRI coupled with a different mechanism
of action.
7,30,32,47
Thase and Rush reviewed the relevant
literature on old trend switching approaches involving
several within and across classes of antidepressants in the
population with treatment-resistant depression and similar
conclusions were drawn, with the recommendation to conduct
larger, controlled, double-blind, crossover studies of SSRI/
SNRI-resistant depression using newer antidepressants and
TCA.
9
A number of relatively well designed studies,
51–67
which focused on switching strategies from SSRI in major
depression, have been conducted to address these issues, and
are summarized in Table 4. A summary of the findings of
these studies is as follows: response rate 26%–76%; remis-
sion rate 28%–87%; a TCA might prove to be a strategy
of first choice for patients who do not respond to an SSRI;
intolerance to one SSRI does not necessarily mean intoler-
ance to the whole class of SSRI; challenges include collecting
controlled data to address the equally important question
about the effectiveness of an alternate SSRI when another
member of this class is not effective; across-class switch is
a good treatment option; in patients unresponsive to SSRI,
administration of antidepressants with different mechanisms
of action is an effective switching strategy; and switching
from an SSRI to a TCA and vice versa in patients who do not
respond to a 4-week trial is not associated with an improved
response. The last observation runs counter to that predicted
by current guidelines.
68
The advantages of this strategy are improved adherence,
reduced medication costs, and fewer drug interactions,
69
while the disadvantages are that therapeutic gains from
original antidepressant are lost, the patient has to wait for
the new agent to become effective, and relapse or withdrawal
symptoms together with adverse effects may occur during
the intervening period. This is particularly true if the
half-life of the first agent is quite long, as is the case with
fluoxetine (35 days), and another SSRI is started before an
adequate washout period has occurred. Other antidepressants
that require longer washout periods of up to 14 days are
clomipramine, tranylcypromine, moclobemide, bupropion,
and phenelzine if switched to another TCA, monoamine
oxidase inhibitor, or SSRI. Serotonin syndrome,
70
reflecting
toxic serotonin levels in the central nervous system and
characterized by hyperalertness, agitation, confusion,
restlessness, myoclonus, hyperreflexia, diaphoresis, shivering,
tremor, and, possibly, death, may occasionally develop if the
washout period was inadequate when switching from one
SSRI antidepressant to another. In summary, the risks of
toxicity are greater with higher dosage regimens and an inad-
equate washout period, although urgent cases may necessitate
a shorter switching interval.
Combination of antidepressants
Combination therapy involves the addition of a second anti-
depressant agent from a different class to the therapeutic
regimen of patients with treatment-resistant depression.
30,71
The additional antidepressant is used for 12 weeks or even
months in optimum doses.
9
Older antidepressants may
be used because they are reported to have good results in
treatment-resistant depression coupled with severe, recurrent
depression.
72–74
Various types of combination are reported in
the literature, but the most common are TCA + SSRI followed
by, eg, venlafaxine + TCA, SSRI + SSRI, and SSRI + venla-
faxine.
75
Venlafaxine + mirtazapine is frequently used in
clinical practice, and this combination produces a good
response in patients with difficult-to-treat depression, which
is attributed to the synergistic action of this combination. In
one study of 32 patients with persistent depressive illness,
the mirtazapine + venlafaxine combination was given at
some point over a 3-year period between 2002 and 2005.
Clinical response rates were 44% at 4 weeks and 50% at 8
weeks. At 6-month review, 56% of the original cohort and
75% of those still receiving treatment had shown a sig-
nificant response. In total, 44% experienced some adverse
effects. Five patients discontinued treatment due to seda-
tion (19%) and weight gain (19%).
76
In another study, the
venlafaxine + mirtazapine combination was given to 22
patients with major depression who had failed one trial
of antidepressant therapy. The mean duration of treat-
ment was approximately 8 weeks, producing a response
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Table 4 Summary of clinical studies of switching from an SSRI in major depression
Reference Initial
treatment
Post-switch
treatment
Design Response rate
Thase et al
51
Sertraline Fluoxetine
n = 106, open, non-response,
or intolerance
63%
Brown and
Harrison
52
Fluoxetine Sertraline
n = 91, open, primarily
intolerant
76%
Zarate et al
53
Fluoxetine Sertraline
n = 31, open, non-response
or intolerance
42% at discharge,
26% at follow-up
Joffe et al
54
Fluoxetine,
Sertraline,
Paroxetine
Second SSRI
n = 55, open,
non-response only
51%
Peselow et al
55
Paroxetine Imipramine
n = 15, double-blind,
prospective nonresponse
73%
Thase et al
56
Sertraline Imipramine
n = 117, double-blind,
cross-over prospective
non-response
60% in the sertraline group and
44% in the imipramine group
Nierenberg et al
57
Various Venlafaxine
n = 84, open, non-response
to 3 prior trials
33%
De Montigny et al
58
Various Venlafaxine
n = 152, open, nonresponse
to at least one prior trial
58% response
28% remission
Kaplan
59
Fluoxetine,
Sertraline,
Paroxetine
Venlafaxine
n = 73, open, nonresponse
to one prior SSRI
87% full remission
Poirer and
Boyer
60
Various, two
thirds SSRIs
Venlafaxine or
Paroxetine
n = 172, double-blind,
randomized, nonresponse to
two prior trials, 1 prospective
Response
52% venlafaxine, 33% paroxetine
Remission
42% venlafaxine, 22% paroxetine
McGrath et al
61
Fluoxetine Bupropion
n = 18, open, nonresponse
to prior prospective
uoxetine trial
28% response
Fava et al
62
Various SSRI Mirtazapine
n = 69, open, nonresponse
to prior prospective SSRI trial
48% response
Thase et al
63
Various SSRI Mirtazapine or
Sertraline
n = 243, double-blind,
randomized, nonresponse
to one prior SSRI, not sertraline
At week 3 and 4 mirtazapine . sertraline,
P , 0.05 (.50% improvement) and at
week 8 mirtazapine and sertraline, P = NS.
Remission rate 37% mirtazapine
and 29% sertraline
Rapaport et al
64
SSRI,
Citalopram
Risperidone
n = 489, multiple designs,
double-blind, placebo-controlled,
nonresponse to 1–3 SSRI failures
Median time to relapse was 97 days
with risperidone augmentation and
56 with placebo (P = 0.05); relapse
rates were 56% and 64%, respectively
(P , 0.05)
Lenox-Smith
and Jiang
65
SSRI Venlafaxine
Citalopram
n = 406, 12-week, double-blind,
randomized, parallel-group,
multicenter study
Venlafaxine and citalopram with similar
efcacy. In severely depressed patients,
venlafaxine ER was signicantly more
effective
Souery et al
66
Citalopram
Despiramine
Despiramine/
citalopram
n = 189, nonresponse,
prospective study, 8 weeks
First 4 weeks, no difference between
citalopram and despiramine or switch,
but in the next 4 week, remitter
rates . among non-switched patients,
switched patients had more score on
HRSD and MADRS, CGI scales
Rosso et al
67
SSRI Duloxetine and
bupropion
n = 49, a randomized,
comparison study,
2 SSRI trial failures
Response rate 60%–70% and remission
rate 30%–40%
Copyright © 2003, Physicians Postgraduate Press. Adapted with permission from Nelson JC. Managing treatment-resistant major depression. J Clin Psychiatry. 2003;64 Suppl 1:5–12.
69
Abbreviations: ER, extended-release; HRSD, Hamilton Rating Scale for Depression; MADRS, Montgomery-Åsberg Depression Rating Scale; CGI, Clinical Global Impression;
NS, not statistically signicant; SSRI, selective serotonin reuptake inhibitors.
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rate of 81.8% and a remission rate of 27.3%. Only one patient
was unable to tolerate the combination, although 50% had
significant side effects during treatment.
77
This approach has certain disadvantages, ie, it does not
allow for adequate evaluation of monotherapy, is associ-
ated with reduced compliance, has an increased likelihood
of adverse effects, is prone to polypharmacy, and has the
potential for increased drug interactions. Advantages of the
combination approach are that it is coupled with a rapid
response, no titration is necessary, initial improvements are
maintained, the strategy builds on therapeutic gains, addition
of the second compound is generally well tolerated, and the
disadvantages of switching strategies are avoided. In addition,
the response rate is comparable or superior to drug substitu-
tion. In this strategy, there might be a synergistic therapeutic
effect, but side effects due to drug–drug interactions also tend
to emerge, so careful drug surveillance is needed.
6,69
Augmentation strategies
Augmentation therapy involves adding a second agent (but
one that is not routinely regarded as an antidepressant) to the
therapeutic regimen when there is only a partial response to
the primary antidepressant agent.
38
The reported strength of
recommendation for augmentation or switching is best sup-
porting evidence.
78
Various augmenting agents, including
lithium, atypical antipsychotics, thyroid hormone, pindolol,
buspirone, dopamine agonists, sex steroids, glucocorticoid-
specific agents, herbal products, and newer anticonvulsants,
have been used in patients with treatment-resistant
depression.
19
Augmentation options, mechanisms, and dosing
strategies for the various agents are summarized in Tables 5–7.
The key points are as follows: downregulation of central
beta-adrenergic receptors, which explains the 4–6-week
delay in obtaining clinical improvement; lithium enhances
not only serotonin neurotransmission but also impacts other
neurotransmitter systems and neuromodulators, with a
response rate of 30%–65% in patients with treatment-resistant
depression who have failed several classes of antidepressants
and coupled with equal augmentation efficacy at serum blood
levels of 0.4 and 0.8 mEq/L; response may take just 2 days or
up to 3–6 weeks, which is considerably shorter than the delay
expected with switching, which involves taper of the first drug,
washout, and delay in onset of the second drug; antagonism
of 5HT
2A
receptors, common among atypical antipsychotics,
is also seen with mirtazapine and nefazodone and is coupled
with enhanced release of frontal dopamine and norepineph-
rine, which is thought to be a key action of antidepressant
agents; fluoxetine–olanzapine reported 40% improvement
among patients with treatment-resistant depression as
compared with 30% and 25% improvement with fluoxetine
and olanzapine alone, respectively; olanzapine, aripiprazole,
quetiapine, and ziprasidone had mixed results in a population
with treatment-resistant depression; T3 25–50 µg/day for
2–3 weeks is more effective than T4 for augmenting TCA,
monoamine oxidase inhibitors, SSRI, and lithium in patients
with treatment-resistant depression; monitoring thyroid
function before T3 administration for a baseline reading as
well as after administration is important; pindolol, a 5-HT
1A
postsynaptic antagonist, accelerates the onset of action of
antidepressants by preventing negative feedback to the pre-
synaptic 5-HT
1A
receptor but is currently not recommended
for this purpose; unlike open-label studies, buspirone is
ineffective in randomized controlled trials; stimulants had
no positive results in randomized controlled trials involving
patients with treatment-resistant depression; after adjusting
for the selection bias inherent in the STAR*D comparison
of augmentation versus switching, clinically meaningful
differences in the adverse event profiles between these
strategies were not observed; risperidone (remission rate
[RR] 26.7%), valproate (RR 48.7%), buspirone (RR 32.6%),
trazodone (RR 42.6%), and thyroid hormone (RR 37.5%)
added to paroxetine 20 mg/day was effective and well toler-
ated in 225 Chinese patients with stage II treatment-resistant
depression; an add-on multicenter trial of 183 patients with
treatment-resistant depression failed to detect a statistically
significant difference between lamotrigine and placebo
given for 10 weeks, but post hoc analysis suggested that
future studies of the efficacy of lamotrigine should focus
on specific subgroups with depression; a double-blind,
placebo-controlled study found that topiramate augmenta-
tion potentiates the efficacy of SSRI (fluoxetine, citalopram,
sertraline) in the treatment of resistant depression; and further
large, comparative, double-blind, randomized clinical trials
of augmentation agents in patients with treatment-resistant
depression are needed.
9,30,79–99
The level of evidence for common augmentation agents
is as follows: lithium and T3 (best evidence); atypical
antipsychotic drugs (some evidence); stimulants, inositol,
estrogen, omega-3 fatty acids, and dopamine agonists (little
evidence); herbal supplements, lamotrigine (no evidence);
and tetraiodothyronine and pindolol (not effective).
46
Comorbidity
Patients with treatment-resistant depression need to be
assessed for comorbid medical and other psychiatric
conditions. This is mandatory because 75.5% and 46.9%
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Table 5 Augmentation options for treatment-resistant depression
Medication Available data Remarks
Traditional agents
Mirtazapine
77
Positive RCTs,
77
STAR*D Limited data
Bupropion
100
Multiple open-label trials, RCTs, STAR*D Rapidly effective and more data are needed
Buspirone
96
Negative RCTs, STAR*D Ineffective in RCTs
T3 Limited RCTs with SSRI,
78,96
positive
when combined with TCA
91,93
Comparable with lithium in STAR*D but fewer
side effects
Lithium Limited RCTs with SSRI,
78,80
positive when
combined with TCA
93
Comparable to T3 in STAR*D but more side effects
Lamotrigine
97
Negative RCTs Small numbers, mixed populations
Valproate
96
Pilot RCT, effective and well tolerated Data are limited and larger sample size RCTs are needed
Topiramate
98
Positive RCT
98
RCTs with larger sample needed
Pindolol
94
Negative RCTs
94
Positive data for antidepressant effect acceleration,
not recommended for augmentation
Stimulants
81
Negative RCTs
81
May have a role for adjunctive treatment of apathy.
Accelerates the antidepressant effect
Sex hormones Mixed data, most for testosterone Signicant long-term side effects
Atypical antipsychotics
Aripiprazole
89
3 positive RCTs,
89
FDA indication Negative self-report outcomes
Olanzapine/uoxetine
23
One positive RCT,
23
multiple equivocal
RCTs,
85
FDA indication
Weight gain, metabolic syndrome
Quetiapine
99
One negative RCT, two positive unpublished
RCTs with extended-release formulation
Weight gain, metabolic syndrome, helpful adjunctive
agent for some patients with TRD but
placebo-controlled trials are needed
Risperidone
96
Two positive RCTs, one negative Trials with short treatment lead-in
(4–5 weeks on previous antidepressant treatment)
Ziprasidone
85
Mixed open-label data only
85
All antipsychotics
Response (odds ratio = 1.69) and
remission (odds ratio = 2.00) versus
placebo from RCTs
Discontinuation rates for adverse events higher versus
placebo (odds ratio = 3.91)
Note: Information sourced from a number of papers.
11,13–14,23,31,77–98,100
Abbreviations: RCTs, randomized controlled trials; FDA, Food and Drug Administration; SSRI, selective serotonin reuptake inhibitor; STAR*D, Sequenced Treatment
Alternatives to Relieve Depression; TRD, treatment-resistant depression.
of patients with unipolar and bipolar treatment-resistant
depression (n = 49) were reported to have at least one other
Axis I and two additional Axis I diagnoses, respectively,
which included anxiety disorder and substance abuse. Axis
I comorbidity appears to be differentially associated with
treatment resistance in unipolar and bipolar depression.
101
It is also true with treatment-resistant depression, which is
probably associated with a variety of physical diseases at an
etiological level, including painful syndromes.
102
In addition,
both physical and psychiatric comorbid conditions contribute
to treatment resistance in patients with depression. Patients
with comorbidities who showed a partial response to TCA,
monoamine oxidase inhibitors, SSRI, and SNRI may derive
benefit from the use of stimulants, ie, methylphenidate 10 mg
three times daily, dextroamphetamine 5 mg three times
daily, or modafinil 100–200 mg once daily. These medica-
tions are reported to accelerate the effects of antidepressant
therapy, but have a potential for abuse and randomized
controlled trials failed to produce any treatment benefits.
76,81
However, these medications may have a role in the adjunctive
treatment of apathy.
30,81
Nefazodone, another compound used
concurrently with prescribed medications in patients with
treatment-resistant depression (n = 20) and high psychiatric
comorbidity (post-traumatic stress disorder, substance use
disorder, and personality disorder) produced good results,
with 50% of patients (n = 11) showing substantial improve-
ment, and a smaller proportion having a more modest clini-
cal response.
84
Duloxetine and venlafaxine have also been
used in several studies with fairly good results.
103
The basic
principles of treating treatment-resistant depression with
comorbidities remain the same and all options need to be
used sequentially.
104
Electroconvulsive therapy
ECT is a recognized mode of treatment for a variety of mental
disorders, including treatment-resistant depression.
105,106
ECT is still the most consistently effective in patients
with treatment-resistant depression, with a response rate
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of 50%–70%.
30
Furthermore, ECT remains the treatment
of first choice for the most severe, incapacitating forms of
treatment-resistant depression, though the strength of the
recommendation of ECT is level C.
78
Surprisingly, relapse
rates are significantly higher in patients with treatment-
resistant depression after a successful course of therapy.
107
Research is needed to establish the efficacy of alternative
methods to prevent relapse following successful ECT, includ-
ing maintenance ECT and combination pharmacotherapy
strategies. Patients who fail to respond to ECT as proposed
in Stage 5 treatment-resistant depression represent some
of the most challenging cases. Predictors of nonresponse
to ECT need to be in place. In a large patient population
with treatment-resistant depression, ECT was an effective
treatment for approximately two thirds of cases. A lack of
response to ECT was associated with bipolar subtype, pres-
ence of manic symptoms during depression, slightly less
severe depressive symptomatology, and protracted duration
of the depressive episode.
108
In a recent study of adolescents
with treatment-resistant depression, continuation ECT and
maintenance ECT were useful and safe treatment strategies
for selected adolescents with severe treatment-resistant
depression, and symptom remission was achieved without
cognitive impairment.
109
Other somatic therapies
These reversible but more invasive therapies were developed
to avoid the adverse effects and complications of ECT and
at the same time to be more effective in treatment-resistant
depression. rTMS and VNS are approved by the US Food
and Drug Administration for the treatment of intractable sei-
zure disorders and treatment-resistant depression. However,
with regard to treatment-resistant depression, other neu-
romodulation therapies, including DBS, magnetic seizure
therapy, and tDCS, are in the experimental stages.
30,88,110–112
Notably, the Food and Drug Administration has approved
DBS for compassionate use in severe obsessive-compulsive
disorder.
Studies of somatic therapies seem to be producing
promising results. In an open-label study, 21 patients who
failed two antidepressant trials were given rTMS therapy
(high-frequency, 10 Hz, intensity of 110%) for 4 weeks,
keeping the dose of pre-existing antidepressants unchanged.
Nineteen patients completed the study and were assessed.
In intention-to-treat analysis, the mean HRSD-17 scores
were reduced from 30.80 ± 5.00 to 19.00 ± 6.37. Only four
patients reported headache, but there was no discontinuation
due to adverse effects. The study indicated the potential
utility of rTMS as an augmenting agent in treatment-
resistant depression. Both high frequency left-sided and
low frequency right-sided unilateral rTMS are efficacious
in treatment-resistant depression. Similar benefits have been
suggested for sequential bilateral rTMS (low frequency
right-sided then high frequency left-sided).
113
In another
study, subjects aged 18–85 years were recruited from a
tertiary care university hospital. Seventy-four subjects with
treatment-resistant depression and a 17-item HRSD score
greater than 21 were randomized to receive unilateral, bilat-
eral, or sham rTMS. The rates of remission were compared
between the three treatment groups. The remission rates
differed significantly between the groups using a modified
intention-to-treat analysis that excluded subjects who did
not respond to ECT during the current episode. The remis-
sion rate was significantly higher in the bilateral group than
in the sham group. The remission rate in the unilateral group
did not differ in either group.
114
These studies, including a
meta-analysis, call for larger controlled studies to compare
the efficacy of sequential bilateral rTMS and high frequency
Table 6 Mechanism of action of agents used as augmentation for
treatment-resistant depression
Augmentation agent Mechanism of action
Lithium Potentiate serotonergic neurotransmission,
modulates phosphatidyl-inositol pathway
Triiodothyronine Potentiate norepinephrine neurotransmission,
corrects subclinical hypothyroidism that
causes depression-like symptoms
Atypical antipsychotics Improve frontal serotonin, norepinephrine,
and dopamine functions, and other
neurotransmitters such as glutamate
Psychostimulants Improve norepinephrine and dopamine
neurotransmission
Inositol Precursor of diacylglycerol and inositol
triphosphate
Estrogen Affects gamma aminobutyric acid,
serotonergic, noradrenergic and cholinergic
neurotransmission
Omega-3 fatty acids Normalize communication in nerve cells;
lower tumor necrosis factor-α; lower
interleukin-B; lower prostaglandins
E 2, 3, 4; and increase brain-derived
neurotrophic factor
Dopamine agonists Increase dopamine tone
Herbal supplements May impact monoaminergic
neurotransmission
Lamotrigine Blocks 5-hydroxytriptamine 3 receptors,
potentiates dopamine
Tetraiodothyronine Potentiates norepinephrine
neurotransmission
Pindolol Increases serotonergic tone
Copyright © 2005, MBL Communications. Adapted with permission from Gotto J,
Rapaport MH. Treatment options in treatment-resistant depression. Prim Psychiatry.
2005;12:42–50.
46
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left-sided rTMS in depression and treatment-resistant
depression.
114,115
In another study, 22 patients with major depression were
randomly assigned to a crossover protocol comparing tDCS
and placebo stimulation add-on to a stable antidepressant
medication. The parameters of active tDCS were: 1 mA or
2 mA for 20 minutes daily, with the anode over the left dorso-
lateral prefrontal cortex and the cathode over the contralateral
supraorbital region. Active and placebo tDCS was applied for
2 weeks using indistinguishable direct current stimulators.
Patients, raters, and operators were blinded to the treatment
conditions. The results showed that there was no significant
difference in depression scores after 2 weeks of real tDCS
compared with 2 weeks of sham tDCS. However, subjective
mood ratings showed an increase in positive emotions after real
tDCS compared with sham tDCS. Anodal tDCS, applied for 2
weeks, was not superior to placebo in patients with treatment-
resistant depression. A modified and improved tDCS protocol
should be investigated in controlled pilot trials to develop
effective tDCS for treatment-resistant depression.
116
In an interesting single treatment-resistant depression
patient analysis, VNS produced good results and achieved a
cost saving over modified ECT.
117
Both ECT and VNS could
be combined in managing severe cases of treatment-resistant
depression. VNS has some disadvantages, including hoarse-
ness of voice caused by the stimulator delivering the electri-
cal pulse, and rarely infection due to surgical implantation
of a small device into the left chest wall.
117
In an open-label
study of resistant major depressive episode, the predictors of
response to VNS were a history of resistant depression, mild
to moderate resistant depression, non-severe resistant depres-
sion, and no history of use of ECT.
118
The long-term effects
and tolerability of VNS need to be determined to ascertain
its suitability for use in treatment-resistant depression.
A multicenter pilot study of 21 patients with treatment-
resistant depression who received DBS found that patients
treated with subcallosal cingulate gyrus DBS had an
RESP50 of 57% at one month, 48% at 6 months, and 29%
at 12 months. However, the response rate after 12 months
of DBS increased to 62% when response is defined by 50%
reduction in baseline HRSD-17 score (RESP50). Reductions
in depressive symptoms were associated with amelioration
of disease severity in patients who responded to surgery.
Overall, findings from this study corroborated the results
of previous reports showing that outcome of subcallosal
cingulate gyrus DBS may be replicated across centers.
119
Ward and Irazoqui have provided greater detail on target
structures, motivation, response rates, and the proposed
mechanism of action of somatic therapies used in treatment-
resistant depression.
4
Data from a follow-up study suggested
that in the long term (up to 6 years), DBS remains a safe
and effective treatment for treatment-resistant depression.
120
Finally, psychosurgery, such as subcaudate tractotomy, limbic
leucotomy, anterior capsulotomy, and anterior cingulotomy
remain the last line of somatic treatment for patients with
severe treatment-resistant depression.
30
Table 7 Dosing strategies for augmentation agents for treatment-resistant depression
Augmentation agents Recommended dosing strategies Side effects
Lithium Initially 150 mg twice daily to be increased in accordance
with blood level (0.4–0.8 mEq/L) and clinical response
Tremors, weight gain, polydipsia, polyurea
Triiodothyronine
25–50 µg/day for 3 weeks
Irritability, sweating, palpitation, and anxiety
Olanzapine 2.5–5 mg/day Sedation and weight gain
Ziprasidone 20–40 mg/day Sedation and weight gain
Risperidone 0.5–1 mg/day Sedation and weight gain
Methylphenidate 5–30 mg/day Insomnia, irritability, GI symptoms, abuse
and blood pressure/heart rate variability
Dextroamphetamine 10–20 mg/day Insomnia, irritability, GI symptoms, abuse
and blood pressure/heart rate variability
Modanil 200 mg/day Headache, dizziness, nausea and dry mouth
Primapexole 0.25–2.5 mg/day Nausea and agitation
Inositol 500–1000 mg/day Not available
Estrogen 0.1–0.2 mg patch Risk for breast and uterine cancer,
weight gain, and edema
Omega-3 fatty acids 6 g EPA and 2 g DHA Unpleasant shy burp
Lamotrigine 12.5–25 mg/day initially; increase by 12.5–25 mg/week
up to 100–220 mg/day
Nausea, headache, blurry vision,
rash and sleepiness
Notes: Pindolol, T4, and herbal supplements are not recommended.
Copyright © 2005, MBL Communications. Adapted with permission from Gotto J, Rapaport MH. Treatment options in treatment-resistant depression. Prim Psychiatry. 2005;12:42–50.
46
Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GI, gastrointestinal.
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Complementary and alternative
medicine
The therapeutic role of ethyl eicosapentaenoic acid, an
essential fatty acid, as an augmentation agent for traditional
antidepressants in treatment-resistant depression has been
reported.
30
Puri et al showed that eicosapentaenoic acid
improved some symptoms, including suicidal ideation and
social phobia, in a single patient with severe treatment-
resistant depression. This compound also induced neurobio-
logical changes, such as a 30% increase in the volumetric
niacin response, a 53% increase in the relative concentration
of cerebral phosphomonoesters, a 79% increase in the ratio
of cerebral phosphomonoesters to phosphodiesters, and a
reduction in the lateral ventricular volume of the brain.
121
The therapeutic value of L-methylfolate, a medicinal food,
is emphasized in patients of Hispanic origin with treatment-
resistant depression.
122
The efficacy of other complementary
and alternative medicines in patients with treatment-resistant
depression needs to be studied because these therapies
have minimal adverse effects and their contribution to
the management of various diseases is expanding rapidly.
Conversely, in modern medicine, of about 65% of patients
who discontinue antidepressants, 45% of them do so because
of unpleasant side effects.
123
Regarding lifestyle changes,
researchers reported positive effects of moderate physical
exercise on quality of life in patients with treatment-resistant
depression.
124
Psychotherapy
In general, psychotherapy alone is effective in mild to moder-
ate depression, and when combined with antidepressants, is
associated with better results in severe depression than either
therapy alone. Traditionally, the strength of recommenda-
tion for psychotherapy is B level, and it has been considered
useful in the management of treatment-resistant depression,
primarily as an adjunct to help patients maintain morale and
optimism.
78
Currently, various studies have also justified the
use of psychotherapy, especially cognitive behavior therapy,
when using switching and augmentation approaches in
patients with treatment-resistant depression.
9,30,100
In a com-
parative study that recruited patients with treatment-resistant
depression who responded unsatisfactorily to citalopram and
were assigned randomly to either augmentation of citalopram
with cognitive therapy or sustained-release bupropion or
buspirone or switch to cognitive therapy or another antide-
pressant, sertraline, sustained-release bupropion, or extended-
release venlafaxine, Thase et al
100
found that pharmacologic
augmentation was more rapidly effective than augmentation
of citalopram using cognitive behavioral therapy, whereas
switching to cognitive behavioral therapy was better tolerated
than switching to a different antidepressant. Few randomized
controlled trials
125,126
have investigated interventions for
treatment-resistant depression in young people, and results
from these show modest benefit from antidepressants, with
no additional benefit of cognitive behavioral therapy over
medication. Overall, there is a lack of evidence about effec-
tive interventions to treat young people who have failed to
respond to evidence-based interventions for depression.
Research in this area is urgently required.
125,126
In a related
development, research suggests that children and adolescents
with school difficulties are less likely to respond to fluoxetine
compared with those with no school difficulties. Depressed
adolescents in the Treatment of Resistant Depression in
Adolescents study, who had not responded to a previous
adequate trial of an SSRI, were randomly assigned to one
of the following: another SSRI, venlafaxine, another SSRI +
cognitive behavioral therapy, or venlafaxine + cognitive
behavioral therapy. Participants were classified into four
groups, depending on whether their enrollment in the study
and end of treatment was during school or summer vacation.
There was a significant interaction between school difficulties
and timing of treatment, with the lowest rates of response
being among adolescents having school difficulties and
ending their treatment during the active school year. School
problems are relevant to treatment response in depressed
adolescents and should be incorporated into the treatment
plan. These findings also suggest that the time of year might
need to be taken into consideration for analysis of clinical
trials in school-aged youth.
127
In a systematic review,
128
researchers examined the utility of psychotherapy in the
management of treatment-resistant depression, and found it
to be useful. However, the evidence was sparse and the results
were mixed. Given that quality trials are lacking, rigorous
clinical trials are recommended to guide practice, including
in primary care.
128
A team of researchers examined the long-term outcome of
participants in the Treatment of SSRI-Resistant Depression in
Adolescents, in which 334 adolescents with major depressive
disorder initially resistant to SSRI treatment were randomly
treated for 12 weeks with another SSRI, venlafaxine, another
SSRI + cognitive behavioral therapy, or venlafaxine + cogni-
tive behavioral therapy. Responders then continued with the
same treatment through week 24, while non-responders were
given open treatment. By 72 weeks, an estimated 61.1% of the
randomized adolescents had reached remission. Randomly
assigned treatment, ie, that given for the first 12 weeks,
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did not influence the remission rate or time to remission,
but the group assigned to SSRI had a more rapid decline in
self-reported depressive symptoms and suicidal ideation than
those assigned to venlafaxine. Participants with more severe
depression, greater dysfunction, and alcohol or drug use at
baseline were less likely to remit. The depressive symptom
trajectory of the remitters diverged from that of non-remitters
during the first 6 weeks of treatment. Of the 130 participants
in remission at week 24, 25.4% relapsed in the subsequent
year. While most adolescents achieved remission, more than
one third did not, and one quarter of the patients who remit-
ted experienced a relapse. The investigators suggested more
effective interventions are needed for patients who do not
show robust improvement early on in treatment.
129
Future treatment options
New drugs approved for the management of depression
are on the market (Table 8). These medications include
desvenlafaxine (an SNRI), escitalopram (an SSRI), and a
reformulation of trazodone (Oleptro™). A number of drugs,
including riluzole, that act on glutamate receptors and have
antidepressant activity have also been developed and are
approved for managing major depression.
81,130
Studies have
explored the role of ketamine, an NMDA antagonist, in treat-
ing treatment-resistant depression and acute suicidal ideation.
Ketamine appears to have a rapid antidepressant effect,
within hours or a day, although these effects only last
for 7–10 days. Patients need to be admitted to hospital to
receive ketamine intravenously from an anesthesiologist,
while their vital signs are closely monitored. Ketamine is
a drug of abuse and induces trance-like or hallucinatory
states. Like other anesthetics, ketamine also produces mild
to moderate cognitive side effects. Ketamine treatment
may be akin to ECT and studying ketamine may reveal
mechanisms underlying depression and help to identify
drugs that can be prescribed as antidepressants to a wider
patient population.
131
In a comparative study of 17 patients
with treatment-resistant depression non-responsive to ECT
and 23 patients with treatment-resistant depression who had
not previously received ECT were given a single open-label
infusion of ketamine 0.5 mg/kg and evaluated using the
Montgomery-Åsberg Depression Rating Scale at baseline
(60 minutes before the infusion), as well as at 40, 80, 120,
and 230 minutes after infusion. Depressive symptoms
were significantly improved in the ECT-resistant group at
230 minutes, with a moderate effect size. At 230 minutes,
the group not exposed to ECT showed significant improve-
ment with a large effect size. Ketamine appears to improve
depressive symptoms in patients with major depression who
had previously not responded to ECT. These preliminary
results warrant further investigation in a larger sample size
to determine the effectiveness of ketamine in patients with
depression not responsive to other treatments.
132
In one study,
10 participants with treatment-resistant depression were
given riluzole, another NMDA antagonist, along with their
regular antidepressant. After 6–12 weeks, they experienced
an almost 10-point drop on the HRSD.
130
Triple reuptake inhibitors that block the reuptake of
serotonin, norepinephrine, and dopamine, are the newest
drugs in the stable of monoamine antidepressants.
133
Currently, there are no randomized controlled trials on these
agents and research is preliminary. It is believed that triple
reuptake inhibitors devoid of an effect on sexual function
could be used as second-line treatment when patients with
depression do not respond to an SSRI.
134,135
Non-conventional
antidepressants, such as tianeptine, are also used for treatment-
resistant depression with some benefits.
133
Another new drug,
agomelatine, the first melatonergic antidepressant containing
a 5-HT
2C
receptor antagonist and a melatonin-1 agonist, is
approved in Europe to treat major depression. It has a unique
mechanism of action by targeting the melatonin system in
the brain,
81
and randomized controlled trials in the treatment-
resistant depression population are needed. In another
Table 8 Future treatment options for treatment-resistant
depression
Medication/intervention Comments
Melatonin drugs
(agomelatine)
Preliminary data only, no inclusion of
TRD population in registration trials,
not yet studied as an augmenting agent
Acetylcholine drugs
(scopolamine, mecamylamine,
varenicline)
Intravenous infusions used for
scopolamine, studied as augmenting
agents rather than primary treatment,
small numbers in published results,
large trials underway
Glutamate drugs
(ketamine, NR2 antagonists,
riluzole)
Short-term symptomatic relief, only
intravenous infusions used, further
trials underway
Neurostimulation VNS approved for TRD but long-term
treatment needed, TMS showed less
efcacy in more treatment-resistant
patients but use of TMS in TRD under
investigation, DBS trials underway
Copyright © 2010, Informa Healthcare. Adapted with permission from Philip NS,
Carpenter LL, Tyrka AR, Price LH. Pharmacologic approaches to treatment resistant
depression: a re-examination for the modern era. Expert Opin Pharmacother. 2010;11:
709–722.
81
Abbreviations: NR2, NMDA receptor subunit; TRD, treatment-resistant depression;
VNS, vagus nerve stimulation; DBS, deep brain stimulation; TMS, transcranial magnetic
stimulation.
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development, loss of brain-derived neurotrophic factor was
found in major depression. Brain-derived neurotrophic factor
is a member of the nerve growth factor family, which helps
with the survival and growth of neurons. However, stress
seems to decrease levels of brain-derived neurotrophic factor.
Increasing brain-derived neurotrophic factor may be a new
strategy for developing new antidepressants. Furthermore,
compounds that influence the endocannabinoid system
involved in depression, and neuropeptide systems, such
as galanin and melanin-concentrating hormone, may be
used in the treatment of treatment-resistant depression.
133
Several neuropeptides and their receptors have also been
identified as potential targets for pharmacologic intervention
by corticotropin-releasing factor and substance P.
136
Some
investigators have suggested use of Sertoli cell therapy in
patients with treatment-resistant depression.
137
Acetylcholine
drugs, such as scopolamine, mecamylamine, and varenicline,
have been used in small studies involving patients with
treatment-resistant depression, with positive results.
81,138,139
In summary, preliminary data for the aforementioned
newer antidepressant therapies support the view that larger,
randomized, controlled studies are needed in future. A step-
wise treatment algorithm for patients with treatment-resistant
depression need to be used for better decision-making, better
responses, and a higher remission rate in the population with
treatment-resistant depression.
11,140
Discussion
This paper is a narrative review of the literature on treatment-
resistant depression. In addition to Google Scholar and
Quertle database searches, multiple rounds of computer
searching of PubMed using key words and a combined
strategy might have led to some relevant articles, especially
in young and elderly populations, having been missed, and
possibly biasing our results. However, the astronomical
database on treatment-resistant depression published regu-
larly and globally is difficult to synthesize. Furthermore,
selection and review of all articles by a lone author is an uphill
task and selection bias might have entered into this qualitative
review. Despite these caveats, this review reports important
findings and developments in the therapeutic paradigms
for treatment-resistant depression over two decades. The
prevalence of treatment-resistant depression is 10%–30%,
7
but some researchers have suggested that it could be more
than 30%,
11,12,69
according to definitions of treatment-resistant
depression and other methodological issues. With advances
in the treatment of resistant depression, it is not surprising
that its prevalence would temporally decrease or change.
It seems that depression should only be considered drug-
resistant after at least 6 weeks of two trials of antidepressant
therapy.
9,51
Some researchers suggested extending this period
for up to 10–12 weeks in patients who respond partially to
trials of antidepressant therapy.
15,47
Nonetheless, at least 30%
of patients continue to manifest residual symptoms with
poor quality of life and impairment in overall functioning.
51
In addition to requiring several recommended therapeutic
options, this core group of patients with treatment-resistant
depression warrants a comprehensive search for factors
responsible for the persistence of depression, which include
but are not limited to the patient’s characteristics and
environment, including stresses, a comorbid psychiatric
or somatic disorder, and drug abuse or addiction.
19,40–42,44,45
Arguably, the suggested therapeutic strategies for treatment-
resistant depression have variable outcomes in terms of
response and remission rate, as well as disadvantages due
to multiple factors, including the adverse effect profile of
antidepressants.
It is reported that optimization of a first-line antidepressant
in adequate doses and for an extended period of up to 12 weeks
is based on weak evidence.
19,69,81
Similarly, trials comparing
continuation of the first-line antidepressant versus switching
to another antidepressant from a different class have reported
conflicting results.
9,19
A switching strategy may benefit a
small proportion of patients, but the elimination half-life of
the discontinued drug, such as fluoxetine, and washout period
must be taken into account to limit the risk of interactions
during the transition period.
9,19,69,81
A combination approach
also has some disadvantages because it increases the risk
of adverse effects, possibly without a substantial clinical
benefit.
19
Evidently, a second course of antidepressant
monotherapy tends to treat up to 50% of those who have failed
with the initial treatment effectively, when the second drug
has a profile distinct from the initial medication. It means that
25% of patients with treatment-resistant depression respond
to optimization and combined strategies, and another 50%
tend to respond to switching options. The remaining 25% of
patients with treatment-resistant depression are candidates
for augmentation strategies.
81
The strength of evidence supporting a trial of aug-
mentation or a switch to a new agent is very similar, with
remission rates of 25%–50% in both cases.
141
A review of
comparative trials suggested that adjunctive use of lithium
and thyroid hormone have an established antidepressant
effect in patients with treatment-resistant depression, but
there is no firm evidence that adding lithium to non-TCA
treatment increases the chances of remission.
78,91,93,96,141
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According to other researchers, thyroid hormone, a benzodi-
azepine, buspirone, and pindolol as augmenting agents have
limited proven antidepressant effects.
19,78,94,96
Furthermore,
Connolly and Thase
141
as well as others
46,78,96
have reported
that of these two options, ie, lithium versus thyroid hormone,
T3 augmentation seems to offer the best benefit/risk ratio for
augmentation of modern antidepressants. However, lithium
is known to have a narrow therapeutic window and needs
blood level monitoring to avoid the toxicity and fatalities
associated with high lithium levels.
77,78,80
With regard to
newer generations of antidepressants, after failure of a
first-line SSRI, neither a switch within a class nor a switch
to a different class of antidepressant is unequivocally sup-
ported by the data, although switching from an SSRI to
venlafaxine or mirtazapine may potentially offer greater
benefits.
75–77,141
In an open-label study, mirtazapine was
effective in 38% of patients with depression resistant to
standard antidepressants.
142
It is noted that switching from
a newer antidepressant to a TCA after a poor response to the
former is not supported by strong evidence.
142
Augmentation
with an antiepileptic or a psychostimulant is not supported
unequivocally but they are reported to be more harmful
than beneficial because of adverse effects, including the
addiction potential of stimulants.
46,81,96–98
Conversely, the
use of psychostimulants with conventional antidepressants
is recommended in patients with treatment-resistant depres-
sion because significant improvement was demonstrated, in
particular with respect to energy, mood, and psychomotor
activity. It was concluded that their rapid onset of action
(2–3 hours) after administration may help cover the thera-
peutic latency period of conventional antidepressants and
probably potentiates their effect.
143
According to some stud-
ies, augmentation with atypical antipsychotics has had mixed
results,
23,85,96
but quetiapine and aripiprazole were relatively
supported by the evidence.
89,99
It is noted that Symbyax
®
, a
combination of olanzapine and fluoxetine, is approved for
the acute management of treatment-resistant depression.
ECT has a place in the management of patients fail-
ing multiple optimized monotherapies, switching options,
combined approaches, and augmented treatment strate-
gies
30,105,106,108
but carries a risk of reversible memory
disorders.
19
Surprisingly, patients with treatment-resistant
depression who responded to ECT were found to have a high
relapse rate,
107
which could be prevented by maintenance
ECT. Some studies reported no cognitive impairment with
ECT in adolescents with treatment-resistant depression.
109
In this regard, replication research is required to support or
refute such results. The role of other somatic interventions,
including VNS, rTMS, DBS, and tDCS, in patients with
treatment-resistant depression is expanding with greater
efficacy, but have some side effects and need further research,
especially large controlled randomized studies targeting
particular areas in the brain implicated in major depression
and treatment-resistant depression.
4,112–120
The efficacy of
psychotherapy in patients with treatment-resistant depression
is fairly good, and 50% of patients tend to get benefits from
psychotherapies, especially cognitive behavioral therapy
and mindfulness-based cognitive behavioral therapy.
19,100,144
Additional cognitive behavioral therapy in the young popu-
lation with treatment-resistant depression has limited or no
value and needs further research.
126
Regular exercise and use
of some complementary and alternative medicines impact
positively on treatment-resistant depression and need further
research using herbal supplements.
124
Conclusion
In summary, 70% of patients with major depression respond
to initial antidepressant therapy, leaving 30% of patients
who are refractory to treatment and therefore need special
treatment-resistant depression management strategies.
Twenty-five percent of patients with treatment-resistant
depression tend to respond to optimization and combined
treatment paradigms and another 50% of patients are reported
to respond to switching therapeutic options. Augmentation
strategies target the remaining 25% of patients suffering from
treatment-resistant depression, with inconsistent outcomes.
Overall, although there is no strict compartmentalization of
treatment response and remission rate in the population with
treatment-resistant depression, about one third of patients
with the disorder continue to be resistant to available thera-
peutic options, and hence pose a major therapeutic challenge
to mental health experts.
Recommendations
Based on this narrative review, that has some caveats, the
following recommendations are made:
• Each individual with treatment-resistant depression is a
unique case and needs detailed evaluation to identify the
prior antidepressant response and also to make a correct
diagnosis.
• Assessment of risk factors for treatment-resistant
depression is equally important to guide mental health
professionals in tailoring an appropriate management plan
for patients with treatment-resistant depression.
• There are a wide variety of options for the treatment of
major depression and treatment-resistant depression,
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therefore every therapeutic paradigm needs to be
utilized when helping patients with treatment-resistant
depression.
• In light of the demonstrated importance of truly adequate
treatment to the long-term outcomes of patients with
treatment-resistant depression, further randomized clini-
cal trials involving newer drugs and psychotherapies and
somatic therapies are needed in the future.
Acknowledgment
I would like to express my sincere thanks to Abdullah
Al-Anaizi, Dean of the College of Applied Medical Sciences,
King Saud Bin Abdulaziz University for Health Sciences,
for revising the earlier draft of this manuscript. Also special
thanks is extended to Naseem Akhtar Qureshi for revising
and editing this manuscript in accordance with the reviewers’
comments.
Disclosure
The author reports no conflicts of interest in this work.
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