Neuropsychiatric Disease and Treatment Dovepress

open access to scientific and medical research

Open Access Full Text Article

REVIEW

Management of Treatment-Resistant Depression:

Challenges and Strategies
This article was published in the following Dove Press journal:
Neuropsychiatric Disease and Treatment

Daphne Voineskos 1,2 Abstract: Treatment-resistant depression (TRD) is a subset of Major Depressive Disorder
Zafiris J Daskalakis 1,2 which does not respond to traditional and first-line therapeutic options. There are several
Daniel M Blumberger 1,2 definitions and staging models of TRD and a consensus for each has not yet been established.
1
However, in common for each model is the inadequate response to at least 2 trials of
Centre for Addiction and Mental Health,
Toronto, Ontario, Canada; 2Department antidepressant pharmacotherapy. In this review, a comprehensive analysis of existing litera-
of Psychiatry, University of Toronto, ture regarding the challenges and management of TRD has been compiled. A PubMed search
Toronto, Ontario, Canada was performed to assemble meta-analyses, trials and reviews on the topic of TRD. First, we
address the confounds in the definitions and staging models of TRD, and subsequently the
difficulties inherent in assessing the illness. Pharmacological augmentation strategies includ-
ing lithium, triiodothyronine and second-generation antipsychotics are reviewed, as is
switching of antidepressant class. Somatic therapies, including several modalities of brain
stimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic
seizure therapy and deep brain stimulation) are detailed, psychotherapeutic strategies and
subsequently novel therapeutics including ketamine, psilocybin, anti-inflammatories and new
directions are reviewed in this manuscript. Our review of the evidence suggests that further
large-scale work is necessary to understand the appropriate treatment pathways for TRD and
to prescribe effective therapeutic options for patients suffering from TRD.
Keywords: treatment resistant depression, major depressive disorder, pharmacotherapy,
psychotherapy, brain stimulation, novel therapies

Introduction
Major Depressive Disorder (MDD) and associated mood syndromes are among the
most common psychiatric disorders in specialist and general medical practice.
These syndromes span life stages and present with varying combinations of symp-
toms. While depressive symptoms are at times part of normal human behavior,
MDD can be debilitating and at its worst, life threatening. MDD can present at any
age across the life span, differences in biological vulnerability, age of onset, risk
factors, symptomatic presentation and comorbidities are present among people with
the same diagnosis. MDD is, therefore, a very heterogeneous disorder, and approxi-
mately 30% of people with this illness are resistant to conventional treatments.96
Several large-scale clinical trials have examined response rates to traditional
Correspondence: Daniel M Blumberger therapeutic approaches for depression. In the Sequenced Treatment Alternatives to
Centre for Addiction and Mental Health, Relieve Depression (STAR*D) study, the cumulative remission rate after 4 trials of
1001 Queen Street West, Unit 4-1,
Toronto, Ontario M6J1H4, Canada antidepressant treatment (within 14 months) was 67%.125 Even after sequential treat-
Tel +1 416 535-8501 ments, 10% to 20% of the MDD patients remained significantly symptomatic for 2
Fax +1 416 583-1358
Email [email protected] years or longer.69,70 In general, it is accepted that although antidepressant medications

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16 221–234 221
DovePress © 2020 Voineskos et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/
http://doi.org/10.2147/NDT.S198774
terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing
the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Voineskos et al Dovepress

can be effective in treating MDD, they fail to achieve remis- should be regarding homogeneous biological subtypes or
sion in approximately 1 out of 3 patients.73 endophenotypes.23 However, the argument may be made that
Once 2 adequate antidepressant trials have been unsuc- lack of achieving remission may be classified as an inadequate
cessful, the illness is termed treatment-resistant depression response as residual depressive symptoms can significantly
(TRD).125 TRD can also be associated with prolonged, contribute to difficulty functioning. Chronically depressed
costly periods of inpatient treatment.140 Several definitions patients have a lower chance of recovery,98 and often suffer
and criteria have been proposed to identify true TRD, but from TRD.25,87
a consensus has not yet been agreed to. As such, TRD
presents its own challenges for therapeutic approaches and
Challenges in Assessing TRD
effective treatments. A meta-review of PubMed literature
One of the perils of diagnosing TRD is that of “pseudo-
was performed, recent meta-analyses and original studies resistance”.107 Pseudo-resistance may encompass the profile
were collated. The review was limited to studies. In this of patients who unfortunately were prescribed suboptimal
paper, we will attempt to provide a cohesive review of the doses of AD or had early discontinuation of a medication for
treatment approaches for TRD, as well as the challenges any number of reasons, including intolerable side effects,
unique to managing this illness. patient non-adherence or under-dosing. Further, comorbidities
such as anxiety disorders, personality disorders or substance-
Defining Treatment-Resistant use disorders may complicate the clinical picture and can have
Depression deleterious effects on treatment response.114,127 When inter-
Although many definitions for TRD have been proposed, the viewing patients in assessment of TRD, the potential for recall
general consensus appears to be 2 unsuccessful trials of anti- bias when reporting pharmacological trials and response adds
depressant pharmacotherapy (AD). Several “staging” models a significant layer of difficulty in diagnosing TRD.
to classify levels of treatment resistance have been proposed. Prospectively using objective clinical scales such as the
Hamilton Depression Rating Scale48 and the Inventory of
The initial model proposed by Thase and Rush138 included
Depressive Symptomatology124 and retrospectively using
treatment resistance levels ranging from one failed AD trial to
treatment history forms such as the Antidepressant
a lack of response to electroconvulsive therapy (ECT). Further
Treatment History Form (ATHF)127 can be very helpful in
staging models have included the Massachusetts General
delineating the nature and course of the treatment resistance.
Hospital Staging method117 which carefully documents the
Since the ATHF was initially developed, there have been
optimization of medication doses and number of failed med-
several developments in the treatment of MDD and specifi-
ications. The Souery Operational Criteria for TRD provide
cally TRD, some of which will be elaborated upon in the
a slightly different approach to staging TRD as an illness, by
ensuing sections of this paper. As such, the authors of the
defining TRD as any single failure of an adequate (6–8 week)
original ATHF127 developed an updated and revised version,
trial of an AD.133 The Maudsley Staging Method (MSM)
the short form ATHF (ATHF-SF), as well as an instruction
assesses treatment resistance in depression in a “multi-
manual and scoring checklist, among other documents.128
dimensional” manner.34 The majority of investigations into
Importantly, the ATHF-SF focuses on the current episode of
TRD utilize the definition of at least 2 suitable trials of AD
depression, as opposed to life-time trials of pharmacological
without adequate response, although even the term “adequate
treatments, a more streamlined approach to assessing the level
response” may be fraught with contention, as there is not
of resistance of the current illness episode. Utilizing
consensus on what constitutes “adequate.” In fact, even the
a standardized approach to understand the level of treatment
term TRD may not be the ideal term to define a depressive
resistance in the current episode of depression may provide
illness that is not responding to therapeutic interventions. The
a useful measure of consistency in assessment of TRD.
term “difficult-to-treat depression” has been suggested, with
the benefit of not introducing any “therapeutic nihilism” to the
psychiatrist–patient relationship.103 For consistency in this Therapeutic Options for TRD
manuscript, we will use the term TRD. There has been con- Traditional Pharmacological Approaches
siderable debate regarding what constitutes TRD, and whether Augmentation
medications from more than one class must be trialed prior to Augmentation or adjunctive therapy includes the addition of
meeting criteria for this classification, or that the focus a second medication, not usually considered an antidepressant

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

222
DovePress
Dovepress Voineskos et al

on its own, to a first-line pharmacotherapeutic option. Below, Second-Generation Antipsychotics

we have focused on the three main augmentation strategies In contrast to lithium and T3, second-generation antipsycho-
with strong evidence vs placebo augmentation in detail: tics (SGAs) have been investigated as adjunctive therapies in
lithium, T3 and second-generation antipsychotics.148 combination specifically with current first-line treatment
strategies (i.e. SSRIs and SNRIs). As SGAs are relatively
Lithium recently developed medications, it has been in the interest of
Lithium is a naturally occurring salt that was first used in pharma companies to investigate whether these medications
psychiatric treatment in the 1960s.146 The best evidence can be helpful to treat affective illnesses and therefore be
for augmenting antidepressant pharmacotherapy with approved to encompass a further class of disorders. This has
lithium comes from studies involving tricyclic antidepres- resulted in several large-scale placebo-controlled RCTs.
sants (TCAs).24 Less evidence exists for augmentation of SGAs are known to have some effect on serotonin receptors
and therefore may be effective in combination with SSRI/
current first-line antidepressant pharmacotherapy (from the
SNRIs in treating TRD. Specifically, quetiapine,8,31
selective serotonin reuptake inhibitor class). A study by
aripiprazole,12,13,88 olanzapine132 and risperidone68,86 have
Baumann et al9 demonstrated benefit to augmenting cita-
good evidence in the augmentation of ADs for TRD.
lopram with lithium, resulting in a 60% response rate in 24
Quetiapine at a dose of 300mg per day demonstrated up to
patients, compared to a 14% response rate in the placebo
48% response and 24.5% remission in combination with
arm. The STAR*D trial reported a 16% remission in the
SSRIs and has since been approved for adjunctive treatment
group of patients taking citalopram augmented by lithium.
of MDD by the FDA.8,31 Olanzapine was examined specifi-
However, in this large-scale study, lithium levels were kept
cally in combination with fluoxetine, with the combination
quite low, which may have contributed to the low-response
demonstrating 60% response in a sample of 28 patients with
rate.108 Large-scale guidelines, including from the
TRD.132
American Psychiatric Association (APA)3 and the World
Federation of Societies of Biological Psychiatry7 strongly
Optimizing, Combining and Switching Classes of
recommend lithium as an effective augmentation strategy
Antidepressant Pharmacotherapy
in MDD. In fact, a meta-analysis more recently compiled
Both the CANMAT and NICE guidelines for treating
compelling data that lithium is just as effective as the more
MDD have recommendations for how to best optimize
common second-generation antipsychotics prescribed for
pharmacotherapy when a patient presents with partial or
augmentation.104 Despite this evidence, and the anti-
no symptom response to an initial antidepressant trial. For
suicidal nature of lithium,22,47 it continues to be under-
brevity, we direct readers to these two documents.
utilized and under-prescribed.118
The majority of patients seeking pharmacotherapy for
MDD are initially started on selective serotonin reuptake
T3 inhibitors or serotonin-norepinephrine reuptake inhibitors
Thyroid hormone levels are known to have a significant effect as first-line treatments for MDD. Older classes of antidepres-
on mood. Triiodothyronine (T3) is usually the form of sant pharmacotherapy are reserved for trials of medication
thyroid hormone prescribed in augmentation of AD once SSRI/SNRI options have been exhausted. Importantly,
pharmacotherapy.5 This is in contrast to the treatment of there is little concrete evidence that switching to medication
hypothyroidism, as T3 is the hormone form which may have from the same antidepressant class is an effective strategy for
CNS activity. As with lithium, the initial T3 studies were MDD.112 However, several studies have reported that chan-
performed in augmentation of TCA pharmacotherapy.5,119 In ging classes of medication after non-response to the initial
the meta-analysis referenced here, the augmentation of TCA class of antidepressant pharmacotherapy significantly
with T3 had a number needed to treat of 4.3.5 In the augmenta- increases response rates. Thase et al139 and Peselow et al116
tion of SSRIs, open-label studies have shown some each examined switching from SSRI/SNRI medications to
promise.2,63,72 However, in the STAR*D trial, no statistically tricyclic antidepressants (TCAs), specifically imipramine,
significant superiority over augmentation with lithium was and reported response rates of 44–73% in total. Monoamine
discovered,108 with the T3 augmentation remission rate at Oxidase Inhibitors (MAOIs) include medications such as
24.7%. Importantly, however, T3 is generally better tolerated tranylcypromine, phenelzine and moclobemide. These are
than lithium and requires significantly less clinical monitoring. inhibitors of MAO-A and B enzymes and are very effective

submit your manuscript | www.dovepress.com

Neuropsychiatric Disease and Treatment 2020:16 223
DovePress
Voineskos et al Dovepress

antidepressants. The majority of studies examining efficacy (bilateral ECT). In ECT, repetitive electrical stimulation over
of switching to an MAOI were conducted by switch from the cortex results in an entrainment of pyramidal cell firing
a TCA,95,137 and demonstrated response rates of up to 60%. with the subsequent generalization of cortical activity and
One step of STAR*D compared tranylcypromine to production of a generalized, tonic-clonic seizure, which typi-
a combination of mirtazapine and venlafaxine in a group of cally self-terminates within 30–60 s.
patients who had not responded to three medication trials. In the treatment of TRD, ECT is applied 2–3 times per
Unfortunately, no significant difference was found in week and acute courses can range between 6–18 total
response between the two groups, with only 6.9% remission sessions. A report from the Consortium for Research in
in the tranylcypromine group, which also suffered from ECT (CORE)57 revealed that over half of the subjects
poorer tolerance of the MAOI.94 showed an improvement within the first week. Other stu-
dies have reported that over 50% of patients who have
Psychotherapy failed to respond to one or more adequate antidepressant
Psychotherapeutic approaches may be undertaken in com- medication trials respond to ECT.120 Meta-analyses have
bination with somatic or pharmacological treatments, or on shown that ECT is superior to sham ECT, placebo or
their own once several other interventions have been antidepressant medications.45,111
attempted. There appears to be a significant comorbidity Unfortunately, ECT has suffered from extensive stigma
of personality disorders with MDD, which then leads to in the public eye, likely due to the invasive nature of the
diminishing returns with respect to first line pharmacolo- treatment and largely due to subsequent negative and abu-
gical treatments.105,106,134 As such, psychotherapy may be sive portrayals in the media91 including in One flew over the
employed to address a comorbid diagnosis. A recent Cuckoo’s Nest, where ECT was portrayed as a punishment,
Cochrane review examined 6 studies of psychological delivered to an individual who did not have a psychotic or
interventions for TRD,59 including dialectical behavioural affective illness as a form of behavioural control. Along
therapy, cognitive behavioural therapy, interpersonal ther- with restriction to access due to availability and risk of
apy and intensive short-term dynamic psychotherapy. In memory side effects, this stigma has resulted in ECT
combination with usual care, psychotherapy overall con- being administered to an exceptionally small proportion of
tributed to an improvement in depressive symptoms, espe- individuals with MDD. In fact, a recent investigation of
cially when the psychotherapy employed was cognitive American health insurance databases identified that only
behavioural analysis system of psychotherapy (CBASP), 0.25% of almost 1 million patients with a mood disorder
cognitive behavioural therapy, interpersonal therapy or received ECT.142 This gross underutilization of ECT per-
mindfulness-based cognitive therapy.141 Interestingly, cog- sists, despite significant progress in reducing the cognitive
nitive behavioural therapy appeared to have good effects side effect profile and alterations in the method of ECT,
in the “medium” and “long term” ranges (12 and 46 including seizure threshold titration, inclusion of highly
months, respectively) after the acute treatment phase in tolerable anaesthetic agents and improvements in peri-
terms of lower depression scores. procedural care. In 2001, however, the American
Psychiatric Association published guidelines4 advising
Brain Stimulation that ECT should be used more frequently than just in “last
There are multiple modalities of somatic or brain stimula- resort” scenarios in severe medication-resistant patients or
tion therapies which have been investigated and applied in where the psychiatric condition is “life-threatening.”
the treatment of TRD and are not first line but are turned to ECT remains the most effective option to treat TRD,
once several trials of pharmacotherapy and/or psychoso- especially in situations where a patient’s life may be at
cial therapies have been ineffective. risk.149,45 ECT was initially thought to be the most effec-
tive in what was previously termed “melancholic depres-
Electroconvulsive Therapy sion”, but evidence has demonstrated that a depressive
ECT is the established best therapeutic option for TRD, but episode with catatonic or psychotic symptoms has
its neurophysiological mechanism of action is yet to be a greater likelihood of responding to a course of ECT.113
elucidated.66,126 ECT is delivered as a series of high fre- There are several different forms of ECT which have
quency electrical pulses to either the non-dominant right different response rates and side effect profiles in TRD.
hemisphere and vertex (i.e., unilateral ECT) or bitemporally Bitemporal Standard pulse ECT is the most commonly

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

224
DovePress
Dovepress Voineskos et al

used form,76 with a response rate of up to 75%. While the (RCT) and minor adverse effects were no different in the
response rate for Right Unilateral Ultrabrief ECT is active vs sham arms of the trial. The remission rate was
slightly lower, it remains highly effective. A report by likely low as patients had fewer stimulus trains and fewer
the CORE Group57 found that 65% of patients who under- days of treatment. In 2014, Berlim et al reported response
went bilateral ECT 3 times per week achieved remission rates of 29.3% in 1371 TRD patients,149 almost double the
by the tenth treatment. In the entire sample, 75% of 16.8% response rates seen with antidepressant medications
patients achieved remission by the end of the course, beyond the third sequential trial.125 A systematic review
reinforcing the impressive efficacy rate of ECT. and meta-analysis published in the Journal of Clinical
Psychiatry relatively recently, reported that rTMS was 5
Repetitive Transcranial Magnetic times more likely to help TRD patients achieve remission
Stimulation than placebo (“sham”) TMS.40 Moreover, rTMS has an
rTMS is a relatively recently developed form of brain adverse effect discontinuation rate of only 4.5% in stark
stimulation targeting TRD, among other psychiatric diag- contrast to the 25.1% discontinuation rate for antidepres-
noses. Focused pulses of an electromagnetic coil are repe- sant medication.21,64
titively discharged over the scalp to stimulate cortical
neurons and alter neural excitability without a seizure. Deep rTMS
Stimulation is applied non-invasively, on the scalp and A second approach with rTMS is to apply the stimulus
usually targeted over the DLPFC using a handheld mag- with rTMS coils of different designs, which allow pulses
netic coil. rTMS has been approved as a treatment for to target areas deeper into the cortex.29 These coil designs
TRD by Health Canada (2002), the US FDA (2008), and may include double-cone coils,81 Hesel-coils (H-coils)123
equivalent agencies in the European Union, Australia and and halo coils.130 Early research into these alternate coil
Israel. The efficacy of rTMS has been established in sev- designs and configurations determined that by increasing
eral dozen randomized controlled trials of thousands of the strength and depth of the stimulus in the cortex, there
patients over the past 20 years and affirmed in several was a reciprocal relationship with focality of the
large meta-analyses. stimulus.28 That is, the potential of the coil to target
rTMS was initially tested in healthy volunteers, who structures further from the cortical surface is accompanied
demonstrated moderate mood improvements44,115 after by a broader area of stimulus. Deep TMS devices were
application over the left DLPFC. Interestingly, in the approved by the FDA beginning in 2013 (the H1-coil) in
initial studies applying treatment to patients with MDD, the treatment of depression, based largely on a study by
rTMS was applied over the vertex, not the DLPFC. In two Levkovitz et al.77 In this study of 212 patients with MDD,
patients with MDD, Hoflich et al only found small the remission rate with deep TMS was 32.6%, compared
improvements to mood, although this was likely due to to 14.6% with sham rTMS. Deep TMS has been shown to
very low frequency of stimulation (0.3Hz) over the vertex be relatively well tolerated, especially in late-life
and comparatively few number of stimuli.50 Using focal, populations.65 Thus, deep TMS is emerging as a further
high-frequency TMS, George and colleagues found strik- therapeutic rTMS option in TRD.
ingly beneficial effects of rTMS to the left prefrontal
cortex in four of six patients with TRD;43 in one of these Theta-Burst Stimulation
patients, the beneficial effects of rTMS were associated Theta-burst stimulation (TBS) is a recently developed form
with normalisation of prefrontal hypometabolism, as of rTMS that appears to more closely target and induce
shown by positron emission tomography. cortical plasticity than conventional rTMS by approximat-
ing the endogenous theta frequency emitted by the brain.136
Conventional High Frequency Left DLPFC rTMS Bursts of 3 stimuli are delivered at a frequency of 50Hz, 5
The first large clinical trials for rTMS in MDD were times per second. TBS can be delivered in either an inter-
published in 2007110 and subsequently in 2010.42 mittent (2 s of stimuli then 8 s off for a 10-s train) or
This second study produced a 14.1% remission rate in continuous pattern. Intermittent TBS (iTBS) is delivered
the blinded study and approximately 30% remission rate in this 10-s train manner for 190 s (just over 3 mins),
in the follow-up open-label trial. Importantly, the retention consisting of a total of 600 pulses. Several small trials
rate was 88% overall in the randomized controlled trial initially indicated that iTBS had the potential to be effective

submit your manuscript | www.dovepress.com

Neuropsychiatric Disease and Treatment 2020:16 225
DovePress
Voineskos et al Dovepress

in TRD.19,53,78 These studies prompted a large-scale non- ultra-accelerated rTMS in severely treatment refractory
inferiority RCT directly comparing iTBS with conventional patients who would greatly benefit from rapid response
10Hz rTMS.14 In this trial, 414 patients were randomized to to treatment.
either 10Hz rTMS or iTBS and the efficacy of iTBS was As there are several forms of rTMS and numerous
found to be noninferior to conventional rTMS. Importantly, approaches attempting to maximize response, it can be
tolerability was high in both arms and pain/discomfort challenging to keep track of the best rTMS approach for
scores were similar in each treatment arm. This trial, the patients with TRD. Brunoni et al15 examined data regarding
largest brain stimulation trial to date, prompted the FDA to the bulk of the existing rTMS therapies available with
approve iTBS as a novel treatment for TRD. respect to efficacy and tolerability with the goal of estab-
lishing a treatment hierarchy. This novel analysis of 81
Accelerated rTMS Protocols rTMS studies examined 8 different rTMS approaches and
As daily rTMS is quite well tolerated but requires several compared them with sham rTMS. All rTMS interventions
days to weeks of treatment to induce symptom response, were well tolerated, in a similar manner to sham. High
newer protocols of multiple treatment sessions per day frequency, low frequency, bilateral rTMS and TBS were
have been proposed, especially in TRD patients who all found to be superior to sham stimulation in terms of
require urgent response, such as those with acute and response. The analysis suffered from small sample sizes of
severe suicidal ideation. Accelerated treatment schedules several investigatory trials and called for new, large-scale,
have been proposed for both conventional rTMS and TBS high quality randomized controlled trials to further categor-
treatment paradigms. ize rTMS paradigms by efficacy. The evidence, therefore,
Neurophysiological evidence supporting these propo- reinforces that rTMS is an effective and well-tolerated
sals demonstrates higher levels of neuroplasticity and cor- therapeutic option for TRD, but more evidence is needed
tical excitability with multiple rTMS sessions in one day.85 to create a clear hierarchy of rTMS approaches.
The question of a dose–response relationship has also been
posed.41 Several open-label trials of differing accelerated Magnetic Seizure Therapy
rTMS schedules have been conducted and all found In magnetic seizure therapy (MST), a powerful repetitively
improved remission and response rates, when compared discharged magnet induces focal synchronous activity in
to once daily rTMS6,51,93 including response rates of up to the targeted cortical region which then spreads, resulting
56%.93 More recently, Fitzgerald et al36 directly compared in a generalized seizure in a similar procedure to ECT.56 It is
accelerated rTMS to standard rTMS in a randomized con- focally discharged over the prefrontal cortex and evidence
trol trial of 115 patients and found no discernible differ- shows significantly fewer cognitive side effects with MST.
ence in either response or remission rates between the two As the magnetic field passes freely through the scalp and
groups. In this study, patients in the accelerated treatment skull to discharge cortical neurons, there is no shunting of
arm received 3 treatments per day over 3 days in the first energy toward subcortical structures,80 thus sparing the
week, 3 treatments per day over 2 days in the second week memory centres of the brain. As with ECT, several treat-
and a single day of 3 treatments in the final, third week, ments are necessary to result in significant mood symptom
which was compared to daily treatment (5 days per week) improvement. Few clinical trials have yet to be reported
for 4 weeks in the standard rTMS arm. There were, how- regarding the efficacy of MST when compared to other
ever, higher rates of treatment discomfort in the acceler- therapeutic options for TRD, but those published consis-
ated arm, and this contributed to slightly higher rates of tently demonstrate a clear antidepressant effect with fewer
treatment discontinuation in this arm. Most recently, cognitive or memory side effects. A study by Kayser et al67
Williams et al143 examined the effects of multiple iTBS reported a 69% response rate in 26 patients with TRD,
treatments per day in a small sample of patients who did comparable to ECT response rates. Comparably, an earlier
not previously respond to a full course of rTMS and an pilot study of 13 patients37 reported a response rate of 38%
acute course of ECT. Specifically, patients received 10 and remission rate of 15%. It should be noted that these
sessions of iTBS each day for 5 days, a total of 90,000 studies utilized lower powered MST devices and newer
pulses. Interestingly, the treatment was well tolerated and devices have been developed with higher power capacity,
4 out of the 6 patients achieved remission at the final comparable to high-dose ECT. The majority of these early
session. This intensive study makes an excellent case for studies of MST applied stimulation to the vertex of the

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

226
DovePress
Dovepress Voineskos et al

skull. A recent paper by Daskalakis et al27 reported an open- long-term therapy for TRD, specifically in patients who have
label trial applying MST to the prefrontal cortex, with 3 not responded to 4 or more different medications.17
different study arms – each arm applied a different MST Interestingly, there appears to be a bimodal distribution
frequency, ranging from 25–100Hz. This larger scale trial with respect to the timing of response. A portion of VNS
analysed outcomes for 86 patients with moderately resistant patients respond “acutely,” whereas for others, the main
TRD, as assessed by the ATHF. The high-frequency MST effects appear to emerge after approximately 3 months of
resulted in the highest remission rates in patients who treatment.17
underwent at least 8 treatments (33.3%), although this In summary, there are several modalities of brain stimu-
jumped significantly in patients who completed the full lation which have proven effective in TRD. A large meta-
MST treatment protocol (to 60%). Cognitive scores analysis of non-surgical brain stimulation in TRD reported
remained unaffected, aside from autobiographical memory on studies of different electrode placements in ECT, several
scores, which would be expected to decrease over time.92 types of rTMS and transcranial direct current stimulation
The results of this open-label trial27 appear promising and (tDCS).100 Over 6000 patients underwent one of these brain
comparable to ECT, opening the door for further careful stimulation treatments, despite many trials being of small
direct comparison with ECT and possibly a new favourable sample size. As expected, evidence lent itself to ECT, high
brain stimulation option for TRD. frequency left and low-frequency right rTMS, with less
evidence for the more recently developed forms of brain
Deep Brain Stimulation stimulation. As with the majority of studies in brain stimu-
In DBS, a permanent neurosurgical implant is placed in the lation, the bulk of evidence supporting the efficacy of these
brain, with a specific target to activate or silence. The implant treatments was assessed by depression scores at the end of
is connected to a pulse generator in the chest wall that is the acute course of treatment, with few strategies reported to
externally controlled to repetitively stimulate the target describe continuation treatment or prevention of relapse.
area.83 Several regions have been investigated as targets in Overall, ECT has the best evidence in the literature to
TRD, namely the nucleus accumbens, ventral capsule and enter a maintenance or continuation phase of therapy, with
striatum, and the subgenual cingulate cortex (SCC). In small 84% of individuals who have remitted with ECT relapsing
studies, each area has demonstrated promise, and the single within 6 months if no further treatment (ECT or pharma-
high dose study targeting the SCC reported a 92% response cotherapy) ensued.129 In the PRIDE Study,71 patients were
rate at 2 years post-implantation in a TRD sample.52 Earlier randomized to a pharmacotherapeutic arm or a combination
studies of DBS applied to the SCC report variable response of continuation ECT with pharmacotherapy, with relapse
rates over several months that appear to improve over time, rates of 20.3% and 13.1%, respectively at the 6-month
ranging from 29% to 75%.74,82,90 mark. There is some emerging evidence for a maintenance
course of rTMS after effective acute treatment, although
Vagus Nerve Stimulation this has largely been limited to open-label studies.10,35,109
Vagus nerve stimulation (VNS) is proposed to modulate Large scale, clear data on how best to prevent relapse with
brain activity via stimulation of the tenth cranial nerve, the rTMS is urgently needed in the field.
vagus nerve. It is believed that the stimulation of this cranial
nerve alters various networks of the brain in order to treat
psychiatric disease. All VNS systems have required surgical Novel Therapeutics
implantation until recently, with the development of transcu- Ketamine
taneal systems, which are not yet FDA approved for Ketamine is a widely investigated N-methyl-D-aspartate
TRD20,54 The implanted VNS system consists a pulse gen- (NDMA) antagonist as a potential therapeutic option for
erator, inserted underneath the skin of the chest. This is then TRD and is considered a rapid acting antidepressant
connected to an electrode attached to the left vagus nerve in (RAADs). More recent evidence purports that ketamine’s
the neck; together this system delivers pulsed electrical sig- antidepressant effects are at least in part due to action
nals to the vagus nerve. A separate device programs the pulse on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
generator stimulation parameters and the implanted device (AMPA) receptors downstream from the initial NMDAR
can be temporarily deactivated by holding a magnet over the effects.147 Although initially investigated as a psychomime
pulse generator. The FDA approved VNS as an adjunctive tic substance,75 the antidepressant effect of ketamine was

submit your manuscript | www.dovepress.com

Neuropsychiatric Disease and Treatment 2020:16 227
DovePress
Voineskos et al Dovepress

quickly recognized after a low dose intravenous infusion.11 responded to infusions of infliximab and their CRP levels
Interestingly, the antidepressant effects were not thought to dropped post-treatment in a corresponding manner,
be due to intoxication but were noted around 3 hrs after the whereas patients without elevated inflammatory markers
IV infusion had been discontinued and appeared to continue did not seem to fall into the responder category. The
over several days. This rapid response was reinforced by neurosteroid brexanolone, an intravenous formation of
several randomized blinded and open-label studies and allopregnanolone which acts by enhancing GABAergic
included a significant reduction in suicidal ideation in TRD inhibition, was FDA approved this year for the treatment
patients.1,58,89,99 On average, the effects of ketamine appear of post-partum depression.144 By allosterically enhancing
to come on rapidly and last approximately 5–7 days145 with GABAA receptor function, the antidepressant activity of
a preferential treatment effect in individuals with comorbid allopregnanolone is attributed to an increase in
anxiety or an “anxious depression”.60,61 More recently, an GABAergic inhibition.97,102 Taken together, these results
intranasal form of esketamine (a ketamine enantiomer) has suggest that anti-inflammatory therapy may have a novel
been developed, which has shown good effect with continued role in treating TRD patients, but largely only in those who
treatment in combination with an oral antidepressant26 and demonstrate markers of inflammation.
has now been approved by the FDA for restricted use
in TRD.
Novel Therapeutic Compounds and
Psilocybin Rapid Acting Antidepressants
Psilocybin is the psychedelic compound isolated from hal- As further investigations into MDD and specifically TRD
lucinogenic mushrooms. It is metabolized by the body into result in the clarification of the disorder’s pathophysiology,
psilocin, which is a partial serotonin receptor agonist. The the development of novel therapeutic compounds has begun
majority of research into this compound has been limited to to emerge. These include, but are not limited to, modulators
small, open label or pilot trials of patients with TRD. In of other central neurotransmitters, such as opioid modula-
a group of 12 patients with TRD, a feasibility study of high- tors, cholinergic modulators and γ-aminobutyric acid
dose psilocybin demonstrated response rates of 58% up to 3 (GABA) modulators. Of particular interest as medications
months after 2 doses of psilocybin, an initial low dose to are RAADs, of which ketamine is the most widely accepted.
assess safety and a subsequent high dose (25mg) one week Novel compounds are now being developed or existing
later, despite the psychedelic effects lasting approximately compounds re-examined in this light. In recent years, atten-
6 hrs.16 In this study the substance was relatively well tion has turned to the endogenous opioid system as one of
tolerated, although transient anxiety was frequently experi- interest in TRD, particularly when comorbid with anxiety
enced, as was mild tachycardia. symptoms, as happens relatively frequently, with a negative
impact on treatment response.62 Novel compounds target-
Anti-Inflammatories ing the delta opioid receptor have shown promise in small
Inflammation is increasingly thought to play a role in initial drug development trials.122 Existing medications
TRD, as elevated C-reactive protein and cytokines appear such as buprenorphine have been combined with other
to be elevated in patients with MDD and specifically compounds to better target the mu and kappa opioid recep-
TRD.18,55,135 Cyclooxygenase-2 inhibitors (COX-2 inhibi- tors in the hopes of achieving an antidepressant response.
tors) were initially the focus of anti-inflammatory research These novel combination compounds were deemed toler-
in TRD and were investigated as augmentation options for able and did not result in opioid withdrawal or tolerance and
traditional antidepressant pharmacotherapy.32,101 COX-2 induced a moderate antidepressant effect,33 showing most
inhibitors are known to block prostaglandin production, promise as an adjunctive therapy. Evidence of hypercholi-
which appears to be elevated in blood samples of some nergic states in MDD39 has also guided research towards the
patients with TRD.79 More recently, a tumour necrosis development and examination of anticholinergic com-
factor (TNF) antagonist, infliximab, has been investigated pounds, such as the repurposing of scopolamine, an anti-
specifically in TRD patients with elevated plasma CRP muscarinic medication. In a sample of patients with MDD,
levels, compared to TRD patients without elevated periph- an initial intravenous infusion of scopolamine resulted in
eral inflammatory markers.121 The depressive symptoms significantly reduced depression and anxiety symptoms
of patients with elevated CRP levels preferentially within a few days, when compared to placebo.30 The

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

228
DovePress
Dovepress Voineskos et al

GABA system has been of particular interest in the field of recent depressive episode. With further understanding of
TRD research as it has downstream effects on the seroto- the pathophysiology of TRD, patterns of response and
nergic and noradrenergic systems84 and there is evidence of how these differ from MDD, we, as treating physicians,
reduced GABA levels in patients with MDD.49,131 may be able to save patients the time, frustration and
A recently developed positive allosteric GABAA receptor hopelessness that accompanies numerous failed treatment
modulator, SAGE-217, was investigated in a multi-site trial trials.
of 89 patients with MDD for its potentially acute antide-
pressant effects.46 On the 15th day of medication adminis-
Disclosure
tration, of the 45 patients in the active drug arm, 79% met
Dr. Zafiris J Daskalakis reports grants from Magventure
response criteria (>50% reduction in Hamilton Rating Scale
Inc. and grants from Brainsway Inc., during the conduct of
for Depression scores), whereas 41% met response criteria
the study. The authors report no other conflicts of interest
in the placebo arm. These novel therapeutics all show
in this work.
promise in effectively treating TRD and warrant further
investigation and comparison to existing efficacious TRD
therapies. References
1. Aan Het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy
of repeated-dose intravenous ketamine for treatment-resistant
Conclusions depression. Biol Psychiatry. 2010;67(2):139–145. doi:10.1016/j.
There are several challenges which accompany the treat- biopsych.2009.08.038
ment of TRD, not the least of which is the relatively large 2. Abraham G, Milev R, Stuart Lawson J. T3 augmentation of SSRI
resistant depression. J Affect Disord. 2006;91(2–3):211–215.
proportion of patients with MDD who may be classified doi:10.1016/j.jad.2006.01.013
as having TRD. While several approaches, both tradi- 3. APA. Practice guideline for the treatment of patients with major
depressive disorder. Available from: https://psychiatryonline.org/
tional and novel, have been developed as described pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf.
above, further work is necessary to understand the TRD Accessed January 8, 2020.
as an illness to adequately treat TRD and notably, to 4. APA Committee on Electroconvulsive Therapy. The Practice of
Electroconvulsive Therapy: Recommendations for Treatment,
ensure sustained response or continued remission. Training and Privileging: A Task Force Report of the American
Several guidelines outlining the treatment of MDD may Psychiatric Association; 2001; APA.
5. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine
help to direct practitioners in a logical, step-wise augmentation in the treatment of refractory depression. A
approach (CANMAT, APA, NICE), however, specific meta-analysis. Arch Gen Psychiatry. 1996;53(9):842–848.
doi:10.1001/archpsyc.1996.01830090090013
guidelines for TRD have not been widely accepted to
6. Baeken C, Vanderhasselt MA, Remue J, et al. Intensive HF-rTMS
our knowledge and is certainly out of the scope of treatment in refractory medication-resistant unipolar depressed
a review such as this. A logical approach would likely patients. J Affect Disord. 2013;151(2):625–631. doi:10.1016/j.
jad.2013.07.008
include beginning with the least invasive and intensive 7. Bauer M, Pfennig A, Severus E, Whybrow PC, Angst J,
interventions which have the most evidence for efficacy Moller HJ, D. World Federation of Societies of Biological
Psychiatry. Task Force on Unipolar Depressive. World
in TRD. Particular promise may be emerging with the
Federation of Societies of Biological Psychiatry (WFSBP) guide-
newer acute treatments that have recently been approved lines for biological treatment of unipolar depressive disorders,
by the FDA to specifically treat TRD (iTBS and intranasal part 1: update 2013 on the acute and continuation treatment of
unipolar depressive disorders. World J Biol Psychiatry. 2013;14
esketamine). However, large multi-centre trials are still (5):334–385. doi:10.3109/15622975.2013.804195
necessary to examine the overarching patterns of TRD 8. Bauer M, Pretorius HW, Constant EL, Earley WR, Szamosi J,
illness and treatment response as a whole. Moreover, Brecher M. Extended-release quetiapine as adjunct to an antide-
pressant in patients with major depressive disorder: results of
despite several guidelines touching on recommendations a randomized, placebo-controlled, double-blind study. J Clin
for maintaining response or remission from MDD with Psychiatry. 2009;70(4):540–549. doi:10.4088/JCP.08m04629
9. Baumann P, Nil R, Souche A, et al. A double-blind,
effective treatment, aside from continuation strategies placebo-controlled study of citalopram with and without lithium
with ECT, there is little known about maintaining remis- in the treatment of therapy-resistant depressive patients: a clinical,
pharmacokinetic, and pharmacogenetic investigation. J Clin
sion from TRD. In a recent editorial in JAMA Psychiatry,
Psychopharmacol. 1996;16(4):307–314. doi:10.1097/00004714-
Dr. M. Freeman addresses this specific topic, with recom- 199608000-00006
mendations to individualize maintenance interventions.38 10. Benadhira R, Thomas F, Bouaziz N, et al. A randomized,
sham-controlled study of maintenance rTMS for treatment-resistant
That is, the importance of continuing with the treatment depression (TRD). Psychiatry Res. 2017;258:226–233. doi:10.1016/j.
that helped the patient reach remission from the most psychres.2017.08.029

submit your manuscript | www.dovepress.com

Neuropsychiatric Disease and Treatment 2020:16 229
DovePress
Voineskos et al Dovepress

11. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects 26. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of
of ketamine in depressed patients. Biol Psychiatry. 2000;47 intranasal esketamine adjunctive to oral antidepressant therapy in
(4):351–354. doi:10.1016/S0006-3223(99)00230-9 treatment-resistant depression: a randomized clinical trial. JAMA
12. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of Psychiatry. 2018;75(2):139–148. doi:10.1001/jamapsychiatry.
aripiprazole as adjunctive therapy in major depressive disorder: 2017.3739
a multicenter, randomized, double-blind, placebo-controlled study. 27. Daskalakis ZJ, Dimitrova J, McClintock SM, et al. Magnetic
J Clin Psychiatry. 2007;68(6):843–853. doi:10.4088/JCP.v68 seizure therapy (MST) for major depressive disorder.
n0604 Neuropsychopharmacology. 2019;45(2):276–282.
13. Berman RM, Thase ME, Trivedi MH, et al. Long-term safety 28. Deng ZD, Lisanby SH, Peterchev AV. Electric field depth-focality
and tolerability of open-label aripiprazole augmentation of tradeoff in transcranial magnetic stimulation: simulation compar-
antidepressant therapy in major depressive disorder. ison of 50 coil designs. Brain Stimul. 2013;6(1):1–13.
Neuropsychiatr Dis Treat. 2011;7:303–312. doi:10.2147/NDT. doi:10.1016/j.brs.2012.02.005
S18333 29. Deng ZD, Lisanby SH, Peterchev AV. Coil design considerations
14. Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. for deep transcranial magnetic stimulation. Clin Neurophysiol.
Effectiveness of theta burst versus high-frequency repetitive tran- 2014;125(6):1202–1212. doi:10.1016/j.clinph.2013.11.038
scranial magnetic stimulation in patients with depression 30. Drevets WC, Furey ML. Replication of scopolamine’s antidepres-
(THREE-D): a randomised non-inferiority trial. Lancet. sant efficacy in major depressive disorder: a randomized, placebo-
2018;391(10131):1683–1692. doi:10.1016/S0140-6736(18) controlled clinical trial. Biol Psychiatry. 2010;67(5):432–438.
30295-2 doi:10.1016/j.biopsych.2009.11.021
15. Brunoni AR, Chaimani A, Moffa AH, et al. Repetitive transcranial 31. El-Khalili N, Joyce M, Atkinson S, et al. Extended-release que-
magnetic stimulation for the acute treatment of major depressive tiapine fumarate (quetiapine XR) as adjunctive therapy in major
episodes: a systematic review with network meta-analysis. JAMA depressive disorder (MDD) in patients with an inadequate
Psychiatry. 2017;74(2):143–152. doi:10.1001/jamapsychiatry.2016. response to ongoing antidepressant treatment: a multicentre, ran-
3644 domized, double-blind, placebo-controlled study. Int J
16. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with Neuropsychopharmacol. 2010;13(7):917–932. doi:10.1017/
psychological support for treatment-resistant depression: an S1461145710000015
open-label feasibility study. Lancet Psychiatry. 2016;3 32. Faridhosseini F, Sadeghi R, Farid L, Pourgholami M. Celecoxib:
(7):619–627. doi:10.1016/S2215-0366(16)30065-7 a new augmentation strategy for depressive mood episodes.
17. Carreno FR, Frazer A. Vagal nerve stimulation for treatment-resistant A systematic review and meta-analysis of randomized
depression. Neurotherapeutics. 2017;14(3):716–727. doi:10.1007/ placebo-controlled trials. Hum Psychopharmacol. 2014;29
s13311-017-0537-8 (3):216–223. doi:10.1002/hup.v29.3
18. Cattaneo A, Ferrari C, Uher R, et al. Absolute measurements of 33. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with
macrophage migration inhibitory factor and interleukin-1-beta buprenorphine/samidorphan as adjunctive treatment for inade-
mRNA levels accurately predict treatment response in quate response to antidepressants: a randomized double-blind
depressed patients. Int J Neuropsychopharmacol. 2016;19(10): placebo-controlled trial. Am J Psychiatry. 2016;173(5):499–508.
pii: pyw045. doi:10.1176/appi.ajp.2015.15070921
19. Chistyakov AV, Rubicsek O, Kaplan B, Zaaroor M, Klein E. 34. Fekadu A, Wooderson S, Donaldson C, et al. A multidimensional
Safety, tolerability and preliminary evidence for antidepressant tool to quantify treatment resistance in depression: the Maudsley
efficacy of theta-burst transcranial magnetic stimulation in staging method. J Clin Psychiatry. 2009;70(2):177–184. doi:10.4
patients with major depression. Int J Neuropsychopharmacol. 088/JCP.08m04309
2010;13(3):387–393. doi:10.1017/S1461145710000027 35. Fitzgerald PB, Grace N, Hoy KE, Bailey M, Daskalakis ZJ. An
20. Cimpianu CL, Strube W, Falkai P, Palm U, Hasan A. Vagus nerve open label trial of clustered maintenance rTMS for patients with
stimulation in psychiatry: a systematic review of the available refractory depression. Brain Stimul. 2013;6(3):292–297.
evidence. J Neural Transm (Vienna). 2017;124(1):145–158. doi:10.1016/j.brs.2012.05.003
doi:10.1007/s00702-016-1642-2 36. Fitzgerald PB, Hoy KE, Elliot D, Susan McQueen RN,
21. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and Wambeek LE, Daskalakis ZJ. Accelerated repetitive transcranial
acceptability of 12 new-generation antidepressants: a magnetic stimulation in the treatment of depression.
multiple-treatments meta-analysis. Lancet. 2009;373 Neuropsychopharmacology. 2018;43(7):1565–1572. doi:10.1038/
(9665):746–758. doi:10.1016/S0140-6736(09)60046-5 s41386-018-0009-9
22. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the 37. Fitzgerald PB, Hoy KE, Herring SE, Clinton AM, Downey G,
prevention of suicide in mood disorders: updated systematic Daskalakis ZJ. Pilot study of the clinical and cognitive effects of
review and meta-analysis. BMJ. 2013;346:f3646. doi:10.1136/ high-frequency magnetic seizure therapy in major depressive
bmj.f3646 disorder. Depress Anxiety. 2013;30(2):129–136. doi:10.1002/
23. Conway CR, George MS, Sackeim HA. Defining treatment-resistant da.22005
depression-reply. JAMA Psychiatry. 2017;74(7):759. doi:10.1001/ 38. Freeman MP. Relapse prevention after recovery in patients with
jamapsychiatry.2017.0970 persistent major depressive disorder-an active pursuit. JAMA
24. Crossley NA, Bauer M. Acceleration and augmentation of Psychiatry. 2019. doi:10.1001/jamapsychiatry.2019.3637
antidepressants with lithium for depressive disorders: two 39. Furey ML, Drevets WC. Antidepressant efficacy of the antimus-
meta-analyses of randomized, placebo-controlled trials. carinic drug scopolamine: a randomized, placebo-controlled clin-
J Clin Psychiatry. 2007;68(6):935–940. doi:10.4088/JCP. ical trial. Arch Gen Psychiatry. 2006;63(10):1121–1129.
v68n0617 doi:10.1001/archpsyc.63.10.1121
25. Crown WH, Finkelstein S, Berndt ER, et al. The impact of 40. Gaynes BN, Lloyd SW, Lux L, et al. Repetitive transcranial
treatment-resistant depression on health care utilization and magnetic stimulation for treatment-resistant depression:
costs. J Clin Psychiatry. 2002;63(11):963–971. doi:10.4088/JCP. a systematic review and meta-analysis.”. J Clin Psychiatry.
v63n1102 2014;75(5):477–489. doi:10.4088/JCP.13r08815

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

230
DovePress
Dovepress Voineskos et al

41. George MS. Transcranial magnetic stimulation for the treatment 59. Ijaz S, Davies P, Williams CJ, Kessler D, Lewis G, Wiles N.
of depression. Expert Rev Neurother. 2010;10(11):1761–1772. Psychological therapies for treatment-resistant depression in
doi:10.1586/ern.10.95 adults.”. Cochrane Database Syst Rev. 2018;5:CD010558.
42. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal 60. Ionescu DF, Luckenbaugh DA, Niciu MJ, et al. Effect of baseline
transcranial magnetic stimulation therapy for major depressive anxious depression on initial and sustained antidepressant
disorder: a sham-controlled randomized trial. Arch Gen response to ketamine. J Clin Psychiatry. 2014;75(9):e932–e938.
Psychiatry. 2010;67(5):507–516. doi:10.1001/archgenpsychiatry. doi:10.4088/JCP.14m09049
2010.46 61. Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM,
43. George MS, Wassermann EM, Williams WA, et al. Daily repeti- Zarate CA Jr. A single infusion of ketamine improves depression
tive transcranial magnetic stimulation (rTMS) improves mood in scores in patients with anxious bipolar depression. Bipolar
depression. Neuroreport. 1995;6(14):1853–1856. doi:10.1097/ Disord. 2015;17(4):438–443. doi:10.1111/bdi.2015.17.issue-4
00001756-199510020-00008 62. Ionescu DF, Niciu MJ, Richards EM, Zarate CA Jr.
44. George MS, Wassermann EM, Williams WA, et al. Changes in Pharmacologic treatment of dimensional anxious depression: a
mood and hormone levels after rapid-rate transcranial magnetic review. Prim Care Companion CNS Disord. 2014;16(3).
stimulation (rTMS) of the prefrontal cortex. J Neuropsychiatry 63. Iosifescu DV, Nierenberg AA, Mischoulon D, et al. An open
Clin Neurosci. 1996;8(2):172–180. study of triiodothyronine augmentation of selective serotonin
45. Group UER. Efficacy and safety of electroconvulsive therapy in reuptake inhibitors in treatment-resistant major depressive
depressive disorders: a systematic review and meta-analysis. disorder. J Clin Psychiatry. 2005;66(8):1038–1042. doi:10.4088/
Lancet. 2003;361(9360):799–808. JCP.v66n0812
46. Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in 64. Janicak PG, O’Reardon JP, Sampson SM, et al. Transcranial
patients with major depressive disorder. N Engl J Med. 2019;381 magnetic stimulation in the treatment of major depressive disor-
(10):903–911. doi:10.1056/NEJMoa1815981 der: a comprehensive summary of safety experience from acute
47. Guzzetta F, Tondo L, Centorrino F, Baldessarini RJ. Lithium exposure, extended exposure, and during reintroduction
treatment reduces suicide risk in recurrent major depressive treatment. J Clin Psychiatry. 2008;69(2):222–232. doi:10.4088/
disorder. J Clin Psychiatry. 2007;68(3):380–383. doi:10.4088/ JCP.v69n0208
JCP.v68n0304 65. Kaster TS, Daskalakis ZJ, Noda Y, et al. Efficacy, tolerability, and
48. Hamilton M. A rating scale for depression. J Neurol Neurosurg cognitive effects of deep transcranial magnetic stimulation for
Psychiatry. 1960;23:56–62. doi:10.1136/jnnp.23.1.56 late-life depression: a prospective randomized controlled trial.
49. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J,
Neuropsychopharmacology. 2018;43(11):2231–2238. doi:10.103
Drevets WC. Reduced prefrontal glutamate/glutamine and
8/s41386-018-0121-x
gamma-aminobutyric acid levels in major depression determined
66. Kato N. Neurophysiological mechanisms of electroconvulsive
using proton magnetic resonance spectroscopy. Arch Gen
therapy for depression. Neurosci Res. 2009;64(1):3–11. doi:10.
Psychiatry. 2007;64(2):193–200. doi:10.1001/archpsyc.64.2.193
1016/j.neures.2009.01.014
50. Hoflich G, Kasper S, Hufnagel A, Ruhrmann S, Moller HJ.
67. Kayser S, Bewernick BH, Matusch A, Hurlemann R, Soehle M,
Application of transcranial magnetic stimulation in treatment of
Schlaepfer TE. Magnetic seizure therapy in treatment-resistant
drug-resistant major depression: a report of two cases. Human
depression: clinical, neuropsychological and metabolic effects.
Psychopharmacol. 1993;8(5):361–365. doi:10.1002/hup.470080
Psychol Med. 2015;45(5):1073–1092. doi:10.1017/S0033291714
510
002244
51. Holtzheimer PE 3rd, McDonald WM, Mufti M, et al. Accelerated
68. Keitner GI, Garlow SJ, Ryan CE, et al. A randomized,
repetitive transcranial magnetic stimulation for treatment-resistant
placebo-controlled trial of risperidone augmentation for patients
depression. Depress Anxiety. 2010;27(10):960–963. doi:10.1002/
with difficult-to-treat unipolar, non-psychotic major depression.
da.v27:10
J Psychiatr Res. 2009;43(3):205–214. doi:10.1016/j.jpsychires.
52. Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingu-
2008.05.003
late deep brain stimulation for treatment-resistant unipolar and
69. Keitner GI, Ryan CE, Solomon DA. Realistic expectations and
bipolar depression. Arch Gen Psychiatry. 2012;69(2):150–158.
a disease management model for depressed patients with persis-
doi:10.1001/archgenpsychiatry.2011.1456
tent symptoms. J Clin Psychiatry. 2006;67(9):1412–1421. doi:10.
53. Holzer M, Padberg F. Intermittent theta burst stimulation (iTBS)
ameliorates therapy-resistant depression: a case series. Brain 4088/JCP.v67n0912
70. Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major
Stimul. 2010;3(3):181–183. doi:10.1016/j.brs.2009.10.004
depressive disorder: analysis with the life table and regression
54. Howland RH. New developments with vagus nerve stimulation
therapy. J Psychosoc Nurs Ment Health Serv. 2014;52(3):11–14. models. Arch Gen Psychiatry. 1982;39(8):905–910. doi:10.1001/
55. Howren MB, Lamkin DM, Suls J. Associations of depression with archpsyc.1982.04290080025004
C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 71. Kellner CH, Husain MM, Knapp RG, et al. A novel strategy for
2009;71(2):171–186. doi:10.1097/PSY.0b013e3181907c1b continuation ECT in geriatric depression: phase 2 of the PRIDE
56. Hoy KE, Fitzgerald PB. Magnetic seizure therapy for study. Am J Psychiatry. 2016;173(11):1110–1118. doi:10.1176/
treatment-resistant depression. Expert Rev Med Devices. 2011;8 appi.ajp.2016.16010118
(6):723–732. doi:10.1586/erd.11.55 72. Kelly TF, Lieberman DZ. Long term augmentation with T3 in
57. Husain MM, Rush AJ, Fink M, et al. Speed of response and remis- refractory major depression. J Affect Disord. 2009;115(1–-
sion in major depressive disorder with acute electroconvulsive ther- 2):230–233. doi:10.1016/j.jad.2008.09.022
apy (ECT): a Consortium for Research in ECT (CORE) report. 73. Kennedy SH, Giacobbe P. Treatment resistant depression–
J Clin Psychiatry. 2004;65(4):485–491. doi:10.4088/JCP.v65n0406 advances in somatic therapies. Ann Clin Psychiatry. 2007;19
58. Ibrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid (4):279–287. doi:10.1080/10401230701675222
decrease in depressive symptoms with an N-methyl-d-aspartate 74. Kennedy SH, Giacobbe P, Rizvi SJ, et al. Deep brain stimulation for
antagonist in ECT-resistant major depression. Prog treatment-resistant depression: follow-up after 3 to 6 years. Am
Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1155–1159. J Psychiatry. 2011;168(5):502–510. doi:10.1176/appi.ajp.2010.10
doi:10.1016/j.pnpbp.2011.03.019 081187

submit your manuscript | www.dovepress.com

Neuropsychiatric Disease and Treatment 2020:16 231
DovePress
Voineskos et al Dovepress

75. Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of 93. McGirr A, Van den Eynde F, Tovar-Perdomo S, Fleck MP,
the noncompetitive NMDA antagonist, ketamine, in humans. Berlim MT. Effectiveness and acceptability of accelerated repetitive
Psychotomimetic, perceptual, cognitive, and neuroendocrine transcranial magnetic stimulation (rTMS) for treatment-resistant
responses. Arch Gen Psychiatry. 1994;51(3):199–214. major depressive disorder: an open label trial. J Affect Disord.
doi:10.1001/archpsyc.1994.03950030035004 2015;173:216–220. doi:10.1016/j.jad.2014.10.068
76. Leiknes KA, Jarosh-von Schweder L, Hoie B. Contemporary use 94. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus
and practice of electroconvulsive therapy worldwide. Brain venlafaxine plus mirtazapine following three failed antidepressant
Behav. 2012;2(3):283–344. doi:10.1002/brb3.37 medication trials for depression: a STAR*D report. Am
77. Levkovitz Y, Isserles M, Padberg F, et al. Efficacy and safety of J Psychiatry. 2006;163(9):1531–1541. doi:10.1176/ajp.2006.16
deep transcranial magnetic stimulation for major depression: 3.9.1531
a prospective multicenter randomized controlled trial. World 95. McGrath PJ, Stewart JW, Harrison W, Quitkin FM. Treatment of
Psychiatry. 2015;14(1):64–73. doi:10.1002/wps.20199 tricyclic refractory depression with a monoamine oxidase inhibi-
78. Li CT, Chen MH, Juan CH, et al. Efficacy of prefrontal tor antidepressant. Psychopharmacol Bull. 1987;23(1):169–172.
theta-burst stimulation in refractory depression: a randomized 96. McLachlan G. Treatment resistant depression: what are the
sham-controlled study. Brain. 2014;137(Pt 7):2088–2098. options? BMJ. 2018;363:k5354. doi:10.1136/bmj.k5354
doi:10.1093/brain/awu109 97. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al.
79. Lieb J, Karmali R, Horrobin D. Elevated levels of prostaglandin Brexanolone injection in post-partum depression: two multicen-
E2 and thromboxane B2 in depression. Prostaglandins Leukot tre, double-blind, randomised, placebo-controlled, Phase 3 trials.
Med. 1983;10(4):361–367. doi:10.1016/0262-1746(83)90048-3 Lancet. 2018;392(10152):1058–1070. doi:10.1016/S0140-6736
80. Lisanby SH. Update on magnetic seizure therapy: a novel form of (18)31551-4
convulsive therapy. J ECT. 2002;18(4):182–188. doi:10.1097/ 98. Mueller TI, Leon AC. Recovery, chronicity, and levels of psy-
00124509-200212000-00003 chopathology in major depression. Psychiatr Clin North Am.
81. Lontis ER, Voigt M, Struijk JJ. Focality assessment in transcranial 1996;19(1):85–102. doi:10.1016/S0193-953X(05)70275-6
magnetic stimulation with double and cone coils. J Clin Neurophysiol. 99. Murrough JW, Perez AM, Pillemer S, et al. Rapid and
2006;23(5):462–471. doi:10.1097/01.wnp.0000229944.63011.a1 longer-term antidepressant effects of repeated ketamine infusions
82. Lozano AM, Giacobbe P, Hamani C, et al. A multicenter pilot in treatment-resistant major depression. Biol Psychiatry. 2013;74
study of subcallosal cingulate area deep brain stimulation for (4):250–256. doi:10.1016/j.biopsych.2012.06.022
treatment-resistant depression. J Neurosurg. 2012;116 100. Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY,
(2):315–322. doi:10.3171/2011.10.JNS102122 Young AH. Comparative efficacy and acceptability of
83. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, non-surgical brain stimulation for the acute treatment of major
Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation depressive episodes in adults: systematic review and network
for treatment-resistant depression. Biol Psychiatry. 2008;64 meta-analysis. BMJ. 2019;364:l1079. doi:10.1136/bmj.l1079
(6):461–467. doi:10.1016/j.biopsych.2008.05.034 101. Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive
84. Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of celecoxib treatment for patients with major depressive disorder: a
major depressive disorder. Mol Psychiatry. 2011;16(4):383–406. meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry.
85. Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A. 2014;48:79–85. doi:10.1016/j.pnpbp.2013.09.006
Modulation of corticospinal excitability by repetitive transcranial 102. Naguy A. Brexanolone and postpartum depression: what does it
magnetic stimulation. Clin Neurophysiol. 2000;111(5):800–805. have to do with GABA? Arch Womens Ment Health. 2019;22
doi:10.1016/S1388-2457(99)00323-5 (6):833–834. doi:10.1007/s00737-019-00986-0
86. Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for 103. Naguy A, Alamiri B, Al Awadhi DS. Treatment-resistant depres-
treatment-refractory major depressive disorder: a randomized sion: A plea to mull over! Asian J Psychiatr. 2018;36:69–70.
trial. Ann Intern Med. 2007;147(9):593–602. doi:10.7326/0003- doi:10.1016/j.ajp.2018.06.014
4819-147-9-200711060-00003 104. Nelson JC, Baumann P, Delucchi K, Joffe R, Katona C.
87. Malhi GS, Parker GB, Crawford J, Wilhelm K, Mitchell PB. A systematic review and meta-analysis of lithium augmentation
Treatment-resistant depression: resistant to definition? Acta Psychiatr of tricyclic and second generation antidepressants in major
Scand. 2005;112(4):302–309. doi:10.1111/acp.2005.112.issue-4 depression. J Affect Disord. 2014;168:269–275. doi:10.1016/j.
88. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and jad.2014.05.053
safety of aripiprazole as adjunctive therapy in major depressive 105. Newton-Howes G, Tyrer P, Johnson T. Personality disorder and
disorder: a second multicenter, randomized, double-blind, the outcome of depression: meta-analysis of published studies. Br
placebo-controlled study. J Clin Psychopharmacol. 2008;28 J Psychiatry. 2006;188:13–20. doi:10.1192/bjp.188.1.13
(2):156–165. doi:10.1097/JCP.0b013e31816774f9 106. Newton-Howes G, Tyrer P, Johnson T, et al. Influence of person-
89. Mathew SJ, Murrough JW, Aan Het Rot M, Collins KA, Reich DL, ality on the outcome of treatment in depression: systematic
Charney DS. Riluzole for relapse prevention following intravenous review and meta-analysis. J Pers Disord. 2014;28(4):577–593.
ketamine in treatment-resistant depression: a pilot randomized, pla- doi:10.1521/pedi_2013_27_070
cebo-controlled continuation trial.”. Int J Neuropsychopharmacol. 107. Nierenberg AA, Amsterdam JD.Treatment-resistant depression:
2010;13(1):71–82. doi:10.1017/S1461145709000169 definition and treatment approaches. J Clin Psychiatry. 1990;51
90. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation (Suppl):39–47.
for treatment-resistant depression. Neuron. 2005;45(5):651–660. 108. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of
doi:10.1016/j.neuron.2005.02.014 lithium and T(3) augmentation following two failed medication
91. McDonald A, Walter G. The portrayal of ECT in American treatments for depression: a STAR*D report. Am J Psychiatry.
movies. J ECT. 2001;17(4):264–274. doi:10.1097/00124509- 2006;163(9):1519–1530. doi:10.1176/ajp.2006.163.9.1519
200112000-00006 109. O’Reardon JP, Blumner KH, Peshek AD, Pradilla RR,
92. McElhiney MC. The Autobiographical Memory Interview-Short Pimiento PC. Long-term maintenance therapy for major depres-
Form. In: Psychiatry DoB. New York: New York State sive disorder with rTMS. J Clin Psychiatry. 2005;66
Psychiatric Institute; 2001. (12):1524–1528. doi:10.4088/JCP.v66n1205

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

232
DovePress
Dovepress Voineskos et al

110. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and 128. Sackeim HA, Aaronson ST, Bunker MT, et al. The assessment of
safety of transcranial magnetic stimulation in the acute treatment resistance to antidepressant treatment: rationale for the
of major depression: a multisite randomized controlled trial. Biol Antidepressant Treatment History Form: Short Form
Psychiatry. 2007;62(11):1208–1216. doi:10.1016/j. (ATHF-SF). J Psychiatr Res. 2019;113:125–136. doi:10.1016/j.
biopsych.2007.01.018 jpsychires.2019.03.021
111. Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in 129. Sackeim HA, Haskett RF, Mulsant BH, et al. Continuation phar-
depression: a meta-analytic review. J ECT. 2004;20(1):13–20. macotherapy in the prevention of relapse following electrocon-
doi:10.1097/00124509-200403000-00004 vulsive therapy: a randomized controlled trial. JAMA. 2001;285
112. Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant (10):1299–1307. doi:10.1001/jama.285.10.1299
depression: a meta-analysis comparing within- versus across-class 130. Samoudi AM, Tanghe E, Martens L, Joseph W. Deep transcranial
switches. Biol Psychiatry. 2008;63(7):699–704. doi:10.1016/j. magnetic stimulation: improved coil design and assessment of the
biopsych.2007.08.010 induced fields using MIDA model. Biomed Res Int. 2018;
113. Parker G, Roy K, Hadzi-Pavlovic D, Pedic F. Psychotic (delusional) (2018:7061420.
depression: a meta-analysis of physical treatments. J Affect Disord. 131. Sanacora G, Gueorguieva R, Epperson CN, et al. Subtype-specific
1992;24(1):17–24. doi:10.1016/0165-0327(92)90056-C alterations of gamma-aminobutyric acid and glutamate in patients
114. Parker GB, Malhi GS, Crawford JG, Thase ME. Identifying with major depression. Arch Gen Psychiatry. 2004;61
“paradigm failures” contributing to treatment-resistant depres- (7):705–713. doi:10.1001/archpsyc.61.7.705
sion. J Affect Disord. 2005;87(2–3):185–191. doi:10.1016/j. 132. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation
jad.2005.02.015 strategy for treating resistant major depression. Am J Psychiatry.
115. Pascual-Leone A, Catala MD, Pascual-Leone A. Lateralized 2001;158(1):131–134. doi:10.1176/appi.ajp.158.1.131
effect of rapid-rate transcranial magnetic stimulation of the pre- 133. Souery D, Amsterdam J, de Montigny C, et al. Treatment resistant
frontal cortex on mood. Neurology. 1996;46(2):499–502. depression: methodological overview and operational criteria. Eur
doi:10.1212/WNL.46.2.499 Neuropsychopharmacol. 1999;9(1–2):83–91. doi:10.1016/S0924-
116. Peselow ED, Filippi AM, Goodnick P, Barouche F, Fieve RR. The
977X(98)00004-2
short- and long-term efficacy of paroxetine HCl: A. Data from a
134. Souery D, Oswald P, Massat I, et al., D. Group for the Study of
6-week double-blind parallel design trial vs. imipramine and Resistant. Clinical factors associated with treatment resistance in
placebo. Psychopharmacol Bull. 1989;25(2):267–271.
major depressive disorder: results from a European multicenter
117. Petersen T, Papakostas GI, Posternak MA, et al. Empirical testing
study. J Clin Psychiatry. 2007;68(7):1062–1070. doi:10.4088/JCP.
of two models for staging antidepressant treatment resistance.
v68n0713
J Clin Psychopharmacol. 2005;25(4):336–341. doi:10.1097/01.
135. Strawbridge R, Arnone D, Danese A, Papadopoulos A, Herane
jcp.0000169036.40755.16
Vives A, Cleare AJ. Inflammation and clinical response to treat-
118. Post RM. The new news about lithium: an underutilized treatment
ment in depression: A meta-analysis. Eur Neuropsychopharmacol.
in the United States. Neuropsychopharmacology. 2018;43
2015;25(10):1532–1543. doi:10.1016/j.euroneuro.2015.06.007
(5):1174–1179. doi:10.1038/npp.2017.238
136. Suppa A, Huang YZ, Funke K, et al. Ten years of theta burst stimula-
119. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement
tion in humans: established knowledge, unknowns and prospects.
of imipramine antidepressant activity by thyroid hormone. Am
Brain Stimul. 2016;9(3):323–335. doi:10.1016/j.brs.2016.01.006
J Psychiatry. 1969;126(4):457–469. doi:10.1176/ajp.126.4.457
137. Thase ME, Frank E, Mallinger AG, Hamer T, Kupfer DJ. Treatment
120. Prudic J, Haskett RF, Mulsant B, et al. Resistance to antidepres-
of imipramine-resistant recurrent depression, III: efficacy of mono-
sant medications and short-term clinical response to ECT. Am
J Psychiatry. 1996;153(8):985–992. amine oxidase inhibitors. J Clin Psychiatry. 1992;53(1):5–11.
121. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized 138. Thase ME, Rush AJ. Treatment resistant depression. In: Bloom FE,
controlled trial of the tumor necrosis factor antagonist infliximab Kupfer DJ, editors. Psychopharmacology: The Fourth Generation
for treatment-resistant depression: the role of baseline inflamma- of Progress. New York: Raven Press Ltd.; 1995:1081–1097.
tory biomarkers. JAMA Psychiatry. 2013;70(1):31–41. doi:10.100 139. Thase ME, Rush AJ, Howland RH, et al. Double-blind switch study
1/2013.jamapsychiatry.4 of imipramine or sertraline treatment of antidepressant-resistant
122. Richards EM, Mathews DC, Luckenbaugh DA, et al. A randomized, chronic depression. Arch Gen Psychiatry. 2002;59(3):233–239.
placebo-controlled pilot trial of the delta opioid receptor agonist doi:10.1001/archpsyc.59.3.233
AZD2327 in anxious depression. Psychopharmacology (Berl). 140. Ustun TB, Kessler RC. Global burden of depressive disorders: the
2016;233(6):1119–1130. doi:10.1007/s00213-015-4195-4 issue of duration. Br J Psychiatry. 2002;181:181–183.
123. Roth Y, Zangen A, Hallett M. A coil design for transcranial doi:10.1192/bjp.181.3.181
magnetic stimulation of deep brain regions. J Clin 141. van Bronswijk S, Moopen N, Beijers L, Ruhe HG, Peeters F.
Neurophysiol. 2002;19(4):361–370. doi:10.1097/00004691-200 Effectiveness of psychotherapy for treatment-resistant depression:
208000-00008 a meta-analysis and meta-regression. Psychol Med. 2019;49
124. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The (3):366–379. doi:10.1017/S003329171800199X
Inventory of Depressive Symptomatology (IDS): psychometric 142. Wilkinson ST, Agbese E, Leslie DL, Rosenheck RA. Identifying
properties. Psychol Med. 1996;26(3):477–486. doi:10.1017/S003 recipients of electroconvulsive therapy: data from privately
3291700035558 insured Americans. Psychiatr Serv. 2018;69(5):542–548.
125. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and doi:10.1176/appi.ps.201700364
longer-term outcomes in depressed outpatients requiring one or 143. Williams NR, Sudheimer KD, Bentzley BS, et al. High-dose
several treatment steps: a STAR*D report. Am J Psychiatry. spaced theta-burst TMS as a rapid-acting antidepressant in highly
2006;163(11):1905–1917. doi:10.1176/ajp.2006.163.11.1905 refractory depression. Brain. 2018;141(3):e18. doi:10.1093/brain/
126. Sackeim HA. Central issues regarding the mechanisms of action awx379
of electroconvulsive therapy: directions for future research. 144. Wisner KL, Stika CS, Ciolino JD. The first food and drug
Psychopharmacol Bull. 1994;30(3):281–308. administration-indicated drug for postpartum depression-brexano-
127. Sackeim HA. The definition and meaning of treatment-resistant lone. JAMA Psychiatry. 2019;76:1001. doi:10.1001/jamapsychiatry.
depression. J Clin Psychiatry. 2001;62(Suppl 16):10–17. 2019.1546

submit your manuscript | www.dovepress.com

Neuropsychiatric Disease and Treatment 2020:16 233
DovePress
Voineskos et al Dovepress

145. Xu Y, Hackett M, Carter G, et al. Effects of low-dose and 148. Zhou X, Ravindran AV, Qin B, et al. Comparative efficacy, accept-
very low-dose ketamine among patients with major ability, and tolerability of augmentation agents in treatment-resistant
depression: a systematic review and meta-analysis. Int J depression: systematic review and network meta-analysis. J Clin
Neuropsychopharmacol. 2016;19(4). Psychiatry. 2015;76(4):e487–e498. doi:10.4088/JCP.14r09204
146. Zall H, Therman PG, Myers JM. Lithium carbonate: a clinical 149. Berlim MT, van den Eynde F, Tovar-Perdomo S, Daskalakis ZJ.
study. Am J Psychiatry. 1968;125(4):549–555. doi:10.1176/ Response, remission and drop-out rates following high-frequency
ajp.125.4.549 repetitive transcranial magnetic stimulation (rTMS) for treating
147. Zanos P, Gould TD. Mechanisms of ketamine action as an major depression: a systematic review and meta-analysis of ran-
antidepressant. Mol Psychiatry. 2018;23(4):801–811. doi:10.103 domized, double-blind and sham-controlled trials. Psychol Med.
8/mp.2017.255 2014;44(2):225–39.

Neuropsychiatric Disease and Treatment Dovepress

Publish your work in this journal
Neuropsychiatric Disease and Treatment is an international, peer- is the official journal of The International Neuropsychiatric
reviewed journal of clinical therapeutics and pharmacology focusing Association (INA). The manuscript management system is comple-
on concise rapid reporting of clinical or pre-clinical studies on a tely online and includes a very quick and fair peer-review system,
range of neuropsychiatric and neurological disorders. This journal is which is all easy to use. Visit http://www.dovepress.com/testimo-
indexed on PubMed Central, the ‘PsycINFO’ database and CAS, and nials.php to read real quotes from published authors.

Submit your manuscript here: https://www.dovepress.com/neuropsychiatric-disease-and-treatment-journal

submit your manuscript | www.dovepress.com Neuropsychiatric Disease and Treatment 2020:16

234
DovePress