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Challenges of Treatment-resistant Depression

Authors:
  • 5 boroughs partnership nhs trust

Abstract

Guidelines for the management of treatment-resistant depression (TRD) do not meet the criteria of evidence-based medicine and better-quality research is required to inform clinical practice. Current treatments of resistant depression remains largely empirical. There are no bench-mark antidepressants. Clear and justifiable rationale should be followed while initiating new treatment strategies; systematic planning and careful monitoring of progress implemented while new treatment components are added. Biological psychiatrists should give due importance to the non-biological aspects of depression and psychotherapists should not overlook the biological correlates. Unidimensional solution will not work for a complex illness like refractory depression and a single answer should not be sought as a cure because the aetiology of depression is multifactorial and the pathophysiology itself remains unknown. Psychopharmacological interventions are still the main stay of treatment of TRD. There are two major alternatives to pharmacotherapy: neuromodulation and psychotherapy. Alternative terminologies for TRD like MTR-MDD (Multiple Therapy Resistant-Major Depressive Disorder) are being introduced reflecting the frustrations of clinicians and patients with the conventional definition of TRD and treatment modalities.
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Psychiatria Danubina, 2018; Vol. 30, No. 3, pp 273-284 https://doi.org/10.24869/psyd.2018.273 Narrative Review
© Medicinska naklada - Zagreb, Croatia
CHALLENGES OF TREATMENT-RESISTANT DEPRESSION
James Paul Pandarakalam
Department of Psychiatry, Northwest Boroughs Healthcare NHS Foundation Trust, Hollins park Hospital,
Warrington, United Kingdom
received: 16.7.2018; revised: 10.8.2018; accepted: 4.9.2018
SUMMARY
Guidelines for the management of treatment-resistant depression (TRD) do not meet the criteria of evidence-based medicine and
better-quality research is required to inform clinical practice. Current treatments of resistant depression remains largely empirical.
There are no bench-mark antidepressants. Clear and justifiable rationale should be followed while initiating new treatment
strategies; systematic planning and careful monitoring of progress implemented while new treatment components are added.
Biological psychiatrists should give due importance to the non-biological aspects of depression and psychotherapists should not
overlook the biological correlates. Unidimensional solution will not work for a complex illness like refractory depression and a
single answer should not be sought as a cure because the aetiology of depression is multifactorial and the pathophysiology itself
remains unknown. Psychopharmacological interventions are still the main stay of treatment of TRD. There are two major
alternatives to pharmacotherapy: neuromodulation and psychotherapy. Alternative terminologies for TRD like MTR-MDD (Multiple
Therapy Resistant-Major Depressive Disorder) are being introduced reflecting the frustrations of clinicians and patients with the
conventional definition of TRD and treatment modalities.
Key words: depression – antidepressants – psychotherapy – ECT – TMS – VNS - healing therapies
* * * * *
INTRODUCTION
Depression is a highly controversial topic in psy-
chiatry as there are long-standing disputes between the
biologically and the analytically oriented psychiatrists.
At present it is not advisable to hold any strong views
about this universal phenomenon with its varied trans-
cultural aspects. Depression may be a psycho-bio, social
condition, but there may be contribution from non-ordi-
nary states of consciousness to their aetiology (Pandara-
kalam 2018). The popular misconception that depres-
sion is due to lack of will power has contributed to the
stigma of this affliction (Bhugra 2013). Depressive
illness has become time-consuming and a financial
burden for all the health systems. TRD patients have
been reported to have significantly higher medical costs
and to be twice likely to be hospitalised resulting in a 6-
fold increase in overall medical costs compared to non-
TRD patients (Crown et al. 2002). In the year 2000, the
total cost of adult depression was estimated at over £9
billion in England and the direct treatment costs were
£370 million (Thomas & Morris 2003). In fact, depres-
sion including the treatment of co-morbid conditions are
estimated to have cost the U.S. economy more than
$210 billion in 2010 (Greenberg et al. 2015).
Depression and suicide are connected, with an esti-
mate that up to 60 percent of people who commit sui-
cide have major depression. Clinical depression is asso-
ciated with social, occupational and physical impair-
ment and mortality, despite the recent advancements
made in its treatment. Older studies using stricter defi-
nitions showed the incidence of suicides linked to major
depression was around 15 percent. Unipolar depression
and hopelessness is among the most frequently appre-
hended risk factors for suicidal thoughts and behaviours
(Ribeiro et al. 2018).
DEFINING AND ASSESING
TREATMENT RESISTANCE
A major depressive disorder (MDD) is indicated by
the presence of at least five of the following symptoms
(American psychiatric association 2013) occurring inde-
pendent of physical illness, normal bereavement, alco-
hol or drugs:
Abnormal depressed mood;
Abnormal loss of interest and pleasure;
Appetite or weight disturbance;
Sleep disturbance;
Disturbance in activity (agitation or slowing);
Abnormal fatigue or loss of energy;
Abnormal self-reproach or inappropriate guilt;
Poor concentration or indecisiveness;
Morbid thoughts of death or suicide.
At least one symptom must be abnormal depressed
mood or loss of interest and pleasure, persisting for most
of nearly every day for at least two weeks and signi-
ficantly impairing function and daily life. When fewer
than five symptoms are present, the disorder is called
minor depression. Dysthymia is defined by the presence
of at least three symptoms, including depressed mood,
on most days for at least 2 years.
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Table 1. Assessment of treatment- refractory depression
Re-evaluate current treatment
Adequate trial given? Suboptimal dose and
non-adherence lead to pseudo resistance
Exceed BNF limits (in specialist centres only)
Check blood levels if facility available
Review the differential diagnosis- sub-clinical
bipolar disorder?
Assess for psychotic symptoms
Exclude schizoaffective disorder
and non-affective disorders
Partial response or no response
Re-evaluate personal history
Explore interpersonal and family dynamics
Exclude soft bipolar disorder
Investigate co- morbid physical conditions (hypothyro-
idism, cushing’s syndrome, parkinsonism, malignancy,
anaemia, viral infections, vitamin deficiencies, and
dietary deficiencies etc)
Co-morbid psychiatric conditions:
Substance misuse, dependency-alcohol
can cause tryptophan depletion;
Anxiety disorders;
Eating disorders;
Personality disorders;
Post traumatic disorders.
Assess suicidal risk
Asses pre-morbid personality
Concurrent non-psychiatric drug usage
eg. Methyl dopa, beta blockers, reserpine, steroids,
immunosuppressants, anticholinergics, sedatives etc.
Organic factors
Explore the maintenance factors
Investigate compliance
Check the negative pressure from the part of the
relatives and friends reg. medication intake.
Variable day routines and travelling habits affect dosing
Examine whether the team’s expectations are realistic,
eg time scale for improvement.
Asses motivation of the patient – it is the
very nature of the illness to be hopeless
There is not a standard definition for treatment resi-
stance. It may be defined as an unsatisfactory response
to two adequate trials of two different classes of anti-
depressants at optimum dosage for sufficient duration
(Thase & Rush 1997, Souery 1999). Some consider
treatment resistance only after trials of several different
classes of antidepressants (Judd 2000) or even electro-
convulsive therapy (Fink 2001). But there are no strict
criteria to measure clinically meaningful improvements
and the number and type of treatment trials that a patient
should experience before being labelled as refractory
depression. Multiple factors are involved in treatment
resistance (Table 1). Several severity indicators, such as
longer duration of depressive episode, moderate-high
suicide risk, anxious comorbidity, high number of hos-
pitalizations, age factors and higher dosage of anti-
depressants may account for non-response to multiple
therapeutic interventions (Vera et al. 2016).
Professor Anderson has opined that the standard defi-
nition of TRD raises several questions (Anderson 2018).
He questions the rationale of specifying two antidepres-
sants and the meaning of an adequate trial. He also
wonders whether sequential drugs from the same and
different antidepressant classes be treated as the same.
Professor Anderson is also seeking the validation of
how to incorporate psychological therapies and alterna-
tive medicines in the current treatment regime of TRD.
He thinks that treatment adherence, intolerance, partial
response and non-response in past episodes of depres-
sion also matters but not given specifications in the cri-
teria for TRD (Anderson 2018). Psychological resistance
is sometimes not distinguished from biological resistance.
Over the last few decades, the assessment of TRD has
improved, but because of lack of consensus, clinical and
nosological debate continues (Fornaro et al. 2010).
NEWER TERMINOLOGIES
Despite newer medications, TRD literature indicates
that the investigatory endeavours came to a standstill a
decade ago. TRD field has failed to progress beyond
classifications and treatment strategies (Moller et al.
2013). A new vocabulary is needed to define this ter-
rible and disabling condition. Moller et al. suggest borro-
wing prefixes from general medicine and name treat-
ment resistant nonpsychotic major depression as malig-
nant, pernicious or virulent nonpsychotic depression and
psychotic TRD could be termed malignant, pernicious
or virulent psychotic depression (Moller et al. 2013).
McCallister and colleagues propose the development
and adoption of another useful terminology as one step
toward improving medical treatment. They suggest an-
other terminology- MTR-MDD (Multiple Therapy Resi-
stant Major Depressive Disorder). These recent proposals
to modify the very time old terminology TRD is welco-
ming. The newer terms could spawn productive discus-
sions and re-evaluations of medical practices. These la-
bels could get further modified as research progress. De-
pression needs urgent timely intervention because of its
spiralling nature in the psychological and social sphere;
cognitive distortions spiral down with their domino effect
and social causes lead to loss of job and breakdown of
relationships to the detriment of the sufferers.
RESPONSE TO PHARMACOTHERAPY
Between 20 to 40% respond only minimally to
monotherapy (Shelton 1999). Only 50% of patients not
responding to a primary antidepressant improve when
another antidepressant is introduced (Depression Guide-
line Panel 1993). Faster onset of action and greater
therapeutic efficacies with minimal side effects are the
main prescription- criteria of antidepressants (Table 2).
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Table 2. Key points of selection of antidepressants
Fast onset of action
Sustained response
Sustained remission
Sustained prevention of relapse
Monotherapy
Single regime
Better tolerability
Fewer discontinuation symptoms
Early detection and vigorous treatment with aggressive
treatment of residual symptoms followed by continued
maintenance treatment should be the policy of mana-
ging pharmacotherapy resistant depression (Trivedi &
Kleiber 2001).
To avoid a higher chance of adverse reactions; clini-
cians tend to prescribe a low dose of antidepressants
even though such a practice reduces the chance of
improvement slightly, but this could lead to partial
response. It is important to distinguish partial response
and no response for the future course of treatment. Past
drug response, adverse effect profile differences, conco-
mitant medical disorders and concurrent drug therapy
are some of the considerations to be well-thought-out
while choosing between switching and combination/
augmentation therapies. Switch is indicated for no res-
ponse and those experiencing adverse effects; partial
response signal combination therapy or augmentation.
However, switching is less effective than augmentation
(Posternack & Zimmerman 2001).
Comorbidities such as substance abuse, personality
disorders, and general medical conditions including
hypothyroidism, anaemia etc can also greatly influence
the overall success of a treatment plan. Genetic and
metabolic variations that may make the biology of the
patient unique contributing to poor response to medi-
cations should also be considered (Perils 2008). Despite
the fact that phenomenal advances have been made in
genetic testing, these tools have not been established for
guiding psychiatric care. Multiple-loci genotyping tests
are anticipated to provide information regarding patients
at higher risk of TRD, drug related side effects and the
recurrent nature of MDD (Serretti et al. 2011).
INCIPIENT BIPOARITY
Unrecognised or bipolarity in disguise is another
issue to be excluded when challenging TRD and when
bipolarity is diagnosed, addition of mood stabiliser is
the first step towards treatment or even therapeutic
diagnosis. Bipolarity should be screened in all cases of
monopolar depression (Table 3). While this cannot be
always accurate, one way of preventing treatment
emergent bipolarity is co prescribing antipsychotics or
mood stabilisers to prevent hypomanic switch. Such a
view needs further investigation. Some antipsychotics
and mood stabilisers have more anti manic properties
than others.
Table 3. Features of incipient bipolarity
Non-response to antidepressants
Family history of bipolar disorder
Family history of completed suicide
Psychotic features
Atypical symptomatology
Retarded presentation
Higher suicidal risk
Violent mood swings
Co-morbid anxieties
Past history of mood elevation
Thinking people are unfriendly
Legal problems
An adjunctive therapy has the advantage of negating
the treatment emergent agitation. Without sufficient
knowledge, experience and care, doctors can deteriorate
as licensed drug dealers and a sound knowledge of
psychopharmacology is essential for general practitio-
ners in these days of shift of psychiatry from the secon-
dary care to primary care. The risk of suicide is higher
among bipolar patients than monopolar patients and this
is particularly so in the mixed affective states. The
newer antidepressants unmask incipient bipolarity and
most often result in mixed state. This may be true of
younger adults while the older depressed adults would
have more likely declared their mania.
DIFFERENT TREATMENT
STRATEGIES
Now that there are a variety of medication and treat-
ment strategies, the good news is that most patients have
the potential to respond to treatment (Table 4). Full
symptom remission (wellness) and return of optimal
psychosocial function with minimal side effect burden
is the clinical goal of treatment of prophylaxis resistant
depression. Increasing the dose of the antidepressant
carries the unavoidable risk of increasing the chances of
adverse effects but can also have favourable effects. In
the same vein, it has to be stated that the clinician may
be thrown into the dilemma that increasing the dose
may delay the recognition of early state TRD and
increase the incidence of discontinuation symptoms in
the event of discontinuing it due to failure of response
(Kasper & Montgomery 2013). The evidence supporting
the benefits of different treatment strategies is oddly
slender and clinicians should have realistic expectations
and tolerance to deal with ambivalences.
DRUG SUBSTITUTION
A change from one antidepressant to another one in
the same class seldom produces any additional benefit
whereas switching to an antidepressant with a different
mechanism of action has proven to produce more
impressive response rate. Switching from a tricyclic to
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an alternate antidepressant agent has been always shown
better efficacy. Because SSRIs are structurally diverse,
switching from one SSRI to another may also be logical.
SNRI is worth considering if an SSRI fails. If the half-
life of the first SSRI is quite long, switching without a
prudent wash out period can cause drug interactions.
When switching antidepressant drugs, one of the
problems is discontinuation symptoms and disappoint-
ment from the part of the patients that they have lost
some initial benefits gained out of the first drug in
addition to the disadvantage that patient must cope with
another waiting period for the substituted drug to
produce desirable results. Switching is found effective if
the clinical syndrome is atypical. In the past, M.A.O.
inhibitors and I.V. Clomipramine were popular treat-
ment for TRD.
The term combination and augmentation are used
interchangeably. In general, combination refers to the
use of more than one type of disease specific treatment
applied to the therapeutic management of an illness
(Shelton 2002). Thus, combination therapy involves the
addition of a second antidepressant to the therapy regi-
me and is different from adjunctive therapy in the sense
it means to employ a second agent to reverse an emer-
gent side effect or obtain a complimentary clinical
effect. Augmentation involves the use of a non-antide-
pressant agent along with the antidepressant. The modus
operandi of this approach (combination and augmen-
tation) is that two different treatments together may
have different mechanism of action and therapeutic
response which is different from either drug alone.
Table 4. Strategies for managing refractory depression
Optimise dose, if partial response
Lengthening therapy
Use what has worked for the patient in the past.
Drug substitution
SSRIs. These are agents of first choice due
to ease of use, more tolerable side effects
and safety in overdose;
Another class-venlafaxine, mirtazapine;
High dose tricyclics.
Combination of classes
SSRI + reboxetine;
SSRI + tricyclics.
Augmentation
Electro convulsive therapy
Retrial of ECT for those previously administered ECT
Trans- cranial magnetic therapy
Vagal nerve stimulation
Psychotherapy
Light therapy and medication
Physical activities and medication
Sleep deprivation
Consciousness based healing
Neurosurgery is still available for severe
treatment-resistant depression.
COMBINATION
The use of combination therapies is on the increase
because of more confidence and experience with anti-
depressants. Dual antidepressant treatment strategy has
the disadvantage of drug interactions. Even newer gene-
ration antidepressants have only 70% efficacy rate, a
figure which includes partial and full response. A sig-
nificant number of depressed patients who do not ade-
quately respond to SSRIs could benefit from the ad-
dition of their therapeutic predecessors-tricyclic antide-
pressants, but they are all small studies. Noradrenergic
one is the choice for combination with the SSRI.
It is now increasingly recognised that SSRIs are not
as effective as tricyclic antidepressant therapy in certain
subsets of depressed patients, indicating the importance
of norepinephrine re uptake inhibitors in the manage-
ment of such patients. The recent explosion of SSRIs
camouflaged the role of nor adrenaline in the causation
of depression. Noradrenaline may preferentially impro-
ve vigilance, motivation and self- perception. There is
evidence from controlled investigations that venlafa-
xine, an SNRI. is effective in treating treatment resistant
depression. One way of achieving the clinical effect of
an S.N.R.I is by combining an SSRI with an NRI,
thereby converting a narrow spectrum antidepressant to
a broad spectrum one (Devarajan & Dursun 2000,
Dursum & Devarajan 2001). SSRIs and SNRIs may be
working by parallel and independent pathways even
though there are suggestions without clear evidences
that NRIs influence depression by indirectly facilitating
serotonergic transmission and SSRIs act by facilitating
noradrenaline.
Tricyclic antidepressant therapy is associated with
relative risk but reboxetine has a good safety profile.
The safer side effect profile of reboxetine bodes well for
long term patient compliance. Citalopram is a chiral anti-
depressant and is found to be effective in combination
with Reboxetine (Forbes & Rogers 2003). Its eutomer,
escitalopram appears to be suitable for combination
therapy. In the olfactory bulbectomized rat model of de-
pression, reboxetine, sertraline and their combination
were tested and, the combination treatments had better
outcome (Harkin et al. 1999). Reboxetine is not cardio-
toxic and it is not associated with an increased risk of
seizures or orthostatic hypotension. Reboxetine has mild
anticholinergic effects and produces sexual side effects.
It is safer in overdose and seems to have negligible
interference with the pharmacokinetics of other drugs.
Venlafaxine and mirtazapine combination has been
dubbed as ‘California rocket fuel’ and Duloxetine-
Mirtazapine combination as ‘Limerick rocket fuel.’
AUGMENTATION
Patients with depression respond variably and unpre-
dictably to various antidepressants. There are now a
plethora of clinical trials showing the efficacy of non-
antidepressant agents. Augmentation therapy is an active
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Table 5. Combination/augmentation
Patients unresponsive to the initial antidepressant
may achieve clinical response when the second
agent is added.
Discontinuation symptoms due to withdrawal of the
original antidepressant avoided and patient does not
have to cope with another waiting period for the
substituted drug to produce desirable results.
The strategy builds on therapeutic gains obtained
with the primary antidepressant and allows patients to
continue to reap whatever benefits they have from the
original drugs but with the additive or synergetic
benefits of the augmentor or the additional combined
antidepressant; switching has the disadvantage of
losing the little gain already obtained.
Switching requires care in the changeover of drugs,
which can cause delay and discontinuation reactions;
these are avoided with the addition of a second drug.
Second compound is generally well tolerated
and does not substantially alter the side effect profile
of the first antidepressant.
Rapid onset of antidepressant action
Response rate is comparable or superior to substitution
which involves tapering off the first drug wash out and
delay in onset of the second drug.
Disadvantage is reduced concordance and increased
side effect as a result of taking two agents than one.
area of research and has certain advantages over
switching (Table 5). Different classes of drugs are taken
advantage for augmentation.
Lithium
Lithium is essentially used for preventing recurrence
of mania and depressive disorder. Lithium has several
pharmacological actions and it is unclear which of these
explains the therapeutic effect. Its effect in increasing
brain 5HT has clinical relevance. Lithium is thought to
enhance serotonin transmission by the activity of post-
synaptic serotonin or 5HT receptors. This reduces the
negative feedback of serotonin-releasing cells and the-
reby increases serotonin levels in synaptic cleft. Lithium
may also have favourable effect on other neurotrans-
mitters and neuromodulators (Montigny 1994). The
therapeutic dose and toxic dose of lithium are close
together and that means regular scrutiny of its plasma
measurement during treatment. Because of the side
effects of lithium, this treatment strategy is under-
utilized. Lithium augmentation to an ongoing antide-
pressant trail was widely used in the 1980s and early
1990s. Low dose (300mg to 600mg per day) to higher
doses were used to treat antidepressant resistant de-
pression. But there has been a disenchantment with its
use recently as clinicians found only acceleration than
augmentation response (Fredman et al. 2000).
Lithium augmentation has been the most widely
studied strategy in the literature of treatment involving
11 published double-blind trials and most of the studies
involved tricyclics, but the clinical predictors of its effi-
cacy regarding polarity and bipolarity are poorly under-
stood. To this effect, a randomised controlled study re-
vealed that lithium augmentation was more effective in
patients with a final diagnosis of bipolar disorder than with
MDD and subjects with more than three major depressive
episodes showed a significant response to lithium aug-
mentation (Sugawara et al. 2010). More recently, rando-
mized controlled trials with more than 30 open-label and
comparator studies have confirmed the efficacy of this
combination and the rapidity of response (Bauer 2010).
Anticonvulsants
There is an observed shift of prescription practice
from lithium to valproate across the Atlantic and is not
based on reliable evidence of efficacy but, it is
justifiable because of the safer side effect profile of
valproate. Augmenting antidepressants with anticonvul-
sants has shown variable effects in trials. Carbama-
zepine has only a weak antidepressant property. There is
an increasing interest in glutamate action although these
drugs are essentially anticonvulsants.
Lamotrigine sold as the brand name Lamictal is a
glutamate enhancing drug and is a potentiating agent for
antidepressants. It is associated with more antidepres-
sant potency than either carbamazepine or valproate.
Carbamazepine induces enzymes that facilitate the
metabolism of lamotrigine; blood levels of lamotrigine
are somewhat lower when these two agents are taken
together. Valproate could double plasma levels of lamo-
trigine. It has usefulness in treating bipolar depression
and TRD. Among the well tested anticonvulsant in
augmenting antidepressants, lamotrigine stands first
(Barbee et al. 2011, Ivkovic et al. 2009). Isolated cases
where lamotrigine has been more effective in treating
TRD than ECT are reported (Mihara et al. 2016).
Antipsychotics
Typical antipsychotic used in conjunction with
antidepressants have been found to have only modest
effect in the treatment of depression. Clinical trial
employing augmenting SSRIs with atypical antipsycho-
tics hint that this novel augmentation strategy is a
promising therapeutic avenue. Risperidone (Ostroff &
Nelson 1999), olanzapine (Shelton et al. 2002) and most
other atypical antipsychotics are now used by many
clinicians to augment the effect of SSRIs. In Europe,
quetiapine has been approved as an add-on medication
to the antidepressant treatment and aripiprazole or
olanzapine along with fluoxetine have been used in
USA for MDD (Kasper & Montogomery 2013). Neither
the use of SSRI nor the novel antipsychotic alone
produces the effect similar to that produced by the
combination of the two.
The biological or chemical mechanism for the bene-
ficiary effect of these combinations are not clear. Novel
antipsychotics are potent serotonin-2A receptor anta-
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gonists, which is similar to the effects of some of anti-
depressants. Another hypothesis is based on the data
suggesting that serotonin binding to 2C receptors
inhibits the release of dopamine and norepinephrine in
the frontal cortex preventing serotonin from binding to 2
C receptor sites that may result in increased dopamine
levels in the prefrontal cortex and nucleus accumbens.
Novel antipsychotics are also serotonin -2 Cblocking.
The combination of antipsychotics and SSRIs anta-
gonise serotonin receptors and elevate the frontal cortex
dopamine levels. These effects could probably explain
the additive effects on depression.
Thyroxine
There are numerous clinical reports favouring the
view that thyroid hormones can influence mood and
changes of thyroid status has bearing to depressive
symptomatology; the relation between hypothyroidism
and depression is well established (Bauer et al. 2008).
Thyroid hormones may modulate the effect of anti-
depressants. Both T3(triidothyroinine ) and T4 (levo-
thyroxine) are used for augmenting the effect of tradi-
tional antidepressants. Efficacy of augmenting TCAs
with triidothyroxine has been supportive in the early
open trials. Studies of thyroid augmentation of SSRIs
are not many and warrants further research. L-tri-
iodothyronine is said to enhance sensitivity to nor-
adrenergic receptors and is more active than T4.
Depressed patients receiving T4 replacement some-
times respond only when T3 is added to their treatment
regimen (Coper-Kazaz et al. 2007) but, the results
have been inconsistent.
Buspirone
Buspirone when used in conjunction with an antide-
pressant is found to have antidepressant property (Ja-
cobsen 1991). Buspirone acts as a full agonist at the
presynaptic autoreceptor and as a partial agonist at the
postsynaptic autoreceptor (Sussman 1995). Administra-
tion of buspirone decreases extracellular serotonin con-
centration over the short term through activation of 5-
HT1A presynaptic autoreceptors. Buspirone also acti-
vate postsynaptic 5-HT1A receptors. Regular buspirone
administration desensitises and downregulate 5 HT1A
presynaptic autoreceptors, but not postsynaptic 5-HT1A
receptors thereby encouraging further serotonin release.
Using serotonergic agents to augment SSRIs can result
in serotonin syndrome (Fava 2001).
Pindolol
One of the mechanisms responsible for the delayed
onset or lack of response to antidepressants is thought to
be due to an initial increase in the 5HT concentration in
the synaptic cleft prompting a negative feedback mecha-
nism that decreases further release of the neurotrans-
mitter; a process appearing to be mediated by presy-
naptic somatoderitic 5HT 1A receptors and this is the
basis of strategies making use of 5HT1A antagonists.
The betablocker pindolol which is a 5HT 1A-receptor
antagonist has been used to augment antidepressant
therapy; several open and controlled studies have yiel-
ded only mixed results warranting further investigation.
Pindolol speed up the onset of SSRIs rather than aug-
menting the antidepressant effect (Maes et al. 1999).
“Triple therapy” (L-tryptophan+ lithium+ Antide-
pressant) of the 80s is no more used. Psychostimulants
such as amphetamine or methyldopa has only academic
interest as antidepressants and not recommended in
TRD. Likewise, L-dopa though helpful in promoting a
degree of psychomotor activation has no proven anti-
depressant effectiveness. Adding clonazepam to SSRIs
is found to reduce the lag time for the onset of anti-
depressant action. Positive results with hormonal/
omega-3fatty acid augmentation need to be replicated
(Anderson 2003).
Transdermal Selegiline is thought to be effective for
patients with atypical depression (Pae et al. 2007).
Modafinil is included in the BAP guidelines for TRD
for use in specialist centres (Cleare et al. 2015), but not
included in the NICE. Pramipexole is another drug that
may be used in TRD when other means fail and has
endorsement in two conflicting RCTs (Kleebiatt et al.
2017). Intravenous Ketamine is another addition to the
psycho-pharmacological armamentarium of TRD
treatment (Bobo et al. 2016) but involves invasive pro-
cedure with limited duration of effect.
BRAIN STIMULATION THERAPIES
ECT is still considered as a gold standard for relie-
ving depression by many clinicians who also believe
that by not considering it sooner, psychiatrists are con-
signing many patients to less effective treatments and
the risk of chronic illness. Much has been written about
ECT. National institute guide lines (NICE 2003) states
ECT should only be given to achieve a rapid, short-term
improvement when other treatment strategies have
failed, or when the patient’s condition is potentially life
threatening. One of the side effects highlighted is a
temporary memory impairment-retrograde and antero-
grade amnesia. As this type of cognitive disturbance is
encountered in the psychiatric condition itself, it is
difficult to differentiate the effect of the ECT from the
associated mental health problem itself.
Prolonging Remission in Depression in Elderly
(PRIDE) study revealed that ECT combined with an anti-
depressant was effective in preventing relapses in pa-
tients 60 years and older who had severe depression
(Kellner et al. 2016a, 2016b). ECT survived despite seve-
re periodic attack from outside and inside the medical
profession. ECT is a treatment which falls within the
provisions of Section 58 (in England and Wales). It can
be administered only if the patient consents or, if not, a
second opinion must be sought. It can be administered
under common law in an emergency.
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TRANSCRANIAL MAGNETIC
STIMULATION
Like ECT, Transcranial magnetic stimulation (TMS)
and Vagal nerve stimulation (VNS) employ electro-
magnetic energy to alter brain activity and are potential
therapies requiring more study. They are not going to
replace any other therapies but are another option. The
research studies about TMS has risen exponentially
whereas evidences for the effectiveness of VNS is still
fragmentary. TMS is based on the use of pulsed
magnetic field. Earlier TMS machines produced a pulse
every three seconds and was developed as a diagnostic
aid for neurologists. Modern machines produce up to 50
stimuli per second (rapid rate TMS or rTMS) and can
modify the activity of specific brain areas; pathological
neural activity could also be corrected.
TMS stimulation modulates the activity of cortical
neurones. The excitability of the cortical areas can be
increased or decreased by using the TMS stimulation
and, combining TMS and neuroimaging techniques
have demonstrated that functionally related sub cor-
tical structures can also be influenced. It is assumed
that left prefrontal cortex becomes less active in
clinical depression and these areas are accessible to
TMS stimulation. Preliminary reports suggest that
TMS may be effective as an add on therapy similar to
lithium augmentation or an alternative when pharma-
cotherapy fails (Reid et al. 1998). Unlike ECT it does
not produce any cognitive impairment, does not re-
quire a general anaesthetic and not invasive. In 2008,
FDA approved rTMS for use in moderate TRD
(O’Reardon et al. 2007).
VAGAL NERVE STIMULATION
The use of anticonvulsants medications as mood
stabilizers suggests a shared aetiology in convulsive
and mood disorders. Vagus nerve stimulation (VNS)
had its origin in serendipitous observation; VNS trea-
ted drug resistant epilepsy patients showed improve-
ment in mood and cognition (Rosenbaum & Henninger
2000). Vagus nerve is one of the information-high-
ways to and from the brain. Central afferent projection
goes to the nucleus tractus solitarius from where there
are homological connections to several key structures
that regulate affect (locus coerulus, thalamus, hypo-
thalamus, amygdala and hippocampus). A generator
about the size of a cardiac pacemaker is implanted in
the patient’s upper chest and connected via electrode
to the left vagus nerve in the neck near the carotid
artery. This device is programmed to stimulate every 3
to 5 minutes and the impulse can last for 30 seconds.
The programmer can also be used to modify the
electrical impulses in frequency, intensity, duration or
to turn the impulses off altogether.
Adverse effects are minimal. Relationship of auto-
nomic signals to limbic and cortical function has been
of great investigatory interest to physically alter brain
function and it is also hypothesized that VNS instigate
changes in norepinephrine and serotonin, dopamine and
GABA and normalization of CRH -induced ACTH
secretion. It may promote neural network activation or
some sort of reinduction of synchronicity in brain waves
or timing of various neural circuits. It is found to
increase activity in the thalamus and brain stem. We
must confirm whether it truly works before figuring out
how it works. VNS is already used for treatment
resistant patients with epilepsy in U.K. A European
study claimed a response rate of 53% after 2 years
(Bajbouj et al. 2010) and thus, not an acute treatment
option for TRD.
PSYCHOSURGERY
Specialized centres for neurosurgical interventions
are still available for chronic, severe and disabling
depression that are completely refractory to all
conventional therapies even though social, political
and moral issues as well as certain scientific and
philosophical questions of psychosurgery remain
unanswered. Fears that psychosurgery was being used
on minority and disadvantaged population for social
control are unsubstantiated. The two main procedures
used are anterior cingulotomy and subcaudate
tractotomy and are aimed at severing the neural
connections between the prefrontal cortex and the
emotion centres of the limbic system. The theoretical
basis for this treatment is not well established.
Psychosurgery cannot be given to any patient, whether
formal or informal, without the patient’s consent and a
second opinion.
PSYCHOTHERAPY
Even though antidepressants are the first line treat-
ment for depression, only one third of patients respond
fully to pharmacotherapy. An integral package of treat-
ment of refractory depression should address the physi-
cal, psychological and social aspects of care. Interper-
sonal psychotherapy is to identify and change problems
in social and personal relationship that contribute to de-
pression. Psychodynamic therapy focusses on the past
experiences and how they might be contributing to
current mental state in ways of which the person is not
conscious. Psychoanalysts have been trying to bring
out past traumatic memories to find the cause of de-
pression. Memories repeated get multiplied and beco-
me more emphatic. Patients would benefit by opening
the “jewel box of the past” and not the “worm box”.
COGNITIVE THERAPY
The effective non-pharmacological therapies are now
lumped together as Psychosocial-interventions, they also
include cognitive-behavioural approaches (Pandarakalam
James Paul Pandarakalam: CHALLENGES OF TREATMENT-RESISTANT DEPRESSION
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2004). Depressive cognitions are generally divided into
three groups: 1) negative automatic thought, 2) a set of
unrealistic expectations, 3) a series of cognitive distor-
tions. Therapy resistant depressed patients who are trap-
ped in the cob-web of cognitive distortions experience all
emotions as sorrow like patients suffering from thalamic
syndrome feel all their sensory experiences as pain.
The CoBalT randomised controlled trial demonstra-
ted that among patients who have not responded to
antidepressants, augmenting usual care with CBT is
effective in reducing depressive symptoms, and these
effects, including outcomes reflecting remission, are
maintained over 12 months (Wiles et al. 2014). The
intervention was cost-effective based on the National
Institute for Health and Care Excellence threshold and
they also noted that patients may experience CBT as
difficult but effective. An economic evaluation of the
CoBalT trial revealed that adding CBT to pharmaco-
therapy for patients with TRD could substantially
alleviate the burden of the disease (Hollinghurst et al.
2014).
After analysing the literature pertaining to the effec-
tiveness of various forms of psychotherapy in patients
who have not responded to antidepressant pharmaco-
therapy, Kasper and Montgomery reveal that patients
who have not responded to one or two trials of anti-
depressant medication have a 30-50% chance of respon-
ding to a focused psychotherapy (Kasper & Montgomery
2013) recognizing that diagnosis of treatment-resistant
depression far outstrips the development and availability
of effective treatments. Well-controlled and adequately
powered studies have not yielded satisfactory evidence
to support focussed psychotherapy and this is a
hindrance in integrating such modalities into evidence-
based algorithms for TRD (Trivedi et al. 2009, Gaynes
et al. 2011). Psychodynamic psychotherapy for TRD
has also started re-emerging (Driessen et al.2010) and
possibly indicates the frustrations of managing this
potentially malignant condition.
ALTERNATIVE MEDICINES
The current popularity of alternative medicines and
complementary therapies reflect the despair and help-
lessness of patients with severe refractory depression
(The term “Complementary medicines” is sometimes
used to comprise both alternative medicines and com-
plementary therapies). Herbal medicine with its bran-
ches of Bach’s flower remedies, Chinese and Ayurvedic
medicine, Homeopathy and Unani are a few of the
alternative medicines available in U.K.
St John’s wort (Hypericum perforatum) has gained
great media attention. It contains a combination of at
least ten different components including hypercins,
flavonoids and xanthons. Investigators conclude that it
has no usefulness in severe depression (Davidson et al.
2002). Some studies have been unable to differentiate
hypericum from placebo (Montegomery 2000, Shelton
2001). There is a risk that people with clinically signi-
ficant depression may self-medicate with hypericum
rather than receive medication. Concerns have been
raised about adverse interactions of hypericum with
certain drugs.
Readily available herbal medicines have led to con-
fusing choices for patients. Valeriana and Kava Kava
are two other herbal remedies for depression without
any trial data. Other alternative medicines have also no
proven value in “difficult to treat depression”. Many
people are not aware that such remedies can cause side
effects or interact with other drugs. Alternative medi-
cines are more popular among the inner-city population
and among the ethnic minorities.
COMPLEMENTARY THERAPIES
Parallel to the marketing of newer antidepressants,
complementary therapies have also, been flourishing
and they are very popular among patients suffering
from resistant depression. Most of them are based on
the principles of progressive muscular and mental
relaxation. If anxiety is the first symptom to manifest
in depression, it is also the last symptom to disappear
and practioners of complementary medicines are pro-
bably helping to relieve the anxiety component of this
mental illness but some of them exploit such patients
offering false expectations. Hypnotherapy, Reflexo-
logy, Aromatherapy, Reiki, Osteopathy, Acupuncture
are some of the complementary therapies practiced in
U.K. and interestingly they are popular even among
the highly educated.
Among the complementary therapy techniques,
hypnotherapy seems to have gained a renaissance in
recent years. Hypnosis does not relieve the psychic
pain of depression; it has no value in correcting bio-
logical symptoms. One of the meta-analytical studies
has established that hypnosis enhances the efficacy of
both psychodynamic and cognitive behavioural thera-
pies (Kirsch & Lyme 1995). But hypnosis is not a
panacea or a substitute for physical and various psycho-
therapeutic treatment methods. Kirsch (1996) consi-
ders hypnotherapy an empirically validated, non-
deceptive placebo and the effects are mediated by
response expectancies. This is probably one of the
several psychological mechanisms that explain the
working of hypnosis. Hypnosis is contra-indicated in
actively suicidal patients and patients with psychotic
features. The traditional view in using hypnotherapy
for depressed patients are that of extreme caution and
not favourable to its unitary use.
Some evidence exists to think broad spectrum light
exposure used for the treatment of seasonal affective
disorder has efficacy in non-seasonal depression or as
an augmenting agent with antidepressant medications.
Physical activity and exercises also augment other anti-
depressant treatment methods. Medications resistant
depressions ultimately evolve as a form of dysthymic
James Paul Pandarakalam: CHALLENGES OF TREATMENT-RESISTANT DEPRESSION
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disorder with multiple physiological and psychological
symptoms and, tend to be episodic, recurrent and have
a longitudinal course. Whether treated or untreated,
chronicity is ascribed to depression when it runs be-
yond two years.
HEALING DEPRESSION
With the progress in consciousness studies, the view
that depression is a disorder of consciousness is getting
popular and consciousness-based medicine has started
emerging in different quarters of healing professions.
Spiritual therapies are also gaining ground as a last
resort for therapy resistant depression. Change of life
style and a philosophical outlook towards life are the
basic principles of such therapies. Depression must be
neutralised with medications and positive life events but
has to be rehabilitated at a deeper level where medi-
cations may not reach, and spiritual therapies become
relevant in such inner healing.
The U.S. anaesthetist, Dr Rajiv Parti who had a near
death experience is a strong advocate of such a healing
medicine and claims that consciousness-based medicine
he promotes is based on several widely held perpetual
truths (Parti 2016). They may include the belief that
consciousness exists outside of the body, there is life
after death, we are all connected to each other and
celestial beings exist to help and guide us. In downward
causation of depression proposed by non-reductionists
as opposed to the upward causation of depression
promulgated by reductionist scientists, the biological
correlates of depression become an epiphenomenon of
an underlying deranged psycho-spiritual activity. Their
emerging school of thoughts would involve spiritual
resistance along with the psychological and biological
resistance as a feature of TRD. The subjective expe-
rience of depression may respond to consciousness-
based healing methods, but the tormenting psychic pain
must be addressed through the highly precious psycho-
tropic medications. But, some healers believe that
pharmacotherapy might silence the spirit and therein
lies the perils from poorly trained spiritual therapists.
In the past, insightful patients used to claim that
there is something wrong with their mind, but now
days, patients state that there is something dysfunc-
tional about their brain and want a quick fix. Such
patients require several months of preparation to be-
come psychologically minded to receiving some form
of psychological therapies whereas they might require
years of preparation to become spiritually minded for
spiritual therapies.
FUTURE DIRECTIONS IN
PSYCHOPHARMACOLOGY
New techniques of fluorescence histochemistry- im-
munohistochemistry and in situ hybridization has per-
mitted the elucidation of chemically defined neural
circuits providing tools for burgeoning field of neuro-
chemical pathology. Consequently, novel biological
concepts of depression have germinated recently, and
they involve other receptor systems or intracellular
targets. Branching out of the current monoamine cycle-
based antidepressants, the possibility of non-monoami-
nergic antidepressants is being explored. During recent
years many new potentially relevant brain transmitters
and proteins have been identified.
There are several neuropeptide-based approaches to
develop novel antidepressants (Iversen 2003). They are
substance P antagonists, vasopressin antagonists, me-
lanocortin-concentrating hormone antagonists and
corticotrophin-releasing factor receptor antagonists.
Various recent findings show that there are changes in
neurotrophins or corticotrophin releasing hormones
associated with depression. New interventions to stop
the stress hormone cascade before it gets rolling are
being thought about; an input to psychopharmacology
from the endocrinology.
DISCUSSION
An important reason for the high occurrence of re-
fractory depression is our ignorance and tunnel vision
about the aetiology of depression. With increasing
knowledge of the physiological functions of monoamine
neuronal system, the monoamine hypothesis is still in
the forefront of scientific research. It is unquestionable
that depression can stem from pure chemical causes and
the present author does not question the value of the
precious biological information gathered over the years
but dubious about an extreme biological view held by
some medical scientists.
Depression comprises a neurobiological or brain ill-
ness, but “medicalisation” of depression runs the risk of
overlooking the psycho-social factors. Because of wide
choice of antidepressants, clinicians are now able to
tailor medication to symptomatology and patient’s life
situations and minimise side effects with selective
prescribing. The invisibility of depression and, both
subtle and flagrant discrimination against people with
chronic depression make the treatment and management
of this condition more complex. The newer techniques
of brain imaging techniques like functional MRI or
fMRI could unravel why some people may not be
responding to the drug treatment.
Augmentation strategies have caught the maximum
attention of the investigators, but robust evidence is
lacking regarding its effectiveness. Lithium and thyroid
augmentation are the two older established ones. Newer
combination and augmentation strategies are only
supported by case reports and open trial data; theoretical
advantages of multiple mechanism are the basis of these
approaches. This is done a la carte and sometimes in an
irrational way. Much attention has not been paid to the
evaluation of psychological approach. There is also a
critical gap in data on the comparative benefits of
James Paul Pandarakalam: CHALLENGES OF TREATMENT-RESISTANT DEPRESSION
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various psychosocial therapies and herbal treatment
with newer pharmacotherapies; gaps in knowledge
should be filled including transcultural aspects. TMS is
being experimented in several UK centres. VNS re-
mains as a distant therapeutic promise.
Individual temperaments and their specific neurobio-
logical substrates are still poorly understood, and this
causes problems for the clinicians to find matching of
antidepressants to specific temperament types. Practi-
tioners have to depend on their own clinical judgement
in deciding upon treatment and considering the diversity
of clinical presentation, treatment intervention should be
tailored to each clinical circumstance (Nelson 1998).
What constitutes an adequate dose is not at all a well-
researched issue and it is the quality more important
than the quantity of the therapy (US DHSS 1993).
Cognitive therapists sometimes run the risk of
overlooking the biological correlates of depression.
Beck has rightly stated that depression is due to a
cognitive revolution following a coup in the mind and
the coup takes place in the inaccessible dark valleys of
the unconscious mind, resulting in the formation of the
negative hypnotic script (Pandarakalam 2005). But
cognitive theories do not fully explain the mechanism of
how the unconscious mind prepares the "negative
hypnotic script". A sequential strategy encompassing
pharmacotherapy in the acute phase of illness and CBT
in the residual phase has been found to be effective in
decreasing relapse rate of TRD.
Acknowledgements: None.
Conflict of interest: None to declare.
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James Paul Pandarakalam, MBBS, DPM, RCPSI, DCP, MDCH
Department of Psychiatry, Northwest Boroughs Healthcare NHS Foundation Trust,
Hollins park Hospital
Warrington WA2 8WN, United Kingdom
E-mail: James.pandarakalam@nwbh.nhs.uk; jpandarak@hotmail.co.uk
... Since factors other than resilience were not measured, a clear analysis of this is not possible. However, it has been reported that certain depressed patients are refractory and resistant to treatment, 26,27 and the presence of subjects whose symptoms did not actually improve may have influenced the results. It is presumed that psychosocial conflicts and anxiety about adjustment persist only with symptom improvement by pharmacotherapy. ...
... It is presumed that psychosocial conflicts and anxiety about adjustment persist only with symptom improvement by pharmacotherapy. Although the importance of psychosocial approaches when pharmacotherapy is not successful has already been pointed out, 27 the presence of various treatment options is desirable from the viewpoint of resilience. ...
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The aim of this study was to identify factors that influence changes in resilience among workers with mental health disorders, leading to effective treatment and support. Among the new patients at an institution, 81 who were working and had the ICD‐10 diagnoses F3 and F4 were included. Resilience was measured at the initial visit and 3 months later using the S‐H resilience test. Univariate and multiple regression analyses were conducted using the change in resilience between the two measurements as the objective variable, and treatment and attendance at work as explanatory variables. There were no significant differences in resilience abilities between pre‐ and postmeasurement for the subjects as a whole. However, tests for the subgroups of diagnostic category, attendance at work, and treatment showed that resilience improved significantly in the mood disorder group, the leaving employment group, and the group receiving additional treatment. The results of the multiple regression analysis showed that treatment type (with or without additional treatment) had an effect on the degree of change in resilience, and among these “inpatient treatment” and “re‐work program” were suggested to have an effect. The resilience of workers with mental health disorders was found to improve even after only 3 months of treatment, depending on the content of the treatment. We believe the significance of this study is the quantitative indication of the transition of resilience, which has not been made concrete until now.
... Treatment-resistant depression (TRD) has become one of the major concerns of psychiatry nowadays. Pharmacotherapy, psychotherapy and electroconvulsive therapy are usually used as standard treatment options for, however not all of the patients respond to these methods, even when combined (1,2). Novel methods such as Transcranial Magnetic Stimulation (including deep and theta burst protocols, iTBS) and Deep Brain Stimulation (DBS) can be considered as alternative treatment options for TRD patients (2)(3)(4). ...
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Background Treatment-resistant depression remains one of the main concerns of modern psychiatry. Novel methods such as Transcranial Magnetic Stimulation (including deep and theta burst protocols, iTBS) and Deep Brain Stimulation (DBS) can be considered as alternative treatment options. Case presentation Twenty-nine-year-old Caucasian female, single, higher-educated was treated with major depressive disorder initially with standard pharmaco- and psychotherapy. Due to diagnosed treatment resistance additional therapeutic approaches were introduced sequentially: Electroconvulsive therapy (efficient only 4 months) and Transcranial Magnetic Stimulation (intermittent Theta Burst Stimulation, iTBS improved just insomnia). Finally the patient was enrolled to the Deep Brain Stimulation (DBS) study with the medial forebrain bundle target. After 20 months of active DBS a reduction of over 80% of depressive symptom severity was observed (Montgomery-Asberg and Hamilton Depression Rating Scales), together with an 87% reduction of anxiety symptoms intensity (Hamilton Anxiety Rating Scale) and a 90% increase in social and occupational functioning. Subjective assessment of the patient performed with questionnaires and visual analog scales showed less pronounced improvement in terms of depressive and anxiety symptoms, and high reduction of anhedonia. Some mild, transient side effects of neurostimulation were eliminated with an adjustment in stimulation parameters. Conclusions The presented clinical case confirms the possibility of achieving remission after the use of MFB DBS in treatment-resistant depression, but postponed for many months. Nevertheless, personalization of every combined therapy with DBS is necessary with exploration of individual factors as past traumas and personality traits. More reports on long-term observations in DBS treatment in TRD trials (especially focused on MFB target) are needed.
... Although matching the pathology to a certain extent with the molecules and pathways involved can draw a subjective classification, more evidence is needed to extrapolate findings to the therapeutic regimens [1]. The major challenge in treating the patients with MDD is the inherent heterogeneity in response rates toward the commonly used antidepressants, the serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) [2]. Therefore, it is imperative to work systematically toward understanding the underlying causative and predictive biological differences in the patients. ...
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Background BDNF exon IV promoter methylation is a potential biomarker for treatment response to antidepressants in MDD. We have previously shown CpG-87 methylation as a successful biomarker for the prediction of non-response to monoaminergic antidepressants like the SSRI Fluoxetine or the SNRI Venlafaxine. This study aimed to dissect the biological evidence and mechanisms for the functionality of CpG-87 methylation in a cell culture model. Results We observed a significant interaction between methylation and antidepressant-mediated transcriptional activity in BDNF exon IV promoter. In addition, antidepressant treatment increased the promoter methylation in a concentration-dependent manner. Further single CpG methylation of -87 did not change the promoter activity, but methylation of CREB domain CpG-39 increased the transcriptional activity in an antidepressant-dependent manner. Interestingly, DNMT3a overexpression also increases the BDNF exon IV transcription and more so in Venlafaxine-treated cells. Conclusions The study strengthens the previously reported association between antidepressant treatment and BDNF exon IV promoter methylation as well as hints toward the mechanism of action. We argue that potential CpG methylation biomarkers display a complex synergy with the molecular changes at the neighboring CpG positions, thus highlighting the importance of epiallele analyses.
... Treatment-resistant depression (TRD) is characterized by resistance to antidepressant medications, although there is no universal de nition of TRD, and it remains controversial what exactly quali es as TRD in terms of the number of antidepressant classes used in treatment, duration of pharmacotherapy, and number of unsatisfactory responses to medications (Pandarakalam, 2018). However, in essence, TRD is generally de ned as 'failure to respond' to two or more treatments in an 'adequate dose and duration' of antidepressants (Jaffe et al., 2019;Olchanski et al., 2013). ...
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Background The objectives of this study were to investigate the proportion of treatment-resistant depression (TRD) among patients with diagnosed major depressive disorder (MDD), to estimate the economic cost of MDD and TRD, and to examine the differences between MDD and TRD in a Thai public tertiary hospital. Methods This was a combined study between retrospective review of medical records and a cross-sectional survey. The sample size was 500 dyads of MDD patients and their unpaid caregivers. The concept of healthcare resource utilization, the Work Productivity and Activity Impairment Questionnaire: depression and mood & mental state versions (WPAI: D, MM), the Class Impairment Questionnaire (CIQ), and the Family Experiences Interview Schedule (FEIS) were applied as the tools of the study. Pearson Chi’s square, Fisher’s Exact test, and independent T-test were employed for statistical analysis. Results The proportion of TRD was 19.6% among MDD patients in a Thai tertiary public hospital. Age, age of onset of MDD, BMI, history of suicide attempt and self-harm, and frequent smoking behavior were significantly associated with TRD. The annualized economic cost of TRD was 276,059.97 baht per person ($7,668.33), which was significantly higher than this cost of non-TRD (173,487.04 baht or $4,819.08). The aggregated economic costs of MDD were 96.8 million baht annually ($2.69M) if calculated from 500 MDD patients and unpaid caregivers. This contributed to the economic cost of TRD 27.05 million baht (98 respondents) and the economic cost of non-TRD 69.74 million baht (402 respondents). Conclusions The economic cost of TRD was significantly higher than those of non-TRD, especially direct medical costs and indirect costs.
... The WHO has declared depression to be the leading cause of disability worldwide, affecting more than 264 million people (WHO 2020), with anxiety disorders affecting similar numbers (Ritchie and Roser 2018). While there are psychological and pharmaceutical treatments available, a considerable proportion of individuals are unresponsive to these approaches and/or suffer severe side effects (Ansara 2020;Hui Poon et al. 2015;Pandarakalam 2018). Moreover, it is difficult to study the neurobiology of affective disorders in humans because diagnosis is generally based on subjective self-reported symptoms which tend to be highly heterogeneous; for example, depression is multifaceted, and not all depressive symptoms are found in each individual with depression (Krishnan and Nestler 2008;Wang et al. 2017). ...
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Rationale There is an urgent need to identify behaviours in animals that can provide insight into the aetiology and potential treatment of depression in humans. Objectives This study aimed to validate a repeated measures cognitive affective bias (CAB) test in a rat model of chronic stress and compare CAB with forced swim test (FST) measures. Methods Male and female Sprague Dawley rats were trained to associate large and small rewards with scent, spatial, and tactile cues, and their response to an ambiguous tactile stimulus tested. Rats underwent weekly CAB testing for 4 weeks with no intervention, or for 2 weeks of chronic restraint stress (CRS), followed by 2 weeks of fluoxetine, vehicle, or no treatment. CRS rats also underwent the FST at selected timepoints. Results In control rats, CAB was positive and remained stable over the 4-week period. In CRS-fluoxetine and CRS-vehicle groups, CAB was initially positive, became negative during chronic restraint stress, and returned to positive by 2 weeks after treatment. However, in the CRS-no treatment group, CAB was variable at the outset and unstable over time. Behaviour in the FST was not affected by treatment, and there was no correlation between CAB and FST outcomes. Conclusions Instability in the CRS-no treatment group precluded interpretation of the impact of fluoxetine on CAB post-CRS. Our results suggest that behaviour in the FST does not reflect or alter affective state and support the use of CAB tests as part of the behavioural testing repertoire for preclinical animal models of affective disorders.
... The first search yielded a total of fourteen review studies focusing specifically on the topic of how the concept of TRD is defined and operationalized. They either focused on definitions of TRD and staging models (Brown et al., 2019;Demyttenaere & Van Duppen, 2019;Gaynes et al., 2020;Malhi & Byrow, 2016;McIntyre et al., 2014;Ng et al., 2019;Pandarakalam, 2108;Ruhé, Van Rooijen, Spijker, Peeters, & Schene, 2012;Sackeim et al., 2019;Trevino, McClintock, McDonald Fischer, Vora, & Husain, 2014), or on the emerging shift away from the concept of TRD, in favor of the alternative notion of 'difficult to treat' depression (Cosgrove, Naudet, Hiogberg, Shaughnessy, & Cristea, 2020;Demyttenaere, 2019;McAllister-Williams et al., 2020;Rush, Aaronson, & Demyttenaere, 2019). All were published after 2012, the year in which PubMed started using the MeSH index term 'Treatment-Resistant Depression'. ...
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Background: Irremediability is a key requirement for euthanasia and assisted suicide for psychiatric disorders (psychiatric EAS). Countries like the Netherlands and Belgium ask clinicians to assess irremediability in light of the patient's diagnosis and prognosis and 'according to current medical understanding'. Clarifying the relevance of a default objective standard for irremediability when applied to psychiatric EAS is crucial for solid policymaking. Yet so far, a thorough examination of this standard is lacking. Methods: Using treatment-resistant depression (TRD) as a test case, through a scoping review in PubMed, we analyzed the state-of-the-art evidence for whether clinicians can accurately predict individual long-term outcome and single out irremediable cases, by examining the following questions: (1) What is the definition of TRD; (2) What are group-level long-term outcomes of TRD; and (3) Can clinicians make accurate individual outcome predictions in TRD? Results: A uniform definition of TRD is lacking, with over 150 existing definitions, mostly focused on psychopharmacological research. Available yet limited studies about long-term outcomes indicate that a majority of patients with long-term TRD show significant improvement over time. Finally, evidence about individual predictions in TRD using precision medicine is growing, but methodological shortcomings and varying predictive accuracies pose important challenges for its implementation in clinical practice. Conclusion: Our findings support the claim that, as per available evidence, clinicians cannot accurately predict long-term chances of recovery in a particular patient with TRD. This means that the objective standard for irremediability cannot be met, with implications for policy and practice of psychiatric EAS.
... Consequently, the discovery of better, safer, and more effective pharmaceuticals is continually required across the globe. Antidepressants based on the monoaminergic insufficiency theory, in particular, play an important role in medical practice, but they are also linked to treatment resistance in 33% of cases [9]. ...
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Evidence shows that inflammatory responses may encompass the onset of severe depressive illness. Traditionally used licorice contains 18β-glycyrrhetinic acid (18βGA), which has been demonstrated to reduce inflammation and oxidative stress. This study investigates the antidepressant effects of 18βGA and the underlying mechanism in rats exposed to chronic unpredictable mild stress (CUMS). Wistar rats were exposed to CUMS for 36 consecutive days to establish depression. 18βGA (10, 20, and 50 mg/kg) or fluoxetine was given once daily (from day 30 to day 36). Thereafter, behavior parameters (sucrose preference test, forced-swimming test, open-field test, body weight), pro-inflammatory cytokines, neurotransmitters, adrenocorticotropic hormone (ACTH), corticosterone (CORT), and liver biomarkers were studied. Immunohistochemistry and western blot analyses were conducted to investigate the protein’s expression. 18βGA (20 and 50 mg/kg) treatment increased sucrose intake, locomotion in the open-field test, decreased immobility time in the forced swim test, and improved body weight in CUMS-exposed rats. The therapy of 18βGA dramatically declined cytokines, ACTH and CORT and improved 5HT and norepinephrine in CUMS rats. Furthermore, BDNF and TrkB proteins were down-regulated in CUMS group, which was increased to varying degrees by 18βGA at doses of 20 and 50 mg/kg. Therefore, 18βGA ameliorates depressive-like behavior persuaded by chronic unpredictable mild stress, decreases neuroinflammation, liver biomarkers, stress hormones, and improves body weight, brain neurotransmitter concentration via activating on BDNF/TrkB signaling pathway in both PFC and hippocampus in rats. Graphical Abstract
... It is also very common a decrease in therapeutic efficacy with each new treatment, leading to treatment-resistant depression (TRD) [4]. Besides the social and economic burden in terms of health care costs and unemployment, [5], TRD is also associated with increased mortality, functional impairment, and recurrent episodes in the long term [6]. All these aspects suggest that an effective management of MDD may have a huge impact in society, both from an economic and social perspective. ...
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Major depressive disorder (MDD) is a debilitating mental illness. For years, the research and development of drugs to treat MDD focused on the monoaminergic system, leading to the introduction in the market of several drugs, namely tricyclic antidepressants, selective serotonin/noradrenaline reuptake inhibitors and monoamine oxidase inhibitors. Nonetheless, patients continue to experience low remission rates, frequent relapses and persistent functional impairment. These drawbacks emphasize the need to studying alternative therapeutic targets in order to improve depression treatment efficacy. Herein, ascorbate role in the pathophysiology of MDD will be discussed, particularly through the modulation of the glutamatergic system. Moreover, pre-clinical and clinical data regarding the antidepressant effect of ascorbate in affective disorders will be reviewed. The electronic database Pubmed was searched from 2005 to the present date, and the following keywords were searched: “ascorbate”, “glutamate”, “major depressive disorder”, “depression”, “ascorbic acid”, and “vitamin C”. Overall, 31 studies were retrieved, evidencing ascorbate efficacy on reversing depressive symptoms associated with MDD through the modulation of glutamatergic signalling, namely the L-Arginine-NO-cGMP pathway. The collected evidence supports the high potential of ascorbate in the research of new treatment strategies for MDD and it is expected to be very useful for the development of new target-antidepressant drugs.
... In the past decades, with further research on the mechanism of depression, several effective medication are available, however, the therapeutic effect is variable and incomplete and only up to 50 % of patients achieve remission with receiving conventional antidepressant therapies targeting on restoring the balance of monoaminergic neurotransmitters and/or neuromodulators, such as 5-hydroxytryptamine (5-HT), dopamine and noradrenaline (Pandarakalam, 2018;Paris, 2014). Therefore, innovative conceptual frameworks are urgently needed for further research the mechanism of depression and to develop efficient therapeutic strategies. ...
Article
Depression is accompanied by excessive neuroinflammation. Liver X receptor β (LXRβ) has been reported as a newly emerging target that exerts systemic and organic inflammation modulation. However, the modulatory mechanism in alleviating neuroinflammation are far from being revealed. In the current study, depression-related behaviors in mice were induced by chronic unpredictable mild stress (CUMS) and corticosterone (CORT) drinking. Mice received either TO901317, PLX-5622 and intra- bilateral basolateral amygdale (BLA) injection of rAAV9-hSyn-hM3D(Gq)-eGFP to activate LXRβ, eliminate microglia and pharmacogenetic activate neurons in BLA, respectively, followed by behavioral tests. Microglial pro-inflammatory and pro-phagocytic activation, as well as nuclear factor-κB (NF-κB) signaling pathway, NLRP3 inflammasome activation and interleukin-1β (IL-1β) release in BLA were investigated. Moreover, pro-inflammatory activation of BV2 cells-induced by CORT with or without TO901317 was detected. Neuroinflammation indicated by IL-1β release was measured in a co-culture system of HT22-primary microglia with or without TO901317. Our results indicated that chronic stress induced depression-related behaviors, which were accompanied with microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation in BLA. Accordingly, pharmacological activation of LXRβ inhibited microglial pro-inflammatory and pro-phagocytic activation, as well as NF-κB signaling pathway and NLRP3 inflammasome activation, and IL-1β release both in vivo and in vitro. Finally, both elimination of microglia and pharmacogenetic activation of neurons in BLA protected mice from chronic stress-induced depression-related behavior. Collectively, pharmacological activation of neuronal-microglial LXRβ alleviates depression-related behavior by modulating excessive neuroinflammation via inhibiting NF-κB signaling pathway and NLRP3 inflammasome activation.
Article
S-adenosyl-l-methionine (SAMe), a methyl donor, induces antidepressant effects in preclinical and clinical studies of depression. However, the mechanisms behind these effects have been poorly investigated. Since SAMe is involved in monoamine metabolism, this work aimed at 1) testing the effects induced by systemic treatment with SAMe in mice submitted to the forced swimming test (FST) and tail suspension test (TST); 2) investigating the involvement of serotonergic neurotransmission in the behavioral effects induced by SAMe. To do that, male Swiss mice received systemic injections (1 injection/day, 1 or 7 days) of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), SAMe (10, 25, 50, 100, and 200 mg/kg), or vehicle (10 ml/kg) and were submitted to the FST or TST, 30 min after the last injection. The effect of SAMe (50 mg/kg) was further investigated in independent groups of male Swiss mice pretreated with p-chlorophenylalanine (PCPA, serotonin synthesis inhibitor, 150 mg/kg daily, 4 days) or with WAY100635 (5-HT1A receptor antagonist, 0.1 mg/kg, 1 injection). One independent group was submitted to the FST and euthanized immediately after for collection of brain samples for neurochemical analyses. Serotonin (5-HT) and noradrenaline (NA) levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, to investigate if the treatments used could induce any significant exploratory/motor effect which would interfere with the FST results, the animals were also submitted to the open field test (OFT). The administration of imipramine (30 mg/kg), L-methionine (400, 800, 1600, and 3200 mg/kg), and SAMe (10 and 50 mg/kg) reduced the immobility time in the FST, an effect blocked by pretreatment with PCPA and WAY100635. None of the treatments increased the locomotion in the OFT. In conclusion, our results suggest that the antidepressant-like effects induced by SAMe treatment are dependent on serotonin synthesis and 5-HT1A receptor activation.
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Depression has been considered essentially a psycho-bio, social condition. In this paper, a hypnotic/quantum approach to understanding depression is attempted and parallel or co-thinking is designated as quantum thinking, one of the main sources of depressive cognitions. It is the flexibility of the quantum brain that accounts for cognitive distortions. Hypnosis may involve a spectrum of quantum consciousness and has great research value in uncovering non-biological depression. Like many of the alternate states of consciousness, hypnosis may be a neuro-quantum state. In the earlier part of the 2oth century, Frederic Myers recognised that the middle realm of the unconscious mind is the “hypnotic stratum” and is associated with deep hypnosis. The unconscious is increasingly allied with the quantum and it is time to revise the concept of the Freudian unconscious accordingly. The co-existence of a quantum mechanical body and brain is all the time more recognised now in parasciences. If consciousness is transmitted through rather than actually produced by the brain, depression may have a downward causation rather than an upward causation arguable in biological disorders like schizophrenia and bipolar disorder. Consciousness-based healing is warranted in the treatment of depression. Whether consciousness is the primary generator of clinical depression or it only contributes to the genesis of depression will continue to be a matter for debate in the foreseeable future.
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Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such ‘non-standard’ interventions. This analysis proposes a framework to aid this decision. Declaration of interest In the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck. In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.
Article
Although in common use, treatment-resistant depression is unhelpful both conceptually and practically. In this issue a new term, multiple-therapy-resistant major depressive disorder, is proposed; although it may be useful in guiding treatment options for patients with persisting depression, it should not be an automatic trigger for further, more invasive treatments. Declaration of interests I.M.A. has been a consultant for pharmaceutical companies developing and marketing antidepressants and has been an author on publications that have used the term treatment-resistant depression.
Article
Background Many studies have documented robust relationships between depression and hopelessness and subsequent suicidal thoughts and behaviours; however, much weaker and non-significant effects have also been reported. These inconsistencies raise questions about whether and to what degree these factors confer risk for suicidal thoughts and behaviours. Aims This study aimed to evaluate the magnitude and clinical utility of depression and hopelessness as risk factors for suicide ideation, attempts and death. Method We conducted a meta-analysis of published studies from 1971 to 31 December 2014 that included at least one longitudinal analysis predicting suicide ideation, attempt or death using any depression or hopelessness variable. Results Overall prediction was weaker than anticipated, with weighted mean odds ratios of 1.96 (1.81–2.13) for ideation, 1.63 (1.55–1.72) for attempt and 1.33 (1.18–1.49) for death. Adjusting for publication bias further reduced estimates. Effects generally persisted regardless of sample severity, sample age or follow-up length. Conclusions Several methodological constraints were prominent across studies; addressing these issues would likely be fruitful moving forward. Declaration of interest None.
Article
Objective: The Prolonging Remission in Depressed Elderly (PRIDE) study evaluated the efficacy of right unilateral ultrabrief pulse electroconvulsive therapy (ECT) combined with venlafaxine for the treatment of geriatric depression. Method: PRIDE was a two-phase multisite study. Phase 1 was an acute course of right unilateral ultrabrief pulse ECT, combined with open-label venlafaxine at seven academic medical centers. In phase 2 (reported separately), patients who had remitted were randomly assigned to receive pharmacotherapy (venlafaxine plus lithium) or pharmacotherapy plus continuation ECT. In phase 1, depressed patients received high-dose ECT (at six times the seizure threshold) three times per week. Venlafaxine was started during the first week of treatment and continued throughout the study. The primary outcome measure was remission, assessed with the 24-item Hamilton Depression Rating Scale (HAM-D), which was administered three times per week. Secondary outcome measures were post-ECT reorientation and safety. Paired t tests were used to estimate and evaluate the significance of change from baseline in HAM-D scores. Results: Of 240 patients who entered phase 1 of the study, 172 completed it. Overall, 61.7% (148/240) of all patients met remission criteria, 10.0% (24/240) did not remit, and 28.3% (68/240) dropped out; 70% (169/240) met response criteria. Among those who remitted, the mean decrease in HAM-D score was 24.7 points (95% CI=23.4, 25.9), with a mean final score of 6.2 (SD=2.5) and an average change from baseline of 79%. The mean number of ECT treatments to remission was 7.3 (SD=3.1). Conclusions: Right unilateral ultrabrief pulse ECT, combined with venlafaxine, is a rapidly acting and highly effective treatment option for depressed geriatric patients, with excellent safety and tolerability. These data add to the evidence base supporting the efficacy of ECT to treat severe depression in elderly patients.
Article
Objective: The randomized phase (phase 2) of the Prolonging Remission in Depressed Elderly (PRIDE) study evaluated the efficacy and tolerability of continuation ECT plus medication compared with medication alone in depressed geriatric patients after a successful course of ECT (phase 1). Method: PRIDE was a two-phase multisite study. Phase 1 was an acute course of right unilateral ultrabrief pulse ECT, augmented with venlafaxine. Phase 2 compared two randomized treatment arms: a medication only arm (venlafaxine plus lithium, over 24 weeks) and an ECT plus medication arm (four continuation ECT treatments over 1 month, plus additional ECT as needed, using the Symptom-Titrated, Algorithm-Based Longitudinal ECT [STABLE] algorithm, while continuing venlafaxine plus lithium). The intent-to-treat sample comprised 120 remitters from phase 1. The primary efficacy outcome measure was score on the 24-item Hamilton Depression Rating Scale (HAM-D), and the secondary efficacy outcome was score on the Clinical Global Impressions severity scale (CGI-S). Tolerability as measured by neurocognitive performance (reported elsewhere) was assessed using an extensive test battery; global cognitive functioning as assessed by the Mini-Mental State Examination (MMSE) is reported here. Longitudinal mixed-effects repeated-measures modeling was used to compare ECT plus medication and medication alone for efficacy and global cognitive function outcomes. Results: At 24 weeks, the ECT plus medication group had statistically significantly lower HAM-D scores than the medication only group. The difference in adjusted mean HAM-D scores at study end was 4.2 (95% CI=1.6, 6.9). Significantly more patients in the ECT plus medication group were rated "not ill at all" on the CGI-S compared with the medication only group. There was no statistically significant difference between groups in MMSE score. Conclusions: Additional ECT after remission (here operationalized as four continuation ECT treatments followed by further ECT only as needed) was beneficial in sustaining mood improvement for most patients.
Article
Up to one third of pa­tients ad­e­quately treated for Ma­jor De­pres­sive Dis­or­der (MDD) do not re­spond to mul­ti­ple in­ter­ven­tions. Many stud­ies in­ves­ti­gated pre­dic­tors in MDD out­come, but no study fo­cused on pre­dic­tors of non-re­sponse or non-re­mis­sion to an­ti­de­pres­sants in sub­jects with treat­ment re­sis­tant de­pres­sion (TRD). The pre­sent study aimed to eval­u­ate pos­si­ble so­cio-de­mo­graphic and clin­i­cal pre­dic­tors of non-re­sponse and non-re­mis­sion in MDD pa­tients who failed to ben­e­fit from at least one an­ti­de­pres­sant trial. A to­tal of 51 pa­pers were in­cluded. A num­ber of sever­ity in­di­ca­tors, such as longer du­ra­tion of de­pres­sive episode, mod­er­ate-high sui­ci­dal risk, anx­ious co­mor­bid­ity, higher num­ber of hos­pi­tal­iza­tions and higher dosage of antidepressants, were as­so­ci­ated with non-re­sponse as well as age. In­ter­est­ingly, sever­ity of ill­ness, as well as co­mor­bid per­son­al­ity dis­or­ders and anx­i­ety symp­toms, had also a pre­dic­tive value in non-re­mis­sion with the ad­di­tion of mar­i­tal sta­tus. Con­sid­er­ing lim­i­ta­tions, se­lected stud­ies were ob­ser­va­tional or ran­dom­ized non con­trolled/ con­trolled tri­als and dif­fer­ent TRD de­f­i­n­i­tions and out­come mea­sures were used. Over­all, pre­dic­tors of out­come were sim­i­lar to MDD, but spe­cific so­cio-de­mo­graphic and clin­i­cal fac­tors should be con­sid­ered in clin­i­cal prac­tice to for­mu­late a more fo­cused treat­ment in TRD pa­tients.
Article
What is the role of electroconvulsive therapy (ECT) in the treatment of mood disorders, especially treatment-resistant depression (TRD)? While many have thought that ECT has been replaced by pharmacotherapy, ECT is still frequently used, with the number of treatments conducted annually in the United States exceeding coronary bypass, appendectomy, tonsillectomy, and hernia repair. Controlled studies and clinical experience indicate that the short-term efficacy of ECT in major depression is comparable, and likely superior, to that of any other antidepressant treatment. Patients with TRD consume a disproportionate share of medical resources and this condition often presents extraordinary burdens to the individual, family, and society. Relative to any other antidepressant treatments, ECT has the highest rate of response/remission, the fastest onset of symptom relief, and the most complete symptom relief. However, ECT has two major drawbacks that limit its use: its effects on memory and high rate of relapse. Current research is directed at improving cognitive outcomes and identifying more effective prophylactic treatment following ECT. Novel innovations include methods to produce seizures with focal onset and limited propagation. Such modifications have the potential to markedly reduce the adverse effects of ECT without compromising efficacy.
Article
Context Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. Objective To test the efficacy and safety of a well-characterized H perforatum extract (L1-160) in major depressive disorder. Design and Setting Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Participants Adult outpatients (n=340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Interventions Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Main Outcome Measures Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. Results On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was-9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P=.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P=.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P=.21) and 24.8% of sertraline-treated patients (P=.26). Sertraline was better than placebo on the CGI improvement scale (P=.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. Conclusion This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.