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The Management of
Treatment Resistant
Depression
Rajini Ramana
Outline of talk

Definitions of Treatment Resistant
Depression (TRD)

Disease burden

Course and outcome
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Evaluation of adequacy/efficacy of
treatment
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Treatment strategies
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Service delivery issues
Stages of Treatment and
Response
Definition of TRD
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Syndrome of unipolar depression.
Failure of at least two to three courses of
different antidepressant treatment which has
been adequate in terms of dose, duration and
concordance ( plus psychotherapy).
Absence of any untreated co-morbid physical
or psychiatric condition or psychosocial
dysfunction.
Consider rapid/ultrarapid metabolizers:
cytochrome P450 2D6 (CYP2D6 gene
duplication).
Wijeratne and Sachdev , ANZJPsych 2008; 42, 751-762
Definition(s) of TRD
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Little consensus on how many trials of
treatment should fail before TRD is
diagnosed.
What is treatment failure?

Failure to achieve remission
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Failure to maintain remission
Pseudo-resistance ( non-response to Rx
due to inadequate dose/duration or
inaccurate Dx) in 50% of people with MDD
who are diagnosed as TRD.
What is the scale of the
problem?
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Estimates vary from 15% to 30% of those
with MDD, depending on criteria used.
If absence of remission is used as a
criterion this rises to 40- 60%.
Prolonged duration and disability results in
protracted periods of impaired functioning.
High economic burden.
Co-morbid physical and mental disorders
are common.
Who is likely to get TRD
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Those with co-morbid conditions- physical
illness/personality disorders/substance misuse.
Sub-types of depression- unrecognised bipolar
depression, psychotic depression.
Patient characteristics- early age of onset, females,
family history, environmental stressors.
Treatment issues- poor concordance, pseudo resistance, poor service delivery leading to delays in
onset of Rx.
Course and outcome

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Treatment resistance portends treatment
resistance, even to ECT
Prolonged duration of an episode is one of
the most consistent predictors of TRD.
Prolonged duration of depression is also
associated with evidence of hippocampal
atrophy
Inadequate treatment may be an iatrogenic
cause of TRD due to prolongation of
episode
NICE Guidelines for Depression (Updated
2009)
For a person whose depression has failed to respond to
pharmacological or psychological interventions:

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Consider combining them
Consider referral to a practitioner with a specialist interest
Conduct full assessment
Develop a multidisciplinary care plan (NICE, 2009)
Re-introduce treatments that have been inadequately
delivered
Operational definitions of
antidepressant response.

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Non -response
Partial response- >25% and <50%
reduction in depression rating scale scores
Treatment response- > 50% reduction with
a final HDRS score of <15
Remission- absence of symptoms and/or
no residual symptoms for a sustained
period
Recovery – sustained remission for at least
8 weeks.
Staging criteria for treatment
resistant depression
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Thase and Rush Staging Model { J Clin Psych 1997 58(S13)
23-29}
Hierarchical model that assumes that drugs will be
prescribed in a sequential manner, with those at the
higher level being more efficacious and ECT is the
treatment of last resort.
No clear provisions for augmentation and combination
strategies.
Limited flexibility and hard to use when many drugs
have been used.
Assumes that switching within classes is superior to
between classes.
Massachusetts General Hospital
(MGH) Staging Method for TRD
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Nonresponse to each adequate ( at least 6 wks
of an adequate dose) trial generates an overall
score of resistance ( 1 point per trial)
Optimization of dose, duration and
augmentation/combination of each trial ( based
on the MGH or Antidepressant Response
Questionnaire) increase the overall score ( 0.5
point per trial per optimization/strategy)
ECT increases score by 3 points
(Fava, M,2003 Biol Psychiatry, 53, 649-659)
Maudsley Staging Method
Fekadu et al J Clin Psychiat 2009 70 177-183
Parameter/dimension
Parameter Specification
Score
Duration
Acute (12 months)
1
Sub-acute (13-24mths)
2
Chronic (>24 mths)
3
Subsyndromal
1
Symptom severity at baseline
Syndromal
Mild
2
Moderate
3
Severe without psychosis
4
Severe with psychosis
Treatment Failures
Augmentation
ECT
Total
5
Level 1
1-2 Rx
1
Level 2
3-4 Rx
2
Level 3
5-6 Rx
3
Level 4
7-10 Rx
4
Level 5
>10 Rx
5
Used
0
Not used
1
Used
0
Not used
1
( 15)
Evaluating adequacy of
treatment
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Dosage/maximum dosage ( blood levels).
Duration- acute/continuation and
maintenance phase Rx.
Concordance – very difficult to evaluate
adequately. 80 % is probably 'good
enough'.
Outcome – remission (partial or full) or
recovery .
Assessment of Adequacy

Antidepressant Treatment History Form
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Most commonly used instrument
Adequate doses (  3) are the minimal dose
shown to be effective in RCTs.
Does not distinguish between response and
remission
Does not rate other interventions

Sackeim J Clin Psychiatry 2001 62 (suppl 16) 10-17
Initial Assessment

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Careful history of course of the illness
Meticulous drug history.
Comprehensive personal, physical, psychiatric
and social history.
History from an informant is essential.
Physical examination/ investigations
Consider using rating scales/other tools
Develop a shared understanding with the
patient about the pathogenesis and the
progression of the illness as well as that of
maintaining factors.
General measures

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Psycho-education and collaborative care plan involving
carers is essential.
Develop a stepped treatment model, explaining the steps
of treatment ( pharmacological, psychological and
support).
Address deficits in functioning- whether these are due to
ruminations or lack of motivation and concentration.
Activity scheduling can help.
General physical measures including diet and exercise.
Careful and objective monitoring of response ( HDRS,
MADRS, QIDS, IDS-SR) and tolerance to Rx.
Instillation of (realistic) hope - no therapeutic nihilism!
Treatment options
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Pharmacological
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Somatic treatments
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Optimise current regime
Switching : within class or between classes of ADs
Combination
Augmentation
ECT
Vagus nerve stimulation
Transcranial magnetic stimulation
Deep brain stimulation
Ablative limbic system surgery
Psychological
Ensure Rx adherence
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Patient self- report
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Pill diaries
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Pill counts
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Medication event monitoring (MEM)
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Plasma drug levels even if there is no
correlation with Rxic effect
Enlist help of carers/partners
Evidence for increased
duration
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How long is an adequate trial?
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Some studies, especially drug company
funded studies say 4 weeks
STAR*D showed that patients were still
responding at 12 weeks
NORDEP showed that there can be a 4-14%
response in weeks 6-12 ( BMJ 318, 1180-1184)
Co-morbid conditions, physical frailty,
personality disorders, elderly may need longer
Dosage optimization
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Use maximum or maximum tolerated dose for
all drugs.
Decrease dose if adverse effects are
outweighing drug effects.
Evidence supporting increase dose is mainly
anecdotal, though it is standard practice.
No direct evidence for increasing dose after
initial non-response. Indirect evidence
suggests dose response (II) for TCAs,
venlafaxine and escitalopram. (BAP 2008)
Evidence for Switching ADs
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Limited data
Treatment of SSRI-Resistant Depression: A Meta-Analysis
Comparing Within-Versus Across-Class Switches(Papakostas
et al. 2008)
–Data from four clinical trials (n = 1496)
–Patients randomized to switch to a non-SSRIantidepressant
(bupropion, mirtazapine, venlafaxine) vs second SSRI
•Out of class more likely to experience remission(risk ratio =
1.29, p = .007).
•Remission rates 28% (for non-SSRIs) and 23.5% (for SSRIs).
•NNT = 22(NB NICE suggest should be < 10)
MAOIs
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Used less frequently due to side effects, need for
wash-outs and dietary restrictions, but are useful
especially with ‘atypical symptoms’.
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Quitkin et al 1989; Archives of General Psychiatry, 46, 787–793
Tranylcypromine was included in Level 4 of STAR*D,
but was found to be non-significantly less effective
that the combination of venlafaxine and mirtazepine.
Can be combined with Lithium and TCAs ( with
caution and as inpatients only)

Kennedy, N. & Paykel, E. S. (2004) Treatment and response in
refractory depression: results from a specialist affective
disorders service. Journal of Affective Disorders, 81, 49–53.
Augmentation
Using a psychotropic drug that is not primarily indicated for
depression to enhance the effect of an antidepressant.

In doing so the augmenting drug either broadens the
therapeutic effect or the neurochemical effect .
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Advantages include
Quicker initiation
No loss of initial response
Avoidance of withdrawal symptoms
Disadvantages- polypharmacy and reduced concordance


Cowen P J Advances in Psychiatric Treatment (2005), vol. 11, 19–27
Lithium
Good evidence supporting the use of lithium for many years
from the 1980s.
Montigny de C, Grunberg F, Mayer A, Deschenes JP: Lithium induces rapid
relief of depression in tricyclic antidepressant drug
non-responders. Br J Psychiatry 1981; 138:252–256
A pooled odds ratio of 3.31 for response with lithium
augmentation compared to response with placebo was found
for the trials that used a minimum dose of 800 mg/day of
lithium carbonate or a dose sufficient to obtain serum lithium
levels of ≥0.5 meq/liter and had a minimum treatment duration
of 2 weeks.
Bauer M, Döpfmer S: Lithium augmentation in treatmentresistantdepression: meta-analysis of placebo-controlled studies. J Clin
Psychopharmacol 1999; 19:427–434
Thyroid hormones
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T3- at doses of 20 to 40 mcgs
Evidence largely for use with TCAs, but evidence of
effectiveness is not compelling
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High dose T4 to induce mild hyperthyroidism, though
risks are considerable.

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Joffe et al 1993; Archives of General Psychiatry, 50, 387–393
Aronson et al (1996) Archives of General Psychiatry, 53, 842–848.
Bauer et al 1990; Neuropsychopharmacology, 18, 444–455
Monitor for decreased bone density and atrial
fibrillation in patients at risk.
Other drugs
Pindolol:
β-adrenoceptor antagonist with 5-HT1A
receptor antagonist properties. Might augment
the action of SSRIs by blocking the inhibitory
action of 5-HT1A autoreceptors in the raphe
nucleus.
Buspirone
5HT1A partial agonist that blunts the negative
effects of increased synaptic serotonergic
effects on the pre-synaptic 5HT1A receptor.
Other drugs
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Anticonvulsants- lamotrigine, gabapentin,
topiramate, carbamazepine and Na valproate.
Side effects and drug interactions can be a
problem.
Psychostimulants that affect dopaminemethylphenidate, dextroamphetamine.
Negative findings in two small RCTs.
Modafinil- found to be effective patients with
hypersomnia and fatigue in two small trials.
Potential newer drugs
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Agomelatine – 5HT2C antagonist and
melatonin-1 agonist, but no data on TRD
Acetylcholine Receptor drugs
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Varenicline -nAChR partial agonist
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Mecamylamine- nAChR antagonist
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Scopolamine -mAChR antagonist
N-Methyl-D aspartate( NMDA) receptor
antagonists ; intravenous ketamine
Summary of evidence for augmentation
(
Philips; 2011 Expert Opin Pharamcother)
Medication
Available data
Comments
Mirtazepine
Positive RCTs STAR*D
Limited data
Bupropion
Multiple open label trials,
STAR*D
No RCTs
Buspirone
Negative RCTs, STAR*D
Ineffectiive in RCTs
T3
Limited RCTs with SSRIs,
positive when combined with
TCAs
Comparable to Lithium in
STAR*D
Lithium
Limited RCTs with SSRIs,
positive with TCAs
Comparable to T3 in STAR*D,
more side effects
Lamotrigine
Negative RCTs
Small Ns, mixed population
Pindolol
Negative RCTs
Positive data for acceleration
Stimulants
Negative RCTs
May have a role for apathy
Summary of evidence for augmentation
with atypicals ( Philips et al 2011)
Medication
Available data
Comments
Aripiprazole
3 positive RCTs, FDA
indication
Negative self reported
outcomes
Olanzapine
One positive RCT, multiple
equivocal RCTs, FDA
indication
Weight gain, metabolic
syndrome
Quetiapine
One negative RCT, two
positive RCTs with XR
formulation
Weight gain, metabolic
syndrome
Risperidone
Two positive RCTs
Trials with short treatment
lead in ( 4 weeks)
All antipsychotics
Response (odds ratio =
1.69) and remission (odds
ratio = 2.00) vs. PBO from
RCTs
Discontinuation rates for
adverse events higher vs.
PBO (odds ratioo=3.91)
Combination
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Aim to supplement the antidepressant effect of an ineffective or partially
effective medication with another antidepressant agent. Use of two agents
produces a broader spectrum of activity on monoamine pathways- adding
noradrenergic or dopaminergic drugs to serotonergic drugs.
Strategies include the use of
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SSRIs/SNRIs with TCAs/mirtazepine
Bupropion with SSRIs
Buspirone to SSRIs
TCAs with MAOIs with/without Lithium
Limited evidence SSRI+mirtazepine ( Level I) , venlafaxine +mirtazepine (
Level III)
Potentiation of side effects and toxicity can be a problem.
(Dodd S, et al To combine or not to combine: a literature
review of antidepressant combination therapy. Journal of Affective
Disorders 2005; 89(1-3): 1-11)
Tryptophan as an AD ( Thomson et al 1982) or in combination ( Levitan et
al 2000)
Summary from STAR*D
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Augmentation with bupropion probably useful.
Switching Step 2 – 1 in 4 remitted- no differences b/w
drugs. Switching to another SSRI is probably
acceptable.
In non-responders to Citalopram- cognitive Rx and
AD comparable outcomes-AD more rapidly effective.
Switching to a third AD monoRx after two
unsuccessful AD’s resulted in low remission rates
(<20%)
Li and T3 had modest effects- T3 appeared more
effective- but Li doses used were lower.
Headlines
When more treatment steps are required,
lower acute remission rates (especially in
the third and fourth treatment steps) and
higher relapse rates during the follow-up
phase are to be expected .
ECT
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Used as a last resort usually.
Earlier use can improve outcome.
Resistance to medication often predicts poor
response to ECT
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Prudic et al 1990 Psychiatric Research, 31 287–296
Relapse rates high after ECT. Those given adequate
Rx prior to ECT are twice as likely to relapse than
those who had inadequate Rx.
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Sackeim et al 1990; Journal of Clinical Psychopharmacology, 10, 96–
104.
Somatic therapies
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Vagal Nerve stimulation
Transcranial magnetic stimulation
Ablative limbic system surgery
Deep brain stimulation
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Good review of these can be found in Dougherty and
Rauch 2007; Psychiatric Clinics of North America 30,
31-38.
Vagus Nerve Stimulation (
VNS)
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Approved by the FDA in 1997 but still controversial in many
countries.
Electrodes placed around the left vagus nerve(LVN) which are
then attached to an internal pulse generator placed
subcutaneously in the subclavicular region.
Intermittent electrical charges of varying magnitude, duration
and frequency can be delivered to the LVN, which innervates
the nucleus tractus solitarius.
VNS device is programmed to deliver intermittent electrical
stimulation to the vagus nerve for 30 seconds every 5 min.
Evidence from clinical trials supports its use in addition to
TAU.
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George et al 2005 Biol Psychiatry 58; 364-373
Transcranial Magnetic stimulation
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Uses a strong magnetic field induced on the scalp
surface to generate focal electrical stimulation of the
cortical surface. Unlike ECT ( where there is a
global stimulation of the cortex) TMS does not need
anaesthesia or generate seizures and is not
associated with cognitive deficits.
High-frequency rTMS administered to the left
dorsolateral prefrontal cortex.
OR
low-frequency stimulation to the right dorsolateral
prefrontal cortex.

Fitzgerald et al Am J Psychiatry 163:1, 2006
Ablative limbic system surgery
Anterior cingulotomy ( AC)
 Subcaudate tractotomy (ST)
 Limbic leucotomy ( AC + ST)
 Anterior capsulotomy
Controversial due to the misuse of lobotomies in the
40s and 50s.
Response rates vary from 30- 70%.
Serious adverse effects include infection,weight gain,
seizures, cerebral infarcts or haemorrhage, cognitive
deficits surprisingly rare and infrequent.
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Deep Brain Stimulation
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Involves the placement of electrodes in specified
brain regions so that electrical stimulation can be
delivered in a targeted manner.
Electrodes are placed in the subgenual cingulate
cortex (Cg25 DBS).
Non – ablative and therefore reversible.
Stimulation can be increased or decreased
depending on the clinical state.

Neimat et al Am J Psychiatry 165:6, June 2008 – an interesting
case report on DBS after failure to respond to a cingulotomy.
Psychological therapies
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Robust evidence that CBT reduces relapse rates and
reduces residual symptoms.

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Considerable local expertise in CBT for chronic
depression
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Paykel et al 1999; Archives of General Psychiatry, 56, 829–835
Moore, R. & Garland, A. (2003) Cognitive Therapy for Chronic and
Persistent Depression. John Wiley and Sons
Cognitive behavioural analysis system (CBASP)

In which bio-psychosocial signs and symptoms of chronic
depression are viewed as the result of either arrested
maturational development at a Piagetian preoperational stage (in
early-onset patients) or heightened emotionality and general
functional regression (in late-onset patients).

Swan and Hull 2007 Advances in Psychiatric Treatment (2007), vol.
13, 458–469
Cognitive Therapy for residual
depressive symptoms
(Paykel et al, 1999, Arch Gen Psychiat)
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Significant residual symptoms following adequate medication
(N=158)
CT+ADM vs ADM over 20 wks
At 20wks, CT more remission (26 vs 12%); less
guilt/hopelessness; better social function
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Over 68wks follow-up, CT reduced relapse (29% vs 47%)

Benefits extended to 3½ years after Tx
Prevention of TRD
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Early identification of depression.
Adequate treatment.
Full remission of symptoms should always
be the goal of treatment in depression.
Identifying those with residual symptoms
(RS) and aggressively treating them.

Paykel E S, Ramana R et al(1995) Residual symptoms after
partial remission- an important outcome in depression; 25:
1171-1180
Useful guidelines
ANDERSON, I. M. et al. Evidence-based guidelines for treating
depressive disorders with antidepressants: a revision of the 2000
British Association for Psychopharmacology guidelines. J
Psychopharmacol, v. 22, n. 4, p. 343-96
LAM, R. W. et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) clinical guidelines for the management of major depressive
disorder in adults. III. Pharmacotherapy. J Affect Disord, v. 117
Suppl 1, p. S26-43, Oct 2009.
Depression: the treatment and management of depression in adults
(update). National Institute for Clinical Excellence. 2009 (CG90)
http://guidance.nice.org.uk/CG90
American Psychiatric Association (2000) Practice guideline for the
treatment of patients with major depressive disorder (revision).
American Journal of Psychiatry, 157, 1-45.