This document discusses treatment options for treatment-resistant depression (TRD). It defines TRD as major depression that does not resolve with adequate antidepressant treatment. Approximately 15-20% of depressed patients will have TRD. Treatment options discussed include optimization or augmentation of antidepressants, switching antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, and vagus nerve stimulation. Future treatment options discussed are novel agents like S-adenosylmethionine and devices like deep brain stimulation. TRD poses substantial economic and disability burdens.

1. TREATMENT OF
RESISTANT
DEPRESSION

3. Depression: a prison
► By the year 2020, unipolar major depression is
projected to be the second leading cause of disability-
adjusted life years (DALYS) all over the world.
► Depressive disorders have great impact morbidity,
health care utilization, and medical costs.
► Despite advances in psychopharmacology, less than
half of patients beginning a course of antidepressant
treatment will reach remission with that treatment
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4. Treatment resistant
depression
► A significant proportion of depressed patients either
do not respond or continue to have residual
symptoms despite treatment with antidepressants.
► Major depression that does not resolve with
adequate antidepressant treatment is termed
Treatment-resistant depression (TRD).
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5. ANNALS OF CLINICAL PSYCHIATRY 2014;26(3):222-232

6. European staging method
ANNALS OF CLINICAL PSYCHIATRY 2014;26(3):222-232

8. Impact of TRD
TRD is associated with extensive use of depression-related and
general medical services and poses a substantial economic
burden.
TRD was also associated with use of 1.4 to 3 times more
psychotropic medications (including antidepressants).
Patients in the hospitalized TRD group had over 6 times the mean
total medical costs of non-TRD patients
Treatment-resistant patients were at least twice as likely to be
hospitalized (general medical and depression related) and had at
least 12% more outpatient visits.
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9. Prevalence of TRD
 TRD is the most debilitating or distressing form of MDD.
 Multiple studies found that approximately 20% of depressed
patients continued to suffer from depression for up to 2 years
after initial onset of a major depressive episode (MDE).
 Despite the completion of multiple antidepressant medication,
15% of patients diagnosed with MDD will continue to suffer from
depression.
 Even among patients who experience a significant reduction in
their depressive symptoms following an adequate antidepressant
trial, 60% to 70% of these patients fail to obtain complete
remission of depressive symptoms.

10. Factors contributing to TRD
► Unrecognized comorbid medical or psychiatric illness,
► The use of concomitant medications, intolerance
► Inadequate treatment of earlier episodes
► Greater number of somatic symptoms and reported history of childhood
emotional abuse and sequelae of that abuse
► Psychotic and melancholic depression
► Noncompliance (up to 50% of patients do not take the medication as
prescribed, and tend to stop treatment when symptoms remit)
► Individual differences in drug metabolism
► Nutritional status of the patient (deficiencies in folate, thiamine, vitamin
B6, vitamin B12, copper, and zinc)
► Psychosocial stressors.
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11. Absolute and relative treatment
resistance
► Absolute treatment resistance: Failure to respond to
one adequate antidepressant trial (i.e, 20-40 mg
fluoxetine or its equivalent, or 4 weeks of 150 mg
imipramine or its equivalent)
► Relative treatment resistance: nonresponse to an
inadequate treatment.
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12. Treatment-refractory depression
► Failure to respond to two drugs of different
pharmacological classes, each used in an adequate dose
for an adequate duration.
► The term Treatment-Refractory Depression also has
been used to describe and/or refer to patients
experiencing TRD.
► Although the term REFRACTORY suggests a greater
degree of resistance, the terms RESISTANCE AND
REFRACTORY appear to represent overlapping constructs
and have been used interchangeably within the literature
Annals of Clinical Psychiatry Vol. 26 No. 3 2014
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13. Brain imaging studies
► Patients with chronic TRD had reduced gray matter
density in the left temporal cortex including the
hippocampus, with a trend toward reduction in the
right hippocampus.
► SPECT: significant increase in hippocampus
amygdala activity
► PET scan: cingulate hypometabolism
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14. Am Fam Physician. 2009;80(2):167-172

15. Approaches in the management of
TRD
► Optimization: Increase dose of antidepressants
► Augmentation strategy: adding another agent to an
ongoing antidepressant treatment that has failed.
► Combination strategies: TCAs and SSRIs, TCAs and
MAOIs, bupropion and SSRIs, anticonvulsants and
antidepressants, and benzodiazepines and antidepressants.
► However, SSRIs, venlafaxine, or clomipramine should not
be combined with MAOIs and the MAOI and TCA
combination should be used with caution.
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16. Drugs used in augmentation approach
for TRD
 Lithium
 Bupropion/mirtazepine combination therapy
 Anticonvulsants
 Thyroid hormones (T3)
 Dopamine agonist (pramipraxole)
 pindolol
 Buspirone
 Modafinil
 Testosterone, oestrogen
 Burpenorphine, SAMe, Inositol

17. Switching strategies
► Switching involves stopping the antidepressant to which
the patient is not responding and switching to another
antidepressant, usually from a different class
► The options for SSRI non-responders: bupropion,
nefazodone, venlafaxine, tianeptine, and mirtazapine.
► MAOI can be used in TCA- or SSRI-resistant patients.
However, Dietary restrictions are essential and an
appropriate washout period is required after SSRI
discontinuation before initiating treatment with MAOIs.
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18. STAR*D (Sequenced Treatment Alternatives to
Relieve Depression) study, a seven-year
randomized controlled trial (RCT) that evaluated
medication switching and augmentation in 3,671
outpatients with unipolar depression.
Am Fam Physician. 2009;80(2):167-172

19. Am Fam Physician. 2009;80(2):167-172

20. Other treatment modalities
► ECT: Potent, though underutilized, option for resistant
depression.
► Newer biological approaches: repetitive transcranial
magnetic stimulation (rTMS) and vagus nerve stimulation
► Novel psychopharmacological agent: S-adenosylmethionine
(SAMe), second-messenger system modulators (inositol), and
neuroendocrine system–modulating agents, eg,
dexamethasone
► Cognitive behavioural therapy
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21. Comparison of devices for Treatment Resistant Depression (TRD).
ECT : Electroconvulsive Therapy; TMS Transcranial Magnetic
Stimulation; VNS : Vagal Nerve Stimulation, DBS; Deep Brain
Stimulation
Cusin and Dougherty Biology of Mood & Anxiety Disorders 2012, 2:14

22. Future treatment options
Patient Preference and Adherence 2012:6 369–388