1) Depression has a lifetime prevalence of 10-30% and is the third leading cause of disability worldwide. 2) Only about 33% of patients achieve full remission after their first antidepressant, and 30-45% fail to respond adequately to two treatments. 3) Achieving full remission is important for preventing relapse and reducing risks of suicide, medical comorbidities, and impaired functioning. Treatment resistance is defined as failing to respond to two adequate antidepressant trials.

1. Dr. B C MALTHESH
JR-3
BJGMC

2. Epidimiology

 1-year prevalence of 3–5%, Lifetime prevalence varying
from 10 to 30% [Hasin et al. 2005; Waraich et al. 2004].
 Depression is ranked by the WHO as the 3rd highest
cause of disability across the world.
 Projected to become the second by 2020 [Murray and
Lopez, 1997; World Bank, 2004].

3. Operational definitions of
treatment response

Remission >75%
Response 50% - 74%
Partial Response 25% - 49%
Nonresponse <25%
Recovery – failure to meet criteria for MDD for at least 8 wks.

4. Operational definitions of
treatment response


5. STAR*D Cumulative Remission Rates

80
70
60
50
40
30
20
10
0
33%
50%
Level 1 Level 2 Level 3 Level 4
Cumulative Remission Rate (%)
Gaynes B, et al. Clev Clin J Med. 2008;75(1):57-65.
63%
67%

6. Rates of Response

 Only a third of patients achieve full remission after
their first antidepressant treatment in naturalistic
conditions [Rush et al. 2006]
 30-45% - Fail to respond to adequate trial of
antidepressant.
 10-15% - show partial response.
 20-35% - are nonresponsive

7. Is Achieving Remission Important?

 High risk of relapse and recurrence
 TRD is more likely to cause suicide or a suicide attempt,
 Confers poor prognosis kindling, episode frequency
increases.
 Poor functioning (e.g., work, family)
 Psychiatric or general medical complications (e.g.,
substance abuse)
 Increased Health service utilization
 Death from Medical comorbidities also increase

8. Definition of TRD

 Poorly defined term
 Failure to respond to a trial of more than one
antidepressant drug in a dose equivalent to 250-300 mg
of IMN given for duration of 6-8 wks.
 Unremitting depression despite treatment with at least
2 different antidepressant or an antidepressant & a
course of ECT.

9. Definition of TRD

 Failure to respond to 2 adequate trials (adequate
dosage for adequate duration) of different chemical
classes.
 Several Staging Methods
 Thase & Rush (1997)
 Massachusetts General Hospital
 CPMP Guidelines

10. Thase and Rush stages

STAGE I
FAILURE OF AT LEAST ONE ADEQUATE TRIAL OF
ANTI DEPRESSANT MONOTHERAPY
STAGE II
STAGE I +FAILURE OF TRAIL OF DIFFERENT
ANTIDEPRESSANT CLASS
STAGE III STAGE II +FAILURE OF TRAIL OF TCA
STAGE IV STAGE III +FAILURE OF TRIAL OF MAO-I
STAGE V STAGE IV +FAILURE OF ECT COURSE

11. Causes of Resistance

 Incorrect primary diagnosis
 Is there any other primary Psychiatric disorder (e.g., substance-induced
mood disorder) not being treated?
 Is there a primary medical condition not being treated?
 Is there an unrecognized depressive subtype?
 Psychotic depression
 Bipolar depression
 Depressive severity
 Chronicity of depression (illness lasting 2 years or more)
 Greater number of somatic symptoms
 History of childhood emotional abuse and sequelae
Parik MR et al, Current perspectives in the management of treatment-resistant
depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004

12. Causes of Resistance

Factors related to antidepressant treatment
 Inadequate treatment of earlier episodes may lead to
kindling and sensitization at the receptor/synaptic
levels leading to the development of resistance.
Parik MR et al, Current perspectives in the management of treatment-resistant
depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004

13. Causes of Resistance

 Primary Medical diagnosis -hypercholesterolemia,
hypothyroidism, diabetes, Cushing’s syndrome, Parkinson’s
disease, Huntington’s disease, cerebrovascular disease, and
seizure disorder.
 Comorbid psychiatric disorders
 Anxiety disorders
 Commonly coexist with major depression
 Increase the likelihood of more severe depressive symptoms,
suicide attempts, decreased responsiveness, and greater
susceptibility to side effects
 Substance abuse
 Personality disorders
 Eating disorders Parik MR et al, Current perspectives in the management of treatment-resistant
depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004

14. Causes of Resistance

 Patient factors
 Compliance
 Individual differences in drug metabolism
 Nutritional status - deficiencies in folate, thiamine,
vitamin B6, vitamin B12, copper, and zinc
 psychosocial stressors and poor social support.
 Physician factors
 Underdosing
 Inadequate length of treatment
Pseudo resistance
Parik MR et al, Current perspectives in the management of treatment-resistant
depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004

15. Management

 Re-evaluation of pts history & presentation
 Assessment of treatment adequacy
 Dose
 Duration
 Drug compliance
 Drug monitoring
 Treatment strategies –
 Pharmacological - optimization, augmentation,
combination, switching.
 Somatic treatments. – DBS, VNS, rTMS
 Non pharmacological.

16. Optimization

 Ensure that the current drug is being used for sufficient
duration(6-8 weeks), at the ideal dosage with maximum
adherence.
 Does may have to be decreased or increased
 Address adherence issues by using pill dairy or pill
counts or supervised medications.

17. Augmentation strategies

• Augmentation – adding an agent that is not
conventionally used as monotherapy to an existing
antidepressant.
• Advantages – rapid onset of action, no withdrawal sxs,
no loss of partial response.
• Disadvantage – drug-drug interaction, increased cost,
compliance.

18. Augmentation strategies

 Lithium
 0.5 - O.8 meq/lt
 Most of the literature available is regarding TCA
augmentation with Lithium, sparse data available on SSRI
augmentation with Lithium
 Side effects monitoring and blood level monitoring has to
be done stringently.
Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression:
A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)

19. Augmentation strategies

 Triiodothyronine (T3) – 20-50 micg/day
 generally well tolerated and has a favourable side effect profile
compared to lithium.
 Similar to lithium augmentation, much of the data supporting
thyroid augmentation comes from studies with TCA
 Repeat TFTs may be needed
 Antiepileptic drugs
 Valproate, CBZ, Lamotrigine
 Pindolo (5mg TDS)
 Mainly to accelerate the response than to overcome resistance

20. Atypical antispychotics

 Olanzapine, Quetiapine (300-600mg/day) and to some extent
aripiprazole (5-20mg/day) have good supportive data from
controlled clinical trials as augmenters of SSRIs
Eg: Olanz + Floux combination
 Data for risperidone (0.5-2 mg/day) are not robust, but can be used
as an augmenting agent
 Research supporting the augmentation effects of ziprasidone is
much more limited
 Use of Clozapine is limited due to its adverse effect profile, but can
be used as last resort after other Aps fail
RC Shelton, GI Papakostas - Augmentation of antidepressants with atypical antipsychotics
for treatment‐resistant major depressive disorder Acta Psychiatrica Scandinavica, 2008

21. Stimulants as Augmenting drug

 Amphetamine, Methylphenidate, Modafinil can be used
 Methylphenidate enhances Dopaminergic transmission
and has euphorigenic action
 Stimulants mainly decrease fatigue and apathy
 Risk of abuse in patients with history of substance use
disorder.

22. Summary of Augmentation options

23. Combination therapy

 The use of at least 2 antidepressants that have well established
efficacy.
 Advantages & disadvantages similar to augmentation.
 SSRI + bupropion / Buspirone.
 TCA + SSRI.
 SSRI or SNRI can be combined with Mirtazapine / trazodone.
 SSRI + SNRI I not a good combination
 TCA & MAOI may lead to seratonin syndrome.
 SSRIs, venlafaxine, or clomipramine should not be combined with
MAOIs

24. Switching Strategies

 Switching can be either within same class or between two classes
of drugs.
 Advantages – improved compliance, fewer adverse effects, cost
effective.
 Disadvantages – withdrawal sxs, time lag between initiation of
new drug & treatment response.
 Switching to older class of drug can also be done like : SSRI  TCA
or SSRI  MAOI,
Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression:
A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)

25. Switching Strategies

 SSRI ► SSRI (Zarate et al, 1996)
 SSRI ► SNRI (Poirier&Boyer,1999)
 SSRI ► Bupropion (Fava et al, 2003)
 SSRI ► TCA (Fava, 2001)
 SSRI ► MAOI (Thase & Rush, 1995)

26. Al-Harbi ., Treatment-resistant depression: therapeutic trends, challenges,
and future directions.; Patient Preference and Adherence 2012:6 ,369–388

28. Summary of the findings of the
above studies

 Response rate 26%–76%; remission rate 28%–87%.
 TCA might prove to be a strategy of first choice for
patients who do not respond to an SSRI;
 Intolerance to one SSRI does not necessarily mean
intolerance to the whole class of SSRI;
 Between-class switch is a good treatment option.
 In patients unresponsive to SSRI, administration of
antidepressants with different mechanisms of action is
an effective switching strategy.

29. rTMS for Treatment Resistant
Depression

 24 studies (n = 1092 patients) compared active & sham
rTMS in TRD
 Active rTMS was significantly superior to sham conditions
in producing clinical response.
 The pooled response and remission rates were 25% and
17%, and 9% and 6% for active rTMS and sham conditions,
respectively.
 Relatively low response and remission rates, the short
durations of treatment, and the relative lack of systematic
follow-up studies suggest that further studies are needed.
Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial Magnetic stimulation for treatment
resistant-depression: a systematic review and metaanalysis. Can J Psychiatry 2008 ; 53(9): 621-31.

30. DBS for Treatment Resistant
Depression

 DBS for TRD is an experimental area of investigation.
 costs and the risks related to the surgical procedure are
limiting factors,
 Used only in most treatment-refractory cases of
depression.
 The data on efficacy in TRD are limited to a series of
open-label studies.
 DBS is not a treatment indicated for acute worsening,
as the effects of stimulation can take weeks to months
to manifest.
Cusin and Dougherty, Somatic therapies for treatment-resistant depression:
ECT, TMS, VNS, DBS., Biology of Mood & Anxiety Disorders 2012, 2:14

31. VNS for Treatment Resistant
Depression

 Useful in case of mild to moderate treatment
resistance, but not in severe resistance
 VNS is usually considered as an adjunct to
pharmacologic treatment, and it can safely be
combined with ECT in case of an acute relapse
Cusin and Dougherty, Somatic therapies for treatment-resistant depression:
ECT, TMS, VNS, DBS., Biology of Mood & Anxiety Disorders 2012, 2:14

32. Bilateral Epidural Prefrontal
Cortical Stimulation (ECS) for TRD

 Leads are placed through a burr hole in the skull but above the
dura mater and thus remain separated from the underlying cortical
region by the arachnoid space.
 ECS is more direct than transcranial magnetic stimulation (TMS) or
vagus nerve stimulation (VNS) and potentially safer than deep
brain stimulation (DBS),
 Appears relatively safe, feasible.
 Five adults with an average of 5.8 failed antidepressant treatments
and currently depressive episode were enrolled
 At 7 month follow up 3 had reached remission, almost all had
shown response
Nahas et al.,Bilateral Epidural Prefrontal Cortical Stimulation for
Treatment Resistant Depression; Biol Psychiatry. 2010 January 15; 67(2):

33. Cognitive Behavioral Therapy

 Efficacy of CBT was analyzed in STAR-D study.
 CBT is both an acceptable switch and augmentation
option in the second step of STAR-D
 Benefit of CBT as augmentation was slower (up to 3
weeks) compared to augmenting with medication.

35. Ketamine Mechanism of action

 Ketamine acts as antagonist at NMDA receptor,
potentiates transmission at AMPA,
 Increased stress hormones in depression leads to
disruption in hippocampal LTP, which is NMDA
dependent process.
 Acts on m-TOR pathway to leading to increased
synaptic signaling
 Increases BDNF concentration
 Through these mechanisms it causes enhanced synaptic
plasticity
Murrough et al.,Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions
in Treatment-Resistant Major Depression; Biol Psychiatry. 2013 August 15; 74(4)

36. Ketamine infusions for TRD

 24 patients of TRD were selected
 They underwent a washout of antidepressant medication followed by a series
of up to six intravenous (IV) infusions of ketamine (0.5 mg/kg) over 12 days.
 Participants meeting response criteria were monitored for relapse for up to 83
days from the last infusion.
 Overall response rate at study end was 70.8%.
 There was a large mean decrease in Montgomery–Asberg Depression Rating
Scale (MADRS) score at two hours following the first ketamine infusion
 Suicidal ideation (SI) rapidly decreased within 6 hours of 1st infusion, even
among study non-responders.
 But even Among responders, median time to relapse following the last
ketamine infusion was 18 day
Murrough et al.,Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions
in Treatment-Resistant Major Depression; Biol Psychiatry. 2013 August 15; 74(4)

37. Dopamine Agonists for TRD

 Six studies (1996-2010) have investigated the effect of adjunctive
dopamine agonists in the treatment of refractory depression
 These studies have generally found marked improvement in
depressive symptoms. however, most of these studies targeted
stage I treatment-resistant depression, with only one study for
stage II refractory depression which evaluated Pramipexole.
 It is thus suggested that pramipexole augmentation, among
various dopamine agonists, may be a worthwhile option for
refractory depression.
Hori H et al.,The Efficacy of Pramipexole, a Dopamine Receptor Agonist, as an Adjunctive Treatment
in Treatment-Resistant Depression: An Open-Label Trial.; The Scientific World Journal Volume 2012,

38. S-adenosyl metheonine for TRD

 Used as an Augmenting agent
 SAM-e has shown antidepressant efficacy that is
superior to placebo and equivalent to the effects of
TCAs in a meta- analytic studies.
Seo RJ et al.,Atypical Antipsychotics and Other Therapeutic Options for Treatment
of Resistant Major Depressive Disorder.; Pharmaceuticals 2010, 3, 3522-3542

39. Melatonin Receptor Agonists

 Agomelatine
 Agonist at MT1 & MT2.. Antagonist at 5HT2C
 Given 25mg/day in HS dosage.

40. Metyrapone in treatment-resistant
depression

 There is blunted ACTH response to CRH.
 Dysregulation of the HPA axis has been found to be
linked to nonresponse to antidepressants and relapse
following successful treatment.
 Metyrapone – a cortisol synthesis inhibitor, targeted at
altered HPA axis.
 With repeated administration of Metyrapone the
plasma cortisol level normalises and the ACTH levels
increase to normal level.
Ther Adv Psychopharmacol (2012) 2(4) 139 –149

41. Metyrapone in treatment-resistant
depression

 Rogoz and colleagues did a open-label trial of
augmentation of imipramine with metyrapone in
patients with TRD.
 Patients were treated with imipramine for first 6 weeks,
followed by 6 weeks of the addition of metyrapone
(250 mg twice daily) treatment
 Metyrapone augmentation significantly reduced the
scores on the depression rating scales [HDRS (46%) and
Beck Depression Inventory (39%)].
Rogoz, Z., Skuza, G., Wojcikowski, J., Daniel, W.A., Wrobel, A., Dudek, D. et al. (2004) Effect of metyrapone supplementation
on imipramine therapy in patients with treatment-resistant unipolar depression. Pol J Pharmacol 56: 849–855.

42. Metyrapone in treatment-resistant
depression

 Jahn et al did a double-blind randomized, placebo-controlled
study of augmentation of serotonergic
antidepressants with either metyrapone or placebo for
3 weeks.
 At 5 weeks post intitiation of the study, metyrapone
(1gm) group showed significantly more improvement in
HDRS scores compared to placebo group .
Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A. and Wiedemann, K. (2004) Metyrapone as additive
treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry 61: 1235–1244.

43. Erythropoietin in treatment-resistant
depression

 It has got few direct neurobiological actions mediated
through a non-haematopoietic Epo receptor situated in
the brain.
 Systemically administered Epo crosses the blood-brain
barrier (BBB) and has neuroprotective and
neurotrophic effects in animal models of acute brain
damage and chronic neurodegenerative conditions.
 With Epo administration there is rapid up-regulation of
neuroplasticity mechanisms including BDNF and
neurogenesis, and anti-inflammatory actions.

44. Erythropoietin in treatment-resistant
depression

 Miskowiak et al (2007-2008)
 4 articles on the effect of erythropoeitin on mood, cogniotion, face
detection
 Epo improves recognition of all facial expressions, in particular of
low intensity happiness. This is similar to behavioural effects
observed with acute administration of serotonergic
antidepressants.
 Epo improved self-reported mood for all 3 days post-administration.
 Epo directly modulates brain responses to emotional information
in humans in a manner consistent with the actions of conventional
antidepressants.
Miskowiak et al. Effects of erythropoietin on depressive symptoms and
neurocognitive deficits in depression and bipolar disorder Trials 2010, 11:97

45. Erythropoietin in treatment-resistant
depression

 One ongoing study to assess the effects of long term
administration of Epo. Results are awaited.
 Miskowiak et al did a double-blind, placebo-controlled,
parallel-group design.
 40 patients with treatment-resistant major depression
are recruited and randomised to receive weekly
infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%)
for 8 weeks.
 The primary outcome parameters for the two studies
are: depression severity measured with the Hamilton
Depression Rating Scale 17 items (HDRS-17).
Miskowiak et al. Effects of erythropoietin on depressive symptoms and
neurocognitive deficits in depression and bipolar disorder Trials 2010, 11:97

46. Summary

 A working definition of TRD:
Failure to remit after 8-12 weeks at a adequate doseage
 Key considerations with TRD
 Clarify diagnosis and potential risk factors for
persistence
 Patient factors: compliance and/or rare
pharmacokinetics
 Physician factors: underdosing and/or inadequate
treatment length

47. Summary

 No clear direction for augmenting vs. switching
 Each appear successful for ~ 50% of patients
 If patient tolerating, first try to maximize dose
 When switching antidepressants after one failure,
within class or different class choices are reasonable
 Available evidence supports lithium and T3 as most
effective augmenting agents

48. Summary – We don’t know

 We Have Little Evidence Guiding Treatment Choice After the first
drug fails
 We Have No Evidence For Those with Two or More Treatment
Failures
 We Do Not Know Where Psychotherapy is helpfull
 Reviews suggest that psychotherapy plays a significant role in the
management of treatment resistant depression
 We do not know about the benefits of switching to psychotherapy
compared to augmenting medications with psychotherapy
 Vast majority of studies excluded patients with common general
medical and psychiatric comorbidities

50. References

 Hasin, D.S., Goodwin, R.D., Stinson, F.S. and Grant, B.F. (2005) Epidemiology of major depressive
disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions.
Arch Gen Psychiatry 62: 1097–1106.
 Waraich, P., Goldner, E.M., Somers, J.M. and Hsu, L. (2004) Prevalence and incidence studies of
mood disorders: a systematic review of the literature. Can J Psychiatry 49: 124–138.
 Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D. et al.
(2006) Acute and longer-term outcomes in depressed outpatients requiring one or several
treatment steps: a STAR*D report. Am J Psychiatry 163: 1905–1917.
 Rogoz, Z., Skuza, G., Wojcikowski, J., Daniel, W.A., Wrobel, A., Dudek, D. et al. (2004) Effect of
metyrapone supplementation on imipramine therapy in patients with treatment-resistant
unipolar depression. Pol J Pharmacol 56: 849–855.
 Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A. and Wiedemann, K. (2004)
Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled
trial. Arch Gen Psychiatry 61: 1235–1244.

51. References

 Miskowiak K, O'Sullivan U, Harmer CJ: Erythropoietin reduces neural and cognitive processing
of fear in human models of antidepressant drug action. Biol Psychiatry 2007, 62:1244-1250.
 Miskowiak K, O'Sullivan U, Harmer CJ: Erythropoietin enhances hippocampal response during
memory retrieval in humans. J Neurosci 2007, 27:2788-2792.
 Miskowiak K, Inkster B, O'Sullivan U, Selvaraj S, Goodwin GM, Harmer CJ: Differential effects of
erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration.
Exp Brain Res 2008, 184:313-321.
 Miskowiak K, Inkster B, Selvaraj S, Wise R, Goodwin GM, Harmer CJ: Erythropoietin improves
mood and modulates the cognitive and neural processing of emotion 3 days post
administration. Neuropsychopharmacology 2008, 33:611-618.