Treatment Resistant Depression:
Current Concepts & Treatment Applications
Bradley N. Gaynes, M.D., M.P.H.
Associate Professor
Department of Psychiatry
UNC School of Medicine
Key Questions for Today

What is treatment resistant depression (TRD)?

Why is it important?

What clinical features are associated with TRD?
What is the evidence base for TRD
management strategies?
 What are the future research directions?

What Is Treatment Resistant
Depression?

There is no single accepted definition
– It may mean a failure to reduce depressive
severity by at least 50% following treatment
– It may mean a failure to reduce absolute
depressive score below a specific cut point
– It may mean a failure of symptoms to entirely remit
– It may mean failure to respond to one or more
prior antidepressant trials
Why Is Achieving Remission
Important?

Residual symptoms put patients at high risk of
relapse and recurrence
– Patients with residual symptoms after medication
treatment are 3.5 times more likely to relapse
compared to those fully recovered (Judd et al,
1998)
– This risk is greater than the risk associated with
having ≥ 3 prior depressive episodes
– Similar finding exists after response to cognitive
therapy
Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE):
comparing patients with unipolar major depressive disorder who recovered from intake
MDE with residual subsyndromal depressive symptoms vs. asymptomatic status.
Wilcoxon Chi Square Test of Difference=47.96; P<0.0001.
Treatment Response Categories
STATE
OBJECTIVE
CRITERION
CLINICAL STATUS
Remission
HAM-D ≤ 7
No residual
psychopathology
~ 40%
Response
≥ 50% decrease in
HAM-D without
remission
Substantially improved,
but with residual sxs
~ 25%
Partial
response
25%-50% decrease Mild-moderate
in HAM-D
improvement
~ 10%
Nonresponse
< 25% decrease
in HAM-D
~ 25%
No clinically meaningful
response
PREVALENCE
IN RCTS
When Do You Characterize a
Response As Treatment Resistant?


After a patient has been on an antidepressant at for
a reasonable amount of time at an adequate dose
No commonly accepted time point
– Most drug trial data comes from 8 week long studies
– If no onset of response by weeks 4 or 6, there is a 7388% chance of not having onset of response by end of 8
wk trial (Nierenberg et al, 2000), so 4 weeks is a
reasonable point to increase dose
– An 8-12 week course is consistent with acute treatment
framework and allows patients 8 weeks at a dose
expected to produce response
When Do You Characterize a
Response As Treatment Resistant?

No commonly accepted determination of
adequate dose
– Range from minimal (e.g., 20 mg fluoxetine) to
moderate dose (e.g., 60 mg fluoxetine)
– Most clinicians consider middle range doses
likely “adequate”
A Working Definition of
Treatment Resistant Depression
6-8 weeks of at least a middle range dose
without remission
What Are the Clinical Features
Associated With TRD?

Incorrect primary diagnosis
– Is there a primary 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 disorder
What Are the Clinical Features
Associated With TRD?

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

Depressive severity

Chronicity of depression (illness lasting 2 years or
more)
What Are the Clinical Features
Associated With TRD?

Patient factors
– Compliance
– Unusual pharmacokinetics

Physician factors
– Underdosing
– Inadequate length of treatment
What Evidence Exists
to Guide Treatment?

Switching versus Augmentation
– Few controlled studies compare the efficacy of these two
options
– A review of available literature suggests response rate of
~50% for each
– Augmentation is favored by clinicians in patients with
partial response, although partial and non-responders
have comparable chances of response
– Adequate trial at optimal dosing a prerequisite to decision
Switching Antidepressants
Limited controlled data to guide decision
 If side effects led to switch, then use drugs
with different side effect profiles
 If failure to respond led to switch, consider
switching to a different biochemical profile or
to a broader biochemical profile

Switching Antidepressants

No clear guide about switching to different class
versus same class
– Available clinical trials show benefit with switching to
different class, but within class not yet tested
– Open trials label trials show similar benefits
– Current recommendations suggest switching classes if 2
antidepressants of same class are ineffective
– Are results generalizable?


Recent meta-analysis of clinical trials suggest
venlafaxine has quicker onset of action than SSRIs
(Thase et al, BMJ, 2001)
RCTs support MAOIs for atypical depression (relative
to TCAs)
Augmenting antidepressants:
Strategies with Clear Benefit

Lithium: 300 mg bid or tid (blood levels> 0.4
meq/L)
– 11 double blind RCTs averaged ~ 50% response
rate
– Of the 3 studies involving SSRIs, 2 showed little
benefit
– Side effects and monitoring issues remain a
concern to clinicians
Augmenting antidepressants:
Strategies with Clear Benefit

Thyroid hormone (T3): 25-50ug/day
– 1 clinical trial and a meta-analysis support benefit
– All published studies involve TCAs and not newer
antidepressants
– Side effects: nervousness, insomnia
Strategies With Disputed Benefit

Buspirone: 5-15 mg bid
– Open studies showing benefit
– 1 clinical trial showing no statistically meaningful
difference (51% vs. 47%)

Pindolol (for SSRI): 2.5 mg tid
– Controlled studies suggest acceleration of onset
of response
– The 2 controlled studies in TRD patients showed
no benefit
Potential Pharmacologic
Strategies Untested
Psychostimulants (methylphenidate: 10-40
mg/day)
 Atypical antipsychotics
 Dopaminergic agents
 Chromium
 Anticonvulsants

Where Does Psychotherapy Fit In?

Cognitive behavioral therapy has received
the greatest amount of study
From DeRubeis
et al, AJP, 1999
Other Options

Electroconvulsive Therapy
– Response rate in patients with
• inadequate medication trials: 86%
• adequate trials: 50%
– Probably treatment of choice for catatonic states
Summary

A working definition of TRD:
Failure to remit after 6-8 weeks at a middle range
dose

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
Summary

No clear direction for augmenting vs. switching
– Each appear successful for ~ 50% of patients
– If patient tolerating, first try to maximize dose
– Four weeks is a critical decision point to modify treatment


When switching antidepressants after one failure,
within class or different class choices are reasonable
Available evidence supports lithium and T3 as
effective augmenting agents
What We Don’t Know

We Have Little Evidence Guiding Treatment Choice
After the First Fails

We Have No Evidence For Those with Two or More
Treatment Failures

We Do Not Know Where Psychotherapy Fits In
– 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
STAR D
http://www. star-d.org
BASELINE: Distribution of HRSD17 by Setting
Distribution of IDSC30 by Setting
Primary
P rSpecialty
im a r y
S p e c ia lt y
Percent
P ercent
20
20
18 1 8
16 1 6
14 1 4
12 1 2
10 1 0
8
8 6
6 4
4 2
2 0
0
<=15
<12
1 6 -2 0
2 1 -2 5
2 6 -3 0
3 1 -3 5
3 6 -4 0
4 1 -4 5
4 6 -5 0
5 1 -5 5
5 6 -6 0
6 1 -8 4
ID SC
c o r e 27-29 30-32 33-35 36-52
3 0 S 24-26
12-14 15-17 18-20
21-23
Kolmogorov-Smirnov Two-Sample Test Statistic 0.56
HRSD
17 Score
p-value
0.91
Kolmogorov-Smirnov Two-Sample Test Statistic 0.84
Figure 1
p-value 0.48
Figure 2
Baseline Suicide Risk: PC vs SC


SC patients reported nearly twice the likelihood of a
history of attempted suicide than PC patients (21% vs.
12%, x2=21.05, p<0.0001).
Other measures showed less substantial differences
– Slightly more SC patients endorsed suicidal ideation in the last
week (i.e., had thoughts within the week that life was not worth
living: 50.8% vs. 45.3%, p=0.0456 by IDS- C30, Table 4; 45.4%
in PC, 50.8% in SC, p=0.0471 by HAM-D17,).
– Slightly more SC patients endorsed suicidal ideation in the last
week (i.e., had thoughts within the week that life was not worth
living: 50.8% vs. 45.3%, p=0.0456 by IDS- C30, Table 4; 45.4%
in PC, 50.8% in SC, p=0.0471 by HAM-D17, Table 5).
Overall, 2.3% of PC patients and 3.4% of SC
patients were clinically determined to be a
current suicide risk at study entry (p=ns).
 There was no difference between the
proportion reporting a family history of suicide
(approximately 5% of patients in each setting
provided such a history).

How Effective is an SSRI in Real
World Practice?
~ 30% met criteria for remission (HAM-D ≤ 7)
 ~ 50% met criteria for response (≥ 50%
decrease in depressive severity)
 40% of those who remitted, and 56% of
those who responded, did so only at or after
8 weeks of treatment

Trivedi et al, Amer J Psychiatry, 2006)
Treatment Outcomes (% Remission)
(L-2 Switch)
HRSD-17
30
QIDS-SR-16
26.6
25.5
24.8
25.0
Percent
21.3
20
17.6
10
0
BUP-SR
(n=239)
Rush et al., N Engl J Med 2006;354(12):1231-42
SERT
(n=238)
VEN-XR
(n=250)
Treatment Outcomes (% Remission)
(L-2 Augmentation)
HRSD-17
50
39.0
Percent
40
30
QIDS-SR-16
29.7
30.1
32.9
20
10
0
BUP-SR
(n=279)
Trivedi et al., N Engl J Med 2006;354(12):1243-52
BUS
(n=286)
QIDS-SR16 Remission Rates
Through Levels 1 and 2
80
Percent
60
40
53.0%
32.9%
30.6%
L-1
L-2*
20
0
* Theoretical
Overall
References






Fava M, “Augmentation and Combination Strategies in Treatment Resistant
Depression”. J Clin Psychiatry, 2001; 62 (suppl 18): 4-11.
Judd LL, Akiskal HS, Maser JD, et al. “Major Depressive Disorder: A Prospective
Study of Residual Subthreshold Depressive Symptoms as Predictor of Rapid
Relapse”. J Affect Disord, 1998; 50: 97-108.
Gaynes, B.N., Rush, A.J., Trivedi, M., et al., A direct comparison of presenting
characteristics of depressed outpatients from primary vs. specialty care settings:
preliminary findings from the STAR*D clinical trial. General Hospital Psychiatry,
2005. 27(2): 87-96.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or
venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. Mar 23
2006;354(12):1231-1242.
Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure
of SSRIs for depression. N Engl J Med. Mar 23 2006;354(12):1243-1252.
Trivedi M.H., Rush A.J, Wisniewski S.R. et al, “Evaluation of Outcomes with
Citalopram for Depression Using Measurement-Based Care in STAR*D:
Implications for Clinical Practice, Amer J Psychiatry, 2006. 163:1-13.