Serotonin and Depression: A Clinical Perspective
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Transcript Serotonin and Depression: A Clinical Perspective
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.