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 PREVALENCE IN RCTS

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 in HAM-D

Mild-moderate improvement

~ 10%

Nonresponse < 25% decrease

in HAM-D

No clinically meaningful response

~ 25%

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 73-

88% 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 remitremit 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

Distribution of IDSC 30 by Setting

0

2

4

6

8

10

12

14

16

18

20

<=15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-84

IDSC30 Score

Per

cent

PrimarySpecialty

BASELINE: Distribution of HRSD17 by Setting

02468

101214161820

<12 12-14 15-17 18-20 21-23 24-26 27-29 30-32 33-35 36-52

HRSD17 Score

Per

cen

t PrimarySpecialty

Kolmogorov-Smirnov Two-Sample Test Statistic 0.84p-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)

21.3

17.6

24.825.5 26.625.0

0

10

20

30

BUP-SR(n=239)

SERT (n=238)

VEN-XR(n=250)

Perc

ent

HRSD-17 QIDS-SR-16

Rush et al., N Engl J Med 2006;354(12):1231-42

Treatment Outcomes (% Remission)(L-2 Augmentation)

29.7 30.1

39.032.9

0

10

20

30

40

50

BUP-SR BUS

Perc

ent

HRSD-17 QIDS-SR-16

(n=279) (n=286)Trivedi et al., N Engl J Med 2006;354(12):1243-52

QIDS-SR16 Remission RatesThrough Levels 1 and 2

53.0%

30.6%32.9%

0

20

40

60

80

L-1 L-2* Overall

Perc

ent

* Theoretical

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.