1. Treatment Resistant Depression: Current Concepts & Treatment Applications Bradley N. Gaynes, M.D., M.P.H. Associate Professor Department of Psychiatry UNC School of Medicine

2. Key Questions for Today l What is treatment resistant depression (TRD)? l Why is it important? l What clinical features are associated with TRD? l What is the evidence base for TRD management strategies? l What are the future research directions?

3. What Is Treatment Resistant Depression? l 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

5. Why Is Achieving Remission Important? l 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

6. 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. Send feedback to ScienceDirect Software and compilation © 2001 ScienceDirect. All rights reserved. ScienceDirect® is an Elsevier Science B.V. registered trademark.feedback

7. Treatment Response Categories STATEOBJECTIVE CRITERION CLINICAL STATUSPREVALENCE IN RCTS Remission HAM-D ≤ 7No 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%

8. When Do You Characterize a Response As Treatment Resistant? l After a patient has been on an antidepressant at for a reasonable amount of time at an adequate dose l 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

10. When Do You Characterize a Response As Treatment Resistant? l 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”

11. A Working Definition of Treatment Resistant Depression 6-8 weeks of at least a middle range dose without remission

12. What Are the Clinical Features Associated With TRD? l 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

13. What Are the Clinical Features Associated With TRD? l 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 l Depressive severity l Chronicity of depression (illness lasting 2 years or more)

14. What Are the Clinical Features Associated With TRD? l Patient factors –Compliance –Unusual pharmacokinetics l Physician factors –Underdosing –Inadequate length of treatment

15. What Evidence Exists to Guide Treatment? l 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

16. Switching Antidepressants l Limited controlled data to guide decision l If side effects led to switch, then use drugs with different side effect profiles l If failure to respond led to switch, consider switching to a different biochemical profile or to a broader biochemical profile

17. Switching Antidepressants: Same Class Or Different Class? AuthorsPreswitchPostswitchDesignResponse Rate Stern et al, 1983 TCA nonresponse or intolerance Bupropion or placebo RCT, n=30Positive McGrath et al, 1987 Imipramine or phenelzine Randomized crossover, n=101 Phenelzine, 65%; imipramine, 29% Thase et al, 2002 Sertaline or imipramine Sertraline or imipramine Randomized crossover, n=168 Over 50% in each group

18. Switching Antidepressants l 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? l Recent meta-analysis of clinical trials suggest venlafaxine has quicker onset of action than SSRIs (Thase et al, BMJ, 2001) l RCTs support MAOIs for atypical depression (relative to TCAs)

19. Augmenting antidepressants: Strategies with Clear Benefit l 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

20. Augmenting antidepressants: Strategies with Clear Benefit l 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

21. Strategies With Disputed Benefit l Buspirone: 5-15 mg bid –Open studies showing benefit –1 clinical trial showing no statistically meaningful difference (51% vs. 47%) l 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

22. Potential Pharmacologic Strategies Untested l Psychostimulants (methylphenidate: 10-40 mg/day) l Atypical antipsychotics l Dopaminergic agents l Chromium l Anticonvulsants

23. Where Does Psychotherapy Fit In? l Cognitive behavioral therapy has received the greatest amount of study

24. From DeRubeis et al, AJP, 1999

25. Other Options l Electroconvulsive Therapy –Response rate in patients with inadequate medication trials: 86% adequate trials: 50% –Probably treatment of choice for catatonic states

27. Summary l A working definition of TRD: remit Failure to remit after 6-8 weeks at a middle range dose l 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

28. Summary l 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 l When switching antidepressants after one failure, within class or different class choices are reasonable l Available evidence supports lithium and T3 as effective augmenting agents

29. What We Don’t Know l We Have Little Evidence Guiding Treatment Choice After the First Fails l We Have No Evidence For Those with Two or More Treatment Failures l 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 l Vast majority of studies excluded patients with common general medical and psychiatric comorbidities

30. STARD http://www. star-d.org

32. Baseline Suicide Risk: PC vs SC l SC patients reported nearly twice the likelihood of a history of attempted suicide than PC patients (21% vs. 12%, x 2 =21.05, p<0.0001). l 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- C 30, Table 4; 45.4% in PC, 50.8% in SC, p=0.0471 by HAM-D 17,). –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- C 30, Table 4; 45.4% in PC, 50.8% in SC, p=0.0471 by HAM-D 17, Table 5).

33. l 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). l There was no difference between the proportion reporting a family history of suicide (approximately 5% of patients in each setting provided such a history).

34. How Effective is an SSRI in Real World Practice? l ~ 30% met criteria for remission (HAM-D ≤ 7) l ~ 50% met criteria for response (≥ 50% decrease in depressive severity) l 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)

35. Treatment Outcomes (% Remission) (L-2 Switch) Rush et al., N Engl J Med 2006;354(12):1231-42

36. Treatment Outcomes (% Remission) (L-2 Augmentation) (n=279)(n=286) Trivedi et al., N Engl J Med 2006;354(12):1243-52

37. QIDS-SR 16 Remission Rates Through Levels 1 and 2 * Theoretical

38. References l Fava M, “Augmentation and Combination Strategies in Treatment Resistant Depression”. J Clin Psychiatry, 2001; 62 (suppl 18): 4-11. l 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. l 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. l 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. l 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. l 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.