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  1. 1. Hilik Levkovitz MD Professor Director Day Hospital & Cognitive and Emotional Lab. School of Medicine, Tel Aviv University, Israel.
  2. 2. First-Step Strategies in MDD: “An antidepressant medication is recommended as an initial treatment choice for patients with mild to moderate MDD and defintely should be provided for those with severe MDD…. For most patients SSRI, SNRI, Mirtazapine or Bupropion is optimal “ APA Guidelines for MDD , Am J Psyc. 2010
  3. 3. First-Step Strategies in MDD: Based on page 33 APA Guidelines for MDD , Am J Psyc. 2010 SSRI SNRI Mirtazapine Buproprion TCA= < fatigue and sleepiness < quite smoking < overweight or obese < sexual problem < agitation < anxiety < sexual problem < melancholia < severe depression < hospitalized
  4. 4. What makes a clinician a great clinician?  Great clinician uses measurement-based care  Identify putative moderators of treatment response to improved patient outcomes  Optimizes each treatment step before moving to the next step
  5. 5. Measurement-based care in MDD Measurement-based care, may enhance the quality of care and improve clinical outcome. APA Guidelines for MDD , Am J Psyc. 2010 Trivedi MH, Neuropsychopharmacology. 2007
  6. 6. What Are Moderators? Moderators are baseline variables that predict response to treatment.
  7. 7. Moderators can be prognostic or prescriptive. • Prognostic moderators predict relative response regardless of the type of treatment. • Prescriptive moderators predict differential response to particular treatments.
  8. 8. Remission Rates in Anxious Vs. Non-anxious Depression RemissionratesperHDRS,% P<0.0001 P<0.0001 0 5 10 15 20 25 30 35 40 45 50 fava et al. papacostas and lamen anxious depression nonanxious depression Patients with anxious depression have been shown to have significantly lower remission rates than those without anxiety Prognostic moderators
  9. 9. Prognostic moderators that have a less robust response : • Chronic Depression • Low intelligence • Older age (>40 years) • Limited education • Living alone/being unmarried • Unemployed • Comorbidities such as:  Drug and alcohol abuse  Vascular depression  Cluster A personality disorders  PTSD Provide more intensive treatment or move patients more rapidly through treatment stages Prognostic moderators
  10. 10. Demographic variables • Gender • Age • Menopausal status Prescriptive moderators: Predict response to specific antidepressant treatments
  11. 11. Remission Rates for Woman with Depression According to Age and Menopausal Status variable placebo SSRI SNRI >50 years ≥50 years + HRT - HRT 26% 17 % 36 % 44 % 48% 44% 50% 28 % 35% 27 % 20 % 16 % Older woman who is not taking HRT should typically be treated with an SNRI, not an SSRI Predict response to specific antidepressant treatments Prescriptive moderators Thase et al
  12. 12. Illness features • Subtype • Age at onset • Chronicity • Severity Prescriptive moderators :
  13. 13. Remission Rates With SSRIs Vs. TCAs in Melancholic MDD Remissionrates,% 0 10 20 30 40 50 60 70 DUAG 1986 DUAG 1990 ROOSE 1994 SSRI TCA Patients with melancholic features of depression are more likely to respond to TCAs than to MAOIs or SSRIs Prescriptive moderatorsPredict response to specific antidepressant treatments
  14. 14. 1. Start with an SNRI (venlafaxine or duloxetine) 2. Move quickly to a TCA (eg, nortriptyline, plasma level = 120– 150 ng/ml) 3. Augment with lithium 4. Switch to clomipramine ( lithium) In patients with melancholic depression, CBT monotherapy would preferably not be used; however, CBT could be combined with medication. Treating patients with melancholic depression Perry PJ J Affect Disord. 1996 Prognostic moderators
  15. 15. Prescriptive moderators: Severity of depression In severe depression, APA guidelines recommend the use of antidepressants with psychotherapy rather than psychotherapy alone.
  16. 16. Prescriptive moderator Moderators favoring cognitive therapy over antidepressants (in mild to moderate depression):  Unemployed  Married  Multiple recent stressful life events Fournier J Consult Clin Psychol. 2009
  17. 17. What makes a clinician a great clinician?  Great clinician uses measurement-based care  Identify putative moderators of treatment response to improved patient outcomes  Optimizes each treatment step before moving to the next step
  18. 18. STAR*D Algorithm INITIAL TREATMENT: citalopram for up to 14 weeks SWITCH TO: bupropion, cognitive therapy, sertraline, venlafaxine OR AUGMENT WITH: bupropion, buspirone, cognitive therapy (Only for those receiving cognitive therapy in Level 2) SWITCH TO: bupropion or venlafaxine (if exiting Level 2a) SWITCH TO: mirtazapine or nortriptyline OR AUGMENT WITH: lithium or triiodothyronine SWITCH TO: tranylcypromine or mirtazapine combined with venlafaxine Level 1 Level 2 Level 3 Level 4 Level 2a Trivedi et al Am J Psychiatry 2006;163:28-40. Sinyor et al.. Can J Psychiatry 2010; 55:126-135.
  19. 19. Overall Remission Rates by Treatment Steps 36.8 30.6 13.7 13.0 0 10 20 30 Level 1 Level 2 Remission(%) Level 3 Level 4 40 Rush et al. Am J Psychiatry 2006; 163:1905–1917
  20. 20. There May be a Correlation Between Volumetric Changes in MDD and Clinical Symptoms Vasic et al. J Affect Disord 2008;109(1-2):107-16.). Comparison of 15 MDD subjects and 14 healthy controls -0.1 -0.05 0 0.05 0.1 15 17 19 21 23 25 27 29 31 Adjusted VBM Responses MADRSScore -0.1 -0.05 0 0.05 0.1 15 17 19 21 23 25 27 29 31 Adjusted VBM Responses MADRSScore DLPFC (BA 46) MOPFC (BA 11) Regions showing a negative correlation between gray matter concentration and depression severity
  21. 21. Major Depressive Disorder is Associated With Significant Functional Impairment Overall Functional Impairment as Reported by MDD Patients (n=622) Kessler et al. JAMA 2003;289(23):3095–105. Very Severe 19.1% Severe 40.2% None 3.1% Mild 9.5% Moderate 28.1% • Most (96.9%) respondents with 12-month MDD reported at least some role impairment • More than half (59.3%) of respondents with 12-month MDD reported severe to very severe impairment
  22. 22.  “TRD” been removed from guidance ◦Now “Sequencing treatments after initial inadequate response”
  23. 23.  Responders at endpoint on imipramine, fluoxetine and placebo evolve response at same rate Stassen et al 1993, Tollefson et al 1994  20% improvement at 1 week predicts responder at 4 weeks in 70% Stassen et al 1993 Prognostic moderators
  24. 24. Second-Step Strategies: • Increasing the dose • Switching • Combining two antidepressants • Augmentation.
  25. 25. No evidence of increased efficacy with higher doses in fixed dose studies of fluoxetine No significant advantage to raising dose of fluoxetine from 20mg to 60mg in non- responders at 2 weeks Fixed dose study Low fixed dose study Fluoxetine efficacy: low versus high dose No advantage for raising dose Wernicke et al 1989 Int Clin Psychopharmacol 4 S1
  26. 26. Fixed dose studies show no increased response with higher dose fluoxetine no sertraline no citalopram no duloxetine no venlafaxine no ? escitalopram yes
  27. 27. Ruhe et al. Neuropsychopharmachology 2009
  28. 28. Ruhe et al. Neuropsychopharmachology 2009
  29. 29. Second-Step Strategies: • Increasing the dose • Switching • Combining two antidepressants • Augmentation.
  30. 30. Second-Step Strategies: • Increasing the dose • Switching • Combining two antidepressants • Augmentation.
  31. 31. Second-Step Strategies: Combining two antidepressants Rush et al. Am. J. Psychiatry July 2011
  32. 32. Meta-Analysis of Response Rates of Atypical Antipsychotic Agents in Treatment-Resistant Major Depressive Disorder The overall pooled response rate for treatment with an atypical agent was 44.2%, compared with 29.9% for placebo. Nelson & Papakostas . Am . J. Psychiatry 2009
  33. 33. Am J Psychiatry. 2010 Jul 1. S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M  73 non-responder to SSRI with MDD  6-week trial  800 mg/twice a day  Response and remission were higher for adjunctive SAMe than placebo (response rate 36.1% vs. 17.6, remission rate 28.5 vs. 11.7)  Well-tolerated.
  34. 34. A dose-ranging study (n=711) identified agomelatine 25mg daily as the target dose when com-pared with agomelatine 1mg and 5mg daily In the first study, 212 patients received agomelatine (n=106) or placebo (n=105). For the ITT population the between group difference for the mean final HAMD scores was 2.30 (S.E. 1.02), p=0.026. In the second study, 238 patients received agomelatine (n=118) or placebo (n=120). For the ITT population the between group difference for the mean final HAMD scores was 3.44 (S.E. 0.92), p<0.001 Zajecka J. J Clin Psychopharmacol. 2010, Stahl SM J Clin Psychiatry. 2010 Kennedy SH Eur Neuropsychopharmacol. 2006 Agomelatine: a novel atypical antidepressant
  35. 35. First-Step Strategies in MDD: Based on page 33 APA Guidelines for MDD , Am J Psyc. 2010 SSRI SNRI Mirtazapine Buproprion TCA= < fatigue and sleepiness < quite smoking < overweight or obese < sexual problem < agitation < anxiety < sexual problem < melancholia < severe depression < hospitalized
  36. 36. Conclusions:  Use measurement-based care  Try to identify prognostic and prescriptive moderators Optimizes each treatment step
  37. 37. Thanks !!!

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