Augmentation of Standard Antidepressant Therapy for Major Depressive Disorder Derek S. Mongold MD Assistant professor WVU School of medicine

Objectives Show why treatment of depression to remission is important. Set realistic expectations for treatment. Show alternative treatments for resistant major depressive disorder (MDD).

Outline Why should family docs care? Efficacy of treatment. Treatment resistance. STAR*D. Other augmenting agents.

What is Major Depressive Disorder?

Why Should Family Docs Care?

Why Should Family Docs Care? CAD:

Why Should Family Docs Care? CAD: SADHART trial 1 : – Greater baseline severity of MDD within a few weeks of hospitalization for ACS resulted in twice the risk of mortality (HR = 2.30). – Lack of improvement in MDD during antidepressant treatment resulted in twice the risk of mortality (HR = 2.39).

Why Should Family Docs Care?

Why Should Family Docs Care? MDD interacts with Diabetes 18.

Why Should Family Docs Care? MDD interacts with Diabetes 18. – Over 6 years, the relative risk for all cause mortality was: – Depression alone: – Diabetes alone: – Depression and Diabetes combined:

Why Should Family Docs Care? MDD interacts with Diabetes 18. – Over 6 years, the relative risk for all cause mortality was: – Depression alone: 1.76 – Diabetes alone: 1.71 – Depression and Diabetes combined:3.11

Why Should Family Docs Care? COPD:

Why Should Family Docs Care? COPD: – Depressive symptoms at baseline almost double the odds of mortality 2. (OR = 1.93; 95% CI, ; P<0.5).

Why Should Family Docs Care? Rehospitalization:

Why Should Family Docs Care? Rehospitalization: – MDD triples the odds of rehospitalization 3. (OR = 3.34; 95% CI, 1.20 – 9.25; P=0.02).

Why Should Family Docs Care? MDD is also a risk factor for developing:

Why Should Family Docs Care? MDD is also a risk factor for developing: – CAD. – Obesity. – DM-II. – Pulmonary disorders. – Neurodegenerative disorders. – Osteoporosis.

Why Should Family Docs Care? Patients with serious mental illness DIE 25 YEARS EARLIER than the general population.

Why Should Family Docs Care? Prevalence of major depressive disorder in primary care settings.

Why Should Family Docs Care? Prevalence of major depressive disorder in primary care settings % in adults. 6-9% in older adults

Efficacy of Treatment

Efficacy of Treatment Question: What percent of patient’s are in remission after first line therapy?

Efficacy of Treatment Question: What percent of patient’s are in remission after first line therapy? Answer: 30-35% 5.

Efficacy of Treatment Question: How much response do you have to get to function normally?

Efficacy of Treatment

Question: How much response do you have to get to function normally? Answer: Complete remission is needed to function normally 6.

Efficacy of Treatment

Treatment Resistance Definition:

Treatment Resistance Definition: Not responding to two trials of antidepressants from different pharmacologic classes with adequate dose, duration, and compliance.

Treatment Resistance Prevalence:

Treatment Resistance Prevalence: – 2% of the US population 7.

Treatment Resistance Causes:

Treatment Resistance Causes: – Medication nonadherence. 30% discontinuation rate at 1 month. 50% discontinuation rate at 4 months. – Inadequate dose. – Inadequate duration of treatment. – Wrong diagnosis (eg. Bipolar disorder, substance induced mood disorder, adjustment D/O, Bereavement, personality D/O, etc.).

Treatment Resistance Final results of the STAR*D trail show that after 4 steps of treatment about 67% of patients can eventually attain remission of depression 8.

STAR-D 8

STAR-D

STAR-D Citalopram Bupropion SR Sertraline Venlafaxine XR Cognitive Therapy (CT ) Citalopram + CT Citalopram + Bupropion SR Citalopram + Buspirone SwitchAugment/combine Switch Bupropion SR Venlafaxine XR Mirtazapine Nortriptyline Lithium + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram T 3 + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram Tryanylcypromine Mirtazapine + Venlafaxine SR Switch Augment

STAR-D Step 1:Response Rate – Citalopram (Celexa).

STAR-D Step 1:Response Rate – Citalopram (Celexa). (32.9%)

STAR-D Step 2a (switch):Response Rate – Bupropion SR (Wellbutrin). – Sertraline (Zoloft). – Venlafaxine (Effexor XR). Step 2b (Augment): – Citalopram + Bupropion SR. – Citalopram + Buspirone.

STAR-D Step 2a (switch):Response Rate – Bupropion SR (Wellbutrin).(25.5%) – Sertraline (Zoloft).(26.8%) – Venlafaxine (Effexor XR).(25.0%) Step 2b (Augment): – Citalopram + Bupropion SR.(39.0%) – Citalopram + Buspirone.(32.9%)

STAR-D Step 3a (Switch):Response Rate – Mirtazapine (Remeron). – Nortriptyline (Pamelor). Step 3b (Augment): – Lithium + Original antidepressant. – T3 + Original antidepressant.

STAR-D Step 3a (Switch):Response Rate – Mirtazapine (Remeron).(8.0%) – Nortriptyline (Pamelor).(12.4%) Step 3b (Augment): – Lithium + Original antidepressant.(13.2%) – T3 + Original antidepressant.(24.7%)

STAR-D Step 4 (Switch)Response Rate – Tranylcypromine (Parnate). – Mirtazapine + Venlafaxine SR.

STAR-D Step 4 (Switch)Response Rate – Tranylcypromine (Parnate).(13.8%) – Mirtazapine + Venlafaxine SR.(15.7%)

STAR-D

STAR-D 30% Dropout rate 40% Dropout rate n=65n=36

STAR-D Citalopram Bupropion SR Sertraline Venlafaxine XR Cognitive Therapy (CT ) Citalopram + CT Citalopram + Bupropion SR Citalopram + Buspirone SwitchAugment/combine Switch Bupropion SR Venlafaxine XR Mirtazapine Nortriptyline Lithium + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram T 3 + Bupropion SR, Sertraline, Venlafaxine XR, or Citalopram Tryanylcypromine Mirtazapine + Venlafaxine SR Switch Augment

STAR-D

Other Augmenting Agents

Atypical Antipsychotics Aripiprazole (Abilify):

Atypical Antipsychotics Aripiprazole (Abilify): – The first atypical antipsychotic approved in the US as add-on therapy. – At least 3 trials show its efficacy over placebo – Added to patients failing to remit when taking antidepressant monotherapy (eg. During first failure).

Atypical Antipsychotics

Atypical Antipsychotics – Quetiapine (Seroquel XR):

Atypical Antipsychotics – Quetiapine (Seroquel XR): Two trials show better response and remission rates over placebo However, the 150mg dose was barely significantly better in one trial and the 300mg dose was barely significantly better in one trial. Added to patients failing to remit when taking antidepressant monotherapy (eg. During first failure).

Atypical Antipsychotics

Atypical Antipsychotics – Olanzapine-Fluoxetine (Symbyax) 14 :

Atypical Antipsychotics – Olanzapine-Fluoxetine (Symbyax) 14 : At least 5 studies. Added after patient’s failed to respond to 2 different antidepressants in the current episode. Remission rate of 25.5% for Symbyax. – Fluoxetine (Prozac) alone (17.3%, P=.006). – Olanzapine (Zyprexa) alone (14.0%, P<0.001).

Other Antidepressants Mirtazapine (Remeron) 15 :

Other Antidepressants Mirtazapine (Remeron) 15 : – Patient’s received the following drug combinations:Remission Rates Fluoxetine (Prozac). Fluoxetine + Mirtazapine. Venlafaxine (Effexor) + Mirtazapine. Bupropion (Wellbutrin) + Mirtazapine.

Other Antidepressants Mirtazapine (Remeron) 15 : – Patient’s received the following drug combinations:Remission Rates Fluoxetine (Prozac).(25%) Fluoxetine + Mirtazapine.(52%) Venlafaxine (Effexor) + Mirtazapine.(58%) Bupropion (Wellbutrin) + Mirtazapine.(46%)

Other Antidepressants

Psychotherapy

Psychotherapy In the STAR*D trial 16, psychotherapy was either added to Citalopram (augmentation) or used alone after initial failure of Citalopram (switch).

Psychotherapy In the STAR*D trial 16, psychotherapy was either added to Citalopram (augmentation) or used alone after initial failure of Citalopram (switch). – Remission rate with augmentation: (29.4%). – Remission rate with switching to therapy: (41.9%).

Psychotherapy

Psychostimulants

Psychostimulants Dexamphetamine, methylphenidate, methlamphetamine, pemoline, Modafinil:

Psychostimulants Dexamphetamine, methylphenidate, methlamphetamine, pemoline, Modafinil: – A recent systematic review in the Cochrane Database fond only modest support for psychostimulents 17. – In the 3 small trials that showed short-term benefit, the improvement in depressive symptoms was of questionable clinical significance. – No benefit found for Modafinil.

Other Agents

Other Agents Insufficient evidence to recommend for or against. – Pindolol. – L-methylfolate (Deplin). – Estrogens. – Testosterone.

Conclusions

Conclusions Major depressive disorder is common and relevant to the family doctor’s practice.

Conclusions Major depressive disorder is common and relevant to the family doctor’s practice. Treatment resistance is a common phenomenon in Major depression.

Conclusions Major depressive disorder is common and relevant to the family doctor’s practice. Treatment resistance is a common phenomenon in Major depression. Several alternatives to first line treatment of major depressive disorder exist.

Review of Augmentation Strategies.

Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR).

Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar).

Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). Lithium.

Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). Lithium. T 3 (Cytomel).

Review of Augmentation Strategies. Bupropion SR (Wellbutrin SR). Buspirone (BuSpar). Lithium. T 3 (Cytomel). 2 nd generation antipsychotics. – Aripiprazole (Abilify). – Quetiapine SR (Seroquel XR). – Olanzapine + Fluoxetine (Symbyax).

Review of Augmentation Strategies. Mirtazapine (Remeron).

Review of Augmentation Strategies. Mirtazapine (Remeron). Psychotherapy.

Review of Augmentation Strategies. Mirtazapine (Remeron). Psychotherapy. Psychostimulats.

References 1. Glassman AH, Bigger JT Jr, Gaffney M. Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression: seven- year follow-up of SADHART participants. Arch Gen Psychiatry. 2009;66(9): de Voogd JN, Wempe JB, Koeter GH, et al. Depressive symptoms as predictors of mortality in patients with COPD. Chest. 2009;135(3): Kartha A, Anthony D, Manasseh CS, et al. Depression is a risk factor for rehospitalization in medical inpatients. Prim Care Companion J Clin Psychiatry. 2007:9(4): O’Conner EA, Whitlock EP, Gaynes B, et al. Screening for Depression in Adults and Older Adults in Primary Care: An Updated Systematic Review. Rockville, MD: Agency for Healthcare Research and Quality: Evidence Report No. 75 AHRQ Publication No EF Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term out=comes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry. 2006;163(11): Thase ME. Update on partial response in depression. J Clin Psychiatry. 2009:70(suppl 6): Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68(suppl 8): US National Institutes of Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D). trials.gov/show/NCT Published September 24, Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of Aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6): Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of Aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(2):

References 11. Berman RM, Fava M, Thase ME, et al. Aripiprazole augmentation in major depressive disorder: a double blind, placebo-controlled study in patients with inadequate response to antidepressants. CNS Spectr. 2009;14(4): Bauer M, Protorius HW, Constant EL, et al. Extended-release Quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo- controlled, double-blind study. J Clin Psychiatry. 2009;70(4): El-Khalili N, Joyce M, Atkinson S, et al. Extended-release Quetiapine fumarate (Quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 14. Trivedi MH, Thase ME, Osuntokun O, et al. An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression. J Clin Psychiatry. 2009:70(3): Blier P, Qard HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry. 2010;167(3): Tush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11): Candy B, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev. 2008;(2):CD Pan A, Lucas M, Sun Q, Van Dam RM, et al. Increased Mortality Risk in Women with Depression and Diabetes. JAMA Archives of General Psychiatry. 2011:68(1):

The Bluebird of Happiness long absent from his life, Ned is visited by the Chicken of Depression.

Measurement-Based Care Defining and measuring therapeutic endpoints. Has been demonstrated to independently contribute to improved outcomes in MDD. Has been referred to as the “Standard of care”.

Measurement-Based Care Symptom Assessment Tools:

Measurement-Based Care Objective Symptom Assessment Tools: – 17-item Hamilton Depression Rating Scale (HDRS 17 ). – Toronto 7-item Hamilton Depression Rating Scale (HDRS 7 ). – Montgomery-Asberg Depression Rating Scale (MADRS).

Measurement-Based Care Subjective Symptom Assessment Tools: – Beck Depression Inventory (BDI). – 9-Item Patient Health Questionnaire (PHQ-9)

Measurement-Based Care Functional Assessment Tools: – Sheehan Disability Scale (SDS). – Social Adjustment Scale – Self Report (SAS-SR).

Measurement-Based Care Quality of Life Assessment Tools: – Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). – Quality of life in Depression Scale (QLDS).

Measurement-Based Care

Measurement-Based Care Who Cares?

Measurement-Based Care Who Cares? – Remission rates with first-line pharmacotherapy is 30-35%. – Patients have to wait 4-6 weeks to see if a patient will respond to a first-line treatment.

Measurement-Based Care Who Cares? – Emerging evidence shows that early (2week) improvement can be detected with depression rating scales. Symptomatic improvement at 2 weeks predicts remission at 6-8 weeks. Nonimprovement at week 2 may be a more robust negative predictor of nonremission at weeks