EARLY OPTIMIZED TREATMENT IN DEPRESSION

Transcription

1 EARLY OPTIMIZED TREATMENT IN DEPRESSION A Recipe for Successful Recovery Mar. 28, 2017 Jeffrey Habert MD CCFP FCFP Assistant Professor, University of Toronto, Dept. of Family and Community Medicine Investigating Coroner, City Of Toronto This program is supported by Pfizer Canada Inc.

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 CONTENT DEVELOPMENT COMMITTEE CONTENT DEVELOPMENT: Angelo Fallu, MD, FRCPC Clinique Woodward, Sherbrooke QC Jeff Habert, MD, CCFP, FCFP University of Toronto REVIEW Kevin Kjernisted, MD, FRCPC University of British Columbia Michael Rosenbluth, MD, FRCPC University of Toronto Diane McIntosh, MD, FRCPC University of British Columbia Toba Oluboka, MD, FRCPC University of Calgary 4

4 LEARNING OBJECTIVES 1. Describe the importance of early optimized treatment and functional recovery in major depressive disorder (MDD) 2. Demonstrate the importance of measurement-based practice in the management of patients with MDD in Primary Care 3. Discuss the predictive values of early response to antidepressants to encourage a 2- to 4-week follow-up 5

5

6 DEPRESSION QUOTES

7 CONTEXT IN DEPRESSION

8 PREVALENCE AND BURDEN OF MDD IN CANADA Canadian prevalence estimates: Lifetime: 10.8% 1 Past year: 4.0% 1 Past 30 days: 1.3% 1 Work-related economic losses in Canada are estimated at $6.1 billion per year 2 (7 out of 10 patients with MDD are in the workforce) Depression affects a person s daily functioning at work, at home, and in their social relationships 2 1.Patten & al. Journal of Affective Disorders, Lam RW, et al. J Affect Disord. 2011;132(suppl 1):S9-S13

9 PREVALENCE AND BURDEN OF MDD IN CANADA According to the WHO, it is expected that by the year 2030, MDD will rise to one of the leading causes of disability globally, second only to ischemic heart disease 2 Today, 10.8% Canadians will suffer from MDD in their lifetime 1 The WHO ranked MDD as third in 2004 in terms of the overall burden of all diseases in the world 2 1.Patten & al. Canadian Journal of Psychiatry, WHO,

10 PREVALENCE OF MDD IN PATIENTS WITH CHRONIC CONDITIONS While the prevalence of MDD in the general population is about 5%, rate of depression in patients with chronic illnesses range between 25-50% 1 Depression Rates in People with Co-Existing Medical Illness Illness % Affected Cancer 42% (inpatients) Heart Disease 18% - 26% Diabetes 33% Multi-infarct dementia 27% - 60% Multiple sclerosis 6% - 60% Parkinson's disease 40% Stroke 30% - 50% Alcohol or drug abuse 50% 1.Canadian Mental Health Association,

11 CRITERIA FOR MDD DIAGNOSIS (DSM-5) 1 CRITERIA A The patient needs to present with 5 (or more) of the following symptoms Depressed mood Markedly diminished interest or pleasure Weight or appetite changes Insomnia or hypersomnia Psychomotor agitation Or retardation Fatigue or loss of energy Feelings of worthlessness or excessive or inappropriate guilt Executive dysfunction Recurrent thoughts of death or suicidal ideation / attempt Symptoms must have been present during the same 2-week period, and must represent a change from previous functioning At least 1 of the symptoms must be either depressed mood or markedly diminished loss of interest or pleasure 1.DSM-5, Patten & al. Journal of Affective Disorders, 2009.

12 CRITERIA FOR MDD DIAGNOSIS (DSM-5) 1 CRITERIA B The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning CRITERIA C The episode is not attributable to the physiological effects of a substance or to another medical conditions Note: response to a significant loss (e.g. bereavement), the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. CRITERIA D The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders 1.DSM-5, CRITERIA E There was never been a manic episode or a hypomanic episode

13 SIGECAPPS (VEGETATIVE SYMPTOMS OF DEPRESSION) S Sleep Disturbances-insomnia or hypersomnia I Interest reduced G Guilt or self-blame E Energy loss/fatigue C Concentration issues A Appetite changes (gain or loss) P Psychomotor changes (retardation/agitation) P Physical complaints (pain and somatic symptoms) 1.British Columbia Medical Association, Caplan & al., Oluboka OJ. Personal communication S Suicidal thoughts 14

14 CANMAT 2016 GUIDELINES: PHYSICAL IMPACT OF MDD MDD is associated with: High rates of many chronic conditions (e.g. ischemic heart disease, arthritis, asthma, migraine) Disruption in sleep (e.g. insomnia, hypersomnia) Disruption of social and biological rhythms that can further disrupt sleep and mood Somatic symptoms (e.g. pain, fatigue) The presence and severity of somatic symptoms, especially pain, is associated with poor outcomes in depression Lam RW et al. Can J Psychiatry 2016;61(9):506-9

15 DEPRESSION QUOTES

16 DEPRESSION CONSISTS OF SEVERAL SYMPTOM CLUSTERS Emotional Symptoms Sadness Anxiety Hopelessness Physical Symptoms Eating problems Sleeping problems Low energy Cognitive Symptoms Difficulty concentrating Indecisiveness Forgetfulness American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

17 DEPRESSION AFFECTS MANY IN MANY DIFFERENT WAYS Patients have different treatment needs: Symptoms Tolerability Severity Every patient can present with different Antidepressant side effects represent Patients may experience depressive symptoms, for example: 1 Insomnia or hypersomnia Weight loss or weight gain Psychomotor agitation or psychomotor retardation different burdens to different individuals 2 1.DSM-5, Gelenberg & al. Journal of the American Psychiatric Association, Kessler & al. Journal of the American Medical Association, symptoms and functional impairment ranging from mild to very severe 3

18 EVOLUTION OF DEPRESSION TREATMENT GOALS Symptom Reduction s Significant improvement in mood symptoms (e.g., HAM-D) Evolution of treatment goals Symptom Response s 50% improvement in mood symptoms (e.g., HAM-D) Symptom Remission 1990s Mood symptoms (e.g., HAM-D) not different from healthy controls Normalization of Functioning 2000s Symptom remission & improved functioning Measuring Functional Outcomes Present Functional Recovery Development and use of functional assessment tools (e.g., Sheehan Disability Scale, etc.) to measure: Motivation & Energy Cognition & Memory Occupational Functioning Social Functioning Family Functioning Overall Quality of Life HAM-D, Hamilton Depression Rating Scale; SDS, Sheehan Disability Scale. 1. Stahl SM. Mood Disorders and Antidepressants. Stahl s Essential Psychopharmacology. 4th ed. Cambridge, UK: Cambridge University Press; APA. Practice guideline for the treatment of patients with MDD CANMAT. Can J Psychiatry. 2016;61(9):

19 WHAT ARE RESPONSE AND REMISSION? Response: Reduction in symptom levels (>50%) 1,2 Inadequate because residual symptoms impair function, increase risk of relapse, and are negative predictors of long-term outcome Remission: Resolution of depressive symptoms 1 Monitoring symptoms with validated quantitative scales is essential to measuring outcomes Patients achieve remission when scores are in normal range (i.e. HAM-D 7; MADRS 10; PHQ-9 < 5); ideally no disabling residual symptoms 1. Patten et al. Journal of Affective Disorders 2009;117:S5 S McIntyre & O'Donovan. Can. J. Psychiatry 2004;49(3 Suppl 1):10S 16S. 21

20 Response rate (%) EFFICACY OF ANTIDEPRESSANTS Meta-analysis including 262 drug-placebo comparisons from 182 clinical trials (n=36,385) *p < Antidepressant (n=23,278) Placebo (n=13,107) Papakostas, Fava. Eur Neuropsychopharmacol 2009:19:34-40

21 SEQUENCED TREATMENT ALTERNATIVES TO RELIEVE DEPRESSION (STAR*D) Real world effectiveness study of moderate to severe depression Sponsored by National Institute of Mental Health (NIMH) n=4,041 outpatients with MDD Specialist & primary care settings Pre-defined sequenced treatment steps Outcome: remission (measured by QIDS-SR) QIDS-SR: Quick Inventory of Depression Symptomatology (Self-Report) Trivedi MH, et al. Am J Psychiatry 2006; 163:28-40

22 REMISSION RATES IN STAR*D Level Interventions Remission Rate + Cumulative Remission Step 1 N=3,671 CITALOPRAM 36.8% 36.8% Step 2 N=1,439 Switch: VEN / BUP / SER Combine: BUP / BUS Switch / Combine: CT 30.6% 56.1% Step 3 N=390 Step 4 N=123 Switch: NOR / MIR Augment: LI / T3 13.7% 62.1% Switch: TCP / MIR+VEN 13.0% 67.0% + QIDS-SR 16 5 Rush AJ et al. Am J Psychiatry 2006;163:

23 SEQUENCED TREATMENT ALTERNATIVES TO RELIEVE DEPRESSION (STAR*D) Real world effectiveness study of moderate to severe depression Sponsored by National Institute of Mental Health (NIMH) n=4,041 outpatients with MDD Specialist & primary care settings Pre-defined sequenced treatment steps Outcome: remission (measured by QIDS-SR) QIDS-SR: Quick Inventory of Depression Symptomatology (Self-Report) Trivedi MH, et al. Am J Psychiatry 2006; 163:28-40

24 INCREASING DIFFICULTY ACHIEVING REMISSION WITH REPEATED TREATMENT FAILURES a Treatment resistance to first-line antidepressants is common and remission harder to achieve with each treatment failure. After four optimized, well-delivered treatments, approximately 70% of patients achieve remission. However, an estimated 30% continue to experience significant impairment even after four levels of treatment. With each prior treatment failure, remission rates decrease, and relapse rates increase. b Percentages reflect approximate remission rates per level. 1. Greden. Am J Psychiatry. 2013;170: Greden et al. Treatment resistant depression: overview of the University of Michigan Depression Center Roadmap, in Treatment Resistant Depression: A Roadmap for Effective Care. Edited by Greden et al.. Washington, DC, American Psychiatric Publishing, 2011

25 Anti-depressants tested for MDD Comparative Efficacy & Acceptability Of Newer Antidepressants In Depression (Cipriani) Efficacy (reduction of 50% at week 8 from baseline on the HAM-D, MADRS or CGI) Acceptability (number of patients who terminated the study early for any reason during the first 8 weeks) Adapted from Cipriani et al. Lancet 2009; 373 (9665): (Source: Kennedy et al. Can Jour Diag 2009; (26): 81 86) 14 27

26 Gartlehener G et al. Ann Intern Med. 2011;155:

27 WHAT IS FUNCTIONAL RECOVERY? DSM-5 diagnosis of MDD includes functional impairment 1 The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning Function: Ability to perform the tasks of daily life and to engage in mutual relationships with other people 2 A return to usual level of function is a critical patient-reported goal in the treatment of depression 1,3,4 Refers to performance in occupational, social, or family functioning 2 Functional recovery: For today s purposes, defined as resolution of symptoms and full restoration of function 1. DSM-5 (Diagnostics and Statistics Manual of Mental Disorders, 5th Edition). American Psychiatric Association, 2013; 2. Lam et al. Ann Clin Psychiatry. 2015;27(2): Oakes et al. Hum Psychopharmacol Clin Exp. 2012;27:47-56; 4. Zimmerman et al. Am J Psychiatry. 2006;163: ;. 29

28 SYMPTOM REMISSION IS NOT SUFFICIENT FOR FULL FUNCTIONAL RECOVERY Functional improvement often lags behind symptomatic improvement 1 Residual functional impairment can persist despite symptomatic improvement 2 Greater symptom relief may be necessary to achieve a normal level of function 3 1.Papakostas. Am J Manag Care. 2009;15:S316-S321 2.Miller et al. J Clin Psychiatry. 1998;59: ; 3.Sheehan et al. Int Clin Psychopharmacol. 2011;26:

29 SYMPTOMS AND FUNCTION CAN IMPROVE INDEPENDENTLY Pooled analysis (N=1419) of data from 3 randomized, double-blind, 8-week studies Symptomatic remission: 38% Combined remission: 23% Functional remission: 32% Symptomatic remission: Hamilton Rating scale for depression (HAM-D17) 7 Functional remission: Sheehan Disability Scale (SDS) 6 Conclude that assessing both symptoms and functional status in patients with MDD is highly important Sheehan et al. Int Clin Psychopharmacol. 2011;26:

30 WHAT IS EARLY OPTIMIZED TREATMENT? Definition: Early diagnosis, assessment and treatment for optimal management of MDD To achieve early optimized treatment, it is crucial to: Monitor symptoms and function early in treatment 1-4 weeks onwards Ensure that patients do not remain on ineffective or poorly tolerated treatment, which may: Delay recovery Heighten the risk of residual functional deficits Habert et al. Prim Care Companion CNS Disord. 2016;18(5): /PCC.15r

31 Symptomatic Remission Functional Recovery EARLY OPTIMIZED TREATMENT HAS AN IMPORTANT ROLE IN FUNCTIONAL RECOVERY MDD DSM-5 Core Symptoms Early Optimized Treatment* Anhedonia Depressed Mood Diminished ability to think/concentrate Indecisiveness Guilt/Feeling of Worthlessness Low Energy/ Fatigue Psychomotor Agitation or Retardation Sleep Disturbance Suicidality Weight, Appetite Change Tolerability Adherence Efficacy Time to Full Recovery Repeated Assessment, Measurement-Based Care, Treat-To-Target *Early diagnosis followed by rapid, optimal treatment; Alphabetical order MDD: Major Depressive Disorder; Adapted from DSM-5. APA, 2013 Habert et al. Prim Care Companion CNS Disord. 2016;18(5): /PCC.15r

32 INTRODUCTION Measurement-Based Care and Early Optimized Treatment 34

33 Do you use quantitative measures of depression symptoms and function in your practice? 35

34 Would you ever diagnose Diabetes without an A1c or glucose? Would you ever treat hypertension with measuring BP? 36

35 How do you assess whether a treatment is improving symptoms and function in your patients with depression? 37

36 INITIAL VISIT PATIENT HEALTH QUESTIONNAIRE (PHQ-9) Multipurpose instrument for screening, diagnosing, monitoring, and measuring severity of depression symptoms Self-report completed by patient in minutes and rapidly scored Can be administered repeatedly to assess improvement or worsening of depression Kroenke et al. J Gen Intern Med. 2001;16:

37 SHEEHAN DISABILITY SCALE (SDS) Brief self-report tool Patient rates impairment in work/school, social life, and home life or family responsibilities on 10-point scale Scores of 5 or greater on any of the 3 scales are associated with significant functional impairment Treatment goals should be scores of 2 or less on each item and 6 or less in total score (functional remission) Rush et al. Handbook of Psychiatric Measures, American Psychiatric Associaton, David V. Sheehan. All rights reserved. 39

38 DEPRESSION

39 Once you have initiated treatment for depression, when do you make an assessment of whether it is effective? 41

40 Once you have initiated treatment for depression, when do you make an assessment of whether it is effective? IDEALLY should be at 2-3 WEEKS 42

41 EARLY OPTIMIZED TREATMENT REFLECTS CANMAT GUIDELINES Select and initiate a first-line antidepressant 1 Early improvement after 2-4 weeks? YES Continue treatment for 6-8 weeks Symptom remission? NO 2 NO 4 Switch to a 2 nd -line or 3 rd -line antidepressant YES Consider factors for switch vs adjunct Switch to an antidepressant with superior efficacy Early improvement after 2-4 weeks? Add an adjunctive medication NO Early improvement (defined as >20% 30% reduction from baseline in a depression rating scale after 2 4 weeks) is correlated with response and remission at 6 to 12 weeks. CANMAT recommends increasing the antidepressant dose for non-improvers at 2 to 4 weeks if the medication is tolerated and switching to another antidepressant if tolerability is a problem YES Risk factors for recurrence? NO YES Maintain treatment for 6-9 months Maintain treatment for 2 years or longer CANMAT. Can J Psychiatry. 2016;61(9): (1) Monitor outcomes using measurement-based care. (2) Depending on tolerability, first optimize antidepressant by increasing dose. (3) For early treatment resistance, consider adjunctive use of psychological and neurostimulation treatments. (4) After failure of 1 or more antidepressants, consider switch to a second-line or third-line antidepressant. (5) For more resistant depressions, consider longer evaluation periods for improvement. (6) Depending on tolerability, increase dose if not at maximal doses. (7) For more chronic and resistant depressions, consider a chronic disease management approach, with less emphasis on symptom remission and more emphasis on improvement in functioning and quality of life. 43

42 EARLY OPTIMIZED TREATMENT ONGOING SYMPTOM IMPROVEMENT Improvement of depressive symptoms within 2 3 weeks predicts symptom improvement at 4 52 weeks Negative predictive value is the most reliable if 20% improvement is not reached, unlikely to achieve remission PHQ-9: Patient Health Questionnaire Click here to see tables summarizing these data

43 CHANGING CLINICAL PRACTICE? Week 2 Assessment Week 8 Assessment PPV 20% Improvement Stable Response Stable Remission 53% 25% NPV <20% Improvement Stable Response Stable Remission 11% 4% Szegedi et al. J Clin Psychiatry 2003, 64:4 Szegedi et al. J Clin Psychiatry 2009; 70: Henkel et al. J Affect Disord 2009; 115: PPV: Positive predictive value NPV: Negative predictive value 45

44 CLINICAL POINTS EARLY OPTIMIZED TREATMENT Delays in effective treatment MDD are associated with lower remission rates and residual functional impairment Negative predictive value is most reliable patients who do not meet week 2 improvement thresholds have slim chances of achieving remission of symptoms or functional impairments Early optimized treatment may improve functional outcomes and likelihood of full functional recovery Quantitative assessment of symptoms allows the early optimization of treatment Assessment at baseline should be followed with further assessments after 1 4 weeks Actions to optimize treatment include dose optimization, switching, or add-on treatment Habert et al. Prim Care Companion CNS Disord. 2016;18(5): /PCC.15r

45 CANMAT 2016 GUIDELINES: GOALS OF ACUTE AND MAINTENANCE TREATMENT Treatment Phase Acute Maintenance Duration 8-12 weeks >6-24 months Goals Remission of symptoms Restoration of functioning Return to full functioning and quality of life Prevention of recurrence Activities Establish therapeutic alliance Educate and support selfmanagement Select and deliver evidence-based treatment(s) Monitor progress Educate and support selfmanagement Rehabilitate Treat comorbidities Monitor for recurrence Lam RW et al. Can J Psychiatry 2016;61(9):

46 Symptomatic Remission Functional Recovery EARLY OPTIMIZED TREATMENT HAS AN IMPORTANT ROLE IN FUNCTIONAL RECOVERY MDD DSM-5 Core Symptoms Early Optimized Treatment* Anhedonia Depressed Mood Diminished ability to think/concentrate Indecisiveness Guilt/Feeling of Worthlessness Low Energy/ Fatigue Psychomotor Agitation or Retardation Sleep Disturbance Suicidality Weight, Appetite Change Tolerability Adherence Efficacy Time to Full Recovery Repeated Assessment, Measurement-Based Care, Treat-To-Target *Early diagnosis followed by rapid, optimal treatment; Alphabetical order MDD: Major Depressive Disorder; Adapted from DSM-5. APA, 2013 Habert et al. Prim Care Companion CNS Disord. 2016;18(5): /PCC.15r

47 PATIENT CASE AND RECIPE FOR SUCCESS 49

48 CASE STUDY* 29 years old, single, teacher Non-smoker, minimal alcohol intake JANET MDD episode 7 years ago; stopped treatment after 5 months due to weight gain and sexual dysfunction Mother has a history of depression Body mass index: 26 6-week history of: Low mood/energy/libido, sleeping poorly, weight loss, etc. Difficulty concentrating, has stayed home from job for last 5 days Anxiety contributing to functional impairment *Note this case study is hypothetical 50

49 INITIAL VISIT RECIPE FOR SUCCESS Subjective: PHQ-9 Objective: Mental status examination (MSE); e.g. Patient appears sad, irritable and anxious; tearful and restless; no make-up and not dressed meticulously as usual; has lost weight compared to 6 months ago; slow to respond to questions Relevant physical exams (vitals/thyroid/cardiac) Assessment: MDD Plan: Standard labs: Complete blood count, glucose, thyroid-stimulating hormone (TSH), alanine transaminase (ALT), creatinine Initiate pharmacotherapy Follow-up should be in 1 4 weeks to assess for tolerability, adherence, symptom improvement, functional improvement (if any), and need for early treatment optimization: Book appointment before patient leaves office PHQ-9: Patient Health Questionnaire; MDD: Major depressive disorder 51

50 JANET S INITIAL VISIT ASSESSMENT AND PSYCHOEDUCATION Janet s PHQ-9 score: 19 JANET Very hesitant to take meds due to her previous experience Values her job, and realizes she is not functional at work, and a few coworkers have noticed She realizes she needs help now, but will not take a drug that causes weight gain and sexual dysfunction You discuss antidepressant options with Janet in terms of efficacy and tolerability/side effects Will take 2 3 weeks before initial improvement, others may notice improvement before they do Common side effects may be experienced Not addictive Should not be stopped when you feel better PHQ-9: Patient Health Questionnaire 52

51 WHY PATIENTS SHOW DIFFERENT RESPONSES TO ANTIDEPRESSANTS PATIENT FACTORS Clinical features and dimensions Comorbid conditions Response and side effects during previous use of antidepressant Patient preference MEDICATION FACTORS Comparative efficacy Comparative tolerability (potential side effects) Potential interactions with other medications Simplicity of use Cost and availability CANMAT. Can J Psychiatry. 2016;61(9):

52 EVOLUTION OF ANTIDEPRESSANTS Broad-spectrum agents (multiple action) More selective agents (single action) Novel agents affecting multiple monoamine targets 1960s 1970s 1980s 1990s 2000s 2010s Imipramine Clomipramine Maprotiline Fluoxetine Nefazodone* Escitalopram Vilazodone Nortriptyline Amoxapine Sertraline Mirtazapine Duloxetine Levomilnacipran Amitriptyline Paroxetine Venlafaxine Desvenlafaxine Vortioxetine Desipramine Fluvoxamine Moclobemide Phenelzine Citalopram Isocarboxazid Bupropion Tranylcypromine TCAs MAOIs SSRIs α 2 -adrenergic antagonist SNRIs NDRI RIMA TCA: Tricyclic antidepressant; MAOI: Monoamine oxidase inhibitor; SSRI: Selective serotonin reuptake inhibitor; SNRI: Selective norepinephrine reuptake inhibitor; RIMA: Reversible Monoamine Oxidase Inhibitor *Withdrawn from the Canadian Market 5-HT 2 antagonist modulator of serotonergic neurotransmission 54

53 SUMMARY ALGORITHM FOR SELECTING AN ANTIDEPRESSANT Consider clinical factors in selecting an antidepressant Is the patient on concomitant medications? NO YES Consider potential for drugdrug interactions Avoid particular side effects? NO YES Consider tolerability differences Select and initiate a first-line antidepressant CANMAT. Can J Psychiatry. 2016;61(9):

54 CANMAT PHARMACOTHERAPY RECOMMENDATIONS* 1 st LINE 2 nd LINE 3 rd LINE Bupropion (NDRI) Citalopram (SSRI) Desvenlafaxine (SNRI) Duloxetine (SNRI) Escitalopram (SSRI) Fluoxetine (SSRI) Amitriptyline, clomipramine, others (TCAs) Levomilnacipran (SNRI) Moclobemide (reversible inhibitor MAO-A) Quetiapine (AAP) Phenelzine (irreversible inhibitor MAO) Tranylcypromine Reboxetine (NRI) Fluvoxamine (SSRI) Mirtazapine (a 2 -adrenergic agonist; 5-HT 2 antagonist) Paroxetine (SSRI) Sertraline (SSRI) Venlafaxine (SNRI) Vortioxetine (Multimodal) Quetiapine (AAP) Selegiline transdermal (irreversible inhibitor MAO-B) Trazodone (SRI; 5-HT 2 antagonist) Vilazodone (SRI, 5-HT 1A partial agonist) * All recommendations are LEVEL 1 evidence. MT, melatonin; 5-HT, serotonin; MAO, monoamine oxidase; NDRI, noradrenaline and dopamine reuptake inhibitor; SNRI, serotonin and noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA; tricyclic antidepressant; AAP, atypical antipsychotic SECTION 3 - Pharmacological Treatments Kennedy SH et al. Can J Psychiatry 2016;61(9):540-60

55 CANMAT RECOMMENDATIONS FOR FIRST-LINE ANTIDEPRESSANTS Agent Mechanism Dose Agomelatine MT 1 and MT 2 agonist; 5HT 2 antagonist mg Bupropion NDRI mg Citalopram SSRI mg Desvenlafaxine SNRI mg Duloxetine SNRI 60 mg Escitalopram SSRI mg Fluoxetine SSRI mg Fluvoxamine SSRI mg Mianserin α 2 antagonist; 5HT 2 antagonist mg Milnacipran SSRI 100 mg Mirtazapine α 2 antagonist; 5HT 2 antagonist mg Paroxetine SSRI mg* Sertraline SSRI mg Venlafaxine SNRI mg Vortioxetine * mg for CR version CANMAT. Can J Psychiatry. 2016;61(9): SSRI; 5HT 1A agonist; 5HT 1B partial agonist; 5HT 1D, 5HT 3A, and 5HT 7 antagonist mg

56 MDD SYMPTOM CLUSTERS Functional domains of 5-HT and NE 1-3 Sex Appetite Aggression Depressed Mood Anxiety Vague Aches and pain Irritability Thought process Concentration Interest Motivation 1. Stahl. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, Stahl. Journal of Clinical Psychiatry, Nutt & al. Journal of Clinical Psychiatry, 2008.

57 DOSING OF COMMON ANTIDEPRESSANTS (MINIMAL THERAPEUTIC DOSES) Desvenlafaxine 50 mg 100 mg Duloxetine HCL 30 mg 60 mg Escitalopram 10 mg 20 mg Bupropion HCL 150 mg 300 mg Sertraline HCL 50 mg 100 mg 150 mg 200 mg Venlafaxine HCL 37.5 mg 75 mg 150 mg 225 mg Desvenlafaxine (50 and 100 mg tablets) Product Monograph. Wyeth Canada. (January 2009) Bupropion HCL (100 and 150 mg tablets) Product Monograph. Biovail. (2005) Escitalopram (10 and 20 mg tablets) Product Monograph. Lundbeck (September 2007) Duloxetine (30 and 60 mg delayed-released capsules) Product Monograph. Eli Lilly Canada Inc. (October 2007) Sertraline (25, 50, and 100 mg capsules) Product Monograph. Pfizer Canada Inc. (January 1992) Venlafaxine (37.5, 75, and 150 mg capsules) Product Monograph. Wyeth Canada. (January 2007) Refer to the Product Monograph, including warnings and precautions

58 CANMAT 2016 GUIDELINES: GENERAL PRINCIPLES OF PHARMACOLOGICAL TREATMENT Conduct a detailed clinical assessment Discuss evidence-based treatment options Elicit patient preference on use of pharmacotherapy Evaluate previous treatments Refer for laboratory testing where clinically indicated Reassess patients no more than 2 weeks after starting a medication; further follow-up every 2-4 weeks Follow measurement-based care to monitor outcomes and guide clinical decisions Kennedy SH et al. Can J Psychiatry 2016;61(9):540-60

59 BAC TO JANET: INITIAL VISIT OUTCOMES After discussion, she agrees to take a prescription JANET You prescribe an antidepressant that will meet her requests (low chances of weight gain, sexual dysfunction) You decide to take her off work at least until the next visit, as she is functioning poorly at work, feeling self-conscious, and her confidence has been shaken Discussion Question: Based on the data in the previous section, when should you follow up with Janet to assess her response? 61

60 JANET S FOLLOW-UP VISIT (2-4 weeks later) JANET On re-assessment, Janet s PHQ-9 score is 11 >20% improvement from baseline Has not reached remission (requires PHQ-9 score <5) Partial response (full response is 50% improvement) Recommendations: Optimize antidepressant dose: Go to maximum tolerated dose within usual range for your first-line treatment choice Consider switching to another class if at maximum dose of first-line treatment choice and improvement reaches a plateau Discussion Question: Based on what you ve learned today, when should you schedule a follow-up appointment with Janet? PHQ-9: Patient Health Questionnaire 62

61 FOLLOW-UP VISIT RECIPE FOR SUCCESS Less than 20% PHQ-9 score reduction (non-responder) Failure to achieve this at 2-4 weeks strongly suggests need to adjust treatment plan as chosen treatment unlikely to result in long-term remission Consider increasing dose (optimizing dose) if <20% PHQ-9 reduction or switching class of treatment if medication not tolerated Greater than 20% PHQ-9 score reduction but not at remission (PHQ-9 score 5) Maintain dose if patient continues to improve Optimize antidepressant dose (increase dose to maximum tolerated) if patient improvement reaches plateau; follow up again in 2 3 weeks Consider add-on (adjunct therapy) once dose optimized and/or at clinical discretion Greater than 20% PHQ-9 score reduction and remission (PHQ-9 score <5) Maintain current therapy and assess for recurrence risk (residual symptoms, comorbidities such as substance abuse, anxiety disorder) Arrange additional assessments for residual symptoms, side effects, and adherence Maintain current therapy for 6 9 months AFTER remission (first episode) PHQ-9: Patient Health Questionnaire 63

62 EARLY OPTIMIZED TREATMENT REFLECTS CANMAT GUIDELINES Select and initiate a first-line antidepressant 1 Early improvement after 2-4 weeks? YES Continue treatment for 6-8 weeks Symptom remission? N O 2 N O 4 Switch to a 2 nd -line or 3 rd -line antidepressant YES Consider factors for switch vs adjunct Switch to an antidepressant with superior efficacy Early improvement after 2-4 weeks? Add an adjunctive medication N O Early improvement (defined as >20% 30% reduction from baseline in a depression rating scale after 2 4 weeks) is correlated with response and remission at 6 to 12 weeks. CANMAT recommends increasing the antidepressant dose for non-improvers at 2 to 4 weeks if the medication is tolerated and switching to another antidepressant if tolerability is a problem YES Risk factors for recurrence? N O YES Maintain treatment for 6-9 months Maintain treatment for 2 years or longer CANMAT. Can J Psychiatry. 2016;61(9): (1) Monitor outcomes using measurement-based care. (2) Depending on tolerability, first optimize antidepressant by increasing dose. (3) For early treatment resistance, consider adjunctive use of psychological and neurostimulation treatments. (4) After failure of 1 or more antidepressants, consider switch to a second-line or third-line antidepressant. (5) For more resistant depressions, consider longer evaluation periods for improvement. (6) Depending on tolerability, increase dose if not at maximal doses. (7) For more chronic and resistant depressions, consider a chronic disease management approach, with less emphasis on symptom remission and more emphasis on improvement in functioning and quality of life. 64

63 CANMAT FIRST-LINE RECOMMENDATIONS FOR INADEQUATE RESPONSE TO AN ANTIDEPRESSANT Action Switch to an agent with evidence for superiority Add on another agent (adjunctive therapy) Drug choice (level of evidence) Agomelatine (level 2) Citalopram (level 2) Escitalopram (level 1) Mirtazapine (level 1) Sertraline (level 1) Venlafaxine (level 1) Aripiprazole (level 1) Quetiapine (level 1) Risperidone (level 1) CANMAT = Canadian Network for Mood and Anxiety Treatments Kennedy SH et al. Can J Psychiatry 2016; 61(9):

64 CHOOSING BETWEEN SWITCHING MEDICATIONS AND ADJUNCTIVE TREATMENT 1 CONSIDER SWITCH WHEN: It is the first antidepressant trial There are poorly tolerated side effects to the initial antidepressant There is <25% improvement to the initial antidepressant There is more time to wait for a response (less severe, less functional impairment)* Patient prefers to switch to another antidepressant CONSIDER ADJUNCT WHEN: There have been 2 antidepressant trials The initial antidepressant is well tolerated There is >25% improvement to the initial antidepressant There are specific residual symptoms or side effects to the initial antidepressant that can be targeted There is less time to wait for a response (more severe, more functional impairment)* Patient prefers to add on another medication *Note that studies on switching and adjunctive treatment strategies are not considered to be of a high quality. The CANMAT recommendation is to use adjunctive medications when patients have high ratings on depression scales and have not responded to multiple lines of treatment. Switch strategies might be a better choice in patients who do not respond, but have lower depression scale scores CANMAT. Can J Psychiatry. 2016;61(9): McIntosh, D. Personal Communication, 2016.

65 CANMAT-RECOMMENDED ADJUNCTIVE MEDICATIONS Agent First-line Recommendations Level of Evidence Dose Aripiprazole Level mg Quetiapine Level mg Risperidone Level mg Agent Second-line Recommendations Level of Evidence Dose Brexpiprazole Level mg Bupropion Level mg Lithium Level mg* Mirtazapine Level mg Modafinil Level mg Olanzapine Level mg Triiodothyronine Level mcg *Therapeutic serum levels CANMAT. Can J Psychiatry. 2016;61(9):

66 ANTIDEPRESSANT GENERICS Majority of antidepressants are generic: (Only following remain In Canada) Fetzima (Levomilnacipran) Pristiq (Desvenlafaxine) Trintellix (Vortioxetine) Health Canada requires bioequivalence of % Thus: Escitalopram 20 mg= 16-25mg Venlafaxine 150mg= mg

67 GENERIC SUBSTITUTION: 2016 CANMAT POSITION Substitution for branded medications is a common practice in Canada and may involve alternative drug formulations Canadian and US regulatory agencies define pharmacokinetic similarity for generics as bioequivalence between 80% to 125% of brand-name agents Kennedy SH et al. Can J Psychiatry. 2016; 61(9):

68 2016 CANMAT GUIDELINES: BIOINEQUIVALENCE Bioinequivalence may result in loss of efficacy or increased side effects Has led to withdrawal of some approved generic agents E.g FDA withdrawal of Budeprion* Generic medications are safe and reliable for most patients A careful risk-benefit assessment should be conducted prior to switching patients who are doing well from a braded medication to a generic version Consider risk for potential loss of efficacy or increased side effects * Kennedy SH et al. Can J Psychiatry. 2016; 61(9):

69 JANET HOW TO PROCEED You explain to Janet that she is still not in remission and explain the importance of achieving remission of symptoms and full functional recovery JANET To address her continued functional impairment, you prescribe Janet an adjunctive medication Low-dose aripiprazole (2 mg) You follow up with Janet 3 weeks later PHQ-9 score: 3 Total SDS score: 2 Has gained 2 lbs and feels good - mood better, sleep better, more energy, motivated, interest in things returning, concentration better, exercising Seeing friends and going out PHQ-9: Patient Health Questionnaire; SDS: Sheehan Disability Scale 71

70 JANET FUNCTIONAL IMPAIRMENTS What if: Janet comes back on follow-up with PHQ-9 score 6, but is only able to work part-time and does not feel like she is working productively? JANET You administer a Sheehan Disability Scale (she did not complete one at baseline, saying I can t concentrate to do all this paperwork ) Work/School: 7 Social Life: 3 Family life/home responsibilities: 7 Tells you her functioning is still impaired by low motivation, decreased interest, low energy, and poor concentration How would you address these residual symptoms? Another Scenario: What if Janet comes back with <20% improvement? 72

71 RECIPE FOR SUCCESS RECAP At each visit: Subjective: Objective: Assessment: PHQ-9 score, enquire about adherence and tolerability Mental status examination, relevant physical exams (vitals/thyroid/cardiac) Diagnostic considerations: Are all symptoms, comorbidities, and side effects being addressed? Use rating scales for screening, diagnosis and monitoring of symptoms and functioning Plan: PHQ-9 score improvement <20%: Increase dose or consider med switch to different class Follow up in 1 4 weeks PHQ-9 score improvement >20% but still 5 (not yet in remission): Optimize dose if not done, switch or consider adjunct therapy now or in future if symptom improvement reaches plateau Consider a functional recovery scale such as SDS Follow up in 1 4 weeks PHQ-9 score <5 (remission): Maintain current therapy ( 2 years if risk factors for recurrence) and long-term follow-up (monthly at first) Consider a functional recovery scale such as SDS looking for residual functional impairment PHQ-9: Patient Health Questionnaire; MDD: Major depressive disorder; SDS: Sheehan Disability Scale 73

72 SUMMARY Self-report rating scales are efficient and useful tools that simplify practice and improve outcomes by quantifying symptoms and making it easy to track progress Early optimized treatment improves chances of success Delays in effective treatment of MDD are associated with lower remission rates and residual functional impairment Rapid diagnosis and early optimized treatment of MDD improves outcomes and increases the likelihood of returning to full function Patients who do not show 20 30% improvement in PHQ-9 scores after 2 4 weeks are unlikely to improve Consider dose optimization, switching class of agent, or add-on treatment MDD: Major depressive disorder; PHQ-9: Patient Health Questionnaire 74

73 IMPORTANCE OF TOLERABILITY AND ADHERENCE FOR EARLY OPTIMIZED TREATMENT 75

74 TREATMENT ISSUES IN MDD Untreated MDD Up to 50% are untreated 1,2 Overall non-adherence up to 70% 3 Non-adherence in MDD 60% of patients stop antidepressant therapy before 6 months 4 28% of primary care patients stop antidepressant therapy at 1 month 4 Treatment Failures in MDD 40% to 60% 5 Recurrence/Relapse in MDD Up to 80% 5 Subsequent Episodes of MDD After 1 MDD episode, there is a 50% probability of a 2 nd episode 5 After 2 MDD episodes, there is an 80% to 90% probability of a 3 rd episode 5 Residual symptoms are associated with risk of relapse and recurrence 6,7 1. Patten. Can J Psychiatry. 2006;51:84-90; 2. Lecrubier. J Clin Psychiatry. 2007; 68 Suppl 2: 36-41; 3. Cassano Ann Clin Psychiatry. 2004;16(1):15-25; 4. Lin. Med Care. 1995;33(1):67-74; 5. Masand. Clin Ther. 2003;25(8): ; 6. McIntyre. Can J Psychiatry. 2004;49(3Suppl 1):10S-16S; 7. Zajecka. J Clin Psychiatry. 2013;75(4):

75 % discontinuing antidepressant therapy EARLY NON-ADHERENCE TO ANTIDEPRESSANTS IS HIGH 1 80% 70% 60% 50% 40% 42.4% 52.1% 72.4% CANMAT 2016 Guidelines for the Management of Adults with MDD 2 maintain treatment with antidepressants for 6 to 9 months after achieving symptomatic remission, while those with risk factors for recurrence extend antidepressant treatment to 2 years or more. 30% 20% 10% 0% 30 days 60 days 90 days Risk factors for recurrence include: Frequent, recurrent episodes Severe episodes (psychosis, severe impairment, suicidality) Chronic episodes Presence of comorbid psychiatric or other medical conditions Presence of residual symptoms Difficult-to-treat episodes 1. Olfson et al. Am J Psychiatry. 2006;163: CANMAT. Can J Psychiatry. 2016;61(9):

76 WHY DO PATIENTS STOP ANTIDEPRESSANT TREATMENT? Reasons for stopping treatment (n = 272 patients with DSM-IV MDD)* "Feeling better" "Adverse events" "Fear of drug dependence" "Feeling uncomfortable taking drugs" "Lack of efficacy" "I have to solve my problems without drugs" "My GP told me to stop" 0% 10% 20% 30% 40% 50% 60% *16% of patients gave 2 reasons for dropping out Demyttenaere et al. J Clin Psychiatry. 2001; 62 (Suppl 22):

77 PATIENT SURVEY OF ANTIDEPRESSANT-RELATED ADVERSE EVENTS & ADHERENCE Weight gain Unable to have erection Difficulty reaching orgasm Tired during the day/no energy Lost interest in sex Feeling agitated/jittery Insomnia Headaches Dry mouth Nausea/diarrhea Weight loss Frequency of AEs reported by patients* as extremely difficult to live with *Survey of 350 patients with mild to severe depression Ashton et al. Curr Ther Res. 2005;66(2): % of patients 79

78 MANAGING SIDE EFFECTS FOR TREATMENT ADHERENCE Adherence to medication is important in the treatment of depression 1 Manage side effects to maintain treatment if remission is achieved Strategies for some common side effects found on next slide General strategies: Patient education 2 Use of adjunctive medications 1,2 Choose agents with low potential for drug-drug interactions No consistent evidence to support specific adjunctive agents to target specific residual symptoms or side effects Switching antidepressant agent 2 1. CANMAT. Can J Psychiatry. 2016;61(9): Anderson et al. J Psychopharmacol. 2008;22:

79 STRATEGIES TO PROMOTE TREATMENT ADHERENCE SIDE EFFECTS POSSIBLE STRATEGIES 1,2 Weight gain 1 Sexual side effects 1-3 Central nervous system side effects (sleep disturbance, headache, tremor) 1,3 Nausea (early in treatment) 2,4 Select antidepressant with low weight gain liability Select antidepressant with low sexual side effect profile; judicious selection of pharmacologic treatments Judicious use of benzodiazepine or nonbenzodiazepine hypnotics Dose reduction, symptomatic treatment of GI side effects, co-administration with food, once-daily dosing at night, use of gastric motility agents 1. APA,Practice guideline for the treatment of patients with MDD CANMAT. Can J Psychiatry. 2016;61(9): Anderson et al. J Psychopharmacol. 2008;22: Cleare et al. J Psychopharmacol. 2015;29(5):

80 EFFECTS OF NEWER ANTIDEPRESSANTS ON WEIGHT* Weight change at >12 weeks (95% CI) SSRI Sertraline 0.12 kg ( 1.65 to 1.42) 1 Citalopram 1.69 kg ( 0.97 to 4.34) 1 Escitalopram 0.65 kg ( 0.16 to 1.45) 1 Fluoxetine 0.31 kg ( 1.04 to 0.43) 1 Fluvoxamine 0.02 kg ( 0.49 to 0.45) 1 Weight loss >0.5 kg Weight change 0.5 kg Weight gain >0.5 kg Paroxetine 2.73 kg (0.78 to 4.34) 1 SNRI Venlafaxine 0.50 kg ( 0.74 to 0.27) 1 Desvenlafaxine 0.5 kg 2 Duloxetine 0.71 kg ( 0.23 to 1.65) 1 Levomilnacipran 0.59 kg 3 Other Bupropion 1.87 kg ( 2.37 to 1.37) 1 Vortioxetine 0.4 kg 4 *These data do not include all recorded adverse events. They are presented as guidance and should be considered in the context of individual patients. Evidence based on exposure <12 weeks. SSRI: Selective serotonin reuptake inhibitor; SNRI: Selective norepinephrine reuptake inhibitor 1. Dent et al. PLoS One 2012; 7(6): e doi: /journal.pone Pristiq Product Monograph 12/2014. Pfizer Canada, Inc. 3. Fetzima Product Monograph 05/2015. Actavis Specialty Pharmaceuticals Co. 4. Trintellix Product Monograph 10/2014. Lundbeck Canada, Inc. 82

81 DRUG-DRUG INTERACTIONS CYTOCHROME P450 2D6 ENZYME Many antidepressants in current use are substrates of the cytochrome P450 2D6 enzyme (CYP2D6) 1 CYP2D6 poor metabolizers (7 10% of Caucasians) have a higher exposure to parent compound and lower exposure to active metabolites 2,3 Poor CYP2D6 metabolism more common than genetics suggest 3 One study found 4% of patients were genotypic CYP2D6 poor metabolizers, but 27% were phenotypic CYP2D6 poor metabolizers Poor CYP2D6 metabolism has been associated with lower efficacy and tolerability of antidepressants, depending on the characteristics of the drug 3 1. Lobello et al. J Clin Psychiatry 2010;71: Sasche et al. Am J Hum Genet 1997;60: Preskorn et al. J Clin Psychiatry 2013:74:

82 Median [ODV] (ng/ml) Median [ODV] (ng/ml) DESVENLAFAXINE PLASMA CONCENTRATIONS UNAFFECTED BY CYP2D6 PATHWAY Desvenlafaxine (50 mg) Consistent Exposure with desvenlafaxine Regardless of 2D6 Metabolizer Status Venlafaxine XR (75 mg) Marked Difference in Exposure Depending on 2D6 Metabolizer Status Poor Metabolizers (n=7) Extensive Metabolizers (n=7) Poor Metabolizers (n=7 Extensive Metabolizers (n=7) Time (hours) Time (hours) 120 Desvenlafaxine 50 mg as single dose Venlafaxine XR 75 mg as single dose ODV: O-desmethylvenlafaxine Nichols et al. Clin Drug Investig 2011;31: Refer to the Product Monograph, including warnings and precautions

83 Median [desvenlafaxine] (ng/ml) Median [ODV] (ng/ml) VENLAFAXINE PLASMA CONCENTRATIONS UNAFFECTED BY CYP2D6 PATHWAY Pristiq (100 mg) Consistent Exposure with Pristiq Regardless of 2D6 Metabolizer Status Effexor XR (75 mg) Marked Difference in Exposure Depending on 2D6 Metabolizer Status PM (n=7) EM (n=7) PM (n=6) EM (n=7) Time (hours) Pristiq 100 mg as single dose Time (hours) Venlafaxine XR 75 mg as single dose 120 Preskorn S et al. Journal of Psychopharmacol. Volume Refer to the Product Monograph, including warnings and precautions 42 85

84 SUMMARY Early nonadherence is common in patients with depression Minimizing adverse events is important for adherence Weight gain, sexual side effects, fatigue, and agitation are reported as extremely difficult to live with Adverse events interfere with functional recovery Lack of motivation or interest, insomnia, low physical energy, somnolence, emotional indifference, anxiety/tension/nervousness/tremor, and trouble concentrating are common and are often responsible for clinically important interference in occupational function 86