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Pearls from the 2023 CANMA T Depression Guidelines Sagar V. Parikh, MD, FRCPC Co-Author, CANMAT MDD Guidelinesmail: parikhsa@umich.edu Objectives At the end of this presentation, participants will be able to: 1. Describe the methodology of the 2023 Update of the CANMAT Guidelines for the Management of Adults with Major Depressive Disorder 2. Discuss various 2023 CANMAT recommendations for treatment and for augmentation and combination strategies 3. Identify additional strategies for Difficult to Treat Depression / “DTD” What is CANMAT? --CANMAT (Canadian Network for Mood and Anxiety Treatments) is a project-driven organization governed by a volunteer, unpaid advisory board with no permanent staff. • CANMAT has published 10 editions of guidelines, and 12 Task Group reports in MDD and BD since 1997 • World’s most cited guidelines (over 2500 citations to 2016 MDD guidelines and over 1300 to 2018 Bipolar guideline) • 2023 Guidelines published in 2024 (Lam et al, Can J Psychiatry) with 42 authors (I am section editor/coauthor); many drafts reviewed by patients and others --US Partner: National Network of Depression Centers will be helping disseminate these guidelines in the US. Case 1 - Peter • 48-year-old plumber • Recurrent major depressive episodes • Now treated with escitalopram 20 mg/d, with some response and improvement in his mood. Still depressed. • What is your management?Clinical Utility of the CANMAT Guidelines Question and answer format Level of evidence supplemented by “lines of treatment” Incorporates “clinical support” CANMAT 2023 Update on Guidelines for MDD General Methods: • Similar process to the 2016 depression guidelines • Evidence-informed, clinically useful method • Retains question-answer format • Balances systematic evidence review with consensus expert opinion by experienced academic clinicians • People with lived experience included at each step • Evidence review focused on umbrella reviews of systematic reviews and meta-analyses • Rigorous consensus process used • Single article with selected reference list, open access Can J Psychiatry • Full evidence review and references in online supplement • No pharma or external funding Literature Search CANMAT 2023 Update on Guidelines for Major Depressive Disorder 5266 studies imported Literature Search: for screening Systematic reviews and 154removedcates meta-analyses published from 2015 to 3725 studies screened May 31, 2023 2626 studies not relevant 1098 full-text studies assessed for eligibility 380 studies excluded 718 studies included CANMAT 2023 Update on Guidelines for MDD Definitions for Level of Evidence Ratings CANMAT 2023 Update on Guidelines for MDD Definitions for Line of Treatment Recommendations CANMAT 2023 Update on Guidelines for MDD 8 primary questions representing a patient’s care journey from assessment through treatment to maintenance 1. Who should be treated for depression? 2. What are management principles for a patient with depression? 3. How do you select the initial treatment? 4. What is the role of digital health care? 5. How do you monitor treatment? 6. What do you do when a patient is better? 7. What do you do if the patient is not getting better? 8. What if these treatments haven’t worked? CANMAT 2023 Update on Guidelines for MDD How do you choose the initial treatment? Considerations for selecting treatment(s) include : • Collaborative decision-making • Patients’ attitudes and preferences • Informed awareness of treatments • Quality of evidence • Availability of treatments • Risk from delay in treatment initiation • Severity of depression Depression Severity Recommendation Severe, high-risk Start a treatment that is immediately available. Consider all treatment modalities. Mild to Moderate, Choice between psychological treatment and medications, low-risk based on patient preference and availability. Psychotic depression Pharmacotherapy with both antidepressant and antipsychotic, or electroconvulsive therapy.CANMAT Recommendations for Psychological Treatments for MDD CANMAT 2023 Update on Guidelines for Major Depressive Disorder Red indicates new since 2016. CANMAT 2023 Update on Guidelines for MDD 3. How do you select the initial treatment? a. How do we assess the evidence for treatment? b. How do you use shared decision-making? c. How do we choose the initial treatment for depression? d. What factors are important in selecting initial psychotherapy? e. How many sessions of psychological treatment are required? f. What factors are important to selecting an initial antidepressant? g. Which treatments have new evidence? h. Are antidepressants associated with suicidality? i. Are there differences in formulations of specific antidepressants? j. When do you combine psychotherapy and pharmacotherapy? k. What alternative treatments are effective? l. What are important safety and drug interaction concerns? m. Can pharmacogenetics testing assist decision-making? n. Can other biomarkers assist decision-making? o. How do you deal with comorbid conditions? p. How do you integrate cultural and religious practices into treatment? CANMAT 2023 Update on Guidelines for MDD 3f. What factors are important to selecting an initial antidepressant? • 16 antidepressants made list of first-line agents • Choose on balance of efficacy AND tolerability • Based on landmark LANCET 2018 Cipriani meta-analysis, 21 antidepressants were good, but on balance, the top three were agomelatine, escitalopram, and vortioxetine • Patient choice, age, and previous experiences with meds are additional factorsCANMAT Medication Treatment Recommendations for MDD CANMAT Antidepressant Side Effects Frequency of adverse effects* of first-line Note: When data from multiple antidepressants doses were reported separately, the data from the minimum therapeutic dose was 1sed (indicated by foot2otes). Data from 50 mg dose; data from 50 mg dose; data from * Not included are side 100-150 mg dose; effects in Table 3.4 (sedation, 4data from 40 mg dose; data weight gain, sexual from 10 mg dose. dysfunction). Lam RW, Kennedy SH, et al. Can J Psychiatry 2024, in press. Side Effects Table Simplified CANMAT 2023 Update on Guidelines for Major Depressive Disorder Antidepressants: Consensus Comparative Ratings Algorithm for selecting an antidepressant CANMAT 2023 Update on Guidelines for Major Depressive Disorder Selection of an antidepressant depends on: • Efficacy • Tolerability • Clinical presentation • Past medication history • Concomitant medications • Cost • Patient preference. CANMAT 2023 Update on Guidelines for MDD 7. What do you do if the patient is not getting better? a) How do you sequence strategies for poor response to initial treatment? b) What are medication strategies for poor response to initial treatment? c) When do you switch antidepressants versus adding an adjunct medication? d) How do you select another antidepressant for switching? e) How do you select an adjunct medication? f) What are psychological strategies for poor response to initial treatment? Difficult-To-Treat Depression ▪ Treatment-Resistant Depression (TRD) usually refers to “failure” or non-response to 2 or more antidepressants from different classes. ▪ Problems with TRD definition: – Does not account for psychological treatments – Does not account for augmentation/combination treatments – Does not account for neurostimulation treatments – Does not account for partial response or residual symptoms – Does not account for functional recovery ▪ “Difficult-to-treat depression” is a better descriptor McAllister-Williams RH et al. J Affect Disord 2020;267:264-82. Difficult-to-Treat Depression Pharmacologic Approach: ✔ Diagnostic re-evaluation ✔ Assess adherence and drug-drug interactions ✔ Consideration of previous medication trials ✔ Rational use of adjunctive medications ✔ Discontinuation of nonbeneficial medications ✔ Careful monitoring of symptoms, side effects and functioning VA Augmentation and Switching Treatments for Depression (VAST-D) trial 12 weeks Switch: bupropion-SR 150-400 mg/d n=511 Suboptimal response to SSRI, SNRI or mirtazapine Augment: bupropion-SR 150-400 mg/d n=506 N=1522 • Age ≈ 54 years Augment: aripiprazole 2-15 mg/d n=506 • 85% men • 69% white, 25% black • 47% comorbid PTSD • 62% receiving psychotherapy • BMI ≈ 32 VA, Veteran’s Administration; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin noradrenaline reuptake inhibitor; PTSD, posttraumatic stress disorder; BMI, body mass index. Mohamed S et al. JAMA 2017;318:132-45. VA Augmentation and Switching Treatments for Depression (VAST-D) trial: Remission and Response Switch: bupropion-SR Augment: bupropion-SR Augment: aripiprazole (n=511) (n=506) (n=505) p=0.003 p<0.001 t e a f o p=0.02 % Baseline QIDS-C ≈ 16.7 (severely depressed). VA, Veteran’s Administration; QIDS-C, Quick Inventory of Depressive Symptomatology–Clinician; Remission ≤5; Response ≥50% decrease; Mohamed S et al. JAMA 2017;318:132-45. 23 Switching or Adding an Adjunctive Medication Factors to Consider Consider Switching when: Consider Adjunctive Therapy when: st • It is the 1 ADT trial • ≥2 ADT trials • Initial ADT is poorly tolerated • Initial ADT is well tolerated • No response (<25%) to the initial ADT* • Partial response (>25%) to the initial ADT • More time to wait for a response • Less time to wait for a response • Patient prefers to switch • Patient prefers to add-on • Specific residual symptoms or side effects can be targeted *For the initial ADT trial. In subsequent trials, lack of response (<25% improvement) may not be a factor for choosing between switch and adjunctive strategies. ADT, antidepressantCANMAT Strategies for Difficult to Treatment Depression • Optimize (one dose increase if mid-range usually enough, but some need more) • Switch – for non-response (one switch) • Consider earlier: Adjunctive/augmentation agents • Stop: Medications that have no benefit • (Consider Psychotherapy or Neurostimulation)CANMAT Adjunctive Medication Treatments for MDD Agents in red are new recommendations since the 2016 guidelines Add-On with Atypical Antipsychotics • Side effect burden must be considered (especially in elderly): • Extrapyramidal symptoms, sedation*, hyperprolactinemia, weight gain*, metabolic syndrome*, QTc prolongation* Agent Dosing Recommendations Initiate and maybe stay Acute Treatment Aripiprazole ▪2-5 mg/d ▪ Increase to 10 mg if needed ▪50 mg XR qhs x 2 days Quetiapine XR ▪ Increase to 300 mg XR qhs if needed ▪150 mg XR qhs on day 3 ▪0.5-1.0 mg Brexpiprazole ▪Target dose = 2 mg ▪ Increase to 3 mg if needed Olanzapine ▪5 mg qhs x 1 week ▪ Increase to 7.5-10 mg if needed Risperidone ▪0.25 mg qhs ▪ Increase to 2.0 mg qhs if neededCANMAT Adjunctive Medication Treatments for MDD Agents in red are new recommendations since the 2016 guidelines CANMAT 2023 Update on Guidelines for MDD 8 primary questions representing a patient’s care journey from assessment through treatment to maintenance 1. Who should be treated for depression? 2. What are management principles for a patient with depression? 3. How do you select the initial treatment? 4. What is the role of digital health care? 5. How do you monitor treatment? 6. What do you do when a patient is better? 7. What do you do if the patient is not getting better? 8. What if these treatments haven’t worked?CANMAT Recommendations for Digital Health Intervention Digital Health Interventions (DHIs): Examples* Digital Health Intervention Description Unguided (self-guided) DHIs Catch-It Mobile app with CBT-based activities. Headspace Self-guided meditation and mindfulness techniques with some CBT approaches. MoodGYM ** Internet-based CBT self-help program, with very structured modules. MoodKit ** Toolkit mobile app for CBT and behavioral activation. * These DHIs are not SPARK-RX Mobile app providing core elements of CBT and behavioral activation. endorsed by Woebot A mobile app conversational agent (chatbot) using AI to deliver empathic responses and personalized CBT exercises and activities. CANMAT Guided (facilitated) DHIs Good Days Ahead ** Designed for CBT therapists to provide additional CBT instruction outside of session. BounceBack Online CBT program with various formats: self-directed version, or with telephone-delivered lay coaching. Deprexis ** Online CBT program with tailored guidance provided by AI conversational agent. Pacifica Mobile- and web-based app intended to relieve stress, anxiety, and depression. examples to illustrate digital tools based on criteria including having at least one published study, being available and popular, and having been personally evaluated for suitability by at least one guidelines co-author. They are not endorsed by CANMAT. **DHI has at least one positive RCT in patients with MDD.Primary Questions for CANMAT MDD Guidelines 1. What are important issues for assessment and diagnosis? 2. What are the principles for depression management? 3. How are treatments selected? 4. What is the role of digital health interventions? 5. How is treatment monitored? 6. What should be done when a patient is better? 7. What should be done when a patient is not better? 8. When should neuromodulation treatments be used?CANMAT Recommendations on Medication Continuation All patients should continue antidepressants for 6-12 months after remission of symptoms, but longer-term (≥ 2 years) maintenance is recommended* for patients with: ✔ Frequent, recurrent episodes ✔ Severe episodes (psychosis, severe impairment, suicidality) ✔ Chronic episodes ✔ Difficult-to-treat episodes ✔ Persistent residual symptoms ✔ Psychiatric or non-psychiatric comorbidities ✔ Poor social support or persistent stressful life events ✔ History of trauma or childhood maltreatment * Few RCTs have specifically evaluated risk factors to guide longer term treatment; therefore, these recommendations.are Level 3 evidence RCT, randomized controlled trial CANMAT 2023 Update on Guidelines for MDD 8 primary questions representing a patient’s care journey from assessment through treatment to maintenance 1. Who should be treated for depression? 2. What are management principles for a patient with depression? 3. How do you select the initial treatment? 4. What is the role of digital health care? 5. How do you monitor treatment? 6. What do you do when a patient is better? 7. What do you do if the patient is not getting better? 8. What if these treatments haven’t worked? Management of Inadequate Response* • E(25-49%) or no response (<25%) to initial treatment • Re-evaluate diagnosis and consider treatment issues that may be affecting response (e.g. poor adherence) • Consider psychotherapy and neurostimulation for inadequate antidepressant response Optimize treatment! Many patients receive subtherapeutic doses and/or inadequate duration of treatment commonly defined as inadequate response to ≥2 antidepressantssistant depression; it is mostCANMAT Recommendations for Neurostimulation ECT Recommendations • ECT is generally considered a second-line recommendation for treatment-resistant depression. • ECT can be considered as a first-line recommendation for patients with: Severe psychotic features Severe catatonic features Severe suicidality Severe physical deterioration Prior good response to ECT Preference for ECTTMS Recommendations Case 1 - Peter • 48-year-old plumber • Recurrent major depressive episodes • Previously failed venlafaxine. Now treated with escitalopram 20 mg/d, with some response and improvement in his mood, but can’t tolerate dose increase. • QIDS-SR is 10 (mild-moderately depressed) (baseline = 16, remission ≤ 5). • What is your management? Case 1 - Peter • 48-year-old plumber • Recurrent major depressive episodes • Previously failed venlafaxine. Now treated with escitalopram 20 mg/d, with some response and improvement in his mood, but can’t tolerate dose increase. • QIDS-SR is 10 (mild-moderately depressed) (baseline = 16, remission ≤ 5). • His residual symptoms include insomnia and cognitive complaints. • What is your management? Summary • Major depression requires a process of care, not just a treatment • Assessment and monitoring is essential • Add-on strategies are probably more effective for non- or incomplete response than switching • Remember psychological and neurostimulation treatments • Other add-on treatments include exercise, light therapy, and complementary and alternative medicine treatments Must still customize treatment strategies for each patient, based on individual benefit-risk ratio