Pharmacotherapy Update for Major Depressive Disorder: Focus on Adjunct Antipsychotics Dan McGraw, PharmD, BCPP Clinical Pharmacy Specialist in Psychiatry Medical University of South Carolina

I have no conflicts of interest to disclose I will discuss off-label indications of some medications

Goals Utilize validated psychometric scales to assess depression severity and response to treatment Recall the place in therapy for antipsychotics in treating major depressive disorder Compare the risks and benefits of the antipsychotics covered Apply presented data and clinical pearls to patient case

Background Many patients with major depressive disorder (MDD) fail to achieve remission with first-line therapies Failure to achieve remission is associated with higher risk of relapse Many second generation antipsychotics (SGA) have shown efficacy in MDD as adjunct to conventional antidepressants There is incomplete understanding of magnitude of benefit, side effect risk, and long-term effects of antipsychotics in MDD treatment

Disease Assessment Hypertension – blood pressure measurement Asthma – pulmonary function test Diabetes – blood glucose level & hemoglobin A1c Mental health – no direct measurements available

MDD Assessment Numerous models available to “objectify” major depression and other mental health conditions Psychometric scales are the bedrock on which most of the psychiatric literature is built “Alphabet soup” of rating scales now exist, all with nuanced differences, strengths, and weaknesses e.g. HAMD, BDI, PHQ-9, MADRS, EPDS, IDS, CGI, QIDS, ETC.

MDD Assessment Example – PHQ-9 Patient Health Questionnaire – 9 Item Example of a useful scale for clinical practice Validated in primary care setting Brief (9 items) Self-reported (in waiting room or at home) Inclusive (6th grade reading level, available in several languages) Highly sensitive and selective for major depression PHQ-9 scores can be used to grade depression by severity Kroenke K, et al. J Gen Intern Med. 2001;16(9):606-13.

MDD Assessment Non-response vs. Response Remission

PHQ-9 score reduction from 26 to 21 MDD Assessment Example: “I feel the same” Example: PHQ-9 score reduction from 26 to 21 Non-response vs. Response Remission SUBJECTIVE OBJECTIVE

MDD Assessment SUBJECTIVE OBJECTIVE Non-response vs. Response Remission SUBJECTIVE Example: “I feel better but still depressed” Example: PHQ-9 score reduction from 26 to 12 OBJECTIVE

MDD Assessment SUBJECTIVE OBJECTIVE Non-response vs. Response Remission SUBJECTIVE OBJECTIVE Example: “I feel like my old self again” Example: PHQ-9 score reduction from 26 to 2

Why is Remission so Important? This graph shows, for STAR-D cohorts throughout steps 1-4 of protocol, that patients who achieved remission were less likely to relapse within 12 months than patients that did not achieve remission. So even those patients that had significant symptom improvement (ie response) were more likely to relapse than those in remission. Rush AJ, et al. Am J Psychiatry. 2006;163:1905-17.

Second Generation Antipsychotics: Role in Treatment of Depression

 *Treatment-resistant depression in combination with fluoxetine Second-Generation Antipsychotic FDA Approval as Adjunct in MDD RCT Data as Adjunct in MDD Quetiapine (Seroquel™, Seroquel XR™)  *Seroquel XR only  Olanzapine (Zyprexa™)  *Treatment-resistant depression in combination with fluoxetine Aripiprazole (Abilify™) Brexpiprazole (Rexulti™) Cariprazine (Vraylar™)  +/- Risperidone (Risperdal™) Ziprasidone (Geodon™) Paliperidone (Invega™) Iloperidone (Fanapt™) Lurasidone (Latuda™) Asenapine (Saphris™) RCT = randomized controlled trial; FDA = Food and Drug Administration

Guideline Status of Adjunctive SGA in MDD Guideline, Year Place in Therapy of SGA National Institute of Clinical Effectiveness (NICE), 2016 Augmentation to antidepressant in those who do not respond well to initial treatment Canadian Network for Mood and Anxiety Treatments (CANMAT), 2016 1st line augmentation to antidepressant in partial/non-response [Level I Evidence] Department of Veterans Affairs/Department of Defense (VA/DoD), 2016 Augmentation therapy in partial/non-response only when other strategies have failed due to significant side effect risk World Federation of Societies of Biological Psychiatry (WFSBP), 2013 Augmentation with aripiprazole or quetiapine in monotherapy failure [Level of Evidence A; Recommendation Grade 2] Korean Medication Algorithm Project for Depressive Disorder (KMAP-DD), 2012 2nd line augmentation to antidepressant in partial responders (but not non-responders) [Expert Opinion] American Psychiatric Association (APA), 2010 2nd line augmentation to antidepressant [moderate confidence of recommendation]

SGA Utilization – Trends 2013: retrospective review of commercial health care plan claims from 2008 – 2011 Objective: assess diagnoses associated with SGA prescriptions N = 18,352 patients age 18 – 64 that received SGA during study period included in analysis ~50% of patients located in Southeastern United States region Citrome L, et al. Clin Ther. 2013;35(12):1867-75.

SGA Utilization – Trends Variable Aripiprazole, % (N = 7164) Olanzapine, % (N = 1420) Quetiapine, % (N = 7360) Risperidone, % (N = 1903) Ziprasidone, % (N = 505) Female 68.3 53.5 57.5 52.9 67.5 SCZ 1.2 4.6 1.3 6.6 5.9 BPAD 31.8 34.2 32.8 35.5 51.1 MDD 53.0 39.5 41.8 34.7 29.9 No diagnosis code 14.0 21.8 24.1 23.1 13.1 SCZ = schizophrenia; BPAD = bipolar affective disorder; MDD = major depressive disorder Citrome L, et al. Clin Ther. 2013;35(12):1867-75.

SGA Utilization – Trends 2014: retrospective review of National Ambulatory Medical Care Survey (NAMCS) data from 1999 – 2010 Objective: estimate prevalence and trends of SGA use for treatment of nonpsychotic depression in outpatient setting N = 7,767 patients with nonpsychotic depression age ≥ 18 Gerhard T, et al. J Clin Psychiatry. 2014;75(5):490-7.

SGA Utilization – Trends Variable 1999 – 2002, % (N = 2,506) 2003 – 2006, % (N = 2,686) 2007 – 2010, % (N = 2,575) Adjusted OR for Time Trend (95% CI) Overall 6.1 8.4 11.2 2.78 (1.84 – 4.20) Private Insurance 4.9 5.7 7.1 2.63 (1.31 – 5.25) Public Insurance 8.6 14.7 18.4 3.44 (1.79 – 6.60) MDD 11.0 14.2 20.0 2.67 (1.62 – 4.39) DM, HLD, or CVD 1.7 7.3 7.2 9.65 (1.76 – 53.07) Antipsychotic Monotherapy 3.6 Not reported 6.8 3.36 (1.63 – 6.90) MDD = major depressive disorder; DM = diabetes mellitus; HLD = hyperlipidemia; CVD = cardiovascular disease Gerhard T, et al. J Clin Psychiatry. 2014;75(5):490-7.

Antipsychotic Utilization – Trends 2016: retrospective review of Oklahoma Medicaid claims 2006 – 2011 Objective: determine if depressed patients receive adequate antidepressant trial prior to starting 2nd line treatment N = 1,797 patients age ≥ 18 with unipolar depression who were prescribed a 2nd line agent for augmentation ~50% of patients were prescribed SGA as augmentation Hassan A, et al. Int J Clin Pharm. 2016;38:429-37.

SGA Utilization – Trends Variable SGA Augmentation, % (N = 893) Adequate AD Dose 90.8 Two AD Trials 50.6 AD Duration: < 4 Weeks 43.2 AD Duration: 4 – 8 Weeks 5.6 AD Duration: > 8 Weeks 51.2 AD Adherence 50.3 AD = antidepressant Hassan A, et al. Int J Clin Pharm. 2016;38:429-37.

Meta-analysis of adjunct SGA in MDD studies Risperidone, quetiapine, olanzapine/fluoxetine combo (OFC), aripiprazole 14 RCTs; N = 3,549 participants Primary outcomes: response, remission, & side effect rates Other outcomes: aggregate of quality of life and functioning scores Spielmans G, et al. PLoS Med. 2013;10(3):e1001403.

Results – Efficacy SGA Remission NNT Symptom Improvement, Hedges g Effect Size (95% CI) QoL/Functioning, Hedges g Effect Size (95% CI) Risperidone 9 0.48 (0.22 – 0.73) 0.49 (0.26 – 0.73) Quetiapine 0.40 (0.26 – 0.53) NS Aripiprazole 0.35 (0.23 – 0.48) 0.22 (0.09 – 0.34) OFC 19 0.26 ( 0.04 – 0.45) NNT = number needed to treat; OFC = olanzapine/fluoxetine combo; QoL = quality of life; NS = not significant Remission more likely with risperidone, quetiapine, aripiprazole Less likely with olanzapine/fluoxetine combination Effect size of “small to moderate” was observed in overall symptom improvement Risperidone and aripiprazole only agents to show QoL/functioning improvement Effect size for risperidone/QoL, though positive, is small and clinically negligible Though positive here, other risperidone studies not included in this meta-analysis indicate that benefits may be short-lived Spielmans G, et al. PLoS Med. 2013;10(3):e1001403.

Results – Safety Olanzapine/fluoxetine demonstrated worst tolerability SGA Sedation NNH Akathisia NNH Weight Gain NNH Elevated Metabolic Labs NNH Risperidone NS Not assessed Quetiapine 3 37 (≥ 7% body weight) 6 Aripiprazole 14 4 29 (≥ 7% body weight) OFC 5 9 (≥ 10% body weight) 10 NNH = number needed to harm; OFC = olanzapine/fluoxetine combo; NS = not significant Olanzapine/fluoxetine demonstrated worst tolerability Sedation, weight gain, metabolic parameters, prolactin levels Mean weight gain: 9 pounds OFC vs. 2 pounds risperidone/quetiapine/aripiprazole These are short-term studies: mean 7 weeks; range 4 – 12 weeks These RCT data most likely underestimate long-term metabolic risk Another long-term study found that olanzapine had >7% weight gain in >50% of patients Spielmans G, et al. PLoS Med. 2013;10(3):e1001403.

Newly-Approved Second-Generation Antipsychotics and Role in Depression

What’s New? Cariprazine (Vraylar™) Brexpiprazole (Rexulti™) FDA-approved for schizophrenia, acute treatment of manic/mixed episodes, and bipolar depression Mixed RCT data in MDD as adjunct to antidepressant; not FDA approved Brexpiprazole (Rexulti™) FDA-approved for schizophrenia and MDD as adjunct to antidepressant

Mechanism of Action Like aripiprazole, both brexpiprazole and cariprazine are partial agonists at the D2 and D3 receptor Receptor binding profiles differ widely between these agents resulting in variable clinical effects

Relative Affinity at Key Receptors Aripiprazole Brexpiprazole Cariprazine Clinical Effects D2 ++ +++ + Antipsychotic EPS D3 5-HT1A Antidepressant Anxiolytic 5-HT2A Anti-EPS 5-HT2C 5-HT7 H1 Sedation Weight gain α1 Orthostasis +/++/+++: relative magnitude of affinity Frankel J, Schwartz T. Ther Adv Psychopharmacol. 2017;7(1):29-41.

Cariprazine (Vraylar™) 3 RCTs evaluating cariprazine efficacy in MDD 1 positive, 2 negative 2 studies ongoing but not completed Multiple RCTs and meta-analyses investigating cariprazine in schizophrenia and bipolar disorder http://www.clinicaltrials.gov

Cariprazine (Vraylar™) Durgam S, et al. J Clin Psychiatry. 2016;77(3):371-8. Earley W, et al. Psychopharm Bull. 2018;48(4):62-80.

Cariprazine RCT Results – Efficacy Outcomes (8 weeks) Durgam, et al N = 812 Earley, et al N = 527 Mean dose, mg Low dose group: 1.4 High dose group: 2.6 2.97 MADRS change from baseline vs. placebo Low dose: -0.9 (NS) High dose: -2.1* -0.2 (NS) MADRS response vs. placebo, NNT Low dose: 11 High dose: 9 NS MADRS remission vs. placebo, NNT Low dose: NS High dose: NS Earley: lower baseline severity of illness (MADRS ~25 vs 29), more diverse population (more equal sex distribution, higher % of non-white subjects) compared to Durgam. Recruited in U.S. only (Durgam recruited in Europe and US). Durgam dosing: 1 – 2 mg/day flexible dosing or 2 – 4.5 mg/day flexible Earley dosing: 1.5 – 4.5 mg/day flexible with target dose of 3 mg/day but specific criteria allowing for titration to max dose. MADRS = Montgomery-Asberg Depression Rating Scale; MADRS Response = ≥50% score reduction from baseline; MADRS Remission = MADRS total score ≤10; NS = not statistically significant; NNT = number needed to treat *p <0.05 Durgam S, et al. J Clin Psychiatry. 2016;77(3):371-8. Earley W, et al. Psychopharm Bull. 2018;48(4):62-80.

Cariprazine RCT Results – Safety Outcomes (8 weeks) Durgam, et al N = 812 Earley, et al N = 527 Akathisia or restlessness, NNH Low dose: 11 High dose: 4 5 Insomnia, NNH Low dose: 26 High dose: 14 NS Change in body weight ≥ 7% from baseline, NNH Discontinuation due to side effect, NNH Low dose: 28 High dose: 10 14 NS = not statistically significant; NNH = number needed to harm Durgam S, et al. J Clin Psychiatry. 2016;77(3):371-8. Earley W, et al. Psychopharm Bull. 2018;48(4):62-80.

Cariprazine Takeaways Mild-to-negligible reduction in depressive symptoms per MADRS compared to placebo No significant difference in functioning between groups No significant difference in remission rate between groups Studies not powered to detect this, however Mild increase in treatment response in Durgam study but not yet replicated in subsequent trials Akathisia/restlessness is primary side effect Dose-dependent Durgam S, et al. J Clin Psychiatry. 2016;77(3):371-8. Earley W, et al. Psychopharm Bull. 2018;48(4):62-80.

Brexpiprazole (Rexulti™) 5 RCTs evaluating brexpiprazole efficacy in MDD 4 positive, 1 negative 1 study ongoing but not completed Multiple RCTs investigating brexpiprazole in schizophrenia 1 large unpublished study (1 – 3 mg/day vs PBO) beat PBO in remission and response but not total MADRS reduction. http://www.clinicaltrials.gov

Brexpiprazole (Rexulti™)

Brexpiprazole RCT Results – Efficacy Outcomes (6 weeks) Polaris N = 643 Pyxis N = 353 Sirius N = 394 Delphinus N = 503 Mean dose, mg Low dose: 1 High dose: 3 2 2.2 MADRS change from baseline vs. placebo Low dose: NS High dose: -1.96* -3.21* -2.3* -1.4* MADRS response vs. placebo, NNT Low dose: 12 High dose: 12 13 NS MADRS remission vs. placebo, NNT MADRS = Montgomery-Asberg Depression Rating Scale; MADRS Response = ≥50% score reduction from baseline; MADRS Remission = MADRS total score ≤10; NS = not statistically significant; NNT = number needed to treat *p <0.05 Thase M, et al. J Clin Psychiatry. 2015;76(9):1232-40. Thase M, et al. J Clin Psychiatry. 2015;76(9):1224-31. Hobart M, et al. J Clin Psychiatry. 2018;79(4):17m12508. Hobart M, et al. Curr Med Res Opin. 2018;34(4):633-42.

Brexpiprazole – Pooled Analysis Results from these 4 RCTs were pooled in a meta-analysis for patients receiving brexpiprazole 2 -3 mg/d (2019) Outcomes (6 weeks) Pooled Analysis N = 1588 MADRS change from baseline vs. placebo -2.15* MADRS response vs. placebo, NNT 17* MADRS remission vs. placebo, NNT 25* MADRS = Montgomery-Asberg Depression Rating Scale; MADRS Response = ≥50% score reduction from baseline; MADRS Remission = MADRS total score ≤10; NS = not statistically significant; NNT = number needed to treat; *p <0.05 Thase M, et al. Exp Opin Pharmacother. 2019:doi.10.1080/14656566.2019.1638913.

Brexpiprazole RCT Results – Safety Outcomes (6 weeks) Polaris N = 643 Pyxis N = 353 Sirius N = 394 Delphinus N = 503 Mean dose, mg Low dose: 1 High dose: 3 2 2.2 Akathisia or restlessness, NNH Low dose: 26 High dose: 7 11 15 Somnolence or fatigue, NNH Low dose: 21 High dose: 13 27 NS 17 Change in body weight ≥ 7% from baseline, NNH Low dose: 25 High dose: NS 32 31 Discontinuation due to side effect, NNH Low dose: NS NS = not statistically significant; NNH = number needed to harm Thase M, et al. J Clin Psychiatry. 2015;76(9):1232-40. Thase M, et al. J Clin Psychiatry. 2015;76(9):1224-31. Hobart M, et al. J Clin Psychiatry. 2018;79(4):17m12508. Hobart M, et al. Curr Med Res Opin. 2018;34(4):633-42.

Brexpiprazole – Long-Term Effects 6-week studies may under-estimate certain side effects that take time to manifest, e.g. weight gain and metabolic effects Hobart et al (2019) published a 52-week continuation study from 3 of the short-term studies (Pyxis, Polaris, Delphinus) [N = 2938] Open-label continuation , no placebo group Flexible dose 0.5 – 3 mg/day Rates of akathisia and somnolence were similar to 6 week trials Metabolic side effects were much more pronounced in long-term Hobart et al. J Clin Psychopharmacol. 2019;39:203-9.

Brexpiprazole – Long-Term Effects Mean weight increase from baseline 6 week: 1.4 kg 26 week: 2.7 kg 52 week: 3.2 kg Clinically significant weight gain (≥ 7% increase from baseline at any point) Initial 6 weeks: 4.3% Over 52 weeks: 25.8% Categorical change from ‘normal’ to ‘high’ for select metabolic labs: Total cholesterol: 9.5% LDL: 4.3% Fasting triglycerides: 16.8% Fasting glucose: 8.2% Mean change in body weight (kg) over 52-week follow-up study Mean increase from baseline at 6 weeks in the pooled analysis: 1.4 kg 26 week from this paper: 2.7 kg 52 week from this paper: 3.2 kg Hobart et al. J Clin Psychopharmacol. 2019;39:203-9.

Brexpiprazole Takeaways Mild-moderate symptom reduction seen vs. placebo Target dose = 2 – 3 mg/day Akathisia/restlessness = primary side effect Dose-dependent Weight gain and metabolic derangements over the long-term

SGA Monitoring

Extrapyramidal Symptoms (EPS) Akathisia – inner restlessness Days to weeks after starting SGA Aripiprazole, brexpiprazole, cariprazine Barnes Akathisia Rating Scale used to quantify Dose reduction trial warranted Propranolol (1st line), benztropine (2nd line), benzodiazepine (3rd line) Parkinsonism – involuntary movements similar to Parkinson’s Disease Higher-potency agents most likely to cause (e.g. risperidone, paliperidone) Simpson-Angus Scale used to quantify Dose reduction or drug discontinuation warranted Benztropine or diphenhydramine (1st line), trihexiphenidyl (2nd line)

Extrapyramidal Symptoms (EPS) Dystonia – acute involuntary muscle contraction Can occur early in therapy, after just a few doses Higher-potency agents most likely to cause Risk is low, but counsel patient to seek emergency care if it occurs Dose reduction or drug discontinuation warranted Tardive dyskinesia – chronic involuntary muscle movements Months to years after starting SGA Abnormal Involuntary Movement Scale used to quantify Specialty referral warranted

Metabolic Effects Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Personal/family history X Weight/BMI Waist circumference Blood pressure Fasting lipids Fasting glucose or hgbA1c Olanzapine, risperidone, quetiapine ADA. Diabetes Care. 2004;27:596-601.

Takeaways Remission is the goal of depression management…don’t settle for less SGAs can improve symptoms when added to conventional antidepressants Degree of benefit is typically mild to moderate These agents pose significant side effect risks (EPS, metabolic effects) Re-assess need for continuation after the depressive episode has resolved

Takeaways Place in therapy 1: optimize antidepressant dose and treat for sufficient duration (~8 weeks). Confirm compliance. 2a: if metabolic risk factors present, consider augmentation with non-SGA options (e.g. non-SRI antidepressant, buspirone, T3, lithium) 2b: if benefit outweighs risk, consider SGA addition with appropriate monitoring

Case 1 DB is a 42 year old female with PMH of gout, hypertension, MDD. Her current medications include Lisinopril 20 mg QD, fluoxetine 20 mg QD, and acetaminophen 500 mg TID prn. The fluoxetine was started at her last appointment 4 weeks ago. At her visit today she tells you that she continues to feel sad, lethargic, hopeless, and guilty. Her PHQ-9 score is 21, down from 27 at baseline. What is the best option to manage this patient currently? Add aripiprazole 5 mg PO QD for MDD augmentation Optimize fluoxetine dose as tolerated and follow-up in 2 weeks Counsel patient that this is normal as fluoxetine takes > 8 weeks to have an effect Switch to an alternative antidepressant as fluoxetine has failed

Case 1 DB is a 42 year old female with PMH of gout, hypertension, MDD. Her current medications include Lisinopril 20 mg QD, fluoxetine 20 mg QD, and acetaminophen 500 mg TID prn. The fluoxetine was started at her last appointment 4 weeks ago. At her visit today she tells you that she continues to feel sad, lethargic, hopeless, and guilty. Her PHQ-9 score is 21, down from 27 at baseline. What is the best option to manage this patient currently? Add aripiprazole 5 mg PO QD for MDD augmentation Optimize fluoxetine dose as tolerated and follow-up in 2 weeks Counsel patient that this is normal as fluoxetine takes > 8 weeks to have an effect Switch to an alternative antidepressant as fluoxetine has failed

Case 2 TR is a 25 year old male returning to clinic for depression management. He has been taking escitalopram 20 mg daily for nearly 3 months. His PHQ-9 score has improved from a score of 25 to 15 but he remains moderately depressed. You are considering an SGA trial. What baseline information do you need prior to choosing an agent? Family history of diabetes or metabolic syndrome Body mass index Hemoglobin A1c All of the above

Case 2 TR is a 25 year old male returning to clinic for depression management. He has been taking escitalopram 20 mg daily for nearly 3 months. His PHQ-9 score has improved from a score of 25 to 15 but he remains moderately depressed. You are considering an SGA trial. What baseline information do you need prior to choosing an agent? Family history of diabetes or metabolic syndrome Body mass index Hemoglobin A1c All of the above

Case 2a You learn that TR has a family history significant for type 2 diabetes (father) and his hgbA1c is 6.3% (prediabetes). What is the best option regarding his depression management? Try non-SGA options due to his high risk of developing diabetes Initiate brexpiprazole as it has not been shown to increase risk of metabolic side effects Initiate quetiapine with close metabolic monitoring Initiate aripiprazole for MDD augmentation and metformin to prevent metabolic side effects

Case 2a You learn that TR has a family history significant for type 2 diabetes (father) and his hgbA1c is 6.3% (prediabetes). What is the best option regarding his depression management? Try non-SGA options due to his high risk of developing diabetes Initiate brexpiprazole as it has not been shown to increase risk of metabolic side effects Initiate quetiapine with close metabolic monitoring Initiate aripiprazole for MDD augmentation and metformin to prevent metabolic side effects

Case 3 VC is a 45 year old female with MDD. After initial treatment with SSRI monotherapy you have initiated adjunctive brexpiprazole 3 mg QD for further symptom improvement. Today in clinic VC notes that she is having trouble sitting still. She constantly bounces her legs and taps her feet. It even affects her at night and she is losing sleep. What side effect could this be and how can you manage it? Parkinsonism – switch to risperidone Parkinsonism – reduce the dose from 3 mg to 2 mg daily Akathisia – switch to cariprazine Akathisia – reduce the dose from 3 mg to 2 mg

Case 3 VC is a 45 year old female with MDD. After initial treatment with SSRI monotherapy you have initiated adjunctive brexpiprazole 3 mg QD for further symptom improvement. Today in clinic VC notes that she is having trouble sitting still. She constantly bounces her legs and taps her feet. It even affects her at night and she is losing sleep. What side effect could this be and how can you manage it? Parkinsonism – switch to risperidone Parkinsonism – reduce the dose from 3 mg to 2 mg daily Akathisia – switch to cariprazine Akathisia – reduce the dose from 3 mg to 2 mg

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