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#FSHP2019 Disclosure #FSHP2019

I do not have (nor does any immediate family member have): Treatment Resistant Depression – a vested interest in or affiliation with any corporate organization offering financial support or grant monies Samantha Themas, PharmD, BCPP for this continuing education activity Clinical Pharmacy Specialist – Psychiatry – any affiliation with an organization whose philosophy Memorial Regional Hospital could potentially bias my presentation [email protected]

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Pharmacist Objectives #FSHP2019 Technician Objectives #FSHP2019 • Examine the differences between depression and • Identify symptoms of treatment resistant treatment resistant depression depression • Critique medication strategies in the • List medications used to manage treatment management of treatment resistant depression resistant depression • Discuss the use of non-pharmacologic treatment • Recognize the role of pharmacy staff in the options management of treatment resistant depression • Explore the role of the pharmacist in the management of treatment resistant depression

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#FSHP2019 Suicide Rates: US 1999-2017 #FSHP2019

CDC 2018

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#FSHP2019 #FSHP2019

Major Depressive Disorder (MDD) Chart Title 6 • Common disorder Environment • Leading cause of disability 5

worldwide 4 • Major contributor to overall global burden of disease Biology Genes 3 • Worst case  suicide 2

1 Psychology 0 Category 1 Category 2 Category 3 Category 4 Series 1 Series 2 Series 3 National Institute of Mental Health 2019 World Health Organization 2019 78

Symptoms #FSHP2019 MDD Diagnosis #FSHP2019 • At least five symptoms over a two week period • S – Sleep changes and represent a change from previous function • I – Interest decrease • One of the following must be presenting • G – Guilt • Depressed mood • E – Energy decrease • Loss of interest or pleasure • C – Concentration decrease • Symptoms cause significant distress or impairment in important area of functioning • A – Appetite changes • Not attributable to the physiological effects of a • P – Psychomotor disturbances substance or medical condition • S – • No history of mania or hypomania

DSM-5 DSM-5 Image courtesy of: depressioncomix.tumblr.com 910

#FSHP2019 #FSHP2019 Cause? Assessment of Symptoms

• Multiple theories exist • Utilization of validated scales allows for simpler assessment • Monoamine deficiency most popular of symptom improvement, or lack thereof • Examples • Hamilton Depression Rating Scale (HAM-D) • Montgomery-Asberg Depression Rating Scale (MADRS) • Quick Inventory of Depression Symptomology (QIDS) • Patient Health Questionnaire 9 (PHQ-9)

Mulinari S. J Hist Neurosci. 2012. APA Guidelines 2010 Image courtesy of: https://www.jax.org/news-and-insights/jax-blog/2015/december/happy-or-sad-the-chemistry-behind-depression 11 12

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#FSHP2019 Depression Treatment Options - #FSHP2019 Depression Treatment Options – Non Pharmacologic Pharmacologic • Selective Serotonin Reuptake Inhibitors (SSRIs) • Cognitive Behavioral Therapy (CBT) • Serotonin Partial /Reuptake Inhibitors (SPARIs) • Electroconvulsive Therapy (ECT) • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) • Repetitive Transcranial Magnetic Stimulation (rTMS) • Norepinephrine- Reuptake Inhibitors (NDRIs) • Serotonin Antagonist/Reuptake Inhibitors (SARIs) • • Monoamine Oxidase Inhibitors (MAOIs) • (TCAs)

Stahl SM. Antidepressants. Essential Psychopharmacology Online. 2008. DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach. 2014. 13 14

#FSHP2019 #FSHP2019 SARIs Mirtazapine MAOIs TCAs SSRIs SPARIs SNRIs NDRIs , , Mirtazapine , , , , , , , Examples , , , , , , Examples , , Serotonin reuptake Alpha 2 Irreversibly block Inhibit reuptake of 5HT and Selective, potent Inhibits serotonin Inhibits reuptake Inhibits reuptake inhibition and adrenergic MAO-A and NE, also have non-selective inhibition of serotonin reuptake and is of serotonin and of both antagonism at one or antagonist MAO-B  inhibits alpha1 adrenergic, MOA MOA reuptake 5HT1A partial norepinephrine dopamine and two serotonin receptors  increased breakdown of muscarinic and agonist (varying norepinephrine release of NE NE, DA and 5HT histaminergic blocking degrees) and 5HT properties Nausea/vomiting, Headache, Headaches, Hypertension, V - sexual side effects, Sedation, Hypertensive Arrhythmias, activation/insomnia, diarrhea, nausea hypertension, headaches, nausea, diarrhea, dry weight gain, crisis, serotonin adverse sexual side effects, sexual side activation, mouth constipation, syndrome, effects, sedation, weight Adverse Adverse headaches, falls, effects, nausea, insomnia, lower N – hepatoxicity dry mouth, orthostatic gain, seizures, sexual side Effects Effects bleeding, diaphoresis, insomnia, seizure threshold T&N– orthostatic increased hypotension, effects akathisia diaphoresis, hypotension, sedation cholesterol sexual side akathisia effects Stahl SM. Antidepressants. Essential Psychopharmacology Online. 2008. APA Guidelines 2010. Stahl SM. Antidepressants. Essential Psychopharmacology Online. 2008. APA Guidelines 2010. 15 16

Depression Treatment Options – #FSHP2019 Phases of Treatment of MDD #FSHP2019 Augmenting Agents

• • • Second generation (SGAs) •

Ann Intern Med. 2016;164(5):350-359. APA Guidelines. 2010. 17 18

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#FSHP2019 #FSHP2019 STAR*D Trial STAR*D Trial

Rush AJ et al. Am J Psychiatry. 2006. Rush AJ et al. Am J Psychiatry. 2006. 19 20

#FSHP2019 #FSHP2019 STAR*D Trial – Recovery Rates

APA Guidelines 2010 Stahl SM. Essential Psychopharmacology Online. 2008. 21 22

#FSHP2019 #FSHP2019 TRD and the Guidelines

TMAP APA WFSBP Most Recent 2008 2010 2013 Update

Mention TRD? No No Yes

“No universally accepted definition… failed to show clinically meaningful improvement after treatment with Definition of TRD N/A N/A at least two difference agents prescribed in adequate dosages for adequate duration… with treatment adherence” MAOIs, ECT for Recommended patients that “do ECT, MAOIs may be used Treatment not respond to other treatment”

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#FSHP2019 #FSHP2019 TRD and the Guidelines Quiz Time!

VA / DoD – MDD ACP NICE How long does a person have to experience symptoms of Most Recent depression in order for a diagnosis of MDD to be made? 2016 2016 2018 Update A) 1 week Mention TRD? Yes No No Lack of full response despite at B) 2 weeks Definition of TRD least two adequate treatment N/A N/A trials C) 3 weeks

Recommended ECT when “other D) 4 weeks MAOIs or TCAs, ECT, rTMS N/A Treatment treatments have failed”

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#FSHP2019 #FSHP2019 Quiz Time! Quiz Time!

How long does a person have to experience symptoms of According to the STAR*D trial, how many patients fail to depression in order for a diagnosis of MDD to be made? achieve remission after 4 treatments? A) 1 week A) 7% B) 2 weeks B) 18% C) 3 weeks C) 33% D) 4 weeks D) 40%

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#FSHP2019 #FSHP2019 Quiz Time! MAOIs

• Typically reserved for MAO-A MAO-B According to the STAR*D trial, how many patients fail to patients that have not achieve remission after 4 treatments? Substrates Serotonin, Dopamine, responded to alternate norepinephrine, tyramine, A) 7% antidepressants due to side dopamine, phenyl- effect profile and tyramine ethylamine B) 18% drug/food interaction C) 33% • Must avoid food high in D) 40% tyramine, serotonergic medications or medications that increase norepinephrine

Stahl SM. Essential Psychopharmacology Online. 2008. 29 30

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#FSHP2019 #FSHP2019 MAOIs – Foods to Avoid MAOIs for TRD • Dried, aged, smoked, fermented, spoiled meat, • Recent study found Clinical Global Impressions / Severity poultry or fish (CGI/S) scores to be higher (worse) in patients treated with • Broad bean pods TCAs vs. MAOIs at the end of treatment • Aged cheeses • Previous studies also demonstrated superiority with MAOIs • Tap/unpasteurized beer vs. TCAs • Marmite • Retrospective chart review, n=147 • Sauerkraut • Effect decreases as number of previous treatments • Soy products/tofu increases • Banana peel

Stahl SM. Essential Psychopharmacology Online. 2008. Kim T, et al. J of Affective Disorders. 2019. 31 32

#FSHP2019 #FSHP2019 Electroconvulsive Therapy (ECT) ECT

• Nothing like the “Cuckoo’s Nest” • Benefits from ECT noticed earlier than oral • General and muscle relaxant administered medication • Electrodes attached to precise locations on scalp • Adverse effects include • Goal is to produce controlled and monitored seizure headache, upset stomach, lasting 30-90 seconds; patient wakes up 5-10 minutes after muscle aches and memory procedure ends loss • Typically administered 3x per week until improvement observed (often at least 6-12 treatments)

Zolezzi M. Neuropsychiatr Dis Treat. 2016. National Institute of Mental Health 2019 33 34

Repetitive Transcranial Magnetic #FSHP2019 #FSHP2019 1st or 2nd therapy failed. Now what? Stimulation (rTMS)

• Uses a magnet to activate the brain – can be targeted to specific site • Sessions last 30-60 minutes, do not require anesthesia • Side effects include head discomfort, mild headaches or brief lightheadedness National Institute of Mental Health 2019 35 36

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Irritability – Overlooked Clue to #FSHP2019 #FSHP2019 Clinical Utility of Irritability Response • Irritability = core diagnostic criteria in adolescents but not • Goal of study by Manish K Jha et al. to determine if adults percent of improvement in irritability after four weeks of • 40-50% of adults reporting presence of irritability for more antidepressant therapy could predict remission or no than ½ of current depression episode meaningful benefit at eight weeks of therapy • These patients are more likely to experience a greater • Study assessed changes in irritability in Combining number of weeks in a depressive episode Medications to Enhance Depression Outcomes (CO-MED) trial, then assessed for replication of results in a separate, • Guidelines do not systematically assess or incorporate unrelated sample of patients from the Suicide Assessment irritability in clinical decision making Methodology Study (SAMS)

Jha MK, et al. Am J Psychiatry. 2019. Jha MK, et al. Am J Psychiatry. 2019. 37 38

#FSHP2019 #FSHP2019 Clinical Utility of Irritability - Methods Population Data

•Concise Associated Symptom Tracking (CAST-IRR) CO-MED SAMS Baseline •QIDS-C Timeline March 2008 - February 2009 July 2007 – February 2008 N 431 163 •CAST-IRR % female 67.1 69.9 % Caucasian 69.2 71.2 Week 4 •QIDS-C % non-Hispanic 84.2 90.2 Medication used to - Single blind - Open label •QIDS-C treat - Escitalopram & placebo - SSRI (escitalopram, Week 8 - Escitalopram & bupropion SR citalopram, sertraline, - Venlafaxine ER & mirtazapine paroxetine, controlled- release paroxetine or fluoxetine) Jha MK, et al. Am J Psychiatry. 2019. Jha MK, et al. Am J Psychiatry. 2019. 39 40

#FSHP2019 General Predictors and Moderators of #FSHP2019 Results Depression Remission • In CO-MED trial, higher baseline to week 4 reduction in CAST- IRR score was independently associate with higher likelihood of • U.S. Department of Veterans Affairs (VA) Augmentation reaching remission (p=0.0001) and decreased chance of no and Switching Treatments for Improving Depression meaningful benefit (p=0.036) at week 8. Outcomes (VAST-D) • A 25.7% greater reduction in CAST-IRR score predicted a 1.73 • Large, multisite, randomized, single-blind, parallel- times higher chance of remission and 0.72 times lower chance of no meaningful benefit assignment, three-arm VA study • Sex or treatment arm did not significantly predict remission or • Evaluated factors that predict which of three common no meaningful benefit “next-step” medications are best used for individual • Estimates in individual outcomes were replicated in SAMS trial patients

Zisook S, et al. Am J Psychiatry. 2019. Jha MK, et al. Am J Psychiatry. 2019. 41 42

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#FSHP2019 #FSHP2019 Treatment Arms Variables Evaluated • Gender • Mixed hypomanic symptoms Inadequate • Age • Childhood adversity Response to • Ethnicity • Grief Antidepressant • Employment • Co-occurring general • Depressive symptom severity medical conditions • Depressive symptom • Co-occurring general psychiatric conditions Switch to Combine with Augment with chronicity • Positive mental health bupropion SR bupropion SR • Depressive symptom subtype • Anxiety • Quality of life

Zisook S, et al. Am J Psychiatry. 2019. Zisook S, et al. Am J Psychiatry. 2019. 43 44

#FSHP2019 #FSHP2019 Study Population Results

N = 1,522 Two potential moderators of treatment identified Male White Black Hispanic Mean Age 85% 69% 26% 10% 54.4 years Age Mixed Hypomanic Symptoms Treated with Mean Higher remission rates with Higher remission rates with either Mean Duration of Married Unemployed three or more Baseline augmentation with aripiprazole augmentation with aripiprazole or Current Episode antidepressants QIDS-C score for patients 65 or older addition of bupropion rather than switch to bupropion 43% 45% 35% 87 months 16.7

Zisook S, et al. Am J Psychiatry. 2019. Zisook S, et al. Am J Psychiatry. 2019. 45 46

#FSHP2019 #FSHP2019 Looking Beyond Monoamines

• Low dose ketamine infusions have been used off label for treatment of depression • Typical dose 0.5mg/kg IV twice a week for 6 weeks • MOA: Non-competitive NMDA that blocks glutamate • Abnormalities in transition with synaptic and dendritic atrophy found in neural circuits that modulate behavior in patients with mood disorders

Daly EJ, et al. JAMA Psychiatry. 2018. Muller J, et al. Ther Adv Psychopharmacol. 2016. 47 48

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S(+) ketamine Compared with R(-)#FSHP2019 #FSHP2019 Esketamine Trial Ketamine

• Higher affinity for NMDA receptor • Phase 3 randomized, double-blind, active-controlled, multicenter study • Higher potency • Faster clearance • August 2015-June 2017 • Better analgesia • Eligible participants • Less drowsiness • 18-64 years old • Less lethargy • Single episode (≥ 2 years) or recurrent MDD without psychotic • Less cognitive impairment features • Less memory decline • Total QIDS-C score of ≥ 34 • Less agitated behavior • TRD

Muller J, et al. Ther Adv Psychopharmacol. 2016. Popova, Vanina. Paper presented at the 2018 Annual Meeting of the American Psychiatric Association (APA), May 8, 2018, New York, NY. 49 50

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#FSHP2019 #FSHP2019 Esketamine Trial New Kid on the Block – Spravato™

• N = 223 • Intranasal formulation • Randomized 1:1 to receive either esketamine (56 or 84mg) • Received FDA approval March 5, 2019 or placebo nasal spray administered twice weekly with • First medication approved for indication of TRD newly initiated oral antidepressant administered daily • Must be administered in conjunction with oral • MADRS score assessed 24 hours after first nasal spray dose antidepressant therapy and weekly thereafter • Must be administered under direct supervision of health • Decrease in MADRS score significantly greater in care professional and monitored for at least two hours esketamine group (p=0.010) after

Spravato® [package insert]. Inc; 2019. Popova, Vanina. Paper presented at the 2018 Annual Meeting of the American Psychiatric Association (APA), May 8, 2018, New York, NY. 51 52

#FSHP2019 #FSHP2019 Spravato™ Spravato™ - Alerts

• Boxed Warnings • Contraindications • Risk for sedation and • Aneurysmal vascular disease dissociation after or arteriovenous administration malformation • Potential for abuse and • Intracerebral hemorrhage misuse • Hypersensitivity to • Only available through esketamine, ketamine or any Spravato REMS program of the excipients • Increased risk of suicidal behaviors in pediatric and young adult patients taking

antidepressants Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019. Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019. 53 54

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TS1 Themas, Samantha, 5/23/2019 7/14/2019

#FSHP2019 #FSHP2019 Spravato™ - Precautions Spravato™ - Dosing

• Increase in blood pressure Induction Phase Maintenance Phase • Cognitive impairment • Weeks 1 to 4 • Weeks 5 to 8 • Impaired ability to drive or • Start 56mg day 1 • Administer once weekly operate machinery • Subsequent doses 56mg or • 56mg or 84mg • Embryo-fetal toxicity 84mg • Administer twice per week • Weeks 9+ • Administer every other week (or weekly) • 56 or 84mg

Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019. Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.

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#FSHP2019 #FSHP2019 Spravato™ - Administration Spravato™ - Common Side Effects

• Have patient blow nose • Patient to administer one • Dissociation • Anxiety • Insure indicator has two spray in each nostril • Dizziness • Lethargy green dots • Patient to rest in semi • Nausea • Blood pressure increase • Ensure patient is reclined reclined position for 5 • Sedation • Vomiting minutes after each device ~45 degrees • Vertigo • Feeling drunk • Instruct patient to • Hypoesthesia administer – each device contains two sprays

Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019. Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.

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#FSHP2019 #FSHP2019 Spravato™ - REMS Pharmacist Role

• All pharmacies must be • Educate patients on appropriate expectations from certified before they can antidepressant therapy including efficacy, adverse purchase or dispense effects, and drug/food interactions • All heath care settings must • Notify prescriber of lapse in compliance or if interacting be enrolled before medication added to patient’s regimen supervising administration • Communicate noticeable changes in patient • All patients must be presentation to interdisciplinary team enrolled before receiving • Provide education and/or offer screenings to community to increase mental health awareness and reduce stigma

Spravato® [package insert]. Janssen Pharmaceuticals Inc; 2019.

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#FSHP2019 #FSHP2019 Wrapping Up

• TRD most commonly defined as inadequate response to two or more antidepressant trials • Untreated (or inadequately treated) depression can have dire consequences • Multiple factors may contribute to non-response and need to be considered before altering patient’s treatment plan • Most current treatment guidelines recommend MAOIs or ECT to manage TRD, and esketamine is the first medication to receive FDA approval for the indication • More research needed on pathophysiology of TRD and effective treatment options

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#FSHP2019 #FSHP2019 References References Continued

• Depression. World Health Organization. 2019. Retrieved from https://www.who.int/mental_health/management/depression/en/ • Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressants versus monoamine oxidase • Depression. National Institute of Mental Health. 2019. Retrieved from https://www.nimh.nih.gov/health/topics/depression/index.shtml. inhibitor monotherapy for treatment-resistant depression. J of Affective Disorders. 2019. 250(1): 199-203. • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association, • Zolezzi M. Medication management during electroconvulsant therapy. Neuropsychiatr Dis Treat. 2016;12:931– Arlington, VA. 2013. 939. Published 2016 Apr 19. doi:10.2147/NDT.S100908 • Mulinari S. Monoamine theories of depression: historical impact on biomedical research. J Hist Neurosci. 2012;21(4):366-92 • Brain Stimulation Therapist. National Institute of Mental Health. 2019. Retrieved from: • Teter CJ, Kando JC, Wells BG. Teter C.J., Kando J.C., Wells B.G. Teter, Christian J., et al.Chapter 51. Major Depressive Disorder. In: DiPiro JT, https://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L Eds. Joseph T. DiPiro, et al.eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. • Jha MK, Minhajuddin A, South C, Rush AJ, Trivedi MH. Irritability and its clinical utilization in major depressive disorder: prediction http://accesspharmacy.mhmedical.com.ezproxylocal.library.nova.edu/content.aspx?bookid=689§ionid=45310502. Accessed May of individual-level acute-phase outcomes using early changes in irritability and depression severity. Am J Psychiatry. 2019. 17, 2019.n 176(5):358-366. • Stahl SM. Antidepressants. Essential Psychopharmacology Online. 4th edition 2008. Retrieved May 15, 2019 • Kim T, Xu C, Amsterdam JD. Relative effectiveness of tricyclic antidepressants versus monoamine oxidase inhibitor from https://stahlonline.cambridge.org/essential_4th_chapter.jsf?page=chapter7_introduction.htm&name=Chapter%207&title=General monotherapy for treatment-resistant depression. J of Affective Disorders. 2019. 250(1): 199-203. %20principles%20of%20antidepressant%20%20action#c02598-7-1 • Zolezzi M. Medication management during electroconvulsant therapy. Neuropsychiatr Dis Treat. 2016;12:931–939. Published • American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder, third edition. APA, 2016 Apr 19. doi:10.2147/NDT.S100908 2010. • Brain Stimulation Therapist. National Institute of Mental Health. 2019. Retrieved from: • Ann Intern Med. 2016;164(5):350-359. doi:10.7326/M15-2570 https://www.nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml • Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer term outcomes in depressed outpatients requiring one or several treatment • Jha MK, Minhajuddin A, South C, Rush AJ, Trivedi MH. Irritability and its clinical utilization in major depressive disorder: prediction of individual-level steps: A STAR*D Report. Am J Psychiatry. 2006; 163:1905-1917 acute-phase outcomes using early changes in irritability and depression severity. Am J Psychiatry. 2019. 176(5):358-366. • The World Journal of Biological Psychiatry, 2013; 14: 334–385

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#FSHP2019

Treatment Resistant Depression Samantha Themas, PharmD, BCPP Clinical Pharmacy Specialist – Psychiatry Memorial Regional Hospital [email protected]

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