Treatment of Depression: What Has the Last Decade Brought Us?

Treatment of Depression: What has the last decade brought us?

Stacey Pascoe, PharmD, BCPP, CPP Bozeman Health Learning Objectives

• Recall the mechanism of effect for antidepressants approved by the FDA after 2010.

• Summarize when these agents are indicated in the treatment of depression.

• Identify important patient counseling information for patients receiving vilazodone, vortioxetine, levomilnacipran, and esketamine. Disclosures

• None

• Will not discuss off-label use of medications Outline

• Review treatment of depression • Pharmacologic treatment • Goals of treatment • Overview of newer agents • Indications • Mechanisms • Studies for FDA approval • Counseling points • In-depth look at esketamine nasal spray • Advocating for patients in Montana General Considerations

• Everyone’s brain is different • It can be hard to “prove” things in behavioral health • Lots of medications used to treat depression • Several “classes” • Varying FDA approval dates • Variety of mechanisms • Medications other than “antidepressants” used for depression • Will focus on newer treatments for depression What Causes Depression?

• Prevailing theory is monoamine deficiency

• Is it the monoamines or the receptors? • Expression could be genetic or environmental • Or something downstream? • Are there pathways downstream that we are neglecting to acknowledge/study? • What about hormones? • Glucocorticoids, sex hormones, etc. Our friends, the monoamines… Depression Guidelines What are our goals?

LEAST Common MOST Common Residual Symptoms Residual Symptoms depressed mood insomnia

suicidal ideation fatigue/pain psychomotor concentration/ retardation interest anxiety

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/essential_4th.jsf What are our goals?

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/essential_4th.jsf What should we expect?

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/essential_4th.jsf Who?

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/essential_4th.jsf When and Why?

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/essential_4th.jsf Vilazodone

Brand name: Viibryd • Dosing: 10 mg once daily x7 days, then 20 mg daily; can increase to 40 mg if needed

• MOA: SSRI + 5HT1A partial agonist • Important Kinetics: • Bioavailability 72% w/food, 50% without • Hepatic metabolism: 3A4 major • Half-life: ~25 hrs • SSRI + buspirone?

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/prescribers_guide.jsf Viibryd (vilazodone) [prescribing information]. Irvine, CA: Allergan USA, Inc; May 2018. MADRS Montgomery–Åsberg Depression Rating Scale

• Completed by clinician (patient version is MADRS-S) • Ten items scored 0-6 • Total score 0 – 60: • 0 to 6 – normal /symptom absent • 7 to 19 – mild depression • 20 to 34 – moderate depression • >34 – severe depression

Montgomery, SA. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382. Vilazodone

• Indications: • Depression in adults N Trx MADRS ∆ vs Arms Score ∆ placebo • Anxiety (off-label) Study 1 198 40 mg -12.9 -3.2 • OCD (off-label) (8 wk) 199 Placebo -9.6 Study 2 231 40 mg -13.3 -2.5 • Approval Process: (8 wk) 232 placebo -10.8 • Four, multicenter, Study 3 253 40 mg -16.1 -5.1 randomized, double-blind, (8 wk) 252 placebo -11.0 placebo-controlled trials; Study 4 288 20 mg -17.3 -2.6 MDD diagnosis (DSM-IV) (10 wk) 284 40 mg -17.6 -2.8 281 placebo -14.8 • Mean MADRS score at initiation ranged from 30-32

Brand name: Trintellix (formerly Brintellix) • Dosing: 10 mg once daily • Increase to 20 mg as tolerated • Can maintain on 5 mg if higher dose not tolerated

• MOA: SSRI + 5HT1A ag + 5HT3 antag + more! • Important Kinetics: • Half-life: 66 hrs • Hepatic metabolism: 2D6, 3A4 major

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/prescribers_guide.jsf Trintellix (vortioexetine) [prescribing information]. Deerfield, IL: Lundbeck; July 2019. N Trx MADRS ∆ vs Vortioxetine Arms Score ∆ placebo Study 1 108 5 mg -20.4 -5.9 100 10 mg -20.2 -5.7 105 placebo -14.5 • Indications: Study 2 139 5 mg -15.4* -4.1 • MDD in adults 139 10 mg -16.2* -4.9 139 placebo -11.3* • GAD (off-label) Study 3 149 15 mg -17.2 -5.5 • Cognitive smx w/ depression 151 20 mg -18.8 -7.1 (off-label) 158 placebo -11.7 Study 4 145 15 mg -14.3 -1.5** • Geriatric depression (off-label) 147 20 mg -15.6 -2.8 • Approval Process: 153 placebo -12.8 Study 5 154 10 mg -13.0 -2.2** • Six, 6-8 wk, randomized, double- 148 20 mg -14.4 -3.6 blind, placebo-controlled, fixed- 155 placebo -10.8 dose trials; MDD dx (DSM-IV) Study 6 155 5 mg -13.7* -3.3 • Mean MADRS score at initiation (elderly) 145 placebo -10.3* ranged from 31-34 * HAM-D 24 used for scoring ** Not statistically significant

Brand name: Fetzima • Dosing: 20 mg daily x2 days, then 40 mg daily • Increase by 40 mg increments as tolerated • Max 120 mg total daily dose

• MOA: SNRI (N > S) • Important Kinetics: • Half-life: 12 hrs • No major CYP pathways • 58% renally eliminated unchanged

• Indications: N Trx MADRS ∆ vs Arms Score ∆ placebo • MDD in adults Study 1 178 40 mg -14.8 -3.2 • Fibromyalgia (off-label) (fixed-dose) 179 80 mg -15.6 -4.0 • Neuropathic/chronic pain 180 120 mg -16.5 -4.9 (off-label) 176 placebo -11.6 • Approval Process: Study 2 188 40 mg -14.6 -3.3 (fixed-dose) 188 80 mg -14.4 -3.1 • Three, 8-wk, randomized, 186 placebo -11.3 double-blind, placebo- controlled trials; MDD Study 3 217 40-120mg -15.3 -3.1 diagnosis (DSM-IV) (flex-dose) 217 Placebo -12.2 • Mean MADRS score at initiation range 31-36

• BBW – suicidality in ≤ 25 years old • Bleeding risk • Fractures • Narrow angle glaucoma • Serotonin syndrome • Sexual dysfunction • Vortioxetine better? • Levomilnacipran ER less for women? • SIADH

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/prescribers_guide.jsf Fetzima (levomilnacipran) [prescribing information]. Irvine, CA: Allergan USA Inc; December 2017. Trintellix (vortioexetine) [prescribing information]. Deerfield, IL: Lundbeck; July 2019. Viibryd (vilazodone) [prescribing information]. Irvine, CA: Allergan USA, Inc; May 2018. Counseling Points (Vilazodone, Vortioxetine, Levomilnacipran ER)

• Titration and discontinuation syndrome: focus on first few weeks • Vilazodone (tablet) • GI side effects very common • With food – increased absorption • Vortioxetine (tablet) • Nausea very common • Sexual ADRs and cognitive ADRs less common • Levomilnacipran ER (capsule) • Take at the same time each day more important • GI ADRs are less common • NE effects: hypertension, cardiovascular ADRs, sweating, constipation

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/prescribers_guide.jsf Sanacora, G., Schatzberg, A. Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?. Neuropsychopharmacol 40, 259–267 (2015). https://doi.org/10.1038/npp.2014.261 Why (es)ketamine?

• NMDA receptor antagonist • Results in increased glutamate release downstream • S-ketamine > R-ketamine in receptor binding • Some evidence suggests that low dose (0.2 mg/kg) S-ketamine IV infusion lessens depression while racemic ketamine does not1 • Mu-opioid receptor agonism – coadministration IV with naltrexone lessened improvement in depression2 • Activity at AMPA receptors3 • Another glutamate sensitive receptor • Signaling in mTOR (mammalian target of rapamycin) pathway3 • Increases density of dendritic spines – very fast change!

Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved February 8, 2020 from https://stahlonline.cambridge.org/prescribers_guide.jsf 1 Singh JB, Fedgchin M, Daly E, et al. Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biol Psychiatry 2016; 80:424. 2 Williams NR, Heifets BD, Blasey C, et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry 2018; 175:1205. 3 Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533:481. Esketamine (intranasal) Brand name: Spravato

• Important Kinetics: • Half-life esketamine: 7-12 hrs; noresketamine: 8 hrs • Bioavailability: ~48% • Time to peak: 20-40 minutes • Hepatic metabolism: 2B6, 3A4 to active noresketamine • AUC and Cmax increased in elderly and hepatic impairment

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Esketamine (intranasal)

• Dosing: 56 mg twice weekly, may increase up to 84 mg after first dose • Evaluate response at 4 weeks (8 doses) • Week 5: if response, decrease frequency to once weekly • Week 9: continue once weekly or decrease to once every other week • Missed doses or returning symptoms: consider returning to previous dosing schedule (i.e. increase frequency) • Special considerations: • Only comes as 28 mg/device (14 mg/spray) • Use one spray each nostril • 5 minute rest between devices • Cost = ~$350 per device

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Esketamine (intranasal)

• C-III Controlled Substance • Indications: • Treatment-resistant depression in combination with oral antidepressant in adults • Approval Process: • Three major trials • Those included in trials had current MDD episode, had not responded adequately to at least two antidepressant (AD) trials; MDD diagnosis (DSM-V)

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Study 1 - TRANSFORM

N = 223 • Randomized to: • Flexible-dose esketamine nasal + new AD • Placebo nasal + new AD • New AD = duloxetine, sertraline, venlafaxine ER, or escitalopram • New AD selected based on trx history • 32% SSRI, 68% SNRI • MADRS Δ • Mean MADRS score at initiation 37 • -19.8 esketamine nasal + new AD • -15.8 placebo nasal + new AD • Difference: -4.0 at 4 weeks

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Study 2 - SUSTAIN

• Study 1 responders and new enrollees that went through 4-wk initiation phase • Maintenance phase: 16 wks esketamine nasal + oral AD 1. Remission = MADRS ≤ 12 in last 3 of 4 weeks (N = 176) 2. Response = MADRS reduction ≥ 50% for last 2 of 4 weeks (N = 121) • Groups 1 and 2 randomized: • Esketamine nasal + oral AD • Placebo nasal + oral AD • Maintenance phase stats:

% wkly % q2wk % on 56 % on 84 dosing dosing mg dose mg dose Remitters 23 69* 39 61 Responders 55* 34 * Percent that received dosing schedule MAJORITY of the time

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Study 2 - SUSTAIN

Stable Remitters Stable Responders

• Relapse = – MADRS ≥ 22 for 2 consecutive wks, – Hospitalization for worsening depression, or – Any other clinically relevant event indicative of relapse

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. REMS Program

Designed to manage sedation and dissociation ADRs • Everyone must register • Healthcare Setting • Must have DEA number • Two options: pharmacy delivers patient-specific doses to practice or practice acquires bulk supply from Janssen specialty distributor • Pharmacy • Not needed if Healthcare Setting gets from specialty distributor • Patient • Have to self-administer and be monitored for a minimum of 2 hours • Healthcare provider decides when patient is ready to leave facility • No driving until the next day “following a restful sleep” • Reporting required of healthcare setting at every administration • Must document other medications: MAOI, stimulant, benzo, hypnotic use • Vitals, ADRs

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Spravato (esketamine). Janssen Pharmaceuticals. http://www.spravatorems.com. Accessed: Febuary 8, 2020. Esketamine (intranasal): Things to Know

• Unused patient-specific doses need to be discarded; cannot return or restock • Janssen has disposal program or “be appropriately disposed of ” • No-go in pregnancy, breastfeeding • GI ADRs • no eating 2 hours before administration • no drinking 30 minutes before administration • Concerns about health of nasal passages • Can you administer during respiratory/sinus illness? • Difference in absorption between patients

• Many questions still to be answered… • Who is administering and who is paying? • Is this the best of (es)ketamine?

Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Healthcare Settings Registered with REMS Program in MT

JENNINGS, DONNA KAY, Currently APRN PMHNP Treating 690 SW Higgins Ave Ste E Patients MISSOULA, MT, 59803

BOESE, KRISTY ST. PETER'S OLSON, STILES, TROY PONDERA KAY, APRN HEALTH KENNETH ROBERT, DO MEDICAL PMHNP FNP BROADWAY CORNELL, MD CENTER PHARMACY 820 DIVISION PHARMACY Registration 4185 N 2040 N. 22ND STREET MONTANA AVE, 2550 EAST AVENUE, BILLINGS, MT, 805 SUNSET In Process SUITE 5 BROADWAY SUITE 2 59101 BOULEVARD, P. HELENA, MT, HELENA, MT, BOZEMAN, MT, O. BOX 668 59602 59601 59718 CONRAD, MT, 59425

Spravato (esketamine). Janssen Pharmaceuticals. https://www.spravato.com/find-a-center?zipcode=59718&=Search. Accessed: Febuary 8, 2020. Is this the best of (es)ketamine?

• Not yet established: • Ideal admin route: IM, IN, IV, PO, SQ, SL • Optimal dose/serum concentration/AUC not established • Only FDA approved for depression is intranasal • Issues with first pass and absorption of oral products1 • Some small trials show less effective with chronic benzos2 • One-time IV infusions for suicidality/depression2 • Best estimate: effect dissipates ~10-14 days • No clear dose established • Possible predictors of response2 • Dissociation during infusion • Less residual symptoms at day one • Family h/o alcohol UD • Much debate about the “gold standard”

1 Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. Am J Psychiatry 2015; 172:950. 2 Pennybaker SJ, Niciu MJ, Luckenbaugh DA, Zarate CA. Symptomatology and predictors of antidepressant efficacy in extended responders to a single ketamine infusion. J Affect Disord 2017; 208:560. Spravato (esketamine) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; May 2019. Ketamine Treatment in MT

Practice Location Provider Treatments Payment Indications Name Offered Big Sky Kalispell Dr. William IV infusion (cash pay) $3000 for initial 6 infusions Anxiety, depression, Ketamine (Missoula Stratford bipolar disorder, PTSD, (Med North location soon) OCD, migraine, Urgent Care suicidality for infusions)

New Health Missoula Donna Kay IV infusion (cash pay) $4200 for initial 6 Depression, suicidality, Montana Jennings, infusions; also includes a anxiety, PTSD, OCD, PMHNP-B Nasal spray (Medicaid month of “nutriceuticals” bipolar disorder II and Medicare paying; (omega3, folic acid, lithium some private insurers) orotate, vit b, etc.)

Montana Billings Dr. Erin IV infusion (payment?) Initial treatment is 6 Depression, bipolar Psychiatry Amato infusions over 2-3 weeks; disorder, post-partum Would not disclose cost depression, OCD, PTSD St. James Butte Scott Ridgon, IV infusion Unknown Primarily pain Hospital CRNA treatment, some PTSD Questions?

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