Leah Wonderful, PharmDCommunity-University Health Center

Regularly Scheduled SeriesFebruary 3, 2016

Utilize brexpiprazole, cariprazine, levomilnacipran, vilazodone and vortioxetine to manage behavioral

health conditions for which they are indicated.

Assess the efficacy and safety of brexpiprazole, cariprazine, levomilnacipran, vilazodone and

vortioxetine.

Evaluate the place in therapy brexpiprazole, cariprazine, levomilnacipran, vilazodone and

vortioxetine for patients at CUHCC.

TL;DR

Measuring Efficacy• Mongomery-Asberg Depression Rating

Scale (MADRS)– Scale 0-60

• Hamilton Rating Scale for Depression (HAM-D)– Scale 0-29

• For both:–>7 indicates depression–>20 indicates at least moderate depression

Measuring Efficacy• Narrow inclusion criteria• Patient population tends to be

homogenous

Measuring Safety• Reported adverse effects– Sexual side effect questionnaires– Time

IndicationsMDD MDD -

adjunct Schizophrenia Bipolar disorder

Levomilnacipran(Fetzima) X

Vilazodone(Viibryd) X

Vortioxetine(Brintellix) X

Brexpiprazole(Rexulti) X X

Cariprazine(Vraylar) trials X X

Levomilnacipran (Fetzima™)• Approved in 2013• Levo enantiomer of milnacipran

(Savella™)• Indicated for major depressive

disorder• MOA– SNRI– Greater NE reuptake inhibition

compared to serotonin

Levomilnacipran (Fetzima™)• Available in 20 mg, 40 mg, 80 mg

and 120 mg capsules• Initial dosing: – 20 mg daily x 2 days– 40 mg daily x 2 days– Increase by intervals of 40 mg every 2

days based on efficacy and tolerability–Maximum dose 120 mg– Reduced dose in renal impairment

Levomilnacipran (Fetzima™)

Levomilnacipran (Fetzima™)

Levomilnacipran (Fetzima™)

Levomilnacipran (Fetzima™)• Adverse effects– GI effects–Urinary hesitation/retention– Sexual side effects– Increased HR, BP– Increased bleed risk

Levomilnacipran (Fetzima™)• TL;DR– Increased noradrenergic effects– Increased functionality at higher doses– Could consider trying another SNRI

first

Vilazodone (Viibryd™)• 2011• Indicated for Major Depressive

Disorder• MOA– Serotonin receptor (5-HTP1A ) partial

agonist and reuptake inhibitor

Vilazodone (Viibryd™)• Available in 10 mg, 20 mg and 40 mg

tablets• Dosing– 10 mg daily x7 days– 20 mg daily x7 days–May increase to 40 mg if needed– Take with food– Do not exceed 20 mg if taken with a

strong CYP3A4 inhibitor

Vilazodone (Viibryd™)

Vilazodone (Viibryd™)

Vilazodone (Viibryd™)

Vilazodone (Viibryd™)• Adverse effects– GI effects–Urinary hesitation/retention– Increased bleed risk– Sexual side effects could be fewer

Vortioxetine (Brintellix™)• 2013• Major depressive disorder• MOA– Serotonin Modulator and Stimulator– Serotonin reuptake inhibitor– 5-HTP3 antagonist– 5-HTP1A agonist

Vortioxetine (Brintellix™)• Available 5 mg, 10 mg, 15 mg, 20

mg tablets• Dosing– 10 mg starting dose– 20 mg maintenance dose–Max dose 10 mg daily for known poor

CYP2D6 metabolizers or in patients taking CYP2D6 inhibitors

Vortioxetine (Brintellix™)

Vortioxetine (Brintellix™)

NNT NNH

Vortioxetine (Brintellix™)• Adverse effects– GI effects–Urinary hesitation/retention– Increased bleed risk– Decreased sexual side effects

Vortioxetine (Brintellix™)• TL;DR–Well-tolerated– Could be a good option for patients that

need a little more than an SSRI that do not respond well to SNRIs

– Increased executive functioning

IndicationsMDD MDD -

adjunct Schizophrenia Bipolar disorder

Levomilnacipran(Fetzima) X

Vilazodone(Viibryd) X

Vortioxetine(Brintellix) X

Brexpiprazole(Rexulti) X X

Cariprazine(Vraylar) trials X X

Measuring Efficacy• Positive and Negative Symptoms

Scale (PANSS)– Scored on positive, negative and

psychopathology scale• Clinical Global Impressions –

Improvement Scale– Scored based on clinical judgment of

improvement compared to baseline

Brexpiprazole (Rexulti™)• 2015• Indications– Schizophrenia– Adjunctive therapy for major depressive

disorder• MOA– Partial agonist at 5-HT1A and D2– Antagonist at 5-HT2A and alpha1a and

alpha2c

Brexpiprazole (Rexulti™)• Available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and

4 mg tablets• Dosage adjustments for renal function, hepatic

function and CYP 2D6 and 3A4 interactions• Dosing

– Schizophrenia• Initial 1mg daily• Maintenance 2-4 mg daily (titrate over 8 days)• Maximum dose 4 mg daily

– Adjunctive therapy for major depressive disorder• Initial 0.5 mg-1mg daily• Maintenance 2 mg daily (titrate weekly)• Maximum dose 3 mg daily

Brexpiprazole (Rexulti™)

Brexpiprazole (Rexulti™)• Adverse effects– Increased weight– Akathisia– Somnolence

Brexpiprazole (Rexulti™)• TL;DR– Target dose of 2-4 mg– Try aripiprazole first in patients

concerned with weight gain– Patients with akathisia or somnolence

on aripiprazole– Patients w/ anxiety or irritability and

depression

Cariprazine (Vraylar™)• Approved in 2015 – not yet available• Indications: – Schizophrenia– bipolar disorder (manic/mixed episodes)– Phase III trials for major depressive

disorder (adjunct)• MOA– D2 and D3 partial agonist

Cariprazine (Vraylar™)• Available in 1.5 mg, 3 mg, 4.5 mg, 6

mg• Dosing– Schizophrenia• Starting dose 1.5 mg daily• Maintenance dose 1.5-6 mg daily

– Bipolar disorder (manic/mixed episodes)• Starting dose 1.5 mg daily• Maintenance dose 3-6 mg daily

Cariprazine (Vraylar™)• Adverse effects– Extrapyramidal symptoms–Metabolic changes– Orthostatic hypotension and syncope–Hypersomnia, sedation, somnolence

Comparison*

*Indirect comparison of short-term trials, NNT for schizophrenia

Comparison*Brexpiprazole Cariprazine Aripipazole

Weight gain +++ + ++Somnolence ++ + +++Akathisia + +++ ++

*Indirect comparison of short-term trials

Pricing per MonthDrug Retail

Levomilnacipran(Fetzima) $300

Vilazodone(Viibryd) $220

Vortioxetine(Brintellix) $300

Brexpiprazole(Rexulti) $870

Cariprazine(Vraylar) N/A

Treating Patients at CUHCC with New Agents

• Access– Insurance– Drug room– Coupons

• Sustainability– Patient assistance

Access & SustainabilityUCar

eMHP

Blue

Plus

Medica

HP Drug Room

Patient Assistan

ceLevomilnacipran

- - - - NF - Y

Vilazodone - - - ST NF - YVortioxetine - - - ST NF - YBrexpiprazole - - - - PA - YCariprazine* - - - - - N/A N/A

*Scheduled to be available in the first quarter of 2016

Treating Patients at CUHCC with New Agents

• Step 1– Choose a drug

• Step 2– Choose an access point with

sustainability in mind• PA process• Patient assistance

• Patients who need to see a treatment effect quickly

• Patients with anxiety in addition to depression

• Patients experiencing sexual side effects from other antidepressants

• Take with a meal

• Patients who need increased motivation and functionality

• Patients without hypertension• Patients experiencing sexual side

effects from other antidepressants

• Patients who view themselves as sensitive to medications

• Patients with depression-induced cognitive dysfunction

• Patients experiencing sexual side effects from other antidepressants

• Target dose of 2-4 mg• Compared to aripiprazole:–More weight gain– Less akathisia

• Patients w/ anxiety or irritability and depression

• Stay tuned!

• Rickels K, Athanasiou M, Robinson D, Gibertini M, Whalen H, Reed C. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(3):326–33.

 • Hellerstein D, Flaxer J. Vilazodone for the treatment of major depressive disorder: an evidence-

based review of its place in therapy.Core Evid. 2015:49. doi:10.2147/CE.S54075. • Citrome L. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a

systematic review of the efficacy and safety profile for this newly approved antipsychotic – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2015;69(9):978–997. doi:10.1111/ijcp.12714.

 • Citrome. Vilazodone for major depressive disorder: a systematic review of the efficacy and

safety profile for this newly approved antidepressant – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2012;66(4):356–368. doi:10.1111/j.1742-1241.2011.02885.x.

• Alvarez E, Perez V, Dragheim M, Loft H, Artigas F. A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol. 2012;15(5):589–600. doi:10.1017/S1461145711001027.

 

• Citrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2013;67(11):1089–1104. doi:10.1111/ijcp.12298.

• Boulenger J-P, Loft H, Olsen C. Efficacy and safety of vortioxetine (Lu AA21004), 15 and 20 mg/day: a randomized, double-blind, placebo-controlled, duloxetine-referenced study in the acute treatment of adult patients with major depressive disorder. Int Clin Psychopharm. 2014;29(3):138. doi:10.1097/YIC.0000000000000018.

•  Caccia S, Invernizzi R, Nobili A, Pasina L. A new generation of antipsychotics: pharmacology and clinical utility of cariprazine in schizophrenia. Ther Clin Risk Management. 2013;9:319. doi:10.2147/TCRM.S35137.

 • Citrome L. The ABC’s of dopamine receptor partial agonists – aripiprazole, brexpiprazole and cariprazine:

the 15‐min challenge to sort these agents out. Int J Clin Pract. 2015;69(11):1211–1220. doi:10.1111/ijcp.12752.

• Citrome L. Vilazodone, levomilnacipran and vortioxetine for major depressive disorder: the 15-min challenge to sort these agents out. Int J Clin Pract. 2015;69(2):151–5. doi:10.1111/ijcp.12620.

• Citrome L. Vortioxetine for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant – what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2014;68(1):60–82. doi:10.1111/ijcp.12350.