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New Kids BH Presentation
- 1. Leah Wonderful, PharmD Community-University Health Center Regularly Scheduled Series February 3, 2016
- 4. 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.
- 5. TL;DR
- 8. 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
- 9. Measuring Efficacy • Narrow inclusion criteria • Patient population tends to be homogenous
- 10. Measuring Safety • Reported adverse effects – Sexual side effect questionnaires – Time
- 13. Levomilnacipran (Fetzima™) • Approved in 2013 • Levo enantiomer of milnacipran (Savella™) • Indicated for major depressive disorder • MOA – SNRI – Greater NE reuptake inhibition compared to serotonin
- 14. 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
- 18. Levomilnacipran (Fetzima™) • Adverse effects – GI effects – Urinary hesitation/retention – Sexual side effects – Increased HR, BP – Increased bleed risk
- 19. Levomilnacipran (Fetzima™) • TL;DR – Increased noradrenergic effects – Increased functionality at higher doses – Could consider trying another SNRI first
- 21. Vilazodone (Viibryd™) • 2011 • Indicated for Major Depressive Disorder • MOA – Serotonin receptor (5-HTP1A ) partial agonist and reuptake inhibitor
- 22. 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
- 26. Vilazodone (Viibryd™) • Adverse effects – GI effects – Urinary hesitation/retention – Increased bleed risk – Sexual side effects could be fewer
- 28. Vortioxetine (Brintellix™) • 2013 • Major depressive disorder • MOA – Serotonin Modulator and Stimulator – Serotonin reuptake inhibitor – 5-HTP3 antagonist – 5-HTP1A agonist
- 29. 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
- 32. Vortioxetine (Brintellix™) • Adverse effects – GI effects – Urinary hesitation/retention – Increased bleed risk – Decreased sexual side effects
- 33. 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
- 36. 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
- 38. 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
- 39. 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
- 41. Brexpiprazole (Rexulti™) • Adverse effects – Increased weight – Akathisia – Somnolence
- 42. 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
- 44. 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
- 45. 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
- 46. Cariprazine (Vraylar™) • Adverse effects – Extrapyramidal symptoms – Metabolic changes – Orthostatic hypotension and syncope – Hypersomnia, sedation, somnolence
- 47. Comparison* *Indirect comparison of short-term trials, NNT for schizophrenia
- 48. Comparison* Brexpiprazole Cariprazine Aripipazole Weight gain +++ + ++ Somnolence ++ + +++ Akathisia + +++ ++ *Indirect comparison of short-term trials
- 50. Pricing per Month Drug Retail Levomilnacipran (Fetzima) $300 Vilazodone (Viibryd) $220 Vortioxetine (Brintellix) $300 Brexpiprazole (Rexulti) $870 Cariprazine (Vraylar) N/A
- 51. Treating Patients at CUHCC with New Agents • Access – Insurance – Drug room – Coupons • Sustainability – Patient assistance
- 52. Access & Sustainability UCare MHP Blue Plus Medica HP Drug Room Patient Assistance Levomilnacipra n - - - - NF - Y Vilazodone - - - ST NF - Y Vortioxetine - - - ST NF - Y Brexpiprazole - - - - PA - Y Cariprazine* - - - - - N/A N/A *Scheduled to be available in the first quarter of 2016
- 53. 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
- 55. • 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
- 56. • Patients who need increased motivation and functionality • Patients without hypertension • Patients experiencing sexual side effects from other antidepressants
- 57. • Patients who view themselves as sensitive to medications • Patients with depression-induced cognitive dysfunction • Patients experiencing sexual side effects from other antidepressants
- 58. • Target dose of 2-4 mg • Compared to aripiprazole: – More weight gain – Less akathisia • Patients w/ anxiety or irritability and depression
- 59. • Stay tuned!
- 60. • 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.
- 61. • 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.
Editor's Notes
- New kids!
- MADRS -> = response = 50% decrease from baseline, remission = <10
- Clinical trials tend to not reflect real life, limit the factors that would make it difficult to tell the difference between the placebo and treatment groups No comorbid psychological conditions Mostly middle-aged white ladies -> may not be reflective of actual patients suffering from depression, may be reflective of the population that has the ability to seek treatment, or may just be the population willing to participate in a clinical trial
- Weight gain
- Look at these names! Studying levomilnacipran for fibromyalgia, brexpiprazole may be the new aripiprazole
- Milnacipran treats fibromyalgia in the US, approved for depression in European countries Like venlafaxine Venlafaxine 30:1 vs Levomilnacipran 1:2 S:NE When studied levomilnacipran showed an increase in functional improvement in responders Sheehan Disability Scale (can you get out of bed, go to work, have friends, take care of your home life)
- Requires titration, if looking to improve functionality may need to use higher doses 80-120 mg
- Responders -> 50% decrease in MADRS score from baseline Remitters -> score <10
- Significant – most less than 10
- Clinical significance Baseline 30, <7 not depressed Things to think about: -Still depressed, but less depressed! -Also speaks to the importance of multidisciplinary team -> therapist, medical Change in MADRS –Inclusion: 30 or higher 11 weeks total - 1 week run in, 8 week trial, 2 week taper down 40-120 mg based on patient response & tolerability at set times Treatment group had a better response, but Phase III multicenter randomized double blind placebo controlled parallel group flexible dose study comparing 40-120mg levomilnacipran to placebo in adult outpatients with MDD . Patients were started at 20 mg, titrated up to 40 mg on day 3, then titration by
- Diarrhea most common, followed by nausea. HR dose dependent 7-9 BPM, BP not clinically significant - <1% with sustained HTN), differences compared to placebo negligible
- 50% occupancy of SERT transporters/50% 5-HTP1A Faster onset due to the partial agonist action, greater tolerability, Partial agonist -> artificial serotonin MOA combines the action of an SSRI and buspirone -> could be particularly helpful in patients with depression with anxious depression -Need to take w/ a meal (bioavailability decreased by 50% in the unfed state)
- CYP 3A4 inhibitors: protease inhibitors (ritonavir), macrolide abx (clarithromycin), azole antifungals (ketoconazole)
- Similar to levomilnacipran
- potential for greater GI Ses but in trials these did remit, ostly nausea ASEX scores similar in both treatment and placebo groups however studies had a mix of patients with and without preexisting sexual dysfunction – further study is ongoing
- Inhibits the reuptake of serotonin, but also binds at serotonin receptors. Modulation of glutaminergic transmission at certain serotonin receptors decreases cognitive dysfunction increases executive functioning
- Package insert provides no guidance on titration CYP2D6 -> fluoxetine, paroxetine, bupropion, ritonavir, sertraline
- Compared to placebo and venlafaxine or duloxetine to validate vs placebo effect, venlafaxine and duloxetine performed better
- Comparing efficacy vs. tolerability
- Well-tolerated GI effects -> nausea the worst Both nausea and sexual SEs were dose dependent
- Well-tolerated -Use it for pts that feel that they are “sensitive” to medications -Worth a try for pts
- Reduction 30% from baseline Note about safety – trials are short and weight gain is often a side effect. Metabolic effects over time are unknown
- Abilify 2, same manufacturer Investigated for PTSD and alzheimers, a whole host of other things More potent at serotonin receptors, less potent at D2 agonism aripiprazole -> decreased akathisia, nausea, restlessness, insomnia
- Titrating
- Only dose that met statistical significance for efficacy was 2 and 4 mg Efficacy for depression – 2 of trials results not significant, others NNT 12 Subgroup analysis found increased efficacy in pts w/ anxiety or irritability components
- More weight gain, less somnolence and akathisia No changes in lipid profile or prolactin levels
- High affinity for D3
- T ½ 1-3 weeks for active metabolite
- High affinity for D3
- 30% reduction in PANSS score
- I hate that cost comes into this
- Insurance may or may not cover these We do not currently have these in the drug room -Pharmacy will be conducting a formulary review this spring of BH drugs Coupons generally only work with insurance (not medicare/medicaid) Patient assistance is an option
- -PA process can take time, may need to try and fail other meds first -In medicine, we are used to this: inhalers -BH meds have increased dramatically in the last 15 years. Options abound! With options, comes red tape and rules -!0 yrs ago, I worked for an evil PBM –BH PAs were easy -Criteria can change at any time -Talk to Nancy, Somali tea TL;DR -Do the PA first, then have the patient start the drug -Same with patient assistance
- Due to the prominent noradrenergic component
- Response or remission was more likely than discontinuation due to adverse effects