WHAT S NEW. Vilazodone (Viibryd ) Vilazodone - Dosing ANTIDEPRESSANT UPDATE: What s New? The Cardiac Debate The Efficacy Debate?Pharmacogenomics?

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1 ANTIDEPRESSANT UPDATE: What s New? The Cardiac Debate The Efficacy Debate?Pharmacogenomics? Rex S. Lott, Pharm.D., BCPP Professor, ISU College of Pharmacy Mental Health Clinical Pharmacist, Boise VAMC Clinical Associate Professor, University of Washington, School of Medicine, Department of Psychiatry & Behavioral Sciences WHAT S NEW Short Answer???? Vilazodone (Viibryd ) SSRI with partial agonist activity at 5HT 1A receptors. Pharmacology of buspirone built in CYP3A4 Substrate No clinically significant CYP inhibition Vilazodone - Dosing Initiate at 10 mg/day X 7days, then 20 mg/day X 7 days Target dose = 40 mg/day Reduce dose by 50% if co-medication with potent CYP3A4 inhibitors (ketoconazole, some macrolide antibiotics) QD dosing 25 hour half-life 1

2 Vilazodone Pluses / Minuses Potential Pluses: Less sexual dysfunction than other SSRI s? Enhanced anti-anxiety activity (NOT FDA labeled for anxiety)? Potential Minuses: Still an SSRI GI side effects Sleep disturbance Cost Ketamine NMDA Receptor Antagonist THEORY: NMDA Antagonism Glutamate release (?compensatory?) Stimulation of AMPA glutamate receptors, AND Repair / regeneration of glutamate-related circuits. Ketamine IV Sub-anesthetic doses 0.5 mg/kg IV infused over ~40 min One study of repeated doses (6) RAPID (hours) remission of depression symptoms in treatment-resistant patients Possible significant reduction in suicidality Moderate to Large Statistical Effect Sizes SHORT duration of effect days - weeks Ketamine Relevant PK T 1/2 = ~ 2.5 hours Distribution T 1/2 = ~ 10 min Hepatic Metabolism: CYP 450 2B6, 3A4 2C9 (minor) Bioavailability: IM: 93% Intranasal: 25 50% Oral: 16 20% Mathew et. CNS Drugs.2012;26:

3 Ketamine - Results Ketamine: Adverse Effects Relatively well-tolerated at studied doses Side effects generally transient Transient BP elevations Mild dissociative effects (short-lived) Non-specific psychiatric/neurlogic Heady or Muzzy feelings Visual distortions Dizziness Rot et al. Biol Psychiatry 2012;72: ; Rot et al. Biol Psychiatry 2010; 67: FDA Warning Cardiac Debate What do we know about QTc prolongation and citalopram? 8/24/2011 & 3/27/2012 Post-marketing reports of QTc interval prolongation and Torsade de Pointes Thorough QT study of 20 mg and 60 mg of citalopram in 119 patients showing doserelated QTc prolongation Thou shalt no longer Rx 60 mg doses and thou shalt not use > 20 mg in those over 60 or those on CYP2C19 inhibitors Doses above 40 mg confer no added benefit 3

4 Dose 20 mg 40 mg* 60 mg Moxifloxacin 400 mg Citalopram Change in QTc (90% Confidence Interval) (ms) 8.5 (6.2, 10.8) 12.6 (10.9, 14.3) 18.5 (16.0, 21.0) 13.4 (10.9, 15.9) FDA Data Dose 10 mg 20 mg* 30 mg Moxifloxacin 400 mg Escitalopram Change in QTc (90% Confidence Interval) (ms) 4.5 (2.5, 6.4) 6.6 (5.3, 7.9) 10.7 (8.7, 12.7) 9.0 (7.3, 10.8) * Estimate based on the relationship between citalopram (and escitalopram) blood concentrations and QT interval The Clinical Evidence?? Published cases of citalopram-related cardiotoxicity (TdP) are extremely rare CIT was the most widely Rx d antidepressant in the U.S. Prudence Is it true that 60 mg offers no additional benefit over 40 mg? Population phenomenon? vs Individual Patient Phenomenon? Vieweg et al. Am J Med. 2012;125: Negative Publications - ADs The Efficacy Debate Do Antidepressants Work in Other than Very Severe Depression? How Well do Antidepressants Work? PUBLISHED AD Trials 94% positive outcomes UNPUBLISHED AD Trials (FDA) 51% positive outcomes Statistical Effect Sizes were 25% smaller in entire FDA AD Study database than in published literature EH Turner, Matthews AM, Linardatos E et al. NEJM 2008;358:

5 Are ADs better than placebo? Multiple Meta-analyses AD Meta-Analysis Pooled data; mean changes in rating scale scores Kirsch: AD 9.6 vs 7.8 placebo, difference 1.8 Fountoulakis reanalysis: AD vs 7.85, difference 2.15 Overall drug versus placebo difference = ~2 points NICE criterion for clinical significance = 3 points Is NICE right? Mean not valid in skewed distribution Severe depression about 5 point benefit ADs are INEFFECTIVE in all but most severe Kirsch I, et al. PLoS Med 2008;5(2):e45. Turner EH, et al. N Engl J Med 2008;358(3): Fournier JC, et al. JAMA. 2010;303(1): Fountoulakis KN, Möller HJ. Int J Neuropsychopharmacol2011; Kirsch I, et al. PLoS Med 2008;5(2):e45. Floor Effect Comparing absolute rating scale score changes or differences ignores this - Scores can t go below Zero 50% drug improvement 25% placebo improvement Severe depression Drug vs. placebo is 10 pts Mild depression Drug vs placebo is 5 pts Ghaemi SN. Making Sense of Antidepressants. CPNP Annual Meeting Drug Baseline End Baseline End Depression Severity * Mean baseline HDRS score Drug Mean final change in HDRS score Relative effect size measure (%) ** Mean Baseline HDRS score Placebo Mean Final change in HDRS score Relative effect size measure (%) Mild (23%) Moderate (54%) Severe (23%) Relative Effect Size Difference (Hamilton Depression Rating Scale HDRS) * Mild= At least one arm (drug or placebo) is rated <24 on HDRS Moderate= At least one arms is rated > 24< 28 on HDRS Severe= At least one arm (drug or placebo) is rated > 28 on HDRS ** Relative effect size = absolute mean HDRS change/mean baseline HDRS score Vohringer PA, Ghaemi SN. Clinical Therapeutics 2011;33:B49 B61. Ghaemi SN. Making Sense of Antidepressants. CPNP Annual Meeting

6 Efficacy Debate: Conclusions Antidepressants are not placebos Not accurate that ADs are less effective in mild depression ADs appear about equally effective in all severity of depression PBO is less effective in more severe depressions Pharmacogenomics & Depression ACTIVE Research Effort Pharmacodynamic Effects Serotonin Transporter Gene variability 5HTTLPR-promoter region Long (l) allele associated with twice the expression of serotonin transporter & improved outcomes with SSRI antidepressant therapy Pharmacokinetic Effects CYP450 metabolizer status Poor metabolizers of 2D6 substrates experience more side effects. Martin & Lee. Ment Health Clin. 2012;1(9):17 CYP2D6 & Antidepressants CYP2D6 Substrates Most TCAs (amitriptyline, nortriptyline, imipramine, etc.) Duloxetine, venlafaxine, paroxetine CYP2D6 Inhibitors Paroxetine, Bupropion & Fluoxetine ++++ Duloxetine +++ CYP2D6 & Antidepressants: PK Interactions Genetic Range: Poor Ultra-Rapid Metabolizers PM s Lower dose requirements Poor tolerance to med UM s Higher dose requirements Improved tolerance to med Phenoconversion: 2D6 inhibitors can convert good metabolizers to poor metabolizers. 6

7 CYP2D6 & Antidepressants: More of the Story Pooled data from four DBPC clinical trials of venlafaxine Desvenlafaxine/venlafaxine ratios >1 Extensive 2D6 metabolizers Significantly higher rates of response & remission compared to both placebo AND poor 2D6 metabolizers. Why? Pharmacology of desvenlafaxine and venlafaxine is the same. D Emaaire et al.j Psychiatr Practice 2011;17:330339; Meyer UA. Nat Rev Genet.2004;5: Lobello et al. J Clin Psychiatry. 2010:71: a EM vs PM p < 0.02 b VEN vs Placebo p < 0.04 Lobello et al. J Clin Psychiatry. 2010:71: CYP2D6 & Antidepressants: More of the Story (cont.) CYP2D6 significantly expressed in CNS role in serotonin metabolism Metabolizer status may correlate with some personality subtypes CYP2D6 Poor metabolizer status MAY be a genetic marker for poor or non-responders to noradrenergic or serotonergic antidepressants ( 40% per STAR*D) And there may be more. D empaire et al. J Psychiatric Practice. 2011;17: ; Macaluso & Preskorn. J Clin Psychopharmacol. 2011;31:

8 * * H A M D S C O R E * * 7 >20 Nortriptyline TX Window? Nortriptyline Plasma Concentration ng/ml CYP2D6 & Antidepressants: The Rest of the Story??? Relationship between CYP2D6 metabolizer status and antidepressant response MAY also explain: Curvilinear Therapeutic Window for nortriptyline plasma concentrations Population phenomenon vs. individual patient phenomenon NOT known if drug-induced phenoconversion is problematic Macaluso & Preskorn. J Clin Psychopharmacol. 2011;31: