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3/9/2016 Disclosures o I have no personal or financial conflicts of interest to disclose o I will be discussing off-label use of medications Objectives: Pharmacists Objectives: Pharmacy Technicians o Describe four evidence-based clinical pearls of depression pharmacotherapy o Identify common medications used to treat depression o Explain five ways older medications may be reformulated into “new” products o Recognize how older medications may be reformulated into “new” products o Identify three compelling comorbid conditions that my guide antidepressant selection o Describe medication options for depression o Develop a rational treatment plan for a patient with depression Patient Case BC is a 60 yo female presenting with: o ↓ sleep, interest, energy, concentration and weight (20# over 2 months, not intentional) o ↑ ‘worrying about everything’ o Off work x 1 week, unable to get out of bed PMH: hypertension, ‘nerve pain’, and migraines SH: no tobacco, ‘occasional’ alcohol, works full time as a retail clerk, financial stressors Patient Case o Relevant assessment o BP 130/55 HR 70 Wt 75 kg (down from 84 kg) o CMP, CBC and thyroid studies WNL o Current medications o Metoprolol, ibuprofen o PRN hydrocodone/acetaminophen, tramadol and rizatriptan o Past medications o Fluoxetine ‘a long time ago’ – ‘helped a lot’ 1 3/9/2016 Patient Case Depression Rating Scales HAM-D 17 QIDS-SR (0-3 each) Depressed mood (0-4) o Is this patient depressed? o If so, what should be our first line treatment for depression in this patient? o Is there a role for the ‘new’ antidepressants in her treatment? Guilt (0-4) Suicide (0-4) Insomnia – early, middle, late (0-2 each) Work and activities (0-2) Retardation (0-4) Agitation (0-4) Anxiety - psychic (0-4) Anxiety - somatic (0-4) Somatic symptoms - GI (0-2) Somatic symptoms general (0-2) Genital - libido (0-2) Hypochondriasis (0-4) Loss of Weight (0-2) Insight (0-2) Based on hx this patient’s score: 21 (severe) Insomnia – early, middle, late Total sleep hours Feeling sad Appetite Weight Concentration Self-worth/guilt Thoughts of death/suicide Interest Energy Feeling slowed down Feeling restless Based on hx this patient’s score: 17 (severe) http://www.ids-qids.org Medications By Class Medications Therapeutic Uses Selective Serotonin Reuptake Inhibitors (SSRIs) Celexa (citalopram) Depression Lexapro (escitalopram) OCD, GAD, PTSD Luvox (fluvoxamine) Social Phobia Paxil/Paxil CR (paroxetine) Panic Disorder Prozac (fluoxetine) Bulemia Zoloft (sertraline) Premenstrual dysphoric disorder Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Effexor/Effexor Depression XR/venlafaxine extended GAD release (venlafaxine) Social anxiety disorder Panic disorder Pristiq (desvenlafaxine) PTSD OCD Cymbalta (duloxetine) Diabetic neuropathic pain Chronic musculoskeletal pain Savella (milnacipran) Fibromyalgia Menopausal flushing Fetzima (levomilnacipran) Side Effects/Issues Nausea, diarrhea Headache Anxiety upon initiation or dose increase Sexual dysfunction Sweating Sedation/agitation Same as SSRIs Increased blood pressure Increased heart rate Liver toxicity (duloxetine) Side Effects/Issues: Less sexual dysfunction than SSRIs and SNRIs Remeron (mirtazapine) Depression Serzone (nefazodone) Depression, PTSD Desyrel (trazodone) Wellbutrin/Zyban (bupropion) Depression, insomnia Depression, Smoking cessation, ADHD Sedation, weight gain, increased triglycerides Sedation, drug interactions Sedation Agitation, insomnia, appetite suppression Viibryd (vilazodone) Depression Similar to SSRIs Depression Similar to SSRIs Therapeutic Uses Side Effects/Issues Tricyclic Antidepressants (TCAs) Anafranil (clomipramine) Elavil (amitriptyline) Norpramin (desipramine) Pamelor (nortriptyline) Sinequan (doxepin) Tofranil (imipramine) Vivactil (protriptyline) Depression OCD (clomipramine) Neuropathic Pain Sleep Migraine headaches ADHD (desipramine) Anticholinergic Orthostatic hypotension Arrhythmia Sedation Sexual dysfunction Sweating Weight gain Monoamine Oxidase Inhibitors (MAOIs) Nardil (phenelzine) Parnate (tranylcypromine) Emsam (selegiline) patch A Class of Their Own Therapeutic Uses Medications By Class Medications Depression Panic disorder Other anxiety disorders Sedation Sexual dysfunction Blurred vision Tachycardia Serotonin syndrome Hypertensive crisis What Is The Best Traditional Treatment? o How do you compare across classes? o How do you assess efficacy in ‘real world’ environment? o What do you do if one treatment does not effectively reduce/eliminate symptoms? o STAR-D show us the way… SSRI and partial 5HT1A agonist Brintellix (vortioxetine) SSRI, 5HT1A agonist, 5HT3 antagonist 2 3/9/2016 STAR-D STAR-D Patient Mix o Sequenced Treatment Alternatives for Remission in Depression o Demographics (N=2,876) o How do ‘real world’ patients respond/remit? o How often can we achieve remission vs response? o Is it better to switch medications or augment with another medication? o What do patients prefer? o Can you use rating scales in practice? o Do outcomes differ between primary care and psychiatry specialty clinics? Trivedi MH, et al. Am J Psych 2006; Gaynes BN et al. Cleveland Clinic JOM 2008 o Primarily caucasian women aged 31-50 o Psychiatrist 62% and primary care 38% o Severity: Average HAM-D = 22 at baseline o Had to be ≥14 o Recurrent depression 75% o Average 6 episodes lifetime; 15 yr history o Average duration 2 yrs (25% >2 yrs) o Comorbid psychiatric disorders 65% Trivedi MH, et al. Am J Psych 2006 STAR-D Outcomes Average Dose at Endpoint Response QIDS-SR Remission QIDS-SR* Level 1 Citalopram 40 mg 47% 33% Level 2 switch Bupropion 282 mg Sertraline 135 mg Venlafaxine 194 mg 26% 27% 28% 25% 27% 25% Level 2 augment Bupropion 268 mg Buspirone 41 mg 32% 27% 39% 33% Level 3 switch Mirtazapine 42 mg Nortriptyline 96 mg 13% 17% 8% 12% Level 3 augment Lithium 860 mg (level 0.6) T3 45 mcg 16% 23% 13% 25% Level 4 Mirt/Venl 36 mg/210 mg Tranylcypromine 37 mg 24% 12% 16% 14% Question Considering STAR-D algorithms, what is the best option for patient BC? A. Nortriptyline B. Sertraline C. Tranylcypromine D. Venlafaxine E. New trick *: Comparable to HAM-D remission rates Gaynes BN, et al. Clev Clin JOM 2008 New Tricks o Combination mechanism o “Me too” - same mechanism, new chemical o Active metabolite o Single isomer o Extended-release formulation o Old medication, newly discovered indication New Tricks – Not So New o TCAs (active metabolites) o Amitriptyline and nortriptyline o Imipramine and desipramine o MAOIs (similar mechanism) o Phenelzine o Tranylcypromine o SSRIs (same mechanism) o Fluoxetine, sertraline, fluvoxamine, paroxetine, citalopram, escitalopram 3 3/9/2016 One Chemical – So Many Options Lesser Known Examples o Fluoxetine o Serafem o Prozac Weekly o Paroxetine o Pexeva o Brisdelle o Venlafaxine o VERT (venlafaxine extended release tablets) VandenBerg AM. Mental Health Clinician 2014 SSRI Single Isomer o Wellbutrin® IR and generic 75 mg, 100 mg o Wellbutrin® SR 100 mg, 150 mg, 200 mg o o Generic 100 mg and 150 mg Wax matrix o Wellbutrin® XL 150 mg, 300 mg o o Branded generic Budeprion 150 mg only Diffusion controlled coating o Aplenzin® 174 mg, 348 mg, 522 mg o ForfivoTM XL 450 mg (brand only) VandenBerg AM. Mental Health Clinician 2014 (Es)Citalopram QTc Data o Citalopram vs. escitalopram Citalopram Δ QTc msec (90% CI) Escitalopram ΔQTc msec (90% CI) 20 mg 8.5 (6.2, 10.8) 10 mg 4.5 (2.5, 6.4) o Initial claims 40 mg 12.6 (10.9, 14.3) 20 mg 6.6 (5.3, 7.9) 60 mg 18.5 (16.0, 21.0) 30 mg 10.7 (8.7, 12.7) Mox 400 mg 9.0 (7.3, 10.8) o Fewer side effects o 10 mg escitalopram = 40 mg citalopram o R isomer inhibits binding of S isomer o Final nail Mox 400 mg 13.4 (10.9, 15.9) • Clinically significant QTc prolongation generally considered >500 msec or prolongation of >60 msec • Actual # of patients with clinically significant prolongation not released o QTc prolongation warning http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm J Psychosocial Nursing 49(11) 2011 Two New Tricks in One: Levomilnacipran Duloxetine o Old dog: milnacipran (SNRI) o Old dog: SNRI o New trick: single isomer and extended release o New trick: equal affinity for both serotonin and norepinephrine across the dosing range o Also new indication for MDD o Limitations o Cost o Efficacy similar to other available agents o The caveats o Equal affinity ≠ improved efficacy o Dual mechanism ≠ improved efficacy Montgomery SA et al. J Clin Psych April 2013 4 3/9/2016 Duloxetine: The Facts o FDA approved indications o MDD, generalized anxiety, chronic pain, diabetic peripheral neuropathic pain, fibromyalgia o Recommended dose: 60 mg daily o Practical pharmacokinetic points: o Delayed release capsule o CYP 2D6 moderate inhibitor o Requires renal dosing Cymbalta (duloxetine) [PI] accessed January 10, 2014 Duloxetine: The Facts o Should not be used/avoid use in patients with: o “evidence of chronic liver disease” o “Substantial alcohol use” o Severe renal impairment (GFR<30 mL/min) o Hepatotoxicity risk o No definitive study demonstrating benefit over alternatives for MDD Cymbalta (duloxetine) [PI] accessed January 10, 2014 Desvenlafaxine o Old dog: venlafaxine o New trick: active metabolite o The spin: Not prone to genetic variability of 2D6 metabolism or 2D6 inhibition interactions o Caveat o “venlafaxine and o-desvenlafaxine are pharmacologically approximately equiactive and equipotent” Effexor XR [PI] accessed May 6, 2013 Desvenlafaxine: The Facts Safer in Poor Metabolizers? o Venlafaxine primarily metabolized via CYP 2D6 o o o Prone to genetic variability in <10% of population Rapid/extensive metabolism = “normal” Poor or ultra-rapid metabolism = genetic variant o “The differences between the CYP2D6 poor and extensive metabolizers; however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups” Effexor XR [PI] accessed May 6, 2013 Desvenlafaxine Clinical Trials: MDD Study Arms Response Remission DeMartinis et al N=461 placebo 100, 200, 400 mg 35% 51%, 45%, 48% 19% 30%, 28%, 32% Septien-Velez et al N=375 placebo 200 and 400 mg 38% 60% and 56% 23% 37% and 34% Liebowitz et al N=247 placebo 100 – 200 mg 34% 43% 20% 23% Boyer P et al N=485 placebo 50 and 100 mg 50% 65%, 63% 29% 37%, and 45% o FDA approved indication: MDD o Recommended dose: 50 mg daily o Practical pharmacokinetic points: o t ½ 10 hours o Absorption 80% with no impact of food o Metabolism – primarily conjugation o Minor 3A4 Red results statistically significant compared to placebo Colvard MD. Mental Health Clinician, 2014 Colvard MD. Mental Health Clinician, 2014 5 3/9/2016 Desvenlafaxine: The Verdict o FDA approved dose is likely subtherapeutic The Newest New Tricks o Vilazodone o Solves a problem that was not there o Expensive alternative to venlafaxine o Place in therapy ?? o Vortioxetine Colvard MD. Mental Health Clinician, 2014 Vilazodone o Old dog o o SSRI activity + 5HT1A partial agonist Similar to SSRI + buspirone or pindolol o New trick o o Combine mechanisms into one medication 5HT1A partial agonist activity →↓ sexual dysfunction o Caveat o o Dual mechanism ≠ better efficacy or faster response “…the net result of this action on serotonergic transmission and its role in vilazodone’s antidepressant effect are unknown” Viibryd [PI]; accessed January 10, 2016 Vilazodone: Trials Vilazodone: The Facts o FDA approved indication: MDD o Recommended dose: 40 mg daily with need for 2 week titration o Practical pharmacokinetic points: o t ½ 25 hours o Absorption increased 2-fold with food o Metabolism CYP 3A4 (major), 2D6/2C19 (minor) o Dose adjustment required with 3A4 inhibitors and inducers Viibryd [PI]; accessed January 10, 2016 Vilazodone: Results o Four DB, PC efficacy trials; 6-10 weeks each o Response rates 44-59 % o Standard MDD inclusion/exclusion criteria o Remission rates <30% not significantly different from placebo o Montgomery-Asberg Depression Rating Scale (MADRS) change from baseline primary endpoint o Demographics o o o o Primarily caucasian women ~40 yrs of age Average duration current episode ~6 months Average of 3 lifetime episodes of depression MADRS average 30 baseline (just below severe) Deardorff WJ. Expert Opin Pharmacother 2014 o Nausea /diarrhea 25-35% o Sexual dysfunction 1-2% o However comparable to active control duloxetine Deardorff WJ. Expert Opin Pharmacother 2014 6 3/9/2016 Vilazodone: The Verdict o No studies to demonstrate better efficacy or tolerability than SSRI/SNRIs o High rates of nausea/vomiting o Outcomes comparable to currently available $4 antidepressant medications o Drug interactions o Place in therapy: o ?? Vortioxetine o Old dog o o SSRI + 5HT1A partial agonist + 5HT3 antagonist Similar to SSRI + buspirone + ondansetron o New tricks o o o o o Multiple mechanisms 5HT3 antagonist to minimize nausea/vomiting 5HT1A and 5HT1B partial agonist activity 5HT7 antagonist 5HT1D antagonist o Caveat o Multiple mechanisms ≠ better efficacy or faster response Brintellix [PI]; accessed January 10, 2016 Vortioxetine: The Facts Vortioxetine: The Studies o FDA approved indication: MDD o Twelve DB, PC efficacy trials; 6-10 weeks each o Recommended dose: 10 mg daily (5-20 mg) o Standard MDD inclusion/exclusion criteria o Practical pharmacokinetic points: o MADRS or HAMD change from baseline used for primary endpoint o t ½ 66 hours o Absorption 75% with no impact of food o Metabolism CYP 2D6, 3A4 and others o Max 10 mg with 2D6 inhibitors or poor metabolizers o Increase dose with potent inducers Viibryd [PI]; accessed January 10, 2016 Vortioxetine Results o Four studies demonstrating no difference from placebo on primary outcome o Limited comparative response/remission data o Higher dose of 10 mg appears more effective with higher rates of side effects o Two studies with no difference in primary outcome for active control (duloxetine) o Demographics o o o o Primarily caucasian women ~40 yrs of age Average duration current episode ~6 months Average of 3 lifetime episodes of depression MADRS average variable Deardorff WJ. Expert Opin Pharmacother 2014 Vortioxetine: The Verdict o Unique mechanisms o No demonstrated benefit over older agents o Question regarding optimal dose o High rates of nausea and sexual dysfunction o Drug interactions o Place in therapy ?? Deardorff WJ. Expert Opin Pharmacother 2014 7 3/9/2016 Atypicals as Adjunct o Old dog: atypical antipsychotics Atypicals as Adjunct Agent FDA approval Clinical Trial Outcomes o New trick: indication for MDD as adjunct Olanzapine/ fluoxetine 3-12/25-50 mg Treatment resistant depression Most: No difference from mono tx One trial and pooled analysis OFC>fluoxetine monotherapy o Limitations Quetiapine XR Adjunct to 150-300 mg antidepressants Addition of quetiapine XR > placebo with MADRS score change Response/remission improved in some studies Aripiprazole 2-15 mg Improved response and remission compared to placebo o Definition of ‘non-response’ was as little as 6 weeks on antidepressant o No head to head with other augmentation options o Metabolic syndrome risk Adjunct to antidepressants Wright BM et al. Pharmacotherapy 2013 Patient Case: New Tricks Pros Cons What Else Do We Need To Consider for This Patient? Vilazodone Less sexual dysfunction? $$, must take with food, GI upset dose limiting o Propensity for drug interactions Vortioxetine Less GI upset? $$, drug interactions Duloxetine May help with pain Need more EtOH hx Interacts with metoprolol, hydrocodone o Common side effects Desvenlafaxine ? $$, risk of underdosing Quetiapine Helps insomnia, anxiety Metabolic syndrome, urinary incontinence, hypotension Aripiprazole ? Metabolic syndrome, akathisia Olanzapine/ fluoxetine ? METABOLIC SYNDROME, interactions Levomilnacipran ? $$ o Serious side effects o Cost Drug Interactions The Safe Ones The Risky Ones o Citalopram o Fluoxetine (2D6>>3A4) o Escitalopram o Fluvoxamine (1A2, 3A4) Sertraline o Paroxetine (2D6) o Mirtazapine o Duloxetine (2D6) o Venlafaxine o Bupropion (2D6) o Nefazodone (3A4) o Vilazodone (3A4 substrate) o Vortioxetine (2D6 and 3A4) o o o Desvenlafaxine Milnacipran Question Which of BC’s current medications potentially interact with fluoxetine? A. B. C. D. Hydrocodone/acetaminophen Tramadol Metoprolol All of the above 8 3/9/2016 Common Side Effects Antidepressant Class Serious Side Effects Antidepressant Class SSRIs Anxiety, GI, headache, sexual dysfunction SSRIs Hyponatremia, bleeding, movement disorders SNRIs SSRI + sweating SNRIs SSRI + hypertension, hepatotoxicity Bupropion Insomnia; no sexual dysfunction Bupropion Seizures (?) Vilazodone SSRI, GI may be worse; less sexual dysfunction? Same as SSRIs Vortioxetine Similar to vilazodone Vilazodone/ vortioxetine Mirtazapine Sedation, weight gain, hyperlipidemia (?); less sexual dysfunction Mirtazapine Minimal TCAs Cardiac toxicity TCAs Sedation, anticholinergic, orthostasis MAO inhibitors Orthostasis, serotonin toxicity, hypertensive urgency MAO inhibitors Sedation Cost Generic Available $4 to $40 Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Venlafaxine (IR, XR tablets) Bupropion (IR, SR, XL) Mirtazapine Patient Case >$40 per month Desvenlafaxine Duloxetine (in transition phase) Levomilnacipran Vilazodone Vortioxetine Compelling Patient Specific Target Symptoms Treatment considerations Low energy SNRI or bupropion (still need to treat insomnia) Insomnia, appetite, anxiety Mirtazapine Lipids, overweight AVOID mirtazapine Polypharmacy Choose from the ‘safe list’ Pain, migraines SNRI Financial issues Choose generic My Recommendation Venlafaxine XR + temporary sedative hypnotic and alternatives for pain Final Thoughts o Antidepressants have similar efficacy o Newest agents do not appear to have efficacy or tolerability benefits over older agents o Base treatment on o o o Past history of response Drug interactions Side effects Questions? o Remind patients that medications take 8-12 weeks to have optimal effect o Devise safety plan and coping strategies for the interim 9