Blue Ain t Your Color: MDD Management in the Primary Care Setting

Transcription

1 Blue Ain t Your Color: MDD Management in the Primary Care Setting Cole Larsen, PharmD, PhC, BCPS Pharmacist Clinician University of New Mexico Hospitals October 8, 2017 Objectives Describe the incidence and costs associated with depression Discuss screening methods and diagnosis for depression Select an appropriate first-line therapy for a patient with depression based on reported symptoms and patient comorbidities Provide pharmacologic recommendations for patients with suboptimal responses to initial therapy Describe opportunities for pharmacists to assist in depression management 1

2 Where Do You Practice? A. Ambulatory Care B. Inpatient Pharmacy C. Hospital floor pharmacist D. Retail E. Other? Background 2

3 Epidemiology Prevalence of ~5% in the general population Other estimates closer to 7% with lifetime prevalence of 17% time more common in females Minority groups also disproportionately affected 350 million cases worldwide according to WHO Pratt LA, Brody DJ. Depression in the United States household population, NCHS Data Brief. 2008(7):1 8. Kessler R, Berglund P, Demler O, Jin R, Merikangas K, Walters E. Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry. 2005;62(6):593. doi: /archpsyc Depression. World Health Organization Available at: Epidemiology 3

4 Costs Poor concentration and decreased functionality Significant economic costs Lost employment and productivity 23 times greater than direct costs to healthcare system Those with depression 3X more likely to miss work Decreased productivity while at work Feelings of isolation from others Negative effects on relationships Suicide Risk is quadrupled in Major Depressive Disorder (MDD) population NCCMH. Depression: the Treatment and Management of Depression in Adults (Update). The British Psychological Society and the Royal College of Psychiatrists [Full guideline] Suicide The Ultimate Cost of Depression 10 th leading cause of death in the U.S 3 rd leading cause of death for ages >41,000 completed suicides per year 9.3 million reported suicidal thoughts in the past year Males account for 78% of all suicides Centers for Disease Control and Prevention (CDC). Web-based Injury Statistics Query and Reporting System (WISQARS) [Online]. (2013, 2011) National Center for Injury Prevention and Control, CDC (producer). Available from 4

5 MDD Risk Factors Insomnia Alcohol, tobacco, and drug use Family history History of another mental health disorder Chronic disease Lower socioeconomic status NCCMH. Depression: the Treatment and Management of Depression in Adults (Update). The British Psychological Society and the Royal College of Psychiatrists [Full guideline] VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder Contributing Medications Medications Strength of Association Beta blockers (propranolol, atenolol, +/- metoprolol) Calcium channel blockers +/- ACE-inhibitors +/- Lipid-lowering agents +/- Reserpine, clonidine, methyldopa + Corticosteroids + Benzodiazepines, barbiturates + NSAIDs + Topiramate + Varenicline + VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder

6 Common Comorbidities Medical Conditions Associated with Depression Cardiovascular diseases Coronary artery disease Congestive heart failure Stroke Vascular dementias Chronic pain syndrome Fibromyalgia Reflex sympathetic dystrophy Low back pain Degenerative diseases Hearing loss Alzheimer s disease Parkinson s disease Huntington s disease Immune disorders HIV Multiple sclerosis Systemic lupus erythematosis VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder Almeida S. Arq Neuro-Psiquiatr. 2013;71(9B): Common Comorbidities Medical Conditions Associated with Depression Metabolic/endocrine conditions Hypo/hyperthyroidism Diabetes mellitus Hepatic disease (cirrhosis) Chronic obstructive pulmonary disease Kidney disease Neoplasms Of any kind, especially pancreatic or central nervous system Trauma Traumatic brain injury Amputations Burn injuries VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder

7 Diagnosis and Screening Diagnosis DSM-5 Depressive symptoms lasting 2 weeks with marked clinical impairment 5 of 9 symptoms must be present Must include depressed mood or anhedonia Not attributed to a substance, alternate medical condition, or alternate psychiatric condition History negative for manic or hypomanic episodes 7

8 Depressive Symptoms Sleep Interest Guilt Energy Concentration Appetite Psychomotor Suicidal ideation SIG-E-CAPS Screening Majority of patients with MDD will be treated by their Primary Care Provider (PCP) Often underdiagnosed Patients frequently present with somatic complaints Patient Health Questionnaire-2 (PHQ-2) screening tool Administer annually Does not assess SI or HI VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder

9 Patient Health Questionnaire (PHQ-9) Scored 0 27, higher = more severe Completed by patient Score severity 0 4 = Minimal depression 5 9 = Mild depression = Moderate depression = Moderately severe depression = Severe depression VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder

10 Other Rating Systems Scale Hamilton Depression Rating Scale, 17-item (HAM-D 17 ) None/ Minimal/ Remission Severity of Depression Mild Moderate Severe Very Severe (severe) (very severe) Hamilton Depression Rating Scale, 21-item (HAM-D 21 ) (severe) (very severe) Hamilton Depression Rating Scale, 24-item (HAM-D 24 ) Montgomery-Åsberg Depression Rating Scale (MADRS) (severe) (very severe) Beck Depression Inventory (BDI) Inventory of Depressive Symptomatology (IDS 30 ) (severe) (very severe) Quick Inventory of Depressive Symptomatology (QIDS 16 ) (severe) (very severe) Treatment Selection 10

11 Guideline Recommendations APA VA/DoD NICE RANZCP Release date ( update) Focus MDD MDD MDD Mood Disorders First Line Agents Timeline for assessing efficacy PHQ-9 score to initiate dual therapy SSRIs, SNRIs, bupropion or mirtazapine SSRIs, SNRIs, bupropion or mirtazapine SSRIs SSRIs, bupropion, mirtazapine, others* 4 weeks 4-6 weeks 3-4 weeks 3 weeks *Venlafaxine first-line in severe depression SSRI = Selective Serotonin Reuptake Inhibitor, SNRI = Serotonin Norepinephrine Reuptake Inhibitor Choosing Initial Modality Pharmacotherapy Psychotherapy Prior positive response Significant sleep or appetite disturbance Agitation Anticipated chronic disease course Patient preference Prior positive response Provider availability Symptoms attributable to interpersonal issues, personal loss, etc. Co-occurring personality disorders Pregnancy Patient preference APA. Practice guideline for the treatment of patients with major depressive disorder

12 Agent selection All antidepressants are considered equally efficacious Use patient-specific factors to choose agent based on: Side effect profile Medical and psychiatric comorbidities Drug interactions Prior response Response for family members Monoamine hypothesis Dopamine Motivation Reward Pleasure Attention Interest Alertness Energy Norepinephrine Mood Anxiety Obsession Compulsions Nutt DJ. J Clin Psychiatry. 2008;69 (suppl E1) Serotonin 12

13 Monoamine Hypothesis Normal Neurotransmission Presynaptic neuron Post-synaptic neuron SERT Serotonin is released into the synapse Serotonin Serotonin receptor SERT: Serotonin Reuptake Transporter Monoamine Hypothesis Normal Neurotransmission Presynaptic neuron Signal Transduction SERT Serotonin binds to post-synaptic receptors Serotonin Serotonin receptor SERT: Serotonin Reuptake Transporter 13

14 Monoamine Hypothesis Normal Neurotransmission Presynaptic neuron Post-synaptic neuron SERT Serotonin then dissociates from the receptors and is taken back up by SERT for recycling Serotonin Serotonin receptor SERT: Serotonin Reuptake Transporter Monoamine Hypothesis Neurotransmission w/ SSRIs Presynaptic neuron Post-synaptic neuron SERT In the presence of an SSRI, SERT is blocked, leading to greater serotonin activity SSRI Serotonin Serotonin receptor SERT: Serotonin Reuptake Transporter 14

15 Monoamine Hypothesis Neurotransmission w/ SSRIs Presynaptic neuron Post-synaptic neuron Signal Transduction SERT In the presence of an SSRI, SERT is blocked, leading to greater serotonin activity SSRI Serotonin Serotonin receptor SERT: Serotonin Reuptake Transporter Pharmacotherapy Options 15

16 SSRIs Citalopram (Celexa) Concern for QTc prolongation More sedating due to antihistaminergic activity Escitalopram (Lexapro) Purest SSRI Less cardiotoxicity Fewest drug interactions Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press; QTc Prolongation Recommendations Concern for Torsades de pointes if QTc >500 milliseconds Ensure potassium and magnesium levels are within the normal range Perform ECG prior to initiating citalopram if any of the following present: Congestive heart failure Bradyarrhythmias Concomitant QTc-prolonging agents Crediblemeds.org VHA PBM Bulletin. Updated Guidance: Citalopram hydrobromide and dose-dependent QT interval prolongation. September 29,

17 SSRIs Fluoxetine (Prozac) May be more activating No tapering required due to long half-life Fluvoxamine (Luvox) Not officially labeled for MDD Only approved for OCD, off-label use in eating disorders Multiple drug interactions Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press; SSRIs Paroxetine (Paxil) Anticholinergic activity Only SSRI that requires renal dose adjustments Worst discontinuation symptoms Sertraline (Zoloft) Weak dopamine reuptake inhibition believed to enhance activity Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press;

18 SSRI Dosing Starting dose (mg/day) Dosing range (mg/day) Dose Adjustments Drug Interactions Citalopram Hepatic & age >60, max 20mg Escitalopram Hepatic & age >60, max 10mg Fluoxetine Hepatic & geri: (max 80) lower dose Fluvoxamine IR: 50 ER: 100 Paroxetine (max 60) Hepatic & geri: titrate slowly Renal & geri: 10-40mg Max 20 mg with omeprazole, cimetidine Concern with omeprazole Codeine, tamoxifen, clopidogrel, BBs Strong inhibitor of multiple enzymes Codeine, tamoxifen, BBs, digoxin Sertraline Hepatic: lower dose Vilazodone Renal elimination, dose after HD In Micromedex Solutions [database online]. Truven Health Analytics, inc Spina E. CNS Drugs. 2012;26(1): VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder Macrolides, ritonavir, azoles Substrate of CYP-3A4 SNRIs Duloxetine (Cymbalta) Greater effectiveness for pain Contraindicated if CrCl <30 ml/min or if hepatic dysfunction present Venlafaxine (Effexor) Worse discontinuation symptoms due to short half-life Used off-label for menopausal flushing Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press;

19 SNRIs Desvenlafaxine (Pristiq) Active metabolite of venlafaxine Theoretically more stable levels Slightly more NE activity than venlafaxine Levomilnacipran (Fetzima) Greater NE than 5-HT activity Weight neutral and no QTc prolongation Significantly increased blood pressure Lacks indications for other conditions Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press; Asnis GM and Henderson MA. Neuropsychiatr Dis Treat. 2015;11: SNRI Dosing SNRI s Starting dose (mg/day) Dosing range (mg/day) Dose adjustments Drug interactions Duloxetine CrCl <30: avoid Hepatic: avoid Venlafaxine IR: 37.5 XR: 75 IR: XR: Hepatic and renal: lower dose Desvenlafaxine Max dose of 25 mg/d if CrCl <30 Levomilnacipran Max 80 mg/d CrCl and max 40 mg/d for CrCl Codeine, tamoxifen, BBs Weak 2D6 inhibition Weak 2D6 inhibition Substrate of 3A4 and P- GP In Micromedex Solutions [database online]. Truven Health Analytics, inc

20 Mixed Activity SERTs Vortioxetine (Trintellix) 5-HT1A agonist, 1B partial agonist, 1D/3A/7 antagonist and reuptake activity Fewer discontinuation symptoms compared with duloxetine (boulenger) Vilazodone (Viibryd) 5-HT1A Partial Agonist and Reuptake Inhibitor (SPARI) Proposed benefits of faster onset, less sexual side effects and greater efficacy* Primary side effect of GI upset Boulenger et al. International Clinical Psychopharmacology : Grant JE et al May;32(3): Wang et al. Chonnam Med J : Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press; Mixed Activity SERTs Nefazodone (Serzone) 5-HT2A antagonist/reuptake inhibitor (SARI) Less potently inhibits NE reuptake Use severely limited due to hepatotoxicity Less sedating than trazodone Trazodone Use limited by sedation Kostrubsky SEet al. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci 2006; 90: 451-9) Stahl S. Stahl's Essential Psychopharmacology. Cambridge: Cambridge University Press;

21 Vortioxetine Mixed Activity SERTs Starting dose (mg/day) Dosing range (mg/day) Dose Adjustments Vilazodone Renal elimination, dose after HD Nefazodone Drug Interactions Substrate of CYP-3A4 Trazodone In Micromedex Solutions [database online]. Truven Health Analytics, inc Spina E. CNS Drugs. 2012;26(1): VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder Comparative Data Citrome L. Journal of Affective Disorders :

22 Tolerability Common adverse effects include headache, GI upset, dry mouth, agitation, insomnia, sexual dysfunction, diaphoresis, and weight gain SNRIs also pose risk of hypertension, tremor and tachyarrhythmia's Other risks Bleeding Hyponatremia Osteoporosis (elderly) Moret C et al. Journal of Psychopharmacology. 2009;23: Serotonin Syndrome Rare but serious Counsel patients to discontinue medication and seek care if Diaphoresis, delirium, agitation, muscle rigidity, clonus, or mydriasis Higher risk in patients with multiple serotonergic agents Linezolid, tramadol, valproate, triptans, dextromethorphan, L- tryptophan and other antidepressants (especially MAOIs) Management largely supportive Cyproheptadine considered treatment of choice Benzodiazepines for agitation/clonus Boyer E, Shannon M. New England Journal of Medicine. 2005;352(11):

23 NDRI Bupropion Not efficacious for anxiety Does not cause sexual dysfunction Additional indication for smoking cessation May be used as in combination with SSRI/SNRI Caution in patients with eating disorders and history of seizures Counsel patients to avoid bedtime dosing May increase desipramine levels, CI with ritonavir VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder Bupropion dosing Immediate release Dosed 2-4 times daily Sustained release Bupropion SA Dosed twice daily Formulation typically used for smoking cessation Extended release Bupropion SA 24h Dosed once daily Initial (mg/day) Maintenanc e (mg/day) Hepatic dosing Renal dosing Interactions In Micromedex Solutions [database online]. Truven Health Analytics, inc (max 400 for 12hr sustained release) 75 mg daily for immediate release 150 mg every other day for sustained and extended release Consider dose reduction if CrCl <90 ml/min Codeine, tamoxifen, BBs 23

24 VAST-D Compared change to bupropion, augmentation with bupropion or augmentation with aripiprazole Active treatment phase of 12 weeks with total 36 weeks of follow-up 1522 patients with nonpsychotic MDD and failure to an SSRI, SNRI or mirtazapine were randomized to treatment in a single-blind manner Remission at better in both augmentation groups but aripiprazole only one to achieve statistically significant improvement from switch group Higher rates of anxiety with bupropion (22-24% vs 16%) Higher rates of somnolence, akathisia and weight gain with aripiprazole Mohamed S, Johnson GR, Chen P, et al; VAST-D Investigators. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. VAST-D Remission at 12 weeks Percent Remission Bupropion Switch Bupropion Augment Aripiprazole Augment Mohamed S, Johnson GR, Chen P, et al; VAST-D Investigators. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 24

25 VAST-D Mohamed S, Johnson GR, Chen P, et al; VAST-D Investigators. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. Mirtazapine Use generally limited by sedation and weight gain Does not cause sexual dysfunction Also beneficial for anxiety and insomnia Dosed 15-45mg HS Tends to be less sedating at higher doses Cautious dose titration in geriatric patients, hepatic dysfunction, and CrCl <40 ml/min In Micromedex Solutions [database online]. Truven Health Analytics, inc

26 Discontinuation Symptoms Divided into affective, gastrointestinal, neuromotor, vasomotor, neurosensory, and other neurological symptoms Onset usually within 5 days of stopping antidepressant Counsel against abrupt cessation More pronounced with short-acting agents (paroxetine and venlafaxine) NCCMH. Depression: the Treatment and Management of Depression in Adults (Update). The British Psychological Society and the Royal College of Psychiatrists [Full guideline] A Word About Supplements Some benefit St. Johns Wort Multiple drug interactions Risk of serotonin syndrome when combined with SSRIs Omega-3 Recommend dietary modifications first Consider if other indications for supplementation exist Other dietary supplements possibly beneficial when used adjunctively Sarris J. J Clin Psych. 2012;73: Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Australian & New Zealand Journal of Psychiatry. 2015;49(12):

27 Monitoring Setting Expectations Most side effects should subside after the first 2 weeks Counsel to take with food to avoid GI upset Not for PRN use Adequate trial of at least 4-6 weeks before adjusting dose Increased activity, interest, and cognition in first 1-3 weeks Mood elevation, return of pleasure, decreased hopeless feelings, and fewer suicidal thoughts in 2-4 weeks 60-70% of patients will respond to an initial antidepressant trial 30-40% will achieve remission Nierenberg AA. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatric Clinics of North America. 2007;30:

28 Treatment Response Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Australian & New Zealand Journal of Psychiatry. 2015;49(12): Measuring Progress PHQ-9 at each visit Assess benefit at 4 weeks Consider dose increase if partial improvement and good tolerability Change to alternate medication if no response with adequate dose Ensure adherence Assess willingness to engage in psychotherapy VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder

29 Measuring Progress Variable Nonresponse Partial response Response Remission Recovery Response Minimal or < 25% decrease in baseline severity of symptoms Reduction in severity of symptoms but symptoms still evident; 26-49% decrease in baseline severity of symptoms 50% reduction in baseline severity of symptoms No symptoms, return to normal functioning; PHQ-9 score of 4, maintained for at least 1 month Extended remission, PHQ-9 score of 4, maintained for at least 6 months Mann J. New England Journal of Medicine. 2005;353(17): Measuring Progress Assess tolerability Sexual dysfunction Lower dose Adjunct with bupropion, or buspirone Trial alternative agent Treat with PDE-5 inhibitor Sedation/Insomnia Move dose to alternate time of day VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder

30 Follow-up Strategies Step Patient Condition Options Reassess at: 1 Initial treatment 2 weeks 2 Nonresponse to initial low dose 3 Failed 2 nd trial of antidepressant 4 Failed 3 trials including augmentation Increase dose Consider longer duration Switch Switch Augment Consider referral to specialty care Re-evaluate diagnosis and treatment Consider referral to specialty care VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder weeks 8-12 weeks weeks Special Populations 30

31 Medical Co-Morbidities Cardiovascular disease Caution with SNRIs Avoid citalopram due to QTc prolongation Avoid Tricyclic Antidepressants (TCAs) Parkinson s disease Depression present in 40-60% of patients No evidence to suggest one agent over another SSRIs/SNRIs may worsen tremor APA. Practice guideline for the treatment of patients with major depressive disorder Medical Co-Morbidities Seizure disorders Bupropion and TCAs lower seizure threshold No increased risk with SSRIs/SNRIs Obesity/Diabetes Mirtazapine and TCAs can cause/contribute to weight gain SSRIs/SNRIs associated with weight gain to a lesser extent Bupropion is weight neutral and may promote modest weight loss Traumatic Brain Injury Paroxetine and TCAs can worsen cognition via anticholinergic activity Population with lowered seizure threshold APA. Practice guideline for the treatment of patients with major depressive disorder

32 Medical Co-Morbidities Pain syndromes Neuropathic pain Recommend SNRI or TCA Migraine and tension headaches Highest quality evidence with amitryptiline, some evidence supporting SNRIs Fibromyalgia Duloxetine (FDA approved) Amitriptyline (off-label use) APA. Practice guideline for the treatment of patients with major depressive disorder Patient-Specific Factors Elderly patients Consider alternative to paroxetine due to anticholinergic effects Cautious dose titration Insomnia Consider augmenting with mirtazapine, trazodone, or hydroxyzine Suicidality SSRIs generally least toxic in overdose APA. Practice guideline for the treatment of patients with major depressive disorder

33 Pregnancy/Lactation Depression rate of 10-16% Consider risk/benefit Psychotherapy preferred for mild/moderate cases Untreated depression is not benign (premature birth, low birth weight, postnatal complications, impaired cognitive/emotional development) Pregnancy/lactation risk now a narrative section in package inserts Consider time of initiation and expected duration of therapy Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Australian & New Zealand Journal of Psychiatry. 2015;49(12): Pregnancy/Lactation Paroxetine contraindicated in pregnancy Pulmonary HTN, cardiac defects, neonatal withdrawal Venlafaxine and bupropion also associated with heart defects All other SSRIs/SNRIs previously category C Lactation Lowest risk with fluoxetine, paroxetine, and sertraline If pharmacotherapy selected, use lowest effective dose Sertraline preferred O Connor E. Primary Care Screening for and Treatment of Depression in Pregnant and Postpartum Women. JAMA. 2016;315(4):388. TOXNET. Toxnetnlmnihgov Available at: 33

34 Questions? 34