Depression and Anxiety: Latest in treatment recommendations Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc., North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board Member The Nurse Practitioner Journal, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA Objectives At the conclusion of this presentation the attendee will be able to: Explain the mechanism of action of commonly prescribed psychotropic medications used in the treatment of mood disorders including depression and anxiety. 2 Objectives At the conclusion of this presentation the attendee will be able to: (cont.) Describe factors influencing the choice of a psychotropic medication for the treatment of common mood disorders. Identify common adverse effects and therapeutic advantages of the abovementioned medications. Efficacy of Depression, Anxiety Therapies Pharmacologic therapy 80% Rx written by primary care providers All prescription antidepressants +/- equally effective if taken in therapeutic doses for sufficient length of time Under dosing Too short a treatment interval Source: Hosp Pract. 2000;35:77-84. Available at: http://www.hosppract.com/issues/2000/07/feld.htm 3 4 Are depression, anxiety brain diseases? Neurohumoral disease? Other? What does what in the maintenance of mood? Serotonin AKA 5-hydroxytryptamine or 5-HT Similar in structure to norepinephrine and dopamine Modulates mood, emotion, sleep, appetite, keeps the motor of life running smoothly Source: www.biopsychiatry.com/serotonin.htm 5 6
What does what in the maintenance of mood? Norepinephrine Eye on the prize Associated with focused attention, elevated energy, motivation to win a reward or move towards a goal Source: http://www.acnp.org/docs/ G5/CH4_47-58.pdf What does what in the maintenance of mood? Dopamine In part, helps with the joy of life, attention, pleasure Source: http://www.acnp.org/docs/g5/ ch9_119-132.pdf 7 8 Glutamate and GABA Yin and yang of neurotransmitters Present in nearly all brain synaptic function Glutamate and GABA Glutamate Excitatory capacity Stress modulating when working right GABA Inhibitory role Select receptor site activity regulate excitability as well as anxiety, panic, and stress 9 10 Hormone Effects: Presence of Estrogen Catecholamines* Serotonin function and transport Monoamine oxidase Neurotransmitter balance is key. Most psychotropic medications work through manipulation of serotonin, norepinephrine and/or dopamine *Fink et al. Cell Mol Neurobiol. 1996;16:325. Aylward and Maddock. Lancet. 1973;1:936. Luine et al. Brain Res. 1975;86:293. 11 12
What are the clinical and cost considerations? Choosing a Therapeutic Agent in Mood Disorder Source: Practice Guideline for the Treatment of Patients With Major Depressive Disorder Available at www.psychiatryonline.com/pracguide/pracguide ChapToc_7.aspx What does what? What does the patient need for a clinical response? Vegetative or anxious? Will a given medication provide that help? What depression, anxiety symptoms respond best to a given medication? 13 14 What are the clinical considerations? What is the drug s adverse effect profile? What is the risk of the medication in overdose? What medication is affordable and accessible? What are the clinical and cost considerations? How is the patient sleeping? What is the patient s energy level? Chronic pain? Appetite? 15 16 How to Choose a Therapeutic Agent for the Treatment of Mood Disorders What has worked in the past? Use the tried and true if safe and reasonable What has worked for relatives? May be related to similar action of receptor sites, neurotransmitter activity Commonly Prescribed Psychotropic Medications SSRIs (selective serotonin or serotonin specific reuptake inhibitors) Inhibit reuptake of serotonin (5-HT) Net result is more serotonin at synaptic cleft Citalopram (Celexa ), escitalopram (Lexapro ), fluoxetine (Prozac ), fluvoxamine (Luvox ), paroxetine (Paxil ), sertraline (Zoloft ) Source: Stringer (2011) 17 18
Comparing Psychotropic Medications (Katzung, 2014) Drug Citalopram, escitalopram Fluoxetine Sedation or activation? + sedation +/ ++ activation + sedation ++ activation Paroxetine + + sedation + activation Sertraline 0 sedation +/ ++ activation Anticholinergic Serotonin NE Dopamine 0 +++ 0 0 + +++ 0/+ 0/+ ++ +++ 0 0 0 +++ 0 0 Commonly Prescribed Psychotropic Medications Venlafaxine (Effexor ), duloxetine (Cymbalta ), desvenlafaxine (Pristiq ), others Inhibits reuptake of serotonin, NE Particularly well suited when mood disorder associated with chronic pain, depression resistant to SSRI therapy, anxious depression 20 Commonly Prescribed Psychotropic Medications Bupropion (Wellbutrin ) Inhibits reuptake of dopamine, lesser degree, norepinephrine Typically energizing with lower risk of adverse sexual AE when compared to SSRI, SNRI Potentially well suited for person who is low energy, hx of sexual AE with SSRI, SNRI Commonly Prescribed Psychotropic Medications Mirtazapine (Remeron ) Blocks presynaptic 2 -adrenergic autoreceptor; blocks 5-HT 2, 5-HT 3 Net effect, enhance serotonin and NE activity 21 22 Mirtazapine (Remeron ) Sedating Helpful as a HS dose 7.5 45 mg per day, 15 mg at bedtime for sleep helpful Noted to increase appetite modestly Particularly well suited Depression with anxiety, unintended weight loss, difficulty sleeping 23 Comparing Psychotropic Medications (Katzung, 2014) Drug Sedation or activation Bupropion Sedation 0 Activation +++ Venlafaxine desvenlafaxine Sedation + Activation +/ ++ Duloxetine Sedation + Activation +/ ++ Mirtazapine Sedation ++++ Activation 0 Anticholinergic Serotonin NE Dopamine + 0 + +++ 0 +++ +/ ++ 0 +++ ++ + + 0 0 0 0 0
Commonly Prescribed Psychotropic Medications Nefazodone (Serzone ), trazodone (Desyrel ), vilazodone (Viibryd ) Inhibits reuptake of 5-HT; blocks 5-HT 2A (anxiety receptor site) Issues with use Nefazodone- Seldom used due to liver toxicity Trazodone- Non habituating sleep aid Vilazodone- Low rate sexual AE 25 Commonly Prescribed Psychotropic Medications Tricyclic antidepressants (TCA) Block reuptake of NE, 5-HT Amitriptyline, imipramine, desipramine, nortriptyline, clomipramine Issues with use Significant AE in overdose Sedating, possibly helpful with chronic pain Inexpensive 26 Comparing Psychotropic Medications (Katzung, 2014) Drug Amitriptyline Desipramine Nortriptyline Trazodone Nefazodone Sedation or activation Sedation +++ Activation 0 Sedation +/++ Activation 0 Sedation ++ Activation 0 Sedation +++ Activation 0 Sedation +++ Activation 0 Anticholinergic Serotonin NE Dopamine ++++ +++ ++ 0 ++ 0/+ +++ 0 ++ +++ ++ 0 0 0/+ 0 0 +++ + 0 0 Clinical question What is the given medication s profile? Comment Include T ½, potential drug interactions, adverse effect profile, others. Medication characteristic See tables below. 27 28 SSRI T ½ Paroxetine (Paxil ) 21 h Sertraline (Zoloft ) 26 h Escitalopram (Lexapro ) 27 32 h Citalopram (Celexa ) 33 h Fluoxetine (Prozac ) 84 h, metabolite= 7 15 days CYP450 Isoenzyme Inhibition by SSRIs CYP Isoenzymes 1A2 2C9 2C19 2D6 3A4 Escitalopram 0 0 0 0 0 Citalopram + 0 0 + 0 Fluoxetine + ++ +/ ++ +++ ++ Paroxetine + + + +++ + Sertraline + + +/ ++ + + 0=minimal or weak inhibition; +, ++, +++ =mild, moderate, or strong inhibition*. von Moltke et al., 2001; Greenblatt et al., 2002; Greenblatt et al., 1998 29 30
Discontinuing Psychotropic Therapy Slowly discontinue psychotropic therapy p 4 6 month maximum improvement 1 st episode MDD Family s 1 st depression Treated 9 12 months Repeat episode Strong family hx depression SSRI Withdrawal Syndrome Seen with Use greater than 5 weeks Rapid discontinuation of all products with shorter T ½ 31 32 SSRI, TCA Withdrawal Syndrome Dizziness Paresthesia Anxiety Nausea Sleep disturbance Insomnia Nightmares Shorter T ½ vs. Longer T ½: Pro and Con SSRI Paroxetine (Paxil ) Sertraline (Zoloft ) Escitalopram (Lexapro ) Citalopram (Celexa ) Fluoxetine (Prozac ) T ½ 21 h 26 h 27 32 h 33 h 84 h, metabolite= 7 15 days 33 34 Avoiding SSRI Withdrawal Syndrome Evaluating Nonresponder Taper dose over 4 weeks Reduce ~25% per week Depression relapse can occur. Increase gradually to original dose if this happens. Has there been an adequate medication trial? Adequate dose Adequate length of therapy Adherence 35 36
Evaluating Nonresponder Consider coexisting health issues Medications Clonidine, beta blockers, HCTZ Metabolic issues DM, thyroid Substance abuse Stress, life events Antidepressant Use in Adjustment Disorder with Depressed Mood If depression is with stressor Agent will work well initially. Less well as time goes on if stressor continues If stressor stops, drug will resume its initial efficacy. 37 38 Depression as Part of Bereavement Indications Severe acute bereavement (<4 mo post event) Moderate to severe chronic bereavement Anticipated effect of medications Improves vegetative symptoms No real effect on normative mood fluctuation of grief Medication Augmentation for Nonresponder Maximize dose of original medication if some response Add a second agent Choice dependent on clinical effect SSRI plus buspirone SSRI plus bupropion SSRI plus mood stabilizer/sga SSRI plus low dose stimulant 39 40 If these fail Try meds with different activity Mirtazapine (Remeron ) Nefazodone (Serzone ) Uncommonly used due to rare but random risk of liver toxicity Venlafaxine (Effexor ), desvenlafaxine (Pristiq ) Duloxetine (Cymbalta ) Liver toxicity risk with heavy alcohol use If these fail Psychopharmacology consult Does this person also provide psychotherapy? 41 42
Evaluating Relapse Substance abuse Sleep disturbance Adherence Stress Medical and metabolic issues Psychotropic medication tolerance Atypical or Second Generation Antipsychotics (SGA) as Adjunctive Therapy in MDD 43 44 Antipsychotics: First vs. Second Generation Typical (AKA 1 st generation) Haloperidol, others Atypical (AKA 2d generation) Risperidone, olanzapine, others Mechanism of action Block selective dopamine receptor sites 45 Atypical Antipsychotics Clozapine (Clozaril ) Olanzapine (Zyprexa ) Quetiapine (Seroquel ) Risperidone (Risperdal ) Iloperidone (Fanapt ) 46 Ziprasidone (Geodon ) Aripiprazole (Abilify ) Asenapine (Saphris ) Lurasidone (Latuda ) Paliperidone (Invega ) Others Second Generation Antipsychotics Group of agents with action at a variety of receptor sites Dopamine receptors (D2, D1, D3, and D4 antagonism) Serotonin receptors (5-HT2A, 5-HT2C, 5-HT1A, 5-HT1D, others) Norepinephrine (alpha 1- and alpha 2- adrenergic receptor blockade) Antipsychotics Best effect on positive symptoms Hallucinations, agitation, confusion Improvement plateaus at 3 6 months Less effect on negative symptoms Blunted affect, cognitive dysfunction, inattention Improvement at 2 3 months of treatment, often continue to improve 47 48
Atypical/Second Generation Antipsychotics and MDD When to consider Inadequate response with monotherapy Particularly with depression is severe Potentially helpful with sleep, sexual function Source: Treatment-resistant depression: an update. Pharmacist's Letter/Prescriber's Letter 2009;25(5):250510. Pharm Phun Phacts: BZD True or false? The use of a BZD does not help in decreasing the worry associated with anxiety but is helpful in reducing disease-associated vigilance. BZD abuse is rare in the absence of substance abuse. 49 50 Benzodiazepine Tolerance Higher risk of dose escalation Also prescribed antidepressants Prescribed lorazepam Younger and NOT disabled Filling duplicate prescriptions at different pharmacies Source: Soumerai SB et al. Psychiatry Serv. 2003;54:1006-1011. Benzodiazepine Withdrawal Quickest onset Short T ½ drugs Likely most severe symptoms Slow onset Longer T ½ drugs Likely less severe symptoms 51 52 BZD Pharmacokinetics Dose equivalent Half-life in hours Alprazolam (Xanax ) 0.5 6 20 Chlordiazepoxide (Librium ) 10 30 100 Clonazepam 0.25 18 50 (Clonidine ) Clorazepate (Tranxene ) 7.5 30 100 Diazepam (Valium ) 5 30 100 Lorazepam (Ativan ) 1 10 20 Oxazepam (Serax ) 15 8 12 Source: Arana & Rosenbaum (2000) Handbook of Psychiatric Drug Therapy. 53 54
Benzodiazepine Dependence Reduce dose by 25% per week Rapid withdrawal Tremors Hallucinations Seizures DT-like picture If anxiety is disabling... add short-term benzo while awaiting other agent s action inform that duration of use may be limited 55 56 Folic Acid Deficiency and Mood Disorder Nutritional Supplements and the Treatment of Mood Disorders Folic acid (FA) Required for neurotransmitter production including serotonin FA deficiency common in depression Low folate status or lower dietary folate intake=higher risk for depression, less response to antidepressant treatment 57 58 Treatment of Folic Acid Deficiency and Mood Disorder Folic acid 500 mcg daily vs. placebo All taking SSRI Marked increase in clinical response in women, but not men, in FA arm Source: Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130. Folic Acid Deficiency: Genetic Contribution MTHFR gene action Critical to multistep process folic acid biotransformation, which in turn make proteins and other important compounds including neurotransmitters 59 60
MTHFR Gene Mutation: Up to 40% of the Population Associated disease states Anencephaly, spina bifida Heart disease, stroke, HTN Mood disorder Clinical implication Need to supplement with a FA metabolite such as L-methylfolate Evidence of L-methylfolate Treatment Effect Adjunctive L-methylfolate at 15 mg/day can constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs. Source: Am J Psychiatry. 2012 Dec;169(12):1267-74. doi: 10.1176/appi.ajp.2012.11071114 61 62 L-methylfolate Sources Rx only products Considered medical foods, include L-methylfolate (Deplin ), multivitamin with iron (EnLyte ), multivitamin, prenatal (Optinate ) OTC Optimized folate S-adenosylmethionine (SAM-e ) What is it? Naturally occurring molecule found throughout body Synthesis closely linked to vitamin B12 and folate metabolism Role in 100 biochemical reactions synthesis, activation and/or metabolism of hormones, neurotransmitters, others 63 64 S-adenosylmethionine (SAM-e ) Role in treatment of mood disorders S-adenosylmethionine (SAM-e ) supplement 400 800 mg BID to conventional treatment increases remission rates by ~14% after 6 weeks Source: PL Detail-Document, Combining and Augmenting Antidepressants. Pharmacist s Letter/Prescriber s Letter. September 2014. S-adenosylmethionine (SAM-e ) Possible adverse effect Increased serotonergic effect with given with SSRI, SNRI, TCA, tramadol Source: PL Detail-Document, Combining and Augmenting Antidepressants. Pharmacist s Letter/Prescriber s Letter. September 2014. 65 66
Conclusion Understanding the science behind prescribing medications in depression will help you and your patients to choose the best treatment option. End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC Website: www.fhea.com email: cs@fhea.com 67 68 References Fitzgerald Health Education Associates, Inc. Psychiatric & Mental Health Nurse Practitioner Certification Exam Review and Advanced Practice Update. Available at fhea.com Fitzgerald, M., Miller, S. Comprehensive Clinical Pharmacology Course, Available at fhea.com References Fitzgerald, M., Miller, S. Pathophysiology for Advanced Practice Course, Available at fhea.com Katzung, BG. (2014) Basic and Clinical Pharmacology (13th ed.) New York: Lange Medical Books/McGraw-Hill. 69 70 References Rhoads, J. (2014) Clinical Consult to Psychiatric Nursing for Advanced Practice, New York, Springer Publishing. Available at fhea.com Stringer, J. (2011) Basic Concepts in Pharmacology: All you need to know for each drug class (4th edition). New York: McGraw-Hill. All websites listed active at the time of publication. 71 72
Second Generation Antipsychotics: Rank Order, Weight Gain From greatest to least Clozapine (Clozaril ) Olanzapine (Zyprexa ) Quetiapine (Seroquel ) Risperidone (Risperdal ) Iloperidone (Fanapt ) Source: Comparison of atypical antipsychotics. Pharmacist s Letter/Prescriber s Letter;25(10):251010. Rank Order, Weight Gain Reported low to no weight gain Ziprasidone (Geodon ) Aripiprazole (Abilify ) Asenapine (Saphris ) Lurasidone (Latuda ) Paliperidone (Invega ) Source: Comparison of atypical antipsychotics. Pharmacist s Letter/Prescriber s Letter 2009;25(10):251010. (Full update January 2011). 73 74 Recommendations Torsades de Ponte Risk with SGA Use Prior to starting medication Fasting plasma glucose Repeat q 3 6 months as indicated Lipid profile Hypertriglyceridemia common Life style changes Diet, exercise, smoking cessation, etc. 75 76 Torsades Risk with SGA Use Likely class effect Increasing risk with greater CV disease risk Listed under Drugs with Possible TdP in Crediblemeds.org Consider baseline ECG with particular attention to QT interval prior to initiation. Citalopram and QT Prolongation For all, not recommended above 40 mg/d Causes too large an effect on QT interval and confers no additional benefit 77 78
Citalopram and QT Prolongation Use not recommended With congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute MI, or uncompensated heart failure In patients who are taking other drugs that prolong the QT interval Citalopram and QT Prolongation Do not exceed 20 mg per day Age>60 years, hepatic impairment, CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet ) or another CYP 2C19 inhibitor including many PPIs 79 80 Citalopram and QT Prolongation In patients who are found to have persistent QTc measurements exceeding 500 ms, citalopram should be discontinued. Source: http://www.fda.gov/safety/medwatch/safetyinformation /SafetyAlertsforHumanMedicalProducts/ucm297624.htm 81