Management of Anxiety Throughout Life’s Stages Gabriela Dimitrievski, PharmD, BCPS, BCPP Clinical Pharmacy Specialist – Psychiatry Eskenazi Health Gabriela.Dimitrievski@eskenazihealth.edu April 20, 2016 This speaker has no actual or potential conflicts of interest to disclose in relation to this presentation

Objectives Review the types of anxiety, with a consideration to prevalence at different stages of life Outline pharmacologic treatment options for the management of different types of anxiety Discuss the appropriate use of pharmacologic and non-pharmacologic treatment options at different ages

Overview of Anxiety Disorders Disorders characterized by excessive and persistent fear and anxiety Differentiation based on the items and/or situations linked to the fear, anxiety, or avoidance Significant stress in social, occupational, or other important aspects of life Linked to adverse effects on health and cognitive functioning American Psychiatric Association. (2013)

DSM-5 Anxiety Disorders Separation Anxiety Disorder Substance/Medication- Induced Anxiety Disorder Selective Mutism Anxiety Disorder Due to Another Medical Condition Specific Phobia Social Anxiety Disorder Other Specified Anxiety Disorder Panic Disorder Panic Attack Specifier Unspecified Anxiety Disorder Agoraphobia Generalized Anxiety Disorder American Psychiatric Association. (2013)

DSM-5 Anxiety Disorders Separation Anxiety Disorder Excessive and inappropriate fear and/or anxiety in regards to separation from key individuals Symptoms last > 4 weeks in children/adolescents and > 6 months in adults Cause of significant impairment Selective Mutism Continuing failure to speak in certain social situations, Symptoms persist for > 1 month Not related to lack of knowledge or another communication or mental disorder disorder American Psychiatric Association. (2013)

DSM-5 Anxiety Disorders Specific Phobia Fear and anxiety centered around a specific entity or circumstance Avoidance of specific “trigger” Persistence > 6 months Social Anxiety Disorder Fear and anxiety related to being under the potential scrutiny of others Fear of embarrassment, humiliation, rejection American Psychiatric Association. (2013)

DSM-5 Anxiety Disorders Panic Disorder Recurrent panic attacks, defined as “abrupt surges of intense fear or intense discomfort” Attack is followed by > 1 month of persistent fear/anxiety about subsequent panic attacks or behavioral changes made to avoid further attacks Agoraphobia Fear and anxiety related to: public transportation, open vs. enclosed spaces, lines/crowds, leaving the home alone Avoidance of individual triggers Persistence > 6 months American Psychiatric Association. (2013)

DSM-5 Anxiety Disorders Generalized Anxiety Disorder Anxiety and worry associated with a multitude of situations Defined by: restlessness, fatigue, concentration difficulties, irritability, muscle tension, sleep abnormalities Occurs more days than not within a 6 month period Substance/Medication-Induced Anxiety Disorder Panic attacks and anxiety Symptoms experienced during or closely after substance/medication use or withdrawal American Psychiatric Association. (2013)

DSM-5 Anxiety Disorders Anxiety Disorder Due to Another Medical Condition Panic attacks or anxiety Directly related to another medical condition Other Specified Anxiety Disorder Characteristic anxiety symptoms that do not meet criteria for other defined anxiety disorders Documented reason on why criteria not met Unspecified Anxiety Disorder No documented reason on why criteria not met American Psychiatric Association. (2013)

Prevalence of Anxiety Disorders National Institute of Mental Health.

Prevalence of Anxiety Disorders Lenze et al. Dialogues Clin Neurosci 2011;13(4):381-99

Prevalence of Anxiety Disorders in Adults Diagnosis Prevalence Separation anxiety disorder 0.9%-1.9% Specific phobia 8.7% Social anxiety disorder 6.8% Panic disorder 2.7% Agoraphobia 0.8% Generalized anxiety disorder 3.1% National Institute of Mental Health. American Psychiatric Association. (2013)

Prevalence of Anxiety Disorders in Children/Adolescents Separation anxiety disorder Children: 4% Adolescents: 1.4% Selective mutism: 0.03%-1% Specific Phobia: Children: 5% Adolescents: 16% Social anxiety disorder: 7% National Institute of Mental Health. American Psychiatric Association. (2013)

Prevalence of Anxiety Disorders in Children/Adolescents Panic disorder: Children: <0.4% Adolescents: 2.3% Agoraphobia: Adolescents: 2.4% Generalized anxiety disorder: 0.9% National Institute of Mental Health. American Psychiatric Association. (2013)

Prevalence of Anxiety Disorders in the Elderly Diagnosis Prevalence Specific phobia 3-5% Social anxiety disorder 2-5% Panic disorder 0.7% Agoraphobia 0.4% Generalized anxiety disorder 1.2%-7.3% American Psychiatric Association. (2013) Lenze et al. Dialogues Clin Neurosci 2011;13(4):381-99

Pharmacologic Treatment of Anxiety Disorders

Key Considerations Treatment of each patient must be individualized Treatment may utilize pharmacotherapy, psychotherapy, and/or other therapy modalities Potential risks and benefits should be considered when assessing pharmacologic treatment options

Treatment of Separation Anxiety Disorder Lack of extensive studies related to treatment Multifactoral treatment including pharmacologic and non-pharmacologic therapies recommended SSRIs considered first-line pharmacotherapy option Wehry et al. Curr Psychiatr Rep 2015;17(7):52 Strawn et al. Child Adolesc Psychiatric Clin N Am 2012;21:527-39 Baldwin et al. J Psychopharmacol 2014;28(5):403-39

Treatment of Selective Mutism and Phobias Some data to suggest use of SSRI treatment Fluoxetine most cited in current literature Most evidence to support non-pharmacologic treatment modalities Specific Phobias Treatment based in behavioral interventions Lack of data examining overall role of medications in treatment Role of d-cycloserine in enhancing exposure therapy benefits Hua et al. Curr Opin Pediatr 2016;28(1):114-20 Choy et al. Clin Psychol Rev 2007;27(3):266-86 Smits et al. Biol Psychiatry 2013;73(11):1054-58

Treatment of Social Anxiety Disorder Treatment guidelines: Guideline First Line Pharmacotherapy Recommendation British Association for Psychopharmacology (2014) SSRIs: escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline SNRI: venlafaxine MAOIs: phenelzine, moclobemide Benzodiazepines: bromazepam, clonazepam Anticonvulsants: Gabapentin, pregabalin Olanzapine Canadian Psychiatric Association (2006) SSRIs: escitalopram, fluvoxamine, paroxetine, sertraline World Federation of Biological Psychiatry (2012) SSRIs *SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norephinephrine reuptake inhibitor; MAOI = monoamine oxidase inhibitor Baldwin et al. J Psychopharmacol 2014;28(5):403-39 Canadian Psychiatric Association. (2006) Bandelow et al. Int J Psychiatry Clin Pract 2012;16:77-84

Antidepressant Use in Social Anxiety Disorder Serotonin Reuptake Inhibitors (SSRIs) FDA-approved: sertraline, paroxetine Systemic review and meta-analysis found overall good evidence to support use of escitalopram, fluvoxamine, paroxetine, and sertraline Three-time higher odds of response with SSRIs Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) FDA-approved: venlafaxine XR Hansen et al. Int Clin Psychopharmcol 2008;23(3):170-79 College of Psychiatric and Neurologic Pharmacists. (2014)

Miscellaneous Treatment Options in Social Anxiety Disorder Benzodiazepines Clonazepam linked with significant improvements in clinical presentation 38% response rate with alprazolam Risk vs. benefit profile Monoamine oxidase inhibitors Phenelzine with most consistent data One of the first defined treatment options Consider drug and food interactions and risk for hypertensive crisis Muller et al. CNS Drugs 2005;19(5):377-91

Miscellaneous Treatment Options in Social Anxiety Disorder Anticonvulsants Gabapentin linked to improved scores on Liebowitz Social Anxiety scale as compared to placebo 43% response rate with pregabalin vs. 22% response rate with placebo Beta-blockers Mixed results to support use Lack of efficacy for generalized SAD Potential clinical efficacy in performance- based anxiety Muller et al. CNS Drugs 2005;19(5):377-91 Bruce et al. Am Fam Physician 1999;60(8):2311-2320

Self-Assessment Question Which of the following selective serotonin reuptake inhibitors is FDA- approved for use in social anxiety disorder? Fluoxetine Escitalopram Citalopram Sertraline

Treatment of Panic Disorder Treatment guidelines: Guideline First Line Pharmacotherapy Recommendation American Psychiatric Association (2009) SSRIs SNRI: venlafaxine XR British Association for Psychopharmacology (2014) SNRI: venlafaxine TCAs: clomipramine, desipramine, imipramine, lofepramine NRI: reboxetine Benzodiazepines: alprazolam, clonazepam, diazepam, lorazepam Anticonvulsants: gabapentin, sodium valproate *SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; NRI = norepinephrine reuptake inhibitor American Psychiatric Association. (2009) Baldwin et al. J Psychopharmacol 2014;28(5):403-39

Treatment of Panic Disorder Guideline First Line Pharmacotherapy Recommendation Canadian Psychiatric Association (2006) SSRIs SNRI: venlafaxine XR National Institute for Health and Clinical Excellence (2011) World Federation of Biological Psychiatry (2012) SNRIs: venlafaxine Short acting benzodiazepines (severe attacks) *SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norephinephrine reuptake inhibitor Canadian Psychiatric Association. (2006) National Institute for Health and Care Excellence (2011) Bandelow et al. Int J Psychiatry Clin Pract 2012;16:77-84

Antidepressant Use in Panic Disorder SSRIs FDA approved: fluoxetine, sertraline, paroxetine Clinical data has supported effectiveness of all SSRI medications SNRIs FDA-approved: venlafaxine XR Other antidepressants Tricyclic antidepressants Monoamine oxidase inhibitors Mirtazapine American Psychiatric Association. (2009)

Benzodiazepine Use in Panic Disorder FDA-approved: alprazolam, clonazepam Quick onset may lend itself to use in severe, acute presentations Risk vs. benefit profile: Tolerance Abuse potential Cognitive and motor disturbances Not considered first-line therapy option American Psychiatric Association. (2009)

Treatment of Generalized Anxiety Disorder Treatment guidelines: Guideline First Line Pharmacotherapy Recommendation British Association for Psychopharmagology (2014) SSRIs: citalopram, escitalopram, paroxetine, sertraline SNRIs: duloxetine, venlafaxine Pregabalin Agomelatine Quetiapine Benzodiazepines: alprazolam, diazepam, lorazepam Imipramine Buspirone Hydroxyzine Trazodone *SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norephinephrine reuptake inhibitor Baldwin et al. J Psychopharmacol 2014;28(5):403-39

Treatment of Generalized Anxiety Disorder Guideline First Line Pharmacotherapy Recommendation Canadian Psychiatric Association (2006) SSRIs: paroxetine, escitalopram, sertraline SNRIs: venlafaxine XR International Psychopharmacology Algorithm Project (2006) SSRIs: escitalopram, paroxetine, sertraline SNRIs: venlafaxine XR, duloxetine National Institute for Health and Clinical Excellence (2011) SSRI: sertraline World Federation of Biological Psychiatry (2012) SSRIs SNRIs Pregabalin *SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin norephinephrine reuptake inhibitor Canadian Psychiatric Association. (2006) International Psychopharmacology Algorithm Project (2006) National Institute for Health and Care Excellence (2011) Bandelow et al. Int J Psychiatry Clin Pract 2012;16:77-84

Antidepressant Use in Generalized Anxiety Disorder SSRIs FDA approved: paroxetine, escitalopram Sertraline, citalopram not FDA approved, but found to be effective in short-term clinical trials SNRIs FDA-approved: venlafaxine XR, duloxetine Other antidepressants Imipramine, trazodone, mirtazapine, bupropion, vortioxetine, and vilazodone have all be studied College of Psychiatric and Neurologic Pharmacists. (2014)

Benzodiazepine Use in Generalized Anxiety Disorder Frequently prescribed medications for the acute treatment of anxiety disorders Quick and effective Consideration of risk vs. benefits: Tolerance Abuse potential Cognitive and motor disturbances Should be considered as short-term management Cloos et al. Curr Opin Psychiatry 2009;22(1):90-5 Martin et al. J Psychopharmacol 2007;21(7):774-82

Miscellaneous Treatment Options in Generalized Anxiety Disorder Buspirone FDA approved for the treatment of GAD 5-HT1A partial agonist Appropriate second-line or adjunctive treatment Overall well-tolerated medication Delayed time to onset Hydroxyzine Approved for use in adults and children Histamine receptor antagonist Potential for numerous side effects Lack of long-term use data Stein et al. N Engl J Med 2015;373:2059-2068

Miscellaneous Treatment Options in Generalized Anxiety Disorder Pregabalin Non-FDA approved treatment for GAD Modulates and reduces calcium-dependent excitatory neurotransmitter release Efficacy demonstrated in short-term and long-term clinical trials C-V controlled substance Second Generation Antipsychotics Systematic review has identified potential use as augmentation in treatment-resistant GAD Use limited by more robust supporting data and extensive adverse effect profile Baldwin et al. Neuropsychiatr Dis Treat 2007;3(2):185-191 Lorenz et al. Pharmacotherapy 2010;30(9):942-51

Self-Assessment Question Which of the following medications is a 5-HT1A partial agonist approved for use in generalized anxiety disorder? Buspirone Pregabalin Quetiapine Alprazolam

Antidepressant Clinical Pearls Delayed time to full benefit Individual side effect profiles of each medication “Jitteriness syndrome” Slow taper upon discontinuation Start at a lower dose and titrate as tolerated Black box warning of increased suicidality risk in children and adolescents Consider individual responses to therapy

Benzodiazepine Clinical Pearls Second-line and/or short-term treatment options Abuse and dependence potential Potentially fatal withdrawal syndrome Consider comorbid mental health concerns Potential long-term adverse effects Extensive side effect potential Billioti de Gage et al. BMJ 2014;9:349:g5205 Gray et al. BMJ 2016;2:352:i90

Considerations Throughout the Lifespan

Anxiety Treatment in Children and Adolescents Associated with significant morbidity and mortality concerns Physical symptoms may be prominent in children with anxiety disorders Recommended that psychotherapy be considered part of the treatment plan Exposure-based cognitive behavioral therapy (CBT) Family-child therapy College of Psychiatric and Neurologic Pharmacists. (2014) Connolly et al. J Am Acad Child Adolesc Psychiatry 2007;46(2):267-83 Wehry et al. Curr Psychiatry Rep 2015:17:52

Anxiety Treatment in Children and Adolescents SSRIs considered pharmacologic treatment of choice Short-term efficacy found in the treatment of selective mutism, generalized anxiety, separation anxiety, and social anxiety Combination of non-pharmacologic + pharmacologic treatments should be considered Superior reduction of anxiety symptoms seen with combination of sertraline and CBT Connolly et al. J Am Acad Child Adolesc Psychiatry 2007;46(2):267-83 Wehry et al. Curr Psychiatry Rep 2015:17:52 Walkup et al. N Engl J Med 2008;359(26):2753-66

Medication Use in Children and Adolescents Black box warning on all antidepressants for increased suicidality risk in children and adolescents Consider altered pharmacokinetics when dosing medications Half-life differences Non-linear kinetics Monitor patients closely, particularly when starting pharmacotherapy or with changes in dosing Findling et al. Current Psychaitry 2007;6(6)

Anxiety Treatment in the Elderly Consequences of anxiety in the elderly: Increased disability Increased mortality risk Enhanced cognitive decline Consideration of disease-related or medication-related contribution to anxiety Presentation may include: declining concentration/memory, sleep disturbances, somatic complaints Lenze et al. Dialogues Clin Neurosci 2011;13(4):381-99

Anxiety Treatment in the Elderly Pharmacotherapy and behavioral based treatment considered effective More robust treatment effects noted with pharmacotherapy Consider cognitive functioning if pursuing CBT based therapies Novel treatment approaches: Mindful meditation Guided self-help Lenze et al. Dialogues Clin Neurosci 2011;13(4):381-99 Pinquart et al. Am J Geriatr Psychiatry 2007;15(8):639-51

Medication Use in the Elderly Antidepressants as mainstay of pharmacologic treatment SSRIs and SNRIs Avoid TCAs and MAOIs as able given tolerability and side effect profiles Avoid benzodiazepines “Reverse index” in elderly Associated with falls, disability, cognitive adverse effects Potential paradoxical effects Lenze et al. Dialogues Clin Neurosci 2011;13(4):381-99

Medication Use in the Elderly Risk/benefit of first-line antidepressant therapy Gait impairment Increased fall risk Platelet dysfunction and increased bleeding risk SIADH and hyponatremia Increased fracture risk Serotonin syndrome Start low and go slow Lenze et al. Dialogues Clin Neurosci 2011;13(4):381-99

Self-Assessment Question Antidepressant medications carry a black box warning for an increased risk of which adverse event in children and adolescents? Hyperkalemia Intracranial hemorrhage Suicidality Falls

Review & Considerations

Review & Considerations Anxiety disorders span through life’s stages and can cause significant distress Treatment of each patient must be individualized and may require psychotherapy and/or pharmacologic treatment modalities Antidepressants considered first-line pharmacologic management, but age- specific factors should be considered in use

Management of Anxiety Throughout Life’s Stages Gabriela Dimitrievski, PharmD, BCPS, BCPP Clinical Pharmacy Specialist – Psychiatry Eskenazi Health Gabriela.Dimitrievski@eskenazihealth.edu April 20, 2016 This speaker has no actual or potential conflicts of interest to disclose in relation to this presentation