Objectives. Diagnostic Criteria DSM 5. Before we begin I should tell you that. General Diagnostics for Anxiety Disorders 08/02/2014

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1 Before we begin I should tell you that ANTIDEPRESSANT USE IN ANXIETY, DEPRESSION AND BIPOLAR: HELPFUL OR HARMFUL? Rania Kattura, PharmD, MS, BCPP Clinical Assistant Professor University of Texas at Austin College of Pharmacy 08/02/2014 Antidepressant use in Anxiety, Depression and Bipolar Helpful or Harmful? is accredited by ACPE for pharmacists, ACPE L01 P for 1.5 contact hours Rania Kattura has not disclosed any financial or conflicts of interest in relation to this program Objectives Review diagnostic criteria for Anxiety Disorders, Depression and Bipolar Disorder to differentiate between depression and bipolar disorder in terms of clinical presentation and pharmacotherapy management Discuss the role of antidepressants in management of anxiety disorders, depression and bipolar disorder Determine risks and benefits associated with antidepressant use in patients with bipolar disorder Evaluate dosing and incorporate important counseling tips when dispensing antidepressants to patients with mood disorders Diagnostic Criteria DSM 5 Anxiety Disorders Major Depressive Disorder Bipolar Disorder Texas Pharmacy Association 2014 Conference & Expo Anxiety Disorders Separation Anxiety Disorder Selective Mutism Specific Phobia Social Anxiety Disorder Panic Disorder Agoraphobia Generalized Anxiety Disorder Substance/medication induced anxiety disorder PTSD OCD General Diagnostics for Anxiety Disorders Characteristics Excess fear Excess anxiety Avoidance Cognitive ideations Duration At least 6 months Clinically significant distress and impairment 1

2 Major Depressive Disorder (MDD) 5 of the following symptoms present for the SAME 2 week period and present a change in function Depressed mood Decreased interest Significant weight loss or gain Insomnia or hypersomnia Psychomotor retardation or agitation Fatigue or loss of energy Feeling worthless or guilty Decreased concentration Recurrent thoughts of death Major Depressive Disorder (MDD) Symptoms cause clinically significant distress or impairment in social, occupational or other areas of functioning Episode not related to substance use or medical condition The occurrence of the major depressive episode not better explained by schizophrenia spectrum or other psychotic disorders There has never been a manic or hypomanic episode Bipolar Disorder Previously known as Manic Depressive disorder Characterized by distinct mood episodes Mania Hypomania Depression 2 distinct types of bipolar disorder Bipolar I Disorder Manic Episode Distinct period of abnormally and persistently elevated, expansive, or irritable mood and increased goal directed activity or energy lasting 1 week and present most of the day, nearly every day During the defined period 3 symptoms of the following: Inflated self esteem Decreased need for sleep More talkative than usual or pressured speech Flight of ideas or racing thoughts Distractibility Increased goal directed activity High risk behaviors Impairment in function or need for hospitalization Not due to a substance or medical condition Major Depressive episode Same as MDD criteria Bipolar II Disorder Hypomanic Episode Similar to mania except: Time frame is 4 consecutive days Unequivocal change in functioning observed by others No marked impairment in function or need for hospitalization Major Depressive episode Same as MDD Bipolar Disorder Specifiers With Anxious distress Mixed features Rapid cycling Melancholic features Atypical features Mood congruent psychotic features Mood incongruent psychotic features Catatonia Peripartum onset Seasonal pattern 2

3 A picture worth a million words Manic Hypomanic Bipolar I Euthymia (Normal Mood) Bipolar II Mixed Depression OVERVIEW OF PHARMACOTHERAPY FOR ANXIETY DISORDERS, MDD, AND BIPOLAR DISORDER Treatment: MDD and Anxiety Disorders Disease State First Line Second Line Third Line Anxiety Disorders Antidepressant +/ Benzodiazepine Antidepressant in a different class +/ benzodiazepine MDD Antidepressant Antidepressant in same class or different class Combination treatment Combination treatment (2 antidepressants, Antidepressant + Li, Antidepressant + AAP, Antidepressant + thyroid hormone) Treatment: Bipolar Disorder Disease State First Line Second Line Third Line Bipolar I Disorder (Mania) Bipolar I Disorder (Depression) Initiate Li, VPA, or AAP or a 2 drug combination i.e. Li or VPA + AAP Li, LMG, QTP Li or VPA + SSRI; OLZ + SSRI; Li + VPA; Li or VPA + BUP Li or VPA add or switch to AAP AAP add or switch to Li or VPA 2 drug combination replace one or both agents with 1 st line agents VPA or LUR QTP + SSRI Li or VPA + LMG Li or VPA + LUR Adjunct modafinil Bipolar II Disorder QTP; Li, LMG Li, VPA, LMG, Li or VPA + antidepressant; Li + VPA; AAP + Antidepressant Replace one or both agents with other first line agent Consider switching to 2 nd or 3 rd line agent or ECT CBZ, OLZ, ECT Li + CBZ, Li or VPA + VXL QTP + LMG Li + MAOI Li or VPA or AAP + TCA Antidepressant ECT LMG + QTP Li = Lithium; VPA= valproic acid; AAP= Atypical AntiPsychotic; ECT = Electroconvulsive Therapy; LMG = Lamotrigine; QTP = quetiapine; LUR = lurasidone; SSRI = Selective Serotonin Reuptake Inhibitor; CBZ = carbamazepine; OLZ = olanzapine APA 2010 A Missed Diagnosis BIPOLAR DEPRESSION A clinical problem? Symptom overlap Co morbid substance use Potential lack of insight Stigma Clinical presentation shows more Hypersomnia Mood lability Weight gain Psychotic symptoms Lloyd LC et al. Ther Adv Psychopharmacol 2011;1(5):

4 Patterns of Psychotropic Drug use for Patients with a Bipolar Diagnosis 14.80% 24.60% 10.70% 49.80% Antidpressants Mood Stabilizers Sedative Anxiolytics Antipsychotics Antidepressants and the Bipolar Patient Who receives them? Bipolar II > Bipolar I Previous exposure to antidepressant regardless of severity Factors that don t impact antidepressant use Gender Education Socioeconomic status Psychiatr serv 2007;58(1):85 91 Lorenzo et al 2012 Pharmacologic Mismanagment of Bipolar Disorder Antidepressant monotherapy Evidence is limited Risk for affective switch TCA> Venlafaxine> Bupropion = SSRI Antidepressant Augmentation Antidepressant + mood stabilizer not superior to mood stabilizer alone Risk of recurrence reduced by 27% with antidepressant BUT risk for new manic episode increased by 72% Optimizing Treatment of Bipolar Depression: Why is it Important? Morbidity Risk for Functional impairment Relapse Amit BH, Weizman A. Depress Res Treat 2012; doi: 10115/2012/ Factors Causing Clinicians to Maintain Antidepressants in Acutely Manic Bipolar Episode Depression > mixed > rapid cycling Score on depression scale used Low education level Low YMRS score STUDIES EVALUATING ANTIDEPRESSANT USE IN BIPOLAR DISORDER DEPRESSED 4

5 EMBOLDEN II Evaluate efficacy of quetiapine vs. paroxetine in bipolar depression 4 groups receiving treatment x 8 weeks Quetiapine 300mg/day Quetiapine 600mg/day Paroxetine 20mg/day Placebo Quetiapine but not paroxetine more effective than placebo for treating acute depressive episode in bipolar disorder Treatment emergent hypomania and mania > for placebo and paroxetine group vs. quetiapine McElroy et al. J Clin Psychiatry 2010:;71(2) Antidepressants in Bipolar Depression Bipolar I 8 week trial comparing fluoxetine mg/day vs. olanzapine vs. OFC Depressive symptoms improved, no treatment emergent mania Bipolar II 14 week open label trial, fluoxetine mg/day 4.1% treatment emergent hypomania; 0.7% treatment emergent mania Fluoxetine safe and effect in short term treatment of bipolar II depression OFC = Olanzapine fluoxetine Combination J Affect Disord 2006; 92: ; Antidepressants in Bipolar II Depression Escitalopram Escitalopram 10 mg vs. placebo Significant improvement in depression and functional status No evidence of affective switch Venlafaxine Open label, parallel group trial of venlafaxine vs. Lithium Venlafaxine showed greater reduction in depression and greater rate of remission vs. lithium Treatment emergent mania similar in both groups J Clin Psychopharmacol 2010;30: ; J Affect Disord 2009; 112(1 3): Antidepressants as Adjunct in Bipolar Disorder Depression Systematic Treatment Enhancement Program for Bipolar Disorder (STEP BD) RDBPCT of patients with bipolar depression receiving mood stabilizer + antidepressant or placebo x 26 weeks 23.5% of mood stabilizer + antidepressant group vs. 27.5% of mood stabilizer + placebo showed durable recovery (P = 0.40) Rate of affective switch similar in both groups Adding antidepressant to mood stabilizer did not provide increased efficacy or risk for affective switch N Engl J Med 2007; 356(17): Antidepressants as Adjunct in Bipolar Disorder Depression Literature has mixed results 2004 meta analysis concludes: SSRI effective in acute bipolar depression Rate of switch to mania is low (3.2%) More likely to achieve response with antidepressant use NNT 4.2 More likely to achieve remission with antidepressant use NNT meta analysis showed: No difference between antidepressant use and placebo in terms to response, remission or switch to mania NNT = Number Needed to Treat Treatment Emergent Affective Switch Risk Factors Age of onset Number of affective episodes Prior antidepressant switch Response rate to antidepressants Bipolar type Protective Factors Psychotic symptoms Valenti M et al J Clin Psychiatry 2012; Am J Psychiatry 2013; 170(11) 5

6 Which Antidepressants are Associated with Greatest Mood Switch? Venlafaxine, bupropion or sertraline added to maintenance Lithium treatment No difference in efficacy shown Manic switch varied among agents: Bupropion 4% Sertraline 7% Venlafaxine 15% Paroxetine or amitriptyline added to Lithium 1 patient in paroxetine group experienced hypomania No difference in efficacy Side effects: amitriptyline > paroxetine Switch from Depression to Mania Presence of antidepressant did not increase Risk of switch to mania Time from onset of depression to next manic episode Duration of manic episode > depressive episodes > switches to mania Switch regardless of use of antidepressant associated with more chronic illness J Affect Disord. 2010; 126: ; Br J Psychiatry. 2006;189: Bipolar disorder 2007; 9: ISBD Recommendations for Antidepressant Use in Bipolar Disorder Domain Recommendation May be used when h/o positive response to antidepressant present Acute treatment AVOID adjunctive antidepressant when 2 concomitant core manic symptoms in presence of psychomotor agitation or rapid cycling Maintenance Treatment Consider if patient relapses into depressive episode after antidepressant stopped AVOID in bipolar I Disorder Monotherapy AVOID in Bipolar I or II Disorder depressed type with 2 concomitant core manic symptoms ISBD = International Society of Bipolar Disorders ISBD Recommendation for Antidepressant use in Bipolar Disorder Domain Switch to mania, hypomania, mixed states or rapid cycling Use in Mixed States Drug Class Recommendation Closely monitor patient and discontinue if mania, hypomania develop or psychomotor agitation increases AVOID in patients with high mood instability or h/o rapid cycling Discourage use if h/o mania, hypomania or mixed state with previous exposure to antidepressant Avoid during manic or depressive episodes with mixed features and in patients with predominantly mixed states Discontinue if patient is currently experiencing a mixed episode Adjunctive treatment with SNRIs and TCAs should only be considered after other antidepressants are tried; closely monitor patient due to increase risk of mood switch or destabilization Am J Psychiatry 2013; 170(11): Prevalence of Anxiety Disorders Lifetime Prevalence(%) Anxiety Diagnoses Bipolar Disorder Patients General population Treating Anxiety Disorders in Bipolar Disorder Patients Benzodiazepines Not inferior to antidepressants in acute symptoms Lower level of evidence No studies evaluating use in comorbid bipolar disorder Lithium No studies evaluating use in comorbid anxiety and bipolar disorder Recreated using data published in Vázquez et al 2014 Study 6

7 ANTIDEPRESSANT DOSING BASED ON DIAGNOSIS Antidepressant Dosing: Depression Agent Starting Dose (mg/day) Usual dose (mg/day) Selective Serotonin Reuptake Inhibitors (SSRIs) Citalopram Escitalopram Fluoxetine Paroxetine IR (Paroxetine ER) 20 (12.5) (25 75) Sertraline Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine (all formulations) Desvenlafaxine Duloxetine Miscellaneous Bupropion IR and XR Bupropion SR Mirtazapine Nefazodone Trazodone Texas Pharmacy Association 2014 Conference 150 & Expo Adapted from APA 2010 Antidepressant Dosing: Depression Agent Starting Dose (mg) Dosing Range (mg/day) Tricyclic Antidepressants Amitriptyline Doxepin Imipramine Desipramine Nortriptyline Monoamine Oxidase Inhibitors (MAOIs) Phenelzine Tranylcypromine Isocarboxazid Selegiline transdermal Antidepressant Dosing: Anxiety Disorders Antidepressant Dosing Range (mg/day) Anxiety D/O CIT ESCIT FLU FLUV PAR SERT VLX DUL GAD SAD Panic OCD PTSD Bolded doses FDA approved dosing; Note: chart only includes SSRI/SNRI agents studied and/or FDA approved GAD= Generalized Anxiety Disorder; SAD= Social Anxiety Disorder; OCD = Obsessive Compulsive Disorder; PTSD =Post Traumatic Stress Disorder; CIT = Citalopram; ESCIT= Escitalopram; FLU = Fluoxetine; FLUV = Fluvoxamine; PAR = Paroxetine; SERT = Sertraline; VLX = Venlafaxine XR; DUL = Duloxetine Adapted from APA 2010 Bipolar Disorder No individual antidepressant has an FDA approved indication for management of bipolar disorder Avoid, but if needed, begin at lowest dose possible and titrate slowly Olanzapine fluoxetine Combination (OFC) Initiation dose: 6/25mg PO QHS Usual range: 6/25 to 12/50mg PO QHS WHAT TO TELL YOUR PATIENT ABOUT THEIR ANTIDEPRESSANT(S) 7

8 Review the Basics Generic and Brand for Antidepressants Medication name Dose, indication and administration What to do if a dose is missed Duration of therapy Minor and major side effects Medications and foods to avoid Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine (Prozac ) Paroxetine (Paxil ) Sertraline (Zoloft ) Citalopram (Celexa ) Escitalopram (Lexapro ) Fluvoxamine (Luvox ) Vortioxetine (Brintellix ) Vilazodone (Viibryd ) Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine (Effexor ) Duloxetine (Cymbalta ) Desvenlafaxine (Pristiq ) Levomilnacipran (Fetzima ) Milnacipran (Savella ) Generic and Brand for Antidepressants Minor Side Effects Tricyclic Antidepressants (TCAs) Amitriptyline (Elavil ) Clomipramine (Anafranil ) Doxepin (Sinequan ) Imipramine (Tofranil ) Desipramine (Norpramin) Nortriptyline (Pamelor ) MonoAmine Oxidase Inhibitors (MAOIs) Isocarboxazid (Marplan ) Phenelzine (Nardil ) Tranylcypromine (Parnate ) Selegiline (Emsam ) Misc. Antidepressants Trazodone (Desyrel, Oleptro ) Nefazodone (Serzone ) Mirtazapine (Remeron ) Bupropion (Wellbutrin, Aplenzin, Forfivo ) Occasional stomach upset, diarrhea appetite Mild headache Mild insomnia anxiety Constipation, dry mouth, dry skin, weight gain Mirtazapine TCAs Tired Major Side Effects Emergence of suicidal thoughts/behaviors Sexual side effects Urinary retention Seizures Cardiac conduction Prolonged vomiting or diarrhea (>2 days) Severe body tremors, restlessness, akathesia Severe blood pressure Elevated mood Medications to Avoid Antidepressants + other agents that serotonin (eg: tramadol, opioid analgesics, cyclobenzaprine, St John s Wort) Serotonin Syndrome Confusion, agitation, myoclonus, ataxia, hypertension, hyperthermia, tachycardia, agitation SSRI and/or SNRIs + NSAIDs, aspirin, warfarin risk for GI bleed 8

9 Medications to Avoid Wellbutrin + Zyban same active ingredient (bupropion) Sympathomimetic amines (e.g.: amphetamines, decongestant cold products, pseudoephedrine) + MAOIs hypertensive crisis Severe in BP, HR Severe headache, dilated pupils, photophobia N/V, sweating Medications to Avoid: Dietary Supplements 5 HTP, SAMe, yohimbine, St John s Wort risk for serotonin syndrome esp. when combined with other serotonergic agents Cranberry, SAMe TCA levels Kava kava, ginkgo, yohimbine potentiate MAOI effects Anise oil, green tea, guarana, ephedra/ma Huang hypertensive crisis with MAOIs Adapted from Mican L Foods to Avoid with MAOIs Food Type Avoid Allowed Cheese Aged Combination foods containing cheese Processed and cottage cheese, ricotta, cream cheese Fruits/Vegetables Meat Broad bean pod, fava beans, banana peel Fermented, dried, smoked, spoiled, improperly stored Banana pulp All other fruits/vegetables All fresh and/or processed Beverage Unpasteurized beer Alcohol: 2 bottled or canned beers, or 2x 4 oz. wine/day Miscellaneous Yeast extract, fermented soy products, sauerkraut Brewer yeast or baker yeast, soy milk PUTTING IT ALL TOGETHER Stahl Let s visit with ST 49 yo male with a long h/o of ETOH use, most recently sober for 120 days. Reports feeling depressed over the past 2 weeks with increased ETOH intake, reduced energy and sleeping only after consuming, a fifth to a handle of alcohol a day. Most recently having thoughts of suicide with a plan to kill self by running into traffic. He presents for evaluation at the psychiatric facility and it is determined that he needs to be hospitalized and managed for his mood and Alcohol use. What would you do? ST in the hospital An antidepressant (citalopram) is started due to continued low mood Several days later he is noted to be pacing the hallway, increasingly agitated, and sleeping less every night Required PO lorazepam and olanzapine for reported agitation What went wrong? What would you do? 9

10 BM is stressed BM is a 30 year old male who presents to the psychiatric clinic reporting, my heart is racing, my palms are sweaty, my Dr said I need a psychiatrist! Upon questioning you find out that when BM is in line at the grocery store, the mall, or anywhere else, he starts to shake, feels he is losing control, feels out of touch with reality, his heart pounds and he sweats. He avoids lines at all costs, times his errands during off hours, and always fears his symptoms will return. This has impacted his ability to have lunch at his work s cafeteria. He now makes his own lunches and eats alone. He denies any substance use and any medical illness What is going on? How would you treat? AC cries for help! AC is a 21 yo female who is brought in by EMS after she was found on her bathroom floor with an empty bottle of ibuprofen, acetaminophen and wine next to her. The quantity she ingested is unknown. She sent a text to her boyfriend stating, there is nothing worth living for, I took pills bye bye! Upon medical stabilization, you begin to question AC and find out that she has been feeling sad, has lost interest in horseback riding over 3 months ago, her sleep has gotten worse over the past few weeks, and she has lost 15 lbs, without even trying! Thoughts of death have been persistent for weeks. She denied homicidal thoughts or any changes in concentration but feels guilty for the way she s viewing life and treating her boyfriend. She barely has energy to get out of bed in the mornings. What is going on? How would you treat AC? Conclusion Questions Antidepressants are first line treatment in patients who are diagnosed with MDD and/or an anxiety disorder Antidepressants are not indicated as monotherapy in patients with bipolar depression, but may be used as adjunctive agents Caution should be exercised when using antidepressants in patients with co morbid anxiety disorders and bipolar disorder 10