Objectives. DSM-V Changes: Elimination of Multiaxial Diagnostic System

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1 Conflicts of Interest I have no conflicts to disclose Updates to the Updates in Pharmacotherapy Webinar Psychiatry Updates for Pharmacotherapy Specialists Jacintha S. Cauffield, Pharm.D., BCPS Associate Professor of Pharmacy Practice, The Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, Florida February 25, 2014 Objectives At the end of this lecture, the participant will be able to: Discuss updates to the Diagnostic and Statistical Manual, 5th edition and how they vary from the previous edition (DSM-IV- TR). Distinguish the differences in newly approved medications from previous treatment modalities in the treatment of depression. Construct an effective treatment plan for bipolar disorder using new medication indications. Distinguish between patients with bipolar disorder type I and bipolar disorder type II. Assess the appropriateness of the use of an antidepressant to treat an individual patient with bipolar disorder in light of recent findings. Diagnostic and Statistical Manual, 5 th Edition (DSM-V) Diagnostic criteria for every mental illness recognized in the United States Used in clinical, insurance and research settings Elimination of Multiaxial Diagnostic System Former Axes: I: Psychiatric Diagnoses intellectual disability II: Personality DO and mental retardation III: Medical diagnoses IV: Psychosocial Factors Separate V: Global Assessment of Function (GAF) notations Autism Spectrum Disorder Consolidates DSM-IV-TR diagnoses into one disorder with different levels of severity Autism Asperger s syndrome Childhood disintegrative disorders Pervasive developmental disorder NOS Common characteristics Deficits in social interaction and social communication Restricted repetitive behaviors, interests and activities (RRBs) 1

2 Schizophrenia Elimination of subtypes (paranoid, catatonic, undifferentiated and residual) Substituted more dimension to severity Diagnostic criteria changed: must have one of three positive symptoms for diagnosis: Delusions Hallucinations Disorganized speech Bipolar Disorder Must have an increase in activity or energy in addition to elevated mood Type I: Criteria for mania must be met, but major depressive episode not necessary Type II: must meet criteria for hypomania AND major depression Mixed episode removed Both (hypo)mania and depression criteria had to be met Replaced with with mixed features -depressive symptoms present With Anxious Distress specifier Depression Premenstrual Dysphoric Disorder is recognized as a distinctive diagnosis Depression with mixed features 3 manic symptoms The bereavement exclusion is removed With anxious distress specifier Impacts prognosis and treatment decisions Anxiety Disorders Agoraphobia separated from panic disorder Agoraphobia-Intense fear in 2 or more settings: Using public transportation Being in open spaces Being in enclosed places Standing in line or being in a crowd Being outside of the home alone Removed from Anxiety Disorders Post-Traumatic Stress Disorder (PTSD) and Acute Stress Disorder Moved to Trauma- and Stressor-Related Disorders Obsessive-Compulsive Disorders Part of a new Chapter: Obsessive-Compulsive and Related Disorders OCD Insight specifiers Fair-good: obsessions and compulsions are likely not true Poor: obsessions and compulsions are likely true Absent insight/delusional: absolutely convinced that their obsessions and compulsions are true tic specifier 2

3 Sleep-Wake Disorders Sleep disorders related to either another mental disorder or due to a general medical condition have been removed Primary insomnia is now insomnia Narcolepsy separated from other forms of hypersomnia Hypocretin deficiency New Antidepressants Levomilnacipran (Fetzima ) SNRI Norepinephrine > serotonin Enantiomer of milnacipran Milnacipran Fibromylagia Depression (other countries) Levomilnacipran is not indicated for fibromyalgia Levomilnacipran: Efficacy Short-Term Trials (8 weeks) 5 total: 4 were positive Patients had depression 4-8 weeks Entry scores: HAM-D: 22 MADRS: (goal= <10 for remission) Responders: 36-49% (vs % on placebo) NNT 10 (95% CI 8-16) Remitters: 17-32% (vs % on placebo) NNT 16 (11-35) Int J Clin Pract 2013;67: Levomilnacipran: Efficacy Relapse Prevention Depression > 4 weeks MADRS > 22 (mean 30.7) 75% recurrent depression Open label: mg/day; MADRS < 12 Mean MADRS 5.9 for placebo, 6.0 for treatment) Time to relapse slower on levomilnacipran than placebo Not statistically significant Post-hoc: increased baseline severity associated with less relapse Levomilnacipran: Adverse Effects Treatment emergent AEs: 77% vs. 61% placebo Nausea 17% (NNH 10; 95% CI 8-12; transient) Headache 17% (NNH 25, 95% CI 15-81; transient) Constipation 9% (NNH 17, 95% CI 13-24) Hyperhidrosis 9% (NNH 15, 95% CI 12-19) Dose dependent: Erectile dysfunction 6-10% (NNH 20, 95% CI 14-36) Urinary hesitancy 6-8% (NNH 17-25) Weight neutral Int J Clin Pract 2013;67:

4 Levomilnacipran: Adverse Effects Cardiovascular SBP (mmhg) DBP (mm Hg) HR (bpm) Levomilnacipran Placebo -0.4 no change -0.3 Stage 1 or 2 HTN: 10.4% (NNH 31, 95% CI18-94) Orthostatic hypotension: 11.6% (NNH 59) Minimal QTc changes Suicidal ideation: ~24% vs. ~22% in placebo Suicidal behavior <1% Levomilnacipran Dosing: mg daily Initiate at 20 mg daily x 2 days, then 40 mg daily Increase in increments of 40 mg every 2 days. Strong CYP3A4 inhibitors: Maximum dose 80 mg daily Adjust for renal function ml/min: max dose 80 mg daily ml/min: max dose 40 mg daily Extended release Int J Clin Pract 2013;67: Vortioxetine (Brintellix ) Multimodal Serotonin reuptake inhibitor Activity profile: 5-HT1A receptor agonist 5-HT1B receptor partial agonist 5-HT1D, 5-HT3 and 5-HT7 receptor antagonist Indication: major depression Potentially: generalized anxiety disorder Vortioxetine: Placebo Controlled Trials Results mixed 10 mg daily: HAM-D 24 decreased 16.2 points (vs. 11.3, p <0.001), but other measures not statistically signifcant Several trials with 2.5 mg-10 mg daily did not separate from placebo Trials with 15 mg daily give mixed results Trials with 20 mg daily did show significant differences vs. placebo Vortioxetine: Placebo- Controlled Referenced Trials Vortioxetine Daily Dose Statistically Significant Improvement Duloxetine 60 mg daily Venlafaxine XR 225 mg daily Vortioxetine 2.5 mg and 5 mg Yes --- No (both doses) 5 mg (elderly) Yes --- Yes 15mg and 20 mg Yes --- Yes (both doses) 5 mg and 10 mg --- Yes Yes (both doses) 2.5 mg, 5 mg, 10 mg No --- No (all doses) Int J Neuropsychopharmacol 2012;15:589; Int J Clin Pract 2014;68:60; J Clin Psychiatry 2012;73:953; Int J Neuropsychopharmacol 2013;16:313; Curr Med Res Opin 2013;29:217; Int Clin Psychopharmacol 2012;27:215; Eur Neuropsychopharmacol 2012;22:482.. Vortioxetine: Adverse Effects NNH 36 (95% CI 24-70) for discontinuation >5% Incidence: Nausea (NNH 6, 95% CI 6-7) Constipation (NNH 64, 95% CI ) Vomiting (NNH 28, 95% CI 23-38) Sexual dysfunction: up to 33% (vs. 46% for duloxetine) Weight neutral No changes in vital signs Minimal effect on QTc interval Drugs 2013; Publishing online December 6,

5 Vortioxetine Dosing: 10 mg daily, increase to 20 mg daily 5 mg daily in sensitive patients (elderly) Can be discontinued abruptly Studies suggest efficacy better at mg daily Strong CYP2D6 inhibitor: Max dose 10 mg daily No dose adjustment needed for hepatic or renal function Role of New Antidepressants in Treatment Unique activity characteristics Levomilnacipran: norepinephrine > serotonin Vortioxetine: multimodal serotonin activity Useful in comorbid conditions? Likely held in reserve Not more effective than agents already on the market Comparator duloxetine went generic (as did excitalopram) Lurasidone: Bipolar Depression Lurasidone in Bipolar Depression Atypical antipsychotic Originally approved in 2010 for schizophrenia Approved June 2013 to treat depression in bipolar disorder type I Monotherapy Adjunct to lithium or valproate Dosing: mg/daily Give with food (> 350 kcal) Lurasidone: Monotherapy Lurasidone: Adjunct Lurasidone Lurasidone 80- Placebo mg/day 120 mg/day ITT Population (N) Responders, N (%) 86 (53.4%) 82 (50.6%) 49 (30.2%) NNT (95% CI) 5 (3-8) 5 (4-11) NA Responders vs. placebo Remitters N (%) 68 (42.2%) 64 (39.5%) 40 (24.7%) NNT (95% CI) Remission vs. placebo 6 (4-14) 7 (4-21) NA Lurasidone mg/day ITT Population (N) Placebo Responders, N (%) 102 (57%) 68 (42.2%) NNT (95% CI) Responders vs. placebo 7 (4-24) NA Remitters N (%) 90 (50.3%) 57 (35.4%) NNT (95% CI) Remission vs. placebo 7 (4-23) NA J Affect Disorder 2014;155: J Affect Disorder 2014;155:

6 Lurasidone: Bipolar Depression Lurasidone: Drug Interactions Adverse Effects Nausea (10-17%; NNH 11-39) Somnolence (7-14%; NNH ) Akathisia ( %; NNH 12-30) Extrapyramidal symptoms (5-15%; NNH 16-40) Metabolic effects minimal Metabolized by CYP3A4 Contraindicated with strong inhibitors or inducers Adjusted dose with moderate inhibitors (80 mg/day maximum) Renal impairment CrCL <50 ml/min: 80 mg/day maximum Hepatic Impairment: Moderate: 80 mg/day maximum Severe: 40 mg/day maximum J Affect Disorder 2014;155: Lurasidone: Role in Treating Bipolar Disorder Use in bipolar I depression based upon 2 trials Role in bipolar II unclear Trade-offs with quetiapine Comparable efficacy Possibly lower incidence of metabolic effects More EPS and akathisia No more effective than quetiapine Considered 2 nd line in CANMAT guidelines Bipolar Disorder Bipolar Disorder: Type I vs. Type II Mania Hypomania Diagnosis Bipolar Disorder Type I Bipolar Disorder Type II Duration >1 week > 4 days Severity The mood disturbance is sufficiently severe to cause marked impairment, require hospitalization; may also have psychotic features. The episode is not severe enough to significantly impair function or require hospitalization, but Change in function is uncharacteristic. The functional disturbance is noticed by others. Identification Hallmark of Type I BPD Can be missed in patients who present with depression. Patients are usually very functional during hypomanic phase. Bipolar Disorder Depression: Type I vs. Type II-Treatment Type I 1 st line Lamotrigine Lithium Quetiapine Olanzapine-fluoxetine Lithium or valproate + SSRI or bupropion 2nd line Lurasidone Valproate Various combinations Bipolar Disorders 2013: 15: Type II Lamotrigine (maintenance) Lithium (maintenance) Quetiapine Atypical antipsychotic + antidepressant Lithium or divalproex + antidepressant Valproate 6

7 Antidepressants in Bipolar Disorder: Switching Phenomenon Less common than once thought Do not use as monotherapy in type I Type I > Type II Risk dependent on Class? Highest Risk: TCAs SNRIs, particularly venlafaxine, carry higher risk Low risk: SSRIs and bupropion Mood stabilizers may not entirely mitigate effects ISBD Antidepressant Guidelines Data for antidepressant efficacy is weak Monitor closely for symptoms of switching Appropriate in individual patients With h/o positive response If a patient relapses off of an antidepressant Avoid Monotherapy in type 1 In mixed episodes With > 2 manic symptoms concomitant with psychomotor agitation or rapid cycling In patients with h/o switching on antidepressants Am J Psychiatry 2013;170(11): References American Psychiatric Association. Highlights of Changes from DSM-IV-TR to DSM-5. American Psychiatric Publishing. Available from: last accessed 2/20/2014. Brintellix [package insert]. Takeda Pharmaceuticals America, Inc., Deerfield, IL; CItrome L. Levomilnacipran for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 2013;67: Citrome L, Ketter TA, Cucchiaro J, and Loebel A. Clinical assessment of lurasidone benefit and risk in the treatment of bipolar I depression using number needed to treat, number needed to harm, and likelihood to be helped or harmed. J Affect Disorder 2014;155:20 7. Fetzima [package insert]. Forest Pharmaceuticals, Inc., St. Louis, MO;2013. Gibb A and Deeks ED. Vortioxetine: First Global Approval. Drugs Published online, 12/6/2013. Latuda [package insert]. Sunovion Pharmaceuticals Inc., Marlborough, MA;2013. Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H et al. The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders. Am J Psychiatry 2013;170(11):