ANXIOUS DEPRESSION Ned H. Kalin, MD University of Wisconsin Alan F. Schatzberg, MD Stanford University
NED H. KALIN, MD Disclosures!! Research/Grants: None!! Speakers Bureau: None!! Consultant: None!! Stockholder: Corcept Therapeutics; CeNeRx BioPharma!! Other Financial Interest: Owner of Promoter Neurosciences, LLC; holds patents for the following: promoter sequences for corticotropin-releasing factor CRF2alpha and method of identifying agents that alter the activity of the promoter sequences (U.S. Patent issued on 07-04-06; patent #7071323, U.S. Patent issued on 05-12-09; patent #7,531,356); promoter sequences for urocortin II and the use thereof (U.S. Patent issued on 08-08-06; patent #7087385); and promoter sequences for corticotropinreleasing factor binding protein and use thereof (U.S. Patent issued on 10-17-06; patent #7122650)!! Advisory Board: AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; CeNeRx BioPharma; CME Outfitters, LLC; Corcept Therapeutics; Eli Lilly and Company; Elsevier; Letters & Sciences; Medivation, Inc.; Otsuka America Pharmaceuticals; Sanofi-Aventis; Wyeth Pharmaceuticals
ALAN F. SCHATZBERG, MD Disclosures!! Research/Grants: None!! Speakers Bureau: None!! Consultant: BrainCells Inc.; CeNeRx BioPharma; Corcept Therapeutics; CNS Response, Inc.; Eli Lilly and Company; GlaxoSmithKline; Neuronetics Inc.; PharmaNeuroBoost; Sanofiaventis; Takeda Pharmaceuticals North America, Inc.!! Stockholder: Amnestix, Inc.; BrainCells Inc.; CeNeRx BioPharma; Corcept Therapeutics; Forest Laboratories, Inc.; Merck & Co., Inc.; Neurocrine Biosciences, Inc.; Pfizer Inc.; PharmaNeuroBoost; Somaxon; Synosis!! Other Financial Interest: Named inventor on pharmacogenetic use patents on prediction of antidepressant response and use of glucocorticoid antagonists!! Advisory Board: None
LEARNING OBJECTIVE Employ strategies for improved recognition and management of anxious depression
ANXIOUS DEPRESSION (AD)!! Symptoms of anxiety are common among individuals with Major Depressive Disorder!! Presence of anxiety with depression is associated with poorer treatment outcomes and greater risk of suicide!! Underlying commonalities between MDD and Generalized Anxiety Disorder suggest they may reflect the same phenomenon 1,2,3,4 and are not distinct entities!! Shared genetic factors!! Shared temperament (i.e., negative affectivity)!! Treatment response (i.e., SSRIs) References available in supplemental bibliography.
ANXIOUS DEPRESSION (AD)!!Mixed Anxiety and Depression is present in DSM-IV s Appendix and in ICD-10 but are defined somewhat differently!!dsm-v Mood Disorders Work Group is proposing recognition of AD as a clinically significant syndrome!!may help physicians (esp. PCPs) better identify and treat these patients!!may increase compatibility between U.S. and international definitions of AD American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Washington, DC: American Psychiatric Association 2000.
PROPOSED DSM-V CRITERIA FOR AD!! Presence of 3 or 4 symptoms of major depression (including depressed mood and/or anhedonia)!! Must be accompanied by anxious distress!!defined as having two or more of the following symptoms: irrational worry, preoccupation with unpleasant worries, having trouble relaxing, motor tension, fear that something awful may happen!! Present for at least two weeks!! No other depressive or anxiety disorder is present Proposed criteria available at http://www.dsm5.org/proposedrevisions/pages/ MoodDisorders.aspx.
PROPOSED DSM-V CRITERIA FOR AD (CONT.)!!Will include a dimension of severity to help answer questions about course, stability, and prognosis!!will be examined in DSM-V field trials in large, academic-medical institutions!!later field trials that include primary care settings may offer additional insight into the reliability of the criteria Proposed criteria available at http://www.dsm5.org/proposedrevisions/pages/ MoodDisorders.aspx.
ANXIOUS DEPRESSION Categorical vs. Dimensional Definitions Major Depressive Disorder Anxious Depression: MDD with anxiety comorbidity Anxiety Disorders Depression Anxious Depression: HAM-D-17 Anxiety/ Somatization Score > 6 Anxiety HAM-D = Hamilton Depression Rating Scale, MDD = major depressive disorder
ANXIOUS DEPRESSION Clinical and Demographic Characteristics!!Greater severity of illness 1!!Younger mean age 2!!Earlier age of onset 2!!20.6 ± 10.4 years in MDD with comorbid anxiety disorders!!28.4 ± 13.0 years in MDD alone 1. Joffe RT, et al. Am J Psychiatry 1993;150:1257-1258. 2. Fava M, et al. Compr Psychiatry 2000;41:97-102.
ANXIOUS DEPRESSION Course of Illness!!Chronicity is common 1!!Greater functional impairment 2!!Increased risk of suicide 3!!Greater chance of treatment discontinuation 4 1. Van Valkenburg C, et al. J Clin Psychiatry 1984;45:367-369. 2. Joffe RT, et al. Am J Psychiatry 1993;150:1257-1258. 3. Clayton P, et al. Am J Psychiatry 1991;148:1512-1517. 4. Flint AJ, Rifat SL. Am J Geriatr Psychiatry 1997;5:107-115.
HOW DOES ANXIOUS DEPRESSION RESPOND TO ANTIDEPRESSANT TREATMENT?!!Possible diminished response to antidepressant treatment!!in adults 1!!In elderly 2!!When anxiety persists despite response, greater likelihood of relapse 3 1. Fava M, et al. Biol Psychiatry 1997;42:568-576. 2. Flint AJ, Rifat SL. Am J Geriatr Psychiatry 1997;5:107-115. 3. Flint AJ, Rifat SL. Psychiatry Res 1997;66:23-31.
REMISSION RATES FOLLOWING CITALOPRAM TREATMENT IN LEVEL 1 OF STAR*D 40% 35% Remission Rate 30% 25% 20% 15% 10% 5% * 0% Anxious Depression N = 2,876 * p <.05 Fava M, et al. Am J Psychiatry 2008;165:342-351. Non-Anxious Depression
REMISSION RATES (HAM-D-17 < 8) IN LEVEL 2 OF STAR*D Anxious vs. Non-Anxious MDD 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% * p <.05 Anxious MDD * * Non-Anxious MDD Fava M, et al. Am J Psychiatry 2008;165:342-351. * * BUP SER VEN BUP AUGM BUSP AUGM n = 239 n = 238 n = 250 n = 279 n = 286 *
ANXIOUS DEPRESSION Treatment Approaches!!Monotherapy with antidepressants!!sedating vs. nonsedating!!augmentation with:!!benzodiazepines 1!!Eszopiclone 2!!Buspirone 3!!Gabapentin or other anticonvulsants 1!!Antipsychotics 5 1. Davidson JR. J Clin Psychiatry 2010;71[suppl E1]:e04.; 2. Fava M, et al. Poster 146 at The American College of Neuropsychopharmacology 2008, Scottsdale, AZ.; 3. Fava M, et al. Am J Psychiatry 2008;165:342-351.; 4. Nemeroff CB. J Clin Psychiatry 2005;66:13-21.
USE OF ANXIOLYTICS AND HYPNOTICS DURING SSRI TREATMENT Drug No. of Patients Hypnotic % Hypnotic/ Anxiolytic % Paroxetine 5,704 18 42 Sertraline 13,558 16 36 Fluoxetine 12,607 14 33 From the Texas Medicaid Database Rascati K. Clin Ther 1995;17:786-790.
ANXIOUS DEPRESSION Management Issues!!Antidepressant monotherapy works well in efficacy trials!!concerns about agitation/activation often lead to the use of:!!relatively more sedating antidepressants!!lower starting doses!!polypharmacy (e.g., combination of an antidepressant and a benzodiazepine)!!higher antidepressant doses may be required in some patients
ANXIOUS DEPRESSION Management Issues (Cont.)!!Anxiety sensitivity may predict poorer treatment adherence 1!!Side effect management very important!!concomitant anti-anxiety drugs can be started with the antidepressant or added later!!what is the role of psychotherapy? 1. Tedlow JR, et al. Biol Psychiatry 1996;40:668-670.
SUMMARY!! A common presentation of the many subtypes of depression!! May explain the inability to achieve the expected rates of remission and recovery in the majority of patients with depression!! Has greater morbidity and mortality compared to depression without anxiety if not identified and adequately treated!! Antidepressants are typically equally effective in anxious depression!! Overall efficacy of currently available therapies is modest!! Anxiolytics may be indicated as adjuncts in nonresponders