Age / Sex: Presenting Problem:

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1 William E. Bunney, Jr., MD, and Ned H. Kalin, MD Chart Review: Anxious Depression PATIENT INFO 17 / Female Age / Sex: Presenting Problem: DA is 17 y/o women who presented with intermittent symptoms of depression that include: depressed mood, ruminative negative thinking, insomnia and appetite disturbance. She states that these symptoms occur approximately 3 4 days a week and are triggered by negative thinking when encountering social situations that are stressful. She reports a long standing history of feeling tense and worrying dating back to early childhood. More specifically, she states that in many social situations she gets anxious about what she is going to say which is accompanied by a funny feeling in her chest and facial flushing. This is associated with many thoughts about not being liked or rejected. Frequently, she leaves the social situation and goes home and takes a nap. She says that these symptoms and her behavior keep her from forming more intimate relationships. She frequently feels lonely and worries about going off to college. Background: DA states that she was extremely shy as a child and has had insomnia for years. She states that things worsened as an adolescent and last winter became quite depressed. She states that there were some social precipitants but is unwilling to discuss the details related to this. During that time she reports feeling down every day with some sense of not wanting to be alive. She also reports decreased energy and motivation, sleeping a lot during the day with difficulty at night and some anhedonia. She had difficulty concentrating while at school but her performance was not significantly affected. These symptoms lasted about 3 months and then got better on their own. However, since then she has had the intermittent depressive symptoms described above. Her parents were unaware of her depressive symptoms as she did not want to upset them. She denies any history of symptoms related to OCD, eating disorders, psychosis, or mania. Social History: She is a bright young woman who is performing well in high school. She is very athletic and into numerous sports. She states that she is frequently lonely and does not have intimate relationships. She hinted that there may be an issue related to sexual orientation. She notes that alcohol and marijuana help her anxiety but she denies overuse. She also has stopped caffeine intake because it makes her feel worse. continued on reverse

2 William E. Bunney, Jr., MD, and Ned H. Kalin, MD Chart Review: Anxious Depression PATIENT INFO, cont. Family History: She states that her mother a worrier and gets depressed at times. Her maternal grandfather has a history of depression and alcohol abuse and her paternal grandmother has a history of anxiety, phobias and depression. At times this has been so incapacitating that she would not come out of the house. Medical History: She healthy and takes no medications. Treatment Course: After her initial evaluation, she agreed to have her parents come to the next session. They expressed their concern and confirmed her symptoms. While she wanted to start a medication, her parents were wary of this. She started on 5 mg of citalopram and was informed of potential side effects. She also was referred for cognitivebehavioral therapy. She returned to the clinic 1 week later and said that during the first couple of days of the medication she noticed mild nausea and feeling a little dizzy. She said that these symptoms went away. The citalopram was increased to 10mg/day. She returned 1 week later with her parents and said that she was feeling markedly worse. She reported having a ma jor melt down which included crying, suicidal ideation and panic symptoms. While she has had some minor panic symptoms in the past, she said that she never felt this bad. She said that increased dose of the medicine made her feel shaky all the time, increased her ruminative negative thinking, and made her sleep worse. Best Practices List three best practices agreed to by the group in your chart review session: 1. Importance of including psychosocial interventions. 2. Consider low doses and increased sensitivity to antidepressants and work with family and patient. 3. Work collaboratively and openly with family when patient is accepting of it to understand dynamic.

4 Anxious Depression Chart Review Ned Kalin, MD University of Wisconsin School of Medicine William E. Bunney, Jr., MD University of California - Irvine

5 Ned Kalin, MD Disclosures! Research/Grants: None! Speakers Bureau: None! Consultant: None! Stockholder: Corcept Therapeutics, CeNeRx BioPharma! Other Financial Interest: Owner of Promoter Neurosciences, LLC; Ownership of Patents: 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 ; patent # , divisional patent applied for on 9/26/2005; patent application #11/234916; Promoter sequences for urocortin II and the use thereof: U.S. Patent issued on ; patent # ; Promoter sequences for corticotropin-releasing factor binding protein and use thereof: U.S. Patent issued on ; patent # Method for reducing CRF receptor mrna: Patent applied for on patent application # ! Advisory Board: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, CeNeRx BioPharma, Corcept Therapeutics, Cyberonics, Inc., Elsevier, Eli Lilly and Company, Forest Laboratories, Inc., General Electric Corp (GE Healthcare), GlaxoSmithKline, Jazz Pharmaceuticals, Letters & Sciences, Neuronetics Inc., Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., Sanofi-aventis, Takeda International, Wyeth Pharmaceuticals

6 William E. Bunney, Jr., MD Disclosures! Research/Grants: None! Speakers Bureau: None! Consultant: None! Stockholder: None! Other Financial Interest: None! Advisory Board: None

7 Learning Objective Recognize the clinical characteristics of anxious depression and develop a treatment strategy to improve outcomes

8 Patient Information! DA is a 17-year-old female with intermittent symptoms of depressed mood, ruminative negative thinking, insomnia, and appetite disturbance! Reports symptoms 3 4 days/week triggered by negative thinking when encountering stressful social situations! States that in many social situations, she gets anxious about what she is going to say, accompanied by a funny feeling in her chest and facial flushing Associated with many thoughts about not being liked or rejected! Frequently leaves social situation, goes home and naps! Symptoms keep her from forming more intimate relationships! Frequently lonely and worries about going to college

9 Past History! Extremely shy as a child and has had insomnia for years! Worsened as an adolescent and last winter she became quite depressed! Reports some social precipitants, but unwilling to discuss related details! During that time, reports feeling down every day with some sense of not wanting to be alive! Decreased energy and motivation Sleeping a lot during the day with insomnia at night and some anhedonia

10 Past History! Symptoms lasted about 3 months, got better on their own! However, since then has experienced intermittent depressive symptoms! Parents are unaware of depressive symptoms, she does not want to upset them! Denies history of symptoms related to OCD, eating disorders, psychosis, or mania

11 Social History! Bright young woman performing well in school! Very athletic and into numerous sports! States that she is frequently lonely and does not have intimate relationships! Hints that there may be an issue related to sexual orientation! Alcohol and marijuana help anxiety, but she denies overuse! Stopped caffeine intake because it makes her feel worse

12 Family History! Mother is a worrier and gets depressed at times! Maternal grandfather has history of depression, alcohol abuse! Paternal grandmother has history of anxiety, phobias, and depression at times so incapacitating that she would not come out of the house

13 Medical History! Healthy! No medications

14 Treatment Course! After initial evaluation, agreed to include parents in next session they expressed concern and confirmed her symptoms! DA interested in medications, parents wary! Started on 5mg of citalopram and informed of potential side effects! Referred for cognitive-behavioral therapy! Returned 1 week later reporting relief of symptoms, but mild nausea and dizziness

15 Treatment Course! Increased citalopram to 10 mg/day! Returns 1 week later with markedly worsening symptoms! Major meltdown including crying, suicidal ideation, panic Had minor panic symptoms in the past, but she never felt this bad! Increased dose made her feel shaky all the time, increased her ruminative negative thinking, and made her sleep worse

16 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

17 Anxious Depression Clinical and Demographic Characteristics! Greater severity of illness 1! Younger mean age 2! Earlier age of onset ± 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: Fava M, et al. Compr Psychiatry 2000;41:

18 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: Joffe RT, et al. Am J Psychiatry 1993;150: Clayton P, et al. Am J Psychiatry 1991;148: Flint AJ, Rifat SL. Am J Geriatr Psychiatry 1997;5:

19 How Does Anxious Depression Respond to Antidepressant Treatment?! Lesser likelihood to respond 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: Flint AJ, Rifat SL. Am J Geriatr Psychiatry 1997;5: Flint AJ, Rifat SL. Psychiatry Res 1997;66:23-31.

20 Remission Rates Following Citalopram Treatment in Level 1 of STAR*D * N = 2876 * p <.05 Fava M, et al. Am J Psychiatry 2008;165:

21 Remission Rates (HAM-D-17 < 8) in Level 2 of STAR*D Anxious vs. Non-Anxious MDD * * * * * * p <.05 Fava M, et al. Am J Psychiatry 2008;165:

22 Response & Remission Rates in Open Trial of Duloxetine in Anxious and Non- Anxious MDD * (n = 109) (n = 140) * * p = ns Fava M, et al. Ann Clin Psychiatry 2007;19:

23 Anxious Depression Treatment Approaches! Monotherapy with antidepressants Sedating vs. nonsedating! Augmentation with: Benzodiazepines Eszopiclone Buspirone Gabapentin or other anticonvulsants Antipsychotics

24 Use of Anxiolytics and Hypnotics During SSRI Treatment Drug No. of Patients Hypnotic % Hypnotic/ Anxiolytic % Paroxetine Sertraline 13, Fluoxetine 12, Rascati K. Clin Ther 1995;17: From the Texas Medicaid Database

25 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

26 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:

27 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! However, SNRIs may be better than SSRIs! Overall efficacy of currently available therapies is modest! Anxiolytics may be indicated as adjuncts in nonresponders

28 an educational series offered by CME Outfitters, LLC This CME/CE activity is co-sponsored by

29 Anxious Depression Ned Kalin, MD Clayton PJ, Grove WM, Coryell W, Keller M, Hirschfeld R, Fawcett J. Follow-up and family study of anxious depression. Am J Psychiatry 1991;148: Fava M, Martinez JM, Greist J, et al. The efficacy and tolerability of duloxetine in the treatment of anxious versus non-anxious depression: a post-hoc analysis of an open-label outpatient study. Ann Clin Psychiatry 2007;19: Fava M, Rankin MA, Wright EC, et al. Anxiety disorders in major depression. Compr Psychiatry 2000;41: Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008;165: Fava M, Uebelacker LA, Alpert JE, Nierenberg AA, Pava JA, Rosenbaum JF. Major depressive subtypes and treatment response. Biol Psychiatry 1997;42: Flint AJ, Rifat SL. Anxious depression in elderly patients. Response to antidepressant treatment. Am J Geriatr Psychiatry 1997;5: Flint AJ, Rifat SL. Two-year outcome of elderly patients with anxious depression. Psychiatry Res 1997;66: Joffe RT, Bagby RM, Levitt A. Anxious and nonanxious depression. Am J Psychiatry 1993;150: Rascati K. Drug utilization review of concomitant use of specific serotonin reuptake inhibitors or clomipramine with antianxiety/sleep medications. Clin Ther 1995;17: Tedlow JR, Fava M, Uebelacker LA, Alpert JE, Nierenberg AA, Rosenbaum JF. Are study dropouts different from completers? Biol Psychiatry 1996;40: Van Valkenburg C, Winokur G, Behar D, Lowry M. Depressed women with panic attacks. J Clin Psychiatry 1984;45:

ANXIOUS DEPRESSION. Ned H. Kalin, MD University of Wisconsin Alan F. Schatzberg, MD Stanford University

ANXIOUS DEPRESSION. Ned H. Kalin, MD University of Wisconsin Alan F. Schatzberg, MD Stanford University 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!!