Mood and Anxiety Disorders: The Complexities of Integrating Syndromes

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2 Mood and Anxiety Disorders: The Complexities of Integrating Syndromes Ned Kalin, MD University of Wisconsin School of Medicine Martin B. Keller, MD Brown Medical School David R. Rubinow, MD University of North Carolina

Ned Kalin, MD Disclosures Research/Grants: None Speakers Bureau: None Consultant: None Stockholder: Corcept Therapeutics, CeNeRx BioPharma Other Financial Interest: Owner of Promoter Neurosciences,

3 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

4 Learning Objective Recognize the overlapping symptomatology of mood and anxiety disorders and develop an individualized treatment plan focused on sustained remission

5 Diagnosis, Long- Term Course, and Treatment of Generalized Anxiety Disorder (GAD): Current Knowledge and Future Directions Martin B. Keller, MD Brown Medical School

Martin B. Keller, MD Disclosures Research/Grants: Pfizer Inc.; Wyeth Pharmaceuticals Speakers Bureau: None Consultant: CeNeRx BioPharma; Cephalon, Inc.; Cypress Bioscience, Inc.; Cyberonics, Inc.

6 Martin B. Keller, MD Disclosures Research/Grants: Pfizer Inc.; Wyeth Pharmaceuticals Speakers Bureau: None Consultant: CeNeRx BioPharma; Cephalon, Inc.; Cypress Bioscience, Inc.; Cyberonics, Inc.; Forest Laboratories, Inc.; Janssen, L.P.; JDS, Medtronic, Inc.; Novartis Pharmaceuticals Corporation; Organon Pharmaceuticals USA Inc.; Pfizer Inc.; Roche; Solvay Pharmaceuticals, Inc.; Wyeth Pharmaceuticals Stockholder: None Other Financial Interest: None Advisory Board: Abbott Laboratories; Bristol-Myers Squibb Company; CeNeRx BioPharma; Cyberonics, Inc.; Forest Laboratories, Inc.; Janssen, L.P.; Novartis Pharmaceuticals Corporation; Organon Pharmaceuticals USA Inc.; Pfizer Inc.

7 Learning Objective To identify the prevalence of GAD/MDD comorbidity and differentiate among therapeutic options for GAD

8 Generalized Anxiety Disorder (GAD) Excessive or uncontrolled worry 6 months 3 or more associated physical and psychological symptoms Causes significant distress or impairment Symptoms not better explained by other condition DSM IV-TR. Washington DC: American Psychiatric Association, 2000.

9 GAD and MDD 42% to 70% of patients with GAD have co-existing depressive symptoms or syndromes GAD predicts greater risk of secondary MDD Compared with patients with GAD alone, those with GAD and MDD have: Higher rates of suicide ideation and attempts Greater impairment in all functional domains Lower recovery and greater recurrence Higher rates of chronicity More medical comorbidity Greater health care utilization and costs Keller MB, et al. J Clin Psychiatry 1995;56: Kessler RC, et al. Br J Psychiatry 1996;168 (Suppl 30): Simon NM. J Clin Psychiatry 2009;70 (Suppl 2): Hoffman DL, et al. Depress Anxiety 2008;25:72-90.

10 Which Models Are Consistent with the Frequent Comorbidity Between GAD and MDD? Variations of a broader underlying syndrome erroneously separated Are they different phenocopies of the same genetic diathesis? Different environment or experiences = different syndromes Disorder features are a risk factor for another disorder One disorder causes another? Are they different stages of the same illness? Leckman JF, et al. Am J Psychiatry 1983;140: Breier A, et al. Arch Gen Psychiatry 1984;41: Kendler KS, et al. Am J Psychiatry 1986;143:

11 Longitudinal Course of GAD Two prospective, naturalistic, longitudinal, studies of adults with anxiety disorders Harvard/Brown Anxiety Research Project (HARP) 711 mental health patients Up to 14 years of data Primary Care Anxiety Project (PCAP) 539 primary care patients Up to 5 years of data Keller MB. J Clin Psychiatry 2006;67(Suppl 12):14-19.

Current Available GAD Medications and Psychotherapy FDA-approved: Benzodiazepines, buspirone SSRIs: paroxetine, escitalopram SNRIs: venlafaxine, duloxetine Evidence from RCTs (not FDA-approved)

12 Current Available GAD Medications and Psychotherapy FDA-approved: Benzodiazepines, buspirone SSRIs: paroxetine, escitalopram SNRIs: venlafaxine, duloxetine Evidence from RCTs (not FDA-approved) SSRIs: fluvoxamine, sertraline, citalopram TCAs: imipramine Hydroxyzine, trazodone, pregabalin, tiagabine Cognitive Behavioral Therapy (not FDAapproved) Gorman JM. J Clin Psychiatry 2002;63(suppl):17-23.

Combining Benzodiazepines with Antidepressants Potential Benefits: Provide rapid anxiolysis during antidepressant lag Decrease early anxiety associated with antidepressant initiation Treat residual

13 Combining Benzodiazepines with Antidepressants Potential Benefits: Provide rapid anxiolysis during antidepressant lag Decrease early anxiety associated with antidepressant initiation Treat residual anxiety after successful antidepressant treatment Combination of a benzodiazepine and an antidepressant may be more effective than monotherapy Zamorski MA, et al. Am Fam Physician 2002;66:

14 Psychosocial Treatment Cognitive behavioral therapy (CBT) is a wellestablished treatment for GAD, SAD, and panic disorder Specific CBT treatments for each disorder All include similar components of Psychoeducation regarding anxiety Restructuring anxiety-related cognitions Exposure to avoided situations Possible use of relaxation techniques Chambless DL, et al. J Consult Clin Psychol 1993;61: Leichsenring F, et al. Am J Psychiatry 2009;July:1-7 (epub).

GABA A -receptor modulators Newer 5-HT 2A receptor agonists Others?

15 Pharmacologic Treatments Under Development (These Agents Are Not FDA-Approved for GAD) Neuroactive peptides Selective GABA reuptake inhibitors α2δ ligands GABA A -receptor modulators Newer 5-HT 2A receptor agonists Others? Tassone DM, et al. Clin Ther 2007;29: Millan MJ. Neurotherapeutics 2009;6:53-77.

GAD: Summary Protracted time to recovery Rapid time to recurrence Often chronic course (> 5-year episodes) High rates of comorbidity (MDD) and subsyndromal symptoms Significant impairment in

16 GAD: Summary Protracted time to recovery Rapid time to recurrence Often chronic course (> 5-year episodes) High rates of comorbidity (MDD) and subsyndromal symptoms Significant impairment in social and physical functioning Enormous economic burden on society Improve therapeutics essential for acute episodes and maintenance treatment for GAD patients with and without comorbid MDD

17 Reproductive Endocrine- Related Depression: One Size Does Not Fit All David R. Rubinow, MD University of North Carolina

18 David R. Rubinow, MD Disclosures Research/Grants: Foundation of Hope; National Institutes of Health; National Institute of Mental Health Speakers Bureau: None Consultant: Azevan Pharmaceutical, Inc.; Dialogues in Clinical Neuroscience Stockholder: Amgen Inc.; Vanguard Special Health Mutual Fund Other Financial Interest: None Advisory Board: None

19 Learning Objective Identify 2 issues that are relevant to reproductive endocrine-related depression at different reproductive stages and explain their clinical implications

20 I m pregnant, doc. Should I continue taking my antidepressant?

Retrospective vs. Prospective Depression During Pregnancy Prospective Documentation of Prenatal Depression Retrospective Recall of Depression During Pregnancy Depressed Not Depressed Total PPV: 90.

21 Retrospective vs. Prospective Depression During Pregnancy Prospective Documentation of Prenatal Depression Retrospective Recall of Depression During Pregnancy Depressed Not Depressed Total PPV: 90.4% Depressed NPV: 53.8% Not Depressed Total Statistics Fisher s Exact: p <.0001, k = 0.42 [95% CI: ] NCI = confidence interval; PV = negative predictive value; PPV = positive predictive value Newport DJ, et al. BJOG 2008;115:

22 Now that I m perimenopausal, what do you have for my libido, doc?

23 E 2 Replacement Does NOT Restore Libido (n = 18) (n = 10) DISF = Derogatis Interview of Sexual Functioning-Self Report Schmidt PJ, et al. Neuropsychopharmacology 2009;34:

Hormone-Related Changes in Sexual Interest DISF Total Score 2000 1800 1600 1400 1200 1000 800 600 400 200 0 * * Men (n = 20) Women (n = 20)

24 Hormone-Related Changes in Sexual Interest DISF Total Score * * Men (n = 20) Women (n = 20) Baseline Hypogonadal * p <.05 Schmidt PJ, et al. Neuropsychopharmacology 2009;34: * Testosterone Replaced Estrogen Replaced Progesterone Replaced

25 Effect of Baseline Sexual Interest Scores on Sexual Interest Across Treatment Phase Men DISF Total Score <.01 <.01 0 Lo Libido (n = 6) Hi Libido (n = 6) Schmidt PJ, et al. Neuropsychopharmacology 2009;34:

Effect of Baseline Sexual Interest Scores on Sexual Interest Across Treatment Phase Women 2400 DISF Total Score 2000

26 Effect of Baseline Sexual Interest Scores on Sexual Interest Across Treatment Phase Women 2400 DISF Total Score <.01 Lo Libido (n = 6) Hi Libido (n = 6) Schmidt PJ, et al. Neuropsychopharmacology 2009;34:

27 I got depressed when I was perimenopausal. The HRT did the trick, but will I be OK if I stop it now?

Conclusions Reproductive endocrine-related depression in women is a potential concern at all stages of adult life Pregnancy Concerns about fetal exposure to ADs and other

28 Conclusions Reproductive endocrine-related depression in women is a potential concern at all stages of adult life Pregnancy Concerns about fetal exposure to ADs and other medications Depression during pregnancy Perimenopause E 2 replacement does not restore libido Postmenopause E 2 withdrawal precipitates depressive symptoms in asymptomatic women with past PMD

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

30 Diagnosis, Long-Term Course, and Treatment of Generalized Anxiety Disorder (GAD): Current Knowledge and Future Directions Martin B. Keller, MD Breier A, Charney DS, Heninger GR. Major depression in patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1984;41: Chambless DL, Gillis MM. Cognitive therapy of anxiety disorders. J Consult Clin Psychol 1993;61: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV-TR). Washington, DC: American Psychiatric Association; Gorman JM. Treatment of generalized anxiety disorder. J Clin Psychiatry 2002;63(Suppl 8): Hoffman DL, Dukes EM, Wittchen HU. Human and economic burden of generalized anxiety disorder. Depress Anxiety 2008;25: Keller MB, Hanks DL. Anxiety symptom relief in depression treatment outcomes. J Clin Psychiatry 1995;56(Suppl 6): Keller MB. Social anxiety disorder clinical course and outcome: review of Harvard/Brown Anxiety Research Project (HARP) findings. J Clin Psychiatry 2006;67(Suppl 12): Kendler KS, Eaves LJ. Models for the joint effect of genotype and environment on liability to psychiatric illness. Am J Psychiatry 1986;143: Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG. Comorbidity of DSM-III-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry Suppl 1996 Jun; Leckman JF, Merikangas KR, Pauls DL, Prusoff BA, Weissman MM. Anxiety disorders and depression: contradictions between family study data and DSM-III conventions. Am J Psychiatry 1983;140: Leichsenring F, Salzer S, Jaeger U, et al. Short-term psychodynamic psychotherapy and cognitive-behavioral therapy in generalized anxiety disorder: a randomized, controlled trial. Am J Psychiatry 2009;[Epub ahead of print]. Millan MJ. Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs. Neurotherapeutics 2009;6: Newport DJ, Brennan PA, Green P, Ilardi D, Whitfield TH, Morris N, Knight BT, Stowe ZN. Maternal depression and medication exposure during pregnancy: comparison of maternal retrospective recall to prospective documentation. BJOG 2008;115: Schmidt PJ, Steinberg EM, Negro PP, Haq N, Gibson C, Rubinow DR. Pharmacologically induced hypogonadism and sexual function in healthy young women and men. Neuropsychopharmacology 2009;34: Simon NM. Generalized anxiety disorder and psychiatric comorbidities such as depression, bipolar disorder, and substance abuse. J Clin Psychiatry 2009;70(Suppl 2): Tassone DM, Boyce E, Guyer J, Nuzum D. Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther 2007;29: Zamorski MA, Albucher RC. What to do when SSRIs fail: eight strategies for optimizing treatment of panic disorder. Am Fam Physician 2002;66:

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!!