Mood and AnxietyDisorders:The Complexitiesof IntegratingSyndromesNed Kalin, MDUniversity of WisconsinSchool of Medicine

Martin B. Keller, MDBrown Medical School

David R. Rubinow, MDUniversity of NorthCarolina

Ned Kalin, MDDisclosures

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 methodof identifying agents that alter the activity of the promoter sequences: U.S. Patentissued on 07-04-06; patent #7071323, divisional patent applied for on 9/26/2005;patent application #11/234916; Promoter sequences for urocortin II and the usethereof: U.S. Patent issued on 08-08-06; patent #7087385; Promoter sequences forcorticotropin-releasing factor binding protein and use thereof: U.S. Patent issued on 10-17-06; patent #7122650Method for reducing CRF receptor mRNA: Patent applied foron 07-22-04 patent application #20050042212

Advisory Board: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company,CeNeRx BioPharma, Corcept Therapeutics, Cyberonics, Inc., Elsevier, Eli Lilly andCompany, Forest Laboratories, Inc., General Electric Corp (GE Healthcare),GlaxoSmithKline, Jazz Pharmaceuticals, Letters & Sciences, Neuronetics Inc., NovartisPharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., Sanofi-aventis,Takeda International, Wyeth Pharmaceuticals

LearningObjectiveRecognize theoverlappingsymptomatology ofmood and anxietydisorders and developan individualizedtreatment plan focusedon sustained remission

Diagnosis, Long-Term Course,and Treatment ofGeneralizedAnxiety Disorder(GAD): CurrentKnowledge andFuture DirectionsMartin B. Keller, MDBrown Medical School

Martin B. Keller, MDDisclosures

Research/Grants: Pfizer Inc.; Wyeth Pharmaceuticals

Speakers Bureau: None

Consultant: CeNeRx BioPharma; Cephalon, Inc.; CypressBioscience, Inc.; Cyberonics, Inc.; Forest Laboratories, Inc.; Janssen,L.P.; JDS, Medtronic, Inc.; Novartis Pharmaceuticals Corporation;Organon Pharmaceuticals USA Inc.; Pfizer Inc.; Roche; SolvayPharmaceuticals, Inc.; Wyeth Pharmaceuticals

Stockholder: None

Other Financial Interest: None

Advisory Board: Abbott Laboratories; Bristol-Myers SquibbCompany; CeNeRx BioPharma; Cyberonics, Inc.; ForestLaboratories, Inc.; Janssen, L.P.; Novartis PharmaceuticalsCorporation; Organon Pharmaceuticals USA Inc.; Pfizer Inc.

LearningObjectiveTo identify theprevalence ofGAD/MDD comorbidityand differentiateamong therapeuticoptions for GAD

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.

GAD and MDD

42% to 70% of patients with GAD have co-existingdepressive 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;56:22-29.Kessler RC, et al. Br J Psychiatry 1996;168 (Suppl 30):17-30.Simon NM. J Clin Psychiatry 2009;70 (Suppl 2):10-14.Hoffman DL, et al. Depress Anxiety 2008;25:72-90.

Which Models Are Consistent withthe Frequent Comorbidity BetweenGAD and MDD?

Variations of a broader underlying syndrome erroneouslyseparated

Are they different phenocopies of the same geneticdiathesis?– 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;140:880-882.Breier A, et al. Arch Gen Psychiatry 1984;41:1129-1135.Kendler KS, et al. Am J Psychiatry 1986;143:279-289.

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 GADMedications 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 FDA-approved)

Gorman JM. J Clin Psychiatry 2002;63(suppl):17-23.

Combining Benzodiazepineswith 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 thanmonotherapy

Zamorski MA, et al. Am Fam Physician 2002;66:1477-1484.

Psychosocial Treatment

Cognitive behavioral therapy (CBT) is a well-established treatment for GAD, SAD, and panicdisorder

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;61:248-260.Leichsenring F, et al. Am J Psychiatry 2009;July:1-7 (epub).

Pharmacologic TreatmentsUnder Development(These Agents Are Not FDA-Approved for GAD)

Neuroactive peptides Selective GABA reuptake

inhibitors α2δ ligands GABAA-receptor

modulators Newer 5-HT2A receptor

agonists Others?

Tassone DM, et al. Clin Ther 2007;29:26-48.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 social and physical functioning Enormous economic burden on society Improve therapeutics essential for acute episodes and

maintenance treatment for GAD patients with and withoutcomorbid MDD

ReproductiveEndocrine-RelatedDepression:One SizeDoes Not Fit AllDavid R. Rubinow, MDUniversity of NorthCarolina

David R. Rubinow, MDDisclosures

Research/Grants: Foundation of Hope; NationalInstitutes of Health; National Institute of MentalHealth

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

LearningObjectiveIdentify 2 issues thatare relevant toreproductiveendocrine-relateddepression at differentreproductive stagesand explain theirclinical implications

“I’m pregnant,doc. Should Icontinuetaking myantidepressant?”

NCI = confidence interval; PV = negative predictive value; PPV = positive predictive valueNewport DJ, et al. BJOG 2008;115:681-688.

Retrospective vs. ProspectiveDepression During Pregnancy

ProspectiveDocumentation

of PrenatalDepression

Retrospective Recallof Depression During Pregnancy

TotalDepressed Not Depressed

Depressed 66 42 108

Not Depressed 7 49 56

Total 73 91 164

Statistics Fisher’s Exact: p < .0001, k = 0.42[95% CI: 0.30 – 0.55]

PPV: 90.4%

NPV: 53.8%

“Now that I’mperimenopausal,what do you havefor my libido,doc?”

DISF = Derogatis Interview of Sexual Functioning-Self ReportSchmidt PJ, et al. Neuropsychopharmacology 2009;34:565-576.

E2 Replacement Does NOTRestore Libido

(n = 18)(n = 10)

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Men (n = 20) Women (n = 20)

DIS

F To

tal S

core

Baseline

Hypogonadal

Testosterone Replaced

Estrogen Replaced

Progesterone Replaced

*

*

*

* p < .05Schmidt PJ, et al. Neuropsychopharmacology 2009;34:565-576.

Hormone-Related Changesin Sexual Interest

0

400

800

1200

1600

2000

2400

DIS

F To

tal S

core

< .01< .01

Schmidt PJ, et al. Neuropsychopharmacology 2009;34:565-576.

Effect of Baseline Sexual InterestScores on Sexual Interest AcrossTreatment Phase

Lo Libido (n = 6) Hi Libido (n = 6)

Men

< .01

0

400

800

1200

1600

2000

2400

DIS

F To

tal S

core

Lo Libido (n = 6) Hi Libido (n = 6)

Effect of Baseline Sexual InterestScores on Sexual Interest AcrossTreatment Phase

Women

Schmidt PJ, et al. Neuropsychopharmacology 2009;34:565-576.

“I got depressedwhen I wasperimenopausal.The HRT did thetrick, but will I beOK if I stop itnow?”

Reproductive endocrine-related depression in womenis a potential concern at all stages of adult life

Conclusions

Pregnancy– Concerns about fetal exposure to ADs and other

medications– Depression during pregnancy

Perimenopause– E2 replacement does not restore libido

Postmenopause– E2 withdrawal precipitates depressive symptoms in

asymptomatic women with past PMD

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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;41:1129-1135.

Chambless DL, Gillis MM. Cognitive therapy of anxiety disorders. J Consult Clin Psychol 1993;61:248-260.

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.

Gorman JM. Treatment of generalized anxiety disorder. J Clin Psychiatry 2002;63(Suppl 8):17-23.

Hoffman DL, Dukes EM, Wittchen HU. Human and economic burden of generalized anxiety disorder. Depress Anxiety 2008;25:72-90.

Keller MB, Hanks DL. Anxiety symptom relief in depression treatment outcomes. J Clin Psychiatry 1995;56(Suppl 6):22-29.

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):14-19.

Kendler KS, Eaves LJ. Models for the joint effect of genotype and environment on liability to psychiatric illness. Am J Psychiatry 1986;143:279-289.

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;17-30.

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;140:880-882.

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;6:53-77.

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;115:681-688.

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;34:565-576.

Simon NM. Generalized anxiety disorder and psychiatric comorbidities such as depression, bipolar disorder, and substance abuse. J Clin Psychiatry 2009;70(Suppl 2):10-14.

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;29:26-48.

Zamorski MA, Albucher RC. What to do when SSRIs fail: eight strategies for optimizing treatment of panic disorder. Am Fam Physician 2002;66:1477-1484.