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.