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Clinical and Genetic Epidemiology Myrna M. Weissman, Ph.D., Chief of
Psychiatric Research OVERVIEW CURRENT RESEARCH Linkage and Segregation in Complex Genetic Diseases (S. E. Hodge, P.I.) The objective is to develop new methods to resolve complications arising in the genetic study of complex diseases, with particular focus on linkage analysis, sex differences in recombination fraction, ascertainment and likelihood, and single nucleotide polymorphisms. Addressing the important problems in human genetics, this field moves to accommodate new types of genetic information, large data sets, and analysis of complex common diseases. Psychiatric Genetics and Family Studies: Robust Methods (S.E. Hodge, P.I.) Families represent an important source of information for unraveling the etiology of the psychiatric disorders. Two major tools used by mathematical geneticists and genetic epidemiologists to exploit family studies are linkage analysis and segregation analysis. Dr. Hodge’s work continues to address specific problems arising in both these methods of analysis. The overriding theme of her work is to evaluate the robustness of analysis methods, that is, how well do different methods perform when their assumptions are not met? This is important because psychiatric genetics today is dealing with complex diseases for which the genetics are not known or are poorly understood. Genetic Study of Panic Disorder (M. Weissman, P.I.) The overall aim is to understand the genetic contribution to panic disorder (PD) using 130 well-characterized multiplex families, family-based triads and advanced molecular genetic approaches. Several loci exhibit maximum lod scores of 3.0 or greater under several analytic models (maximum lod scores 4.0). Our initial findings of a possible syndrome involving PD, bladder/kidney problems, mitral valve proplapse, thyroid disorder and migraine was replicated in an extended sample of 60 multiplex families. Since the bladder/kidney problems yielded the highest lod scores, we developed a collaboration with urology, who upon review of the records, thought that interstitial cystitis (IC) best described the problems. A case control study of patients diagnosed with IC by board-certified urologists using urodynamics and/or cystoscopy found increased rates of PD and some of the syndrome disorders in the probands and their first-degree relatives. This finding published in Archives was featured in a report in the Scientist. A pilot open clinical trial of SSRI in patients with IC has been initiated. Genetics of Fear & Anxiety (M. Weissman, P.I.) We have developed a new collaboration and a Program Project with Drs. Gilliam, Kandel, Hen and Fyer to understand the genetic basis of fear and anxiety disorder in humans by identifying variant forms of genes that may contribute to pathological anxiety. The central hypothesis is that there are similarities in fear conditioning circuitry in animals and humans and that genes involved in the pathway associated with fear conditioning or innate fear may be involved in the development of human anxiety disorders particularly panic and social anxiety disorder. We are collecting a clinical sample, conducting diagnostic interviews and collecting bloods in a case-control design. Genetics of Recurrent Early Onset Major Depression (MDD-RE) (M. Weissman, P.I.) As part of a multicenter sibpair study we completed collection of nearly 1,000 affected sibpairs with early-onset recurrent depression (onset <30 years of age). Results of the genome scan are being analyzed (Holmans et al, 2004). Epidemiologic Methods in Psychiatric Family Studies
(P. Wickramaratne, P.I.) The study of familial aggregation of disease
is a first step in determining whether an illness may be genetic. We are
evaluating epidemiologic approaches to determining the presence of and
estimating measures of familial aggregation. We showed that current approaches
to analyzing data from family studies of psychiatric disorders may not
be appropriate when the disorder is suspected of having a genetic component,
e.g., we have shown that the concept of familial aggregation as applied
to parent-offspring disease aggregation (disease transmission) is quite
different from the concept of sibling disease aggregation (disease clustering)
and methods for determining the presence of familial aggregation should
be tailored to the specific type of aggregation that one wishes to detect.
High Risk Longitudinal Studies Depressed Children Grown Up – A.Feder received
a NARSAD Young Investigator Award to study 24-hour cortisol secretion
patterns in prepubertal children with depression, anxiety, and normal
controls, in light of their longitudinal clinical follow-up into young
adulthood. Examining the childhood cortisol-secretion patterns of 20 subjects
who had not been depressed youngsters, yet who developed a major depression
as adults, she found that the patterns were essentially identical to the
atypical childhood cortisol-secretion profile exhibited by the 50 subjects
who had been depressed as youngsters. This finding implied that this abnormal
childhood cortisol-secretion profile might be a biological marker not
just for depression susceptibility during childhood, but also for depression
susceptibility during adulthood, and raised the possibility of identifying,
via childhood cortisol-secretion tests, individuals who were at risk for
depression either during childhood or adulthood. Treatment Studies Group IPT for Depressed Adolescents L. Mufson received a NARSAD award to adapt and pilot test group IPT for 18 depressed adolescents. Twenty 13-17 year old depressed adolescents were eligible to participate. The depressed adolescents are sequentially randomized to either group or individual IPT-A, depending upon which modality is being offered at that time. Interpersonal Psychotherapy and Psychoeducation for Adolescent Children of Bipolar Mothers L. Verdeli received a NARSAD Young Investigator Award for this project. Twenty adolescents whose mothers have Bipolar I disorder are randomized to IPT and family psychoeducation or family psychoeducation and clinical monitoring. A Counseling Intervention for Adolescent Children of Bipolar Mothers L. Verdeli was awarded the Sol Goldman Charitable Trust to conduct an open trial to test the feasibility of Interpersonal and Social Rhythm Counseling for adolescent children of Bipolar mothers. Treatment of Depressed Mothers: A STAR*D Ancillary Study (M. Weissman, P.I., D. Pilowsky, co-P.I.) The overall aim of this NIMH ancillary study to the multi-site Sequenced Treatment Alternatives to Relieve Depression study (STAR-D) is to determine the impact of a reduction of maternal depressive symptoms on children’s psychiatric symptoms and social functioning. One hundred fifty one mother-child pairs have been enrolled into the study and baseline data on the first one hundred cases show the high rate of psychopathology among children of depressed mothers participating in STAR-D. IPT for Prepubertal Depression D. Pilowsky, P.I., was awarded a grant from Klingenstein Foundation to develop the first adaptation of IPT for prepubertal children with depressive symptoms. A draft manual has been submitted to the Foundation. Treatment of Depression in Uganda L. Verdeli, M. Weissman
modified IPT in a group format for depressed patients in Uganda and Verdeli
trained group leaders for a controlled clinical trial. The trial has been
completed and showed the efficacy of IPT as compared to usual treatment.
The manual is being disseminated to investigators in other developing
countries. Medication Management Decisions in Schizophrenia (M. Olfson, P.I.) This study seeks to understand why the medication management of schizophrenia so commonly departs from evidence based treatment recommendations. The study examines clinical decision making from a nationally representative random sample of 1,600 psychiatrists and focuses on the effects of selected modifiable patient, provider, and practice characteristics on the quality of antipsychotic prescription decisions. Sexual Side-Effects of Antipsychotic Medications (M. Olfson, P.I.)This study seeks to determine the prevalence, severity, and clinical consequences of sexual side-effects associated with four antipsychotic medications that are commonly prescribed for the treatment of schizophrenia. Columbia Center for the Health of Urban Minorities, Director Mental Health Research Core (M. Olfson) The overall aim of the Mental Health Research Core is to facilitate and evaluate mental health interventions for low income minority populations. Activities of the core focus on minority groups that have limited access to specialized mental health services. The MHRC pursues this aim through fostering collaborations between mental health researchers trained in service evaluation and community agencies that provide social and health services; promoting research on interventions to improve mental health care access for low income minority adults and children, and encouraging health and mental health researchers to extend their research into area relevant to reducing ethnic and racial disparities in access to mental health care. Psychopharmacoepidemiology Research Unit (PERU) Dr. Olfson is the Director of PERU. The PERU mission is to increase knowledge of the use of prescribed psychotropic medications in children and adolescents through the examination of utilization patterns. Recent projects supported by the PERU include a national overview of psychotropic medication use in children; an examination of recent trends in the pharmacological treatment of ADHD; an analysis of the effects of parental depression on child mental health service utilization; a small geographic area evaluation of antidepressants use and suicide rates in the United States. A planned study involves using Medicaid claims and National Death Index Data to determine whether treatment with antidepressant medications and/or psychotherapy reduces the risk of suicide and suicide attempts in high-risk young people. Medication Noncompliance in Schizophrenia (M.
Olfson, P.I., C.Boyer Co-PI) This study involves a novel psychological
approach to the treatment of medication noncompliance in schizophrenia.
Outpatients who are receiving short-term inpatient care and have a recent
history of medication non-compliance are being randomly assigned to receive
compliance therapy or continued usual care. Compliance therapy draws on
the principles of motivational interviewing to increase the patients'
awareness of discrepancies between their current behavior and long-term
goals. Psychiatric Disorder and Treatment in an Urban Primary Care Practice (M. Weissman, P.I., M. Olfson) This is a study of the frequency and treatment of bipolar disorder or other psychiatric disorders in 1000 adult patients at the Associates in Internal Medicine (AIMS) of the Columbia Presbyterian Medical Center serving urban, poor, adult, primary care patients. Data analysis is underway. A NARSAD grant was awarded to Y. Nuria to understand the relationship between PTSD and major depression in this sample. An NIMH grant was submitted by C. Blanco to develop an intervention for patients experiencing PTSD in this study. Roberto Lewis Fernando was awarded a NARSAD grant to follow up the Hispanic patients reporting psychotic symptoms. EDUCATION AND TRAINING Medical Student Post Doctoral Fellows Training Grant (S. Hodge, P.I.) Genetic Analysis: Psychiatric
& Other Complex Disorders.
CLINICAL SERVICES
Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y. Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci U S A. In press, 2003. Blanco C, Clougherty KF, Lipsitz KF, Mufson L, Weissman
MM. Homework in interpersonal psychotherapy. In: Gabbard G, Beck J, Holmes
J, eds. Journal of Psychotherapy Integration (Special Series): Integrating
between-session homework activities into different psychotherapies. Concise
Oxford Textbook of Psychotherapy. In press, 2003. Charney DS, Reynolds III CF, Lewis L, Lebowitz BD, Sunderland T, Alexopoulos GS, Blazer DG, Katz IR, Meyers BS, Arean PA, Borson S, Brown C, Bruce ML, Callahan CM, Charlson ME, Conwell Y, Cuthbert BN, Devanand DP, Gibson MJ, Gottlieb GL, Krishnan KR, Laden SK, Lyketsos CG, Mulsant BH, Niederehe G, Olin JT, Oslin DW, Pearson J, Persky T, Pollock BG, Raetzman S, Reynolds M, Salzman C, Schulz R, Schwenk TL, Scolnick E, Unützer J, Weissman MM, Young RC. Depression and bipolar support alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Arch Gen Psychiatry. 2003;60:664-672. Cheng R, Park N, Hodge SE, Juo S-H H. Comparing two methods to analyze longitudinal linkage data from the Framingham Family Study. Genetic Analysis Workshop 13. BMC Genet. 2003;4(Suppl 1):S20. Clougherty KF, Verdeli H, Weissman MM. Interpersonal psychotherapy for a group in Uganda (IPTGU). Copyrighted unpublished manual, 2003. Das A, Gross R, Weissman MM. Screening for depression in adults. [Letter to the Editor.] Ann Intern Med. 2003;138:767. Feder A: Hysteria. In: Aminoff MJ, Daroff R(Eds). Encyclopedia of the NeurologicalSciences. Academic Press, 2003, pp. 629-631. Feder A, Coplan JD, Goetz RR, Mathew SJ, Pine DS, Dahl
RE, Ryan ND, Greenwald S, Weissman MM. Feder A, Goetz RR, Coplan JD, Mathew SJ, Pine DS, Greenwald
S, Dahl RE, Ryan ND, Weissman MM. Feder A, Robbins SW, Ostermeyer B: Personality Disorders: In: Feldman MD, Christensen JF (Eds). Behavioral Medicine in Primary Care; A Practical Guide. McGraw-Hill, 2003, pp 231-252. Feenstra B, Greenberg DA, Hodge SE. Using lod scores to detect sex differences in male-female recombination fractions. Hum Hered. In press, 2004. Flodman P, Hodge SE. Sex-specific mutation rates for X-linked disorders: Estimation and application. Hum Hered. 2003;55:51–55. Goodwin RD, Olfson M, Shea S, Lantigua RA, Carrasquillo O, Gameroff MJ, Weissman MM. Asthmaand mental disorders in primary care.Gen Hosp Psychiatry. 2003 Nov-Dec;25(6):479-83. Hamilton SP, Fyer AJ, Durner M, Heiman GA, de Leon AB, Hodge SE, Knowles JA, Weissman MM. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. PNAS. 2003;100:2550–2555. Hamilton SP, Slager SL, Baisre de Leon A, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. Evidence for genetic linkage between a polymorphism in the Adenosine 2A receptor (ADORA2A) and panic disorder. Neuropsychopharmacology. 2004; 29:588-565. Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE, Fyer AJ, Weissman MM, Knowles JA. Investigation of polymorphisms in the CREM gene in panic disorder. Neuropsychiatric Genetics. 2004; 1268:111-115. Holmans P, Zubenko GS, Crowe RR, DePaulo JR, Scheftner WA, Weissman MM, Zubenko WN, Boutelle S, Murphy-Eberenz K, Mackinnon D, McInnis MG, Marta DH, Adams P, Knowles JA, Gladis M, Thomas J, Chellis J, Miller E, Levinson DF. Genowide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. Am J Hum Genet 74: 1154-1167, 2004. Levinson DF, Zubenko GS, Crowe RR, DePaulo JR, Scheftner
WS, Weissman MM, Holmans P, Zubenko WN, Lindholm E, Zhang J, Hodge SE, Greenberg DA. The reliability of haplotyping inference in nuclear families: Misassignment rates for SNPs and microsatellites. Hum Hered. In press. March D, Yonkers KA. Panic disorder during pregnancy. Mental Fitness. 2004;3:43-51. Mathew SJ, Coplan JD, Goetz RR, Feder A, Greenwald S, Dahl
RE, Ryan ND, Mann JJ, Weissman MM. Mathew SJ, Coplan JD, Goetz RR, Feder A, Greenwald S, Dahle
RE, Ryan ND, Mann JJ, Weissman Mojtabai R, Olfson M. Medication costs, adherence, and health outcomes among Medicare enrollees. Health Aff. 2003;22:220-229. Mufson, L. Interpersonal psychotherapy for depressed adolescents. In: Ollendick T, Schroeder C, eds. Encyclopedia of Pediatric and Child Psychology. New York: Kluwer Academic; 2003:320-322. Mufson L, Gallagher T, Pollack-Dorta K, Young JF. Interpersonal psychotherapy for adolescent depression: Adaptation for group therapy. Am J Psychother. In press. Mufson L, Pollack-Dorta K. Interpersonal psychotherapy for depressed adolescents. In: Kazdin A, Weisz J, eds. Evidence-based Psychotherapies for Children and Adolescents. New York: Guilford Publications; 2003:148-164. Mufson L, Pollack-Dorta KE, Moreau D, Weissman MM. Efficacy to effectiveness: Adaptations of interpersonal psychotherapy for adolescent depression. In: Hibbs ED, Jensen PS, eds. Psychosocial Treatments for Child and Adolescent Disorders: Empirically-based Strategies for Clinical Practice, Second Edition. American Psychological Association. In press, 2004. Mufson L, Pollack-Dorta K, Moreau D, Weissman, MM. Interpersonal Psychotherapy for Depressed Adolescents, Second Edition. New York: Guilford Publications. 2004. Mufson, L., Pollack Dorta K., Wickramaratne P., Nomura Y., Olfson M., Weissman MM. The Effectiveness of Interpersonal Psychotherapy for Depressed Adolescents. Archives of General Psychiatry. 2004;61:577-584. Mufson L, Pollack-Dorta KE, Wickramaratne PJ, Nomura Y, Olfson M, Weissman MM. A randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry. In press, 2004. Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Treatment
of childhood depression in the United Olfson M, Marcus SC, Druss B, Pincus HA, Weissman MM. Parental
depression, child mental health problems, Olfson M, Marcus SC, Gameroff MJ, Jensen PS. National trends in the treatment of attention deficit/hyperactivity disorder. Am J Psychiatry. 2003;160:1071-1077. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship
of antidepressant medication use to suicide in Olfson M, Tobin JN, Cassells A, Weissman MM. Improving
the detection of drug abuse, alcohol abuse and Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg
DA. BRD2 (RING3) is a probable major Pilowsky DJ, Birmaher B, Weissman MM. Approaches to chronic
depression in children and adolescents. In: Sohler N, Walkup J, McAlpine D, Boyer CA, Olfson M. Antipsychotic
medication dosing at hospital discharge Spence MA, Greenberg DA, Hodge SE, Vieland VJ. The emperor's
new methods. Am J Hum Genet. Spence MA, Hodge SE. Segregation analysis. In: Rimoin DL,
Connor JM, Pyeritz RE, Korf BR. Emery and Verdeli H, Clougherty K, Bolton P, Speelman L, Ndogoni
L, Bass J, Neugebauer R, Weissman MM. Adapting Verdeli H, Ferro T, Wickaramaratne P, Greenwald S, Blanco
C, Weissman MM. Treatment of depressed mothers Villanueva R, Greenberg DA, Davies TF, Tomer Y. Sibling
recurrence risk in autoimmune thyroid disease. Weissman MM. The epidemiology of bipolar disorder. In:
Goodwin F, Jamison K, eds. Manic Depressive Illness. Weissman MM. Interpersonal psychotherapy for major depression. Therapy Advisor [website]; 2004. Weissman MM. Phobias in primary care and in young children.
[Commentary on: Demyttenaere K, Bruffaerts R, Weissman MM. The psychotherapy of bipolar disorder. In: Goodwin F, Jamison K, eds. Manic Depressive Illness. Oxford University Press. In press, 2004. Weissman MM, Bland R, Canino G, Faravelli C, Greenwald
S, Hai-Guo H, Joyce PR, Karam EG, Chung-Kyoon Weissman MM, Feder AJ, Pilowsky D, Olfson M, Fuentes M,
Blanco C, Lantigua R, Gameroff MJ, Shea S. Weissman MM, Gross R, Fyer AJ, Heiman GA, Gameroff MJ, Kaufman D, Kaplan SA. Interstitial cystitis and panic disorder: A potential genetic syndrome. Arch Gen Psychiatry. 2004;61:273-279. Weissman MM, Sanderson WC. Promises and problems in modern
psychotherapy: The need for increased Weissman MM, Warner V, Wickramaratne PJ, Nomura Y, Merikangas K, Bruder G, Tenke CE, Grillon C. Offspring at high risk for anxiety and depression: Preliminary findings from a three generation study. In: Gorman J, ed. Fear and Anxiety: Benefits of Translational Research. Washington DC: American Psychiatric Association Press, Inc. January, 2004, pp 65-83. Wilson JJ, Nunes EV, Greenwald S, Weissman MM. Verbal deficits and disruptive behavior disorders among children of opiate dependent parents. Amer J Addictions 13:202-22, 2004. Wilson JJ, Pine DS, Cargan A, Goldstein RB, Nunes EV, Weissman MM. Neurological soft signs and disruptive behavior among children of opiate dependent parents. Child Psychiat Hum Developm 34(1): 19-34, 2003. Yonkers KA, March D. Treatment of premenstrual dysphoric disorder. J Gend Specif Med. In press, 2004. Yonkers KA, March D. Treatment of premenstrual dysphoric disorder. Mental Fitness. 2003;2:20-28. Young JF, Mufson L. Interpersonal psychotherapy for
adolescent depression: A guide to techniques and implementation. In: Steiner
H. ed. Handbook on Mental Health Interventions in Children and Adolescents:
An Integrated Developmental Approach. Wiley & Co., 2004.
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