psychiatry march 2010

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Psychiatry MARCH

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2010

A P E E R-R E V I E W E D E-J O U R N A L

P R O V I D I N G E V I D E N C E-B A S E D I N F O R M ATI O N TO P R A CTI C I N G C L I N I C I A N S

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ALSO INSIDE 9

Trend Watch Generic Penetration in the Retail Atypical Antipsychotic Market

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The Interface Personality Dysfunction and Employment Dysfunction: Double, Double, Toil and Trouble

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Psychiatry and Neurology Cranial Nerve VIII: Hearing and Vestibular Functions

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Case Report 48,XXYY in a General Adult Psychiatry Department

37

Case Report Capgras Syndrome in Postictal Delirium

40

Meymandi at Large The Science of Epigenetics

Now Available on PubMed Central!

SELECTIVE MUTISM: A Review of Etiology, Comorbidities, and Treatment 23

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A NEW TEXTBOOK FOR PRACTICING PSYCHIATRISTS MORE THAN MEDICATION: INCORPORATING PSYCHOTHERAPY INTO COMMUNITY PSYCHIATRY APPOINTMENTS addresses one of the major issues of community psychiatric practice—how to incorporate psychotherapy into the standard 15- to 30-minute appointment.

EDITED BY

PAULETTE MARIE GILLIG, MD, PhD PROFESSOR BOONSHOFT SCHOOL OF MEDICINE DEPARTMENT OF PSYCHIATRY WRIGHT STATE UNIVERSITY DAYTON, OHIO

ANN MORRISON, MD

ASSOCIATE PROFESSOR BOONSHOFT SCHOOL OF MEDICINE DEPARTMENT OF PSYCHIATRY WRIGHT STATE UNIVERSITY DAYTON, OHIO

Even when working with a co-therapist or treatment team, whether struggling with dual diagnosis or schizophrenia, a personality disorder or a mood disorder, posttraumatic stress disorder or death and dying bereavement issues, psychotherapy by the psychiatrist often needs to be as integral a part of the patient’s care as the prescribed medication. With contributions from psychotherapy experts across the field of psychiatry and through case examples, Drs. Gillig and Morrison share with the reader how to incorporate psychotherapy into psychiatric patient treatment plans, no matter what the diagnosis or the composition of the treatment team.

ABOUT THE EDITORS PAULETTE M. GILLIG, MD, PhD is Professor of Psychiatry, Wright State University, Dayton, Ohio, and Department Editor of the popular series, Psychotherapy Rounds, published in the peer-reviewed journal, Psychiatry (Edgemont). For about 15 years, Dr. Gillig has developed and led a successful state-academic partnership for training psychiatry residents in underserved locations, and has written extensively about clinical challenges for the psychiatrist in community-based programs and about the clinical research that has been conducted as part of this ongoing partnership. ANN K. MORRISON, MD is Associate Professor and Director of Community Psychiatry, Wright State University, Dayton, Ohio, and coordinates the community psychiatry training for psychiatric residents where she is also the Ohio Department of Mental Health Public Psychiatry Professor. She has practiced for nearly 20 years in a variety of community mental health settings in Ohio. These clinical sites have included comprehensive community mental health centers providing both inpatient and outpatient care, a PACT team, and a clinic for homeless individuals.

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Editor’s Message Issue Highlights, March 2010 Dear Colleagues: Welcome to the March issue of Psychiatry 2010. In this month’s “Trend Watch,” the authors explore the penetration of generic atypical antipsychotics in the United States market before and after the availability of generic risperidone. Based on this analysis, generic penetration into the atypical antipsychotic market has grown from three percent to more than 25 percent. An expert commentary by Peter Buckley, MD, Professor and Chairman, Department of Psychiatry, Medical College of Georgia, Augusta, Georgia. Following this, Sansone and Sansone, in this month’s “The Interface,” analyze and discuss the literature regarding the relationship between personality dysfunction and employment dysfunction. It would appear that the type of personality disorder, degree of neuroticism and disagreeableness, extent of social dysfunction, and severity of symptoms all have an impact on whether or not an individual can hold down a job. And because a steady job promotes stability in an individual’s life, it would seem “further research into these variables is essential,” as suggested by the authors. Next, Sanders and Gillig review cranial nerve VIII and how its dysfunction may tie into psychiatric practice. The authors review the basics of cranial nerve VIII and discuss common problems with hearing and balance as well as hearing and balance problems that might be found in psychiatric practice. They also review assessments that might be utilized in psychiatric clinical practice.

Next, Wong reviews the rare, multidimensional, childhood disorder selective mutism. The author discusses its comorbidities and treatment options, differential diagnoses, and future directions for research. Following this, Borja-Santos et al report a case of a patient with 48,XXYY syndrome who was treated in a general adult psychiatry department. The authors review and discuss the syndrome and describe psychopharmacological and psychosocial treatment options. The authors emphasize the importance of being alert to chromosomal disorders, even in a general adult psychiatry department, as a minority of patients, like the one described in this case, may reach adult care without proper diagnosis, which may negatively impact successful treatment outcomes. Next, Joshi et al. describe a case of a 34-year-old man with a seizure disorder who was not adherent with his anticonvulsant medications. Recent seizure episodes were followed by delirium and a presentation of Capgras syndrome. The authors describe functional and organic etiologies for Capgras syndrome, which resolved in this patient once he was back on his anticonvulsant medicines. Sincerely,

Supplement to March issue of Psychiatry 2010

Physician Concerns about Pressure to Prescribe Generic Medications Physician Concerns about Pressure to Prescribe Generic Medications OF 403 PHYSICIANS SURVEYED, 85 percent agree that pressure to switch stable patients to a generic medication that is not a therapeutic equivalent may reduce the likelihood that prescribing decisions are based on medical knowledge, patient history, and treatment experience.1

INTRODUCTION

In a climate of rising healthcare costs, physicians are under increasing pressure from HMOs, pharmacy benefit providers, and health insurers to prescribe generic rather than branded medications. 1 This pressure likely exists for both newly diagnosed patients and for patients with stable conditions who require prescription refills. Generic medications are an integral and well-accepted part of today’s medical practice; they can help to control medical costs when a direct therapeutic equivalent is substituted for the same brand name drug. Although generic equivalents are available for many commonly prescribed drugs, they are not available for many others, including some antidepressants.2 In such cases, physicians may be pressured to prescribe generic medications that are not direct replacements for or therapeutic equivalents of agents taken by patients with such chronic conditions as major depressive disorder and generalized anxiety disorder, both of which are highly prevalent in the adult United States population.3,4 As physicians can attest, patients suffering from these conditions often need to try several medications before finding one that works.5,6 In light of physicians’ concerns over the impact of pressure on prescribing practices, Forest Laboratories commissioned an online survey to quantify such pressure and understand the basis of physicians’ specific concerns. 1

OBJECTIVES

Survey objectives were to assess the extent to which non-medical factors influence physicians’ prescribing decisions and the effects of such pressure on the delivery of safe, effective patient care. 1 The term non-medical factors refers to cost, access to particular medications, and pharmacist’s request for product switch.

METHODOLOGY

The survey was conducted during the week of August 7, 2008, and consisted of a 20-minute, internet-based questionnaire. A total of 403 physicians were interviewed—201 primary care physicians and 202 psychiatrists. 1 The survey evaluated physicians’ attitudes toward the prescribing of all types of medications and, specifically, physicians’ attitudes toward prescribing antidepressant agents. Respondents were asked to characterize pressure to prescribe generics, first in general, then with respect to antidepressants. In both of these sections, physicians were asked about the impact of such pressure on prescribing decisions. Finally respondents were asked about switching patients stable on an antidepressant to a nontherapeutic equivalent and the perceived impact on clinical outcomes.7

SURVEY FINDINGS

Prescribing criteria. More than 90 percent of physicians polled termed effectiveness, safety, and meeting patients’ individual needs to be factors that influence prescribing decisions. Furthermore, almost all of the surveyed primary care physicians and psychiatrists agreed that all treatment with medications, including antidepressants, should be based on patients’ individual needs and that different patients can respond differently to the same medication.1 Physicians pressured to prescribe generic drugs. Pressure from non-medical factors was characterized in terms of access to particular medications and cost of medication. Ninety-six percent of primary care physicians and 94 percent of psychiatrists in the survey revealed that these non-medical factors play a role in their treatment decisions, including decisions regarding antidepressant treatment. Almost 90 percent of physicians polled felt pressured to prescribe a generic antidepressant, even when it was not their first choice of drug. 1

This outsert was created and financially supported by Forest Laboratories, Inc. This outsert did not undergo peer review by the editorial advisory board of Psychiatry 2010.

Copyright © 2010 Matrix Medical Communications. All rights reserved.

Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Matrix Medical Communications, the editorial staff, or any member of the editorial advisory board. Matrix Medical Communications is not responsible for accuracy of dosages given in the text printed herein. The appearance of advertisements in this outsert is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. Matrix Medical Communication disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in this outsert or advertisements.

Click icon above to access e-edition of outsert. To read text version, click HERE. This outsert was created and financially supported by Forest Laboratories, Inc. This outsert did not undergo peer review by the editorial advisory board of Psychiatry 2010.

Visit the journal’s website, www.psychiatry mmc.com, to acccess text versions of articles, information for authors, or issue archives.

Amir Kalali, MD Editor, Psychiatry 2010

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March 2010

In This Issue

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Editor’s Message .......................................................................................................3 Editorial Advisory Board .........................................................................................6

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TREND WATCH Generic Penetration in the Retail Atypical Antipsychotic Market ......................9 by Susan Lenderts, BA; Amir H. Kalali, MD; and Peter Buckley, MD THE INTERFACE Personality Dysfunction and Employment Dysfunction: Double, Double, Toil and Trouble..........................................................................12 by Randy A. Sansone, MD, and Lori A. Sansone, MD PSYCHIATRY AND NEUROLOGY Cranial Nerve VIII: Hearing and Vestibular Functions .......................................17 by Richard D. Sanders, MD, and Paulette Marie Gillig, MD, PhD

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23

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37

REVIEW Selective Mutism: A Review of Etiology, Comorbidities, and Treatment ..........23 by Priscilla Wong, MD CASE REPORT 48,XXYY in a General Adult Psychiatry Department...........................................32 by Nuno Borja-Santos, MD, MSc; Bruno Trancas, MD; Pilar Santos Pinto, MD; Bárbara Lopes, MD; António Gamito, MD; Sandra Almeida, MD; Berta Ferreira, MD; Antonio Luengo, MD; Carlos Vieira, MD; Jorge Martinho, MD; Bruno Pereira, MD; and Graça Cardoso, MD, PhD CASE REPORT Capgras Syndrome in Postictal Delirium..............................................................37 by Devavrat Joshi, MD; Sharad Koirala, MD; Sachin Lamichhane, MD; Anubha Paladugu, MD; Rupinder Johal, MD; and Steven Lippmann, MD MEYMANDI AT LARGE The Science of Epigenetics ....................................................................................40 by Assad Meymandi, MD, PhD, DLFAPA Information for Authors ........................................................................................44

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[editorial advisory board]

David W. Goodman, MD Assistant Professor, Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences; Director, Suburban Psychiatric Associates, LLC; Director, Adult Attention Deficit Disorder Center of Maryland, Lutherville, Maryland Guy M. Goodwin, DPhil, FRCPsych Professor and Head of University Department of Psychiatry, University of Oxford, United Kingdom John Greist, MD Distinguished Senior Scientist, Madison Institute of Medicine; Clinical Professor of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Philip D. Harvey, PhD Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia Edmund G. Howe, MD, JD Professor, Department of Psychiatry Uniformed Services University of the Health Sciences, Bethesda, Maryland Geetha Jayaram, MD, MBA Associate Professor, Johns Hopkins University, Departments of Psychiatry and Health Policy and Management, Baltimore, Maryland Lewis L. Judd, MD Mary Gilman Marston Professor; Chair, Department of Psychiatry, University of California, San Diego Siegfried Kasper, MD Professor and Chair, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria Jerald Kay, MD Professor and Chair, Department of Psychiatry, School of Medicine, Wright State University, Dayton, Ohio Paul E. Keck, Jr., MD Craig & Frances Lindner Professor, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio Richard S. E. Keefe, PhD Professor of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina Martin Keller, MD Mary E. Zucker Professor and Chairman, Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, Rhode Island

Sidney H. Kennedy, MD, FRCPC Psychiatrist-in-Chief, University Health Network; Professor of Psychiatry, University of Toronto, Toronto, Ontario, Canada Terence A. Ketter, MD Professor of Psychiatry and Behavioral Sciences; Chief, Bipolar Disorders Clinic, Stanford University School of Medicine, Stanford, California Jelena Kunovac, MD, MS Medical Director, Southern California Women’s Psychiatry, Oceanside, California

Dr. Carlos A. Morra Director, Department of Research, Sanatorio Prof. Leon S. Morra S.A.; Vice President, Morra Foundation for the Progress of Psychiatry; Professor, Postgraduate Course of Psychiatry, Cordoba’s National University; Fellow, Psychopharmacology and History of Psychiatry, CINP; Director, Phobia Club Cordoba, Argentina Charles B. Nemeroff, MD, PhD Leonard M. Miller Professor and Chairman, Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida

Joseph A. Kwentus, MD Professor, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi

Joseph V. Penn, MD, CCHP Director, Mental Health Services UTMB Correctional Managed Care Huntsville, Texas

James F. Leckman, MD Neison Harris Professor of Child Psychiatry and Pediatrics, Director of Research, Child Study Center, Yale University School of Medicine, New Haven, Connecticut

Sheldon H. Preskorn, MD Professor of Psychiatry, University of Kansas School of Medicine, Chief Executive Officer and Medical Director, Clinical Research Institute Wichita, Kansas

James B. Lohr, MD Vice Chair, Clinical Affairs, Department of Psychiatry, University of California, San Diego, Director, Center of Excellence for Stress and Mental Health (CESAMH), San Diego, California

Mark H. Rapaport, MD Chairman, Department of Psychiatry and Behavioral Neurosciences; the Polier Endowed Chair of Schizophrenia and Related Disorders, Cedars-Sinai Medical Center; Vice Chairman and Professor in Residence, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California

Maju Mathews, MD, DPM, MRCPsych Assistant Professor of Psychiatry, Drexel University College of Medicine, Medical Director, Psychiatric Medical Care Unit, Hahnemann University Hospital, Philadelphia, Pennsylvania Roger S. McIntyre, FRCPC, MD Head, Mood Disorders, Psychopharmacology Unit, University Health Network, Associate Professor of Psychiatry and Pharmacology, University of Toronto Toronto, Ontario, Canada Philip Merideth, MD, JD Chief Medical Officer, Brentwood Behavioral Healthcare of Mississippi; Clinical Associate Professor, Department of Psychiatry, University of Mississippi Medical Center, Jackson, Mississippi Charles A. Morgan III, MD, MA Associate Professor of Psychiatry; Research Affiliate, History of Medicine, Yale University School of Medicine, New Haven, Connecticut

Jerrold F. Rosenbaum, MD Psychiatrist-in-Chief, Massachusetts General Hospital, Stanley Cobb Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts Gary S. Sachs, MD Associate Professor of Psychiatry, Harvard Medical School; Director Bipolar Clinic and Research Program, Massachusetts General Hospital, Boston, Massachusetts Randy A. Sansone, MD Professor of Psychiatry and Internal Medicine, Wright State University School of Medicine, Dayton; Director of Psychiatry Education at Kettering Medical Center, Kettering, Ohio Alan Schatzberg, MD Kenneth T. Norris, Jr. Professor of Psychiatry and Behavioral Sciences, Chair of the Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford, California

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Thomas E. Schlaepfer, MD Vice Chair of Psychiatry and Psychotherapy, University Hospital, Bonn, Germany; Associate Professor of Psychiatry and Mental Health, The Johns Hopkins University, Baltimore, Maryland David V. Sheehan, MD, MBA Professor of Psychiatry, Director, Depression and Anxiety Disorders Research Institute, University of South Florida College of Medicine, Tampa, Florida Jair C. Soares, MD Yeargan Distinguished Professor, Department of Psychiatry, University of North Carolina, Chapel Hill Stephen M. Stahl, MD, PhD Professor of Psychiatry, University of California San Diego, San Diego, California Michael M. Stone, MD Assistant Professor, Department of Psychiatry and Behavioral Science, University of Texas Medical Branch, Galveston, Texas Steven D. Targum, MD Massachusetts General Hospital, Boston, Massachusetts Michael E. Thase, MD Professor, Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Madhukar H. Trivedi, MD Professor of Psychiatry, Betty Jo Hay Distinguished Chair in Mental Health, Chief, Division of Mood Disorders, University of Texas Southwestern Medical School, Dallas, Texas Cherian Verghese, MD, MRCPsych Certified Physician Investigator, Medical Director, Keystone Clinical Studies, LLC, Norristown, Pennsylvania Gang Wang, MD Associate Professor, Beijing Anding Hospital, Capital Medical University, Beijing, China Peter J. Weiden, MD Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois

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Trend Watch

merchandisers) from a near-census of pharmacies in the United States. The database captures information from all payer types, including cash.

RESULTS

Generic Penetration in the Retail Atypical Antipsychotic Market by Susan Lenderts, BA; Amir H. Kalali, MD; and Peter Buckley, MD Psychiatry (Edgemont) 2010;7(3):9–10

ABSTRACT

In this article, we explore the penetration of generic atypical antipsychotics in the United States market before and after the availability of generic risperidone in July 2008. Analysis suggests that, overall, generic penetration into the atypical antipsychotic market has grown from approximately three percent in January 2008 to more than 25 percent in December 2009. Similar trends are uncovered when branded and generic prescriptions are analyzed by specialty.

KEY WORDS

atypical antipsychotic, generic, trade, brand, generic penetration, risperidone, prescription, psychiatrists

INTRODUCTION

It has been 18 months since generic risperidone entered the atypical antipsychotic market. We investigated the use of branded versus generic agents in the retail atypical antipsychotic market to understand generic penetration in the atypical antipsychotics overall and by physician specialty.

METHODS

We analyzed monthly retail pharmacy prescription data from SDI Health, which captures more than two billion prescriptions per year. This data set includes prescriptions from a variety of retail sources (e.g., national retail chains, mass [VOLUME

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Prescription data suggests that between 2008 and 2009, retail atypical antipsychotic prescriptions grew by 4.3 percent year-on-year. Figure 1 shows that at the beginning of this timeframe, only 3.1 percent of prescriptions in the retail atypical antipsychotic market were for generic products. Between June 2008 and July 2008, generic penetration grew from 3.2 percent to 15.1 percent; a direct result of the availability of generic risperidone beginning in July 2008. Generic penetration, driven mostly by risperidone, reached 25.1 percent of retail atypical antipsychotic prescriptions in July 2009, and held steady around 25 percent through December 2009. We compared prescriptions for branded versus generic atypical antipsychotics by specialty and found that, like the overall market, there was a jump in generic penetration between June 2008 and July 2008 within psychiatrists, primary care physicians (PCPs), and a grouping of all other specialties writing atypical antipsychotics (Figure 2). Generic penetration trends are similar within the major specialties. Within psychiatry, generics represented 4.1 percent of retail atypical antipsychotic prescriptions in January 2008 and 25.4 percent of prescriptions in December 2009. Analysis of PCP prescribing reveals that generic products represented just 0.6 percent of atypical antipsychotic prescriptions in January 2008 and 22.5 percent of prescriptions in December 2009. Generic penetration has remained slightly lower in PCPs than pyschiatrists over this analysis timeframe. NUMBER

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[trend watch]

FIGURE 1. Share of retail atypical antipsychotic prescriptions: branded products vs. generic products Source: SDI Health VONA, January 2008–December 2009.

EXPERT COMMENTARY by Peter Buckley, MD

These provocative data illustrate how generic risperidone, which became available in July 2008, has been used in relation to other second-generation antipsychotics (SGAs). The data are drawn from multiple pharmacy sources and so represent a broad pharmacoeconomic trend analysis. The generic penetration reached 25 percent of prescriptions by July 2009 and retained that rate for the remaining six-month period of observation. The effect is seen among both psychiatrists and primary care physician (PCP) prescribers. This “uptake” of generic risperidone is not surprising, especially given the extent of clinical experience and robust research data concerning “branded” risperidone. Risperidone was one of the first SGAs to become available and it has been widely used. Its use at that early stage in 1993 and onwards displaced first-generation antipsychotics (FGAs) as drugs of choice. When this trend is considered in the context now of a reformulation of the relative 10

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FIGURE 1. Penetration of generic atypical antipsychotic products by specialty Source: SDI Health VONA, January 2008–December 2009.

merits of FGAs versus SGAs, the advent of a generic alternative of a SGA represents a key event; especially since cost has weighted heavily in FGA versus SGA comparisons. Generic alternative to SGAs represent real opportunities for systems of care to save dollars while maintaining a commitment to “modern-day” pharmacotherapy for schizophrenia. It is presently unclear if/when generic substitutes of other current SGAs might become available. This will substantially alter the range of choices for clinicians prescribing SGAs. However, the patents for several SGAs have many years left. It is also of interest that the availability and increasing use of generic risperidone has not been associated with the same concerns about deterioration with switching drugs. This was a concern when generic forms of clozapine became available, and there were inconsistent reports in the literature. Overall, however, it appears that generic and branded clozapine are therapeutically similar. The same is likely, in my 3,

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opinion, for generic and branded risperidone. FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURES: Dr. Buckley has received grant/research support, consulted to, or is on the speakers bureaus of the following companies: National Institute of Mental Health, Janssen Pharmaceutical, and Pfizer. Ms. Lenderts and Dr. Kalali have no conflicts of interest relevant to the content of this article. AUTHOR AFFILIATIONS: Ms. Lenderts is Manager, Strategic Analytics, Quintiles Commercial, Falls Church, Virginia; Dr. Kalali is Vice President, Global Therapeutic Group Leader CNS, Quintiles, Inc., and Professor of Psychiatry, University of California, San Diego, California. Dr. Buckley is Professor and Chairman, Department of Psychiatry, Medical College of Georgia, Augusta, Georgia. ADDRESS CORRESPONDENCE TO: Susan Lenderts, Manager, Strategic Analytics, Quintiles Commercial, 3130 Fairview Park Drive, Suite 501, Falls Church, VA 22042; E-mail: [email protected]

The Interface

be specific mediating variables that modulate the likelihood that an individual with a personality disorder will experience work difficulties. These include the type of personality disorder, degree of neuroticism and disagreeableness, extent of social dysfunction, and severity of symptoms—all of which appear to be interrelated. Because employment generally promotes an individual’s stability, further research into these variables is essential.

KEY WORDS

Axis II disorders, employment, functionality, personality disorders, work

INTRODUCTION

PERSONALITY DYSFUNCTION AND EMPLOYMENT DYSFUNCTION:

Double, Double, Toil and Trouble by Randy A. Sansone, MD, and Lori A. Sansone, MD Psychiatry (Edgemont) 2010;7(3):12–16

This ongoing column is dedicated to the challenging clinical interface between psychiatry and primary care—two fields that are inexorably linked.

ABSTRACT

According to the Diagnostic and Statistical Manual of Mental Disorders, personality disorders are characterized by functional impairment, which may unfold in the work environment. A number of 12

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empirical studies convincingly suggest that the presence of personality dysfunction has substantial negative and diffuse effects on work functioning. However, not all studies are in agreement. In addition, there may 3,

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Personality disorders are relatively prevalent in community populations. For example, through a meta-analysis, Lenzenweger1 found that the median prevalence of any personality disorder in the general populations of three different countries (i.e., an analysis of six major studies) is 10.6 percent. Blanco et al2 conducted face-to-face psychiatric interviews with college students (n=2,188) and noncollegeattending peers (n=2,904), and found rates for any personality disorder of 17.7 and 21.6 percent, respectively (i.e., 1 out of every 5 young adults). Moran et al3 examined 1,469 young adults with a mean age of 24 years and encountered Axis II disorders in 18.6 percent. Finally, in a study that examined the causes for involuntary military separation for psychiatric reasons, personality disorders accounted for 11 percent.4 These data underscore the relatively high prevalence rate of personality disorders in various community samples. In this edition of “The Interface,” we examine the potential effects of personality dysfunction on work functioning.

[ t h e i n t e r f a c e ]

PERSONALITY DISORDERS AND IMPAIRED FUNCTIONALITY

According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV),5 an individual with a personality disorder is characterized by some degree of functional impairment, with examples being social and occupational arenas. While work dysfunction is our focus, social dysfunction keenly relates to impaired occupational functioning among those with Axis II disorders. To emphasize this point, Hill et al6 found that pervasive social dysfunction was associated with a 16-fold increase in the odds of having a personality disorder. Furthermore, while functional impairment is a common defining characteristic for many DSM disorders, Ansell et al7 note that the degree of impairment experienced by those with personality disorders is often equivalent to, and at times exceeds, that encountered in those with mood and anxiety disorders. However, is there any direct empirical evidence that personality dysfunction impairs employment?

PERSONALITY DYSFUNCTION AND WORK DYSFUNCTION

While available studies are few in number, the majority indicates that having a personality disorder compromises work functionality. Most of these studies began to emerge in the late 1980s. In the first, Patrick8 examined a sample of workers compensation claimants who were “work ready” (i.e., willing and able to return to work). None demonstrated mean scores on the Minnesota Multiphasic Personality Inventory (MMPI) indicating psychopathology (i.e., scores were in the normal range). In a study by Gordon et al,9 investigators compared psychiatric

“treatment-seekers” with workmen’s compensation “payment seekers.” Payment-seekers were significantly more likely than treatment seekers to have Axis II disorders. Eliashof and Streltzer10 examined the role of “stress” among 26 workers compensation claimants. In this cohort, stress symptoms were most often precipitated by interpersonal issues (56%), with most participants stating that unfair treatment caused their distress (i.e., an inter-relationship between social and occupational dysfunction). In this cohort, 79 percent met the criteria for a personality disorder. In a study of low-back pain patients (N=324), Gatchel et al11 examined relationships between initial symptoms and subsequent chronic disability. In analyses designed to predict outcome in six months, the researchers found that the presence of a personality disorder was a significant predictor for not returning to work. Ekselius et al12 examined a mixed group of medical patients and found that the presence of a personality disorder within the Cluster B category was associated with an earlier age of longstanding employment disability. Burton et al13 examined the long-term employment outcome of 70 individuals with work-related upper-extremity chronic pain; borderline personality was a predictor for poor return to work. Tartaglini et al14 examined corrections officers (N=1029) who voiced complaints of psychological distress. While V-code diagnoses accounted for most lost workdays, the researchers found that personality disorders, in addition to mood and anxiety disorders, were the most disabling conditions. Among a sample of 45 individuals [VOLUME

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in an internal medicine clinic, Sansone et al15 found that, among the employment-disabled, 72 percent met the criteria for borderline personality disorder (BPD). Jackson and Burgess16 examined data from the Australian National Mental Health and Well-Being Survey (N=10,641) and found that having specific types of personality disorders, especially BPD, was strongly associated with lost days of role functioning. In comparing women with (n=214) versus without (n=1004) antisocial personality disorder features, Pajer et al17 found that participants with these Axis II features were more likely to be unemployed. In another Australian sample, Jovev and Jackson18 compared those with BPD to those with another or no personality disorder. Those with BPD reported the poorest levels of interpersonal functioning and found employment stressful and difficult from a coping standpoint. Finally, in an Australian study examining the vocational rehabilitation of injured workers, Wall et al19 found that personality factors (affecting about one third of this cohort) were associated with poorer outcome. What does this sampling of studies from the literature summarily suggest? Personality pathology may be relatively common in those who seek compensation for work-related injuries, do not successfully rehabilitate, do not return to work, and/or are unemployed. In addition, workers with personality pathology may experience greater interpersonal difficulties at work, perceived job stress, impairment in role functioning, and disability. Succinctly, these data indicate that the presence of a personality disorder has pervasive influences on work functionality. NUMBER

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[ t h e i n t e r f a c e ]

Figure 1. Potential mediating variables between personality dysfunction and work dysfunction

STUDIES REFUTING A RELATIONSHIP

Not all studies affirm an association between personality dysfunction and work dysfunction. For example, Owen20 examined personality pathology in 125 chronic low-back pain patients and concluded that personality pathology was not related to return-to-work status at one-year follow-up. In a Spanish study, Sans et al21 examined employee time off for psychiatric reasons. Depression and anxiety were the most frequent reasons, at 48 and 38 percent, respectively, whereas personality disorders accounted for only one percent of individuals (i.e., this percentage is unexpectedly low, given the anticipated frequency of personality disorders in the general population). Ericsson et al22 examined 184 Swedish pain patients with the Karolinska Scales of Personality; neither baseline personality traits nor the diagnosis of a personality disorder were predictors of subsequent disability status. Finally, in a United States study, Gatchel et al23 examined the successful return-to-work of 152 employees following their rehabilitation for low back pain. In this sample, more than 50 percent had an Axis II diagnosis based upon structured clinical interview, but 14

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personality pathology was not a predictive factor for returning to work at the one-year evaluation point. These preceding studies suggest that there must be tempering variables in the relationship between personality dysfunction and work dysfunction. However, these variables have yet to be fully elucidated.

TEMPERING FACTORS BETWEEN PERSONALITY DYSFUNCTION AND WORK DYSFUNCTION

Given that the majority of available studies indicate that personality dysfunction has a potentially detrimental effect on various aspects of employment, what underlying factors are presently known that might mediate this relationship? Personality volatility. Personality disorders vary greatly in terms of their emotional stylings. In comparing the three personality disorder clusters, Cluster B disorders are characterized by emotional, dramatic, and erratic features, as opposed to the odd/eccentric features in Cluster A disorders and the fearful/anxious features in Cluster C disorders. Given our previous discussion about the relevance of social functioning in the successful 3,

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negotiation of the work environment, Cluster B disorders might predictably be the most imperiling. According to Lang and Helweg,24 Cluster B disorders, in particular, are associated with an earlier age of work disability and failure to return to work. Neuroticism and disagreeableness. Given the ongoing discussion around the categorical versus dimensional diagnosis of personality disorders, the five-factor model of personality is particularly relevant to our discussion because of its potential role in Axis II dimensional assessment. According to this model, the most prominent and consistent personality dimensions underlying a large number of personality disorders are neuroticism (i.e., a tendency to experience unpleasant emotions easily, such as anger, anxiety, depression, or vulnerability) and low agreeableness (i.e., disagreeableness).25 In this regard, in a Dutch study, Michon et al26 found that higher levels of neuroticism are significantly associated with subsequent impairment in work functioning, independent of psychiatric diagnosis. These data suggest that neuroticism, an underlying temperamental feature of most of

[ t h e i n t e r f a c e ]

the personality disorders, is an important factor in work impairment. Social dysfunction. Like all psychiatric disorders, personality disorders vary from individual to individual in terms of their severity. In a United Kingdom study, Newton-Howes et al27 surveyed 2,528 workers and randomly interviewed 282 to assess social dysfunction. In this study, social dysfunction and personality dysfunction were inter-related— and to a greater extent than other types of psychopathology. Symptom severity. Like other psychiatric disorders, symptom severity in personality disorders is likely to contribute to functional impairment. In a multisite study comprising five psychiatric hospitals, investigators examined the effects of various types of psychiatric disorders on social disability.28 In this study, the severity of symptoms was the most significant factor in determining the level of social dysfunction, which is secondarily related to occupational functioning. Figure 1 summarizes these various tempering variables.

employment may be a valuable tool for structuring a patient’s environment and promoting stability. Can interventions be developed for those with personality disorders to alleviate key areas that challenge employment? Clearly, the relationship between personality dysfunction and work dysfunction is highly relevant for both psychiatric and primary care clinicians.

REFERENCES 1.

2.

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CONCLUSION

From our review of the empirical literature, there appears to be reasonably strong evidence that personality dysfunction tends to exert a detrimental effect on employment functioning. Importantly, this association is not invariable and there may be a number of tempering factors that mediate this relationship, such as the type of personality disorder, the degree of neuroticism and disagreeableness, the extent of social dysfunction, and symptom severity. Clearly, these relationships warrant further investigation, particularly because

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Lenzenweger MF. Epidemiology of personality disorders. Psychiatr Clin North Am. 2008;31:395–403. Blanco C, Okuda M, Wright C, et al. Mental health of college students and their non-collegeattending peers. Arch Gen Psychiatry. 2008;65:1429–1437. Moran P, Coffey C, Mann A, et al. Dimensional characteristics of DSM-IV personality disorders in a large epidemiological sample. Acta Psychiatr Scand. 2006;113:233–236. Hoge CW, Toboni HE, Messer SC, et al. The occupational burden of mental disorders in the U.S. military: psychiatric hospitalizations, involuntary separations, and disability. Am J Psychiatry. 2005;162:585–591. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: 1994. Hill J, Pilkonis P, Morse J, et al. Social domain dysfunction and disorganization in borderline personality disorder. Psychol Med. 2008;38:135–146. Ansell EB, Sanislow CA, McGlashan TH, Grilo CM. Psychosocial impairment and treatment utilization by patients with borderline personality

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disorder, other personality disorders, mood and anxiety disorders, and a healthy comparison group. Compr Psychiatry. 2007;48:329–336. Patrick J. Personality characteristics of work-ready workers’ compensation clients. J Clin Psychol. 1988;44:1009–1012. Gordon RE, Eisler RL, Gutman EM, Gordon KK. Predicting prognosis by means of the DSMIII multiaxial diagnoses. Can J Psychiatry. 1991;36:218–221. Eliashof BA, Streltzer J. The role of “stress” in workers’ compensation stress claims. J Occup Med. 1992;34:297–303. Gatchel RJ, Polatin PB, Kinney RK. Predicting outcome of chronic back pain using clinical predictors of psychopathology: a prospective analysis. Health Psychol. 1995;14:415-420. Ekselius L, Eriksson M, von Knorring L, Linder J. Personality disorders and major depression in patients with somatoform pain disorders and medical illnesses in relation to age at onset of work disability. Eur J Psychiatry. 1996;10:35–43. Burton K, Polatin PB, Gatchel RJ. Psychosocial factors and the rehabilitation of patients with chronic work-related upper extremity disorders. J Occup Rehabil. 1997;7:139–153. Tartaglini AJ, Safran DA. A topography of psychiatric disorders among correction officers. J Occup Environ Med. 1997;39:569–573. Sansone RA, Hruschka J, Vasudevan A, Miller SN. Disability and borderline personality symptoms. Psychosomatics. 2003;44:442. Jackson HJ, Burgess PM. Personality disorders in the community: results from the

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Australian National Survey of Mental Health and Well-Being Part III: relationships between specific type of personality disorder, Axis I mental disorders and physical conditions with disability and health consultations. Soc Psychiatry Psychiatr Epidemiol. 2004;39:765–776. Pajer K, Stouthamer-Loeber M, Gardner W, Loeber R. Women with antisocial behaviour: longterm health disability and helpseeking for emotional problems. Crim Behav Ment Health. 2006;16:29–42. Jovev M, Jackson HJ. The relationship of borderline personality disorder, life events and functioning in an Australian psychiatric sample. J Pers Disord. 2006;20:205–217. Wall CL, Ogloff JR, Morrissey SA. The psychology of injured workers: health and cost of vocational rehabilitation. J Occup Rehabil. 2006;16:513–528. Owen EM. Personality pathology in patients with chronic low back disability: assessment and treatment effects. Dissert Abst Int. 1995;55:5082B. Sans M, Batalla C, Villagrasa D, Ezpeleta A, Escorza S, Comin E.

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Temporal disability caused by psychiatric pathology at a health center. Aten Primaria. 2000;25:412–416. Ericsson M, Poston WS, Linder J, et al. Depression predicts disability in long-term chronic pain patients. Disabil Rehabil. 2002;24:334–340. Gatchel RJ, Polatin PB, Mayer TG, Garcy PD. Psychopathology and the rehabilitation of patients with chronic low back pain disability. Arch Phys Med Rehabil. 1994;75:666–670. Lang UE, Hellweg R. Prevalence and role of psychiatric disorders in disability. Versicherungsmedizin. 2006;58:164–169. Saulsman LM, Page AC. The fivefactor model and personality disorder empirical literature: a meta-analytic view. Clin Psychol Rev. 2004;23:1055–1085. Michon HW, ten Have M, Kroon H, et al. Mental disorders and personality traits as determinants of impaired work functioning. Psychol Med. 2008;38:1627–1637. Newton-Howes G, Tyrer P, Weaver T. Social functioning of patients with personality disorder in secondary care. Psychiatr Serv. 2008;59:1033–1037.

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Rymaszewska J, Jarosz-Nowak J, Kiejna A, et al. Social disability in different mental disorders. Eur Psychiatry. 2007;22:160–166.

FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article. AUTHOR AFFILIATIONS: Dr. R. Sansone is a professor in the Departments of Psychiatry and Internal Medicine at Wright State University School of Medicine in Dayton, Ohio, and Director of Psychiatry Education at Kettering Medical Center in Kettering, Ohio; Dr. L. Sansone is a family medicine physician (government service) and Medical Director of the Primary Care Clinic at Wright-Patterson Air Force Base. The views and opinions expressed in this column are those of the authors and do not reflect the official policy or the position of the United States Air Force, Department of Defense, or US government. ADDRESS CORRESPONDENCE TO: Randy A. Sansone, MD, Sycamore Primary Care Center, 2115 Leiter Road, Miamisburg, OH 45342; Phone: (937) 3846850; Fax: (937) 384-6938; E-mail: [email protected].

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SERIES EDITOR: PAULETTE M. GILLIG, MD, PhD Professor of Psychiatry, Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, Ohio

CRANIAL NERVE VIII: Hearing and Vestibular Functions by RICHARD D. SANDERS, MD, and PAULETTE MARIE GILLIG, MD, PhD

Dr. Sanders is Associate Professor, Departments of Psychiatry and Neurology, Boonshoft School of Medicine, Wright State University, and Ohio VA Medical Center, Dayton, Ohio. Dr. Gillig is Professor of Psychiatry and Faculty of the Graduate School, Department of Psychiatry, Wright State University, Dayton, Ohio Psychiatry (Edgemont) 2010;7(3):17–22 In this series, Drs. Sanders and Gillig explain how aspects of the neurological examination can aid in differential diagnosis of some common (and some uncommon) disorders seen in psychiatric practice.

ABSTRACT

Cranial nerve VIII brings sound and information about one’s position and movement in space into the brain. The auditory and vestibular systems subserve several functions basic to clinical medicine and to psychiatry. This article covers the basics of cranial nerve VIII, hearing and vestibular systems, including common problems with hearing and balance, problems with hearing and balance that tend to be found in psychiatric patients, and some simple assessments of value in clinical practice.

INTRODUCTION

The eigth cranial nerve is deeply involved in clinical medicine. Hearing is of course central as patients generally hear our questions and we hear their answers. Routine assessment and treatment depend heavily on intact hearing. Some of the most common complaints in general medicine are vestibular (such as dizziness) and auditory (such as tinnitus and hearing impairment). This article covers the essential anatomy and physiology, abnormal clinical signs found in

FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURE: The authors have no conflicts of interest relevant to the content of this article. ADDRESS CORRESPONDENCE TO: Paulette Gillig, MD, Professor, Dept. of Psychiatry, Boonshoft School of Medicine, Wright State University, 627 S. Edwin C. Moses Blvd., Dayton, OH 45408-1461; E-mail: [email protected] KEY WORDS: psychiatry and neurology, hearing acuity, vestibular testing, deafness, vertigo, tinnitus, Meniere’s disease [VOLUME

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clinical psychiatry, and how to elicit these signs.

RELEVANT ANATOMY AND PHYSIOLOGY

Auditory system. The ear is commonly divided into outer, middle, and inner parts. The outer conducts air pressure waves to the tympanic membrane. The middle conducts pressure through the solid medium of the three ossicles, from the tympanic membrane to the oval window. The inner conducts waves through a fluid medium along the organ of Corti, triggering impulses in its hair cells, which correspond to specific frequencies. These form the auditory branch of the eighth cranial nerve and synapse on the ipsilateral cochlear nuclei in the rostral medulla. A majority cross over to join the lateral lemniscus, traveling rostrally to the midbrain inferior colliculus. From there, short neurons reach the medial geniculate nucleus, which projects via internal capsule to primary auditory cortex on the superior temporal gyrus. Vestibular system. As with the acoustic branch, vestibular nerve impulses encoding motion and position originate in hairs within fluid-filled cavities. These cavities, the semicircular canals, utricle and saccule (collectively the labyrinth), are positioned so that any change or rotation is uniquely codified. The vestibular branch of the eigth cranial nerve closely adjoins the auditory. Its neurons synapse in vestibular nuclei, as well as in the rostral medulla. The vestibular nuclei project to many locations with intuitive relevance, including cerebellum, spinal cord, extraocular nuclei (nystagmus), parietal cortex (spatial orientation), vagal nucleus (vomiting), nucleus solitarius (nausea), and reticular formation (pallor, diaphoresis).

SIGNS AND SYMPTOMS

Auditory system. Poor hearing acuity is a common and disruptive symptom. It affects about 10 percent of the population, with major effects on communication, social

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interaction, and cognition. At least 0.1 percent are congenitally deaf.1 The most common causes of acquired hearing loss are noise exposure (sensorineural damage at the organ of Corti), otosclerosis (conductive damage at the middle ear ossicles), otitis media (middle ear inflammation interfering with conduction), cerumen impaction (mechanical blockage of the outer ear, interfering with conduction), presbycusis (age-associated sensorineural hearing loss), trauma, and Meniere’s disease (transient loss of hearing associated with attacks, sometimes permanent deficits after multiple attacks). Available data suggest that hearing impairment is associated with mental illness and mental retardation.2 Fetal alcohol syndrome is strongly associated with hearing impairment of several types.3 Autism or autistic features may be specifically associated with deafness. Paradoxically, auditory hypersensitivity is quite common in autism.4 Those who are deaf may be more impulsive and may have more personality disorders.2,5 Those with acquired (but not hereditary) deafness are at higher risk for attention deficit hyperactivity disorder (ADHD).5 Hearing acuity deficits are present in at least two percent of people over 65 years of age.6 Like visual deficits, they are thought to contribute to age-related psychopathology, including social withdrawal and depression.7 Hearing deficits are also related to cognitive disability, although hearing aids may not bring sweeping improvements in cognition or behavior to the demented.8 Hearing deficit seems to be a risk factor for future psychosis in healthy young people.9–12 It is uncertain whether the link between poor hearing and future psychosis might be due to reduced or distorted sensory input, or whether sensory disability is a less specific marker of early infection13 or some other neurological handicap. Oddly, most studies find basic auditory acuity measures to be normal in

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schizophrenia14–16 and late-life schizophrenia-like illness.17–20 Lowlevel physiological responses, such as brainstem auditory-evoked potentials, are also normal,21 but many deficits in performance and physiological response appear at many higher levels of processing.21–24 Although low hearing acuity is a risk factor for psychosis, it is not a prominent finding in patients with psychosis. Hearing loss is not a prominent feature of mood disorders,25 but it is a common finding, along with weakness and fatigue, in mitochondrial diseases.26 Thus, hearing loss in a patient with prominent weakness or fatigue should raise the question of mitochondrial disease. Bilateral high-frequency loss is found in alcoholism, related to drinking time but not to age.27 Alcohol acutely diminishes acuity across the frequency spectrum28 and impedes central processing.29 Cannabis seems to not have acute effects on auditory sensitivity, but it has interesting effects on higher order perception.29,30 Auditory hallucinations are among the most familiar symptoms in psychiatry, although reported by less than one percent of the adult population (except for sleepassociated hallucinations, which are common31) and about 75 percent of patients with schizophrenia. The symptom is accepted as unremarkable under certain circumstances, such as severe sleep deprivation and sleep onset. Some believe that healthy preliterate humans routinely hallucinated, as they seemed to in the stories of the Greek epic poet Homer and the Old Testament.32 Whether modern patients and ancient heroes, however, when it comes to the term auditory hallucination, most often we are referring to “voices” (intelligible speech), which is a particular type of complex hallucination. Much less common are musical hallucinations, which are strongly associated with deafness13 and occasionally other neurological conditions.33 Tinnitus affects at least 30 percent of the population at some

point, and leads at least 10 percent to seek medical attention.34 Most tinnitus consists of a continuous higher-pitched tone. Called subjective tinnitus, it could be considered a rudimentary auditory hallucination. Strongly associated with acquired hearing loss, its mechanism is thought to involve disinhibition and cortical remapping, similar to the development of phantom limb pain after loss of normal sensory input. Subjective tinnitus should be distinguished from the uncommon objective tinnitus for which an explanation can be found. Objective tinnitus tends to be intermittent, often pulsatile, and lower pitched. Sources include audible turbulence in a vessel near the ear or abnormal activity of muscles in the palate or middle ear. Evaluation of tinnitus includes listening around the ear (especially if only one ear is affected) and evaluating hearing with audiometry. Audiologists are indispensible in the management as well as assessment of tinnitus.35,36 Vestibular system. First, it is worth noting that the complaint “dizzy” can include many symptoms associated with anxiety and orthostatic lightheadedness (presyncope), both very common in psychiatry. For present purposes, dizziness is a sense of being off balance. Dizziness is among the most common complaints in medicine, affecting at least 20 percent of the general population.37 Vertigo, a type of dizziness, is a false sense that the self or the environment is moving, caused by asymmetric vestibular dysfunction. It has a one-year prevalence of about five percent in the general population.38 In about 75 percent of cases, vertigo is caused by the more benign peripheral vestibular disorders, but the more sinister central lesions must be excluded. Central lesions (of the pons, medulla, or cerebellum) and peripheral lesions (of the semicircular canals, utricle, saccule, or vestibular nerve) can cause a similar presentation of

vertigo, nausea, vomiting, ataxia, and nystagmus. Examination can accurately distinguish central from peripheral causes, which we will describe later. Patients with a peripheral vestibular lesion can usually stand (although often leaning toward the lesion), while those with a central lesion are often unable to stand without support. Dysarthria, incoordination, numbness or weakness—signs of damage elsewhere in the brain— suggest a central origin.39,40 The most common central causes of dizziness and vertigo are disorders of the vertebrobasilar circulation, migraine, multiple

semicircular canal. It can usually be diagnosed without special tests (described later), and it can be readily treated without medication or surgery.41 Meniere’s disease is characterized by fluctuating, progressive, sensorineural hearing loss; spells of vertigo lasting minutes to hours with vestibular nystagmus; tinnitus (usually); a sense of fullness in the ears; and periods of remission and exacerbation. Its etiology seems to involve edema in the labyrinth. Vestibular neuritis is a syndrome of acute unilateral vestibular failure, with vertigo, nausea, and unsteadiness, but no hearing

When confronted with acute vestibular signs and symptoms in routine psychiatric practice (nausea, dizziness or vertigo, nystagmus, impaired balance), it is important to think early of intoxication, particularly with ethanol or an anticonvulsant, or withdrawal, particularly from a serotonergic antidepressant.47 sclerosis, tumors of the posterior fossa, neurodegenerative disorders, and drug effects.37,41 Common peripheral causes include benign paroxysmal positional vertigo (BPPV), Meniere’s disease, and vestibular neuritis. BPPV is the most common single cause of vertigo and is present in a significant proportion of elderly persons not seeking treatment for dizziness. In a nonspecialty setting, BPPV accounts for around 40 percent of vertigo cases, roughly 30 to 40 percent are due to vestibular neuritis/labrynthitis, about 10 to 15 percent are due to migraine, 10 percent are due to Meniere’s disease, and five percent are due to stroke.38,41 BPPV starts fairly abruptly, remits spontaneously after several weeks, and often recurs after months to years. Dizziness is always caused (or at least aggravated) by movement, but dizzy paroxysms last only seconds to minutes. BPPV is caused by debris in one of the vestibular organs, most often the posterior [VOLUME

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changes. It often follows a viral syndrome. It generally remits in weeks to months. It is quite similar in presentation to stroke; in both, dizzy spells can last for days and there is little fluctuation in symptoms.39,40 Investigators of the early 20th century42 found that patients with schizophrenia showed less nystagmus in response to vestibular stimulation than healthy controls. Modern vestibular research gives no clear answers regarding schizophrenia,43 but there does seem to be an association between anxiety and impaired balance across species,44 an excess of vestibular dysfunction in anxiety patients,45 and an excess of anxiety among patients with vestibular disorders.46 The most specific association is between agoraphobia and peripheral vestibular dysfunction.45 When confronted with acute vestibular signs and symptoms in routine psychiatric practice (nausea, dizziness or vertigo, nystagmus, impaired balance), it is important to NUMBER

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think early of intoxication, particularly with ethanol or an anticonvulsant, or withdrawal, particularly from a serotonergic antidepressant.47

EXAMINATION METHODS

Auditory system. Why not simply note whether or not “conversational hearing” is intact? This approach has inadequate sensitivity—around 50 percent.6 Fortunately, another very efficient method is available, with at least 90-percent sensitivity and at least 80-percent specificity. This is the whispered voice test. Stand behind the patient, with your left arm extended about two feet to the patient’s ear. While occluding the left external auditory meatus with a finger in a rubbing motion (to ensure masking the left ear), whisper as softly as possible a letter, a numeral and another letter (e.g. “b, 8, g”). If the patient repeats the triplet correctly, move on to the other side

If the bad side seems to be softer the damage is probably sensorineural. If the bad side seems to be louder, the damage is probably conductive. If they seem equal, the Weber is inconclusive. The Rinne test is a more accurate test, if conductive hearing loss is suspected. The patient is asked to report which seems louder, as bone and air conduction stimuli are applied. The simplest approach is to hold the tuning fork alternately to the mastoid (lightly but firmly) and about one inch from the ear, each for about two seconds. The tuning fork should be held so that its long axis is perpendicular to the line through the ear canals. If bone conduction is definitely heard better than air conduction (BC>AC), this is strong support for conductive hearing loss.6 Vestibular system. The horizontal head impulse test is a quick vestibulo-ocular reflex used to distinguish the more benign peripheral from the more ominous

Why not simply note whether or not “conversational hearing” is intact? This approach has inadequate sensitivity—around 50 percent.6 Fortunately, another very efficient method is available, with at least 90-percent sensitivity and at least 80-percent specificity. This is the whispered voice test. (use an unrelated letter-number-letter stimulus). If there are any errors, whisper a new triplet to the same side. An abnormal result for an ear is if less than half of the letters or numbers are repeated correctly. For abnormal or questionable results, audiometric testing is in order.6 Having discovered a hearing deficit, one might inquire into its origins. A 512Hz tuning fork is useful for distinguishing sensorineural hearing loss (the problem is at the cochlea or beyond) from conductive hearing loss (sound waves are having trouble getting to the cochlea). If there is unilateral hearing loss, do the Weber test; otherwise, the test is misleading. Hold the vibrating fork firmly to the skull at a midline, and ask if it sounds louder on either side. 20

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central lesions causing vertigo. Approaching a seated and relaxed patient from the front, grasp the head from both sides and instruct the patient to relax and (the examiner must do the work) fixate on your nose. Starting from about 20 degrees rotation off center, rapidly rotate the head to midline, observing the eyes. An abnormal response occurs when the head is rotated toward a vestibular lesion and consists of a quick corrective saccade (gaze shift) once the head stops moving. Without vestibular input, the patient cannot maintain fixation during the head rotation, requiring the adjustment. A normal result on this test (no corrective saccade seen) is strong evidence of central nervous system (CNS) involvement.48

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Some cases with brainstem or cerebellar stroke may have falsepositive head-impulse test results, but display skew deviation. Skew deviation is the vertical deviation of an eye. Ask the patient to fixate on a target, and alternately cover each eye for about two seconds. As the skewed eye is uncovered, it is noted to have deviated vertically. This finding suggests brainstem or cerebellar stroke. Thus, a positive head-impulse test supports a peripheral etiology, but skew deviation would over-ride this result in support of a central lesion.49 The Dix-Hallpike test is the acknowledged gold standard test to diagnose BPPV (specifically BPPV of the posterior semicircular canal, which comprises about 90 percent of BPPV). Start with the patient sitting upright with legs extended. Warn the patient that another brief episode of dizziness and nausea is likely to result from the test. Rotate the patient’s head about 45 degrees, then quickly help the patient assume a supine position with the head still rotated and hyperextended approximately 20 degrees. This extension may be achieved by supporting the patient’s head as it hangs off the table or by placing a pillow under the upper back. Then watch the patient’s eyes for about 45 seconds. If upwards, rotatory nystagmus occurs then the test is positive for BPPV. Nystagmus should take 5 to 20 seconds to develop after assuming the supine position. If nystagmus is predominantly downwards or lacks a rotatory component, a central lesion is more likely. After returning to a seated position and resting, the same exercise should be done to the opposite side.41 If the history is suggestive for BPPV, but the Dix-Hallpike test is negative on both sides, the supine roll test should be done. This is the best available test for lateral semicircular canal BPPV, which makes up about 10 percent of BPPV cases. The patient lies in a supine, flat position, facing the ceiling. After due warnings, rotate the head

quickly to the right about 90 degrees, observing the eyes for nystagmus. In this case, a positive response consists of vigorous horizontal nystagmus (either toward the floor of the ceiling). After recovery, repeat the process with the head turned 90 degrees to the left.41 If this test also produces no delayed nystagmus, BPPV is unlikely.

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SUMMARY

Auditory and vestibular problems are common in all patient populations, and particularly among certain groups of psychiatric patients. Poor auditory acuity detracts from social functioning and increases the risk for psychosis. Hearing acuity is very efficiently and accurately screened, and deficits can be assigned with reasonable accuracy to sensorineural or conductive causes. Vestibular problems are associated with anxiety, agoraphobia in particular. Acute vestibular complaints can usually be quickly and accurately diagnosed without using special tests, through history and examination.

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McGee S. Evidence-based Physical Diagnosis. Philadelphia: Saunders; 2001. Heine C, Browning CJ. Communication and psychosocial consequences of sensory loss in older adults: overview and rehabilitation directions. Disabil Rehabil. 2002;24:763–773. Allen NH, Burns A, Newton V, et al. The effects of improving hearing in dementia. Age Ageing. 2003;32:189–193. O’Neal P, Robins LN. Childhood patterns predictive of adult schizophrenia: a 30-year follow-up study. Am J Psychiatry. 1958;115:385–391. David A, Malmberg A, Lewis G, et al. Are there neurological and sensory risk factors for schizophrenia? Schizophr Res. 1995;14:247–251. Stefanis N, Thewissen V, Bakoula C, et al. Hearing impairment and psychosis: a replication in a cohort of young adults. Schizophr Res. 2006; 85:266–272. van der Werf M, van Boxtel M, Verhey F, et al. Mild hearing impairment and psychotic experiences in a normal aging population. Schizophr Res. 2007;94:180–186. Gordon AG. Schizophrenia and the ear. Schizophr Res. 1995;17:289–291. Bartlett MR. The sensory acuity of psychopathic individuals: a comparison of the auditory acuity of psychoneurotic and dementia praecox cases with that of normal individuals. Psychiatr Q. 1935;9:422–425. Ludwig AM, Wood BS, Downs MP. Auditory studies in schizophrenia. Am J Psychiatry. 1962;119:122–127. Gruzelier JH, Hammond NV. Gains, losses and lateral differences in the hearing of schizophrenic patients. Br J Psychol. 1979;70:319–330. Sjogren H. Paraphrenic, melancholic and psychoneurotic states in the presenile-senile period of life: a study of 649 patients in the functional division. Acta Psychiatr Scand. 1964;40 [VOLUME

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Fitzpatrick D, Eviatar A. The effect of alcohol on central auditory processing (comparison with marijhuana). J Otolaryngol. 1980;9:207–214. Roser P, Juckel G, Rentzsch J, et al. Effects of acute oral Delta9tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers. Eur Neuropsychopharmacol. 2008; 18:569–577. Ohayon, MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res. 2000;97:153–164. Jaynes J. The Origin of Consciousness in the Breakdown of the Bicameral Mind. Boston: Houghton Mifflin; 1976. Sacks O. Musicophilia: Tales of Music and the Brain. New York: Knopf; 2007. Heller AJ. Classification and epidemiology of tinnitus. Otolaryngol Clin North Am. 2003; 36:239–248. Noble W, Tyler R. Physiology and phenomenology of tinnitus: implications for treatment. Int J Audiol. 2007;46:569–574. Crummer RW, Hassan GA.

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Diagnostic approach to tinnitus. Am Fam Physician. 2004;69:120–126. Karatas M. Central vertigo and dizziness: epidemiology, differential diagnosis, and common causes. Neurologist. 2008;14:355–364. Neuhauser HK. Epidemiology of vertigo. Curr Opin Neurol. 2007;20:40–46. Chan Y. Differential diagnosis of dizziness. Curr Opin Otolaryngol Head Neck Surg. 2009;17:200–203. Kerber KA. Vertigo and dizziness in the emergency department. Emerg Med Clin North Am. 2009;27:39–50. Bhattacharyya N, Baugh RF, Orvidas L, et al. Clinical practice guideline: benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 2008;139(Suppl 4):S47–S81. Angyal A, Sherman MA. Postural reactions to vestibular stimulation in schizophrenic and normal subjects. Am J Psychiatry. 1942;98:857–862. Levy DL, Holzman PS, Proctor LR. Vestibular dysfunction and psychopathology. Schizophr Bull. 1983;9(3):383–438. Kalueff AV, Ishikawa K, Griffith AJ.

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Anxiety and otovestibular disorders: linking behavioral phenotypes in men and mice. Behav Brain Res. 2008 10;186:1–11. Jacob RG, Furman JM, Durrant JD. Turner SM. Panic, agoraphobia, and vestibular dysfunction. Am J Psychiatry. 1996;153:503–512. Clark DB, Hirsch BE, Smith MG, et al. Panic in otolaryngology patients presenting with dizziness or hearing loss. Am J Psychiatry. 1994;151:1223–1225. Black K, Shea C, Dursun S, Kutcher S. Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry Neurosci. 2000; 25:255–261. Newman-Toker DE, Kattah JC, Alvernia JE, Wang DZ. Normal head impulse test differentiates acute cerebellar strokes from vestibular neuritis. Neurology. 2008;70:2378–2385. Kattah JC, Talkad AV, Wang DZ, et al. HINTS to diagnose stroke in the acute vestibular syndrome. Threestep bedside oculomotor examination more sensitive than early MRI diffusion-weighted imaging. Stroke. 2009;40:3504.

[REVIEW]

SELECTIVE MUTISM: A Review of Etiology, Comorbidities, and Treatment by PRISCILLA WONG, MD

Dr. Wong is from the Department of Pediatrics, Madigan Army Medical Center, Tacoma, Washington. Psychiatry (Edgemont) 2010;7(3):23–31

ABSTRACT

Selective mutism is a rare and multidimensional childhood disorder that typically affects children entering school age. It is characterized by the persistent failure to speak in select social settings despite possessing the ability to speak and speak comfortably in more familiar settings. Many theories attempt to explain the etiology of selective mutism. Comorbidities and treatment. Selective mutism can present a variety of comorbidities including enuresis, encopresis, obsessive-compulsive disorder, depression, premorbid speech and language abnormalities, developmental delay, and Asperger’s disorders. The specific manifestations and severity of these comorbidities vary based on the individual. Given the multidimensional manifestations of selective mutism, treatment options are similarly diverse. They include individual behavioral therapy, family therapy, and psychotherapy with antidepressants and anti-anxiety medications. Future directions. While studies have helped to elucidate the phenomenology of selective mutism, limitations and gaps in knowledge still persist. In particular, the literature on selective mutism consists primarily of small sample populations and case reports. Future research aims to develop an increasingly integrated, multidimensional framework for evaluating and treating children with selective mutism.

FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURE: The author has no conflicts of interest relevant to the content of this article. DISCLAIMER: The views expressed are those of the author and do not reflect the official policy of the Department of the Army, the Air Force, the Department of Defense, or the US government. ADDRESS CORRESPONDENCE TO: Priscilla Wong, MD, Madigan Army Medical Center, 9040 Fitzsimmons Drive, MCHJ-P, Tacoma, WA 98431; E-mail: [email protected] KEY WORDS: selective mutism, elective mutism, social phobia, psychodynamic theory, behavioral theory, family systems perspective, dissociative identity disorder, post-traumatic stress disorder, play therapy, self-reinforcing, stimulus fading, video feed forward, response initiation [VOLUME

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CASE EXAMPLE

Chloe’s parents knew something was wrong when they were told by the four-year-old’s preschool teacher that she had spoken in school that day for the first time after attending preschool for almost eight months. When Chloe entered the classroom, she appeared hesitant and self conscious and avoided eye contact. She would engage in an assigned task, but not with other children. Her comfort level dropped in a larger group, and she would not interact with the others in a group. If the other children talked to her, she would turn away.

category of disorders first diagnosed in infancy, childhood, or adolescence.1 The social contexts in which the persistent failure to speak occurs are at school and with playmates. In the home with parents and siblings, the child tends to engage in normal conversation. The DSM-IV-TR criteria for selective mutism also specifies that the persistent failure to speak in specific contexts should not be explained by the following: 1. An organic inability rooted in language ability (comprehension and comfort speaking the language)

The evaluation of a patient with selective mutism consists of a comprehensive and multimodal approach.3 Beyond information from parents and teachers, health professionals, such as audiologists, psychiatrists, psychologists, and speech/language pathologists may be involved in the multidimensional assessment. She also did not speak in church or with distant family members, but she was a chatterbox at home. In elementary school, it was not until third grade that Chloe spoke to her teacher for the first time after a devoted teacher did behavioral therapy exercises with her in the summer and prior to and after school. Now in fourth grade, Chloe has made much progress and recently read a report on video. Chloe’s battle with this disorder is not completely over, but she has made tremendous progress. (Adopted from actual testimonials from the Selective Mutism Foundation)

INTRODUCTION AND BACKGROUND

Selective mutism is a rare childhood disorder characterized by the persistent failure to speak in specific contexts where speech is typically expected, despite hearing and speaking in other contexts. It is classified in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), under the 24

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2. Another communication disorder, such as stuttering 3. Concurrent diagnosis of pervasive development disorder, schizophrenia, or other psychotic disorder1 Moreover, the disorder must be present for a minimum of one month and not include the first month of school. The disorder substantially interferes with education, occupational achievement, and social communication.2 Children with social mutism often appear their age and lack coexisting mental and physical defects and diseases.3 The prevalence of social mutism ranges from 0.47 to 0.76 percent of the population based on pooled case studies from Western Europe, the United States, and Israel.4 Previous prevalence has been reported much lower, at 0.03 to 0.2 percent reported across several epidemiological and cross cultural studies.3,5 The wide range reflects the lack of uniformity in establishing the diagnosis from chart review and the infrequent use of standardized assessments.4 Nonetheless, the onset of selective

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mutism typically occurs between ages three and six, and diagnosis occurs between ages five and eight, most often discovered after the child enters school.5 It is slightly more common in girls than in boys, although the difference may be accounted for by research limitations, such as small sample populations and the rare nature of the disorder. The disorder can occur over a few months or persist for several years, although the majority of selectively mute children tend to outgrow the disorder spontaneously for unknown reasons.3,6 However, despite apparent remission, talking behaviors over time remain lower than average, and residual social phobia and other anxiety disorders may persist.7 Although a rare disorder lacking a definite etiology, selective mutism was first identified in the 19th century when Kussmaul named it aphasia voluntaria in 1877 to describe the condition where individuals would voluntarily not speak in certain situations (Figure 1).3 In the early 1930s, the disorder was renamed elective mutism, again emphasizing the elective or voluntary nature of the persistent failure to speak.8 The current DSM-IV-TR diagnosis describes the condition as selective mutism, with the word “selective” emphasizing the select situations characterized by failure to speak rather than the intentional withholding of speech as previous terms implied.

CLINICAL ASSESSMENT OF SELECTIVE MUTISM

The evaluation of a patient with selective mutism consists of a comprehensive and multimodal approach.3 Beyond information from parents and teachers, health professionals, such as audiologists, psychiatrists, psychologists, and speech/language pathologists, may be involved in the multidimensional assessment. Early on, a parent interview reviewing the child’s comprehensive medical history, including in-depth review of prenatal and perinatal course, helps screen for neurological, speech, and language

difficulties and assess trends in cognitive ability, such as the Wechsler Individuals with selective mutism meeting developmental milestones. Preschool and Primary Scale of may exhibit broader developmental The clinician’s direct observation of Intelligence (WPPSI-III), the Otisdelays. For example, a 2000 study by the child provides insight into the Lennon OLSAT-8, the Stanford-Binet Kristensen11 highlights the way child’s level of social interaction, Intelligence Scales SB5, the Ross Test children with selective mutism may communication needs, ability to of Higher Cognitive Processes, and show developmental delay as often as establish friendships, participation in the Cognitive Abilities Test, may be they show anxiety disorders (68.5% social activities, and the overall pursued as part of the comprehensive for comorbid developmental delay extent of inhibition. Details such as evaluation.8 compared to 74.1% for comorbid whether the child actually does Finally, because difficulties with anxiety). Moreover, children with attempt to communicate nonverbally speech and language fluency may selective mutism may conceal their are important to assess. Direct impede language development, these developmental delay in their silence.11 observation by the provider in the dimensions should be assessed. Comorbid psychiatric conditions clinic and home environments sheds Useful tools include testing the child associated with selective mutism valuable information on the child’s with audiotapes for fluency, pitch, include depression, panic disorders, behavior in these various settings and rhythm, inflection, and complexity of dissociative disorders, obsessiveenables comparison of the child’s speech. A nonverbal test, such as the compulsive behavior, and Asperger’s behavior and speaking habits. Direct Peabody Picture Vocabulary Test, disorder.5 Asperger’s disorder is a observation also provides the clinician Third Edition (PPVT-III), may be mild form of autism that inhibits with a sense of the child’s overall used to test receptive language in social interactions, peculiar speech, temperament. Observations recorded children with selective mutism.4,9 and nonverbal communication, such by teachers are as excessive undoubtedly clumsiness.3 A 1877 1934 1994 helpful, although study in 1995 by no standardized Kopp and Aphasia Voluntaria Elective Mutism Selective Mutism form for Gillberg12 found assessing that 7.4 percent FIGURE 1. History of selective mutism diagnosis teachers’ of children with observations is selective mutism available at this time. COMORBID DISORDERS also met criteria for Asperger’s Second, psychiatric symptoms Selective mutism is associated with disorder. While this association has should be explored through a a number of comorbid disorders that not been validated in further studies, structured diagnostic interview using complicate the child’s clinical the 7.4-percent rate is significantly tools such as the Diagnostic Interview presentation. As suggested by the higher than the rate of Asperger’s for Children and Adolescents—parent comprehensive clinical assessment, disorder in the general population version. This assessment assists to these comorbid disorders include (0.3%). Clinicians are still urged to rule out other conditions, such as psychiatric or language/speech investigate Asperger’s in children schizophrenia or mental retardation, development disorders. Indeed, the diagnosed with selective mutism. that impede speech but exclude the literature suggests that many children diagnosis of selective mutism.3 While with selective mutism have premorbid DIFFERENTIAL DIAGNOSIS complex, the psychiatric evaluation speech and language problems In addition to the comorbid may also involve evaluating shyness in (38%).7 This finding is consistent with disorders described above, the the psychosocial and family history. theories that children with selective following conditions on the Further, deeper investigation into mutism avoid speaking out of fear of differential diagnosis include the possible trauma and neurological being teased for mispronouncing a following: transient adaptional injuries should also be considered in word.3 Hence, language development shyness in an adjustment disorder, evaluating potential language and deficiencies should be considered intellectual disabilities, pervasive social impediments. ahead of selective mutism, although it developmental disorders, expressive Hearing tests should be performed is possible for both to present language disorders, mood disorders, to assess whether the disorder is concurrently. Children with selective and hearing impairment. rooted in physiological hearing mutism may also have normal difficulties, which could easily lead to receptive language and cognitive TREATMENT delay in the use of language and skills, but they show subtle expressive Treatment for selective mutism manifest as selective mutism. language deficits not attributable to consists of two primary domains: Depending on the individual age, both social anxiety.10 This association nonmedication- and medication-based academic testing and further highlights the important interventions. Within the psychoeducational testing may be component of speech and language nonmedication-based or indicated. For example, tests for assessment in the initial evaluation. psychotherapeutic approaches, [VOLUME

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psychodynamic therapy, behavioral therapy, and family therapy are among the most common. Within medication-based options, selective seratonin reuptake inhibitors (SSRIs) (fluoxetine in particular) have been shown to improve mutism and anxiety. It is important to recognize that the literature on treatment for selective mutism is difficult to generalize given the rare nature of the disorder and the limitations of primarily case report-based data. To date, no studies have contrasted outcomes for different treatments but steps are being taken in that direction. Psychodynamic therapy. Psychodynamic therapy in children is called individual play therapy.3 This form of treatment is time-intensive

reinforcement of teachers and others interacting with the child may be challenging to manage, negative reinforcement should be identified and addressed as early and directly as possible. Self modeling is one approach that involves viewing edited videotapes modeling appropriate behaviors. The child watches himself receive a desired reward (the mystery motivator) for speaking in an audible and clear tone in front of the class.12 Self reinforcement involves receiving an award upon demonstrating the appropriate speaking behavior. Stimulus fading involves attenuating the anxietyprovoking stimulus gradually. For instance, new classmates are gradually introduced into settings

Within the nonmedication-based or psychotherapeutic approaches [to treating selective mutism], psychodynamic therapy, behavioral therapy, and family therapy are among the most common. Within medication-based options, selective seratonin reuptake inhibitors (SSRIs) (fluoxetine in particular) have been shown to improve mutism and anxiety. and involves a comprehensive exploration of the individual case history. The focus is on exposing an underlying intrapsychic conflict.3 Since only a few case studies have been examined, the efficacy of this psychodynamic therapy is unknown. Behavioral therapy. Behavioral therapy is typically a multimethod approach that must account for symptoms in the broader context of the child’s environment. Specific techniques including reinforcement, stimulus fading, token procedures, shaping or prompting, contingency management, self-modeling, and response initiation provide more empirical data-substantiating efficacy.3 Treatment ideally begins with addressing the verbal and nonverbal negative reinforcement that sustains selective mutism behavior. For example, teachers who withdraw requests for children to speak exhibit one form of negative reinforcement that sustains behavior.6 While the 26

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where the individual will likely speak. The spacing effect describes the process of spacing material out rather than presenting one large novel stimulus. This approach is intended to facilitate better context-specific speaking.12 Another treatment approach combines self reinforcement, stimulus fading, and spacing effect along with antidepressant medication and selfmodeling procedure. Among the small population prescribed this regimen (N=2), the self-modeling procedure was identified to precipitate behavior change.12 Other variations of self-modeling employ video technology, such as video feed-forward. This technique videotapes children talking fluently in familiar contexts and then edits the video to show the child talking fluently among strangers or at school. Holmbeck and Lavigne13 found it to be effective in initiating speech. From video self-modeling, audiotapes

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emerged as a more economic alternative. Segments of questions and answer sessions were modified to play the child talking in contexts and situations where the child was previously mute. Blum et al14 also found this method to be effective in specific populations, but was limited in the short duration of the tapes and the need for frequent listening to achieve efficacy. Another bedrock behavioral approach to selective mutism is contingency management, where the aim is to identify and specifically reward verbal behavior and not reinforce mute behavior.3 Often, teachers and peers must be involved for the approach to succeed, and this is not always practical. Moreover, the efficacy of this strategy is equivocal. Another behavioral approach called response initiation involves one-onone time between the child and the therapist.15 The two are left alone to spend an entire day together and the child is required to speak before leaving. This is achieved by the therapist rapidly developing rapport with the child using nonverbal play and empathetic statements. The therapist’s strategy is to provide empathy and support, clarify feelings, provide encouragement, and clearly state the expectation that the child say a minimum of one world prior to leaving.15 If the child remains silent, the therapist pretends to ignore the patient and prolongs the encounter. The therapist directly appeals to the child’s drive toward mastery and control and emphasizes how talking empowers them to show teachers how smart they are, to make more friends, to play like other children, and so forth. Upon speaking, the child is rewarded and permitted to go home. Surprisingly, children who have tried this treatment typically respond by speaking within one to two hours, and only rarely is more than four hours required.15 Family therapy. Family therapy is another treatment option that is especially relevant when family factors play a role in the potential development and perpetuation of selective mutism.16 While the

effectiveness of family therapy is unproven, incorporating the family in the therapeutic process can play a vital role in the child’s recovery. Cooperation and understanding from parents and siblings helps the child overcome anxiety and avoidance. Collaborating with school staff is another vital component of healing given that the diagnosis is usually made as children become school age. Education about selective mutism should be clearly communicated to teachers and guidance counselors, as teachers can play an invaluable role in breaking cycles of negative reinforcement.6 Medication-based interventions. Pharmacotherapeutic interventions play a role in treating selective mutism given the association between selective mutism and social anxiety. In a large survey sent to child and adolescent psychiatrists, Carlson et al17 showed that antidepressants were used most commonly to treat selective mutism. After antidepressants, anti-anxiety medications and other psychotropic interventions are also employed depending on the child’s comorbidities.6 SSRIs (fluvoxamine and fluoxetine in particular), have yielded decreased selective mutism symptoms in selective case reports. The disinhibitory adverse effects of SSRIs theoretically enhance the effectiveness in treating selective mutism, which is considered an inhibitory behavior.9,17 In a trial by Black and Uhde18 among six children with selective mutism, children actively administered fluoxetine over a period of 12 weeks showed improved ratings on mutism and anxiety although other symptoms remained unchanged.18 In a separate case report written by Black and Udhe,16 a 12-year-old girl who had never spoken at school was treated successfully with fluoxetine. Although other approaches to treatment including psychotherapy, behavioral therapy, and despiramine failed to demonstrate efficacy for this individual, taking fluoxetine for one month resulted in this girl speaking freely with teachers and peers.

Moreover, at seven months, other social communication and interactions were normal after evaluation.16 To date, no research data shed light on the difference between exclusive serotonin reuptake inhibition versus both serotonin and norepinephrine reuptake inhibition. This individual case report revealing decreased efficacy of the tricyclic antidepressant despiramine compared to a SSRI suggests that norepinephrine may play less of a role in the neurobiology of selective mutism. In 1996, Dummit et al19 determined that children with selective mutism taking fluoxetine for nine weeks showed decreased anxiety and mutism in public. These studies appear promising but are limited by a small sample size and ambiguity about whether fluoxetine is more efficacious in treating both anxiety and selective mutism or selective mutism alone. Moreover, the data reflect only a few case studies, as children and adolescents are commonly excluded from clinical trials. Other case report studies suggest the enhanced effectiveness of combination treatments. For example, Wright et al20 reported a positive response to treatment with fluoxetine in a combined treatment plan that also included family and behavioral therapy . The four-year-old female patient in the case report at the beginning of this article began talking in familiar surroundings after just five days of medication and continued to improve so that talking in all settings was observed by 20 days.20 Golwyn and Weinstock21 described a case report on the use of phenelzine in a seven-year-old female patient with selective mutism and shyness. After six weeks of phenelzine, the child was observed to respond to the medication. The authors speculate that a positive family history of social phobia in this patient may have played a role in dually treating social phobia and selective mutism.21 Since isolated case reports and small sample sizes characterize the current research on pharmacotherapy in selective mutism, it is difficult to draw clinical conclusions, as no large[VOLUME

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scale pharmacotherapy trials have been performed to date. Still, among the pharmacotherapeutic options available, SSRIs are most commonly recommended for selective mutism. Second-line treatment may involve monoamine oxidase inhibitors (MAOIs), although these drugs are associated with more food and drug interactions compared to SSRIs and pose increased risk for the child. Consideration of proper pediatric administration is of utmost importance.6 To date, no studies have contrasted outcomes for different treatments, but steps are being taken in that direction. For example, a small, preliminary, nonrandomized study suggested that in patients who were severely mute, medication treatment with SSRIs yielded improvement in symptoms in 6 to 8 months.22 This improvement was limited to the severely mute population. This improvement was limited to the severely mute population and was not attained by patients who were not medicated (e.g., only received nonmedication-based therapies such as speech therapy or psychotherapy, or who received no therapy at all), without distinguishing between the types of nonmedicationbased treatment. Moreover, it lacked outcome data on combination medication and therapy. Still, despite the weak evidence and lack of longterm data derived from this type of a comparative study, medication treatment with SSRIs appears to yield promising data given that nonmedication-based therapies are inherently nonuniform in nature, making them difficult to replicate and objectively compare. Nonetheless, this pilot study illustrates that comparative trials are needed to guide decisions regarding interventions and increase the likelihood these children can develop normally.

THEORIES ON THE ETIOLOGY OF SELECTIVE MUTISM

Many theories attempt to explain the etiology of selective mutism. Etiological perspectives are based in psychodynamic theory, behavioral theory, associations with social phobia NUMBER

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and social anxiety, the family systems perspective, dissociative identity disorder, and the response to trauma. Most recently, the developmental psychopathology framework aims to integrate multiple theoretical perspectives (biological, genetic, developmental, psychodynamic, behavioral, family systems, and ecological).4 Psychodynamic theory. Psychodynamic theory emphasizes the concept of unresolved conflict. In the context of selective mutism, the assumption is that the child has an oral and/or anal fixation and may be maintaining a family secret, displacing anger toward a parent, or regressing to a nonverbal stage in his or her development.2 The child’s selective mutism is viewed as a coping mechanism for dealing with anger and anxiety, and represents behavior

significant because it frames selective mutism as a symptom of anxiety rather than consciously manipulative behavior.24 Social phobia and social anxiety. More recently, selective mutism has been explained in the context of social phobia, as proposed by Black and Uhde.16 They propose that selective mutism is a variant of social phobia characterized by excessive social anxiety. Black and Uhde based this theory on data showing high incidences of selective mutism in families with social phobia. They argue that adults with social phobia report higher rates of avoiding public speaking and behaviors consistent with selective mutism in childhood. Under this model, the persistent refusal to speak is a symptom of anxiety.16 Hence, Black and Uhde suggest that selective

Melfsen keenly points out that the age of onset of selective mutism coincides more closely with shyness, a weaker subcategory of social phobia, which manifests on average at age four. intended to punish the parents.3 With little empirical data to support this model, this explanation is currently losing validity. Behavioral theory. Behavioral theory offers a different explanation of selective mutism based in negatively reinforced learning.23 The failure to speak is interpreted as a learned strategy for manipulating the environment in response to a variety of social triggers. Behavioral psychologists argue that mutism is a child’s adaptive response rather than pathological.3 Children with selective mutism appear frozen and inactive due to behavioral inhibition. In novel social situations, the sympathetic nervous system takes inhibitory control over behavior and ability to speak. In this context, selective mutism is portrayed as an unconscious, language-based form of behavioral inhibition or as a defense mechanism. This perspective is

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mutism may belong on the spectrum of childhood speech, inhibition, and social anxiety disorders. While some researchers support this proposal, a more recent study challenges the notion that selective mutism is explained by anxiety and social phobia. Melfsen et al22 investigated the extent of social anxiety in different mental disorders using the Social Phobia and Anxiety Inventory (SPAIK), the German version of the Social Phobia and Anxiety Inventory for Children (SPAIC). The study’s findings did not support the classification of selective mutism as a manifestation of high social anxiety because selectively mute children scored lower on the SPAIK compared to children who had social phobia.22 Based on this data, Melfsen suggests that if selective mutism is an extreme manifestation of social phobia, the SPAIK score for children with selective mutism should

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fall within the same range as those with social phobia. Moreover, the age of onset of selective mutism does not coincide with the age of onset in individuals with social phobia. Selective mutism occurs between ages three and six but social phobia typically manifests between ages 11 and 13. Since social phobia requires a certain degree of cognitive development, the early onset of selective mutism is inconsistent with the development necessary to be considered social phobia. Instead, Melfsen keenly points out that the age of onset of selective mutism coincides more closely with shyness, a weaker subcategory of social phobia, which manifests on average at age four. Lastly, the argument for why selective mutism does not belong under the social phobia classification relates to prognosis. Most children with selective mutism outgrow the disorder spontaneously, while individuals with social phobia do not outgrow the disorder.22 Yaganeh et al26 pursued another comparison of children with selective mutism and social phobia and children with selective mutism alone. This study found that while individuals with selective mutism show a higher prevalence of social anxiety and social phobia, selective mutism is not simply an extreme manifestation of social distress. Instead, self report data revealed only moderate levels of social anxiety in individuals with selective mutism, a finding consistent with previous studies.26,27 Hence, this literature suggests that extreme social distress may not fully account for selective mutism. Moreover, Yaganeh27 explores the oppositional behavior observed in children with selective mutism. This is reflected in earlier labels, such as aphasia voluntaria and elective mutism, emphasizing that children with selective mutism deliberately choose not to speak out of defiance or in an attempt to manipulate others. In this context, children with selective mutism are construed as disobedient,

stubborn, controlling, manipulative, and passive-aggressive.27 In Yaganeh’s study, oppositional behavior was reported by clinician-observers but not reported by parents. This disparity again suggests that the incongruence may be due to both parental bias and/or clinical misinterpretation of observed behavior. On one hand, parental bias occurs when parents reinforce mute behavior by smiling, laughing, or speaking for the child rather than recognize the oppositional component of the behavior. On the other hand, clinicians tended to identify higher rates of speech and language disorders, less developed social skills, and increased social anxiety in selectively mute children despite unproven deficits.27 Still, potential differences in speech, language, subsequent social skills, and social anxiety inadequately explain speech refusal behavior in children with selective mutism. Yaganeh warns against overemphasizing the oppositional nature of selective mutism, wary that the label may itself represent a premature interpretation. Since oppositional characteristics are not observed in a majority of children with selective mutism, the attention given to the oppositional behavior model may be unwarranted. Family systems theory. Another theory for selective mutism is the family systems model. This perspective is based on the observation that many children experience “neurotic” relationships with their parents (most commonly the mother). Typically, parents exhibit an excessive need to control their child along with an associated dependence and ambivalence.3 As a result, children develop unhealthy intense attachments characterized by extreme interdependency and subsequent fear and distrust of the outside world, fear of strangers, language and assimilation difficulties, and withholding speech.27 Indeed, parenting style and the nature of the parent-child relationship play a role in many anxious or inhibited childhood behaviors

TABLE 1. Theories on the etiology of selective mutism ETIOLOGY

DESCRIPTION

Psychodynamic theory

Based on the concept of unresolved conflict. Underlying oral or anal fixation persists. Mutism represents a coping mechanism for anger and anxiety and a means for punishing parents

Behavior theory

Learned behavior for manipulating the environment in response to triggers. An adaptive response to sympathetic nervous system arousal that affects behavior including speech.

Social anxiety and phobia

Association between selective mutism and excessive social anxiety. Selective mutism falls on the extreme end of the spectrum of social anxiety disorders

Family systems perspective

Intense attachments to parents lead to extreme interdependency and distrust of the outside world.

Response to Trauma

Association with posttraumatic stress disorder as a potential, albeit uncommon, cause. Case studies of children exposed to extreme trauma or abuse reveal mutism as an avoidance reaction to trauma.

Dissociative identity disorder

Possessing multiple identities inhibits individual from talking to other people of our fear of revealing traumatic conflicts and experiences

including selective mutism. Parentchild enmeshment and overdependence is shown to be related to the development of selective mutism.27 An abnormal parent-child relationship establishes the incorrect notion that the child needs the parent to survive. Hence, the absence of the parent in a context outside the home triggers an intense phobia that manifests as mutism. The origins of this theory lay in behavioral inhibition, a trait that describes the child’s tendency to withdraw, seek a parent, and inhibit play and vocalization following encounters with unfamiliar people and events.29 Recurrent displays of behavioral inhibition can develop into habitual avoidance of novel situations in the form of withdrawal and mutism.27 [VOLUME

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In studying children with social phobia, psychologists speculate that a child’s perceived maternal acceptance of socially avoidant behavior limits the persistence of such behaviors.26 Yeganeh et al26 compared populations of children with social phobia and children with both social phobia and selective mutism and found that children with both disorders did not differ from normal controls regarding levels of maternal acceptance. However, mothers who expected a child to speak when spoken to and did not tolerate deviation from the normal prevented the development and maintenance of extremely avoidant behaviors. On the other hand, mothers who smiled, laughed, or spoke for the mute child perpetuated the child’s mute NUMBER

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behavior.26 Despite these findings, this theory requires further longitudinal research to elucidate the role of the family environment in shaping mutism. Dissociative identity theory. Selective mutism may also be explained in the context of a dissociative identity disorder. Based on a study of a 15-year-old boy with selective mutism, Jacobsen28 suggests that having multiple identities inhibited the boy from talking to other people out of fear of becoming visible and revealing information about murders he witnessed while assuming different identities.31 This case is unusual in that the individual exhibited selective mutism for years and was clearly outside the typical age of onset before age five. Posttraumatic stress theory. Posttraumatic stress disorder (PTSD) with dissociative features has also been associated as a potential precursor of selective mutism.29,31 Although it is an uncommon explanation for selective mutism, several cases of children who experienced severe abuse and trauma fit the classification of selective mutism. The 15 year-old patient with dissociative identity disorder in the study by Jacobsen28 represents one potential example. In most children with PTSD, symptoms include intrusive thoughts, traumatic play, trauma-related dreams, and flashbacks.30 Children with PTSD may also experience avoidance symptoms, such as avoiding thoughts or feelings associated with the trauma, thus leading to a selective amnesia, decreased interest in activities, and loss of previously acquired developmental skills, such as bowel and bladder control, and communication skills.27 The cessation of speech with the outside world may be a child’s internal coping mechanism for the traumatic event. In these incidences, the child appears to dissociate involuntarily as a result of self defense and display symptoms of PTSD with dissociative features. These include numbness, depersonalization, withholding speech, and displays of restricted 30

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affect, which commonly characterize children with selective mutism. Most often, the connection between selective mutism and PTSD is descriptive and literary rather than linked to actual trauma and highlights the common dissociative characteristics in both disorders. Developmental psychopathology theory. A relatively new and integrated hypothesis for selective mutism derives from a developmental psychopathology framework that emphasizes that multiple contextual variables interact with potential anxious predispositions in children with selective mutism.4 This theory notes that children with early speech or language deficits, previously unaware of their deficits, enter school and face teasing from other children with appropriate language skills. For those children with anxious predispositions, teasing from other children ignites a pattern of avoidance and resultant mutism. This model further incorporates familial interactional styles stating that children who observe familial avoidance as a coping mechanism may reinforce mute behavior in an impressionable child. With a strong emphasis on considering contextual variables interacting with predispositions, the developmental psychopathology approach conceptualizes selective mutism as an avoidant behavior rather than a disorder. Indeed, a wide range of psychological theories and empirical data attempt to explain the etiology of selective mutism (Table 1). However, it is important to emphasize these theories are based on a small set of studies available to date. Given the complexity and rarity of the disorder and the variety of perspectives, a multidisciplinary approach to selective mutism is essential. Theories relating selective mutism and social phobia, anxiety, family history and upbringing, and trauma may intersect as they attempt to explain this disorder, and the developmental psychopathology approach emphasizes the value of a

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multidisciplinary approach to selective mutism.

CONCLUSION

A peculiar yet fascinating childhood disorder, selective mutism is multidimensional in its presentation, proposed etiology, comorbidities, and approach to treatment. Although documented in history since the 19th century, much remains to be elucidated about selective mutism today. Because it is a rare disorder, selective mutism remains challenging to study and many theories persist regarding its etiology and association with other conditions such as social phobia and social anxiety. Hence, the majority of the data on selective mutism derives from case reports and small-scale populations that may not provide an accurate representation of selective mutism in the population. Despite these limitations, much attention has been given to the etiology and comorbidities of selective mutism. These advances ultimately raise awareness of selective mutism as a childhood disorder that can profoundly disrupt the lives of individuals and families. Given the potential impact of this disorder, attention has shifted to the variety of therapeutic approaches to selective mutism, including psychotherapy and pharmacotherapy, both of which show promise especially when employed simultaneously. Undoubtedly, future research is needed to elucidate the biological and psychological components of selective mutism. Ultimately, the goal is to provide patients and families with a comprehensive, empirically proven clinical assessment and treatment options for selective mutism and its comorbidities.

ACKNOWLEDGMENT

The author wishes to thank Edmund G. Howe, MD, JD, Professor of Psychiatry, Uniformed Services University of the Health Sciences.

REFERENCES 1.

American Psychiatric Association. Diagnostic and Statistical Manual

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of Mental Disorders, Text Revision, Fourth Edition. Washington, DC: American Psychiatric Press, Inc.; 2000. Giddan JJ, Milling L. Comorbidity of psychiatric and communication disorders in children. Child Adolesc Psychiatr Clin N Am. 1999;8(1):19–36. Krysanski VL. A brief review of selective mutism literature. J Psychol. 2003;137(1):29–40. Viana AG, Beidel DC, Rabian B. Selective mutism: A review and integration of the last 15 years. Clin Psychol Rev. 2009; 29:57–67. Sharp WG, Sherman C, Gross AM. Selective mutism and anxiety: A review of the current conceptualization of the disorder. J Anxiety Disord. 2006 Aug 30. Kumpulainen K. Phenomenology and treatment of selective mutism. CNS Drugs. 2002;16(3):175–180. Steinhausen HC, Juzi C. Elective mutism: an analysis of 100 cases. J Am Acad Child Adolesc Psychiatry. 1996;35(5):606–614. Dow SP, Sonies BC, Scheib D, et al. Practical guidelines for the assessment and treatment of selective mutism. J Am Acad Child Adolesc Psychiatry. 1995;34(7):836–846. Dunn, LM, Dunn LM. Peabody picture vocabulary test-III. Circle Pines, MN: American Guidance Services, 1997. McInnes A, Fung D, Manassis K, et al. Narrative skills in children with selective mutism: an exploratory study. Am J Speech Lang Pathol. 2004;13(4):304–315. Kristensen H. Selective mutism and comorbidity with developmental disorder/delay, anxiety disorder, and elimination disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(2):249–256. Bray MA, Kehle TJ, Lawless KA, Theodore LA. The relationship of self-efficacy and depression to stuttering. Am J Speech Lang Pathol. 2003;12(4):425–431. Kopp S, Gillberg C. Selective mutism: a population-based study: a research note. J Child Psychol Psychiatry. 1997

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Feb;38(2):257–262. Holmbeck GN, Lavigne JV. Combining self-modeling and stimulus fading in the treatment of an electively mute child. Psychotherapy. 1992;29:661–667. Blum NJ, Kell RS, Starr HL, et al. Case study: audio feedforward treatment of selective mutism. J Am Acad Child Adolesc Psychiatry. 1998;37(1):40–43. Krohn DD, Weckstein SM, Wright HL. A study of the effectiveness of a specific treatment for elective mutism. J Am Acad Child Adolesc Psychiatry. 1992;31(4):711–718. Black B, Uhde TW. Psychiatric characteristics of children with selective mutism: a pilot study. J Am Acad Child Adolesc Psychiatry. 1995;34(7):847–856. Carlson JS, Kratochwill TR, Hohnston HF. Sertraline treatment of 5 children diagnosed with selective mutism: a single-case research trial. J Child Adolesc Psychopharmacol. 1999;9:293–230. Black B, Uhde TW. Treatment of elective mutism with fluoxetine: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1994;33(7):1000–1006. Dummit ES 3rd, Klein RG, Tancer NK, et al. Fluoxetine treatment of children with selective mutism: an open trial. J Am Acad Child Adolesc Psychiatry. 1996;35(5):615–621 Wright HH, Cuccaro ML, Leonhardt TV, et al. Case study: fluoxetine in the multimodal treatment of a preschool child with selective mutism. J Am Acad Child Adolesc Psychiatry. 1995;34(7):857–862. Golwyn DH, Weinstock RC. Phenelzine treatment of elective mutism: a case report. J Clin Psychiatry. 1990;51(9):384–385. Manassis K, Tannock R. Comparing interventions for selective mutism: a pilot study. Can J Psychiatry. 2008;53(10):700–703. Leonard, HL, Dow SP. Elective mutism. Child and Adolescent Psychiatric Clinics of North America. 1993;(2):695–707. Anstendig KD. Is selective mutism an anxiety disorder? Rethinking its [VOLUME

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DSM-IV classification. J Anxiety Disord. 1999;13(4):417–434. Yeganeh R, Beidel DC, Turner SM, et al. Clinical distinctions between selective mutism and social phobia: an investigation of childhood psychopathology. J Am Acad Child Adolesc Psychiatry. 2003;42(9):1069–1075. Yeganeh R, Beidel DC, Turner SM. Selective mutism: more than social anxiety? Depress Anxiety. 2006;23(3):117–123. Melfsen S, Walitza S, Warnke A. The extent of social anxiety in combination with mental disorders. Eur Child Adolesc Psychiatry. 2006;15(2):111–117. Jacobsen T. Case study: Is selective mutism a manifestation of dissociative identity disorder? J Am Acad Child Adoles Psychiatry. 1995; 29:863–866. Manassis K, Fung D, Tannock R, et al. Characterizing selective mutism: is it more than social anxiety? Depress Anxiety. 2003;18(3):153–161. Kagan J, Rezneck S, Snidman N, et al. Origins of panic disorder. In J.C. Ballendger (ed.), Neurobiology of Panic Disorder: Frontiers of Clinical Neuroscience, Volume 8. New York: Wiley-Liss;1990:71–87. Krohn DD, Weckstein SM, Wright HL. A study of the effectiveness of a specific treatment for elective mutism. J Am Acad Child Adolesc Psychiatry. 1992;31(4):711–718.

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48,XXYY in a General Adult Psychiatry Department by NUNO BORJA-SANTOS, MD, MSC; BRUNO TRANCAS, MD; PILAR SANTOS PINTO, MD; BÁRBARA LOPES, MD; ANTÓNIO GAMITO, MD; SANDRA ALMEIDA, MD; BERTA FERREIRA, MD; ANTONIO LUENGO, MD; CARLOS VIEIRA, MD; JORGE MARTINHO, MD; BRUNO PEREIRA, MD; and GRAÇA CARDOSO, MD, PhD

Drs. Borja-Santos, Santos Pinto, Lopes, Gamito, Almeida, and Ferreira are Consultants in Psychiatry, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal. Dr. Trancas is a Resident in Psychiatry, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal and CEDOC, Departamento de Saúde Mental, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Portugal. Drs. Luengo, Vieira, Martinho, and Pereira are Residents in Psychiatry, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal. Dr. Cardoso is Head of Department, Psychiatric Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal and CEDOC, Departamento de Saúde Mental, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa, Portugal Psychiatry (Edgemont) 2010;7(3):32–36

ABSTRACT

The 48,XXYY syndrome is a distinct clinical and genetic entity, with an incidence of 1:17,000 to 1:50,000 newborns. Patients often access mental healthcare services due to behavior problems, such as aggressiveness and impulsiveness, and are frequently intellectually disabled. We report a case of a patient with 48,XXYY syndrome treated in a general adult psychiatry department. A 23-year-old man was frequently admitted to our inpatient psychiatric unit (14 admissions in five years) due to disruptive behavior, including self harm, aggression to objects and animals, and fire-setting behavior, in a context of dysphoric mood and marked impulsivity. Upon observation, the patient had mild intellectual disability, with prominent impulsive and aggressive features and very low tolerance to frustration. His physical examination revealed hypertelorism, increased thickness of neck, acne, sparse body hair, triangular pubic hair distribution, fifth digit clinodactyly, small testicles and penis, and gynecoid pelvis. Laboratory analysis revealed endocrine abnormalities (low plasma 32

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Figure 1. Some of the physical findings of 48,XXYY include tall stature with gynecoid obesity (A), prominent supraorbital ridges and hypertelorism (B), low posterior hairline and multiple hair whorls (C), fifth digit clinodactyly (D), low density facial hair and pronounced forehead (E) FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURE: The authors have no conflicts of interest relevant to the content of this article. ADDRESS CORRESPONDENCE TO: Nuno Borja-Santos, Serviço de Psiquiatria, Hospital Prof. Doutor Fernando Fonseca, 2720-276 Amadora, Portugal;Phone: 00351 968 262 565; Email: [email protected] KEY WORDS: Psychiatry, sex chromosome disorders, family therapy, psychopharmacology, intellectual disability

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testosterone and subclinical hypothyroidism). Cardiac Doppler sonogram was normal. Electroencephalogram revealed only a diffuse slowing electrogenesis, with no etiological specificity. Clinical suspicion of a chromosomal disorder was confirmed by a 48,XXYY karyotype. Subsequent magnetic resonance imaging detected discrete bilateral reduction of the hippocampal formations, possibly related to temporal dysgenesia. Psychopharmacological treatment options met moderate success, with lack of adherence. Other psychosocial treatment interventions ensued, including family therapy and psychoeducation. We underscore the need to be alert for chromosomal disorders, even in a general adult psychiatry department, as a minority of patients may reach adult care without proper diagnosis.

INTRODUCTION

Sex chromosomes aneuploidies occur at a prevalence of 1/400 livebirths.1 The relatively rare 48,XXYY is presumed to be present in 1:17,000 to 1:50,000 male subjects.1–3 Originally described as an infrequent variant of Klinefelter syndrome (KS), it is now regarded as a distinct genetic and clinical entity.1,4,21 Patients usually present with greater severity and prevalence of intellectual disability compared to typical KS and are prone to frequent and severe behavioral and psychiatric problems, including attention deficit hyperactivity disorder (ADHD), autism spectrum, and mood, psychotic, and tic disorders.5,6,21 A significant proportion of patients with 48,XXYY syndrome are intellectually disabled, with up to 26 percent having an intelligence quota (IQ) below 70, with most presenting a significantly impacted adaptive functioning.21 When compared to typical KS (47,XXY) they have a lower IQ and adaptive functioning, with more hyperactivity, aggression, conduct, and depressive disorders.2,3 Described as shy, individuals with 48,XXYY are often aggressive and impulsive.7 Physical

findings are diverse and include eunuchoid habitus with long legs, sparse body hair, small testicles and penis, fifth digit clinodactyly, hypergonadotrophic hypogonadism, gynecomastia, and facial dysmorphic features.2,3,8 Patients are usually tall, and have gynecoid obesity.9–11 Varicosities and skin trophic ulcers are reportedly frequent, and patients may be at increased risk for congenital heart disease.1,12,13 Patients with 48,XXYY syndrome have low scores on socialization and communications skills (Vineland

studies have been performed.11,21 Similarly, testosterone supplementation in 48,XXYY has not been systematically evaluated, although there are reports of its efficacy without promoting behavior disruption and actually leading to better social adjustment.18,19,21 Tartaglia et al21 published a large cross-sectional, multicenter study with a cohort of 95 patients with 48,XXYY, producing a consolidated picture, which allows for a comprehensive review of the syndrome.21

A significant proportion of patients with 48,XXYY syndrome are intellectually disabled, with up to 26 percent having an IQ below 70, with most presenting a significantly impacted adaptive functioning.21 Adaptive Behavior scales) and are generally anxious, easily frustrated, or impatient (Reiss Profile of Fundamental Goals and Motivational Sensitivities for persons with mental retardation).3 Some authors have put forth a neuropsychological phenotype that includes deficits in frontal function, helping to explain the impulsiveness, attention deficit, and aggressiveness.14 Fire-setting behavior has been reported to occur and may be over-represented in these patients.15 Magnetic resonance imaging (MRI) structural anomalies concerning patients with typical 47,XXY syndromes include reduced whole brain volume, enlarged lateral ventricles, reductions of left temporal lobe grey matter, and localized atrophy in the insula, temporal gyri, amydgala, hippocampus, cingulus, occipital gyri, and parietal lobe white matter.16,17 Targaglia et al21 released MRI data on 35 patients with 48,XXYY and reported nonspecific white matter anomalies and enlarged ventricles, 45.7 percent and 22.8 percent, respectively.21 Patients with 48,XXYY benefit from a highly structured environment.3 Standard psychotropic therapy seems to meet success, although no controlled [VOLUME

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CASE REPORT

Informed consent was sought and obtained from the patient and his legal guardian (mother) for the use of personal images and medical data in this scientific presentation. We present the case of a 23-year-old man who was referred to our department for aggressive and suicidal behavior. He was the first child of unrelated parents. There was no significant family history. Preterm labor led his mother to a two-month long admission to an obstetric ward. Delivery, at 40 weeks, was noneventful. His birthweight was 3,130g and he was 46cm long with normal head circumference. His motor abilities developed at a normal pace, without any difference to age-matched peers. He began walking by the first year of age. Bladder control was reached at two and a half years. His appetite was sometimes described as voracious, without food preference. Sleep was undisturbed. Language and learning impairment, however, was soon noticed. He began to say the first words at the age of four and continued up to seven years of age. In kindergarten, he was generally found alone, isolated, and showed difficulty in communicating with other children. No autistic behaviors NUMBER

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Figure 2. A standard karyotype revealed extranumerary X and Y chromosomes.

were reported. Caregivers described him as a sad and distant child. When he was enrolled in elementary school, he said only a few dozen words and no sentences. He failed to reach an acceptable school performance and was referred to a special needs school in which he stayed until age 16. He was then capable of reading and writing colloquial and simple sentences though spelling mistakes were common. His mother reports the beginning of cruelty to animals around the age of 16; he would try to enucleate dogs and pluck feathers out of birds. He was first admitted to our inpatient unit at age 17 due to attempted suicide by defenestration. The pattern of hetero- and autoaggressive impulsive behavior, clinical history, mild intellectual disability, and a set of physical characteristics prompted a thorough investigation. In spite of being episodically impulsive and occasionally aggressive to self and others, the patient was capable of affective warmth and gestures of fondness and attachment to others. He quickly established relationships with the staff.

PHYSICAL EXAMINATION

Examination revealed a tall patient, with prominent forehead and supraorbital ridges, 34

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hypertelorism, high arched palate, low posterior hairline with dense scalp hair and multiple hair whorls, increased thickness of neck, acne, sparse body and facial hair with triangular pubic hair distribution, fifth digit clinodactyly, small testicles and penis, and gynecoid pelvis. Gynecomastia and skin ulcers were absent. He exhibited gynecoid obesity, with a height of 179cm, weight of 98kg, and body mass index of 30.5kg/m2. Karyotype. A karyotype was ordered upon his first admission, revealing 48,XXYY. The study showed the presence of extranumerary X and Y chromosomes in examined metaphases. In-situ hybridization technique (FISH) with D22S75 probe for chromosome 22q11.2 region excluded localized deletion, ruling out 22q11.2 deletion syndrome.20 Electroencephalogram (EEG) revealed abundant alpha activity, irregular morphology, with a relatively stable frequency at 8Hz at medium voltage and posterior symmetrical topography. We concluded there was discrete diffuse slow electrogenesis with no etiological specificity. Endocrine evaluation revealed low serum testosterone (224.0ng/dL; normal 286–1511), dehydroepiandrosterone

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(41.3ug/dL; normal 80–560), and marginally subnormal thyroid hormones. Cardiac Doppler sonogram. Left ventricle had normal dimensions, without wall hypertrophy. Systolic function was normal with no localized kinetic disturbances. Left atria had normal function and area. Valves presented normal pattern and morphology. No valvular regurgitation was detected by color Doppler. Right cavities had normal dimensions. There was no evidence of pericardial effusion. MRI. MRI detected discrete reduction of the heads of hippocampal formations, bilaterally, although more intense on the right side, which might be related to discrete bilateral temporal dysgenesia.

TREATMENT PLAN AND FOLLOW UP

Low levels of testosterone and borderline thyroid function prompted a referral to endocrinology. However, because it meant going to another appointment, to which the parents did not show up despite repeated attempts, testosterone supplementation was never initiated. This lack of adherence to recommended care may have been due to economic difficulties of the family; however, we believe navigating a difficult healthcare system and the disordered structure of family contributed as well. School intervention had begun before the patient was first presented to our team, as the patient was enrolled in a special needs school. As he grew older, he was placed in other schools. At each school, teachers and school staff were informed of the special difficulties the patient might experience during classes and upon interaction with other students. Some behavior containment strategies were suggested. A community support group was offered to the patient but met only transient success, as family adherence was low.

Psychoeducation of the parents (namely of the mother, as the couple had meanwhile divorced) was engaged. The nature of the disease and optimization of family dynamics and medication adherence were central topics. In this regard, special attention was given to the patient’s four-year-old brother, with whom the patient frequently fought. The patient was admitted an additional 14 times to our clinic, usually due to aggressive behavior toward self and others, irritability, dysphoric mood, and very low tolerance to frustration. Most of the ward admissions were of short duration (9 out of 15 lasted less than 10 days), highlighting their behavior containment role. Several parasuicidal events were recorded, most of them occurring due to frustration by the patient when his immediate demands were not met. The patient used lighters to either hurt himself or damage objects at least twice. In two admissions, the patient was transiently psychotic, with nonsystematized and puerile delusional ideas of grandeur and persecution; in one of these admissions, previous cannabinoids consumption was evoked. Caution was taken regarding the respect of his privacy while on the ward, as well as preventing other patients from abusing or provoking him. His forensic history included an arrest for armed robbery, and in one instance he manufactured a puerile explosive device that he threw at a former girlfriend’s house. The care plan team struggled to involve the family. Frequent marital discord (culminating in divorce) and lack of treatment adherence in a disrupted family unit led to considerable difficulties in managing and providing care to this patient. Family intervention was initiated and some sessions of family therapy were arranged, undertaken in our community services. There was an increase in home visits and in the frequency of outpatient clinic appointments in an attempt to solve problems before they manifested. The patient was kept on

anticonvulsants for impulse control, and was initially put on carbamazepine. Insufficient response led to therapy with sodium valproate. In both cases, however, suboptimal adherence, perhaps caused by adverse effects, compromised effectiveness. In an attempt to ensure treatment, we subsequently initiated depot antipsychotics (flupentixol and later fluphenazine). These were chosen because of their sedative profiles and lower risk of extrapyramidal symptoms (EPS), a common adverse effect in patients with intellectual disability. Long-acting risperidone injection was not available at that time. Despite reasonable clinical response, emergence of clinically significant EPS eventually led to discontinuation of depot antipsychotics. Some measures were undertaken to promote adherence to oral drugs, including a simplified regimen: a dosage reduced to the minimum number of intake and concentrated around family meal times. However, adherence was suboptimal, which led to compulsory outpatient treatment. Eventually, follow up was lost as the patient was admitted to a long-term residential care facility.

DISCUSSION

This case highlights the relevancy of psychiatric and behavioral problems in patients afflicted with this rare syndrome. The patient presented a dyad of fire-setting behavior and aggression toward animals, which are sometimes reported in pediatric cases. MRI detected significant bilateral hippocampal atrophy, a finding also present in 47,XXY. Although psychopharmacotherapy met reasonable success, further studies are required in this subgroup of patients regarding psychotropic and testosterone use. We believe family disruption played a significant part in the difficult management of this patient, and we suggest family dynamics and psychoeducation be part of the first line of treatments [VOLUME

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to be offered. As we witnessed, family burnout and dysfunction were key factors in our failed attempt to maintain appropriate treatment and avoid high levels of expressed emotion. These may have contributed to the excessive number of admissions. This patient presented a significant challenge for the adult general psychiatry team. It was regrettable that the diagnosis had not been reached earlier in this patient’s life. However, the literature does suggest that only a minority of cases receive diagnosis in late adolescence or adulthood, usually prompted by a change in medical teams in a context of intellectual disability and mental health problems, as in this case.21 This underscores the need to remain alert for chromosomal syndromes, even in adult general psychiatric services.22,23 Physicians should be particularly focused on a set of symptoms and behavior disorders evoked since childhood, beyond the simple existence of intellectual disability or current psychiatric syndromes.24 A careful review of medical history, including cardiac, endocrine, and respiratory abnormalities, should be performed, as well as a detailed account for developmental milestones. A thorough physical exam and assessment for minor dysmorphic signs should ensue.25 Some recommendations for chromosomal and genetic testing have been put forward, upholding their routine use in specific populations, such as in patients with schizophrenia and a history of intellectual disability or early onset of psychosis.26 We suggest a Bayesian approach, which takes into account positive findings, with each additional evidence lowering the threshold for chromosomal and genetic testing.

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European Congress of Endocrinology; April 28–May 2, 2007; Budapest, Hungary. Behrman R, Kliegman R, Jenson H (eds). Nelson Textbook of Pediatrics, 16th Edition. Pennsylvania: W.B. Saunders Company; 2000. Lolak S, Dannemiller E, Andres F. 48,XXYY syndrome, mood disorder and aggression. Am J Psychiatry. 2005;162(7):1384. Meschede D, Nekarda T, Kececioglu D, et al. Congenital heart disease in the 48,XXYY syndrome. Clin Genet. 1995;48(2):100–102. Jha P, Sheth D, Ghaziuddin M. Austism spectrum disorder and Klinefelter syndrome. Eur Child Adolesc Psychiatry. 2007(16);5:306–308. Díaz-Atienza J, Blánquez-Rodríguez MP. [Behavioral and neuropsychological phenotype of the 48XXYY syndrome: a longitudinal study of a case]. Rev Neurol. 1999 Nov 1630;29(10):926–929. Miiler M, Sulkes S. Fire-setting behavior in individuals with Klinefelter syndrome. Pediatrics. 1988;82(1):115–116. Reiss AL, Eliez S, Schmitt E, et al. Brain imaging in neurogenetic conditions: realizing the potential of behavioral neurogenetics research. Ment Retard Dev Disabil Res Rev. 2000(6):186–197. Shen D, Liu D, Liu H, et al. Automated morphometric study of brain variation in XXY males. Neuroimage. 2004(23):648–653.

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Sourial N, Fenton F. Testosterone treatment of an XXYY male presenting with aggression: a case report. Can J Psychiatry. 1988;33(9):846–850. Heuser I, Hartmann A, Oertel H. Androgen replacement in a 48, XXYY-male patient. Arch Gen Psychiatry. 1999;56:194–195. Shprintzen, RJ. Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev. 2008;14(1):3–10. Tartaglia N, Davis S, Hench A, et al. A new look at XXYY syndrome: medical and psychological features. Am J Med Genet A. 2008;146A(12):1509–1522. Maves SN, Williams MS, Williams JL, et al. Analysis of 88 adult patients referred for genetics evaluation. Am J Med Genet C Semin Med Genet. 2007;145C(3):232–240 Williams MS. Adult dysmorphology: perspectives on approach to diagnosis and care. Am J Med Genet C Semin Med Genet. 2007;145C(3):227–229. Greydanus DE, Pratt HD. Syndromes and disorders associated with mental retardation. Indian J Pediatr. 2005;72(10):859–864. Hunter AG. Medical genetics: 2. The diagnostic approach to the child with dysmorphic signs. CMAJ. 2002;167(4):367–372. Bassett AS, Chow EW, Weksberg R. Chromosomal abnormalities and schizophrenia. Am J Med Genet. 2000;97(1):45–51.

[CASE

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Capgras Syndrome in Postictal Delirium by DEVAVRAT JOSHI, MD; SHARAD KOIRALA, MD; SACHIN LAMICHHANE, MD; ANUBHA PALADUGU, MD; RUPINDER JOHAL, MD; and STEVEN LIPPMANN, MD Drs. Joshi, Koirala, and Lamichhane are from the Mental Hospital in Lagankhel, Lalitpur, Nepal. Drs. Paladugu, Johal, and Lippmann are from University of Louisville, School of Medicine, Department of Psychiatry and Behavioral Sciences, Louisville, Kentucky. Psychiatry (Edgemont) 2010;7(3):37-39

ABSTRACT

A 34-year-old man with a seizure disorder had not been taking anticonvulsant medications regularly. A previous pattern of recurrent seizures resolved after restarting anticonvulsant drugs. Recent seizure episodes were followed by delirium and presentation of Capgras syndrome. A variety of functional and organic etiologies for Capgras syndrome are known. This syndrome has been documented in cases of postictal delirium. These symptoms along with delirium ended with seizure control once back on anticonvulsant medicines.

INTRODUCTION

Capgras syndrome is defined as a delusional condition in which a patient falsely believes that someone, usually a close relative or friend, has been replaced by an imposter.1 This presentation can be part of a functional illness, psychiatric disorders, organic diseases, drug usage, and rarely as an independent phenomenon.2 Capgras syndrome, associated with organic etiologies, usually resolves following resolution of the primary pathology.3,4

CLINICAL VIGNETTE

A 34-year-old man was diagnosed

FUNDING: There was no funding for the development and writing of this article. FINANCIAL DISCLOSURE: The authors have no conflicts of interest relevant to the content of this article. ADDRESS CORRESPONDENCE TO: Steven Lippmann, MD, ACB Clinic, First Floor, 550 South Jackson St., Louisville, KY 40202; Phone: (502) 852-5870; Fax: (502) 852-5098; Email: [email protected] KEY WORDS: Capgras syndrome, delusion, epilepsy, anticonvulsant medication, postictal, delirium [VOLUME

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with epilepsy and had been taking phenytoin and phenobarbital orally for the last 12 years. He did not have a history of high-grade fever, head injury, substance abuse, or any psychiatric disorder prior to the seizure onset. In the past, erratic adherence with medicine resulted in recurrent episodes of generalized tonic-clonic convulsions. His wife reported that, during these episodes, he was confused, disoriented, and frequently misrecognized people after each seizure episode. Over a two-day period following the last ictal event, the patient became fearful and suspicious about somebody trying to attack him. Seizures and these symptoms decreased three days after restarting anticonvulsant medication. The present illness episode began after the patient stopped taking his seizure medicines at the advice of a faith healer. He was apparently well for a few days; but then over a 24-hour period exhibited 8 to 9 episodes of generalized tonic-clonic convulsions, each lasting for less than five minutes. An electroencephalogram (EEG) at that time evidenced wave patterns suggestive of generalized seizure activity. The following day, after seizure control was reestablished, the patient was transferred from the general hospital to a psychiatric facility because of bizarre behavior and thinking. No abnormal neurological findings were detected in the physical examination. Routine blood and urine investigations were within normal limits. On mental status examination, the patient was unkempt and restless. He was disoriented, anxious, muttering, uncooperative, and tried to grasp objects in his vicinity; he became assaultive without provocation. Incontinence of urine was noted. The patient said that he could hear voices arising within a thick smoke in the room. He also claimed that his wife, relatives, and neighbors were “duplicates.” His belief did not change despite logic to the contrary. He even refused food from his wife. The patient began oral valproic acid 1,000mg/day, risperidone 2mg/day, and lorazepam 2mg at night. He slept well 38

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that night and became more cooperative the next day. On the second day of the admission to psychiatry, he revealed Capgras symptoms, persecutory delusions, visual hallucinations, and remained disoriented. His recent memory, judgment, and insight were impaired. Scores of 20 out of 30 on the Mini Mental Status Examination (MMSE) suggested cognitive dysfunction in a presentation of delirium. A computerized tomogram (CT) of the head and an EEG were obtained on the fourth psychiatric hospital day. The CT scan was unremarkable. This second EEG revealed no focal changes or epileptiform discharges during this recording. By the fifth day, he became oriented and the MMSE scores improved to 27 out of 30. He was no longer fearful; the persecutory delusions and visual hallucinations disappeared. However, he still claimed that his wife had been replaced by someone else. Valproic acid was continued, but risperidone and lorazepam were discontinued. He gradually improved by hospital Day 10 and was fully oriented without delusional symptoms. Valproic acid remained as the single pharmacotherapy. The neurological diagnosis remained primary generalized epilepsy, without a known history of aura, focal symptoms, or documented focal neurological deficits before or after seizures; the same characterized past episodes and on this occasion. Previous EEGs were consistently symmetrical in wave forms. There was no evidence for an identifiable brain lesion.

DISCUSSION

Approximately 7 to 10 percent of patients with epilepsy suffer from psychoses, sometimes resembling a schizophreniform disorder.5 Psychotic symptoms in the form of Capgras syndrome or similar delusional misidentifications have been less commonly described in cases of epilepsy.6 Capgras syndrome usually has been observed in cases of functional psychoses, psychiatric diseases, such

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TAKE-HOME POINTS • Capgras syndrome is a delusional condition in which a patient believes that a close relative or friend has been replaced by an imposter. • Capgras syndrome presents during a variety of psychiatric diseases and somatic etiologies. • Capgras syndrome and other delusional misidentification disorders mandate a thorough evaluation for etiological diagnosis. • Capgras syndrome, when associated with organic pathology, usually remits with the resolution of the primary disorder. as schizophrenia (paranoid) and other delusional disorders.7 This phenomenon has also been documented in organic conditions, including systemic infections, nutritional deficiencies (e.g., folate deficiency), head injuries, basilar migraines, dementias, myxedema, cerebrovascular accidents, metabolic encephalopathies, and delirium secondary to epilepsy.2,8–11 Psychotic conditions, such as Capgras syndrome, are occasionally observed after a convulsion, more commonly following complex partial seizures and in some cases after generalized tonic-clonic convulsions.3 It has also been described after electroconvulsive therapy.10,12 Thorough evaluation for organic pathology is recommended in all cases of delusional misidentification.13 Capgras syndrome associated with organic diseases usually remits with improvement of the primary illness.4 These delusions may result from postictal disinhibition of the dominant hemisphere involved in recognition or from dysfunction of nondominant hemisphere centers involved in perceptual integration.12,14,15 Most of the peri-ictal or postictal psychotic symptoms resolve after regaining seizure control without antipsychotic drugs being necessary. In the above case, the patient had delusions during

delirium following generalized tonicclonic convulsions. The symptoms subsided after a few days of establishing seizure control. Anticonvulsant medication was the primary pharmacotherapy.

CONCLUSION

Any patient having Capgras syndrome or other delusional misidentification disorders mandates a thorough evaluation for organic etiologies. Capgras syndrome was observed during a delirium following repeated generalized tonic-clonic convulsions. The delusions were evident even in the presence of a normal follow-up EEG. The resolution of delirium followed seizure control and led to complete disappearance of the Capgras syndrome.

REFERENCES 1.

Munro A. Persistent delusional symptoms and disorders. In: Gelder MG, Lopez-Ibor JJ, Andreasen N (eds). Oxford Textbook of Psychiatry, First Edition, Vol-I. United Kingdom (Oxford): New

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Oxford University Press;2000:651–676. Butler C, Zeman AZJ. Neurological syndromes which can be mistaken for psychiatric conditions. J Neurol Neurosurg Psychiatry. 2005;76 (Suppl I):i31–i38. Chawla HM, Virmani V. Capgras phenomenon in a case of temporal lobe epilepsy. Folia Psychiatr Neurol Jpn. 1977;31(4):615–617. Weston MJ, Whitlock FA. The Capgras syndrome following head injury. Br J Psychiatry. 1971;119:25–31. Quinn D. The Capgras syndrome: two case reports and a review. Can J Psychiatry. 1981;26(2):126–129. Singer SF. Capgras’ Syndrome: the delusion of substitution. J Clin Psychiatry. 1987;48(4):147–150. Silva JA, Leong GB. The Capgras syndrome in paranoid schizophrenia. Psychopathology. 1992;25(3):147–153. MacCallum WA. Capgras symptoms with an organic basis. Br J Psychiatry. 1973;123(577):639–642. Wilcox JA. A case of Capgras’

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phenomenon. Aust N Z J Psychiatry. 1984;18(4):391–392. Orawan S, Chatchawan S. Capgras syndrome in an epileptic patient. J of The Psychiatric Association of Thailand. 1996;41(2):110–114. Dejode JM, Antonini F, Lagier P, Martin C. Capgras syndrome: a clinical manifestation of watershed cerebral infarct complicating the use of extracorporeal membrane oxygenation. Crit Care. 2001;5(4):232–235. Drake ME. Postictal Capgras syndrome. Clin Neurol Neurosurg. 1987;89(4):271–274. Collin MN, Hawthorne ME, Gribbin N, Jacobson R. Capgras syndrome with organic disorders. Postgrad Med J. 1990;66:1064–1067. Anderson DN. The delusion of inanimate doubles: implications for understanding the Capgras syndrome. Br J Psychiatry. 1988;153:694–699. Waziri R. The Capgras phenomenon: cerebral dysfunction with psychosis. Neuropsychobiology. 1978; 4: 353–359.

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Meymandi at Large

THE SCIENCE OF EPIGENETICS by Assad Meymandi, MD, PhD, DLFAPA Psychiatry (Edgemont) 2010;7(3):40–41 This column is devoted to bridging the gap between basic sciences, medicine, the arts, and humanities.

I

t seems a bit odd to start a discussion about a cutting-edge, up-to-the-minute science with an ancient Biblical story, yet the passages in Genesis chapters 41 through 47, which describe the Egyptian Pharaoh’s dream of “seven years of plenty and seven years of famine,” prove to be relevant to the science of epigenetics. Epigenetics, a 21st century science, is the study 40

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of changes in gene activity that does not involve alteration to the genetic code but gets passed down to successive generations. In the 19th century, a province in northern Sweden called Norrbotten literally experienced seven years of famine followed by good harvest and abundance of food. The feast and famine period that occurred in this sparsely populated province 3,

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(only six people per square mile) has offered astonishing epidemiologic and scientific data that have given birth to the science of epigenetics. The years 1800, 1812, 1821, 1836, and 1856 (the year of potato famine in Ireland) were years of total crop failure and famine for the people of Norrbotten. But in 1801, 1822, 1828, 1844, and 1863, there was excellent harvest and an abundance of food. Scientists of the renowned Karolinska Institute, Stockholm, Sweden, have undertaken the painstaking work of evaluating this history of famine and feast to see how it affected the lives of the children. With these studies, they have found that “life conditions could affect your health not only when you were a fetus, but also well into adulthood,” concluding that parents’ experiences early in their own lives change the traits they pass on to their offspring. The result of the study shows that the years the children were well fed, their own subsequent offspring grew up to be healthier and physically bigger. In 1966, when I was director of Cumberland County Mental Health Center applying for a grant for the Head Start program, I used a study by Karolinska Institute published in the Acta Physiologica Scandinavica and Lancet, which demonstrated that fetus and fetal central nervous systems (CNS) exposed to excess secretion of maternal catecholamines, especially metanephrines, vinyl mandellic acid, and 3-methoxy 5-hydroxy methylgleycol (MHPG), produces babies that are more irritable, scrawny, cranky, susceptible to attention deficit hyperactive disorder (ADHD), and prone to anxiety, phobia, and social maladjustment. The project, titled “Intrauterine Head Start,” was

[meymandi at large]

funded and our findings were published. So, the knowledge of environmental influence on the fetus is not new. What is new, however, is the epidemiologic studies from Norrbotten and their defiance of Darwin’s assertion in his seminal work On the Origin of Species (1859) that evolution takes place over millions of years. The Norrbotten studies suggest that evolution and environmental influence affect genes within one or two generations. It does not take millions of years. This is heretical. Suddenly, we have evidence that Darwin was wrong. It takes only 25 to 75 years, 1 to 3 generations, not millennia, for evolution of genes to take place.

A SWITCH

The exciting science of epigenetics is very much like a switch on the outside of the genetic circuits and genome that influences the behaviors of a gene. The very prefix epi, which means to lie outside of the root structure, helps explains that, while not an integral part of an organism’s genetic code, epigenetics can influence the gene’s activites from the outside. Flipping the switch enhances (turns a gene on) or inhibits (turns a gene off) DNA activity.

IN-UTERO CELL DIFFERENTIATION Cells in the kidney and the cells in the brain have the exact same deoxyribonucleic acid (DNA). The nascent cell can differentiate only when crucial epigenetic processes turn on or turn off the right gene in utero. This is why studies of identical twins show that while one sibling might develop asthma, bipolar disorder, or even schizophrenia, the other can be perfectly normal. The studies from Norrbotten clearly show that because of the epigentic switch, one

can pass down epigenetic changes in a single generation.

EPIGENETIC DRUGS

Cutting-edge scientists want to discover how to enhance the activities of the good genes and how to silence and discourage the activities of the bad genes. The task is not very difficult. To chemically flip the “good” switch on, one must introduce a methyl group (CH3) to the side chain of DNA—a very simple procedure; or vice versa, to flip it off, introduce a demethylate compound to suppress the activities of the bad genes. There are several epigenetic drugs on the market. For example, the drug 5-aza-cytidine (Celgene Corporation, Summit, New Jersey) is an epigenetic drug that prolongs the life of patients afflicted by severe myelodysplastic syndromes. In recent years, the United States Food and Drug Administration (FDA) has approved three other epigenetic drugs that are thought to stimulate tumor-suppressing genes. It is hoped that we will find drugs that turn off expression of genes in many diseases, including cancer, autism, schizophrenia, alcoholism, and Alzheimer’s. With the instrument and knowledge of epiginomics, it is conceivable to find the switch (the epigenome) that turns off the dumping of amyloid in the synaptic cleft that causes the devastating dementia of Alzheimer’s. Currently, the National Institute of Health is investing heavily in better understanding and codifying epigenomics. The Human Genome Project, completed in March 2000, found that the human genome contains 25,000 genes. Private enterprise along with Craig Venter, who won the Nobel Prize in Medicine or Physiology in 2005, beat government bureaucracy by [VOLUME

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completing the project two years before the government. Venter has already published his autobiography, A Life Decoded: My Genome—My Life, where he recounts his role in the Human Genome Project. Now, we need a massive project to identify the epigenome and compile the human epigenomic book. The number of epigenomes far exceeds 25,000, and the cost of completing the project will cost hundreds of billions of dollars. It will also cause a bad case of “Darwinitis.” We will keep you posted as the science of epigenetics further develops. AUTHOR AFFILIATION: Dr. Meymandi is in private practice as a psychiatrist and neurologist and serves as an adjunct professor of psychiatry at the University of North Carolina at Chapel Hill. He is a noted physician, editor, and philanthropist who frequently speaks and writes on diverse topics that relate to his interests in medicine, the arts, religion, and philanthropy. He lives in Raleigh with his wife Emily. ADDRESS FOR CORRESPONDENCE: Dr. Assad Meymandi, e-mail: [email protected]

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Information for Authors Submission requirements for Psychiatry 2010 are in accordance with the International Committee of Medical Journal Editors (ICMJE). See “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” at www.icmje.org. EDITORIAL PURPOSE Psychiatry 2010 is a peer-reviewed electronic-only journal (www.psychiatrymmc.com) designed to provide psychiatrists with up-to-date, evidence-based information on the latest treatment options, new techniques, and practice management issues to improve their daily practice. The journal provides practical information in electronic format on a broad range of pertinent topics that is based on the latest research and is presented in a straightforward “how-to” fashion. SCOPE OF MANUSCRIPTS Manuscripts that meet our editorial purpose include but are not limited to: (1) reports of preclinical and clinical research studies that expand existing knowledge; (2) case studies and reports that stimulate research and the exchange of information; (3) in-depth reviews of clinical practice, management, reimbursement, education, ethics, and legal issues; (4) reviews and reports of contemporary topics in psychiatry and psychiatry practice that may affect the delivery, reimbursement, or practice of psychiatric care. Original Research. Reports of investigations that address questions about clinical care or expand existing knowledge. References and illustrative material are recommended. Must include abstract. Recommended length: up to 6000 words, not including references. Review Articles. Comprehensive articles summarizing basic strategies to facilitate the psychiatrist’s approach to diagnosis and treatment and articles highlighting emerging diagnostic and therapeutic modalities. May also include in-depth reviews of clinical practice, management, reimbursement, educational, ethical, and legal issues. At least 25 current references are recommended. Illustrative material is preferred. Must include abstract. Recommended length: up to 6000 words, not

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