TRENDS v37n1

Trends in Psychiatry and Psychotherapy – Volume 37 – Issue 1 – January–March 2015

ISSN 2237-6089

Trends in Psychiatry and Psychotherapy

Volume 37 – Issue 1 – January–March 2015

Associação de Psiquiatria do Rio Grande do Sul

Porto Alegre | 23 de maio de 2015 Centro de Eventos AMRIGS Coordenadores Adriana Denise Dal Pizol Lucas Spanemberg Madeleine Scop Medeiros

GRUPOS DE ESTUDO n A história dos psicofármacos e a psicopatologia psiquiátrica: achados e especulações sobre a natureza dos transtornos mentais / Andrea Poyastro Pinheiro, Flávio Milman Shansis e Lucas Spanemberg n Altas habilidades e superdotação na prática psiquiátrica: tesouros escondidos / Ana Cristina Tietzmann n Aportes da fenomenologia à psicoterapia de orientação psicanalítica / Anna Luiza Kauffmann n Autoestima e depressão / Anneliese Formel Couto Cosner e Patrícia Picon n Avanços em saúde mental da mulher / Camila Ruschel Selbach e Sheila Vardanega n Borderlines na cultura hipermoderna: onde ficam os limites entre o normal e o patológico? / Cristina Plentz Pessi n Complexidades da relação entre religião, espiritualidade e saúde mental / Anahy Fagundes Dias Fonseca e Bruno Paz Mosqueiro n Consultoria hospitalar em transplantes: abordagens farmacológicas e dinâmicas / Aline Kives Berger e Nicole Campagnolo n Violência Doméstica: as drogas são o grande vilão? / Félix Henrique Paim Kessler e Lisieux Elaine de Borba Telles n Esquizofrenia ultrarrefratária: o que pode ser feito além da Clozapina? / Nathalia Janovik da Silva e Rafael Henriques Candiago

Xii Jornada Caminhos

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Psiquiatria

VulneraBilidade Pathways

Brasil / rio Grande

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of

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aPrs

VulneraBility

sul / Gramado / 3 a 5 de Setembro de 2015

Organização

n Maldade humana / Carlos Augusto Ferrari Filho e Fernando Lejderman n Modelos estruturais psicodinâmicos na clínica da obesidade / César Luis de Souza Brito e Juliana Tainski de Azevedo n Núcleo de saúde mental e trabalho / Arthur da Motta Lima Netto n O continuum depressão-transtornos bipolar-esquizofrenia e os fatores de risco compartilhados / Alexei Gil n Psicoterapias de orientação analítica: benefícios e iatrogenias / Idel Mondrzak n Um outro horizonte: curiosas intervenções terapêuticas não farmacológicas usadas em idosos com demência / Eduardo Hostyn Sabbi

www.jornadaaprs.org.br Realização

n Interface entre transtornos neuropsiquiátricos, processos inflamatórios, patologias clínicas e doenças cardíacas / Rose Mary Carvalho Pinheiro Alves

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Trends in Psychiatry and Psychotherapy Editor-in-Chief Marcia Kauer-Sant’Anna Universidade Federal do Rio Grande do Sul – UFRGS

Associate Editors Clarissa Severino Gama Universidade Federal do Rio Grande do Sul – UFRGS

Elisa Brietzke Universidade Federal de São Paulo – Escola Paulista de Medicina – UNIFESP-EPM

Giovanni Abrahão Salum Universidade Federal do Rio Grande do Sul – UFRGS

Jair Segal Hospital de Pronto Socorro de Porto Alegre

Maurício Kunz Universidade Federal do Rio Grande do Sul – UFRGS

Field Editors Benício Noronha Frey (McMaster University, Canada) – Neurosciences Humberto Correa (Universidade Federal de Minas Gerais, Brazil) – Clinical Psychiatry Rodrigo Grassi-Oliveira (Pontifícia Universidade Católica do Rio Grande do Sul, Brazil) – Psychology Sérgio Lewkowicz (Sociedade Psicanalítica de Porto Alegre, Brazil) – Psychotherapy Statistical consulting Hugo Cogo

National Editorial Board Aldo Lucion (Universidade Federal do Rio Grande do Sul – UFRGS) n Antônio E. Nardi (Universida de Federal do Rio de Janeiro – UFRJ) n Aristides Volpato Cordioli (UFRGS) n Beny Lafer (Universidade de São Paulo – USP) n Carlos Alexandre Netto (UFRGS) n Cláudio Laks Eizirik (UFRGS) n Eurípides Miguel Filho (USP) n Flávio Pechansky (UFRGS) n Francisco M. Salzano (UFRGS) n Gisele Gus Manfro (UFRGS) n Hélio Elkis (USP) n Ivan Figueira (UFRJ) n Ivan Izquierdo (Pontifícia Universidade Católica do Rio Grande do Sul – PUCRS) n Jair de Jesus Mari (Universidade Federal de São Paulo – UNIFESP) n Jerson Laks (UFRJ) n José Roberto Goldim (UFRGS) n Luis Alberto Hetem (USP – Faculdade de Medicina de Ribeirão Preto) n Luis Augusto Paim Rhode (UFRGS) n Marcelo Pio de Almeida Fleck (UFRGS) n Maria Lucréscia Zavaschi (UFRGS) n Neury J. Botega (Universidade Estadual de Campinas – UNICAMP) n Patrícia Picon (PUCRS) n Paulo Mattos (UFRJ) n Paulo Roberto Zimmermann (PUCRS) n Paulo Silva Belmonte Abreu (UFRGS) n Ricardo Primi (Universidade São Francisco) n Rodrigo Bressan (UNIFESP) n Romualdo Romanowski (Sociedade Psicanalítica de Porto Alegre – SPPA) n Sidney Schestatsky (UFRGS) n Valentim Gentil Filho (USP)

n

Wagner Farid Gattaz (USP)

International Editorial Board André Green (France) n Andrew A. Nierenberg (USA) n Antonino Ferro (Italy) n Boris Birmaher (USA) n Christhopher Bollas (USA) n David Tuckett (UK) n Eduard Vieta (Spain) n Gary S. Sachs (USA) n George Woody (USA) n German E. Berrios (UK) n Glen O. Gabbard (USA) n Gustavo Turecki (Canada) n Host Kächele (Gemany) n Jorge Folino (Argentina) n Joseph Biedermann (USA) n Júlio Licínio (USA) n Lakshmi N. Yatham (Canada) n Otto Kernberg (USA) n Ricardo Bernardi (Uruguay) n Robert Michels (USA) n Robert N. Emde (USA) n Roger K. Pitman (USA) n Timothy J. Crow (UK)

2014/2015 Board Carlos Alberto Iglesias Salgado / President Carlos Augusto Ferrari Filho / Vice-President Carlos Renato Moreira Maia / Executive Treasurer Flávio Milman Shansis / Adjunct Executive Treasurer Carlos Alberto Machado do Nascimento / Adjunct Executive Secretary of Professional Practice Rodrigo Grassi-Oliveira / Scientific Director Patrícia Fuhro Vilas Boas / Executive Secretary of Norms Anahy Fagundes Dias Fonseca / Media Director Audit Committee Hans Ingomar Hermann Albert Schreen Paulo Henrique Gomes de Seixas Rafael Gomes Karam

Assistant Audit Committee Members Fernando Lejderman Madeleine Scop Medeiros Marcelo Moraes Victor

Editorial Staff Secretary: Sandra Maria Schmaedecke (Reg. Prof. 1464) Managing editor and text editing: Denise Arend Layout: Marta Castilhos Typesetting and cover: HG Design Digital

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Associação de Psiquiatria do Rio Grande do Sul Av. Ipiranga, 5311/202 90610-001 Porto Alegre RS Brazil Tel./fax: +55 (51) 3024.4846 Mobile: +55 (51) 8116.5896 Home Page: www.aprs.org.br E-mail: trends@aprs.org.br

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Trends in Psychiatry and Psychotherapy

Volume 37 – Issue 1 – January-March 2015

Table of contents

Editorial In memory of Dr. José Geraldo Vernet Taborda (1951-2014) ..................................................... 1 Em memória do Dr. José Geraldo Vernet Taborda (1951-2014) Juliana Fernandes Tramontina, Helena Dias de Castro Bins

Review Articles Biomarkers and staging of bipolar disorder: a systematic review ............................................... 3 Dos biomarcadores ao estadiamento do transtorno bipolar: uma revisão sistemática Ângela Roda, Inês Chendo, Mauricio Kunz

Resilience of caregivers of people with dementia: a systematic review of biological and psychosocial determinants ............................................................................................ 12 Resiliência de cuidadores de pessoas com demência: revisão sistemática de determinantes biológicos e psicossociais Rachel Dias, Raquel Luiza Santos, Maria Fernanda Barroso de Sousa, Marcela Moreira Lima Nogueira, Bianca Torres, Tatiana Belfort, Marcia Cristina Nascimento Dourado

Phenomenological aspects of the cognitive rumination construct ............................................. 20 Aspectos fenomenológicos relacionados ao construto de ruminação cognitiva Leonardo Fernandez Meyer, José Geraldo Vernet Taborda, Fábio Antônio da Costa, Ana Luiza Alfaya Galego Soares, Kátia Mecler, Alexandre Martins Valença

Original Articles Variation of plasma cortisol levels in patients with depression after treatment with bilateral electroconvulsive therapy ............................................................................... 27 Variação de cortisol plasmático em pacientes deprimidos após tratamento com eletroconvulsoterapia bilateral Daniel Fortunato Burgese, Débora Pastore Bassitt

Cross-cultural adaptation of the Spence Children’s Anxiety Scale in Malaysia ........................... 37 Adaptação cultural da Escala de Ansiedade Infantil de Spence para a Malásia Atefeh Ahmadi, Mohamed Sharif Mustaffa, AliAkbar Haghdoost, Aqeel Khan, Adibah Abdul Latif

Translation and cross-cultural adaptation of the Brazilian Portuguese version of the Driving Anger Scale (DAS): long form and short form .................................................... 42 Tradução e adaptação transcultural da versão brasileira da Driving Anger Scale (DAS): forma longa e forma curta Jessye Almeida Cantini, George Oliveira Santos, Eduardo de Carvalho Machado, Antonio Egídio Nardi, Adriana Cardoso Silva

Case Report Managing severe behavioral symptoms of a patient with anti-NMDAR encephalitis: case report and findings in current literature ......................................................................... 47 Manejo de sintomas comportamentais severos em um paciente com encefalite anti-NMDAR: relato de caso e literatura atual Vanina Lima Monteiro, Felipe José Nascimento Barreto, Paulo Marcos Brasil Rocha, Paulo Henrique Teixeira do Prado, Frederico Duarte Garcia, Humberto Correa, Maila Castro Lourenço das Neves

Trends in Psychiatry and Psychotherapy

Our Cover

Dominik Piknic and Emanuele Bizzotto Into the light 2014 Photography

Image kindly supplied by Dominik Piknic, Emanuele Bizzotto, Otto Sulzbach, and Arte&Fato Galeria.

Trends

Editorial

in Psychiatry and Psychotherapy

In memory of Dr. José Geraldo Vernet Taborda (1951-2014) Em memória do Dr. José Geraldo Vernet Taborda (1951-2014) Juliana Fernandes Tramontina,1 Helena Dias de Castro Bins2

In August 2014, the psychiatric community mourned the loss of an outstanding psychiatrist, professor, researcher, colleague, and friend, too. Dr. José Geraldo Vernet Taborda was among the most supportive and warmest of colleagues. He was a life enthusiast, and enjoyed each and every moment of life through his passion for psychiatry and spending moments with family and friends. Even in the last month, struggling against a cancer, Dr. Taborda had a full agenda committed to mentoring students, colleagues, and friends. He is survived by his wife, Maria Zenóbia; daughter, Maria Laura; and son, Julio Rafael.

Professor of Psychiatry and affiliated with the Graduate Program in Health Sciences at Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Dr. Taborda first graduated in Legal and Social Sciences from Universidade Federal do Rio Grande do Sul (UFRGS), in 1974. Afterwards, he graduated in Medicine and completed his internship at the same renowned university, in 1983. He completed his psychiatry residency program at Pontifícia Universidade Católica do Rio Grande do Sul in 1986. Since then, Dr. Taborda was involved in forensic matters. He was also former professor of Medicine at UFRGS and at Universidade Luterana do Brasil (ULBRA), former director of the Institute of Criminal Biotypology (Department of Justice of the State of Rio Grande do Sul), and former director of the Criminological Observation Center (Department of Justice of the State of Rio Grande do Sul).

In his clinical activity, Dr. Taborda devoted himself to the treatment of adults and elderly. His practice was focused on patients with mood disorders, anxiety disorders, psychotic syndromes, posttraumatic stress disorder, and somatizers. In addition, he intensely studied the interface between general medical conditions and psychiatric disorders. Until his death, he was a medical staff member at Santa Casa de Misericórdia de Porto Alegre and Instituto de Cardiologia do Rio Grande do Sul, where he served as a psychiatric consultant.

His areas of special interest, research, and scientific production were primarily forensic psychiatry, bioethics, and medical ethics. He received a Master of Science degree in Medicine from UFRGS in 1996. His doctorate degree in Medicine was obtained in 2002, also in Medical Sciences from UFRGS. His doctoral dissertation was in the field of forensic psychiatry, related to the perception of coercion in psychiatric and nonpsychiatric (medical and surgical) inpatients.

Dr. Taborda’s most influential published work describes the criminal justice system in Brazil.1 In that article, he discusses the concepts of dangerousness and penal responsibility, as well as the importance and functions of a forensic psychiatrist. Over the course of his career, he authored and coauthored over 80 articles, books, and book chapters on general psychiatry and forensic psychiatry. His magnificent book, written in cooperation with Dr. Abdalla-Filho and Dr. Chalub, entitled Forensic psychiatry, is considered one of the most important titles in the field in Brazil.2

1 Psychiatrist. Professor, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil. of Rio Grande do Sul, Porto Alegre, RS, Brazil.

2

Forensic psychiatrist, Supreme Court of the State

Financial support: none.

Suggested citation: Tramontina JF, Bins HD. In memory of Dr. José Geraldo Vernet Taborda (1951-2014). Trends Psychiatry Psychother. 2015;37(1):1-2. http://dx.doi.org/10.1590/2237-6089-2015-1001 © APRS

Trends Psychiatry Psychother. 2015;37(1) – 1-2

Editorial

Few professors are as skilled as Dr. Taborda in inspiring students, whatever their academic level. His classes on deontological ethics were famous for his skills as a lecturer – his courses were always well attended.

Dr. Taborda was also a member of several professional societies. At the national (Brazilian) level, he was a member of the Academy of Medicine of Rio Grande do Sul (chair no. 56); of the Psychiatry Technical Chamber, Forensic Medical Board, Federal Council of Medicine; of the Brazilian Psychiatric Association; and of Associação de Psiquiatria do Rio Grande do Sul, the state’s psychiatric association. Moreover, he founded the Bioethics and Legal Psychiatry Chapter of the Brazilian Psychiatric Association.

At the international level, he was a member of the most important organizations associated with psychiatry and law, namely, the American Academy of Psychiatry and the Law and the International Academy of Law and Mental Health. He was also member of the board of the World Psychiatric Association (WPA), serving as Regional Representative (Region 5). He was distinguished as Honorary Member of the WPA in the institution’s world congress held in September 2011.

In the scientific publication scenario, Dr. Taborda served on the editorial boards of several forensic psychiatric journals, e.g., International Journal of Offender Therapy

2 – Trends Psychiatry Psychother. 2015;37(1)

and Comparative Criminology (USA) and the International Journal of Forensic Mental Health (Canada).

At the university, he shouldered the responsibility as director of both the Psychiatric Forensic Residency Program and the General Psychiatric Residency Program at UFCSPA. He was also in charge of bioethics graduate courses and was coordinator of the Research Ethics Committee of the same institution.

With his talent, Dr. Taborda brightened Brazilian and international psychiatry in general and forensic psychiatry in particular. His passing is a tremendous loss to the field, and a deep personal loss to all of us who have known him. We are grateful to have had opportunities to learn and work with Dr. Taborda. We hope that we can sustain the same good energy level, responsibility, and happiness that Dr. Taborda showed us in his life.

As a tribute, this edition of Trends in Psychiatry and Psychotherapy features an article that still counted on the participation of Dr. José Geraldo Vernet Taborda.

References 1.

2.

Taborda JGV. Criminal justice system in Brazil: functions of a forensic psychiatrist. Int J Law Psychiatry. 2001;24:371-86.

Taborda JGV, Abdalla-Filho E, Chalub M. Psiquiatria forense. 2ª ed. Porto Alegre: Artmed; 2012.

Trends

Review Article

in Psychiatry and Psychotherapy

Biomarkers and staging of bipolar disorder: a systematic review Dos biomarcadores ao estadiamento do transtorno bipolar: uma revisão sistemática Ângela Roda,1 Inês Chendo,2 Mauricio Kunz3

Abstract

Resumo

Introduction: A growing body of evidence suggests that bipolar disorder (BD) is a progressive disease according to clinical, biochemical and neuroimaging findings. This study reviewed the literature on the relationship between specific biomarkers and BD stages.

Methods: A comprehensive literature search of MEDLINE and PubMed was conducted to identify studies in English and Portuguese using the keywords biomarker, neurotrophic factors, inflammation, oxidative stress, neuroprogression and staging models cross-referenced with bipolar disorder.

Results: Morphometric studies of patients with BD found neuroanatomic abnormalities, such as ventricular enlargement, grey matter loss in the hippocampus and cerebellum, volume decreases in the prefrontal cortex and variations in the size of the amygdala. Other studies demonstrated that serum concentrations of neurotrophic factors, inflammatory mediators and oxidative stress may be used as BD biomarkers.

Conclusions: The analysis of neurobiological changes associated with BD progression and activity may confirm the existence of BD biomarkers, which may be then included in staging models that will lead to improvements in treatment algorithms and more effective, individually tailored treatment regimens. Biomarkers may also be used to define early interventions to control disease progression.

Keywords: Bipolar disorder, neuroimaging changes, neurotrophic factors, inflammation, oxidative stress, staging.

Introdução: Níveis crescentes de evidência sugerem que o transtorno bipolar (TB) exibe um caráter progressivo, em nível tanto clínico, quanto bioquímico e neuroimagiológico. Este estudo revisa a literatura existente sobre a relação entre biomarcadores específicos e estágios do TB. Métodos: Uma busca extensa da literatura nas bases de dados MEDLINE e PubMed foi conduzida para identificar estudos publicados em inglês e em português utilizando as palavraschave biomarker (biomarcador), neurotrophic factors (fatores neurotróficos), inflammation (inflamação), oxidative stress (estresse oxidativo), neuroprogression (neuroprogressão) e staging models (modelos de estadiamento), em referência cruzada com o termo bipolar disorder (transtorno bipolar).

Resultados: Estudos morfométricos em doentes bipolares mostraram a existência de alterações neuroanatômicas, tais como o alargamento dos ventrículos, a perda de substância cinzenta no hipocampo e no cerebelo, a diminuição do volume de determinadas áreas do córtex pré-frontal e variações no tamanho da amígdala.

Além disso, outros estudos apontam para a potencialidade do uso dos valores séricos dos fatores neurotróficos, de mediadores inflamatórios e de estresse oxidativo como biomarcadores do TB. Conclusões: O conhecimento das alterações neurobiológicas, associadas à progressão e atividade do TB, é fundamental para a identificação de biomarcadores. A incorporação de biomarcadores nos modelos de estadiamento do TB poderá permitir um aperfeiçoamento dos algoritmos terapêuticos, possibilitando a elaboração de esquemas de tratamento mais personalizados e eficazes, com destaque para a importância da intervenção precoce na atenuação da progressão da doença.

Descritores: Transtorno bipolar, alterações neuroimagiológicas, fatores neurotróficos, inflamação, estresse oxidativo, estadiamento.

Faculdade de Medicina de Lisboa, Lisbon, Portugal. 2 Psychiatrist, University Clinic, Faculdade de Medicina de Lisboa, Lisboa, Portugal.

Department of Psychiatry, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.

1

3

MD, PhD. Professor,

This paper was based on the first author’s Master’s dissertation (same title), presented on March 21st 2014 at Faculdade de Medicina de Lisboa, Lisbon, Portugal.

Financial support: none.

Submitted Feb 21 2014, accepted for publication Jul 22 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Roda A, Chendo I, Kunz M. Biomarkers and staging of bipolar disorder: a systematic review. Trends Psychiatry Psychother. 2014;37(1):3-8. http://dx.doi.org/10.1590/2237-6089-2014-0002. Epub Dec 09, 2014. © APRS

Trends Psychiatry Psychother. 2015;37(1) – 3-8

Biomarkers and staging of bipolar disorder - Roda et al.

Introduction Bipolar disorder (BD) is a chronic, often serious psychiatric disease with a prevalence of 1% to 3% worldwide.1 According to the World Health Organization, BD is the 12th most important cause of disability in the world,2 and its morbidity and mortality are significant.

The reduction of mean life expectancy in BD is the result of the high rate of suicides, clearly associated with mood disorders,3 and the increased prevalence of medical comorbidities, such as heart disease, diabetes, obesity and thyroid dysfunction,4 found in over 80% of the patients.5 A growing body of evidence suggests that BP is a progressive disease.6-8 In 1899 Emil Kraepelin found that the intervals between mood episodes become successively shorter as the number of previous

This study reviewed the literature about neuroimaging and neurobiological abnormalities in patients with BD as potential BD biomarkers. The analysis of neurobiological changes will focus on the role of neurotrophic factors, inflammatory mediators and oxidative stress in BD physiopathology, activity and progression, and the importance of BD staging will be reviewed.

Methods A comprehensive literature search of MEDLINE and PubMed was conducted to identify studies in English and Portuguese using the keywords biomarker, neurotrophic factors, inflammation, oxidative stress, neuroprogression and staging models cross-referenced

episodes increases. The same author described that, after a certain number of recurrences, episodes tend to occur more spontaneously, in contrast with initial episodes, which are usually triggered by psychosocial stress factors.7,9,10 The increase of the number of mood episodes is associated with poorer responses to psychopharmacological treatment.6,8,11-13 Moreover, changes in cognitive functions are more marked in advanced stages of the disease than in controls and in patients in the initial phases of this psychiatric disorder.8 Recent studies also showed that cognitive dysfunction and functional deterioration persist even during the euthymic periods in the advanced stages of the disease.14,15 These clinical findings may be understood as a result of the neuroprogressive events that occur during the long course of BD. Neuroprogression involves a pathologic reorganization of the central nervous system (CNS) and is, therefore, associated with structural and functional changes of the neural substrate, which is involved in mood regulation.8 Several studies have demonstrated that, in addition to the progression of

with bipolar disorder. One hundred and fifty-two articles published from 1899 to 2013 were retrieved. Selection for inclusion was based primarily on the information found in the study abstracts. Moreover, the bibliographies of the selected articles were analyzed. Finally, studies published by experts in this area were also examined.

Two articles were excluded because they were written in a language other than English or Portuguese. Other studies were excluded because they did not investigate serum or imaging biomarkers and BD staging.

clinical presentations, there are also biochemical and structural changes that confirm neuroprogression, as biological and neuroimaging patterns are different between the initial and the final phases of BD.6,16 The identification of neurobiological and neuroimaging changes associated with BD progression and activity is fundamental for the definition of biomarkers. Together with a clear understanding of the clinical course of the disease, the definition of biomarkers is fundamental for the development of staging models. BD staging models should be based on the progression from an at-risk to a more severe and refractory presentation and should classify patients according to different stages (I to IV).

A staging system should be used in clinical practice to select the most appropriate treatment and define early interventions that may control BD progression.17

Biomarkers may be genes, proteins or other molecules, as well as morphological characteristics, associated with physiological or biological mechanisms.19 They may be used for several purposes, such as defining prognosis and risk of developing a disease, monitoring response to treatment, establishing new therapeutic targets and elucidating unclear physiopathological processes.19-21 In BD, biomarkers seem to be important to evaluate disease activity and progression associated with different moods (mood biomarkers), as well as to identify specific characteristics of the disease (trait biomarkers).19,22 Serum biomarkers have several advantages: easy collection, low cost, wide availability and possibility of use in large-scale studies.

Studies that investigated serum biomarkers of BD found that neurotrophins, inflammatory factors and

4 – Trends Psychiatry Psychother. 2015;37(1)

Results Potential BD biomarkers According to the definition adopted by the Biomarkers Definitions Working Group, a biomarker is a “characteristic objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.�18

Biomarkers and staging of bipolar disorder - Roda et al.

oxidative stress are potential candidates. At the same time, neuroimaging studies found that certain changes in patients with BD might be potential BD biomarkers.

Potential BD neuroimaging biomarkers The existence of changes in the brain structures of patients with BD has been largely reported in several studies. Morphometric studies of patients with BD found enlargements of the lateral and third ventricles.23,24 However, abnormal ventricular volumes are not evident from the onset of the disease and are often found only after several mood episodes. In fact, Strakowski et al. reported that the volume of ventricles in patients with BD during the first manic episode was similar to that of healthy individuals, whereas enlarged ventricles were

mood episode and in patients not treated with lithium.32 Therefore, the increase in amygdala volume, the focus of several studies,33-36 seems to be associated with treatment with lithium.32,37 Finally, numerous studies have documented the existence of white matter hyperintensities in individuals with BD. The presence of these abnormalities in deep white matter is about 2.5 times more likely to be found in individuals with BD than in healthy individuals.38 Gulseren et al. reported that the number of total brain hyperintensities increases with the number of manic episodes. The same authors suggested that these lesions should be used as a biological BD marker because white matter hyperintensities are frequent findings in family members that do not have BD.39

Potential serum BD biomarkers

a significant finding only in multiple-episode patients.

Eight years after disease onset, lateral ventricles were 122% larger than at the time of the first episode.24 The same study found that first-episode patients had a larger putamen than healthy individuals, although the difference from multiple-episode patients was not significant. The authors concluded that changes in putamen volume were not associated with BD progression. Nevertheless, studies should investigate whether this may be a neuroanatomic marker of BD traits or vulnerability, particularly if this finding is replicated in family members not affected by the disease.24 Other studies found a progressive decline in hippocampal and cerebellar gray matter density in people with BD. As the volume of these structures is smaller in patients with multiple mood episodes than in first-episode patients, the decline in hippocampal and cerebellar gray matter density may be a marker of disease progression.25 In the same line of investigation, Brambilla et al. found an inverse correlation between cerebellar vermis volume and number of BD episodes.26

Neurotrophic factors are a family of essential growth factors for neurogenesis and neuronal differentiation and survival. Neurotrophins also play an important role in synaptic plasticity and modulation of neuronal excitability.40,41 To this date, more than 50 neural growth factors have been identified.42 Some other important neurotrophins are the neuronal growth factor, brain derived neurotrophin factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT-4).43 BDNF, the most abundant neurotrophin in the CNS, has a particularly high expression in the amygdala, hippocampus and prefrontal cortex, brain areas associated with the regulation of emotion and several cognitive functions, such as attention, memory and executive functioning.19,44,45 The role of BDNF in BD pathogenesis has been extensively investigated.41,44 Recent studies suggested that BDNF might also be used as a biomarker of this mood disorder. Some of these

Several studies also found a reduction in the volume of some areas of the prefrontal cortex.23,27 However, the results of several other studies do not always confirm it.19 LĂłpez-Larson et al. found that although the volume of the prefrontal lobe of patients with BD is similar to that of healthy individuals, there are differences in volume of gray matter in both the right and left prefrontal cortex.

Their findings also showed that disease duration may be correlated with a smaller volume of gray matter in the left inferior prefrontal cortex.28 In addition to the neurostructural abnormalities mentioned above, an increase in the size of the amygdala was also found in adults with BD.29 However, studies with children and adolescents with BD have found a decline in amygdala volume.30,31 According to Hallahan et al., the size of the amygdala is smaller in patients after the first

studies showed evidence of promising properties of serum BDNF as a biomarker of BD state. The metaanalyses conducted by Lin and Fernandes et al. indicated that patients in the manic or depressive phase had lower blood concentrations of BDNF than healthy individuals, and that serum BDNF concentrations in euthymic patients were not significantly different from those found in controls.45,46 These results suggest that serum BDNF may be a potential biomarker of acute episodes. Additionally, preliminary studies by Fernandes et al. found that serum BDNF concentrations differentiate patients in a manic or depressive state from those in a euthymic phase, at a sensitivity of 90% and a specificity of 85%.45 In contrast, a recent study found that laboratory measurements of serum BDNF concentrations may distinguish bipolar from unipolar depression at a

Neurotrophic factors

Trends Psychiatry Psychother. 2015;37(1) – 5

Biomarkers and staging of bipolar disorder - Roda et al.

diagnostic accuracy of 88% for values equal to or lower than 0.26 pg/mL. The authors compared plasma BDNF concentrations of patients with BD in a depressive state with patients with unipolar depression, and found that the first group expressed lower levels of BDNF.47 Clinically, the difference between bipolar and unipolar depression remains challenging,47 as the BD diagnosis can only be made if the patient has at least one manic or hypomanic episode.48 Therefore, blood BDNF concentrations may be an important element to establish the differential diagnosis between these diseases.47 Other studies suggest that BDNF may be a biomarker of disease progression and severity. In this sense, BDNF values are inversely correlated with severity of symptoms of patients with BD.49,50 To explore the potential of blood BDNF to discriminate advanced and initial BD states, Kapczinski et

system in response to noxious stimuli. In the CNS, cytokines act in specific pathways and are associated with mood control, energy and activity.69 Moreover, inflammatory factors interact with the neuroendocrine system, specifically the hypothalamus-hypophysisadrenal axis, the autonomous nervous system and the system of neurotransmitters, which includes dopamine, serotonin and glutamate.69,70 In the last years, a growing number of publications have suggested that the immunoinflammatory system may be involved in BD physiopathology. In fact, recent studies with patients with BD confirmed the presence of chronic inflammation in this mood disorder.5 In general, mood episodes may be classified as proinflammatory states.43 Brietzke et al. found that patients with BD in a manic state had higher inteleukin-2

al. raised the hypothesis that serum BDNF concentrations may discriminate patients with BD for less than 3 years from patients that have had it for over 10 years,45 at a sensitivity of 100%, specificity of 88% and accuracy of 95% for values equal to or lower than 0.62 pg/mL.51 Another potential application of serum BDNF concentrations is the prediction of response to treatment and the control of pharmacological efficacy. In fact, Tramontina et al. found that there is a normalization of blood BDNF levels after appropriate treatment of acute mania.52,53 Rybakowski and Suwalska, in turn, found that patients with an excellent response to lithium had higher plasma BDNF levels than patients refractory to treatment with this drug.54 To clarify the mechanisms that underlie the decline of BDNF levels in patients with BD, several studies have investigated the existence of polymorphisms in the bdnf gene. One of the most frequently investigated polymorphisms is a methionine substitution for valine at codon 66 (val66met) in the region of the promoter of the bdnf gene. However , studies found divergent results

(IL-2), IL-4 and IL-6 concentrations than controls, whereas in patients with BD in a depressive state, only the proinflammatory cytokine IL-6 was elevated. The same authors found that, during euthymic states, only the IL-4 levels were elevated.71 These findings suggest that mania and depression, at a lower grade, are associated with a proinflammatory state.72 Similarly, Kim et al. found that patients in a manic state have significantly higher concentrations of IL-6 and tumor necrosis factor alpha (TNF-α) than individuals without BD. After six weeks of treatment with mood stabilizing drugs, the same patients had normal IL-6 levels, but TNF-α concentrations remained high. Therefore, those authors suggested that IL-6 might be a marker of manic states.70 At the same time, preliminary studies found inflammatory biomarkers capable of discriminating bipolar patients in the initial stage of the disease from those in advanced stages.61 According to KauerSant’Anna et al., at advance BD stages, serum IL10 concentrations declined and plasma TNF-α levels increase significantly.16,73 Kapczinski et al. found that when TNF-α concentrations were equal to or greater than 20.36 pg/mL, patients with BD at advanced stages could be discriminated from patients in initial stages of the disease at an accuracy of 91% and sensitivity and specificity of 97% and 85%,51 which indicates that TNF-α may be a potential biomarker of BD progression.

In addition to the changes in inflammatory cytokines described above, moderately elevated levels of C-reactive protein are found during manic episodes.74 Increased concentrations of proinflammatory cytokines, found in patients with BD, may indicate an association with high rates of medical comorbidities, particular heart disease,5 as these inflammatory changes may be risk factors for the development of obesity, hypertension, diabetes and atherosclerosis.75 These findings stress the importance of medical evaluations and physical

when investigating the association between the val66met polymorphism and BD development.55-65 Differences in results may indicate that genetic alterations in different ethnic groups, races or populations may confer different levels of susceptibility to BD development.41 In addition to BDNF, other neurotrophins are also abnormal in the plasma of patients with BD. Patients with BD have higher serum NT-3 concentrations during mood episodes than euthymic patients or healthy individuals.43,50,66,67 Neurotrophin 4/5 (NT-4/5) seems to be persistently higher in the blood of patients with BD, regardless of their mood state.43,68 Inflammatory factors Inflammatory factors, also known as cytokines, are proteins or glycoproteins secreted by cells of the immune 6 – Trends Psychiatry Psychother. 2015;37(1)

Biomarkers and staging of bipolar disorder - Roda et al.

control of patients with BD, as well as of the definition of adequate treatments to reduce early deaths associated with BD. Comorbidities seem to be not only a consequence of treatment and life style characteristic of individuals with BD, but also a symptom of this psychiatric disorder.5 In fact, medical burden is part of the early stages of BD.5 Over 70% of young individuals with BD are estimated to need treatment for chronic medical conditions.76 Middle-aged individuals with BD, in contrast, develop heart disease and hypertension at a younger age than adults without BD.77 Therefore, medical burden should be included in BD staging.

Oxidative stress Oxidative stress is the result of imbalance between oxidant and antioxidant enzymes, which usually results in cell damage. Lower antioxidant levels and an increased production of pro-oxidant agents give rise to oxidative stress, which leads to changes in macromolecules, such as lipid, proteins, carbohydrates and DNA.43,78 The CNS is particularly vulnerable to oxidative lesions, because the brain uses great amounts of oxygen, which promotes the formation of oxygen free radicals and oxygen reactive species. Moreover, the CNS has a limited antioxidant capacity, and glutathione is the main antioxidant in the brain.43,79 The antioxidant system is composed of an enzyme, such as superoxide dismutase (SOD), catalase and glutathione peroxidase, and a non-enzyme component, such as glutathione.43 The role of oxidative stress in the physiopathology of BD has been investigated in several studies, which consistently reported changes in antioxidant enzymes, lipid peroxidation and levels of nitric oxide (NO), an important marker of oxidative stress.19,80,81 The meta-analysis conducted by Andreazza et al. concluded that some of the oxidative stress markers are elevated in plasma or blood cells of individuals with BD, particularly NO and thiobarbituric acid reactive substances (TBARS), markers of lipid peroxidation.80 The analysis of blood TBARS concentrations in patients with BD revealed that they are elevated during all stages of BD.82 These results suggest that lipid damage occurs all along the course of this mood disorder.80 Therefore, these findings suggest that the levels of TBARS may be used as biomarkers of BD progression if future studies confirm that they increase with disease duration. In addition to TBARS, NO concentrations are also elevated in BD, regardless of mood state.19,83 Andreazza et al. found that there are other oxidative stress markers, such as 3-nitrotyrosine (3-NT), that are elevated in the initial stages of BD.84 However, the results of studies about the antioxidant enzyme system are often discordant.

Andreazza et al. and Kunz et al. found an increased SOD activity in patients during acute BD episodes, but not in euthymic patients.43,82,85 Similarly, MachadoVieira et al. reported an increase in the activity of this antioxidant enzyme in unmedicated patients with BD during a manic episode.43,86 In contrast, other studies found a decrease in SOD activity during all BD phases,43 whereas Raffa et al. did not find any differences in SOD levels between patients with BD and healthy individuals.43,87 One of the consequences of oxidative stress is DNA damage, and studies with patients with BD have shown an increase in the frequency of DNA damage.19,43,88 Andreazza et al. described a positive correlation between manic and depressive symptom severity and increased DNA damage.88 At the same time, DNA damage has also been associated with reductions in telomere length in lymphocytes of individuals with BD.19,89 According to Saretzki and Von-Zglinicki, telomere shortening may be indicative of cumulative oxidative stress.90 Moreover, a study with patients with BD concluded that the number of shortened telomeres and mean telomere length are associated with number of depressive episodes along life, but not with type of disease.6,89 Telomere shortening physiologically occurs after each cell division as part of normal ageing.

However, telomere shortening found in individuals with BD seems to be indicative of ageing acceleration in about 10 years. These data may explain the association between BD and early medical comorbidities associated with ageing.91 Another element to support the role of oxidative stress in BD is the evidence that antioxidant compounds, such as N-acetylcystein (NAC) are beneficial in the treatment of BD, according to several studies. NAC, a glutathione precursor, efficiently reduces depressive symptoms in patients with BD and improves their functioning and quality of life.92,93 Treatment effects of mood stabilizers seem to be associated with their action upon oxidative stress pathways.19 Patients with BD treated with lithium have a significant reduction of TBARS concentrations and of the SOD/CAT ratio,19,89 whereas healthy individuals exposed to lithium do not have the same changes.19,94 These findings suggest that lithium has an antioxidant effect favorable for the treatment of BD. To evaluate systemic toxicity in BD, Kapczinski et al. compared the concentrations of several markers in patients with BD, healthy individuals and patients with sepsis. One of their notable findings was the impressive magnitude of oxidative damage during acute BD episodes, as high as the level seen in patients with sepsis in some cases.42,95 Trends Psychiatry Psychother. 2015;37(1) – 7

Biomarkers and staging of bipolar disorder - Roda et al.

The importance of BD staging Staging is a widely used tool in Medicine, particularly in cancer and heart disease, and is the basis for the choice of adequate treatment and the definition of a prognosis.96 However, only recently have the first models of staging of psychiatric disorders been developed.97 To build staging models, the course of the disease should be predictable along time,96 and the disease at the initial stages should usually be associated with a better prognosis and simpler treatment requirements. In addition, treatment efficacy should also be greater in the beginning of the disease, and a subsequent progressive decline should be expected, culminating with resistance to treatment.98 For this reason, staging models should be constructed in parallel to treatment algorithms, as several stages usually have different treatment needs.

with BD may experience a phase characterized by symptom persistence and resistance to treatment, without interepisode symptom remission (stage 4)17,99 (Table 1).

The initial model described by Berk et al. was later developed by Kapczinski et al., who, in 2009, suggested the adoption of a staging model that included a latent phase followed by four stages (stages 1 to 4). This model describes the progression from a latent (at-risk) stage to a more advanced, treatment-refractory stage.

The model developed by Kapczinski et al. requires the longitudinal evaluation of several clinical features, the study of comorbidities, functioning and neurocognition and the definition of biomarkers (Table 1).17,100 The staging models described by Berk et al. and Kapczinski et al. are based on the identification of

Therefore, staging should guide treatment plans and the definition of prognoses.99 In the last years, different staging models have been suggested for BD. In 2007 Berk et al. suggested that BD develops from an asymptomatic at-risk stage during which risk factors are active (stage 0). The next is the prodromal stage, during which symptoms are mild and nonspecific (stage 1). After this stage, the first mood episode, usually a depressive episode, occurs (stage 2). The first episode is usually followed by multiple remissions and relapses (stage 3). Finally, individuals

individuals at risk of developing BD because early diagnosis and treatment may critically improve prognosis.17 According to Berk et al., early interventions are fundamental for neuroprotection.101 Therefore, the treatment during the initial stages of the disease should primarily focus on neuroprotective strategies, but treatment during more advanced stages should be palliative and rehabilitative to control the consequences of disease progression.99 The importance assigned to neuroprotective strategies may take psychiatry to a new era of preventive psychopharmacology.43

Table 1 - Suggested staging models (adapted by permission)

Berk et al.98

Kapczinski et al.73,100

Stage

Description

Stage

Description

Biomarkers

0

Increased risk for mood disorder, asymptomatic period during which a set of risk factors are active.

Latent

Mood change symptoms and anxiety; Increased risk of developing BD; No cognitive dysfunction.

Genetic polymorphisms may determine susceptibility.

1a

Mild or nonspecific symptoms.

1

1b

Prodromal features: ultra-high risk.

Well-defined euthymic periods.

No psychiatric morbidity between episodes.

No cognitive dysfunction.

Serum concentrations: ↑ TNF-α ↑ 3-NT ↑ IL-6, IL-10

2

First major manic or depressive (more common) episode.

2

Inter-episode symptoms due to comorbidities.

Transient cognitive dysfunction.

Serum concentrations: ↑ TNF-α ↑ 3-NT ↑ IL-6, IL-10 ↓ BDNF

3a

First relapse, subclinical symptoms.

3

3b

First clinical relapse.

3c

Subsequent pattern of remissions and relapses.

Clinically relevant pattern of cognitive Morphometric brain abnormalities may and functional impairment (unable be present. to work) Serum concentrations: ↑ ↑ TNF-α ↑ 3-NT ↑ IL-6, IL-10 ↓ ↓ BDNF

4

Refractory to treatment, no symptom remission.

4

Loss of autonomy due to cognitive and functional impairment.

Ventricular enlargement and/or white matter hyperintensities. ↑ ↑ TNF-α ↑ 3-NT ↓ ↓ BDNF ↑ ↑ Glutathione reductase and transferase ↓ IL-6, IL-10

BDNF = brain-derived neurotrophic factor, IL = interleukin, TNF-α = tumor necrosis factor alpha, 3-NT = 3-nitrotyrsosine.

8 – Trends Psychiatry Psychother. 2015;37(1)

Biomarkers and staging of bipolar disorder - Roda et al.

Conclusions Although the physiopathological mechanisms of BD have not been fully clarified, several publications have suggested that neurotrophic and inflammatory factors and oxidative stress may play a role in the pathogenesis of this psychiatric disorder. Recent studies with individuals with BD pointed to the possibility of using plasma concentrations of neurotrophins, inflammatory factors and oxidative stress mediators as biomarkers of BD progression and activity. At the same time, neuroimaging studies of patients with BD also found structural abnormalities that may be potential BD biomarkers. The adoption of biomarkers to stage BD may improve treatment guidelines and algorithms and lead to the development of more efficient, individually tailored treatment regimens.73 However, current literature also points to limitations that should not be ignored. To this date, most studies are cross-sectional, and very few are prospective. Moreover, other psychiatric disorders and neurodegenerative diseases present with biochemical and imaging abnormalities identical to those found in BD, which may compromise the use of isolated biomarkers. Therefore, different combinations of serum concentrations and neuroimaging biomarkers may have to be evaluated to improve their sensitivity and specificity. Finally, study findings should be replicated, and longitudinal studies should be conducted to confirm the clinical and scientific validity of biochemical and neuroanatomic abnormalities as biomarkers of BD.

References 1.

Merikangas KR, Jin R, He JP, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry.

2011;68:241-51.

2. World Health Organization. The global burden of disease: 2004 update. Geneva: WHO; 2008. http://www.who.int/healthinfo/ global_burden_disease/2004_report_update/en/ 3. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord.

2002;68:167-81.

4. Kupfer DJ. The increasing medical burden in bipolar disorder.

JAMA. 2005;293:2528-30.

5. Leboyer M, Soreca I, Scott J, Frye M, Henry C, Tamouza R, et al.

Can bipolar disorder be viewed as a multi-system inflammatory disease? J Affect Disord. 2012;141:1-10. Epub 2012 Apr 11.

6. Fries GR, Pfaffenseller B, Stertz L, Paz AV, Dargél AA, Kunz M, et al. Staging and neuroprogression in bipolar disorder. Curr Psychiatry Rep. 2012;14:667-75.

7. Post RM, Fleming J, Kapczinski F. Neurobiological correlates of illness progression in the recurrent affective disorders. J Psychiatr Res. 2012;46:561-73. Epub 2012 Mar 23.

8. Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors.

Neurosci Biobehav Rev. 2011;35:804-17. Epub 2010 Oct 8.

9. Kraepelin E. Manic-depressive insanity and paranoia. Edinburgh: E. & S. Livingstone; 1899.

10. Post RM. Mechanisms of illness progression in the recurrent affective disorders. Neurotox Res. 2010;18:256-71.

11. Ketter TA, Houston JP, Adams DH, Risser RC, Meyers AL, Williamson DJ, et al. Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. J Clin Psychiatry. 2006;67:95-101.

12. Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry. 1999;156:1264-6.

13. Scott J1, Paykel E, Morriss R, Bentall R, Kinderman P, Johnson T, et al. Cognitive-behavioural therapy for severe and recurrent bipolar disorders: randomised controlled trial. Br J Psychiatry.

2006;188:313-20.

14. Martínez-Arán A, Vieta E, Colom F, Torrent C, Sánchez-Moreno J, Reinares M, et al. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord. 2004;6:224-32.

15. Martinez-Aran A, Vieta E, Torrent C, Sanchez-Moreno J, Goikolea JM, Salamero M, et al. Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord. 2007;9:103-13.

16. Kauer-Sant’Anna M, Kapczinski F, Andreazza AC, Bond DJ, Lam RW, Young LT, et al. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol. 2009;12:447-58.

Epub 2008 Sep 4.

17. Vieta E, Reinares M, Rosa AR. Staging bipolar disorder. Neurotox Res. 2011;19:279-85. Epub 2010 May 12.

18. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.

19. Teixeira AL, Barbosa IG, Machado-Vieira R, Rizzo LB, Wieck A, Bauer ME. Novel biomarkers for bipolar disorder. Expert Opin Med Diagn. 2012;7:147-59. Epub 2012 Dec 16.

20. Puntmann VO. How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. Postgrad Med J. 2009;85:538-45.

21. Schwarz E, Bahn S. The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders.

Br J Pharmacol. 2008;153(Suppl 1):S133-6. Epub 2008 Jan 14.

22. Frey BN, Andreazza AC, Houenou J, Jamain S, Goldstein BI, Frye MA, et al. Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry. 2013;47:321-32. Epub 2013 Feb 14.

23. Soares JC, Kochunov P, Monkul ES, Nicoletti MA, Brambilla P, Sassi RB, et al. Structural brain changes in bipolar disorder using deformation field morphometry. Neuroreport. 2005;16:541-4.

24. Strakowski SM, DelBello MP, Zimmerman ME, Getz GE, Mills NP, Ret J, et al. Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder. Am J Psychiatry.

2002;159:1841-7.

25. Moorhead TW, McKirdy J, Sussmann JE, Hall J, Lawrie SM, Johnstone EC, et al. Progressive gray matter loss in patients with bipolar disorder. Biol Psychiatry. 2007;62:894-900. Epub 2007 Jul 9.

26. Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, et al. MRI study of posterior fossa structures and brain ventricles in bipolar patients. J Psychiatr Res. 2001;35:313-22.

27. Blumberg HP, Krystal JH, Bansal R, Martin A, Dziura J, Durkin K, et al. Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study. Biol Psychiatry 2006;59:611-8. Epub 2006 Jan 18.

28. López-Larson MP, DelBello MP, Zimmerman ME, Schwiers ML, Strakowski SM. Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biol Psychiatry. 2002;52:93-100.

29. Beyer JL, Krishnam KR. Volumetric brain imaging findings in mood disorders. Bipolar Disord. 2002;4:89-104.

30. Chang K, Karchemskiy A, Barnea-Goraly N, Garrett A, Simeonova DI, Reiss A. Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry.

2005;44:565-73.

31. DelBello MP, Zimmerman ME, Mills NP, Getz GE, Strakowski SM. Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder.

Bipolar Disord. 2004;6:43-52.

32. Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, et al. Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry. 2011;69:326-35.

Epub 2010 Oct 27.

33. Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J. Amygdala enlargement in bipolar disorder and hippocampal reduction in

Trends Psychiatry Psychother. 2015;37(1) – 9

Biomarkers and staging of bipolar disorder - Roda et al.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry. 1998;55:663-4.

Altshuler LL, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K, et al. An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia. Biol Psychiatry. 2000;48:147-62.

Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E, et al. MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res. 2003;37:287-95.

Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, et al. Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry.

1999;56:254-60.

Foland LC, Altshuler LL, Sugar CA, Lee AD, Leow AD, Townsend J, et al. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport. 2008;19:221-4.

Kempton MJ, Geddes JR, Ettinger U, Williams SC, Grasby PM. Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry.

2008;65:1017-32.

Gulseren S, Gurcan M, Gulseren L, Gelal F, Erol A. T2 hyperintensities in bipolar patients and their healthy siblings.

Arch Med Res. 2006;37:79-85.

Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action.

Nat Rev Neurosci. 2005;6:603-14.

Post RM. Role of BDNF in bipolar and unipolar disorder: clinical and theoretical implications. J Psychiatr Res. 2007;41:979-90.

Epub 2007 Jan 18.

Magalhães PV, Fries GR, Kapczinski F. [Peripheral markers and the pathophysiology of bipolar disorder]. Rev Psiquiatr Clin.

2012;39:60-7.

Pfaffenseller B1, Fries GR, Wollenhaupt-Aguiar B, Colpo GD, Stertz L, Panizzutti B, et al. Neurotrophins, inflammation and oxidative stress as illness activity biomarkers in bipolar disorder.

Expert Rev Neurother. 2013;13:827-42.

Teixeira AL, Barbosa IG, Diniz BS, Kummer A. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med 2010;4:871-87.

Fernandes BS, Gama CS, Ceresér KM, Yatham LN, Fries GR, Colpo G, et al. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res. 2011;45:995-1004.

Lin PY. State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study.

Neurosci Lett. 2009;466:139-43. Epub 2009 Sep 26.

Fernandes BS, Gama CS, Kauer-Sant’Anna M, Lobato MI, Belmonte-de-Abreu P, Kapczinski F. Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis. J Psychiatr Res. 2009;43:1200-4. Epub 2009 Jun 6.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

Cunha AB, Frey BN, Andreazza AC, Goi JD, Rosa AR, Gonçalves CA, et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett. 2006;398:215-9. Epub 2006 Feb 9.

Grande I, Fries GR, Kunz M, Kapczinski F. The role of BDNF as a mediator of neuroplasticity in bipolar disorder. Psychiatry Investig. 2010;7:243-50.

Kapczinski F, Fernandes BS, Kauer-Sant’Anna M, Gama CS, Yatham LN, Berk M. The concept of staging in bipolar disorder: the role of BDNF and TNF-alpha as biomarkers. Acta Neuropsychiatr 2009;21:272-4.

Tramontina JF, Andreazza AC, Kauer-Sant’anna M, Stertz L, Goi J, Chiarani F, et al. Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neurosci Lett.

2009;452:111-3. Epub 2009 Jan 15.

Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, KauerSant’Anna M, Klamt F, et al. Peripheral biomarkers and illness activity in bipolar disorder. J Psychiatr Res. 2011;45:156-61.

Epub 2010 Jun 11.

Rybakowski JK1, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol. 2010;13:617-22. Epub 2010 Apr 15.

Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim Y-, Tsan G, et al.

Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry. 2002;7:579-93.

Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility

10 – Trends Psychiatry Psychother. 2015;37(1)

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

to bipolar disorder: evidence from a family-based association study.

Am J Hum Genet. 2002;71:651-5. Epub 2002 Aug 2.

Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH Jr. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry.

2004;161:1698-700.

Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M, Kapelski P, et al. Association analysis of brainderived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry. 2004;5:215-20.

Lohoff FW, Sander T, Ferraro TN, Dahl JP, Gallinat J, Berrettini WH. Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet. 2005;139B:51-3.

Green EK, Raybould R, Macgregor S, Hyde S, Young AH, O’Donovan MC, et al. Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK. Br J Psychiatry. 2006;188:21-5.

Strauss J, Barr CL, George CJ, King N, Shaikh S, Devlin B, et al.

Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:16-9.

Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T, et al.

Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Lett. 2003;337:17-20.

Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology. 2003;48:186-9.

Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, et al. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biol Psychiatry.

2004;56:376-8.

Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry. 2005;10:208-12.

Walz JC, Andreazza AC, Frey BN, Cacilhas AA, Ceresér KM, Cunha AB, et al. Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder. Neurosci Lett.

2007;415:87-9. Epub 2007 Jan 17.

Fernandes BS, Gama CS, Walz JC, Ceresér KM, Fries GR, Colpo G, et al. Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes. J Psychiatr Res. 2010;44:561-5. Epub 2010 Jan 8.

Walz JC, Magalhães PV, Giglio LM, Cunha AB, Stertz L, Fries GR, et al. Increased serum neurotrophin-4/5 levels in bipolar disorder. J Psychiatr Res. 2009;43:721-23. Epub 2008 Dec 10.

Brietzke E, Kapczinski F. TNF-alpha as a molecular target in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry.

2008;32:1355-61. Epub 2008 Jan 16.

Kim YK, Jung HG, Myint AM, Kim H, Park SH. Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord. 2007;104:91-5. Epub 2007 Apr 16.

Brietzke E, Stertz L, Fernandes BS, Kauer-Sant’anna M, Mascarenhas M, Escosteguy Vargas A, et al. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord. 2009;116:214-7. Epub 2009 Feb 28.

Hamdani N, Doukhan R, Kurtlucan O, Tamouza R, Leboyer M. Immunity, inflammation, and bipolar disorder: diagnostic and therapeutic implications. Curr Psychiatry Rep. 2013;15:387.

Kapczinski F1, Dias VV, Kauer-Sant’Anna M, Brietzke E, Vázquez GH, Vieta E, et al. The potential use of biomarkers as an adjunctive tool for staging bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatr. 2009;33:1366-71. Epub 2009 Aug 8.

Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. Elevated serum levels of C-reactive protein are associated with mania symptoms in outpatients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:952-5. Epub 2007 Mar 6.

Drake C, Boutin H, Jones MS, Denes A, McColl BW, Selvarajah JR, et al. Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immun. 2011;25:1113-22. Epub 2011 Feb 26.

Evans-Lacko SE, Zeber JE, Gonzalez JM, Olvera RL. Medical comorbidity among youth diagnosed with bipolar disorder in the United States. J Clin Psychiatry. 2009:70:1461-6. Epub 2009 Sep 8.

Biomarkers and staging of bipolar disorder - Roda et al.

77. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70:1078-90. Epub 2009 Jun 2.

78. Halliwell B, Gutteridge JM. Free Radicals in Biology and Medicine.

4th ed. New York: Oxford University Press; 2007.

79. Olmez I, Ozyurt H. Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int. 2012;60:208-12. Epub 2011 Nov 22.

80. Andreazza AC, Kauer-Sant’anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, et al. Oxidative stress markers in bipolar disorder: a metaanalysis. J Affect Disord. 2008;111:135-44. Epub 2008 Jun 9.

81. Frey BN, Andreazza AC, Kunz M, Gomes FA, Quevedo J, Salvador M, et al. Increased oxidative stress and DNA damage in bipolar disorder: a twin-case report. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:283-5. Epub 2006 Jul 20.

82. Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P, et al. Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res. 2007;41:523-9. Epub 2006 Sep 7.

83. Savas HA, Gergerlioglu HS, Armutcu F, Herken H, Yilmaz HR, Kocoglu E, et al. Elevated serum nitric oxide and superoxide dismutase in euthymic bipolar patients: impact of past episodes.

World J Biol Psychiatry. 2006;7:51-5.

84. Andreazza AC, Kapczinski F, Kauer-Sant’Anna M, Walz JC, Bond DJ, Gonçalves CA, et al. 3-Nitrotyrosine and glutathione antioxidant system in patients in the early and late stages of bipolar disorder. J Psychiatry Neurosci. 2009;34:263-71.

85. Kunz M, Gama CS, Andreazza AC, Salvador M, Ceresér KM, Gomes FA, et al. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry.

2008;32:1677-81. Epub 2008 Jul 6.

86. Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V Jr, da Silva Vargas R, et al. Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett. 2007;421:33-6. Epub 2007 May 22.

87. Raffa M, Barhoumi S, Atig F, Fendri C, Kerkeni A, Mechri A. Reduced antioxidant defense systems in schizophrenia and bipolar I disorder. Prog Neuropsychopharmacol Biol Psychiatry.

2012;39:371-5. Epub 2012 Jul 27.

88. Andreazza AC, Frey BN, Erdtmann B, Salvador M, Rombaldi F, Santin A, et al. DNA damage in bipolar disorder. Psychiatry Res. 2007;153:27-32. Epub 2007 Jun 20.

89. Elvsåshagen T, Vera E, Bøen E, Bratlie J, Andreassen OA, Josefsen D, et al. The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder.

J Affect Disord. 2011;135:43-50. Epub 2011 Aug 30.

90. Saretzki, G, Von-Zglinicki T. Replicative aging, telomeres, and oxidative stress. Ann N Y Acad Sci. 2002;959:24-9.

91. Simon NM1, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH, et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry. 2006;60:432-5. Epub 2006 Apr 11.

92. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al.

N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry.

2008;64:468-75. Epub 2008 Jun 5.

93. Magalhães PV, Dean OM, Bush AI, Copolov DL, Malhi GS, Kohlmann K, et al. N-acetylcysteine for major depressive episodes in bipolar disorder. Rev Bras Psiquiatr. 2011;33:374-8.

94. Khairova R, Pawar R, Salvadore G, Juruena MF, de Sousa RT, Soeiro-de-Souza MG, et al. Effects of lithium on oxidative stress parameters in healthy subjects. Mol Med Report. 2012;5:680-2.

Epub 2011 Dec 22.

95. Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, KauerSant’Anna M, Klamt F, et al. A systemic toxicity index developed to assess peripheral changes in mood episodes. Mol Psychiatry.

2010;15:784-6. Epub 2010 Mar 30.

96. Berk M, Berk L, Dodd S, Cotton S, Macneil C, Daglas R, et al.

Stage managing bipolar disorder. Bipolar Disord. 2014;16:471-7.

Epub 2013 Jun 20.

97. McGorry PD, Purcell R, Hickie IB, Yung AR, Pantelis C, Jackson HJ. Clinical staging: a heuristic model for psychiatry and youth mental health. Med J Aust. 2007;187(7 Suppl):S40-2.

98. Berk M, Hallam KT, McGorry PD. The potential utility of a staging model as a course specifier: a bipolar disorder perspective. J Affect Disord. 2007;100:279-81. Epub 2007 Apr 11.

99. Berk M, Conus P, Lucas N, Hallam K, Malhi GS, Dodd S, et al.

Setting the stage: from prodrome to treatment resistance in bipolar disorder. Bipolar Disord. 2007;9:671-8.

100.Kapczinski F1, Dias VV, Kauer-Sant’Anna M, Frey BN, GrassiOliveira R, Colom F, et al. Clinical implications of staging bipolar disorders. Expert Rev Neurother. 2009;9:957-66.

101.Berk M, Malhi GS, Hallam K, Gama CS, Dodd S, Andreazza AC, et al. Early intervention in bipolar disorders: clinical, biochemical and neuroimaging imperatives. J Affect Disord. 2009;114:1-13.

Correspondence: Ângela Roda Faculdade de Medicina de Lisboa Av. Professor Egas Moniz 1649-028 - Lisbon, Portugal E-mail: angela.neto.roda@gmail.com

Trends Psychiatry Psychother. 2015;37(1) – 11

Trends

Review Article

in Psychiatry and Psychotherapy

Resilience of caregivers of people with dementia: a systematic review of biological and psychosocial determinants Resiliência de cuidadores de pessoas com demência: revisão sistemática de determinantes biológicos e psicossociais Rachel Dias, Raquel Luiza Santos, Maria Fernanda Barroso de Sousa, Marcela Moreira Lima Nogueira, Bianca Torres, Tatiana Belfort, Marcia Cristina Nascimento Dourado

Abstract

Resumo

Introduction: Although caregivers of people with dementia may face difficulties, some positive feelings of caregiving may be associated with resilience.

Objective: This study systematically reviewed the definitions, methodological approaches and determinant models associated with resilience among caregivers of people with dementia.

Methods: Search for articles published between 2003 and 2014 in ISI, PubMed/MEDLINE, SciELO and Lilacs using the search terms resilience, caregivers and dementia.

Results and conclusions: Resilience has been defined as positive adaptation to face adversity, flexibility, psychological well-being, strength, healthy life, burden, social network and satisfaction with social support. No consensus was found about the definition of resilience associated with dementia. We classified the determinant variables into biological, psychological and social models. Higher levels of resilience were associated with lower depression rates and greater physical health. Other biological factors associated with higher levels of resilience were older age, African-American ethnicity and female sex. Lower burden, stress, neuroticism and perceived control were the main psychological factors associated with resilience. Social support was a moderating factor of resilience, and different types of support seemed to relieve the physical and mental overload caused by stress.

Keywords: Psychological resilience, caregiver, dementia, depression.

Introdução: Apesar das dificuldades enfrentadas por cuidadores de pessoas com demência, sentimentos positivos quanto aos cuidados podem estar relacionados à resiliência.

Objetivo: Revisamos sistematicamente a literatura sobre a conceituação, abordagens metodológicas e modelos determinantes relacionados à resiliência dos cuidadores de pessoas com demência.

Métodos: Foi realizada uma busca por artigos publicados entre 2003 e 2014 nas bases de dados ISI, PubMed/MEDLINE, SciELO e Lilacs, usando os descritores resilience [resiliência], caregivers [cuidadores] e dementia [demência].

Resultados e conclusões: A resiliência foi definida como adaptação positiva para enfrentar adversidades, flexibilidade, bem-estar psicológico, força, vida saudável, sobrecarga, rede social e satisfação com o apoio social recebido. Não se encontrou consenso sobre o conceito de resiliência em relação à demência.

As variáveis determinantes foram classificadas em modelos biológicos, psicológicos e sociais. Níveis mais altos de resiliência foram relacionados com taxas mais baixas de depressão e melhor saúde física. Os outros aspectos biológicos relacionados a níveis mais altos de resiliência foram idade avançada, etnia de origem africana e sexo feminino. Menos sobrecarga, estresse, neuroticismo e percepção de controle foram os principais aspectos psicológicos relacionados à resiliência. O apoio social foi um fator moderador da resiliência, pois uma variedade de tipos de apoio parece aliviar a sobrecarga física e mental causada pelo estresse.

Descritores: Resiliência psicológica, cuidador, demência, depressão.

Center for Alzheimer’s Disease and Related Disorders, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.

Financial support: Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (grant no. E-26/102.256/2010).

Submitted Jul 21 2014, accepted for publication Sep 10 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Dias R, Santos RL, de Sousa MF, Nogueira MM, Torres B, Belfort T, et al. Resilience of caregivers of people with dementia: a systematic review of biological and psychosocial determinants. Trends Psychiatry Psychother. 2014;37(1):12-19. http://dx.doi.org/10.1590/2237-6089-2014-0032. Epub Jan 30, 2015. © APRS

Trends Psychiatry Psychother. 2015;37(1) – 12-19

Resilience in dementia - Dias et al.

Introduction Dementia leads to progressive and irreversible cognitive and functional impairment, and people with dementia become dependent on caregivers, generally family members.1-4 The negative health consequences of looking after an older family member with dementia, particularly the effects on mental and physical health, are well documented.5-12 People with dementia often have an array of neuropsychiatric symptoms, such as mood disorders, delusions, hallucinations, vegetative symptoms and psychomotor abnormalities.

Neuropsychiatric symptoms are the most important factors in caregiver burden.7,13 Although caregivers of people with dementia face many difficulties, they may also experience positive

understandable or predictable and to perceive one’s ability to cope in a difficult situation and to find meaning in everyday events or problems faced.25 Resilience helps caregivers maintain their mental and physical stability, fostering caregiving and providing better health and quality of life for the care recipient.3 Therefore, resilience is a complex construct, as it involves the interaction between adverse life events and internal and external individual factors.2,26 However, differences in the definition of resilience result in the use of diverse methodological approaches.

This systematic review compared the definitions, methodological approaches and determinant models of resilience among caregivers of people with dementia. It also investigated how resilience is defined in the field of

emotional responses,12,14 which may be associated with resilience3 and, consequently, with positive feelings about caring.12 Resilience may be defined as a dynamic process involving the interaction between both risk and protective factors, internal and external to the individual, that act to modify the effects of an adverse life event.15,16 It is a process related to adaptive capacities or to a positive trajectory of functioning and adaptation after a traumatic situation.1,2,4,5,13,14,17,18 Resilience is not invulnerability to stress, but, rather, the ability to recover from negative events.19 It corresponds to a transactional process mediated by the interaction between the individual and the environment. Therefore, risk and protective factors, typically associated with patterns of negative and positive adaptation in the face of risk, are important aspects of resilience. Both risk and protective factors have relevant elements in various domains of human functioning, such as personal attributes, family structure and dynamics, social context, cultural

dementia and which factors significantly determine low and high levels of resilience among caregivers of people with dementia.

aspects and specific events.20 Trombeta & Guzzo21 suggested that resilience is a balanced scale between a stressful event, threats, suffering and adverse conditions. These reveal vulnerability and strengths, skills, capacity of reaction and coping, some of the characteristics of resilient individuals.

Resilience, satisfaction with caregiving, coping, social support and a strong sense of spirituality have been posited as protective factors that mediate negative health outcomes.18,22-24 Other mediating mechanisms are coping strategies and a sense of coherence.8,12,19 Coping strategies are a dynamic set of cognitive and behavioral efforts to cope with internal and external demands perceived as burdens when compared with personal resources.20 In contrast, the sense of coherence depends on the ability to realize that the situation is

of elderly people not diagnosed with dementia; resilience of people with dementia or mourning; caregivers of people with other pathologies; assessment and validation of instruments for caregivers or patients; euthanasia; efficacy of non-pharmacological interventions not designed to investigate resilience; effect of caregiver attachment on patient care; healthy aging and systematic reviews; and articles with no patient samples.

Two independent reviewers read the abstracts and included studies according to their contents. In case of disagreement, a third reviewer made the decision after reading the title and abstract. After that, full manuscripts were read to check inclusion and exclusion criteria. We used a standardized form, according to the recommendations of the Cochrane Collaboration.27

Method A literature search was conducted using the Web of Knowledge Cross Search (Thomson Scientific/ISI Web Services), MEDLINE (PubMed) and SciELO databases to select studies about resilience of caregivers of people with dementia published in Portuguese, English or Spanish from January 2003 to June 2014. The search terms were resilience, caregivers and dementia, in the following combination: resilience AND caregivers AND dementia.

Inclusion criteria were: studies about resilience of caregivers of people with the dementia; crosssectional or longitudinal; randomized or nonrandomized, controlled or not controlled.

We excluded studies about: resilience of caregivers

Trends Psychiatry Psychother. 2015;37(1) – 13

Resilience in dementia - Dias et al.

Results

Sample We found 56 articles: 25 in the Web of Knowledge Cross Search, 30 in PubMed/MEDLINE and one in SciELO. After the exclusion of redundant crossreferences (n = 11), 45 studies were selected. Thirtyone studies were excluded for different reasons, as shown in Table 1. We added one study manually, and our sample comprised the complete texts of 15 studies.

In the studies reviewed, resilience was defined as positive adjustment in case of adversity,1,2,4,5,13,14,18 beliefs about one’s own abilities and internal locus of control,6 psychological well-being and strength,12 coping development of healthy life,3 perceived burden28 and network size or satisfaction with social support.29 Only two studies did not define resilience.7,24

Table 1 - Studies excluded according to criterion

Domains

Exclusion criteria

Participants

Excluded

n = 31 ↓ Other pathologies

03

Healthy aging

01

Children that live with people with dementia

01

Caregivers of elderly with or without dementia that live in an institution

03

Resilience of people with dementia

01

Euthanasia of people with severe dementia

01

Older veteran caregivers

01

Caregivers of healthy elderly

02

↓ n = 18 Study design

Review

03

Conference

01

↓ n = 14 Interventions

Non-pharmacological

03

↓ n = 11 Assessment

Validation of instruments

02

Salivary cortisol

02

↓ n=7 Other factors that affect caregivers and people with dementia

Mourning

01

Implication on caregiving

02

Effects of bonds

01

Job satisfaction and career commitment

01

↓ n=2 Only abstract

Resilience and suicide ↓ n=0

14 – Trends Psychiatry Psychother. 2015;37(1)

02

Resilience in dementia - Dias et al.

Studies were classified into three areas according to determinant factors, as described below.

Resilience and psychological factors (n = 15) Higher levels of resilience were associated with psychological factors, such as coping strategies,10,12 positive cognitions,1 resources,1 optimism,6 self-efficacy,6 internal locus of control,6 full engagement in daily activities4 and search for challenges.4 Higher levels of resilience were also associated with decreased burden,1,2,28 stress,6 neuroticism,2 perceived control4 and distress.5,24 A study found that caregivers that provided care for a longer duration of time had higher levels of resilience.28 Another study showed that resilience did not significantly explain caregiver’s sense of marital satisfaction.13

Resilience and biological factors (n = 9) Higher levels of resilience were associated with less depression4,7,29 and better physical health.2,3 Other biological factors associated with higher levels of resilience were: older age,14 African-American ethnicity29 and female sex.28

Resilience and social factors (n = 5) Studies found a positive association between higher levels of resilience and social factors, such as good social support,2,15,20 satisfaction with social support20 and individual, family, and community resources.19

Methods Most studies were cross-sectional,1-3,5,6,10,12-14,18,24 but longitudinal4,28,29 and descriptive1,3,5,10,14,24 designs were also used.

Most samples included caregivers of people with Alzheimer’s disease (AD).1,3,4,7,12,14,18,29 Caregivers of people with AD and vascular dementia (VD) were included in one study,10 and caregivers of people with AD, VD and mixed dementia (MD) were compared in 13% of the studies.2,6 Two studies compared AD and similar disorders,13,28 and two did not specify the type of dementia under study.5,24 The most frequent assessment instrument was the complete and brief versions of the Resilience Scale developed by Wagnild & Young.3,5,12,13,18 Other instruments were the Connor-Davidson Resilience Scale (CD-RISC)2,7 and the Dispositional Resilience Scale.4 Two studies did not have any specific instrument to assess resilience, but used scales that assess associated constructs, such as the Resourcefulness Scale1 and

the Battery of Generalized Expectancies of Control Scales (BEEGC-20).6 One study28 administered the Zarit Burden Interview to assess resilience and analyzed results according to reports of burden and frequency of demands of the person with dementia. In one study29 the Center for Epidemiological Studies Depression Scale (CES-D), Life Satisfaction Index (LSI-Z) and the brief and revised version of the Social Support Questionnaire (SSQSR) were used. Finally, two studies used qualitative interviews that were fully transcribed and analyzed.10,24 The determinant factors and the methods of studies about resilience are shown in Table 2.

Discussion Resilience definition We conducted a search to retrieve studies that discussed the definitions and determinants of resilience among caregivers of people with dementia. We did not find a consensus about how to define resilience, as several terms are used as synonyms for it: adaptation when faced with adversity;1,2,4,5,13,14,18 flexibility13; belief in oneself and internal locus of control6; efficacious coping2,18; psychological well-being and strength12; development of a healthy life3; perceived burden28; and amount of and satisfaction with social support.29 Therefore, we concluded that each study defined resilience according to its objectives and assessment methods, rather than based on any clearly established theoretical framework of resilience in dementia. These various definitions may explain the differences found in the results of the studies under assessment here.

The lack of a theoretical framework may give rise to several methodological problems, such as the absence of standardized assessment instruments1,4,6,7,14,28 and the heterogeneity of samples.6,12,13,28 However, most studies converged on the definition of resilience as the capacity to adapt successfully when faced with the stress of adversity.1,2,4-6,13,14,18 Therefore, resilience seems to have some degree of conceptual overlap with similar constructs used in dementia caregiving, such as mastery or degree to which individuals attribute outcomes to their own efforts or abilities, self-efficacy, internal locus of control, and learned helplessness.

Other constructs, possibly shared by resilience, are personality traits, such as neuroticism, which may predispose some caregivers of people with dementia to reporting greater feelings of burden, behavior problems or subjective ratings of health. Therefore, it remains unclear whether resilience is a learning ability or a personality trait.

Trends Psychiatry Psychother. 2015;37(1) – 15

16 – Trends Psychiatry Psychother. 2015;37(1)

Assessed whether psychological resilience predicts the relative absence of depressive symptoms one year later.

Explored the association between resilience and marital satisfaction in caregivers of spouses with dementia.

Examined the potential of an antidepressant drug, escitalopram.

Assessed impact of aggression of patient with Alzheimer on caregiver coping strategies and caregiver resilience.

Factors associated with resilience of caregivers of elderly people with AD.

Described demographic and health variables of caregivers of elderly people with AD and associated care provided with resilience.

Investigated the predictors of burden for caregivers of people with dementia.

Assessed the moderating role of generalized expectancies of control (GEC) between caregiver stress and burden.

Analyzed factors associated with resilience among caregivers of patients with dementia.

O’Rourke et al.4

Fitzpatrick et al.13

Lavretsky et al.7

Wilks et al.12

Garces et al.14

Gaiole et al.3

FernándezLansac et al.2

Contador et al.6

Compared resilience between African Americans and whites.

Objectives Ascertained whether resilience influences transitions from dementia caregiving, such as institutionalization, care recipient death, or loss to follow-up.

Examined whether social support functioned as a protective factor and improved resilience among AD caregivers.

Clay et al.29

Wilks & Croom18

Author Gaugler et al.28

n = 53 40 – AD 9 – VD 4 – MD

n = 130 53 – AD 37 – VD 40 – MD

n = 101 AD

n=6 AD

n = 419 AD

n = 40 AD

n = 30 90% AD 10% other types of dementia

n = 105 AD

n = 166 AD

n = 229 AD

Cross-sectional

Cross-sectional

Exploratory and descriptive study

Observational descriptive case study

Cross-sectional

Randomized placebocontrolled double-blinded

Cross-sectional

Longitudinal, 1 year

Longitudinal, 5 years

Cross-sectional

Design Longitudinal, 3 years, randomized

Demographic questionnaire, GDS, IADL, RMBPC, ZBI, CSS, SSQSR, NEO-FFI (NyE scales), SE, RSES, Questionnaire COPE, BDI, HAD-A and CD-RISCK.

Demographic questionnaire, BEEGC, ZBI, GADS.

Demographic questionnaire, BDI and RS.

Demographic questionnaire, SRQ, ZBI and RS.

HRSD, CD-RISC, RMBPC, SERS, HARS, MMSE, CRFPC, Cumulative Illness Rating Scale and ZBI. Demographic questionnaire, RMBPC; CITS and RS.

Demographic questionnaire, GDS, MSQFOP, RS, SE and SCB.

Demographic questionnaire, DRS, CES-D and FRS.

Demographic questionnaire, CES-D, SSQSR and SES.

Demographic questionnaire, PSS, PSSS and RS.

Instrument Demographic questionnaire, ZBI, ADL e IADL.

Table 2 - Selected articles

Sample n = 1,979 AD or similar disorder.

Resilience was associated with poor emotional and physical status. High resilience scores were significantly correlated to burden, neuroticism and extraversion, self-efficacy, self-esteem and less use of emotion-focused coping strategies.

Degree of kinship, medical treatment, use of medication, tiredness, prostration, discouragement and caregivers’ mental health had significant associations with resilience.

Family caregivers with high expectancies of selfefficacy and contingency were less vulnerable to stress.

Although some reported fatigue and overload, most had a high tendency to resilience. There was a significant association between resilience and age.

Task-focused coping was positively associated with resilience, and aggression negatively predicted caregiver resilience.

Results High baseline resilience (low burden, high care demands) was associated with less frequent institutionalization and loss to follow-up, as well as with more frequent care recipient mortality.

Stress negatively influenced and accounted for most variations in resilience. Social support positively influenced resilience, and caregivers with high family support had the highest probability of greater resilience.

The resilience of African American caregivers, as demonstrated by their fewer depressive symptoms and higher levels of life satisfaction, was partially explained by their higher levels of satisfaction with social support.

Baseline resilience (control and challenge) and change in challenge over time contributed significantly to prediction of depressive symptoms one year later.

Spouses perceived greater caregiver burden and reported less marital satisfaction. An inverse association was found with age: older caregivers reported more marital satisfaction. Resiliency, sex, and stage of cognitive impairment were not associated with marital satisfaction.

Depression was less severe and remission rate was greater with drug than with placebo. Measures of anxiety, resilience, burden and distress improved when escitalopram was used.

Resilience in dementia - Dias et al.

Described strategies that family caregivers use to help them continue to provide care, and described these family caregivers’ resilience and psychological distress.

Explored key positive and negative factors that have an impact on grief resolution and health outcomes of caregivers.

Bull5

n = 13 Does not specify type of dementia.

n = 18 Does not specify type of dementia.

n = 18 15 – AD 3 – VD

n = 80 AD

Descriptive and cross-sectional

Descriptive and cross-sectional

Descriptive, correlational, and crosssectional Descriptive and cross-sectional

Demographic questionnaire and qualitative interview.

Demographic questionnaire, RS, SDQ.

Demographic questionnaire, ZBI DCS and Resourcefulness Scale.

Demographic questionnaire and qualitative interview.

Psychological resilience and satisfaction with caregiving were protective against negative outcomes, whereas unresolved grief was a risk factor.

Stressors were role strains, family conflicts and pressure from social environment. Yet, caregivers demonstrated resilience by drawing on their coping resources from several sources, such as personal experience, family, technology and information, religion and governmental support.

Caregivers used four strategies to sustain self: drawing on past life experiences, nourishing self, relying on spirituality and seeking information about dementia

Positive cognitions mediated but did not moderate effects on association between caregiver burden and resourcefulness.

AD = Alzheimer’s disease; ADL = activities of daily living; BDI = Beck Depression Inventory; BEEGC = Battery of Generalized Expectancies of Control Scale; CD-RISC = Connor-Davidson Resilience Scale; CES-D = Center for Epidemiological Studies Depression Scale; CIRS = Cumulative Illness Rating Scale; CITS = Coping in Task Situations; CRFPC = Cerebrovascular Risk Factor Prediction Chart; CSS = Caregiving Satisfaction Scale; DCS = Depressive Cognition Scale; DRS = Dispositional Resilience Scale; FRS = Functional Rating Scale; GADS = Golberg Anxiety and Depression Scale; GDS = Global Deterioration Scale; HAD-A = Hospital Anxiety and Depression Scale; HARS = Hamilton Anxiety Rating Scale; HRSD = Hamilton Rating Scale for Depression; IADL = Instrumental Activities of Daily Living; MD = Mixed Dementia; MMSE = Mini-Mental State Examination; MSQFOP = Marital Satisfaction Questionnaire for Older Persons; PSS = Perceived Stress Scale; PSSS = Perceived Social Support Scale; RMBPC = Revised Memory and Behavior Problems Checklist; RMBPC = Revised Memory and Behavior Problems Checklist; RS = Resilience Scale; RSES = Rosenberg Self-Esteem Scale; SCB = Screen for Caregiver Burden; SDQ = Symptom Distress Questionnaire; SE = Self-Efficacy Scale; SERS = Side Effect Rating Scale; SRQ = Self Report Questionnaire; SSQSR = Social Support Questionnaire; VD = Vascular Dementia; ZBI = Zarit Burden Interview.

Shuter et al.24

Sun10

Examined mediating and moderating effects of positive cognitions on association between caregiver burden and resourcefulness.

Investigated caregiving stressors and coping strategies.

Bekhet1

Resilience in dementia - Dias et al.

Resilience should be understood not only as a personal attribute that may lead to success, but also as the dynamic interaction between biological and psychosocial processes. Resilience of caregivers of people with dementia should be defined in association with caregiving tasks, because it implies resistance to stress due to the perception of caregiving demands and burden. This definition suggests that resilience should be assessed in association with reports of burden and frequency of demands from care recipients, which may be associated with neuropsychiatric symptoms and functional dependence.28

Psychological factors

and improves understanding of the situation, acceptance of changes and confidence of caregivers on their own strength and on the affective bonds shared with care recipients.2 Therefore, resilience may be understood as a force, a strategy and a set of skills used in a specific context by a particular individual to deal with a particular adverse event. The coping strategy adopted by caregivers with greater resilience is task focused.10,12 This strong association between task-focused coping and resilience suggests that task-focused skills training programs may improve and protect caregiver mental health and prolong the time a loved one may remain at home.12 According to Contador et al.,6 optimistic people make a subjective estimate of the probability of achieving goals or desired results based on other factors, such as self-efficacy (belief in their own capacity of starting actions, achieving goals and dealing with life) and internal locus of control or contingency (how individuals expect life events or results to be motivated by their actions). Self-efficacy and internal locus of control are psychological factors that support the construct of resilience and are associated with less suffering from the negative effects of stress and burden. Therefore, people with grounded optimism, high level of self-efficacy and internal locus of control may be more resilient to stressful situations, which may reduce vulnerability to burden.6 O’Rourke et al.4 assessed three constructs that compose resilience. The first was commitment to life, as resilient people tend to engage fully in daily activities.

Second, resilient people enjoy challenges and prefer changes rather than stability, and life travails provide opportunities to develop skills and self-knowledge.4 Finally, psychological resilience entails perceived control, which results in a sense of personal autonomy and a belief in being able to directly affect the course of life events.4

In general, higher control over life helps adaptation

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Resilience in dementia - Dias et al.

These characteristics, associated with burden, stress and distress, may be protective factors or risk factors for people with dementia. Some authors suggest that higher levels of resilience are inversely associated with low burden,1,2,28 stress6 and distress levels.5,24 Bekhet1 concluded that positive cognitions are protective factors for caregivers of people with dementia. Positive cognitions, or positive thinking patterns, enhance mental health and improve the capacity to manage daily activities.1

Biological factors Higher resilience scores were associated with improved physical health.2 Caregivers with lower resilience scores tended to visit the doctor less frequently and take less medicine. This might be related to a lower degree of selfcare. Comparatively, higher degrees of resilience were associated to fewer alterations of health habits2 and better physical health.3 Moreover, higher degrees of resilience were associated to low somatization and depression.3 The role of mood in resilience was demonstrated by Lavretsky et al.,7 who concluded that antidepressant use in depressed family dementia caregivers with either major or minor depression might improve depression symptoms, boost resistance to stress and improve coping strategies.

Moreover, there is a significant association between resilience and aging, which indicates that resilience is acquired as the person gets older.14 This finding is important because caregivers are the same age as elderly people with dementia. Further studies should investigate the neurophysiologic mechanisms of resilience and their association with psychological functioning and social factors.

Therefore, social support is a moderating factor of resilience, as several types of support may relatively relieve the physical and mental burden caused by stress.18 Therefore, resilience is a dynamic process believed to arise from interactions between biological and psychosocial factors. This process involves physiological adaptation to stress, psychological adjustment, selfefficacy, effective coping strategies and cognitive redefinition of experience. However, studies in the area often focus on only one factor, such as coping.1,3,6,7,12-14,18 Clinically, partial assessments of resilience may compromise the development of interventions focused on the improvement of this capacity among caregivers of people with dementia.

Methods and instruments: difficulties in the assessment of resilience

Social support has been positively associated with resilience,2,18,29 but studies have defined support in

Although the assessment of dynamic constructs, such as resilience, may be methodologically limited, most studies in this review were cross-sectional.1,2,5,6,10,12,13,18,24 Longitudinal studies would be more appropriate because they would follow the development of resilience among caregivers and the cognitive decline of people with dementia, as well as the increase of care demands.

Most samples included caregivers of people with AD,1,3,4,7,12,14,18,29 but some assessed, without comparing, caregivers of people with AD, VD, MD, mild cognitive impairment (MCI) or unspecified dementia.2,6,10,13,28 There are important clinical differences between types of dementia and, therefore, between different forms of caring.

Heterogeneous samples, found in some studies, precluded the assessment of some factors, such as resilience.

In all studies, most participants were informal female caregivers1-7,10,12-14,18,24,28,29 and spouses or children of elderly people with dementia,1-6,10,12-14,18,24 whose mean age was 60 years2-5,7,10,13,14,24,28,29 and whose mean

different ways: network size and frequency of contact; support received; frequency of help from other people; and general satisfaction with social network.29 Social support associated with perceived help and satisfaction with support seem to be more consistent than actual support or size of support network.29 A study29 that assessed ethnic differences in resilience found that resilience of Afro-American caregivers was partially explained by higher levels of satisfaction with social support.

Wilks & Croom18 found an inverse association of social support and stress resulting from the combination of: a) negative influence of stress on caregivers’ perception about available social resources; b) negative influence of stress on caregivers’ capacity of using these resources; and c) higher perception of available social resources associated with lower probability of perceived stress.

schooling was eight years.1,2,3,5-7,13,14 This caregiver profile indicates that elderly people have been taking care of elderly people, and the most important challenge is to prevent and treat the diseases that may affect caregivers. The study of resilience may bring results that define a protective factor for caregivers.

The use of assessment instruments that provide only partial data might have limited the understanding of resilience. The instrument most often used to assess resilience was the complete or brief version of the Resilience Scale of Wagnild & Young.3,5,12-14,18 This scale measures factors associated with resilience, such as selfesteem, locus of control, coping styles and sense of humor.

However, the lack of a consensus about the definition of constructs resulted on the use of different instruments, including those designed to assess depression and

Social factors

18 – Trends Psychiatry Psychother. 2015;37(1)

Resilience in dementia - Dias et al.

burden, which makes it difficult to replicate these studies and raises questions about the reliability of their results.

Conclusion Resilience is a process associated with adaptive capacities and a positive history of functioning and adaptation after adversities. This dynamic process involves the interaction between biological and psychosocial factors, which makes its investigation more complex. As studies define resilience differently, consistent results are difficult to obtain, which affects the understanding and the investigation of associated factors.

Clinically, knowledge about factors associated with resilience may lead to the development of psychological and educational support for caregivers of people with dementia. Support groups should be focused not only on information and feelings about the diagnosis and caregiving routines, but also on the factors that may increase resilience among caregivers, such as task-focused coping strategies and self-efficacy. However, future, welldesigned studies should use a clear definition of resilience and adequate instruments to measure it, have coherent objectives and include randomized samples.

Longitudinal studies should be conducted to follow disease progression, examine associations with other variables and understand the dynamics of resilience, which may positively affect the quality of life of caregivers of people with dementia.

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Acknowledgements Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ; grant no. E-26/102.256/2010) financed the expenses with the development of this study.

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References 1.

2.

3.

4.

5.

6.

Bekhet AK. Effects of positive cognitions and resourcefulness on caregiver burden among caregivers of persons with dementia. Int J Ment Health Nurs. 2013;22:340-6. Epub 2012 Sep 25.

Fernández-Lansac V, Crespo López M, Cáceres R, RodríguezPoyo M. [Resilience in caregivers of patients with dementia: A preliminary study]. Rev Esp Geriatr Gerontol. 2012;47:102-9.

Epub 2012 May 11.

Gaiole CC, Furegato AR, Santos JL. Perfil de cuidadores de idosos com doença de Alzheimer associado à resiliência. Texto Contexto Enferm. 2012;21:150-7.

O’Rourke N, Kupferschmidt AL, Claxton A, Smith JZ, Chappell N, Beattie BL. Psychological resilience predicts depressive symptoms among spouses of persons with Alzheimer disease over time.

Aging Ment Health. 2010;14:984-93.

Bull MJ. Strategies for sustaining self used by family caregivers for older adults with dementia. J Holist Nurs. 2014;32:127-35.

Epub 2013 Nov 13.

Contador I, Fernández-Calvo B, Palenzuela DL, Miguéis S,

26.

27.

28.

29.

Ramos F. Prediction of burden in family caregivers of patients with dementia: a perspective of optimism based on generalized expectancies of control. Aging Ment Health. 2012;16:675-82.

Lavretsky H, Siddarth P, Irwin MR. Improving depression and enhancing resilience in family dementia caregivers: a pilot randomized placebo-controlled trial of escitalopram. Am J Geriatr Psychiatry. 2010;18:154-62.

Matsushita M, Ishikawa T, Koyama A, Hasegawa N, Ichimi N, Yano H, et al. Is sense of coherence helpful in coping with caregiver burden for dementia? Psychogeriatrics. 2014;14:87-92.

Santos RL, de Sousa MF, Arcoverde C, Dourado MC. Eficácia de um grupo psicoeducacional com cuidadores de pessoas com demência. Rev Psiquiatr Clin 2013;40:162-4.

Sun F. Caregiving stress and coping: A thematic analysis of Chinese family caregivers of persons with dementia. Dementia (London). 2014;13:803-18.

Truzzi A, Valente L, Ulstein I, Engelhardt E, Laks J, Engedal K. Burnout in familial caregivers of patients with dementia. Rev Bras Psiquiatr. 2012;34:405-12.

Wilks SE, Little KG, Gough HR, Spurlock WJ. Alzheimer’s aggression: influences on caregiver coping and resilience. J Gerontol Soc Work. 2011;54:260-75.

Fitzpatrick KE, Vacha-Haase T. Marital satisfaction and resilience in caregivers of spouses with dementia. Clin Gerontol. 2010;33:165-80.

Garces SB, Krug MR, Hansen D, Brunelli AV, da Costa FT, Rosa CB, et al. Avaliação da resiliência do cuidador de idosos com Alzheimer. Rev Bras Geriatr Gerontol. 2012;15:335-52.

Brandão JM, Mahfoud M, Gianordoli-Nascimento IF. A construção do conceito de resiliência em psicologia: discutindo origens.

Paideia. 2011;21:263-71.

Yunes MA. Psicologia positiva e resiliência: o foco no indivíduo e na família. Psicol Estud. 2003;08:75-84.

Norris FH, Stevens SP, Pfefferbaum B, Wyche KF, Pfefferbaum RL. Community resilience as a metaphor, theory, set of capacities, and strategy for disaster readiness. Am J Community Psychol.

2008;41:127-50.

Wilks SE, Croom B. Perceived stress and resilience in Alzheimer’s disease caregivers: testing moderation and mediation models of social support. Aging Ment Health. 2008;12:357-65.

Cowan PA, Cowan CP, Schulz MS. Thinking about risk and resilience in families. In: Hethering EM, Blecheman EA, editors.

Stress, coping and resilience in children and families. New Jersey: Lawrence Erlbaum; 1996. p. 1-38.

Reppold CT, Mayer JC, Almeida LS, Hutz CS. Avaliação da resiliência: controvérsia em torno do uso das escalas. Psicol Refl Crit. 2012;25:248-55.

Trombeta LH, Guzzo RS. Enfrentando o cotidiano adverso: estudo sobre resiliência em adolescentes. Campinas: Alínea; 2002.

Garity J. Caring for a family member with Alzheimer’s disease: coping with caregiver burden post-nursing home placement. J Gerontol Nurs. 2006;32:39-48.

Hodge DR, Sun F. Positive feelings of caregiving among Latino Alzheimer’s family caregivers: understanding the role of spirituality. Aging Ment Health. 2012;16:689-98.

Shuter P, Beattie E, Edwards H. An exploratory study of grief and health-related quality of life for caregivers of people with dementia. Am J Alzheimers Dis Other Demen. 2013;29:379-85.

Antonovsky A. Unraveling the mystery of health: how people manage stress ans stay well. São Francisco: Jossey-Bass; 1987 Pesce RP, Assis SG, Avanci JQ, Santos NC, Malaquias JV, Carvalhaes R. Adaptação transcultural, confiabilidade e validade da escala de resiliência. Cad Saude Publica. 2005;21:436-48.

Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org.

Gaugler JE, Kane RL, Newcomer R. Resilience and transitions from dementia caregiving. J Gerontol B Psychol Sci Sco Sci. 2007;62:P38-44.

Clay OJ, Roth DL, Wadley VG, Haley WE. Changes in social support and their impact on psychosocial outcome over a 5-year period for African American and White dementia caregivers. Int J Geriatr Psychiatry. 2008;23:857-62.

Correspondence: Rachel Dias Rua Carolina Alves, 07 24322-310 - Niterói, RJ - Brazil Tel.: +55 (21) 99876-1145 E-mail: diasrachel@gmail.com Trends Psychiatry Psychother. 2015;37(1) – 19

Trends

Review Article

in Psychiatry and Psychotherapy

Phenomenological aspects of the cognitive rumination construct Aspectos fenomenológicos relacionados ao construto de ruminação cognitiva Leonardo Fernandez Meyer,1,2 José Geraldo Vernet Taborda,3 Fábio Antônio da Costa,4 Ana Luiza Alfaya Galego Soares,5 Kátia Mecler,2 Alexandre Martins Valença1,6

Abstract

Resumo

Objective: To evaluate the importance of phenomenological aspects of the cognitive rumination (CR) construct in current empirical psychiatric research.

Method: We searched SciELO, Scopus, ScienceDirect, MEDLINE, OneFile (GALE), SpringerLink, Cambridge Journals and Web of Science between February and March of 2014 for studies whose title and topic included the following keywords: cognitive rumination; rumination response scale; and self-reflection. The inclusion criteria were: empirical clinical study; CR as the main object of investigation; and study that included a conceptual definition of CR. The studies selected were published in English in biomedical journals in the last 10 years. Our phenomenological analysis was based on Karl Jaspers’ General Psychopathology.

Results: Most current empirical studies adopt phenomenological cognitive elements in conceptual definitions. However, these elements do not seem to be carefully examined and are indistinctly understood as objective empirical factors that may be measured, which may contribute to misunderstandings about CR, erroneous interpretations of results and problematic theoretical models.

Conclusion: Empirical studies fail when evaluating phenomenological aspects of the cognitive elements of the CR construct. Psychopathology and phenomenology may help define the characteristics of CR elements and may contribute to their understanding and hierarchical organization as a construct. A review of the psychopathology principles established by Jasper may clarify some of these issues.

Keywords: Psychopathology, phenomenology, cognitive rumination.

Objetivo: Verificar a importância de aspectos fenomenológicos relacionados ao construto de ruminação cognitiva (RC) nas pesquisas empíricas psiquiátricas atuais.

Método: Foram pesquisadas as bases de dados SciELO, Scopus, ScienceDirect, MEDLINE, OneFile (GALE), SpringerLink, Cambridge Journals e Web of Science, entre fevereiro e março de 2014, buscando artigos cujo tópico ou título contivessem os seguintes termos-chave: ruminação cognitiva; escala de resposta ruminativa; e autorreflexão. Os critérios de inclusão foram: estudos clínicos empíricos; RC como principal objeto de pesquisa; e estudos que incluíssem uma definição conceitual de RC. Foram considerados apenas artigos em inglês publicados em periódicos biomédicos nos últimos 10 anos. Nossa análise fenomenológica se fundamentou na Psicopatologia Geral de Jaspers.

Resultados: Os conceitos de RC atualmente encontrados nas pesquisas empíricas utilizam majoritariamente elementos fenomenológicos em suas definições. Entretanto, esses elementos cognitivos são indistintamente entendidos como elementos objetivos (empíricos), passíveis de mensuração, e não parecem ser cuidadosamente examinados. Este fato pode contribuir para uma compreensão enganosa sobre RC, além de favorecer a interpretação errônea de resultados e a elaboração de paradoxos teóricos problemáticos.

Conclusão: As pesquisas empíricas atuais sobre RC falham ao avaliar os aspectos fenomenológicos inerentes ao construto de RC. A psicopatologia e o método fenomenológico podem ajudar a definir características relacionadas aos elementos da RC, bem como contribuir para a sua compreensão e organização hierárquica enquanto construto. Um retorno aos princípios da psicopatologia, nos moldes de Jaspers, poderia trazer esclarecimentos ao tema.

Descritores: Psicopatologia, fenomenologia, ruminação cognitiva.

Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil. 2 Instituto de Perícia Heitor Carrilho (IPHC), Rio de Janeiro, RJ, Brazil. 3 Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil. 4 Colégio Pedro II, Rio de Janeiro, RJ, Brazil. 5 Centro de Políticas em Saúde do Trabalhador (CPST), UFRJ, Rio de Janeiro, RJ, Brazil. 6 Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil.

1

Financial support: none.

Submitted Jun 20 2014, accepted for publication Nov 06 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Meyer LF, Taborda JG, da Costa FA, Soares AL, Mecler K, Valença AM. Phenomenological aspects of the cognitive rumination construct. Trends Psychiatry Psychother. 2015;37(1):20-26. http://dx.doi.org/10.1590/2237-6089-2014-0025 © APRS

Trends Psychiatry Psychother. 2015;37(1) – 20-26

Phenomenology and cognitive rumination - Meyer et al.

Introduction Cognitive rumination (CR) is generally defined as recurrent and repetitive thoughts about one’s feelings and quests that intrude consciousness.1-3 The associations of CR with psychiatric disease and psychopathological symptoms have been the focus of an increasing number of empirical studies.1-4 Their findings have led to the development of psychometric scales, such as the Ruminative Response Scale (RRS). These instruments provide data for statistical analyses in studies about CR and for the exploration of possible correlations with specific psychiatric symptoms.5,6 CR should be examined rigorously to limit and define it unambiguously as an object of scientific study.

Current concepts adopt phenomenological descriptions of cognitive elements, more adequate for clinical investigations than for empirical study settings.1,2,6-9 Karl Jaspers’ efforts to study psychopathology played a major role in the development of diagnostic classifications and in clinical (psychic) examination techniques.10-15 According to Jaspers, psychopathology is the science of abnormal conscious psychological phenomena, and phenomenology, the method to investigate these phenomena, which are experienced by the examinee and presented to the examiner through the examinee’s narratives and behavior.10-12 Psychic phenomena are presented to and understood by the examiner as cognitive performances. For teaching purposes, they are divided into objective performances, such as attention, formal logic, thought patterns, memory, speech disturbances and psychomotor function, and subjective performances, such as affect and mood, thought content, volition and self-awareness.10-16 In this sense, they are ongoing aspects of empathy and

92 studies selected for title and abstract analysis

59 excluded

intuition that allow patients and examiners to share common aspects of reality.10-16 This study evaluated the extent to which the phenomenological aspects of the CR construct have been used in current empirical psychiatric studies. It also analyzed findings using the phenomenological approach developed by Jaspers.

Method Figure 1 summarizes the steps of our literature review of studies about CR. We searched SciELO, Scopus, ScienceDirect, MEDLINE, OneFile (GALE), SpringerLink, Cambridge Journals and Web of Science between February and March of 2014 for studies whose title or topic had the following terms: ((cognitive rumination) AND (rumination response scale)) or ((cognitive rumination) AND (self-reflection)).

Inclusion criteria were: original clinical studies; CR as their main object of investigation; clear conceptual definition of CR; written in English; and published in a biomedical journal in the last 10 years. Because of the pioneering nature of the studies about CR conducted by Nolen-Hoeksema et al., we selected their studies despite their publication date whenever all the other inclusion criteria were met. We excluded articles not in English, editor comments, letters, case reports and literature reviews about CR. We also excluded clinical empirical studies in which the main object of study was not CR or that did not provide a clear conceptual definition of CR. Our analysis followed the phenomenological approach described by Jaspers.10-16 We used both English and Portuguese translations of Allgemeine Psychopathologie to avoid misinterpretations of the original.10-12

37 no 09 04 05 04

CR not main study object or conceptual definition of CR not original studies not in English unavailable duplicates

33 studies selected for complete analysis

14 excluded

14 unsatisfactory conceptual definition of CR

19 met all inclusion criteria Figure 1 - Flowchart of review of literature about cognitive rumination (CR)

Trends Psychiatry Psychother. 2015;37(1) – 21

Phenomenology and cognitive rumination - Meyer et al.

We applied the cross-sectional phenomenological method, including its positive and negative perspectives. The positive perspective represents the conscious expressions of CR that uncover its ontic aspects, gathered through direct observation of psychic phenomena.10-16 The negative perspective refers to delimitations of rumination in finite totalities, to its correlation with another psychic totality and to its organization in the context of the psychic whole.10-16 According to Jaspers, phenomenological understanding may be static and genetic.10-12,16 Static understanding is restricted to present observation and objective description of the psychic phenomena as presented to and understood by the examiner’s perception. Psychic phenomena may, therefore, be identified using three approaches: behavior observations, interviews and self-report.10-12 Additional empirical elements include neurochemical and

In another study, CR was defined as the style of thinking repetitively about negative emotions, focusing on symptoms of distress and worrying about meanings of distress.7 Here, CR was described identically and simultaneously as a pattern of response (default response) to depressive mood, as a predisposing factor to mental disorders and as a sign of phenomenological elements of specific clinical symptoms.

For the CR definitions used in psychometric scales, appropriate terms were carefully chosen to respond to the needs of empirical studies.1-9, 17-26 This approach reduces CR to an object of empirical investigation exclusively.

CR was also associated with other psychopathological constructs: maladaptive cognitive styles, dysfunctional attitudes, hopelessness, pessimism, self-criticism and

neuroanatomical factors, whenever observed.10-12 Genetic understanding, described in the second part of Jaspers’ book, concerns the comprehension of motivation or causation that is associated with the sequence of psychic events. Our analysis of CR did not take into consideration the psychological (genetic) explanations and was limited to its static phenomenological elements.

depression.1-3 Phenomenological dissimilarities between these constructs were not analyzed, and they were not classified hierarchically.3-7 All were ontologically identical, equivalent and horizontally distributed, and there was no definition of hierarchical differences between them.1-9 These characteristics may have resulted in misconceptions that, in turn, led to theoretical disagreement, erroneous theoretical models and flawed interpretations of results.3-7,17,20,21,23-25 The analysis of studies in our final sample suggested the existence of causal links between neurophysiological and neuroanatomical findings and CR.17,20,22 These findings are based on the existence of hypothetical cerebral systems that may be responsible for activating and inhibiting specific types of human behaviors (response styles). Electroencephalographic findings showed hippocampus augmentation and neocortex activation during CR activity.17 Functional magnetic resonance results showed hyperactivity in anterior medial cortex in patients with CR activity when compared to controls.20 Decreases of cortisol response levels were

Results Our results are presented in two sections. First, we describe the phenomenological aspects of the main CR concepts used in current empirical studies. After that, we analyze the phenomenological aspects inherent to the CR construct, according to Jaspers’ phenomenology.

We chose this presentation pattern because of the complexity of the theme and the impossibility of presenting results simultaneously. The results are discussed and interrelated below.

Rumination in current research and phenomenology Our final sample had 19 studies about CR. Table 1 summarizes the main CR concepts used in the studies selected and their phenomenological aspects. All definitions were close to the original: persistent and recurring thoughts that unintentionally enter consciousness.5 One author proposed a slightly different definition in the RRS: the process of thinking perseveringly about one’s feelings and problems, and not the specific contents of thoughts.1 Both definitions include characteristically phenomenological elements: persistent and recurring thoughts, process of thinking perseveringly, feelings and thought contents. They refer to transient cognitive states, such as thought, affect and volition.

22 – Trends Psychiatry Psychother. 2015;37(1)

less frequently found among depressive patients.22 Phenomenology contemplates and situates of all these empirical findings within psychopathology, as they are indispensable phenomenological elements and must be analyzed whenever found.10-14,16 Misconceptions arise when they are interpreted as the full representation of their object of study (CR).10-12 This may be explained by the nature of psychopathological objects, which rejects their reduction to exclusively objective or natural concepts, as further stated in the next section.

Our results also revealed hypothetical paradoxes between theoretical models of CR, such as the selfabsorption paradox.27 In this case, CR and self-reflective activity are compared as similar mental processes, but outcomes are ambiguous. This issue will be elaborated further in the Discussion section.

Phenomenology and cognitive rumination - Meyer et al.

Table 1 - Main definitions of cognitive rumination and their phenomenological aspects

Author

Definitions of cognitive rumination

Phenomenological aspects

Andersen et al.17

The class of conscious thoughts that revolve around an instrumental theme.

Thought content disturbance (instrumental theme); formal logic thought disturbance (circular thinking); neurobiological findings (electroencephalographic changes).

Armey et al.8

Characteristic manner in which individuals respond to their own symptoms of distress or depressed mood.

Pattern of psychopathological behavioral response.

Bagby et al.4

Repetitive focus on the fact that one is depressed, on one’s symptoms of depression, and sometimes on meanings and consequences of depression symptoms.

Mood disturbance (depression); thought content disturbance (meanings and consequences).

Brinker & Dozois18

Self-focused thoughts on depressed mood and possible causes and consequences of that mood.

Mood disturbance (depressed mood) thought content disturbance (self-focused thoughts), possible causes and consequences of depression.

Hasegawa et al.19

Repetitive and passive thinking about one’s symptoms of depression and possible causes and consequences of these symptoms.

Mood disturbance (depression); formal logic thought disturbance (repetitive and passive thinking); thought content disturbance (causes and consequences of depression).

Johnson et al.20

Type of self-referential processing.

Neurobiological findings (medial cortex activation); formal logic thought disturbance (pattern of mental processing); thought content disturbance (self-referential).

Joormann et al.2

Trait-like response style that perpetuates depressive symptoms.

Pattern of psychopathological behavior response (response style).

Kocovski & Rector21

Element of post-event processing that follows anxiety-provoking situations.

Cognitive pattern of response that occurs in stressful situations.

Kuehner et al.22

Passive focus of one’s attention on one’s mood, which includes passive focus of one’s attention on one’s dysphoric symptoms and aspects of self and repetitive thinking about possible causes and consequences of one’s symptoms and negative self-aspects.

Attention disturbance (hyperprosexia); mood disturbance (dysphoric symptoms, negative self-aspects); formal logic thought disturbance (repetitive thinking); thought content disturbance (repetitive thinking about possible causes).

McLaughlin & Nolen-Hoeksema23

Response to distress in which individual passively and perseveringly thinks about upsetting symptoms and causes and consequences of these symptoms.

Pattern of behavior response (pattern of response to distress); formal logic thought disturbance (passive and persevering thoughts); thought content disturbance (thinking about upsetting symptoms).

Miranda & NolenHoeksema9

Repetitive focus on causes, meanings and consequences of one’s depressed mood.

Mood disturbance (depression); formal logic thought disturbance (repetitive focus); thought content disturbance (causes, meanings and consequences).

Moberly & Watkins6

Repetitive focus on the fact that one is depressed, on one’s symptoms of depression, and on causes, meanings and consequences of depression symptoms.

Mood disturbance (depression); formal logic thought disturbance (repetitive focus); thought content disturbance (meanings and consequences).

Nolen-Hoeksema & Morrow5

Repetitive focus on the fact that one is depressed, on one’s symptoms of depression, and on causes, meanings and consequences of depression symptoms.

Mood disturbance (depression); formal logic thought disturbance (repetitive focus); thought content disturbance (meanings and consequences).

Nolen-Hoeksema7

Response to distress that involves repetitive and passive focus on symptoms of distress and on possible causes and consequences of these symptoms.

Pattern of behavior response (mode of response to distress); formal logic thought disturbance (repetitive and passive focus).

Nolen-Hoeksema et al.1

Response style of repetitive and passive thoughts about negative emotions, and focus on symptoms of distress and worry about meaning of distress.

Pattern of behavior response (response style); formal logic thought disturbance (repetitive and passive thinking); thought content disturbance (focus on symptoms of distress and worry about meaning of distress).

Schoofs et al.24

Response or coping style involving repetitive self-focused thought on one’s negative feelings, their antecedents or consequences.

Pattern of behavior response (response and coping style); mood disturbance (negative feelings); formal logic thought disturbance (repetitive thought); thought content disturbance (self-focused).

Thomsen et al.25

Self-focused repetitive thoughts associated with negative outcomes.

Formal logic thought disturbance (repetitive thoughts); thought content disturbance (self-focus).

Phenomenology and CR Psychopathology is the science of the abnormal conscious manifestations of psychic life.10-12 Its aim is not the absolute comprehension of human beings

or their psyche, but the investigation of abnormal conscious psychic phenomena.10-12 One of its fundamental theoretical features is the analysis of psychic elements using different and complementary perspectives.10-14 Trends Psychiatry Psychother. 2015;37(1) – 23

Phenomenology and cognitive rumination - Meyer et al.

Among these perspectives, we have the description of psychic phenomena, in the form of psychic examinations and self-narratives, as well as statistical analysis, case studies, genetic aspects, and neurochemical and neurobiological findings.10-12 Each perspective has its own specificities, limitations and intercorrelations.10-12 The foundation of phenomenology, as a research method, is the atheoretical description of psychic phenomena as they are presented to the examiner.10-12 This method provides access to its object of investigation, abnormal conscious psychic phenomena, which may then be appropriately accessed and grasped as a psychopathological object to be further examined using complementary perspectives.10-14 Psychic capacities, or cognitive performances, may be distinguished only for teaching and analytical

the main subject; 3) psychomotor activity - agitation; 4) speech disturbances; and 5) memory disturbances paramnesias.10,12 Except for the first item (formal logic thought disturbances), none of these elements are necessary for CR identification, and all can be signs of and randomly found in other clinical presentations, depending on the disorder and the moment when the examination is performed.10-12 The assessment of subjective performances must rely on empathy and intuition elements primarily.10-16 Subjective and objective performances do not share the same characteristics; the former are exclusively expressed through “as if” descriptions that will only be understood if the examinee’s psyche is interpreted.10-12 In CR, subjective performances correspond to: 1) thought content - monothematic, persevering,

purposes.10-12 The psyche may be defined as a totality, or a whole, that has multiple and indistinguishable intercorrelations between its parts, the psychic elements.

The context of reality, where psyche belongs and in which it participates, also determines and contributes to its change and signification along time. The psychic whole is not the sum or articulation of its parts; in fact, psychic elements, together with other elements that go beyond the scope of this study, compose an individual’s transient whole.10-12 In phenomenology, statistical analyses of psychic phenomena may be appropriately applied. Any statistical analysis implies a previous theoretical hypothesis and some objective knowledge about the object under study, which is, in this case, psychic phenomena.10-12 The boundaries of statistics are its own limitations in measuring psychic phenomena as empirical elements and the impossibility of reaching causal associations based on statistic results only.10-12 Cognitive performances, such as memory and psychomotor functions, have characteristics that make

overvalued, delirious or delusional ideas; 2) affect or mood - sadness, pessimism, apprehension; and 3) volition - will inhibition.10-14 These are similar to objective performances, when present. Thought content is the main subjective characteristic of the CR construct.10-12 The correct understanding of data obtained by means of clinical examinations must be analyzed according to the hierarchy inherent to the psychic whole, which is defined by psychopathology.10-12 The phenomenology of formal logic thought in CR is similar to that found in other psychopathological phenomena, and includes thought persevering, speech stereotypes and mussitation. In all, repetitive thoughts lead to dysfunction of other cognitive performances.10-12 Speech disturbances may be present. The limited variability of themes associated with CR may be associated with experiences, affective and volitional states and intellectual capacity, as in other psychiatric disorders.13-15 Semiology indicates that repetitive thoughts, which may have different presentations, are found in cases of several psychiatry disorders.10-14 Verbigeration, defined

them more suitable to the application of statistical methods than affect and thought.10-12 In CR, only the formal logic aspects of thought disturbances are objective, as their contents are subjective phenomena.

When investigating subjective performances, statistical analysis may lead to miscomprehensions because of inappropriate identification or appropriation of cognitive performance subtypes.

Meaningful objective phenomena are sensitive phenomena and manifestations of psychic life.1012 Objective performances can be assessed directly by the examiner’s sensory perception. CR objective performances correspond to: 1) formal logic thought disturbance - repetitive, perseveration; 2) concentration and vigilance disturbances - diminished concentration; lack of attention to secondary themes not related to

as the repetition of short sentences, embolalia, which is the repetition of short sentences lacking lexical meaning, and mussitation, the soundless repetition of sentences using lip movements only, are examples found in early stages of psychotic disorders.10-12 Repetitive thoughts occur in severe dementia, when the cognitive repertoire is limited, and in psychoactive substance intoxication.10-12 A restricted repertoire is a common characteristic of obsessive-compulsive, developmental, mood and psychotic disorders.10-12 The analysis of phenomenological specificities reveals that CR shares its main characteristics with the psychiatric disorders listed in the paragraph above.

The psychic whole has a variable presentation, which confirms the plasticity and the countless possible articulations of psychic phenomena.10-12 This finding

24 – Trends Psychiatry Psychother. 2015;37(1)

Phenomenology and cognitive rumination - Meyer et al.

disproves the idea that cognitive comprehension is the result of a prior combination of supposedly basic neuropsychiatric mechanisms.10-12 CR may be better defined as a psychopathological construct that refers to phenomenological elements understood in their context of presentation.10-14 This characteristic is also present in other psychopathological constructs.10-15 Psychopathological understanding demands the elaboration of ideal types to organize and shape all the meaningful psychic phenomena grasped.11-14 These characteristics are useful for clinical and psychic examinations, for use in manuals of diagnostic classification and for empirical studies.10-12,28,29

Discussion

examining descriptions of the phenomena presented, considering their specificities and avoiding the indistinct naturalization of all its elements. The negative perspective may set limits to the CR construct and define its hierarchical position in psychopathology. This analysis defines an important task for neuroscience: to formulate appropriate scientific criteria to investigate the subjective performance of psychic phenomena, considering their nature and specificities.

A starting point for this investigation may be the foundations of psychopathology hermeneutics.10-12,30 This analysis may enable the formulation of appropriate theoretical models using appropriate concepts, which would result in the definition of the objects of empirical research. The self-absorption paradox is an example of misunderstanding of identical cognitive processes,

Current trends of research about CR prioritize suitable conceptual definitions that respond to the empirical need of natural sciences. They disregard, however, the psychopathological specificities of CR, which leads to miscomprehension and misconceptions about the object of study about CR. The focus of this study is phenomenology and CR.10-12 Phenomenology classifies and situates empirical psychic elements within the field of comprehension of the psychic totality, including statistical analysis.10-12 Its appropriate application demands the identification of objective performances of the psychic phenomena under analysis, whenever available. The formulation of a theoretical model of psychopathology depends on the meaningful comprehension, or genetic understanding, that should be acquired from subjective phenomena and that cannot be statistically analyzed as objective phenomena.10-12 Phenomenology offers a safe methodological perspective to avoid these misconceptions. In the use of its positive perspective, the elements of psychic

supposedly present in both CR and in self-reflective mental activity.26,27 The distinction is usually made by analyzing outcomes, which are classified as favorable in self-reflective activity and unfavorable in CR.26,27 This issue does not apply when the psychopathological approach is adopted.10-12 As mentioned above, the shared characteristic of CR and self-reflective activity is formal logic thought disturbance, seen in repetitive behaviors and perseveration. The perspective of polarities, as described by Jaspers, may be useful to understand an array of psychic phenomena, as it affects, for example, mood, in the case of polarity between sadness and happiness, and memory, in the case of polarity between amnesia and normal memory.10-12 In this sense, CR and self-reflectivity may be understood as a continuum, that shares the same type of basic cognitive process, that is, formal logic thought disturbance, but that holds differences in other cognitive elements distinctly associated with each other.

As psychopathology studies abnormal conscious psychological phenomena, it may only explore CR, and

phenomena are uncovered through identification, description, experimentation and analysis of the participant’s cognitive functions.10-12 The negative perspective carries the intrinsic limitations of phenomenology and ensures that knowledge will be reliable.10-12 It marks the borders and limits of the psychic phenomena under analysis for the identification and investigation of totalities.10-12 Current advances in neuroscience, such as topographic, encephalographic, neurochemical and statistical analyses, have produced new fundamental data, which should be analyzed in light of psychopathological foundations to assure that meaningful connections will be established.

Empirical studies about CR may benefit from phenomenological analysis. The positive perspective may identify objective psychic elements of CR by

not self-reflective activity. The latter is a natural human existential activity, better addressed by philosophy.10-12 The characteristics of both phenomena may be compared, but never without seriously considering the specificities of each one.

Limitations Jaspers’ definition of phenomenology represents one type of phenomenological method to access psychic phenomena. Other phenomenologists may suggest different and complementary methodological approaches and knowledge perspectives of psychic phenomena.30,31 We have only searched for and analyzed empirical clinical studies about CR. Reviews and case reports may offer a more detailed analysis. As only the studies in Trends Psychiatry Psychother. 2015;37(1) – 25

Phenomenology and cognitive rumination - Meyer et al.

English were included, some current scientific data about CR may have been missed.

Conclusion Phenomenology may contribute to the analysis of CR and improve conceptual definitions and the identification of cognitive elements of CR to be applied in empirical research. It may also benefit empirical psychiatric and psychopathological studies, including those that investigate CR. It may establish more adequate and accurate conceptual definitions to be used in the identification of psychic phenomena and of theoretical and methodological issues associated with them.16 Further studies about psychopathology and phenomenology should focus on the review of classical methods and theoretical models used in current psychiatric and psychological research.32

References 1.

Nolen-Hoeksema S, Wisco BE, Lyubomirsky S. Rethinking rumination. Perspect Psychol Sci. 2008;3:400-24.

2. Joormann J, Dkane M, Gotlib IH. Adaptive and maladaptative components of rumination? Diagnostic specificity and relation to depressive bias. Behav Ther. 2006;37:269-80.

3. Muris P, Roelofs J, Rassin E, Franken I, Mayer B. Mediating effects of rumination and worry on the links between neuroticism, anxiety and depression. Pers Individ Dif. 2005;39:1105-11.

4. Bagby RM, Rector NA, Bacchiochi JR, McBride C. The stability of the response styles questionnaire rumination scale in a sample of patients with major depression. Cognit Ther Res. 2004;28:527-38.

5. Nolen-Hoeksema S, Morrow J. A prospective study of depression and posttraumatic stress symptoms after a natural disaster: the 1989 Loma Prieta Earthquake. J Pers Soc Psychol. 1991;61:115-21.

6. Moberly N, Watkins ER. Ruminative self-focus and negative affect: an experience sampling study. J Abnorm Psychol. 2008;117:314-23.

7. Nolen-Hoeksema S. The role of rumination in depressive disorders and mixed anxiety/ depressive symptoms. J Abnorm Psychol.

2000;109:504-11.

8. Armey MF, Fresco DM, Moore MT, Mennin DS, Turk CL, Heimberg RG, et al. Brooding and pondering: isolating the active ingredients of depressive rumination with exploratory factor analysis and structural equation modeling. Assessment. 2009;16:315-27.

9. Miranda R, Nolen-Hoeksema S. Brooding and reflection: rumination predicts suicidal ideation at 1-year follow-up in a community sample. Behav Res Ther. 2007;45:3088-95.

10. Jaspers K. Allgemeine psychopathologie. 8th ed. New York: Springer Science; 2011.

11. Jaspers K. Psicopatologia geral. 8th ed. Rio de Janeiro: Atheneu; 2005.

12. Jaspers K. General psychopathology. Baltimore: John Hopkins University Press; 1997.

26 – Trends Psychiatry Psychother. 2015;37(1)

13. Fuchs T, Breyer T, Mundt C. Karl Jaspers’s philosophy and psychopathology. New York: Springer Science; 2014.

14. Stanghellini G, Fuchs T. One century of Karl Jaspers’s general psychopathology. Oxford: Oxford University Press; 2013.

15. Jaspers K. The phenomenological approach in psychopathology.

Br J Psychiatry. 1968;114:1313-23.

16. Kumazaki T. The theoretical root of Karl Jaspers‘ General Psychopathology. Part 1: Reconsidering the influence of phenomenological and hermeneutics.

Hist Psychiatry.

2013;24:212-26.

17. Andersen SB, Moore RA, Venables L, Corr PJ. Electrophysiological correlates of anxious rumination. Int J Psychophysiol.

2009;71:159-69.

18. Brinker JK, Dozois DJ. Ruminative thought style and depressed mood. J Clin Psychol. 2009;65:1-19.

19. Hasegawa A, Koda M, Hattori Y, Kondo T, Kawaguchi J. Depressive rumination and past depression in Japanese university students: comparison of brooding and reflection. Psychol Rep. 2014;114:653-74.

20. Johnson MK, Nolen-Hoeksema S, Mitchell KJ, Levin Y. Medial cortex activity, self-reflection and depression. Soc Cogn Affect Neurosci. 2009;4:313-27.

21. Kocovski NL, Rector NA. Predictors of post-event rumination related to social anxiety. Cogn Behav Ther. 2007;36:112-22.

22. Kuehner C, Hujjziger S, Liebsch K. Rumination, distraction and mindful self-focus: effects on mood, dysfunctional attitudes and cortisol stress response. Psychol Med. 2009;39:219-28.

23. McLaughlin KA, Nolen-Hoeksema S. Rumination as a transdiagnostic factor in depression and anxiety. Behav Res Ther.

2011;49:186-93.

24. Schoofs H, Hermans D, Raes F. Brooding and reflection as subtypes of rumination: evidence from confirmatory factor analysis in nonclinical samples using the Dutch Ruminative Response Scale. J Psychopathol Behav Assess. 2010; 32: 609-17.

25. Thomsen DK, Tonnesvang J, Schnieber A, Olesen MH. Do people ruminate because they haven’t digested their goals? The relations of ruminations and reflection to goal internalization and ambivalence. Motiv Emot. 2011;35:105-17.

26. Trapnell PD, Campbell JD. Private self-consciousness and the five factor model of personality: distinguishing rumination from reflection. J Pers Soc Psychol. 1999;76:284-304.

27. Joireman JA, Parrott L III, Hammersla J. Empathy and the selfabsorption paradox: support for the distinction between selfrumination and self-reflection. Self Identity. 2002;1:53-65.

28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington: American Psychiatric Publishing; 2013.

29. World Health Organization (WHO). International statistical classification of diseases and related health problems, 10th revision (ICD-10). Geneva: WHO; 2004.

30. Spiegelberg H. Phenomenology in psychology and psychiatry.

Evanston: Northwestern University Press; 1972.

31. Spiegelberg H. Phenomenological movement, a historical introduction. Netherland: Kluwer Academic Publisher; 1994.

32. Thome J. Centenary of Karl Jaspers’ general psychopathology: implications for molecular psychiatry. J Mol Psychiatry. 2014;2:3.

Correspondence: Leonardo Fernandez Meyer Rua Professor Alfredo Gomes, 01/202, Botafogo 22251-080 - Rio de Janeiro, RJ - Brazil E-mail: lfm1205@gmail.com

Trends

Original Article

in Psychiatry and Psychotherapy

Variation of plasma cortisol levels in patients with depression after treatment with bilateral electroconvulsive therapy Variação de cortisol plasmático em pacientes deprimidos após tratamento com eletroconvulsoterapia bilateral Daniel Fortunato Burgese,1 Débora Pastore Bassitt2

Abstract

Resumo

Introduction: More than 60 years after the introduction of modern psychopharmacology, electroconvulsive therapy (ECT) continues to be an essential therapeutic modality in the treatment of mental disorders, but its mechanism of action remains unclear. Hormones play an essential role in the development and expression of a series of behavioral changes. One aspect of the influence of hormones on behavior is their potential contribution to the pathophysiology of psychiatric disorders and the mechanism of action of psychotropic drugs and ECT. Objective: We measured blood levels of the hormone cortisol in patients with unipolar depression according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and compared results with levels found in healthy adults.

Method: Blood cortisol levels were measured before the beginning of treatment with ECT, at the seventh session, and at the last session, at treatment completion. Depression symptoms were assessed using the Beck Depression Inventory (BDI).

Results: Cortisol levels remained stable in both men and women between the seventh and the last sessions of ECT; values ranged from 0.686±9.6330 g/dL for women, and there was a mean decrease of 5.825±6.0780 g/dL (p = 0.024). Mean number of ECT sessions was 12. After the seventh and the last ECT sessions, patients with depression and individuals in the control group had similar cortisol levels, whereas BDI scores remained different.

Conclusion: Cortisol levels decreased during ECT treatment.

ECT seems to act as a regulator of the hypothalamic-pituitaryadrenal axis.

Keywords: Depression, cortisol, ECT, endocrine disorders, hypothalamic-pituitary-adrenal axis.

Introdução: Mais de 60 anos após a introdução da moderna psicofarmacologia, a eletroconvulsoterapia (ECT) continua essencial para o tratamento de distúrbios mentais, mas seu mecanismo de ação ainda não é totalmente conhecido. Certos hormônios têm um papel fundamental no desenvolvimento e expressão de uma série de alterações comportamentais. Um aspecto da influência dos hormônios nos comportamentos é sua contribuição potencial para a patofisiologia dos distúrbios psiquiátricos e o mecanismo de ação de psicotrópicos e da ECT. Objetivo: Os níveis do hormônio cortisol no sangue foram medidos em pacientes com depressão unipolar classificados de acordo com a 4ª edição do Manual Estatístico e Diagnóstico de Transtornos Mentais (DSM-IV), e os resultados foram comparados com os níveis encontrados em adultos saudáveis.

Métodos: Os níveis de cortisol no sangue foram medidos antes do início do tratamento com ECT, na sétima e na última sessão, após a conclusão do tratamento. Os sintomas de depressão foram avaliados usando o Inventário de Depressão de Beck (BDI).

Resultados: Os níveis de cortisol permaneceram estáveis tanto nos pacientes masculinos quanto femininos entre a sétima e a última sessão de ECT; os valores variaram 0,686±9,6330 g/ dL entre as pacientes femininas, e houve uma diminuição de 5,825±6,0780 g/dL (p = 0,024). O número médio de sessões de ECT foi 12. Após a sétima e a última sessão de ECT, os níveis de cortisol nos pacientes com depressão e nos indivíduos no grupo controle foram semelhantes, enquanto os resultados da escala BDI permaneceram diferentes.

Conclusão: Os níveis de cortisol diminuíram durante o tratamento com ECT. A ECT parece atuar como reguladora do eixo hipotalâmico-hipofisário-adrenal.

Descritores: Depressão, cortisol, ECT, distúrbios endócrinos, eixo hipotalâmico-hipofisário-adrenal.

1 Department of Psychiatry, Instituto de Assistência Médica ao Servidor Público Estadual (IAMSPE), São Paulo, SP, Brazil. 2 Department of Psychiatry, IAMSPE, São Paulo, SP, Brazil. Institute of Psychiatry, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.

Financial support: none.

Submitted Jul 18 2014, accepted for publication Nov 19 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Burgese DF, Bassitt DP. Variation of plasma cortisol levels in patients with depression after treatment with bilateral electroconvulsive therapy.

Trends Psychiatry Psychother. 2015;37(1):27-36. http://dx.doi.org/10.1590/2237-6089-2014-0031. Epub Jan 30, 2015. © APRS

Trends Psychiatry Psychother. 2015;37(1) – 27-36

Cortisol in patients with depression after ECT - Burgese & Bassitt

Introduction The World Health Organization estimates that depression will be the second leading cause of global illness by 2020. Severe depression may significantly decrease quality of life and lead to death by suicide, for which the risk rate is 6% to 15% among patients with this affective disorder. It may also increase mortality associated with general medical conditions, most notably cardiovascular disease.1 More than 60 years after the introduction and use of modern psychopharmacology, electroconvulsive therapy (ECT) continues to be an essential therapeutic modality in the treatment of mental illnesses. The effectiveness of ECT in treating depression has been demonstrated in numerous studies conducted over the past decades.2

vasopressin (AVP) into the pituitary portal blood. In the adenohypophysis, or anterior pituitary, they stimulate the release of the adrenocorticotrophic hormone (ACTH), which leads to the release of cortisol by the adrenal cortex. Cortisol is the final product of the HPA axis, which has central and peripheral functions mediated by at least two types of specific receptors: type 1, or high-affinity mineralocorticoid receptor (MR), first described in the central nervous system by McEwen et al.6; and type 2, or low-affinity glucocorticoid receptor (GR).7 Glucocorticoids interact with their receptors in multiple target tissues, including the HPA axis, and are responsible for the negative feedback of ACTH secretion by the pituitary.8 Recent theories associate depression with physiological changes in the functioning of the HPA axis

The use of pharmacologically induced seizures to treat mental illness was first described by Laszlo Meduna in 1934, but it was only in 1938 that Ugo Cerletti and Lucio Bini used an electric current, or electroshock, for the treatment of patients with depression.3 ECT has been associated with the beginning of modern biological psychiatry.

Research has improved ECT efficacy and safety and reduced its side effects. Variations of antidepressant brain stimulation techniques, such as transcranial magnetic stimulation, magnetic seizure therapy, direct current stimulation, vagus nerve stimulation, and deep brain stimulation, entered the field of modern psychiatry.

None of these techniques proved to be superior to ECT in terms of action time and response rates. Although ECT is the oldest surviving biological therapy in psychiatry and the most effective short-term treatment for major depression, it still faces constant skepticism.4 The precise mechanism of ECT action remains unknown, and the greatest difficulty in understanding ECT function lies in the induction of a generalized seizure

and serotonergic neurotransmission. The high cortisol levels found in plasma, urine and cerebrospinal fluid of people with depression, a sign of HPA axis hyperfunction, are some of the most consistent findings in psychiatry.7,9 Studies about HPA axis activity in patients with depression found an increased cortisol response to ACTH stimulation, decreased cortisol response to hypoglycemia, decreased ACTH response to stimulation with CRH and resistance to cortisol suppression by dexamethasone response.10,11 These responses promote autonomic and behavioral changes associated with depression, which suggests that there is a disruption in the negative feedback of endogenous cortisol. Furthermore, there is an imbalance between GR and MR receptors in patients with depression, or decreased activity of GR receptors and increased activity of MR12 receptors. According to Stefos13 and Nelson & Davis,14 psychotic depression is more closely associated with hypercortisolism and nonsuppression of cortisol. According to Saraiva et al.,7 there are two models of association between depression and

by an electric current that passes through the brain. It is associated with multiple sequences of biochemical and neuroendocrine changes, which are very difficult to isolate. It is also difficult to assign treatment results to a single specific therapeutic effect.5 Hormones play an essential role in the development and expression of a series of behavioral changes. Of all endocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis has been the most studied in psychiatry.

Corticosteroids, a class of steroid hormones produced in the adrenal cortex, act in a wide range of systems and are essential for life because of their multifaceted effect. The HPA axis is a regulatory system that integrates endocrine and neurological functions. The neurosecretory cells of the paraventricular nucleus (PVN) of the hypothalamus secrete corticotropin releasing factor (CRF) and arginine

changes in physiological cortisol levels. In one model, primary factors contribute to the primary event of hypercortisolism. These factors are trauma and biological vulnerability, which may trigger depressive symptoms. Excessive cortisol increases the intensity of affective symptoms and may promote an even greater increase in plasma cortisol levels. In the first model, the affective symptoms of depression generate harmful effects in the hippocampus, such as inhibition of neurogenesis and hippocampal volume loss, which may lead to cognitive symptoms. In the second model, the triggering element of the cognitive effects may be hypercortisolism.15 Acute ECT has been consistently associated with improvement in plasma levels of cortisol.16-19 Studies have found that the levels of cortisol and ACTH measured

28 – Trends Psychiatry Psychother. 2015;37(1)

Cortisol in patients with depression after ECT - Burgese & Bassitt

before treatment with ECT do not change after a series of ECT sessions, whereas other studies have revealed a fall in the levels of cortisol.16,18,20-26

Objective Changes in the HPA axis are a characteristic of depression. This study measured plasma levels of the hormone cortisol in patients with unipolar depression according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).27 Measurements were made in the beginning of the treatment with ECT, at the seventh session and after the completion of a therapeutic course of treatment using ECT. After that, depression symptoms were assessed using the Beck Depression Inventory (BDI), and findings were compared with cortisol blood levels in healthy volunteers.

Method Individuals that met diagnostic criteria for major depressive disorder according to the DSM-IV and had no psychiatric or neuroendocrine comorbidities were invited to participate in the study. Participants had no other axis I diagnoses and did not use alcohol or other substances in the previous year. Exclusion criteria were clinical psychiatric comorbidities and neuroendocrinologic changes that might affect HPA axis. All patients, guardians and volunteers read and signed a Consent Form for Participation in Clinical Research approved by the Research Ethics Committee of Instituto de Assistência Médica ao Servidor Público Estadual (IAMSPE) (protocol no. 112/10).

All individuals underwent clinical and cardiac evaluations before treatment with ECT, and all were physically healthy. Psychotropic medications were discontinued before the beginning of ECT. The washout period was calculated for each individual according to the half-life of their psychotropic medication, and five days was the shortest time to the beginning of the treatment.

All participants remained hospitalized in psychiatric wards during the treatment with ECT and did not resume use of any psychotropic drugs, except bromazepam 3 mg for night sedation, if needed, during all the study time.

The severity of depressive symptoms was classified using the BDI. Values below 10 points were scored as minimum or no depression; 10 to 18 points, mild to moderate depression; 19 to 29 points, moderate to severe depression; and 30 to 63 points, severe depression.

Individuals in the control group, recruited among hospital employees, were matched for sex and age.

Peripheral blood was collected from the upper limb to measure morning cortisol levels, and the BDI was administered. Individuals were excluded if they scored more than 10 points in BDI, or had clinical psychiatric comorbidities or neuroendocrinologic conditions that might affect the HPA axis.

In the group of patients with depression, cortisol was measured during the morning after awakening, and the BDI scale was applied at three time points during the treatment with ECT: the first at the time of the first ECT session, before the procedure; the second, after the seventh ECT session; and the third, after the last ECT session. Biological material was collected through the same venous access used for the administration of anesthetics for ECT by the nursing and medical teams. Laboratory samples of biological material were analyzed in the Department of Clinical Analyses of IAMSPE using an Immulite 2000 XPISIEMENS analyzer.

For ECT, general anesthesia was induced using thiopental sodium, a muscle relaxant (succinylcholine) and hyperventilation. All patients received bitemporal application of ECT using a Somatics-Thymatron IV system and ECT pulses of 0.5 ms. Seizure threshold was estimated in the first session based on the age of the patient and individual adjustments to obtain a seizure lasting between 25 to 30 s. Sessions were held twice a week, and the total number of sessions was determined by the attending physician based on the clinical assessment of response to treatment.

Results In the statistical analysis of the results, a chi-square test was used to evaluate the association between categorical variables and quantitative variables.

The Kolgomorov-Smirnov test was used to check normal distribution, and the t test, to analyze the differences between groups at the same time point. The nonparametric Mann-Whitney test was used to analyze the differences between two groups, and the KruskallWallis test, to analyze the four groups (group and sex; group and age group) at the same time point. For longitudinal comparisons, the Wilcoxon test was used to compare two time points, and the Friedman test, to compare three time points. For the correlations between variables, we used the Spearman correlation coefficient, which evaluated the correlations between variables, and the Bonferroni correction, used for multiple comparisons.

The level of significance was set at p ≤ 0.05.

Trends Psychiatry Psychother. 2015;37(1) – 29

Cortisol in patients with depression after ECT - Burgese & Bassitt

35

30

25

20

15

10

5

0 7th ECT

Last ECT

7th ECT

Cortisol

Last ECT

Cortisol

BDI

BDI Depressed group Mean

Control group Min

Max

SD

Figure 1 - Cortisol levels and Beck Depression Inventory (BDI) scores in depressed group on the 7th and last electroconvulsive therapy (ECT) session compared with results for the control group; baseline cortisol, p = 0.008; BDI, p < 0.001. At the time of the last ECT session, the results for cortisol levels were p ≥ 0.05 between groups. Max = maximum; Min= minimum; SD = standard deviation.

The comparison of the results of the group of patients with depression and of the control group revealed that initially only sex and age were the same between groups, whereas BDI scores and baseline cortisol levels were significantly different: p = 0.008 for baseline cortisol level and p < 0.001 for BDI scores. In the seventh and final ECT session, the groups had similar cortisol levels (p ≥ 0.05), whereas BDI scores remained different at the three time points, but decreased progressively towards the values found for the control group (p = 0.01) (Figure 1).

Mean age in the control group was 54.10±12.324,

mean baseline cortisol level was 11.40±3.098 µg/dL and mean initial BDI score was 5.40±3.565 points on the initial BDI scale Sex and age distribution was equal, and p was ≤ 0.05 for the comparison of cortisol levels and BDI scores (Table 1).

Eleven participants completed the study and had baseline and post-ECT results. Seven were women, there were no differences in sex and age distribution.

Mean age was 59.5±10.93 years, mean baseline cortisol level was 16.36±5.065 µg/dL, and mean BDI score was 44.82±8.424 (Table 1).

Table 1 - Distribution of age, baseline cortisol levels (µg/dL) and Beck Depression Inventory scores in the control group and in the depressed group (level of significance: p ≤ 0.05)

Age Mean Minimum Maximum Standard deviation Cortisol level (µg/dL) Mean Minimum Maximum Standard deviation BDI score Mean Minimum Maximum Standard deviation

30 – Trends Psychiatry Psychother. 2015;37(1)

Control group

Depressed group

p

54.1 42 81 12.324

59.5 37 79 10.93

p ≥ 0.005

11.4 7 17 3.098

16.36 11 26 5.07

p = 0.008

5.4 0 9 3.565

44.82 34 63 8.42

p < 0.001

Cortisol in patients with depression after ECT - Burgese & Bassitt

Younger than 60 years

Older than 60 years

Male

Female

General

-10

-5

0 Variation 7th/Last ECT

5

10

Last ECT

7th ECT

15 1st ECT

20

Figure 2 - Comparison of cortisol levels (µg/dL) in the depressed group in the subgroups older and younger than 60 years at the time of the 1st and 7th ECT session (p = 0.017), and variation in the intervals between the 7th and the last ECT sessions (p = 0.030); the comparison between sex and age was not statistically significant.

In the depressed group, there were no significant differences between age and sex distribution. Women had a cortisol variation of 0.843±6.9916 µg/dL between the first and the last ECT session, while men had a decrease of 6.725±4.0219 µg/dL) in the same period of analysis, and this difference between sexes was significant (p = 0.024) (Figure 2).

Cortisol levels remained stable in both sexes between the seventh and the last ECT sessions; variation values were 0.686±9.6330 µg/dL for women, and mean decrease was 5.825±6.0780 µg/dL (p ≥ 0.05), but the difference was not statistically significant (Table 2,

the cortisol level at the first ECT session, the greater the difference in BDI scores between the first and the seventh ECT sessions (Table 2).

BDI scores decreased progressively and were significantly different at the three time points (p = 0.003).

Some variables were correlated, and findings of the comparisons between age and cortisol variation from the beginning to the end of the treatment with ECT were significant.

The older the patient, the greater the difference between cortisol levels at the first and the last ECT session; the higher the BDI scores at the first time

Figure 3).

The subgroup of individuals 60 years and older in the depressed group had a greater variation in cortisol levels between the first and the last ECT session (p = 0.017) and the seventh and the final session (p = 0.030) than patients younger than 60 years (Figure 2). The comparison of the subgroup of individuals 60 years and older according to sex revealed no statistical differences. The analysis of variables that were correlated revealed that the older the individuals in the depressed group, the greater the difference in the variation of cortisol levels between the last and the first ECT sessions. Also, the higher

point, the greater the cortisol level. There was also a correlation between baseline cortisol levels and BDI score differences at the first and the seventh session.

The comparison of the depressed and control groups revealed that only sex and age at baseline were the same between groups, whereas BDI scores and baseline cortisol levels were significantly different (baseline cortisol: p = 0.008; BDI: p < 0.001). At the seventh and at the final ECT sessions, the groups had similar cortisol levels (p ≥ 0.05), whereas BDI scores remained different between groups at the three different time points, but there was a progressive reduction towards levels in the control group (p = 0.01) (Figure 3).

Trends Psychiatry Psychother. 2015;37(1) – 31

Cortisol in patients with depression after ECT - Burgese & Bassitt

Table 2 - Distribution of absolute values of baseline cortisol levels (µg/dL), BDI scores, variation of cortisol level and BDI score between the first, seventh and last session in the depressed group according to age

Cortisol level (µg/dL)

Age

1st ECT

7th ECT

Variation of the cortisol dosage

BDI score

Last ECT

1st ECT

7th ECT

Variation of the BDI score

Last 7th/1st Last/ Last/1st 7th/1st Last/7th Last/1st ECT ECT 7th ECT ECT ECT ECT ECT

General Mean

59.55

16.36

44.82

26.91

18.45

-0.318

-1

-1.909

17.91

8

26.36

Minimum

37

11

7

4

34

17

13

-5.8

-11.9

-9

6

3

15

Maximum

79

26

30

26

63

33

22

6.8

18.8

13.1

32

16

48

10.93

5

6

5

8

5

2.911

4

8

6

7

5

8

SD

16.18 14.64

Women Mean

56.71

15.71

16

16.71

45.71

28.71

18.86

0.157

0.686

0.843

17

9.86

26.86

Minimum

37

11

7

12

34

22

15

-5.8

-11.5

-7.4

6

3

15

Maximum

79

26

30

26

63

33

22

6.8

18.8

13.1

32

16

48

12.996

5

7

4

10.291

3

2.673

5.3727

9

6.9916

9

5

11

SD Men Mean

64.50

17.5

16.5

11

43.25

23.75

17.75

-1

-5

-6

19.5

6

25.5

Minimum

63

13

11

4

39

17

13

-4.3

-11.9

-9

15

3

22

Maximum

69

25

24

17

48

33

21

2.9

2.6

-7

23

13

28

SD

3.0

5.26

5

5

4

6

3

3

6

4

3

4

2

Older than 60 years Mean

66.83

18

18

12.33

45.5

26.17

17

0.6

-6.5

-5

19

8.5

27.83

Minimum

63

12

11

4

37

17

13

-4.3

-11.9

-9

6

3

17

Maximum

79

26

30

18

63

33

21

4

2.6

-0.1

32

16

48

6

6

6.976

5

9

6

3

3

5.3468

4

8

5

10.647

SD Younger than 60 years Mean

50.80

14.4

13.2

17

44

27.8

19

-1.42

4

2.68

16.2

8.4

24.6

Minimum

37

11

7

12

34

22

17

-5.8

-2.8

-7

10

3

15

Maximum

58

18

18

26

56

33

22

6.8

18.8

13.1

25

16

34

8.497

5.05

4

5

7

4

2

5.6936

9

7

5

5

6

SD

BDI = Beck Depression Inventory; ECT = electroconvulsive therapy; SD = standard deviation.

70 60 50 40 30 20 10 0 1st ECT

7th ECT Cortisol level

Last ECT

1st ECT

7th ECT

Last ECT

BDI score

Figure 3 - Cortisol levels (µg/dL) and Beck Depression Inventory (BDI) scores in absolute values in the depressed group. Cortisol levels remained stable in general (p ≥ 0.05). BDI scores decreased at the three time points (p = 0.003). ECT = electroconvulsive therapy.

32 – Trends Psychiatry Psychother. 2015;37(1)

Cortisol in patients with depression after ECT - Burgese & Bassitt

Discussion Neuroendocrine studies have found variations in cortisol levels and changes in the hypothalamichypophysis-adrenal axis of patients with depression.28-32 Although these biological changes are some of the wellestablished theses in psychiatry, their psychopathological and physiological implications are still unclear.

Abrams & Taylor,33 Fink & Nemeroff34 and Grover et al.3 suggested that ECT corrects a deregulation of neuropeptides by means of diencephalic stimulation. They found an increased production and release of several neuropeptides, some of which had transient antidepressant effects, as well as vegetative and neuroendocrine deregulation, features of depression that are mediated by core brain structures and that are improved by

values after ECT. McKay & Zakzanis39 conducted a metaanalysis of 34 studies and 1049 patients with depression treated with ECT, transcranial magnetic stimulation and antidepressants and compared cortisol levels in saliva, urine and blood. They found that treatment type and cortisol levels did not have any impact on pre- and post-treatment levels, but that depression subtype and disease duration might contribute to changes in cortisol levels. The melancholy subtype, for example, had larger variations in cortisol levels before and after treatment.

Zis et al.28 compared cortisol and prolactin levels in 10 patients with depression treated with unilateral ECT using high and low voltage. They found that seizure duration did not affect cortisol and prolactin levels, but cortisol levels were significantly higher in the high voltage subgroup than in the low voltage group. Ozsoy et al.40

treatment with ECT. Their studies found increased levels of corticotropin, cortisol, prolactin, oxytocin, vasopressin, beta-endorphin and growth hormone after ECT. The effects of corticosteroids on serotonergic receptors (5-HT) may have an important role in vegetative and affective functions: in experiments with laboratory animals, chronically stressed animals had high levels of circulating corticosteroids, decreased levels of 5-HT messenger RNA and predominance of depressive behaviors, such as less locomotion, which reduces exploratory attitudes and leads to anorexia. However, after five to seven days of continuous exposure to stress, the activity of the 5-HT receptors and behaviors were back to normal, and adaptive responses were interrupted by repeated administration of corticosterone, but facilitated by the administration of antiglucocorticoids.7 According to Wolkowitz & Reus,35 hypercortisolism, frequent in patients with major depression, has been associated with various behavioral changes, such as sleep disorders, lassitude, decreased attention and libido, psychomotor disorders, anxiety and suicide ideation.

examined blood samples collected two days before, 10 minutes after the first session and three days after the end of ECT from patients with depression, and compared findings with the results of a blood sample collected from individuals in the control group. They found that baseline cortisol levels did not differ significantly between patients and controls, but that cortisol levels were significantly lower in the group of patients after ECT completion.

Acute treatment with ECT affected ACTH, cortisol, and prolactin levels, which suggests that the ECT regulates serum levels of the hormones of the HPA axis by stimulating the hypothalamus to function normally.18,37,41 In this study we investigated the changes in plasma cortisol levels throughout ECT treatments and analyzed BDI scores. Cortisol levels decreased as ECT treatment progressed. Cortisol levels were greater than those of the control group at baseline, but at the 7th ECT session, cortisol levels were similar to those of the control group.

Values were significantly greater in the group of patients older than 60 years than among individuals in the control group. There were no statistically significant differences

However, the interpretation of these data is difficult because the studies under analysis demonstrated that not all patients with depression have hypercortisolism, and not all patients with hypercortisolism have depression.

Keller et al.36 reported that the patients with depression who attempt suicide violently have higher cortisol levels than patients with depression and non-violent suicide attempts, and suggested that deregulation of the HPA axis may be a factor of violent suicide behavior. Cortisol levels are higher in brain spinal fluid, but return to normal after treatment and recovery from depression.37 Markianos et al.38 studied a group of 13 control individuals and 11 men with depression undergoing eight to 13 ECT sessions and their variation of cortisol levels.

Baseline cortisol levels were 30% greater in patients than in controls, but there were no differences from baseline

between men and women 60 years or older in the depressed group. Reductions of cortisol levels after ECT specifically in elderly patients with depression are not a frequent finding in the literature.

According to Keller et al.,36 high cortisol levels are found in depression, and levels are higher in psychotic depression. There is evidence that this is associated with age, and elderly individuals with depression tend to have higher cortisol levels. Physiological aging is associated with a relative increase in the activity of the HPA axis, associated with a reduction of mineralocorticoid and glucocorticoid receptors. Sapolsky et al.42,43 found consistent evidence that the rupture of glucocorticoid levels resulted in mood and cognition disorders, neurophysiological changes, alterations in the activity of neurotransmitters and neuroanatomic variations.

Trends Psychiatry Psychother. 2015;37(1) â&#x20AC;&#x201C; 33

Cortisol in patients with depression after ECT - Burgese & Bassitt

Pariante & Miller44 and Soskin et al.45 found that physiological stress responses activate the sympathetic nervous system, which releases catecholamine adrenaline and norepinephrine into the portal circulation, followed by HPA-axis activation, which stimulates the release of ACTH by the hypophysis and the consequent release of glucocorticoids by the adrenal glands. Depression is characterized by hyperactivity of the HPA axis and insensitivity of glucocorticoid brain receptors. As a result, inhibition is deficient because of the negative feedback to stress.

Von Cauter et al.46 and Harman47 suggest that ACTH and cortisol secretions are age-related, as mean 24-hour serum cortisol level is 20% to 50% greater in men and older women, and that serum cortisol levels have similar increases in response to fasting in elderly

levels after ECT sessions are consistent with the findings reported by Aperia et al.,16 Aperia et al.,20 Weizman et al.23 and Ozsoy et al.40 Ozsoy et al.40 suggested that the mechanism of action of ECT might be explained by the fact that it changes the instability of levels of neuroactive steroids that affect gamma-aminobutyric acid (GABA) antagonists, such as dehydroepiandrosterone (DHEAS), and GABA agonists, as testosterone and progesterone.

In depression, estrogen and testosterone levels are physiological unstable, which contributes to the symptoms of depression, such as sexual dysfunction and reduced energy. Moreover, ECT might contribute to clinical improvement by means of regular activation of neuroactive steroids. In their study, high DHEAS levels were detected in male patients with depression,

men and young people. Serum cortisol responses to stress are prolonged in older individuals, possibly due to changes in glucocorticoid receptors.

The answer to whether depression is the cause or consequence of hypercortisolism is hard. Depression has been associated with chronic high cortisol levels because of the deregulation of the HPA axis and the reduction of hippocampal volume in humans after recurrent episodes of depression.5,48 High cortisol levels may impair brain function because of mechanisms such as changes in the brain glucose metabolism, which potentiate the toxic effect of excitatory amino acids, such as glutamate, and block the action of neurotrophic factors that are crucial for the recovery of brain damage.49 The area of hippocampal formation is rich in mineralocorticoids and in glucocorticoids and has receptors that maintain the baseline HPA axis and the negative feedback regulation of glucocorticoids during the response to stress. Therefore, the hippocampus is particularly vulnerable to the effects of stress and depression.

whereas no changes were found in women. After ECT, DHEAS elevations were less marked in men and remained stable in women, which indicated an inverse correlation between DHEAS and cortisol levels after ECT. These data are consistent with the findings in our study, in which cortisol levels differed between male and female patients after treatment with ECT. We believe that glucocorticoid receptors in elderly populations with depression are disrupted and that ECT may reestablish the function of the HPA axis.

Cortisol levels decrease during treatments using ECT, which suggests that ECT acts as a regulator of the HPA axis. It remains uncertain, however, whether hypercortisolism is an epiphenomenon or a direct contribution to depressive symptoms and biochemical changes in major depression.

The evaluation of our results should take into consideration study limitations, and our findings should be classified as preliminary. The association of depression severity with hypercortisolism mechanisms is not warranted for several reasons. First, our sample size was too small to establish a correlation between depression severity, cortisol levels and possible changes of the hippocampal volume. Second, cortisol levels in elderly populations were not analyzed because our sample of patients 60 years or older was small.

Studies to evaluate these variables should include a larger sample of patients with depression for a better understanding of the physipathology of depression and the correlations of cortisol levels before and after treatments with ECT. Recent studies have contributed to the improvement of our knowledge about possible mechanisms of action of ECT and to the development of safe and well-tolerated treatments, but some fundamental mechanisms remain unclear. Although the precise mechanism of action of ECT has not been described,

According to Oâ&#x20AC;&#x2122;Brien et al.,50 high cortisol levels during depression may be associated with cognitive changes, and chronic hypercortisolism in depression may cause damage to the hippocampus, which explains why these deficiencies persist in individuals with depression even after the affective symptoms have disappeared. This hypothesis would justify the findings in our study, in which patients with depression had high BDI scores even after ECT and clinical improvement. Patients with depression are usually referred to treatment with ECT when refractory to drug treatments, which would explain the fact that BDI scores are elevated even after the end of treatment with ECT and that there are residual symptoms even when cortisol levels are similar to those found in the control group. Our findings of a reduction of cortisol 34 â&#x20AC;&#x201C; Trends Psychiatry Psychother. 2015;37(1)

Cortisol in patients with depression after ECT - Burgese & Bassitt

this highly effective therapeutic option should not be seen only as a last choice for the treatment of depression.

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007;357:1939-45.

Antunes PB, Rosa MA, Belmonte-de-Abreu PS, Lobato MIR, Fleck MP. Eletroconvulsoterapia na depressão maior: aspectos atuais. Rev Bras Psiquiatr. 2009;31:S26-S33.

Grover S, Mattoo SK, Gupta N. Theories on mechanism of action of electroconvulsive therapy. German J Psychiatry. 2005;8:70-84.

Merkl A, Heuser I, Bajbouj M. Antidepressant electroconvulsive therapy: mechanism of action, recent advances and limitations.

Exp Neurol. 2009;219:20-6.

Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingstrom A. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry. 2000;47:1043-9.

McEwen BS, Davis PG, Parsons B, Pfaff DW. The brain as a target for steroid hormone action. Annu Rev Neurosci. 1992;2:65112.

Saraiva EM, Fortunato JMS, Gavina C. Oscilações do cortisol na depressão e sono/vigília. Rev Port Psicossomática. 2005;7:89-100.

Juruena MF, Cleare AJ, Pariante CM. O eixo hipotálamo-pituitáriaadrenal, a função dos receptores de glicocorticóides e sua importância na depressão. Rev Bras Psiquiatr. 2004;26:189201.

Alheira FV, Brasil MAA. O papel dos glicocorticóides na expressão dos sintomas de humor: uma revisão. Rev Psiquiatr Rio Gd Sul. 2005;27:177-86.

Murphy BE. Steroids and depression. J Steroid Biochem Mol Biol. 1991;38:537-59.

Zobel AW, Yassouridis A, Frieboes RM, Holsboer F. Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remit ted depression.

Am J Psychiatry.1999;156:949-51.

Young EA, Lopes JF, Murphy-Weinberg V, Watson SJ, Akil H. Mineralocorticoid receptor function in major depression. Arch Gen Psychiatry. 2003;60:24-8.

Stefos G. [Neuroendocrine tests and sleep EEG anomalies in psychotic depression]. Acta Psychiatr Belg. 1993;93:311-21.

Nelson JC, Davis JM. DST studies in psychotic depression: a meta-analysis. Am J Psychiatry. 1997;154:1497-503.

Sapolsky RM. Depression, antidepressants, and the shirinking hippocampus. Proc Natl Acad Sci U S A. 2001;98:12320-2.

Aperia B, Thoren M, Zettergren M, Wetterberg L. Plasma pattern of adrenocorticotropin and cortisol during electroconvulsive therapy in patients with major depressive illness. Acta Psychiatr Scand. 1984;70:361-9.

Widerlov E, Ekman R, Jensen L, Borglund L, Nyman K. Arginine vasopressin, but not corticotropin releasing factor, is a potent stimulator of adrenocorticotropic hormone following electroconvulsive treatment. J Neural Transm. 1989;75:101-9.

Kronfol Z, Hamdan-Allen G, Goel K, Hill EM. Effects of single and repeated electroconvulsive therapy sessions on plasma ACTH, prolactin, growth hormone and cortisol concentrations.

Psychoneuroendocrinology. 1991;16:345-52.

Florkowski CM, Crozier IG, Nightingale S, Evans MJ, Ellis MJ, Joyce P, et al. Plasma cortisol, PRL, ACTH, AVP and corticotrophin releasing hormone responses to direct current cardioversion and electroconvulsive therapy. Clin Endocrinol (Oxf). 1996;44:163-8.

Aperia B, Bergman H, Engelbrektson K, Thoren M, Wetterberg L. Effects of electroconvulsive therapy on neuropsychological function and circulating levels of ACTH, cortisol, prolactin, and TSH in patients with major depressive illness. Acta Psychiatr.

Scand. 1985;72:536-41.

Cooper SJ, Kelly JG, King DJ. Adrenergic receptors in depression. Effects of electroconvulsive therapy. Br J Psychiatry.

1985;147:23-9.

Aperia B. Hormone pattern and post-treatment attitudes in patients with major depressive disorder given electroconvulsive therapy. Acta Psychiatr Scand. 1986;73:271-4.

23. Weizman A, Gil-Ad I, Grupper D, Tyanos S, Laron Z. The effect of acute and repeated electroconvulsive treatment on plasma beta-endorphin, growth hormone, prolactin and cortisol secretion in depressed patients. Psychopharmacology (Berl).

1987;93:122-6.

24. Whalley LJ, Eagles JM, Bowler GM, Bennie JG, Dick HR, McGuire RJ, et al. Selective effects of ECT on hypothalamic-pituitary activity. Psychol Med. 1987;17:319-28.

25. Smith J, Williams K, Birkett S, Nicholson H, Glue P, Nutt DJ. Neuroendocrine and clinical effects of electroconvulsive therapy and their relationship to treatment outcome. Psychol Med. 1994;24:547-55.

26. Werstiuk ES, Coote M, Griffith L, Shannon H, Steiner M. Effects of electroconvulsive therapy on peripheral adrenoceptors, plasma, noradrenaline, MHPG and cortisol in depressed patients. Br J Psychiatry. 1996;169:758-65.

27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Arlington: American Psychiatric Publishing; 1994.

28. Zis AP, Yatham LN, Lam RW, Clark CM, Srisurapanont M, McGarvey K. Effect of stimulus intensity on prolactin and cortisol release induced by unilateral electroconvulsive therapy.

Neuropsychopharmacology. 1996;15:263-70.

29. Shapira B, Newman ME, Gelfin Y, Lerer B. Blunted temperature and cortisol responses to ipsapirone in major depression: lack of enhancement by electroconvulsive therapy.

Psychoneuroendocrinoly. 2000;25:421-38.

30. Castro M, Moreira AC. Análise crítica do cortisol salivar na avaliação do eixo hipotálamo-hipófise-adrenal. Arq Bras Endocrinol Metab. 2003;47:358-67.

31. Schatzberg AF, Lindley S. Glucocorticoid antagonists in neuropsychiatric [corrected] disorders. Eur J Pharmacol.

2008;583:358-64.

32. Gronli O, Stensland GØ, Wynn R, Olstad R. Neurotrophic factors in serum following ECT: a pilot study. World J Biol Psychiatry.

2009;10:295-301.

33. Abrams R, Taylor MA. Diencephalic stimulation and the effects of ECT in endogenous depression. Br J Psychiatry. 1976;129:4825.

34. Fink M, Nemeroff CB. A neuroendocrine view of ECT. Convuls Ther. 1989;5:296-304.

35. Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosom Med. 1999;61:698-711.

36. Keller J, Buckluy TM, Shatzber AF. Hypothalamic-pituitaryadrenal axis activity. In: Roose SP, editor. The pychobiology of late life depression. New York: Oxford University Press; 2004. p. 157-64.

37. Fink M, Ottosson JO. A theory of convulsive therapy in endogenous depression: significance of hypothalamic functions.

Psychiatry Res. 1980;2:49-61.

38. Markianos M, Hatzimanolis J, Lykouras L. Serotonergic and dopaminergic neuroendocrine responses of male depressive patients before and after a therapeutic ECT course. Eur Arch Psychiatry Clin Neurosci. 2002;252:172-6.

39. McKay MS, Zakzanis KK. The impact of treatment on HPA axis activity in unipolar major depression. J Psychiatr Res. 2010;44:183-92.

40. Ozsoy S, Esel E, Hacimusalar Y, Candan Z , Kula M, Turan T. [Acute and chronic effects of electroconvulsive therapy on neuroactive steroids in patients with major depressive disorder]. Turk Psikiyatri Derg. 2008;19:341-8.

41. Fluitman SHA, Heijnen CJ, Denys DA, Nolen WA, Balk FJ, Westenberg HG. Electroconvulsive therapy has acute immunological and neuroendocrine effects in patients with major depressive disorder. J Affect Disord. 2011;131:388-92.

42. Sapolsky RM, Krey LC, Mcewen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985;5:1222-7.

43. Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis.

Endocrine Rev. 1986;7:284-301.

44. Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry. 2001;49:391-404.

45. Soskin DP, Cassiello C, Isacoff O, Fava M. The inflammatory hypothesis of depression. Focus. 2012;10:413-21.

46. Von Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996;81:2468-73.

Trends Psychiatry Psychother. 2015;37(1) – 35

Cortisol in patients with depression after ECT - Burgese & Bassitt

47. Harman SM. Endocrine changes with aging. UptoDate [on-line].

2014. http://www.uptodate.com/contents/endocrine-changeswith-aging#top 48. Young EA, Haskett RF, Murphy-Weinberg V, Watson SJ, Akil H. Loss of glucocorticoid fast feedback in depression. Arch Gen Psychiatry. 1991;48:693-9.

49. Neylan TC, Canick JD, Hall SE, Reus VI, Sapolsky RM, Wolkowitz OM. Cortisol levels predict cognitive impairment induced by electroconvulsive therapy. Biol Psychiatry. 2001;50:331-6.

50. O’Brien JT, Lloyd A, Mckeith I, Gholkar A, Ferrier N. A longitudinal study oh hippocampal volume, cortisol levels and cognition in older depressed subjects. Am J Psychiatry. 2004;161:2081-90.

36 – Trends Psychiatry Psychother. 2015;37(1)

Correspondence: Daniel Fortunato Burgese Instituto de Assistência Médica ao Servidor Público Estadual (IAMSPE) Ambulatório de Psiquiatria Rua Borges Lagoa, 1635 04038-034 - São Paulo, SP - Brazil E-mail: danielburgese@yahoo.com.br

Trends

Original Article

in Psychiatry and Psychotherapy

Cross-cultural adaptation of the Spence Children’s Anxiety Scale in Malaysia Adaptação cultural da Escala de Ansiedade Infantil de Spence para a Malásia Atefeh Ahmadi,1 Mohamed Sharif Mustaffa,2 AliAkbar Haghdoost,3 Aqeel Khan,1 Adibah Abdul Latif1

Abstract

Resumo

Introduction: Anxiety among children has increased in recent years. Culturally adapted questionnaires developed to measure the level of anxiety are the best screening instruments for the general population. This study describes the scientific translation and adaptation of the Spence Children’s Anxiety Scale (SCAS) into the Malay language.

Method: The process of scientific translation of this selfreport instrument followed the guidelines of the Task Force for Translation and Cultural Adaptation of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR).

Results: The Malay version and its adaptation for a new cultural context are described.

Conclusion: The Malay version achieved the aims of the original version and its conceptual and operational equivalence. It may be used as the first Malay instrument to measure anxiety among children in research and in clinical and community settings.

Keywords: Anxiety disorders, SCAS-Malay, cross-cultural adaptation, children.

Introdução: A ansiedade infantil tem crescido em anos recentes.

Questionários culturalmente adaptados e desenvolvidos para medir o nível de ansiedade são os melhores instrumentos de triagem para a população em geral. Este estudo descreve a tradução e adaptação científica da Escala de Ansiedade Infantil de Spence para a língua malásia.

Método: O processo de tradução científica deste instrumento de autorrelato seguiu as orientações da Força-Tarefa para a Tradução e Adaptação Cultural da International Society for Pharmacoeconomics and Outcomes Research (ISPOR).

Resultados: A versão malásia e sua adaptação para um novo contexto cultural são descritas.

Conclusão: A versão malásia atingiu os objetivos da versão original e sua equivalência conceitual e operacional. Poderá ser usada como o primeiro instrumento malásio para medir ansiedade entre crianças em contextos de pesquisa, clínicos ou comunitários.

Descritores: Transtornos de ansiedade, Escala de Ansiedade Infantil de Spence - Malásia, adaptação cultural, crianças.

Introduction

prevalence of simultaneous and postponed psychological

The prevalence of anxiety disorders, some of the most common mental health disorders of children, has increased.1 International2-4 and Malaysian5 studies have shown that prevalence during childhood ranges from 6% to 31.9%. Such disorders may affect a child’s social and individual functioning and have a tendency to become chronic.6-8 Moreover, they are highly comorbid with other psychiatric disorders and may lead to an increased

diseases, such as depression and substance abuse,9-12 if left untreated or treated inadequately.13,14 The use of appropriate tools for the screening, assessment, diagnosis and follow-up of children’s anxiety may reduce its side effects.15 The best choices are selfreport questionnaires, which are less time-consuming, easy to administer and focused on symptoms based on standard criteria, such as those defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM).16

1 Faculty of Education, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia. 2 Counseling Center, University Technology Malaysia, Skudai, Johor, Malaysia.

Research Center for Modeling in Health, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran.

3

Financial support: Ministry of Higher Education (MOHE) and Research Management Centre (RMC), Universiti Teknologi Malaysia (UTM) (institutional grant no.

VOT 4F304).

Submitted Sep 04 2014, accepted for publication Nov 25 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Ahmadi A, Mustaffa MS, Haghdoost AA, Khan A, Latif AA. Cross-cultural adaptation of the Spence Children’s Anxiety Scale in Malaysia. Trends Psychiatry Psychother. 2015;37(1):37-41. http://dx.doi.org/10.1590/2237-6089-2014-0038 © APRS

Trends Psychiatry Psychother. 2015;37(1) – 37-41

Cross-cultural adaptation of SCAS to Malay - Ahmadi et al.

Questionnaires designed to assess anxiety symptoms in children usually originate from those for adults.17 A few instruments have been adapted to Malay culture to measure anxiety symptoms in adults (e.g., Generalized Anxiety Disorder 7-item [GAD-7]18; Spielberger StateTrait Anxiety Inventory [STAI]19; Depression Anxiety and Stress Scales [DASS]20), but there are none for children. In addition, some questionnaires do not include developmental characteristics in the evaluation of childhood anxiety,17 and some, such as the StateTrait Anxiety Inventory for Children (STAI-C) and the Revised Children’s Manifest Anxiety Scale (RCMAS), do not evaluate the different domains of anxiety.

These domains should be diagnosed and differentiated before prescribing adequate medical treatments and psychological interventions and therapies. The Spence

items as in the child version, but there is no positive filler.30 The Likert-like scale is the same as the one for the child version. The authors of this study prepared a Malay version of the SCAS, as described here, and evaluated its psychometric properties, as described in another manuscript.

Children’s Anxiety Scale (SCAS)17 was designed to take into account the relevant developmental characteristics of anxiety among children, as well as to assess and specify symptoms of anxiety according to the domains defined in the DSM-IV.15 The original SCAS21 and crossculturally adapted versions to other languages, such as Dutch,22 German,23 Hellenic Greek,24 Mexican,25 Japanese,26 Cypriot,27 English, Swedish, and Italian,28 have achieved acceptable psychometric properties. The aim of this study was to cross-culturally adapt the SCAS (child and parent versions) to the Malay language.

There are 118 tools based on the DSM-IV criteria to measure anxiety in children,29 but the SCAS is the first to be cross-culturally adapted for use in Malaysia.

back translation review; f) harmonization; g) cognitive debriefing; h) review of cognitive debriefing results and finalization; i) proof reading; and j) final report.32 - Preparation phase: The process was initiated by receiving authorization from the original SCAS author for the adaptation of the instrument for use in Malaysia and by then selecting appropriate translators.

- First translation: Two native speakers produced independent translations.

- Reconciliation step: A native Malay speaker synthesized the two forward translations into a single version and reconciled it.

- Back translation: The reconciled version was translated back into the original language for the quality control of the version produced by an independent translator.

- Back translation review: The back translated version was compared with the original by an expert in the field.

- Harmonization: No significant discrepancy needed

Method Spence Children’s Anxiety Scale - Child Version (SCAS-C) The SCAS-C has 44 items, 38 of which are arranged into six domains: separation anxiety; social phobia; obsessive-compulsive problems; generalized anxiety; panic and agoraphobia; and physical injury fears. There are six positive filler items and one open ended question to report any additional fears not considered in the other items.30 A Likert-like scale (never, sometimes, often, and always) is used for answering.

Procedures The procedures for translation and adaptation of the SCAS were based on the guidelines for the Translation and Cultural Adaptation group (TCA group) of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR).31 The adaptation steps, according to ISPOR, are: a) preparation; b) first forward translation; c) reconciliation; d) back translation; e)

-

Spence Children’s Anxiety Scale - Parent Version (SCAS-P) Parents are required to answer the SCAS-P items based on their views of their children’s symptoms.

Thirty-eight items of the parent version follow the same 38 – Trends Psychiatry Psychother. 2015;37(1)

-

harmonization into the Malay context when compared with items adopted and translated into other languages.

Cognitive debriefing: To check understandability, interpretation and cultural relevance of the translated SCAS, child and parent versions were applied to five native Malay children with anxiety, three boys and two girls, and to their parents. Their ages ranged from 8 to 12 years. They were asked to mention any confusing words or statements and comment on what they understood in each item. All participants provided written informed consent. This investigation was approved by the Ethics Committee of the Ministry of Higher Education in medical research.

Review of cognitive debriefing results and finalization: In step eight, a modified version based

Cross-cultural adaptation of SCAS to Malay - Ahmadi et al.

-

on the cognitive debriefing results was prepared to make items easier for the target populations to understand.

Proof reading: Orthographic and syntax changes were made, as needed.

Final report: The process of cultural adaptation of the SCAS was reported to facilitate transferring the experience acquired during this endeavor to others.

Results Table 1 shows the 38 main items of the final version of the SCAS-C-Malay. The SCAS-P items are the same as those in the child version, and so are not mentioned here.

The professionally-checked SCAS-Malay adequately represented each domainâ&#x20AC;&#x2122;s items and the theoretical rationale of the original SCAS. Moreover, the construct would likely be valid in Malaysia.

Table 1 - SCAS original items and corresponding SCAS-Malay items

Domains

Original items

Malay items

Separation anxiety

I would feel afraid of being on my own at home.

Saya akan berasa takut untuk berseorangan di rumah.

I worry about being away from my parents.

Saya bimbang untuk berjauhan daripada ibu bapa.

I worry that something awful will happen to someone in my family.

Saya bimbang untuk sesuatu perkara buruk berlaku terhadap salah seorang ahli keluarga saya.

I feel scared if I have to sleep on my own.

Saya berasa takut jika saya terpaksa tidur sendirian.

I have trouble going to school in the mornings because I feel nervous or afraid.

Saya mengalami masalah pergi ke sekolah pada waktu pagi kerana saya berasa gemuruh dan takut.

I would feel scared if I had to stay away from home overnight.

Saya rasa takut jika saya terpaksa berjauhan dari rumah saya semalaman.

I feel scared when I have to take a test.

Saya berasa takut apabila saya perlu menduduki ujian.

I feel afraid if I have to use public toilets or bathrooms.

Saya takut jika saya terpaksa menggunakan tandas awam atau bilik mandi.

I feel afraid that I will make a fool of myself in front of people.

Saya berasa takut jika saya akan membodohkan diri saya sendiri di hadapan orang.

I worry that I will do badly at my school work.

Saya bimbang jika saya melaksanakan tugasan di sekolah saya dengan teruk.

I worry what other people think of me.

Saya berasa bimbang tentang apa yang orang lain fikir tentang diri saya.

I feel afraid if I have to talk in front of my class.

Saya rasa takut jika saya terpaksa bercakap di hadapan kelas.

I worry about things.

Saya bimbang terhadap banyak perkara.

When I have a problem, I get a funny feeling in my stomach.

Apabila saya ada masalah, perut saya menjadi tidak selesa.

I feel afraid.

Saya berasa takut.

When I have a problem, my heart beats really fast.

Apabila saya menghadapi masalah, jantung saya berdegup kencang.

I worry that something bad will happen to me.

Saya bimbang jika sesuatu yang buruk akan berlaku kepada saya.

When I have a problem, I feel shaky.

Apabila saya ada masalah, saya rasa menggigil.

I suddenly feel as if I canâ&#x20AC;&#x2122;t breathe when there is no reason for this.

Saya berasa seolah-olah sesak nafas secara tiba-tiba walaupun tanpa sebab.

I suddenly start to tremble or shake when there is no reason for this.

Saya tiba-tiba menjadi gementar atau menggigil tanpa apa-apa sebab.

All of a sudden I feel really scared for no reason at all.

Tiba-tiba saya merasa sangat takut tanpa sebarang sebab sama sekali.

I suddenly become dizzy or faint when there is no reason for this.

Saya rasa pening atau hendak pengsan secara tiba-tiba tanpa sebab.

My heart suddenly starts to beat too quickly for no reason.

Jantung saya tiba-tiba berdegup kencang tanpa sebab.

I worry that I will suddenly get a scared feeling when there is nothing to be afraid of.

Saya bimbang jika tiba-tiba saya merasa takut tanpa ada sebarang perkara untuk ditakuti.

I feel scared if I have to travel in the car, or on a bus or a train.

Saya berasa takut jika saya perlu berjalan menaiki kereta, bas atau kereta api.

I am afraid of being in crowded places (like shopping centers, the movies, buses, busy playgrounds).

Saya takut untuk berada di tempat sesak (contohnya pasar raya, pawagam, bas, taman permainan yang sesak).

I am afraid of being in small closed places, like tunnels or small rooms.

Saya takut berada di tempat kecil dan tertutup seperti, terowong atau bilik kecil.

Social phobia

Generalized anxiety disorder

Panic attack agoraphobia

Trends Psychiatry Psychother. 2015;37(1) â&#x20AC;&#x201C; 39

Cross-cultural adaptation of SCAS to Malay - Ahmadi et al.

Physical injury fears

Positive fillers

Obsessive-compulsive disorders

I am scared of the dark.

Saya takutkan gelap.

I am scared of dogs.

Saya takut anjing.

I am scared of going to the doctors or dentists.

Saya takut berjumpa dengan doktor atau doktor gigi.

I am scared of being in high places or lifts (elevators).

Saya takut untuk saya berada di tempat tinggi atau di dalam lif.

I am scared of insects or spiders.

Saya takut kepada serangga atau labah-labah.

I am popular amongst other kids my own age.

Saya dikenali ramai dalam kalangan kawan yang sebaya dengan saya.

I am good at sports.

Saya berkebolehan tinggi dalam bidang sukan.

I am a good person.

Saya seorang budak yang baik.

I feel happy.

Saya berasa gembira.

I like myself.

Saya suka pada diri saya.

I am proud of my school work.

Saya bangga dengan kerja sekolah saya.

I have to keep checking that I have done things right (like the switch is off, or the door is locked).

Saya perlu sentiasa memastikan saya telah melakukan perkara dengan betul (seperti telah menutup suis, atau telah mengunci pintu).

I canâ&#x20AC;&#x2122;t seem to get bad or silly thoughts out of my head.

Saya berasa tidak berupaya untuk mengeluarkan pemikiran buruk daripada minda saya.

I have to think of special thoughts to stop bad things from happening (like numbers or words).

Saya terpaksa memikirkan sesuatu yang istimewa (seperti nombor dan perkataan) untuk menghentikan sesuatu perkara yang buruk daripada berlaku.

I have to do some things over and over again like washing my hands, cleaning or putting things in a certain order).

Saya perlu melakukan sesuatu perkara secara berulangulang (basuh tangan, mengemas atau menyusun barang di tempat tertentu).

I get bothered by bad or silly thoughts or pictures in my mind.

Saya rasa terganggu dengan pemikiran atau gambaran yang buruk atau bodoh dalam fikiran saya.

I have to do some things in just the right way to stop bad things happening.

Saya perlu melakukan perkara dengan betul untuk menghentikan perkara buruk daripada berlaku.

Discussion The final version of the instrument is shown in Table 1. The constructs and symptoms assessed by Malay SCAS, based on the DSM-IV, referred to separation anxiety disorder, social phobia, obsessive-compulsive disorder, panic disorder and agoraphobia, generalized anxiety disorder, and specific phobias, and were the same as those found in the original SCAS.33,34 This study described the process of translation and cross-

An important step in the translation and adaptation process is the selection of experienced translators fluent in both languages to achieve a fault-free instrument.36 In our project, none of the translators except one received financial support for their academic work. Therefore, the process of adaptation took about 4 months, mainly because all experts invited for the evaluation phase were university lecturers. In conclusion, financial issues may impose time constraints on the adaptation process,37 a problem that may also be seen in other studies that

cultural adaptation of SCAS into Malay using the method prescribed by the TCA group for cross-cultural adaptation of self-report questionnaires.31 One of the advantages of this approach lies in its wide and simple applicability and the detailed guide and methodological rigor for each phase of the adaptation process. This method focuses more on semantic and conceptual equivalences than on detailed linguistic issues, which may lead to low content validity.35 To our knowledge, this is the first translation of SCAS to Malay. The Malay version followed the six-domain structure of the original SCAS and included 38 items. Therefore, construct validity of this instrument is equivalent to that of its original English version.

focused on the adaptation of SCAS to other languages, such as Brazilian Portuguese.15 Malaysia has a young population, and the rate of anxiety among the young has increased.38 This trend requires preventive interventions and on-time screening and treatment, which may be more scientifically conducted and are easier and faster when using standard instruments. The SCAS-Malay is the first instrument based on the DSM-IV criteria to measure childrenâ&#x20AC;&#x2122;s anxiety (overall score and six domains of anxiety) in the Malay context. Future cross-cultural studies in community or academic settings may benefit from it. It may also be used in clinical settings to follow up patients or to assess the frequency and severity of anxiety disorders.

40 â&#x20AC;&#x201C; Trends Psychiatry Psychother. 2015;37(1)

Cross-cultural adaptation of SCAS to Malay - Ahmadi et al.

Acknowledgements The authors would like to thank the Ministry of Higher Education (MOHE) and the Research Management Centre (RMC), Universiti Teknologi Malaysia (UTM) for financial support of this research (institutional grant no. VOT 4F304).

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Keeton CP, Kolos AC, Walkup JT. Pediatric generalized anxiety disorder: epidemiology, diagnosis, and management. Paediatr Drugs. 2009;11:171-83.

Liu J, Chen X, Lewis G. Childhood internalizing behaviour: analysis and implications. J Psychiatr Ment Health Nurs. 2011;18:884-94.

Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.

Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, Cui L, et al. Lifetime prevalence of mental disorders in US adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49:980-9.

Gill JS, Koh OH, Pillai SK. Anxiety disorders among incarcerated drug users [Internet]. Malays J Psychiatry eJ. 2010;19 [cited 2014 Dec 16]. http://www.mjpsychiatry.org/index.php/mjp/ article/view/72 Cramer V, Torgersen S, Kringlen E. Quality of life and anxiety disorders: a population study. J Nerv Ment Dis. 2005;193:196-202.

Grover RL, Ginsburg GS, Ialongo N. Psychosocial outcomes of anxious first graders: a 7-year follow-up. Depress Anxiety.

2007;24:410-20.

Reuschel LM. Generalized anxiety disorder in children and adolescents: implication for research and practice [Internet].

2011 Apr [cited 2014 Dec 16]. http://psychology.illinoisstate. edu/cc/Comps/Reuschel%20-%20GAD.pdf Ezpeleta L, Keeler G, Erkanli A, Costello EJ, Angold A. Epidemiology of psychiatric disability in childhood and adolescence. J Child Psychol Psychiatry. 2001;42:901-14.

Beesdo K, Pine DS, Lieb R, Wittchen HU. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Arch Gen Psychiatry. 2009;67:47-57.

Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, Poulton R. Prior juvenile diagnoses in adults with mental disorder: developmental follow-back of a prospective-longitudinal cohort.

Arch Gen Psychiatry. 2003;60:709-17.

Zimmermann P, Wittchen HU, Höfler M, Pfister H, Kessler RC, Lieb R. Primary anxiety disorders and the development of subsequent alcohol use disorders: a 4-year community study of adolescents and young adults. Psychol Med. 2003;33:1211-22.

Emmelkamp P, Wittchen HU. Specific phobias. In: Andrews G, Charney DS, Sirovatka PJ, Regier DA, editors. Stress-induced and fear circuitry disorders: Refining the research agenda for DSM-V. Arlington: American Psychiatric Association; 2009. p. 77-101.

Konnopka A, Leichsenring F, Leibing E, König HH. Cost-of-illness studies and cost-effectiveness analyses in anxiety disorders: a systematic review. J Affect Disord. 2009;114:14-31.

DeSousa DA, Petersen CS, Behs R, Manfro GG, Koller SH. Brazilian Portuguese version of the Spence Children’s Anxiety Scale (SCASBrasil). Trends Psychiatry Psychother. 2012;34:147-53.

Muris P, Merckelbach H, Ollendick T, King N, Bogie N. Three traditional and three new childhood anxiety questionnaires: their reliability and validity in a normal adolescent sample. Behav Res Ther. 2002;40:753-72.

Spence SH. A measure of anxiety symptoms among children.

Behav Res Ther. 1998;36:545-66.

Sidik SM, B Arroll, Goodyear-Smith F. Validation of the GAD-7 (Malay version) among women attending a primary care clinic in Malaysia. J Prim Health Care. 2012:4:5-11.

Quek KF, Low WY, Razack AH, Loh CS, Chua CB. Reliability and validity of the Spielberger State-Trait Anxiety Inventory (STAI) among urological patients: a Malaysian study. Med J Malaysia.

2004;59:258-67.

20. Ramli M, Ariff MF, Zaini Z. Translation,validation and psychometric properties of Bahasa Malaysia version of the Depression Anxiety and Stress Scales (DASS). ASEAN J Psychiatry. 2007;8:82-9.

21. Orgilés M, Spence SH, Marzo JC, Méndez X, Espada JP. Psychometric properties and factorial structure of the Spence Children’s Anxiety Scale (SCAS) in Spanish adolescents. J Pers Assess. 2014;96:95-102.

22. Nauta MH, Scholing A, Rapee RM, Abbott M, Spence SH, Waters A. A parent-report measure of children’s anxiety: psychometric properties and comparison with child-report in a clinic and normal sample. Behav Res Ther. 2004;42:813-39.

23. Essau CA, P Muris, Ederer EM. Reliability and validity of the Spence Children’s Anxiety Scale and the Screen for Child Anxiety Related emotional disorders in German children. J Behav Ther Exp Psychiatry. 2002;33:1-18.

24. Mellon RC, Moutavelis AG. Structure, developmental course, and correlates of children’s anxiety disorder-related behavior in a Hellenic community sample. J Anxiety Disord. 2007;21:1-21.

25. Hernández-Guzmán L, Bermúdez-Ornelas G, Spence SH, González MJ, Martínez-Guerrero JI, Aguilar J, et al. Spanish version of the Spence Children’s Anxiety Scale (SCAS). Rev Latinoam Psicol.

2010;42:13-24.

26. Ishikawa S, Sato H, Sasagawa S. Anxiety disorder symptoms in Japanese children and adolescents. J Anxiety Disord.

2009;23:104-11.

27. Essau CA, Anastassiou-Hadjicharalambous X, Muñoz LC. Psychometric properties of the Spence Children’s Anxiety Scale (SCAS) in Cypriot children and adolescents. Child Psychiatry Hum Dev. 2011;42:557-68.

28. Essau CA, Sasagawa S, Anastassiou-Hadjicharalambous X, Guzmán BO, Ollendick TH. Psychometric properties of the Spence Child Anxiety Scale with adolescents from five European countries. J Anxiety Disord. 2011;25:19-27.

29. da Silva WV, de Figueiredo VL. [Childhood anxiety and assessment instruments: a systematic review]. Rev Bras Psiquiatr.

2005;27:329-35.

30. Spence SH. Structure of anxiety symptoms among children: a confirmatory factor-analytic study. J Abnorm Psychol.

1997;106:280-97.

31. Wild D, Grove A, Martin M, Eremenco S, McElroy S, VerjeeLorenz A, et al. Principles of good practice for the translation and cultural adaptation process for patient‐reported outcomes (PRO) measures: report of the ISPOR Task Force for Translation and Cultural Adaptation. Value Health. 2005;8:94-104.

32. Spanemberg L, Parker G, Caldieraro MA, Vares EA, Costa F, Costa MM, et al. Translation and cross-cultural adaptation of the Temperament & Personality Questionnaire into Brazilian Portuguese. Trends Psychiatry Psychother. Epub 2014 Aug 12.

33. Manfro GG, Isolan L, Blaya C, Santos L, Silva M. Estudo retrospectivo da associação entre transtorno de pânico em adultos e transtorno de ansiedade na infância. Rev Bras Psiquiatr.

2002;24:26-9.

34. Manfro GG, Isolan L, Blaya C, Maltz S, Heldt E, Pollack MH. Relationship between adult social phobia and childhood anxiety.

Rev Bras Psiquiatr. 2003;25:96-9.

35. Baeza FL, Caldieraro MA, Pinheiro DO, Fleck MP. Translation and cross-cultural adaptation into Brazilian Portuguese of the Measure of Parental Style (MOPS)-a self-reported scale-according to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) recommendations. Rev Bras Psiquiatr.

2010;32:159-63.

36. Wang WL, Lee HL, Fetzer SJ. Challenges and strategies of instrument translation. West J Nurs Res. 2006;28:310-21.

37. Gjersing L, Caplehorn JR, Clausen T. Cross-cultural adaptation of research instruments: language, setting, time and statistical considerations. BMC Med Res Methodol. 2010;10:13.

38. Krishnaswamy S, Subramaniam K, Jemain AZ, Low WY, Ramachandran P, Indran T, et al. Common mental disorders in Malaysia: Malaysian mental health survey, 2003-2005. Asia Pac Psychiatry. 2012;4:201-9.

Correspondence: Mohamed Sharif Mustaffa Counseling Center, University Technology Malaysia 81300 - Skudai, Johor, Malaysia Tel.: 0060197386428 E-mail: p-sarif@utm.my

Trends Psychiatry Psychother. 2015;37(1) – 41

Trends

Original Article

in Psychiatry and Psychotherapy

Translation and cross-cultural adaptation of the Brazilian Portuguese version of the Driving Anger Scale (DAS): long form and short form Tradução e adaptação transcultural da versão brasileira da Driving Anger Scale (DAS): forma longa e forma curta Jessye Almeida Cantini,1 George Oliveira Santos,1 Eduardo de Carvalho Machado,1,2 Antonio Egídio Nardi,1 Adriana Cardoso Silva1

Abstract

Resumo

Introduction: Driving anger has attracted the attention of researchers in recent years because it may induce individuals to drive aggressively or adopt risk behaviors. The Driving Anger Scale (DAS) was designed to evaluate the propensity of drivers to become angry or aggressive while driving. This study describes the cross-cultural adaptation of a Brazilian version of the short form and the long form of the DAS. Methods: Translation and adaptation were made in four steps: two translations and two back-translations carried out by independent evaluators; the development of a brief version by four bilingual experts in mental health and driving behaviors; a subsequent experimental application; and, finally, an investigation of operational equivalence.

Results: Final Brazilian versions of the short form and of the long form of the DAS were made and are presented.

Conclusions: This important instrument, which assesses driving anger and aggressive behaviors, is now available to evaluate the driving behaviors of the Brazilian population, which facilitates research in this field.

Keywords: Cross-cultural adaptation, psychometrics, automobile vehicles, automobile driving.

Introdução: A raiva na direção de veículos tem atraído a atenção de pesquisadores nos últimos anos, pois pode induzir as pessoas a dirigirem agressivamente ou a adotarem comportamentos de risco. A Driving Anger Scale (DAS) foi criada a fim de avaliar a propensão de motoristas a se tornarem agressivos ou raivosos enquanto dirigem. Este estudo descreve a adaptação transcultural de uma versão brasileira da forma longa e da forma curta da DAS. Método: O processo consistiu em quatro passos: duas traduções e duas retrotraduções elaboradas por avaliadores independentes; elaboração de uma versão sintética por quatro especialistas em saúde mental e comportamentos na direção bilíngues; posterior aplicação experimental; e, finalmente, investigação da equivalência operacional.

Resultados: Foram definidas e são apresentadas as versões finais da forma longa e da forma curta da DAS em português brasileiro.

Conclusões: Este importante instrumento, que mensura a raiva na direção e comportamentos agressivos, está agora disponível para avaliar os comportamentos na direção da população brasileira, facilitando a pesquisa nesse campo de estudo.

Descritores: Adaptação transcultural, psicometria, veículos automotores, condução de veículos.

Introduction

recent years, because it may induce individuals to drive aggressively or adopt risk behaviors.1,2 Dahlen et al.1 found that anger is a personality trait that may explain a variety of risk behaviors. As a personality trait, driving anger may be linked to the

Driving may trigger many emotions in individuals, such as satisfaction, fear, anxiety and anger. Anger in particular has attracted the attention of researchers in

Panic & Respiration Laboratory, Institute of Psychiatry, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil. 2 Physical Activity Neuroscience Laboratory, Graduate Program in Physical Activity Sciences, Universidade Salgado de Oliveira (UNIVERSO), Niterói, RJ, Brazil.

1

Financial support: none.

Submitted Apr 03 2014, accepted for publication Nov 25 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Cantini JA, Santos GO, Machado EC, Nardi AE, Silva AC. Translation and cross-cultural adaptation of the Brazilian Portuguese version of the Driving Anger Scale (DAS): long form and short form. Trends Psychiatry Psychother. 2015;37(1):42-46. http://dx.doi.org/10.1590/2237-6089-2014-0008 © APRS

Trends Psychiatry Psychother. 2015;37(1) – 42-46

Brazilian version of DAS - Cantini et al.

propensity to become aggressive or angry while driving and may be analyzed especially when individuals with and without this trait are compared.3,4 Deffenbacher et al.5 developed the Driving Anger Scale (DAS) to evaluate the propensity of drivers to become angry or aggressive while driving. This instrument has been used in many studies around the world, and findings have suggested that there is a positive association between risk behaviors and driving aggression.6 Moreover, Sullman & Stephens1 found that the DAS is able to identify situations that might lead to accidents.

There are two versions of the DAS: the short form and the long form. The short version is one-dimensional and consists of 14 items. The 33-item long version is divided into six subscales: discourtesy (9 items), illegal driving

instruments, and the other two were specialists on driving behavior. Comparisons between the translations, back-translations and the original content of the DAS were made to examine the equivalence of the texts. A synthetic version of each item of the instrument was created from the comparison between the translations and the original statement. To examine the synthetic version and the partial translations (T1, T2, B1 and B2), please write to the corresponding author (contact details at the end of the paper).

After this step, the Brazilian version of the DAS was applied experimentally to assess whether it was understood by individuals in the general Brazilian population. This version of the scale was answered by 15 adults (10 men and 5 women). All were able to drive and had different educational levels: 5 had university

(4 items), hostile gestures (3 items), slow driving (6 items), traffic obstruction (7 items) and police presence (4 items). In both versions, respondents should imagine the incidents described and grade the anger level that each situation would induce. The DAS uses a 5-point Likert-like scale (not at all, a little, some, much and very much). The DAS short form yields a single score and is useful for a brief evaluation of driving anger. The DAS long form, in turn, provides specific data about each of its subscales and may be more useful when a detailed data analysis is needed.

The psychometric properties of the 14-item version of the DAS show an alpha reliability between 0.80 and 0.92. Studies examining the 10-week test-retest reliability found an alpha of 0.84.5,7,8 The 33-item version has an alpha reliability of 0.90.8 This study describes the cultural adaptation of the two DAS versions for the Brazilian population.

degrees, 5 had completed secondary education and 5 had completed primary education.

This study was approved by the Research Ethics Committee of the Institute of Psychiatry of Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil (CAAE protocol no. 0028.0.249.000-07). All respondents involved in the experimental application of the Brazilian Portuguese version of the DAS were informed of the objectives of the study and signed an informed consent form.

Results

Methods

When preparing the synthetic version, the experts sometimes considered one of the translations and often considered a combination of the two translations.

The two translations were occasionally similar, and in such cases, both versions were used. For some items, changes were made to the sentences suggested by the translators to improve the semantic equivalence between

Permission to cross-culturally adapt the scale for Brazilian Portuguese was requested from the original author of the DAS. After his permission was obtained, we began a four-step process based on the model proposed by Herdman et al.9 The steps were: translation, back-translation, semantic equivalence analysis and experimental application.

The translation was made by two independent bilingual translators (T1 and T2) that had no previous contact with the scale. After that, two other translators performed a back-translation from Brazilian Portuguese to English (B1 and B2).

The semantic equivalence analysis was performed by four bilingual mental health experts: two of the experts had a vast knowledge of specific psychometric

the questions in the original scale and in the Brazilian version of the DAS. The specialists identified several items that might be misunderstood. When there was any question about the meaning of an item, the original author was consulted for an additional explanation to preserve the semantic characteristics of the original instrument. In the items “Someone in front of you does not start up when the light turns green” and “Someone runs a red light or stop sign,” the specialists realized that the term “lights” could be translated in different ways (“luz,” “sinal de trânsito,” “semáforo,” “sinaleira”). The authors decided to keep the structure “sinal de trânsito (semáforo/sinaleira)” when referring to the term “lights” to reduce the chances of comprehension problems due to the many linguistic variations within the Brazilian territory. Furthermore, the Trends Psychiatry Psychother. 2015;37(1) – 43

Brazilian version of DAS - Cantini et al.

term “mountain road” in the question “A slow vehicle on a mountain road will not pull over and let people by” was translated as “estrada de montanha,” but we decided to use the term “serra” instead.

In general, the respondents of the experimental application of the Brazilian Portuguese version of the DAS had no problems understanding the questionnaire. However, for the questions “You pass a radar speed trap” and “A police officer pulls you over,” two individuals questioned the contextual conditions, that is, whether they should consider conditions to

be normal, or if there were any changes, such as speeding. To solve this problem, a small adjustment was made to the statement.

After performing these changes, the DAS was administered again using 5 new respondents of both sexes and different educational levels. According to these results, we believe that the Brazilian version of the DAS is suitable to be used in studies about driving behaviors and anger of Brazilian drivers.

The final versions of the scale in Brazilian Portuguese are presented in Tables 1 and 2.

Table 1 - The Driving Anger Scale (long form) in Brazilian Portuguese Descrição: Abaixo estão várias situações que você pode encontrar quando está dirigindo em situações consideradas normais. Tente imaginar que os incidentes descritos estão realmente acontecendo com você, e então indique a intensidade de raiva que cada situação provocaria em você. Marque sua resposta preenchendo o quadrado correspondente à direita.

Nada 1. Alguém à sua frente não avança quando o sinal (semáforo/sinaleira) verde acende.

2. Alguém está dirigindo rápido demais para as condições da via.

3. Um pedestre caminha lentamente pelo meio da rua, retardando você.

4. Alguém está dirigindo muito lentamente num trecho de ultrapassagem, retendo todo o trânsito.

5. Alguém está dirigindo muito próximo a seu parachoque traseiro.

6. Alguém está “costurando” o trânsito.

7. Alguém lhe corta na autoestrada.

8. Alguém lhe corta e toma a vaga de estacionamento que você estava esperando.

9. Alguém está dirigindo mais devagar do que o razoável para o fluxo do trânsito.

10. Um veículo lento na subida da serra não oferece passagem para os demais motoristas passarem.

11. Você vê um carro da polícia observando o trânsito em um esconderijo.

12. Alguém dá marcha ré em sua direção sem olhar.

13. Alguém avança o sinal (semáforo/sinaleira) vermelho ou a placa de “pare”.

14. Alguém vindo em sua direção à noite não reduz os faróis.

15. À noite, alguém está dirigindo atrás de você com farol alto.

16. Você passa por um radar de velocidade.

17. Alguém aumenta a velocidade quando você tenta ultrapassá-lo.

18. Alguém demora ao estacionar, atrasando o trânsito.

19. Você está preso no congestionamento.

20. Em uma via com várias faixas, alguém te corta quando não há ninguém atrás de você.

21. Alguém faz um gesto obsceno para você por causa da sua maneira de dirigir.

22. Você atinge um buraco profundo não sinalizado.

23. Um carro de polícia está dirigindo no trânsito perto de você.

24. Alguém buzina para você por causa da sua maneira de dirigir.

25. Alguém está dirigindo além do limite de velocidade.

26. Você está dirigindo atrás de um caminhão que tem material oscilando em sua traseira.

27. Alguém grita com você por causa da sua maneira de dirigir.

28. Um ciclista está andando no meio da pista e congestionando o trânsito.

29. Um policial manda você encostar.

30. Você está dirigindo atrás de um veículo que está soltando muita fumaça.

31. Um caminhão joga areia ou cascalho no carro que você está dirigindo.

32. Você está dirigindo atrás de um caminhão grande e não consegue ver ao redor dele.

33. Você se depara com construções e desvios na estrada.

44 – Trends Psychiatry Psychother. 2015;37(1)

Pouca

Razoável Muita Muitíssima

Brazilian version of DAS - Cantini et al.

Table 2 - The Driving Anger Scale (short form) in Brazilian Portuguese Descrição: Abaixo estão várias situações que você pode encontrar quando está dirigindo em situações consideradas normais. Tente imaginar que os incidentes descritos estão realmente acontecendo com você, e então indique a intensidade de raiva que cada situação provocaria em você. Marque sua resposta preenchendo o quadrado correspondente à direita.

Nada

Pouca

Razoável

Muita

Muitíssima

1. Alguém está “costurando” o trânsito.

2. Um veículo lento na subida da serra não oferece passagem para os demais motoristas passarem.

3. Alguém dá marcha ré em sua direção sem olhar.

4. Você passa por um radar de velocidade.

5. Alguém faz um gesto obsceno para você por causa da sua maneira de dirigir.

6. Um policial manda você encostar.

7. Um caminhão joga areia ou cascalho no carro que você está dirigindo.

8. Alguém avança o sinal de trânsito (semáforo/sinaleira) vermelho ou a placa de “pare”.

9. Alguém buzina para você por causa da sua maneira de dirigir.

10. Você está dirigindo atrás de um caminhão grande e não consegue ver ao redor dele.

11. Um ciclista está andando no meio da pista e congestionando o trânsito.

12. Você está preso no congestionamento.

13. Alguém aumenta a velocidade quando você tenta ultrapassá-lo.

14. Alguém demora ao estacionar, atrasando o trânsito.

Discussion Driving anger has been extensively studied in the past ten years, and its impact on individual behavior may affect road safety.10 According to the American Automobile Association,8 in the early 1990s, aggressive driving behaviors were responsible for about 200 deaths and 12,000 traffic accidents. Furthermore, one in two serious accidents was due to aggressive driving behaviors.10 For every accident resulting from aggressive actions, there may be numerous other instances of anger in traffic, such as driving too close to the back of another car, angrily cutting off other vehicles and making offensive gestures.8 Driving anger may also be induced by environmental conditions, such as the driver’s anonymity and congested or heavy traffic.7 Moreover, individual characteristics may be important factors in inducing rage while driving.

Some authors1,5,7 have found that individuals differ in their tendencies to become angry or aggressive when provoked or when feeling frustrated while driving. This finding suggests that anger may be a personality trait that leads to greater intolerance to certain situations, thereby causing aggressive behaviors.

Other instruments, such as the Propensity of Angry Driving Scale (PADS),11 focus on driving anger within the context of the state-trait theory. However, in addition to assessing anger as a personality trait in drivers, the DAS is unique in that it also identifies situations in which accidents almost occurred.2

Working with two translators and two backtranslators during cross-cultural adaptation of the DAS helped the team of experts reach a satisfactory semantic equivalence to the original instrument. This method also ensured that the differences between the two versions were discussed to define appropriate translations.

The analysis of the experimental application revealed that the questions of the Brazilian version of the DAS were understood by individuals of any educational level. However, small adjustments were made to solve interpretation problems raised by the situational context in some items. Having made these changes, we believe that the instrument is now suitable for research about driving anger in the general Brazilian population.

Cross-cultural adaptation is important when translating an instrument originally created in another language.12 The DAS has satisfactory psychometric properties, has been adapted and validated in several countries and has been used in many studies with diverse samples of individuals with driving anger and aggressive behaviors.2,6,13,14 The Brazilian version of the DAS may significantly contribute to this field of study in Brazil. Future studies should assess the validity and reliability of this instrument.

Conclusion This study described the cross-cultural adaptation of the long and short forms of the DAS to Brazilian Portuguese. Four steps were followed, according to the Trends Psychiatry Psychother. 2015;37(1) – 45

Brazilian version of DAS - Cantini et al.

recommendations found in the literature: translation, back translation, semantic equivalence analysis and experimental application. The semantic equivalence between the original scale and the Brazilian Portuguese version was satisfactory. Therefore, this important instrument, which assesses driving anger and aggressive behaviors, has proven to be adequate for use in the Brazilian population. This finding fills a significant gap in this field of study and may contribute to the development of future studies about driving behaviors.

References 1.

2.

3.

4.

5.

6.

Dahlen ER, Martin RC, Ragan K, Kuhlman MM. Driving anger, sensation seeking, impulsiveness and boredom proneness in the prediction of unsafe driving. Accid Anal Prev. 2005;37:341-8.

Sullman MJM, Stephens AN. A comparison of the Driving Anger Scale and the Propensity of Angry Driving Scale. Accid Anal Prev.

2013;58:88-96.

Deffenbacher JL, Deffenbacher DM, Lynch RS, Richards TL. Anger, aggression and risky behavior: a comparison of high and low anger drivers. Behav Res Ther. 2003;41:701-18.

Dahlen ER, Ragan KM. Validation of the Propensity for Angry Driving Scale. J Safety Res. 2004;35:557-63.

Deffenbacher JL, Oetting ER, Lynch RS. Development of a Driver Anger Scale. Psychol Rep. 1994;74:83-91.

Villieux A, Delhomme P. Driving Anger Scale, French adaption: further evidence of reliability and validity. Percept Motor Skills.

2007;104:947-57.

46 – Trends Psychiatry Psychother. 2015;37(1)

7.

8.

9.

10.

11.

12.

13.

14.

Deffenbacher JL, Huff ME, Lynch RS, Oetting ER, Salvatore NF. Characteristics and treatment of high-anger drivers. J Couns Psychol. 2000;47:5-17.

Deffenbacher JL, Lynch RS, Oetting ER, Yingling DA. Driving anger: correlates and a test of state-trait theory. Pers Indiv Differ.

2001;31:1321-31.

Herdman M, Fox-Rushby J, Badia X. A model of equivalence in the cultural adaptation of HRQol. instruments: the universalist approach. Qual Life Res. 1998;7:323-35.

Deffenbacher JL, Lynch RS, Oetting ER, Swaim RC. The Driving Anger Expression Inventory: a measure of how people express their anger on the road. Behav Res Ther. 2002;40:717-37.

DePasquale JP, Geller ES, Clarke SW, Littleton LC. Measuring road rage: development of the Propensity for Angry Driving Scale. J Safety Res. 2001;32:1-16.

Gserjing, L, Caplehorn, JR, Clausen, T. Cross-cultural adaptation of research instruments: language, setting, time and statistical considerations. BMC Med Res Methodol. 2010;10:13.

Lajunen T, Parker D. Are aggressive people aggressive drivers?

A study of the relationship between self-reported general aggressiveness, driver anger and aggressive driving. Accid Anal Prev. 2001;33:243-55.

Iverson H, Rundmo T. Personality risky driving and accident involvement among Norwegian drivers. Pers Indiv Dif. 2002;33:1251-63.

Correspondence: Jessye Almeida Cantini Laboratório de Pânico e Respiração – IPUB/ UFRJ Rua Visconde de Pirajá, 407/702 22410-003 - Rio de Janeiro, RJ - Brazil Tel.: +55 (21) 7941.2626 E-mail: jessyecantini@yahoo.com.br

Trends

Case Report

in Psychiatry and Psychotherapy

Managing severe behavioral symptoms of a patient with anti-NMDAR encephalitis: case report and findings in current literature Manejo de sintomas comportamentais severos em um paciente com encefalite anti-NMDAR: relato de caso e literatura atual Vanina Lima Monteiro,1 Felipe José Nascimento Barreto,1 Paulo Marcos Brasil Rocha,1 Paulo Henrique Teixeira do Prado,1 Frederico Duarte Garcia,2 Humberto Correa,2 Maila Castro Lourenço das Neves2 Abstract

Resumo

Objective: Psychiatric symptoms emerge in the early stages of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, and patients often seek treatment in psychiatric departments before visiting any other general medical services. Numerous articles about anti-NMDAR encephalitis have been published in the scientific community worldwide, but few emphasize the role of psychiatry in symptom management.

Case description: We describe the case of a patient with anti-NMDAR encephalitis seen in our service and discuss the management of behavioral symptoms based on current scientific literature. High doses of atypical antipsychotics and benzodiazepines were used to control agitation, and trazodone was administered to treat insomnia.

Comments: Consultation-liaison psychiatry may help the healthcare team adjust the management of neuropsychiatric complications that might affect inpatients with anti-NMDAR encephalitis.

Keywords: Anti-NMDAR encephalitis, consultation-liaison psychiatry, behavioral symptoms.

Objetivo: Sintomas psiquiátricos surgem em estágios precoces da encefalite antirreceptor N-metil-D-aspartato (NMDAR), o que faz muitos pacientes procurarem tratamento em serviços de psiquiatria antes de se dirigirem a unidades de clínica geral. Embora muitos artigos sobre encefalite anti-NMDAR venham sendo publicados na comunidade científica internacional, poucos enfatizam o papel do psiquiatra no seu manejo sintomatológico.

Descrição do caso: O presente artigo relata o caso de um paciente que desenvolveu encefalite anti-NMDAR em nosso serviço e discute manejo de alterações comportamentais com base na literatura científica atual. Altas doses de antipsicóticos atípicos e benzodiazepínicos foram usados para controle de agitação, e trazodona foi utilizada para tratar insônia.

Comentários: A interconsulta psiquiátrica pode ajudar no ajuste de condutas de toda a equipe assistente para as complicações neuropsiquiátricas que possam surgir na evolução de pacientes internados por encefalite anti-NMDAR. Descritores: Encefalite anti-NMDAR, interconsulta psiquiátrica, sintomas comportamentais.

Introduction

in the early stages of anti-NMDAR encephalitis, 77% of the patients are not seen in a general healthcare service before seeking treatment in a psychiatric department,4 where this disease may be mistaken for primary psychiatric conditions, such as brief psychosis disorder, drug-induced psychosis or mania.1,5 Moreover, 4% of the patients present with isolated psychiatric symptoms.6 As anti-NMDAR encephalitis is not initially suspected, the treatment of this potentially lethal disorder may be delayed.

The clinical course of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has a myriad of neurological and psychiatric features, such as delusions and hallucinations, but also agitation, disorganized thinking, affective lability and catatonia.1,2 Surprisingly, 7.8% of the patients with schizophrenia or other psychotic disorders have serum antibodies for this disease.3 Because psychiatric symptoms emerge 1

Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.

2

Mental Health Department, UFMG, Belo Horizonte, MG, Brazil.

Financial support: none.

Submitted Aug 17 2014, accepted for publication Oct 09 2014. No conflicts of interest declared concerning the publication of this article.

Suggested citation: Monteiro VL, Barreto FJ, Rocha PM, Prado PH, Garcia FD, Correa H, et al. Managing severe behavioral symptoms of a patient with anti-NMDAR encephalitis: case report and findings in current literature. Trends Psychiatry Psychother. 2015;37(1):47-50. http://dx.doi.org/10.1590/2237-6089-2014-0036.

Epub Jan 30, 2015. © APRS

Trends Psychiatry Psychother. 2015;37(1) – 47-50

Severe behavioral symptoms in anti-NMDAR encephalitis - Monteiro et al.

To this date, numerous articles about anti-NMDAR encephalitis have been published in the scientific community worldwide,1,2,4,7 but few emphasize the role of psychiatrists in the management of this disease while clinical signs and symptoms persist without remission. Furthermore, there is still little information about the pharmacological options for the treatment of the behavioral symptoms of patients with this disease.8-10 We report the case of a patient with antiNMDAR encephalitis seen in our service and discuss psychiatric symptom management based on current literature. This report was approved by our local ethics committee, and the patient signed an informed consent form.

a wandering gaze, uncooperativeness, normal level of consciousness, global disorientation, attention instability, hypervigilance, labile affect, disaggregated thinking, scarce speech, neologisms, no evidence of delusional activity, no changes on sensory perception, lack of pragmatism, passive negativism, restlessness, involuntary facial movements and verbal perseveration.

The patient remained under observation. Serial electroencephalograms showed diffuse disorganized electrical activity without epileptiform tracings.

Antinuclear antibody and lupus anticoagulant tests were negative. Chest, abdomen and pelvis CT scans were all normal. As autoimmune limbic encephalitis was suspected as the most likely diagnosis, an autoantibodies panel was performed using new cerebrospinal fluid and

Case description A 30-year-old Brazilian single male computer technician was taken to the hospital by his mother.

Two days before, he had suddenly begun behaving strangely: his speech included meaningless words and alternated with silence, insomnia and restlessness. His history revealed no fever, seizures or recent physical trauma. Substance abuse, exogenous intoxication or previous contact with heavy metals were excluded, as well as personal and family history of psychiatric illnesses. According to his mother, the patient collected old computer parts and did not have many social interactions. Physical and neurological examinations were normal. During the examination, his behavior was restless and unsuitable: he crouched on the floor, stood up, lay down, sat up, pointed to himself and to his examiner alternately, climbed several times on the scales when not requested.

Faced with the possible diagnosis of primary psychosis or behavioral changes secondary to herpetic

blood samples, and test results revealed positivity for anti-NMDAR. With an established diagnosis of anti-NMDAR encephalitis, immunosuppressive treatment was initiated, and a testicle ultrasound was performed, which did not reveal any neoplastic findings. Intravenous (IV) immunotherapy followed the recommendations made

by Dalmau et al.,7 and consisted of methylprednisolone (1 g/day), seven plasmapheresis treatments and immunoglobulin (117.5 g). As there were no satisfactory clinical results, other options were from HD 43 on: cyclophosphamide (1 g/month for 6 months, continuing after hospital discharge), plasmapheresis and rituximab (675 mg/week for 4 weeks).

Before his first psychiatric evaluation, he was taking lorazepam (1 mg/day) and risperidone (3 mg/day) to control episodes of agitation. However, risperidone had to be replaced with quetiapine (50 mg/day) because drug-induced akathisia was suspected. On HD 15, as the patient developed shortterm episodes of autonomic disruption (erythema,

encephalitis, risperidone was prescribed, as well as lorazepam and acyclovir, although the latter was discontinued because the polymerase chain reaction test to detect herpes simplex virus was negative. The patient remained intermittently agitated and his behavior was severely disorganized. One day, he ran towards his bedroom window, almost jumped out of it and had to be restrained by hospital security.

Brain CT and brain MRI results were normal. A basic metabolic panel showed results within normal limits, and his VDRL test was non-reactive. Cerebrospinal fluid analysis revealed only pleocytosis, at 26 cells/mm3.

On the ninth hospital day (HD 9), the consultationliaison psychiatric team began to follow up the patient.

The first examination of his mental state revealed

hyperthermia, tachycardia, tachypnea, hypertension and restlessness), clonidine (0.2 mg/day) was also administered, if necessary. During his first intensive care unit (ICU), lorazepam and quetiapine doses were increased to 15 mg and 700 mg/day from admission to return to the general ward, although benzodiazepines are not recommended when the patient has respiratory failure. In addition, trazodone was introduced gradually to 150 mg/day to improve behavior and sleep. On his second admission to ICU, lorazepam was administered again to avoid the use of drugs to treat agitation, such as propofol. At discharge, on HD 111, psychiatric drugs were quetiapine (75 mg/day), lorazepam (1 mg/day), trazodone (150 mg/day) and prednisone (40 mg/day) (Figure 1).

48 â&#x20AC;&#x201C; Trends Psychiatry Psychother. 2015;37(1)

Severe behavioral symptoms in anti-NMDAR encephalitis - Monteiro et al.

15 mg 700 mg 600 mg

450 mg

400 mg 9 mg

150 mg 1 mg 1 mg

3 mg

150 mg

50 mg

3 mg

150 mg 9 mg

50 mg

1 mg HD 1

HD 6

75 mg 1 mg

HD 15

HD 20 (ICU first time)

Risperidone

HD 39

Quetiapine

HD 45

Lorazepam

HD 55

HD 61 (ICU second time)

HD 111

Trazodone

Figure 1 - Psychotropic drugs used to manage psychomotor agitation from admission to discharge. Improvement of behavioral symptoms started after HD 85. HD = hospital day; ICU = intensive care unit.

Psychomotor agitation, the main psychiatric complication, may reflect conceptual disorganization, autonomic instability, seizures or dyskinesia, each requiring a specific form of management. Because of that, the patient was physically restrained most of the time and received extra doses of sedatives: IM haloperidol (5 mg), IV diazepam (5-10 mg) and IV propofol (30-50 mg).

On a single day, 20 mg/day of diazepam and 2.5 mg/ day of midazolam were administered. Explanations for family and the healthcare team about the characteristics of each complication and the self-limiting nature of restlessness attacks as part of paroxysmal dysautonomia were important to reduce parenteral medication.

During the 111 days that he remained hospitalized, the patient had to be transferred to the ICU twice. First on HD 22, he suddenly developed acute respiratory failure and had to be treated with antibiotics for pneumonia and mechanical ventilation. His breathing pattern gradually improved, he was weaned from mechanical ventilation and returned to the general ward on HD 40. On HD 59, he was transferred to the ICU again due to septic shock secondary to urinary infection. He was treated with vasoactive drugs, mechanical ventilation and antibiotics until he improved clinically, and transferred back to the general ward on HD 87.

From HD 85 on, the patient’s interaction with the examiners gradually improved, as demonstrated by his response to some verbal commands, such as to press and release the examiner’s hand and to stretch and flex his limbs. This outcome was only possible because of the essential involvement of the psychiatry, speech

therapy, physiotherapy, nutrition, occupational therapy and psychology teams, in addition to the neurology team (main clinical assistant).

In the last days of evaluation before discharge, he remained disoriented and reported amnesia during hospitalization. Psychomotor agitation episodes became sparse, controlled due to the verbal support of family members, and autonomic episodes were rare. After discharge, the patient received three more doses of cyclophosphamide. He is currently being followed up in our outpatient service. He still has some degree of apathy, but takes only trazodone (150 mg/day) and prednisone (10 mg/day).

Comments Anti-NMDAR encephalitis requires specific treatment (immunotherapy or tumor removal, when detected) that should be initiated as soon as possible to decrease anti-NMDAR levels and ensure good outcomes. Before these measures have an effect, psychiatric management is crucial to minimize the consequences of psychiatric symptoms for patients and clinical teams.

Only a few case reports of anti-NMDAR encephalitis mention the use of psychotropic drugs, and some describe the doses of the medication used.10-12 Except for catatonia, for which lorazepam and electroconvulsive therapy are well-established treatments,9 no standard drug class, medication or dosage have been defined for anti-NMDAR encephalitis. Low doses of typical

Trends Psychiatry Psychother. 2015;37(1) – 49

Severe behavioral symptoms in anti-NMDAR encephalitis - Monteiro et al.

and atypical agents to treat adult patients have been described in current literature: haloperidol (1-2 mg/day), olanzapine (5 mg/day), aripiprazole (2.5 mg/day) and risperidone (1 mg/day).8,9 In two cases of adolescents, van de Riet et al.13 described the combination of haloperidol and risperidone, but neither the use of low doses nor slow titration prevented both patients from having extrapyramidal side effects.

Risperidone has been suggested as an early treatment for first episode psychotic disorders because it has less frequent extrapyramidal side effects than typical antipsychotics.14 In our case, it was prescribed immediately before quetiapine, because the patient presented with agitation and because akathisia was included in the differential diagnosis. High doses of quetiapine and lorazepam were administered to contain restlessness and were reduced as the patient’s neurological status improved.

Trazodone was a good option to treat insomnia, in agreement with previously reported findings.8,10 Although promethazine and phenothiazine are possible options for sedation,12 their anticholinergic effects may lower the consciousness level and promote delirium.

As consultation-liaison professionals, psychiatrists may help adjust the procedures of the whole healthcare team to treat neuropsychiatric complications that may affect patients with anti-NMDAR encephalitis while hospitalized.13 Non-pharmacological interventions should considered in the treatment of agitation and insomnia, as they may prevent the use of more sedative medications that may expose a patient already at risk of clinical deterioration to harmful, and unnecessary, events. Likewise, dangerous conditions, such as malignant neuroleptic syndrome and respiratory failure, should be seen as confounding factors, as they may be outcomes of the disease itself or adverse drug effects.15 Furthermore, a multidisciplinary approach is essential for the successful treatment of patients with anti-NMDAR encephalitis and the prevention of physical and cognitive sequelae.8,9 This case report contributes information about the psychiatric management of a patient with anti-NMDAR encephalitis, a diagnosis with which psychiatrists should be familiar.

50 – Trends Psychiatry Psychother. 2015;37(1)

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol.

2011;231:86-91.

Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol.

2011;10:63-74.

Pollak TA, McCormack R, Peakman M, Nicholson TR, David AS. Prevalence of anti-N-methyl-d-aspartate (NMDA) antibodies in patients with schizophrenia and related psychoses: a systematic review and meta-analysis. Psychol Med. 2014;44:2475-87.

Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti- NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091-8.

Maneta E, Garcia G. Psychiatric manifestations of anti-NMDA receptor encephalitis: neurobiological underpinnings and differential diagnostic implications. Psychosomatics. 2014;55:37-44.

Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-daspartate receptor encephalitis. JAMA Neurol. 2013;70:1133-9.

Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al.

Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25-36.

Chapman MR, Vause HE. Anti-NMDA receptor encephalitis: diagnosis, psychiatric presentation, and treatment. Am J Psychiatry. 2011;168:245-51.

Mann A, Machado NM, Liu N, Mazin AH, Silver K, Afzal KI. A multidisciplinary approach to the treatment of anti-NMDAreceptor antibody encephalitis: a case and review of the literature.J Neuropsychiatry Clin Neurosci. 2012;24:247-54.

Barry H, Hardiman O, Healy DG, Keogan M, Moroney J, Molnar PP, et al. Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis. Br J Psychiatry. 2011;199:508-9.

Kung DH, Qiu C, Kass JS. Psychiatric manifestations of anti-NMDA receptor encephalitis in a man without tumor. Psychosomatics.

2011;52:82-5.

Kuo YL, Tsai HF, Lai MC, Lin CH, Yang YK. Anti-NMDA receptor encephalitis with the initial presentation of psychotic mania. J Clin Neurosci. 2012;19:896-8.

Van de Riet EH, Esseveld MM, Cuypers L, Schieveld JN. AntiNMDAR encephalitis: a new, severe and challenging enduring entity. Eur Child Adolesc Psychiatry. 2013;22:319-23.

Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU. Efficacy and safety of individual second-generation vs. firstgeneration antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol.

2013;16:1205-18.

Jones KC, Benseler SM, Moharir M. Anti–NMDA receptor encephalitis. Neuroimag Clin N Am. 2013;23:309-20.

Correspondence: Maila Castro Lourenço das Neves Mental Health Department Universidade Federal de Minas Gerais Av. Professor Alfredo Balena, 190/235, Santa Efigênia 30130-100 - Belo Horizonte, MG - Brazil Fax: +55 (31) 3409.9785 E-mail: mailacln@gmail.com

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These texts should be brief and written by experts in the field. Complete bibliographic information on the book should be provided before the text, and the name, academic degree and affiliation of the author submitting the book review should be included following the text.

Preparing the manuscript 1. General principles

The text of articles reporting original research should be divided into Introduction, Methods, Results, and Discussion sections, but subheadings within these sections may be needed to further organize their content. Other types of articles, such as meta-analyses, may require different formats, while case reports, narrative reviews, and editorials may have less structured or unstructured formats. All pages should be numbered. Electronic formats have created opportunities for adding details or sections, layering information, cross-linking, or extracting portions of articles in electronic versions. Supplementary electronic-only material should be submitted and sent for peer review simultaneously with the primary manuscript.

2. Authorship and Acknowledgments

The ICMJE recommends that authorship be based on the following four criteria: n Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND n Drafting the work or revising it critically for important intellectual content; AND n Final approval of the version to be published; AND n Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

In addition to being accountable for the parts of the work he or she has done, an author should be able to identify which co-authors are responsible for specific other parts of the work. In addition, authors should have confidence in the integrity of the contributions of their co-authors. The corresponding author takes primary responsibility for communication with the journal during the manuscript submission, peer review, and publication process.

All those designated as authors should meet all four criteria for authorship, and all who meet the four criteria should be identified as authors. It is the collective responsibility of the authors to determine that all people named as authors meet all four criteria. Those who do not meet all four criteria should be acknowledged.

The Acknowledgments section should disclose any sources of financial support received by the study. In addition, this section should acknowledge people, groups or institutions which have made important contributions to the study but do not meet the criteria for authorship (e.g., technical assistance, statistical analysis, writing, etc.).

3. Reporting guidelines

Reporting guidelines have been developed for different study designs; examples include CONSORT for randomized trials, STROBE for observational studies, PRISMA for systematic reviews and meta-analyses, and STARD for studies of diagnostic accuracy. Authors are encouraged to follow these guidelines. Moreover, authors of review manuscripts are encouraged to describe the methods used for locating, selecting, extracting, and synthesizing data; this is mandatory for systematic reviews.

Randomized clinical trials. Trends in Psychiatry and Psychotherapy will only accept for publication clinical trials that have been registered in Clinical Trials Registries. The registration number will be disclosed at the end of the abstract.

In the text, whenever a registration number is available, authors should list that number the first time they use a trial acronym to refer to the trial they are reporting or to other trials that they mention in the manuscript.

4. Manuscript sections

The following are general requirements for reporting within sections of all study designs and manuscript formats.

Title Page General information about an article and its authors is presented on a manuscript title page. This page should include the article title, author information, any disclaimers, sources of support, word count, and the number of tables and figures.

Detailed instructions are provided below.

1) Article title. The title should provide a distilled description of the complete article and should include information that, along with the Abstract, will make electronic retrieval of the article sensitive and specific. Whenever deemed appropriate, information about the study design should be a part of the title (particularly important for randomized trials and systematic reviews and meta-analyses).

2) A short title of no more than 50 characters should be provided.

3) Author information should include full names typed exactly as they should appear in print, emails, and main affiliation(s). The name of the department(s) and institution(s) or organization(s) where the work should be attributed should be specified.

4) The corresponding author should be identified, and a full mailing address (including ZIP code), telephone and fax numbers, and an email address should be provided.

5) Source(s) of support. These include grants, equipment, drugs, and/or other support that facilitated conduct of the work described in the article or the writing of the article itself. Any relevant role of the funder in the study should be disclaimed. Studies that have received no financial support should indicate so.

6) Conflict of interest declaration. Conflict of interest information for each author needs to be part of the manuscript.

A general statement should be included in the title page, attesting to the existence (or non-existence) of any conflicts of interest concerning the publication of the article. In addition, all authors are required to fill and submit an ICMJE conflict of interest disclosure form (one for each author) at the time of submission.

7) Articles based on academic theses or dissertations, or previously presented at scientific meetings, should disclose this on the title page. Please provide as many details as possible (e.g., the title of the original work, year, name of institution/venue/event, etc.).

8) A word count for the paper’s text, excluding the abstract, acknowledgments, tables, figure legends, and references, should be provided.

9) The date of the last literature review performed by the authors on the manuscript topic should be informed.

Abstract Abstracts should be no longer than 250 words. The abstract should provide the context or background for the study and should state the study’s purpose, basic procedures (selection of study participants, settings, measurements, analytical methods), main findings (giving specific effect sizes and their statistical and clinical significance, if possible), and principal conclusions. It should emphasize new and important aspects of the study or observations, note important limitations, and not overinterpret findings. Because abstracts are the only substantive portion of the article indexed in many electronic databases, and the only portion many readers read, authors need to ensure that they accurately reflect the content of the article. For clinical trials, the clinical trial registration number will be disclosed at the end of the abstract.

Keywords Following the abstract, three to six keywords should be provided in accordance with the Medical Subject Headings (MeSH, http://www.nlm.nih.gov/mesh/meshhome.html). If possible, a Brazilian Portuguese translation of the abstract (resumo) and keywords (palavras-chave) should also be provided; in this case, the palavras-chave should be compliant with the DeCS database (DeCS – Descritores em Ciências da Saúde, http://decs.bvs.br/).

Statistical analysis Describe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to judge its appropriateness for the study and to verify the reported results. When possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty (such as confidence intervals). Avoid relying solely on statistical hypothesis testing, such as p values, which fail to convey important information about effect size and precision of estimates. References for the design of the study and statistical methods should be to standard works when possible (with pages stated). Define statistical terms, abbreviations, and symbols. Specify the statistical software package and version used. Distinguish prespecified from exploratory analyses, including subgroup analyses.

For additional guidance on how to prepare each section of the main text, please refer to the Recommendations.

References Authors should provide direct references to original research sources whenever possible. Although references to review articles can be an efficient way to guide readers to a body of literature, review articles do not always reflect original work accurately. On the other hand, extensive lists of references to original work on a topic can use excessive space. Do not use conference abstracts as references; they can be cited in the text, in parentheses. References to papers accepted but not yet published should be designated as “in press.” Information from manuscripts submitted but not accepted should be cited in the text as “unpublished observations” with written permission from the source. Avoid citing a “personal communication” unless it provides essential information not available from a public source, in which case the name of the person and date of communication should be cited in parentheses in the text. The accuracy of references is the responsibility of the authors.

References should be numbered consecutively in the order in which they are first mentioned in the text. Identify references in text, tables, and legends by superscript Arabic numerals. References cited only in tables or figure legends should be numbered in accordance with the sequence established by the first identification in the text of the particular table or figure.

References should be listed at the end of the article according to their order of citation in the text and should comply with the style set forth in the NLM’s International Committee of Medical Journal Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals: Sample References webpage. The titles of journals should be abbreviated according to the style used for MEDLINE (www.ncbi.nlm.nih.gov/nlmcatalog/journals).

These resources are regularly updated as new media develop, and currently include guidance for print documents; unpublished material; audio and visual media; material on CD-ROM, DVD, or disk; and material on the Internet. Please consult published issues for style details. An EndNote style can also be downloaded from the Instructions & Forms section at our submission web site (http://mc04.manuscriptcentral.com/trends-scielo).

Journal article example: Halpern SD, Ubel PA, Caplan AL. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.

Tables Tables should complement, not duplicate information contained in the text. They should not exceed 30,000 characters (including spaces); larger tables may be considered if the authors justify their need. Tables should not be submitted as images, but should be created using specific word processor tools. Do not underline or draw lines inside the tables. Do not insert spaces to separate columns. Number tables consecutively in the order of their first citation in the text using Arabic numerals and supply a title for each.

Titles in tables should be short but self-explanatory, containing information that allows readers to understand the table’s content without having to go back to the text. Be sure that each table is cited in the text. Give each column a

short or an abbreviated heading. Authors should place explanatory matter in footnotes, not in the heading. Explain all nonstandard abbreviations in footnotes, and use symbols to explain information if needed (*, †, ‡, §, ||, ¶, **, ††, etc.).

Identify statistical measures of variations, such as standard deviation and standard error of the mean.

If you use data from another published or unpublished source, obtain permission and acknowledge that source fully.

Additional tables containing backup data too extensive to publish in print may be appropriate for publication in the electronic version of the journal, as supplementary online material, or made available to readers directly by the authors.

An appropriate statement should be added to the text to inform readers that this additional information is available and where it is located. Submit such tables for consideration with the paper so that they will be available to the peer reviewers.

Figures Digital images of manuscript illustrations (all referred to as “Figure”) should be submitted in a suitable format for print publication (preferably .tif, with a minimum resolution of 300 dpi). Letters, numbers, and symbols on figures should be clear and consistent throughout, and large enough to remain legible when the figure is reduced for publication. Figures should be made as self-explanatory as possible. Titles and detailed explanations belong in the legends, not on the illustrations themselves.

Figures should be numbered consecutively according to the order in which they have been cited in the text. If a figure has been published previously, acknowledge the original source and submit written permission from the copyright holder to reproduce it. Permission is required irrespective of authorship or publisher except for documents in the public domain.

Photographs should not allow patient identification.

In the manuscript, legends for illustrations should be on a separate page, with Arabic numerals corresponding to the illustrations. When symbols, arrows, numbers, or letters are used to identify parts of the illustrations, identify and explain each one clearly in the legend.

5. Units of Measurement

Measurements of length, height, weight, and volume should be reported in metric units (meter, kilogram, or liter) or their decimal multiples. Temperatures should be in degrees Celsius. Blood pressures should be in millimeters of mercury.

6. Abbreviations and symbols

Use only standard abbreviations; use of nonstandard abbreviations can be confusing to readers. Avoid abbreviations in the title of the manuscript. The spelled-out abbreviation followed by the abbreviation in parenthesis should be used on first mention unless the abbreviation is a standard unit of measurement.

7. Drugs

Drugs should be referred to by their generic name only.

Submitting the manuscript Manuscripts submitted to Trends in Psychiatry and Psychotherapy should not have been published elsewhere in whole or in part and should not have been or be submitted simultaneously for publication in any other journal(s). Previous presentation of the manuscript as abstract or poster at scientific meetings (conferences, workshops, etc.) is allowed, but should be informed on the title page.

Submissions to Trends should be made using the ScholarOne Manuscripts online system, available at http://mc04. manuscriptcentral.com/trends-scielo. Registration (login and password) is required on first access, prior to submission.

The submission system has several required fields and also some optional fields. One of the required fields is related to the indication of potential reviewers for the submitted manuscript. Authors should inform the name, email address and affiliation of five preferred reviewers, i.e., experts in the field who do not have conflicts of interest that may impede them from revising the authors’ work (for example, indicated reviewers should not be from the same institutions as authors).

The final decision on the reviewers assigned for each manuscript lies with the editors.

All manuscripts should be accompanied by ICMJE conflict of interest disclosure forms for each author. A cover letter including the following information is also recommended. n A full statement to the editor about all submissions and previous reports that might be regarded as redundant publication of the same or very similar work. Any such work should be referred to specifically and referenced in the new paper.

Copies of such material should be included with the submitted paper to help the editor address the situation. n A statement of financial or other relationships that might lead to a conflict of interest, if that information is not included in the manuscript itself. n A statement on authorship. It is the collective responsibility of the authors to determine that all people named as authors meet all authorship criteria. All authors should have read and approved the version submitted. n Contact information for the corresponding author, if that information is not included in the manuscript itself.

The letter or form should give any additional information that may be helpful to the editor, such as the type or format of article that the manuscript represents. If the manuscript has been submitted previously to another journal, it is helpful to include the previous editor’s and reviewers’ comments with the submitted manuscript, along with the authors’ responses to those comments. Editors encourage authors to submit these previous communications. Doing so may expedite the review process and encourages transparency and sharing of expertise.

The manuscript must also be accompanied by permission to reproduce previously published material, use previously published illustrations, report information about identifiable persons, or to acknowledge people for their contributions.

For system support and information on the status of submitted manuscripts, please contact Denise Arend at trends. denise@gmail.com. For general information about the journal, please contact the editorial office at trends@aprs.org.br.