© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Bipolar Disorders 2014
BIPOLAR DISORDERS
Commentary
Staging a protest! Malhi GS, Rosenberg DR, Gershon S. Staging a protest! Bipolar Disord 2014: 00: 000–000. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Gin S Malhia,b, David R Rosenbergc and Samuel Gershond,e a Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, bCADE Clinic, Department of Psychiatry, Royal North Shore Hospital, St Leonards, NSW, Australia, c Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, dEmeritus Professor of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA, eHonorary Fellow, Mind and Brain Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Key words: biomarkers – diagnosis – staging
Staging has been increasingly promulgated over the past decade as an alternative approach for appraising psychiatric disorders. Presumably the intention is to provide a better lexicon for classification—one that informs clinicians with respect to treatment and that allows researchers to systematically interrogate brain pathophysiology. But staging is not a novel concept in medicine and a number of conditions must be satisfied for it to be meaningful.
Staging Clinical staging
Clinical staging attempts to map phases in the development or progression of an illness onto pathophysiology, so as to inform management and to predict outcome. This approach holds potential, not only for determining treatment and prognosis, but also for developing a framework for the study and investigation of a disease (1). Furthermore, a disease schema consisting of successive stages automatically invokes the concept of a prodrome, comprising subsyndromal symptoms, which is useful because it encourages consideration of aetiology (2). However, accurate and reproducible clinical staging is only possible where an illness is known to progress along a specific and reasonably predictable course. For staging to be clinically meaning-
ful, it is necessary to have an understanding of the pathophysiology that actuates and drives the illness, and for the transition from one stage to the next to correlate with either clinical or pathophysiological changes. Thus, it is important to recognize that the staging paradigm is not applicable to all diseases in medicine. Staging cancer
Staging has proven to be of immense value in oncology, especially where the disease process and core pathology are known. For example, breast cancer can be diagnosed by taking a history and performing a clinical examination and mammography. Its lymphatic spread can be determined via sentinel node biopsy and histopathological examination. In addition, a range of imaging techniques [chest X-ray, computed tomography (CT) scan, bone scan, and positron emission tomography scan] can be used to map the spread of cancer to tissues via lymph and blood. The size and type of cancer, its infiltration locally and its spread more distally determine its stage, which in turn informs treatment. Therapeutic options for breast cancer include surgery, radiation therapy, hormone therapy, antibody therapy and chemotherapy, and staging the type and extent of cancer guides management. Clearly, the accurate staging of breast cancer is predicated on a detailed
1
Malhi et al. knowledge of its pathophysiology and, for it to be of clinical value, the findings from clinical investigations need to be reliably reproducible. This is necessarily contingent upon understanding underlying processes and clinical trajectory.
The nature of bipolar disorders Clinical phenomenology and diagnosis
The taxonomy of psychiatric disorders is not derived from aetiology and remains tethered to psychopathology—clinical phenomena and characteristics such as family history, course of illness, and response to treatment. Consequently, contemporary classificatory systems comprise diagnoses that are, as in the case of bipolar disorder, heterogeneous categories that can be arrived at via a variety of pathophysiological processes. In an attempt to gain diagnostic clarity, recent years have witnessed a surge in research into the phenomenology of bipolar disorder. But satisfactory delineation of this disorder has remained elusive, because its putative boundaries are ill defined and permeable. Part of the reason for this diagnostic fluidity is the difficulty in determining true cutoffs (number and severity of signs and symptoms), some of which have been derived arbitrarily via clinical consensus. This has created a number of ‘boundary issues’ for bipolar disorder, for example, (i) partitioning unipolar and bipolar disorder, (ii) delineating bipolar disorder from schizophrenia (3), (iii) separating bipolar II disorder and borderline personality disorder (4, 5), and (iv) drawing a distinction between hypomania and normalcy (6). An ongoing inability to develop meaningful categorical mood disorder diagnoses has encouraged the development of dimensional perspectives, including the bipolar spectrum alluded to by Kraepelin, and a complete conceptual reconstruction whereby research diagnostic criteria have been proposed for investigating psychiatric disorders without reliance on DSM-5 (7, 8). In sum, perhaps psychiatric disorders such as bipolar disorder cannot yet be classified as true illnesses, given the lack of consistently reproducible biomarkers and their, at times, ambiguous signs and symptoms. Difficult nature
The onset of bipolar disorder poses inevitable challenges; it usually emerges during teenage years and young adulthood—a time of marked change and development. The emotional, cognitive, and social growth that normally takes place during this phase of life readily obscures the signs and symptoms of
2
the disorder (9); this is to be expected. Teenage angst is often indistinguishable from symptoms of anxiety and depression, while feelings of exuberance and unbounded confidence, characteristics of the typical teenage perspective, can easily be mistaken for manic symptoms. Such ambiguity has plagued the criteria for bipolar disorder in children and adolescents (10) and, coupled with diagnostic fervour and confusion around how to detect and diagnose paediatric bipolar disorder, has eventuated in marked over-diagnosis and misdiagnosis, which extends to adults (11). The most worrying consequence of this is that, in practice, diagnosis begets treatment. The natural history of bipolar disorder dictates that the majority of cases initially present with depressive episodes. This means that bipolar disorder remains undetected and undiagnosed within major depression until it reveals its ‘true self’ with the appearance of hypomanic/manic episodes. The diagnosis of bipolar disorder is therefore often delayed. The task of detecting bipolar disorder is complicated further by the fact that bipolar depression is indistinguishable from major depression, and, at the other extreme, the symptoms of severe mania are miscible with those of schizophrenia or drug-induced psychosis, and therefore readily confused. Even within bipolar disorder, partitioning is problematic. For example, the DSM-IV or DSM5 division of mania to create hypomania is quite arbitrary—marked impairment is poorly defined and hospitalization is actually a consequence of the disorder and not a defining clinical feature per se, yet both are used to specify cleavage. Similarly, the lower boundary of hypomania does not correspond to any phenomenological or biological trend break, and the discrimination of subsyndromal symptoms from normalcy and facets of personality is a further, seemingly insurmountable, obstacle to identifying where the illness begins (6). Added to these many difficulties, the core phenomenology of bipolar disorder, namely mood, is also being questioned. Manic episodes are clearly the most consistent and reliably identifiable clinical markers of this disorder, but, by its very nature, it appears to have a multitude of patterns and trajectories, with varying predominance of depression and mania (12). Bipolar disorder’s fluctuating lifelong course means that the number of episodes individuals experience can range from just a few to a state of perpetual cycling. This has made investigation of the disorder extremely challenging and staging on the basis of phenomenology alone a near-impossible endeavour.
Staging a protest Some of these difficulties reflect the innate complexity of bipolar disorder (13), but others are of our own making and have arisen largely because of imprecise modelling. For example, the fact that mixed presentations are commonly encountered in clinical practice suggests that our view of bipolar disorder as biphasic and comprising two opposites (mania and depression) is axiomatically erroneous and incomplete (14). Furthermore, it is difficult to integrate the occurrence of DSM-5 mixed features, superimposed on all forms of bipolar disorder (mania, hypomania, and bipolar depression) (15), with a staging paradigm. Aetiology and pathogenesis
Bipolar disorder has a heritable component, but it is evident that many additional factors contribute to its development. For example, life stress of all kinds can be an instigator and catalyst, but when and how, and indeed to what extent, are unclear. The only thing we can surmise with some confidence is that both genes and environment contribute significantly to the inception of bipolar disorder. Thus, with our current knowledge, an aetiology-based classification is not yet possible. Useful insights are now emerging in some fields of research. For instance, neuroimaging studies of patients with bipolar disorder have shown altered functioning and connectivity in networks that subserve emotion and cognition (16, 17). However, it is important to emphasize that, thus far, not a single finding with clinically significant predictive specificity has been found. Similarly, the quest for answers from genetic data has not been as fruitful as originally hoped and, although many candidate genes have been identified, an actual ‘smoking gun’ is yet to be uncovered. Denouement
A fundamental mistake that has obscured our understanding is that disorders or syndromes, defined on the basis of symptoms and signs, have been gradually reified as disease entities. There may prove to be identifiable pathophysiological processes at the core of some diagnoses, such as melancholia and manic-depressive disorder, but the aetiology and trajectory for most current psychiatric disorders are probably varied, complex and difficult to predict. Some proponents of staging have identified cutoffs based on clinical phenomenology and disorder characteristics, whereas others have focused on inter-episode clinical features and functionality. Staging has also been applied to prodromal phases of psychiatric
illnesses such as bipolar disorder, but, critically, validation and operationalization are needed if it is to be of real clinical value. Thus far, only modest efforts have been made in this regard. Longitudinal follow-up of bipolar disorder patients diagnosed using structured and standardized instruments has revealed that, even in these stringent circumstances, the diagnosis is not stable and lacks consistency. Therefore, in the absence of a robust biomarker or clinical exactitude, the staging of bipolar disorder is likely to be a futile undertaking. So what’s next? Successful and meaningful staging of bipolar disorder is contingent on a significant advance that provides a firm foundation upon which to build. One possible ‘bottom-up’ approach is to focus efforts on the identification of a demonstrable biological deficit that leads to mania, and use this as a building block for future research. An alternative ‘top-down’ approach is to achieve greater phenotypic homogeneity by studying only pristine clinical samples of strictly defined patients with bipolar I disorder, refined further, for example, by sensitivity to treatment (lithium responsiveness). A failure to adopt such strategies that may provide greater clinical and biological specificity, and the premature uptake of staging, is only likely to generate specious models of bipolar disorder, which could potentially misdirect future research. This is a crucial problem and part of a larger difficulty facing the field—namely, the vast gap between our understanding of neurobiology and our understanding of how it relates to clinical phenomenology. Presently, we lack sufficient knowledge of the basic disease processes that underpin bipolar disorder. Put simply, we have too little to work with and, until this changes, we are unlikely to be successful in identifying reliable markers of bipolar disorder. Hence, although interesting, the staging of bipolar disorder remains largely a theoretical exercise. Acknowledgements This work was supported in part by the Lycaki-Young Funds, Detroit Wayne County Mental Health Authority, Miriam Hamburger Endowed Chair at the Children’s Hospital of Michigan, Elliott Luby Endowed Professorship, and the Paul and Anita Strauss Endowment (DRR).
Disclosures GSM has received research support from AstraZeneca, Eli Lilly & Co., Organon, Pfizer, Servier, and Wyeth; has been a speaker for AstraZeneca, Eli Lilly & Co., Janssen-Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and has been a consultant for AstraZeneca, Eli Lilly & Co., Janssen-Cilag,
3
Malhi et al. Lundbeck, and Servier. DRR is a consultant to Shire Pharmaceuticals. SG does not have any conflicts of interest to report.
References 1. Berk M, Brnabic A, Dodd S et al. Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. Bipolar Disord 2011; 13: 87–98. 2. Malhi GS, Bargh DM, Coulston CM, Das P, Berk M. Predicting bipolar disorder on the basis of phenomenology: implications for prevention and early intervention. Bipolar Disord 2014; 16: 455–470. 3. Malhi GS. Making up schizoaffective disorder: cosmetic changes to a sad creation? Aust N Z J Psychiatry 2013; 47: 891–894. 4. Coulston C, Tanious M, Mulder RT et al. Bordering on bipolar: the overlap between borderline personality and bipolarity. Aust N Z J Psychiatry 2012; 46: 506–521. 5. Bassett D. Borderline personality disorder and bipolar affective disorder. Spectra or spectre? A review. Aust N Z J Psychiatry 2012; 46: 327–339. 6. Malhi GS, Chengappa KN, Gershon S, Goldberg JF. Hypomania: hype or mania? Bipolar Disord 2010; 12: 758– 763. 7. Insel T. Director’s Blog: Transforming Diagnosis, 2013. Available from: http://www.nimh.nih.gov/about/director/ 2013/transforming-diagnosis.shtml [accessed August 2014]. 8. Youngstrom E, Van Meter A, Algorta GP. The bipolar spectrum myth or reality? Curr Psychiatry Rep 2010; 12: 479–489. 9. Cahill CM, Green MJ, Jairam R, Malhi GS. Bipolar disorder in children and adolescents: obstacles to early diagnosis and future directions. Early Interv Psychiatry 2007; 1: 138– 149. 10. Biederman J. Developmental subtypes of juvenile bipolar disorder. Harv Rev Psychiatry 1995; 3: 227–230.
4
11. Zimmerman M, Ruggero CJ, Chelminski I, Young D. Psychiatric diagnoses in patients previously over diagnosed with bipolar disorder. J Clin Psychiatry 2010; 71: 26–31. 12. Angst J, Gamma A, Bowden CL et al. Diagnostic criteria for bipolarity based on an international sample of 5,635 patients with DSM-IV major depression episodes. Eur Arch Psychiatry Clin Neurosci 2012; 262: 3–11. 13. Malhi GS, Bargh DM, Cashman E, Frye MA, Gitlin M. The clinical management of bipolar disorder complexity using a stratified model. Bipolar Disord 2012; 14 (Suppl. 2): 66–89. 14. Malhi GS, Lampe L, Coulston CM et al. Mixed state discrimination: a DSM problem that won’t go away? J Affect Disord 2014; 158: 8–10. 15. Angst J, Cui L, Swendsen J et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry 2010; 167: 1194–1201. 16. Townsend J, Altshuler LL. Emotion processing and regulation in bipolar disorder: a review. Bipolar Disord 2012; 14: 326–339. 17. Strakowski SM, Adler CM, Almeida J et al. The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord 2012; 14: 313–325. Corresponding author: Gin S. Malhi CADE Clinic, Department of Psychiatry Royal North Shore Hospital Level 3, Main Building St Leonards NSW 2065 Australia Fax: +61-2-9926-4063 E-mail: [email protected] doi: 10.1111/bdi.12254
Bipolar Disorders 2014
BIPOLAR DISORDERS
Commentary
Staging a protest! Malhi GS, Rosenberg DR, Gershon S. Staging a protest! Bipolar Disord 2014: 00: 000–000. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Gin S Malhia,b, David R Rosenbergc and Samuel Gershond,e a Discipline of Psychiatry, Sydney Medical School, University of Sydney, Sydney, bCADE Clinic, Department of Psychiatry, Royal North Shore Hospital, St Leonards, NSW, Australia, c Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, MI, dEmeritus Professor of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA, eHonorary Fellow, Mind and Brain Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia
Key words: biomarkers – diagnosis – staging
Staging has been increasingly promulgated over the past decade as an alternative approach for appraising psychiatric disorders. Presumably the intention is to provide a better lexicon for classification—one that informs clinicians with respect to treatment and that allows researchers to systematically interrogate brain pathophysiology. But staging is not a novel concept in medicine and a number of conditions must be satisfied for it to be meaningful.
Staging Clinical staging
Clinical staging attempts to map phases in the development or progression of an illness onto pathophysiology, so as to inform management and to predict outcome. This approach holds potential, not only for determining treatment and prognosis, but also for developing a framework for the study and investigation of a disease (1). Furthermore, a disease schema consisting of successive stages automatically invokes the concept of a prodrome, comprising subsyndromal symptoms, which is useful because it encourages consideration of aetiology (2). However, accurate and reproducible clinical staging is only possible where an illness is known to progress along a specific and reasonably predictable course. For staging to be clinically meaning-
ful, it is necessary to have an understanding of the pathophysiology that actuates and drives the illness, and for the transition from one stage to the next to correlate with either clinical or pathophysiological changes. Thus, it is important to recognize that the staging paradigm is not applicable to all diseases in medicine. Staging cancer
Staging has proven to be of immense value in oncology, especially where the disease process and core pathology are known. For example, breast cancer can be diagnosed by taking a history and performing a clinical examination and mammography. Its lymphatic spread can be determined via sentinel node biopsy and histopathological examination. In addition, a range of imaging techniques [chest X-ray, computed tomography (CT) scan, bone scan, and positron emission tomography scan] can be used to map the spread of cancer to tissues via lymph and blood. The size and type of cancer, its infiltration locally and its spread more distally determine its stage, which in turn informs treatment. Therapeutic options for breast cancer include surgery, radiation therapy, hormone therapy, antibody therapy and chemotherapy, and staging the type and extent of cancer guides management. Clearly, the accurate staging of breast cancer is predicated on a detailed
1
Malhi et al. knowledge of its pathophysiology and, for it to be of clinical value, the findings from clinical investigations need to be reliably reproducible. This is necessarily contingent upon understanding underlying processes and clinical trajectory.
The nature of bipolar disorders Clinical phenomenology and diagnosis
The taxonomy of psychiatric disorders is not derived from aetiology and remains tethered to psychopathology—clinical phenomena and characteristics such as family history, course of illness, and response to treatment. Consequently, contemporary classificatory systems comprise diagnoses that are, as in the case of bipolar disorder, heterogeneous categories that can be arrived at via a variety of pathophysiological processes. In an attempt to gain diagnostic clarity, recent years have witnessed a surge in research into the phenomenology of bipolar disorder. But satisfactory delineation of this disorder has remained elusive, because its putative boundaries are ill defined and permeable. Part of the reason for this diagnostic fluidity is the difficulty in determining true cutoffs (number and severity of signs and symptoms), some of which have been derived arbitrarily via clinical consensus. This has created a number of ‘boundary issues’ for bipolar disorder, for example, (i) partitioning unipolar and bipolar disorder, (ii) delineating bipolar disorder from schizophrenia (3), (iii) separating bipolar II disorder and borderline personality disorder (4, 5), and (iv) drawing a distinction between hypomania and normalcy (6). An ongoing inability to develop meaningful categorical mood disorder diagnoses has encouraged the development of dimensional perspectives, including the bipolar spectrum alluded to by Kraepelin, and a complete conceptual reconstruction whereby research diagnostic criteria have been proposed for investigating psychiatric disorders without reliance on DSM-5 (7, 8). In sum, perhaps psychiatric disorders such as bipolar disorder cannot yet be classified as true illnesses, given the lack of consistently reproducible biomarkers and their, at times, ambiguous signs and symptoms. Difficult nature
The onset of bipolar disorder poses inevitable challenges; it usually emerges during teenage years and young adulthood—a time of marked change and development. The emotional, cognitive, and social growth that normally takes place during this phase of life readily obscures the signs and symptoms of
2
the disorder (9); this is to be expected. Teenage angst is often indistinguishable from symptoms of anxiety and depression, while feelings of exuberance and unbounded confidence, characteristics of the typical teenage perspective, can easily be mistaken for manic symptoms. Such ambiguity has plagued the criteria for bipolar disorder in children and adolescents (10) and, coupled with diagnostic fervour and confusion around how to detect and diagnose paediatric bipolar disorder, has eventuated in marked over-diagnosis and misdiagnosis, which extends to adults (11). The most worrying consequence of this is that, in practice, diagnosis begets treatment. The natural history of bipolar disorder dictates that the majority of cases initially present with depressive episodes. This means that bipolar disorder remains undetected and undiagnosed within major depression until it reveals its ‘true self’ with the appearance of hypomanic/manic episodes. The diagnosis of bipolar disorder is therefore often delayed. The task of detecting bipolar disorder is complicated further by the fact that bipolar depression is indistinguishable from major depression, and, at the other extreme, the symptoms of severe mania are miscible with those of schizophrenia or drug-induced psychosis, and therefore readily confused. Even within bipolar disorder, partitioning is problematic. For example, the DSM-IV or DSM5 division of mania to create hypomania is quite arbitrary—marked impairment is poorly defined and hospitalization is actually a consequence of the disorder and not a defining clinical feature per se, yet both are used to specify cleavage. Similarly, the lower boundary of hypomania does not correspond to any phenomenological or biological trend break, and the discrimination of subsyndromal symptoms from normalcy and facets of personality is a further, seemingly insurmountable, obstacle to identifying where the illness begins (6). Added to these many difficulties, the core phenomenology of bipolar disorder, namely mood, is also being questioned. Manic episodes are clearly the most consistent and reliably identifiable clinical markers of this disorder, but, by its very nature, it appears to have a multitude of patterns and trajectories, with varying predominance of depression and mania (12). Bipolar disorder’s fluctuating lifelong course means that the number of episodes individuals experience can range from just a few to a state of perpetual cycling. This has made investigation of the disorder extremely challenging and staging on the basis of phenomenology alone a near-impossible endeavour.
Staging a protest Some of these difficulties reflect the innate complexity of bipolar disorder (13), but others are of our own making and have arisen largely because of imprecise modelling. For example, the fact that mixed presentations are commonly encountered in clinical practice suggests that our view of bipolar disorder as biphasic and comprising two opposites (mania and depression) is axiomatically erroneous and incomplete (14). Furthermore, it is difficult to integrate the occurrence of DSM-5 mixed features, superimposed on all forms of bipolar disorder (mania, hypomania, and bipolar depression) (15), with a staging paradigm. Aetiology and pathogenesis
Bipolar disorder has a heritable component, but it is evident that many additional factors contribute to its development. For example, life stress of all kinds can be an instigator and catalyst, but when and how, and indeed to what extent, are unclear. The only thing we can surmise with some confidence is that both genes and environment contribute significantly to the inception of bipolar disorder. Thus, with our current knowledge, an aetiology-based classification is not yet possible. Useful insights are now emerging in some fields of research. For instance, neuroimaging studies of patients with bipolar disorder have shown altered functioning and connectivity in networks that subserve emotion and cognition (16, 17). However, it is important to emphasize that, thus far, not a single finding with clinically significant predictive specificity has been found. Similarly, the quest for answers from genetic data has not been as fruitful as originally hoped and, although many candidate genes have been identified, an actual ‘smoking gun’ is yet to be uncovered. Denouement
A fundamental mistake that has obscured our understanding is that disorders or syndromes, defined on the basis of symptoms and signs, have been gradually reified as disease entities. There may prove to be identifiable pathophysiological processes at the core of some diagnoses, such as melancholia and manic-depressive disorder, but the aetiology and trajectory for most current psychiatric disorders are probably varied, complex and difficult to predict. Some proponents of staging have identified cutoffs based on clinical phenomenology and disorder characteristics, whereas others have focused on inter-episode clinical features and functionality. Staging has also been applied to prodromal phases of psychiatric
illnesses such as bipolar disorder, but, critically, validation and operationalization are needed if it is to be of real clinical value. Thus far, only modest efforts have been made in this regard. Longitudinal follow-up of bipolar disorder patients diagnosed using structured and standardized instruments has revealed that, even in these stringent circumstances, the diagnosis is not stable and lacks consistency. Therefore, in the absence of a robust biomarker or clinical exactitude, the staging of bipolar disorder is likely to be a futile undertaking. So what’s next? Successful and meaningful staging of bipolar disorder is contingent on a significant advance that provides a firm foundation upon which to build. One possible ‘bottom-up’ approach is to focus efforts on the identification of a demonstrable biological deficit that leads to mania, and use this as a building block for future research. An alternative ‘top-down’ approach is to achieve greater phenotypic homogeneity by studying only pristine clinical samples of strictly defined patients with bipolar I disorder, refined further, for example, by sensitivity to treatment (lithium responsiveness). A failure to adopt such strategies that may provide greater clinical and biological specificity, and the premature uptake of staging, is only likely to generate specious models of bipolar disorder, which could potentially misdirect future research. This is a crucial problem and part of a larger difficulty facing the field—namely, the vast gap between our understanding of neurobiology and our understanding of how it relates to clinical phenomenology. Presently, we lack sufficient knowledge of the basic disease processes that underpin bipolar disorder. Put simply, we have too little to work with and, until this changes, we are unlikely to be successful in identifying reliable markers of bipolar disorder. Hence, although interesting, the staging of bipolar disorder remains largely a theoretical exercise. Acknowledgements This work was supported in part by the Lycaki-Young Funds, Detroit Wayne County Mental Health Authority, Miriam Hamburger Endowed Chair at the Children’s Hospital of Michigan, Elliott Luby Endowed Professorship, and the Paul and Anita Strauss Endowment (DRR).
Disclosures GSM has received research support from AstraZeneca, Eli Lilly & Co., Organon, Pfizer, Servier, and Wyeth; has been a speaker for AstraZeneca, Eli Lilly & Co., Janssen-Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; and has been a consultant for AstraZeneca, Eli Lilly & Co., Janssen-Cilag,
3
Malhi et al. Lundbeck, and Servier. DRR is a consultant to Shire Pharmaceuticals. SG does not have any conflicts of interest to report.
References 1. Berk M, Brnabic A, Dodd S et al. Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. Bipolar Disord 2011; 13: 87–98. 2. Malhi GS, Bargh DM, Coulston CM, Das P, Berk M. Predicting bipolar disorder on the basis of phenomenology: implications for prevention and early intervention. Bipolar Disord 2014; 16: 455–470. 3. Malhi GS. Making up schizoaffective disorder: cosmetic changes to a sad creation? Aust N Z J Psychiatry 2013; 47: 891–894. 4. Coulston C, Tanious M, Mulder RT et al. Bordering on bipolar: the overlap between borderline personality and bipolarity. Aust N Z J Psychiatry 2012; 46: 506–521. 5. Bassett D. Borderline personality disorder and bipolar affective disorder. Spectra or spectre? A review. Aust N Z J Psychiatry 2012; 46: 327–339. 6. Malhi GS, Chengappa KN, Gershon S, Goldberg JF. Hypomania: hype or mania? Bipolar Disord 2010; 12: 758– 763. 7. Insel T. Director’s Blog: Transforming Diagnosis, 2013. Available from: http://www.nimh.nih.gov/about/director/ 2013/transforming-diagnosis.shtml [accessed August 2014]. 8. Youngstrom E, Van Meter A, Algorta GP. The bipolar spectrum myth or reality? Curr Psychiatry Rep 2010; 12: 479–489. 9. Cahill CM, Green MJ, Jairam R, Malhi GS. Bipolar disorder in children and adolescents: obstacles to early diagnosis and future directions. Early Interv Psychiatry 2007; 1: 138– 149. 10. Biederman J. Developmental subtypes of juvenile bipolar disorder. Harv Rev Psychiatry 1995; 3: 227–230.
4
11. Zimmerman M, Ruggero CJ, Chelminski I, Young D. Psychiatric diagnoses in patients previously over diagnosed with bipolar disorder. J Clin Psychiatry 2010; 71: 26–31. 12. Angst J, Gamma A, Bowden CL et al. Diagnostic criteria for bipolarity based on an international sample of 5,635 patients with DSM-IV major depression episodes. Eur Arch Psychiatry Clin Neurosci 2012; 262: 3–11. 13. Malhi GS, Bargh DM, Cashman E, Frye MA, Gitlin M. The clinical management of bipolar disorder complexity using a stratified model. Bipolar Disord 2012; 14 (Suppl. 2): 66–89. 14. Malhi GS, Lampe L, Coulston CM et al. Mixed state discrimination: a DSM problem that won’t go away? J Affect Disord 2014; 158: 8–10. 15. Angst J, Cui L, Swendsen J et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry 2010; 167: 1194–1201. 16. Townsend J, Altshuler LL. Emotion processing and regulation in bipolar disorder: a review. Bipolar Disord 2012; 14: 326–339. 17. Strakowski SM, Adler CM, Almeida J et al. The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord 2012; 14: 313–325. Corresponding author: Gin S. Malhi CADE Clinic, Department of Psychiatry Royal North Shore Hospital Level 3, Main Building St Leonards NSW 2065 Australia Fax: +61-2-9926-4063 E-mail: [email protected] doi: 10.1111/bdi.12254
