Acta Psychiatr Scand 2014: 129: 323–327 All rights reserved DOI: 10.1111/acps.12270
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Editorial
The bipolar maze: a roadmap through translational psychopathology This exciting issue of Acta Psychiatrica Scandinavica focusses on bipolar disorder from different perspectives, including epidemiology on age at onset (1, 2) and comorbidity (3), biomarkers (4), clinical trial methodology (5), treatment (6), and medication adherence (7), thus covering some of the hottest topics in current clinical research on this condition. Indeed, bipolar disorder research has blossomed over the past two decades (8, 9), and bipolar disorder units and programs are more widespread than ever (10). This condition has been now unprecedentedly renamed as ‘the heartland of Psychiatry’ (11, 12). However, there is still a huge disparity between the burden of this particular disease and the (little) amount of funding devoted to research in this area of biomedical research (13). Hence, because of its psychopathologic complexity and limited investment, the translational road from bench to bed and vice versa can be defined as a maze. We are at the point of starting to work on a reasonable roadmap to walk it through.
Epidemiology and diagnosis The first challenge in the maze is the phenotype. DSM-5 has upgraded bipolar disorders at the same level as psychotic disorders and depressive disorders, which may seem reasonable. However, the DSM system seems to lead nowhere over the foreseeing future. There may be small incremental improvements, such as the dimensional assessment of mixed states (14, 15), but the questionable validity of the DSM constructs, along with the limited improvement as regards to their reliability (16), suggests that a shift in paradigm is necessary. This fact prompted a debate in United States between the American Psychiatric Association and the National Institute of Mental Health (NIMH) on the validity of DSM-5 and what were the alternatives, and the NIMH announced their proposal to fund research based on research domains criteria (RDoC), rather than DSM-5. The RDoC initiative can be seen as an attempt to build a neuroscience-based classification of mental disorders (17). The positive side of this project is the will to anchor the new classification to well established circuits and biological mechanisms: the downside, the actual risk of ending nowhere, at least from the clinical use perspective. There is no question that some of the findings that RDoC-related research may bring up over the coming years will enrich our current knowledge on what we call ‘bipolar disorder’ and beyond. But it is hard to foresee an alternative to the traditional phenotype of manic-depressive illness that clinicians may be able to recognize and treat. It is much more likely, thus, that future translational research looking into concepts such as ‘positive valence’ or ‘systems for social processes’ may assist in better defining the bipolar phenotype allowing for a real ‘personalized or stratified medicine’ (18), rather than replacing it. The ROAMER project (Roadmap for Mental Health Research in Europe) may provide guidance on how to implement the foundation for an alternative to the US radical shift in mental health research priorities represented by RDoC, at the European level. The World Health Organization may want to learn from RDoC and ROAMER to make their own proposal
of diagnostic research criteria (which should not necessarily be the same as those used for clinical practice) for the International Classification of Diseases, 11th edition.
Genetics and neuroimaging After decades of research on the heritability of bipolar illness, still the best proof of it are the epidemiological studies (twin, adoption, and population studies), but we certainly made some progress in molecular genetics. The second challenge of the bipolar maze is the genotype. To date, very little of the heritability of bipolar disorder is explained by common polymorphisms (19). Two genes appear to be the strongest candidates from genome-wide association studies, the ANK3, a gene involved in the function of voltage gated sodium channels), and the CACNA1C, a gene encoding a protein that is part of a voltage dependent calcium channel (20, 21). Many other candidate genes have been identified as correlates of certain traits and behaviors, such as impulsivity or suicidality (22, 23), giving further support to the need of a new nosological model based on translational or molecular psychopathology. Hopefully the next generation of genetic studies using whole exome or whole genome screening may shed more light into the genetics of the syndrome and particularly into the molecular genetics of its psychopathological components. The studies that have looked into the structural and functional neuroimaging of bipolar disorder have also increased our understanding of the condition. Again, it would be unfair to say that we have not made substantial progress in our understanding of the brain structures involved in the bipolar phenotype, but it is also true that we lack a compelling model connecting genes, cells, circuits, and structures. Indeed, the third challenge of the bipolar maze is the functional neuroanatomy of the bipolar brain. Brain structural magnetic resonance imaging (MRI) studies suggest cortical and subcortical abnormalities within networks subserving emotional regulation. There is evidence of neuroprogressive loss of gray matter volume in prefrontal and anterior cingulate cortex and the subgenual region (24) and further abnormalities in subcortical structures, including the hippocampus, the thalamus, and the caudate nucleus (25). Moreover, adolescents at risk of bipolar disorder may have some abnormal amygdala neurodevelopment (26). Unfortunately, none of these findings is specific enough to assist in the diagnostic process. Functional neuroimaging techniques have revealed consistent findings with the structural neuroimaging studies. Thus, abnormal amygdala activation during face processing appears to be more pervasive in children and adolescents than in adults with bipolar disorder (27), and neurobiological changes in activation patterns involving fronto-limbic circuitry have been reported in relation to different illness phase and mood states. The difficulties to deactivate the default mode network is another consistent finding across mood states (28, 29), but might be very unspecific. Resting state studies have reported changes in the connectivity of the
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Editorial medial prefrontal cortex and the anterior cingulated cortex with limbic-striatal structures, and in spatial extent in regional homogeneity when studying the default mode network (30).
Cognition and functioning Neurocognitive dysfunctions may not be necessarily present before illness onset (31, 32), but they have been extensively described in first-episode patients (33) and may persist beyond acute episodes (34, 35). Cognitive impairment may be considered a measure of allostatic load (36) and may correlate with some neuroinflammatory and oxidative stress markers (37, 38). Neurocognitive impairment may reflect a poor course and outcome of the disease, especially concerning the number of manic episodes (39, 40), a history of psychosis (41), subthreshold symptoms (42), and comorbidity (43). Although all studies control for the effects of medication, there are very few studies with medication-free patients (44), and the influence of drugs on cognitive performance may be bimodal, with both positive and negative effects (45, 46). The relevance of assessing cognition in patients with bipolar disorder is its high correlation with functional outcome (47–51). This model, which was initially tested in schizophrenia and subsequently in bipolar disorder, is now being analyzed in patients with unipolar depression (52). As cognition is a crucial mediator of functional outcome, cognitive remediation techniques, and particularly functional remediation, have been successfully applied to patients with bipolar disorder (53). Understanding the underlying mechanisms of cognitive deficits, their role as an endophenotype, and their impact in psychosocial outcome is the fourth challenge in the bipolar maze.
Clinical trials and therapies It is customary to say that the progress in the treatment of mental disorders has been slow and limited over the past 30 years and that nothing has matched the success of chlorpromazine, imipramine, or lithium. However, the armamentarium for the treatment of bipolar disorder has increased in quantity and quality, and patients are treated at a much earlier stage, resulting in the practical disappearance of catatonic and severely bizarre psychotic manic and depressive syndromes in the Western world. We have learned to use the available therapies as monotherapies or, most commonly, in combination (54, 55). Guidelines have been developed to reduce the variability of clinical practice (56, 57), and clinicians have become aware of the importance of medication adherence and psychoeducation (58–60). We learned to measure the relative efficacy of drugs for bipolar disorder by means of the number needed to treat (61) and their profile according to the polarity index (62), which is a useful measure that can be easily misunderstood (63) because it provides advice on what not to use, rather than what to use, depending on the predominant polarity of manic and depressive episodes in a given patient (64). The concept is now being used to choose among psychosocial interventions as well (65). Over the past decade, we learnt to better use the second generation of antipsychotics and a good bunch of evidence has been delivered on the use of antipsychotics in combination with lithium or valproate and the combination of the latter two in the long-term treatment of bipolar disorder (66). Unfortunately, on the negative side, the use of lithium is progressively declining despite the strong evidence base in favor of its use (67), and we still lack good data to support the use of antidepressants in this condition (68).
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The fifth challenge of the maze is to overcome the current drug development paradigm and enter a new era in neuropsychopharmacology, which is easy to say, difficult to do. It is now quite obvious that the drug pipelines for psychiatric disorders in general and bipolar disorder in particular are drying up (69). This is one of the reasons for the NIMH shift toward a neuroscience-based classification of mental disorders. We need methodological upgrades (70), technological sophistication, and much better outcomes. We may also need more incentives to CNS research. Only a few, if any, of the forthcoming new drugs may actually represent a significant advance in the treatment of manic-depressive illness; there is some chance with NMDA receptor antagonists and partial agonists for bipolar and unipolar treatment-resistant depression, and little more. Further effort is needed to explore the full potential of brain stimulation techniques and newer psychotherapies. Staging models should be developed to adjust the benefit risk of any intervention to the particular morbidity of every patient, moving toward personalized psychiatry. Clearly, some treatments are more suited for early intervention than others (71), and medicalization is only necessary in patients in whom the diagnosis is solidly confirmed.
The roadmap The bipolar maze is full of challenges and dead ends. Current research is providing slow but incremental progress in our knowledge of the pathophysiology of manic-depressive illness. But if we want to make significant steps forward, a paradigm shift is necessary in defining the phenotype and in drug development. The milestones in the roadmap should likely include: i) A shift toward research on translational psychopathology. The RDoC proposal may be hampered by the conservative exclusion of those manifestations of human behavior that lack a clear neuroscientific background (circuits and mechanisms), which are the ones that actually are the most relevant to psychiatry. Hence, what is needed is a dimensional approach to mental disorders (72) that may enrich the necessary categorical approach for clinical practice, toward stratified medicine. ii) Networking at the global level in describing the full map of whole genome screening and the neuroimaging circuitry of normal and abnormal brain processing. iii) Describing the cold and hot cognition changes at their onset and progression through the life span in patients with bipolar spectrum conditions and their relationship with functional outcome, assisting in developing new targets for drug, brain stimulation, and psychotherapy techniques. iv) Changing the paradigm for drug development in CNS to avoid the declining assay sensitivity of clinical trials and moving toward hard outcomes, such as biomarkers, and ecological measures of functional benefits. v) And finally, introducing expertise, sophistication, and technology in clinical practice. In the era when cost-effectiveness appears to drive every decision, it is time to say that, still, some things are priceless. True expertise can never be replaced by case management, dull pharmacotherapy, or supportive, time-limited psychotherapy. Psychiatry is very vulnerable to cost-saving policies that assume that all mental disorders are the same, some sort of weakness or social defeat. We need actigraphs, monitoring apps, real-time lithium check machines, and many other novel items that may introduce more technology and objectivity to clinical routines.
Editorial This is the envisaged roadmap to the bipolar maze. Needless to say, the maze has no exit, the real success is to enjoy the journey.
Declaration of interest Dr. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: Adamed, Alexza, Almirall, AstraZeneca, Bial, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, PierreFabre, Qualigen, Roche, Sanofi-Aventis, Servier, SheringPlough, Shire, Solvay, Sunovion, Takeda, Teva, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), the Stanley Medical Research Institute, United Biosource Corporation, and Wyeth. E. Vieta Invited Guest Editor Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain E-mail: [email protected]
References 1. Post RM, Leverich GS, Kupka R et al. Increased parental history of bipolar disorder in the United States: association with early age of onset. Acta Psychiatr Scand 2014;129:375–382. 2. Baldessarini RJ, Tondo L, Visioli C. First-episode types in bipolar disorder: predictive associations with later illness. Acta Psychiatr Scand 2014;129:383–392. 3. Amerio A, Odone A, Liapis CC, Ghaemi SN. Diagnostic validity of comorbid bipolar disorder and obsessive–compulsive disorder: a systematic review. Acta Psychiatr Scand 2014;129:343–358. 4. Grande I, Magalhaes PV, Chendo I et al. Val66Met polymorphism and serum brain derived neurotrophic factor: an open-label trial. Acta Psychiatr Scand 2014;129:393– 400. 5. Cipriani A, Barbui C, Rendell J, Geddes JR. Clinical and regulatory implications of active run-in phases in longterm studies for bipolar disorder. Acta Psychiatr Scand 2014;129:328–342. 6. Popovic D, Torrent C, Goikolea JM et al. Clinical implications ofpredominant polarity and the polarity index in bipolar disorder:a naturalistic study. Acta Psychiatr Scand 2014;129:366–374. 7. Sylvia LG, Reilly-Harrington NA, Leon AC et al. Medication adherence in a comparative effectiveness trial for bipolar disorder. Acta Psychiatr Scand 2014;129:359– 365. 8. Lopez-Mu~noz F, Vieta E, Rubio G, Garcıa-Garcıa P, Alamo C. Bipolar disorder as an emerging pathology in the scientific literature: a bibliometric approach. J Affect Disord 2006;92:161–170. 9. Vieta E. Overcoming the current approach in bipolar disorder research: DSM-V and beyond. J Psychopharmacol 2008;22:406–407. 10. Vieta E. Bipolar units and programmes: are they really needed? World Psychiatry 2011;10:152.
11. Goodwin GM, Geddes JR. What is the heartland of psychiatry? Br J Psychiatry 2007;191:189–191. 12. Vieta E. Pros and cons of specialised care in bipolar disorder: aninternational perspective. Br J Psychiatry 2013;202:170–171. 13. Catala-Lopez F, Genova-Maleras R, Vieta E, TabaresSeisdedos R. Theincreasing burden of mental and neurological disorders. Eur Neuropsychopharmacol 2013;23: 1337–1339. 14. Vieta E, Valentı M. Mixed states in DSM-5: implications for clinical care, education, and research. J Affect Disord 2013;148:28–36. 15. Vieta E, Grunze H, Azorin JM, Fagiolini A. Phenomenology of manic episodes according to the presence or absence of depressive features as defined in DSM-5: Results from the IMPACT self-reported online survey. J Affect Disord 2014;156:206–213. 16. Freedman R, Lewis DA, Michels R et al. The initial fieldtrials of DSM-5: new blooms and old thorns. Am J Psychiatry 2013;170:1–5. 17. Culberth BN. The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry 2014;13:28–35. 18. Schumann G, Binder EB, Holte A et al. Stratified medicine for mental disorders. Eur Neuropsychopharmacol 2014; 24:5–50. 19. Price FS, Morris JA. The genetics of bipolar disorder. BMJ 2013;346:1530. 20. Ferreira MA, Meng YA, Jones IR et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40:1056–1058. 21. Soeiro-De-souza MG, Bio DS, Dias VV, Vieta E, MachadoVieira R, Moreno RA. The CACNA1C risk allele selectively impacts on executive function in bipolar typevI disorder. Acta Psychiatr Scand 2013;128:362–369. 22. Jimenez E, Arias B, Mitjans M et al. Association between GSK3b gene and increased impulsivity in bipolar disorder. Eur Neuropsychopharmacol 2014;24:510–518. 23. Jimenez E, Arias B, Mitjans M et al. Genetic variability at IMPA2, INPP1 and GSK3b increases the risk of suicidal behavior in bipolar patients. Eur Neuropsychopharmacol 2013;23:1452–1462. 24. Lim CS, Baldessarini RJ, Vieta E, Yucel M, Bora E, Sim K. Longitudinal neuroimaging and neuropsychological changes in bipolar disorder patients: review of the evidence. Neurosci Biobehav Rev 2013;37:418–435. 25. Canales-Rodrıguez EJ, Pomarol-Clotet E, Radua J et al. Structural abnormalities in bipolar euthymia: A Multicontrast Molecular Diffusion Imaging Study. Biol Psychiatry 2013; doi: 10.1016/j.biopsych.2013.09.027. [Epub ahead of print]. 26. Bechdolf A, Wood SJ, Nelson B et al. Amygdala and insula volumes prior to illness onset in bipolar disorder: a magnetic resonance imaging study. Psychiatry Res 2012;201:34–39. 27. Kim P, Thomas LA, Rosen BH et al. Differing amygdala responses to facial expressions in children and adults with bipolar disorder. Am J Psychiatry 2012;169:642–9. 28. Pomarol-Clotet E, Moro N, Sarro S et al. Failure of deactivation in the medial frontal cortex in mania: evidence for default mode network dysfunction in the disorder. World J Biol Psychiatry 2012;13:616–626. 29. Fernandez-Corcuera P, Salvador R, Monte GC et al. Bipolar depressed patients show both failure to activate and
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46. Dias VV, Balanza-Martinez V, Soeiro-De-souza MG et al. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. Acta Psychiatr Scand 2012;126:315–331. 47. Martinez-Aran A, Vieta E, Torrent C et al. Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord 2007;9:103–13. 48. Bonnın CM, Martınez-Aran A, Torrent C et al. Clinical and neurocognitive predictors of functional outcome in bipolar euthymic patients: a long-term, follow-up study. J Affect Disord 2010;121:156–160. 49. Rosa AR, Gonzalez-Ortega I, Gonzalez-Pinto A et al. Oneyear psychosocial functioning in patients in the early vs. late stage of bipolar disorder. Acta Psychiatr Scand 2012;125:335–341. 50. Sole B, Bonnin CM, Torrent C et al. Neurocognitive impairment and psychosocial functioning in bipolar II disorder. Acta Psychiatr Scand 2012;125:309–317. 51. Reinares M, Papachristou E, Harvey P et al. Towards a clinical staging for bipolar disorder: defining patient subtypes based on functional outcome. J Affect Disord 2013;144:65–71. 52. Papakostas GI. Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. J ClinPsychiatry 2014;75:8–14. 53. Torrent C, Bonnincdel M, Martınez-Ar an A et al. Efficacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. Am J Psychiatry 2013;170:852–859. 54. Vieta E, Langosch JM, Figueira ML et al. Clinical management and burden of bipolar disorder: results from a multinational longitudinal study (WAVE-bd). Int J Neuropsychopharmacol 2013;16:1719–1732. 55. Nivoli AM, Colom F, Pacchiarotti I et al. Treatment strategies according to clinical features in a naturalistic cohort study of bipolar patients: a principal component analysis of lifetime pharmacological and biophysic treatment options. Eur Neuropsychopharmacol 2013;23:263–275. 56. Nivoli AM, Colom F, Murru A et al. New treatment guidelines for acute bipolar depression: a systematic review. J Affect Disord 2011;129:14–26. 57. Nivoli AM, Murru A, Goikolea JM et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord 2012;140:125–141. 58. Scott J, Colom F, Pope M, Reinares M, Vieta E. The prognostic role of perceived criticism, medication adherence and family knowledge in bipolar disorders. J Affect Disord 2012;142:72–76. 59. J onsdottir H, Opjordsmoen S, Birkenaes AB et al. Predictors of medication adherence in patients with schizophrenia and bipolar disorder. ActaPsychiatr Scand 2013; 127:23–33. 60. Murru A, Pacchiarotti I, Amann BL, Vieta E, Colom F. Treatment adherence in bipolar I and schizoaffective disorder, bipolar type. J Affect Disord 2013; 151:1003–8. 61. Popovic D, Reinares M, Amann B, Salamero M, Vieta E. Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder. Psychopharmacology 2011;213:657–667. 62. Popovic D, Reinares M, Goikolea JM, Bonnin CM, Gonzalez-Pinto A, Vieta E. Polarity index of pharmacological agents used for maintenance treatment of bipolar disorder. Eur Neuropsychopharmacol 2012;22:339–346. 63. Alphs L, Berwaerts J, Turkoz I. Limited utility of number needed to treat and the polarity index for bipolar disorder to characterize treatment response. Eur Neuropsychopharmacol 2013;23:1597–1599.
Editorial 64. Baldessarini RJ, Undurraga J, Vazquez GH et al. Predominant recurrence polarity among 928 adult international bipolar I disorder patients. Acta Psychiatr Scand 2012;125:293–302. 65. Popovic D, Reinares M, Scott J et al. Polarity index of psychological interventions in maintenance treatment of bipolar disorder. Psychother Psychosom 2013;82:292–298. 66. BALANCE investigators and collaborators, Geddes JR, Goodwin GM et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375: 385–95. 67. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry 2002;63(Suppl. 10):5–12. 68. Pacchiarotti I, Bond DJ, Baldessarini RJ et al. The International Society for Bipolar Disorders (ISBD) task force
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report on antidepressant use in bipolar disorders. Am J Psychiatry 2013;170:1249–1262. Dean B, Moller HJ, Svensson TH et al. Problems and solutions to filling the drying drug pipeline for psychiatric disorders: a report from the inaugural 2012 CINP Think Tank. Int J Neuropsychopharmacol 2014;17: 137–148. Vieta E, Cruz N. Head to head comparisons as an alternative to placebo-controlled trials. Eur Neuropsychopharmacol 2012;22:800–803. Scott J. M as all a de la psicosis: el retode la intervenci on precoz en los trastornos bipolares. Rev Psiquiatr Salud Ment (Barc.) 2012;5:1–4. Vieta E, Phillips ML. Deconstructing bipolar disorder: a critical review of its diagnostic validity and a proposal for DSM-V and ICD-11. Schizophr Bull 2007;33: 886–892.
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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Editorial
The bipolar maze: a roadmap through translational psychopathology This exciting issue of Acta Psychiatrica Scandinavica focusses on bipolar disorder from different perspectives, including epidemiology on age at onset (1, 2) and comorbidity (3), biomarkers (4), clinical trial methodology (5), treatment (6), and medication adherence (7), thus covering some of the hottest topics in current clinical research on this condition. Indeed, bipolar disorder research has blossomed over the past two decades (8, 9), and bipolar disorder units and programs are more widespread than ever (10). This condition has been now unprecedentedly renamed as ‘the heartland of Psychiatry’ (11, 12). However, there is still a huge disparity between the burden of this particular disease and the (little) amount of funding devoted to research in this area of biomedical research (13). Hence, because of its psychopathologic complexity and limited investment, the translational road from bench to bed and vice versa can be defined as a maze. We are at the point of starting to work on a reasonable roadmap to walk it through.
Epidemiology and diagnosis The first challenge in the maze is the phenotype. DSM-5 has upgraded bipolar disorders at the same level as psychotic disorders and depressive disorders, which may seem reasonable. However, the DSM system seems to lead nowhere over the foreseeing future. There may be small incremental improvements, such as the dimensional assessment of mixed states (14, 15), but the questionable validity of the DSM constructs, along with the limited improvement as regards to their reliability (16), suggests that a shift in paradigm is necessary. This fact prompted a debate in United States between the American Psychiatric Association and the National Institute of Mental Health (NIMH) on the validity of DSM-5 and what were the alternatives, and the NIMH announced their proposal to fund research based on research domains criteria (RDoC), rather than DSM-5. The RDoC initiative can be seen as an attempt to build a neuroscience-based classification of mental disorders (17). The positive side of this project is the will to anchor the new classification to well established circuits and biological mechanisms: the downside, the actual risk of ending nowhere, at least from the clinical use perspective. There is no question that some of the findings that RDoC-related research may bring up over the coming years will enrich our current knowledge on what we call ‘bipolar disorder’ and beyond. But it is hard to foresee an alternative to the traditional phenotype of manic-depressive illness that clinicians may be able to recognize and treat. It is much more likely, thus, that future translational research looking into concepts such as ‘positive valence’ or ‘systems for social processes’ may assist in better defining the bipolar phenotype allowing for a real ‘personalized or stratified medicine’ (18), rather than replacing it. The ROAMER project (Roadmap for Mental Health Research in Europe) may provide guidance on how to implement the foundation for an alternative to the US radical shift in mental health research priorities represented by RDoC, at the European level. The World Health Organization may want to learn from RDoC and ROAMER to make their own proposal
of diagnostic research criteria (which should not necessarily be the same as those used for clinical practice) for the International Classification of Diseases, 11th edition.
Genetics and neuroimaging After decades of research on the heritability of bipolar illness, still the best proof of it are the epidemiological studies (twin, adoption, and population studies), but we certainly made some progress in molecular genetics. The second challenge of the bipolar maze is the genotype. To date, very little of the heritability of bipolar disorder is explained by common polymorphisms (19). Two genes appear to be the strongest candidates from genome-wide association studies, the ANK3, a gene involved in the function of voltage gated sodium channels), and the CACNA1C, a gene encoding a protein that is part of a voltage dependent calcium channel (20, 21). Many other candidate genes have been identified as correlates of certain traits and behaviors, such as impulsivity or suicidality (22, 23), giving further support to the need of a new nosological model based on translational or molecular psychopathology. Hopefully the next generation of genetic studies using whole exome or whole genome screening may shed more light into the genetics of the syndrome and particularly into the molecular genetics of its psychopathological components. The studies that have looked into the structural and functional neuroimaging of bipolar disorder have also increased our understanding of the condition. Again, it would be unfair to say that we have not made substantial progress in our understanding of the brain structures involved in the bipolar phenotype, but it is also true that we lack a compelling model connecting genes, cells, circuits, and structures. Indeed, the third challenge of the bipolar maze is the functional neuroanatomy of the bipolar brain. Brain structural magnetic resonance imaging (MRI) studies suggest cortical and subcortical abnormalities within networks subserving emotional regulation. There is evidence of neuroprogressive loss of gray matter volume in prefrontal and anterior cingulate cortex and the subgenual region (24) and further abnormalities in subcortical structures, including the hippocampus, the thalamus, and the caudate nucleus (25). Moreover, adolescents at risk of bipolar disorder may have some abnormal amygdala neurodevelopment (26). Unfortunately, none of these findings is specific enough to assist in the diagnostic process. Functional neuroimaging techniques have revealed consistent findings with the structural neuroimaging studies. Thus, abnormal amygdala activation during face processing appears to be more pervasive in children and adolescents than in adults with bipolar disorder (27), and neurobiological changes in activation patterns involving fronto-limbic circuitry have been reported in relation to different illness phase and mood states. The difficulties to deactivate the default mode network is another consistent finding across mood states (28, 29), but might be very unspecific. Resting state studies have reported changes in the connectivity of the
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Editorial medial prefrontal cortex and the anterior cingulated cortex with limbic-striatal structures, and in spatial extent in regional homogeneity when studying the default mode network (30).
Cognition and functioning Neurocognitive dysfunctions may not be necessarily present before illness onset (31, 32), but they have been extensively described in first-episode patients (33) and may persist beyond acute episodes (34, 35). Cognitive impairment may be considered a measure of allostatic load (36) and may correlate with some neuroinflammatory and oxidative stress markers (37, 38). Neurocognitive impairment may reflect a poor course and outcome of the disease, especially concerning the number of manic episodes (39, 40), a history of psychosis (41), subthreshold symptoms (42), and comorbidity (43). Although all studies control for the effects of medication, there are very few studies with medication-free patients (44), and the influence of drugs on cognitive performance may be bimodal, with both positive and negative effects (45, 46). The relevance of assessing cognition in patients with bipolar disorder is its high correlation with functional outcome (47–51). This model, which was initially tested in schizophrenia and subsequently in bipolar disorder, is now being analyzed in patients with unipolar depression (52). As cognition is a crucial mediator of functional outcome, cognitive remediation techniques, and particularly functional remediation, have been successfully applied to patients with bipolar disorder (53). Understanding the underlying mechanisms of cognitive deficits, their role as an endophenotype, and their impact in psychosocial outcome is the fourth challenge in the bipolar maze.
Clinical trials and therapies It is customary to say that the progress in the treatment of mental disorders has been slow and limited over the past 30 years and that nothing has matched the success of chlorpromazine, imipramine, or lithium. However, the armamentarium for the treatment of bipolar disorder has increased in quantity and quality, and patients are treated at a much earlier stage, resulting in the practical disappearance of catatonic and severely bizarre psychotic manic and depressive syndromes in the Western world. We have learned to use the available therapies as monotherapies or, most commonly, in combination (54, 55). Guidelines have been developed to reduce the variability of clinical practice (56, 57), and clinicians have become aware of the importance of medication adherence and psychoeducation (58–60). We learned to measure the relative efficacy of drugs for bipolar disorder by means of the number needed to treat (61) and their profile according to the polarity index (62), which is a useful measure that can be easily misunderstood (63) because it provides advice on what not to use, rather than what to use, depending on the predominant polarity of manic and depressive episodes in a given patient (64). The concept is now being used to choose among psychosocial interventions as well (65). Over the past decade, we learnt to better use the second generation of antipsychotics and a good bunch of evidence has been delivered on the use of antipsychotics in combination with lithium or valproate and the combination of the latter two in the long-term treatment of bipolar disorder (66). Unfortunately, on the negative side, the use of lithium is progressively declining despite the strong evidence base in favor of its use (67), and we still lack good data to support the use of antidepressants in this condition (68).
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The fifth challenge of the maze is to overcome the current drug development paradigm and enter a new era in neuropsychopharmacology, which is easy to say, difficult to do. It is now quite obvious that the drug pipelines for psychiatric disorders in general and bipolar disorder in particular are drying up (69). This is one of the reasons for the NIMH shift toward a neuroscience-based classification of mental disorders. We need methodological upgrades (70), technological sophistication, and much better outcomes. We may also need more incentives to CNS research. Only a few, if any, of the forthcoming new drugs may actually represent a significant advance in the treatment of manic-depressive illness; there is some chance with NMDA receptor antagonists and partial agonists for bipolar and unipolar treatment-resistant depression, and little more. Further effort is needed to explore the full potential of brain stimulation techniques and newer psychotherapies. Staging models should be developed to adjust the benefit risk of any intervention to the particular morbidity of every patient, moving toward personalized psychiatry. Clearly, some treatments are more suited for early intervention than others (71), and medicalization is only necessary in patients in whom the diagnosis is solidly confirmed.
The roadmap The bipolar maze is full of challenges and dead ends. Current research is providing slow but incremental progress in our knowledge of the pathophysiology of manic-depressive illness. But if we want to make significant steps forward, a paradigm shift is necessary in defining the phenotype and in drug development. The milestones in the roadmap should likely include: i) A shift toward research on translational psychopathology. The RDoC proposal may be hampered by the conservative exclusion of those manifestations of human behavior that lack a clear neuroscientific background (circuits and mechanisms), which are the ones that actually are the most relevant to psychiatry. Hence, what is needed is a dimensional approach to mental disorders (72) that may enrich the necessary categorical approach for clinical practice, toward stratified medicine. ii) Networking at the global level in describing the full map of whole genome screening and the neuroimaging circuitry of normal and abnormal brain processing. iii) Describing the cold and hot cognition changes at their onset and progression through the life span in patients with bipolar spectrum conditions and their relationship with functional outcome, assisting in developing new targets for drug, brain stimulation, and psychotherapy techniques. iv) Changing the paradigm for drug development in CNS to avoid the declining assay sensitivity of clinical trials and moving toward hard outcomes, such as biomarkers, and ecological measures of functional benefits. v) And finally, introducing expertise, sophistication, and technology in clinical practice. In the era when cost-effectiveness appears to drive every decision, it is time to say that, still, some things are priceless. True expertise can never be replaced by case management, dull pharmacotherapy, or supportive, time-limited psychotherapy. Psychiatry is very vulnerable to cost-saving policies that assume that all mental disorders are the same, some sort of weakness or social defeat. We need actigraphs, monitoring apps, real-time lithium check machines, and many other novel items that may introduce more technology and objectivity to clinical routines.
Editorial This is the envisaged roadmap to the bipolar maze. Needless to say, the maze has no exit, the real success is to enjoy the journey.
Declaration of interest Dr. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: Adamed, Alexza, Almirall, AstraZeneca, Bial, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, PierreFabre, Qualigen, Roche, Sanofi-Aventis, Servier, SheringPlough, Shire, Solvay, Sunovion, Takeda, Teva, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), the Stanley Medical Research Institute, United Biosource Corporation, and Wyeth. E. Vieta Invited Guest Editor Bipolar Disorder Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain E-mail: [email protected]
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