Challenges and developments in research of the early stages of bipolar disorder

Elisa Brietzke Adriane R. Rosa Mariana Pedrini Mariane N. Noto Flavio Kapczinski Jan Scott About the authors

Abstract

Recently, attention in the field of bipolar disorder (BD) has focused on prevention, including early detection and intervention, as these strategies have the potential to delay, lessen the severity, or even prevent full-blown episodes of BD. Although knowledge of the neurobiology of BD has advanced substantially in the last two decades, most research was conducted with chronic patients. The objective of this paper is to comprehensively review the literature regarding the early stages of BD, to explore recent discoveries on the neurobiology of these stages, and to discuss implications for research and clinical care. The following databases were searched: PubMed, PsycINFO, Cochrane Library, and SciELO. Articles published in English from inception to December 2015 were retrieved. Several research approaches were used, including examination of offspring studies, retrospective studies, prospective studies of clinical high-risk populations, and exploration of the progression after the first manic episode. Investigations with neuroimaging, cognition assessments, and biomarkers provide promising (although not definitive) evidence of alterations in the neural substrate during the at-risk stage. Research on BD should be expanded to encompass at-risk states and aligned with recent methodological progress in neuroscience.

Bipolar disorder; mania; early stages; prodromal; at-risk; offspring


Introduction

Bipolar disorder (BD) is a chronic, relapsing, and potentially progressive disorder.11. Berk M, Berk L, Dodd S, Cotton S, Macneil C, Daglas R, et al. Stage managing bipolar disorder. Bipolar Disord. 2014;16:471-7. 2. 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.-33. Correll CU, Olvet DM, Auther AM, Hauser M, Kishimoto T, Carrion RE, et al. The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. Bipolar Disord. 2014;16:505-22. Recently, a focus on prevention, including early detection and intervention, has begun to attract increasing attention, as such strategies have the potential to delay, lessen the severity, prevent progression, or even prevent full-blown BD.44. Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. 2014;16:493-504.,55. Correll CU, Hauser M, Penzner JB, Auther AM, Kafantaris V, Saito E, et al. Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode. Bipolar Disord. 2014;16:478-92. The notion that BD is a condition that follows a reasonable, predictable course across stages was a key aspect in developing proposals for prevention and early intervention.66. Taylor M, Bressan RA, Pan Neto P, Brietzke E. Early intervention for bipolar disorder: current imperatives, future directions. Rev Bras Psiquiatr. 2011;33:s197-212. Indeed, there are consistent data suggesting that, at least for a large subgroup of patients, BD actually follows a progressive course, which can be observed both in clinical outcomes (such as functional impairment) and in neurobiological findings (such as structural brain damage).77. Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev. 2008;32:675-92.,88. Abe C, Ekman CJ, Sellgren C, Petrovic P, Ingvar M, Landen M. Manic episodes are related to changes in frontal cortex: a longitudinal neuroimaging study of bipolar disorder 1.Brain. 2015;138:3440-8.

According to these models, the disorder starts during the “at-risk period” and progresses from the first mood episode through to late-stage disease, where symptoms are more chronic, pervasive, and treatment-resistant, and putatively caused by brain changes related to the action of neurotoxic mediators and reduction of neurotrophic and neuroprotective support.22. 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.,99. Brietzke E, Mansur RB, Soczynska JK, Kapczinski F, Bressan RA, McIntyre RS. Towards a multifactorial approach for prediction of bipolar disorder in at risk populations. J Affect Disord. 2012;140:82-91. The progression of BD results in increasing severity of clinical symptoms, cognitive impairment, and functional deterioration, demanding more complex and expensive treatment alternatives.22. 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. From this perspective, prevention of BD progression is paramount to reducing the major economic, psychosocial, and functional impact of this disorder on patients, families, and societies.

Knowledge of the neurobiology of BD has advanced substantially in the last two decades. Nevertheless, most studies have been conducted with chronic (i.e., late-stage) patients.1010. Walker AJ, Kim Y, Price JB, Kale RP, McGillivray JA, Berk M, et al. Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention. Front Psychiatry. 2014;5:34. Biomarkers seem to play an important role in evaluating disease activity and progression associated with different mood states (mood biomarkers), as well as to identify specific characteristics of the disease (trait biomarkers).1111. Roda A, Chendo I, Kunz M. Biomarkers and staging of bipolar disorder: a systematic review. Trends Psychiatry Psychother. 2015;37:3-11.,1212. Gama CS, Kunz M, Magalhaes PV, Kapczinski F. Staging and neuroprogression in bipolar disorder: a systematic review of the literature. Rev Bras Psiquiatr. 2013;35:70-4. The available evidence indicates that neurotrophins, oxidative stress, and inflammation are linked to the acute and euthymic phases of BD,1313. Andreazza AC, Kauer-Sant'anna M, Frey BN, Bond DJ, Kapczinski F, Young LT, et al. Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord. 2008;111:135-44.,1414. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63:801-8. and indicate the presence of systemic toxicity.1515. Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, Kauer-Sant'Anna M, Klamt F, et al. A systemic toxicity index developed to assess peripheral changes in mood episodes. Mol Psychiatry. 2010;15:784-6.

The use of clinical staging models is emerging as a novel and useful paradigm to inform diagnosis and treatment of BD.1616. Kapczinski F, Dias VV, Kauer-Sant'Anna M, Brietzke E, Vazquez GH, Vieta E, et al. The potential use of biomarkers as an adjunctive tool for staging bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1366-71. 17. Hickie IB, Scott J, McGorry PD. Clinical staging for mental disorders: a new development in diagnostic practice in mental health. Med J Aust. 2013;198:461-2.-1818. Scott J, Leboyer M, Hickie I, Berk M, Kapczinski F, Frank E, et al. Clinical staging in psychiatry: a cross-cutting model of diagnosis with heuristic and practical value. Br J Psychiatry. 2013;202:243-5. Staging models and the concept of neuroprogression represent significant advances in the field and provide a new scientific base for early intervention.77. Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev. 2008;32:675-92.,1919. Kapczinski F, Dias VV, Kauer-Sant'Anna M, Frey BN, Grassi-Oliveira R, Colom F, et al. Clinical implications of a staging model for bipolar disorders. Expert Rev Neurother. 2009;9:957-66. 20. Grande I, Magalhaes PV, Kunz M, Vieta E, Kapczinski F. Mediators of allostasis and systemic toxicity in bipolar disorder. Physiol Behav. 2012;106:46-50.-2121. Scott J. Bipolar disorder: from early identification to personalized treatment. Early Interv Psychiatry. 2011;5:89-90. The term neuroprogression has been increasingly used to define the pathological reorganization of the central nervous system (CNS) that occurs over the course of severe mental disorders.1212. Gama CS, Kunz M, Magalhaes PV, Kapczinski F. Staging and neuroprogression in bipolar disorder: a systematic review of the literature. Rev Bras Psiquiatr. 2013;35:70-4. This reorganization may arise as the result of several “insults,” such as inflammation and oxidative stress.1212. Gama CS, Kunz M, Magalhaes PV, Kapczinski F. Staging and neuroprogression in bipolar disorder: a systematic review of the literature. Rev Bras Psiquiatr. 2013;35:70-4. To refine clinical staging models and identify novel, specific targets for early intervention, it is essential to understand the pathophysiological processes associated with the clinical stages of illness development.1717. Hickie IB, Scott J, McGorry PD. Clinical staging for mental disorders: a new development in diagnostic practice in mental health. Med J Aust. 2013;198:461-2.,2222. Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, Grof P, Andreazza A, et al. Immunological and neurotrophic markers of risk status and illness development in high-risk youth: understanding the neurobiological underpinnings of bipolar disorder. Int J Bipolar Disord. 2014;2:29. Indeed, there is convergent evidence from longitudinal studies to support the hypothesis that BD develops in a series of predictable clinical stages in those at genetic risk.2222. Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, Grof P, Andreazza A, et al. Immunological and neurotrophic markers of risk status and illness development in high-risk youth: understanding the neurobiological underpinnings of bipolar disorder. Int J Bipolar Disord. 2014;2:29.,2323. Mesman E, Nolen WA, Reichart CG, Wals M, Hillegers MH. The Dutch bipolar offspring study: 12-year follow-up. Am J Psychiatry. 2013;170:542-9.

Nevertheless, few studies have approached the early stages of BD, and data on potential neurobiological differences between early- and late-stage BD are scarce.1212. Gama CS, Kunz M, Magalhaes PV, Kapczinski F. Staging and neuroprogression in bipolar disorder: a systematic review of the literature. Rev Bras Psiquiatr. 2013;35:70-4. This is a notable contrast to the field of psychosis, in which a large proportion of research resources has been targeted at understanding, recognizing, and managing early-stage disease.2424. Brietzke E, Araripe Neto AG, Dias A, Mansur RB, Bressan RA. Early intervention in psychosis: a map of clinical and research initiatives in Latin America. Rev Bras Psiquiatr. 2011;33:s213-24. 25. Gardsjord ES, Romm KL, Friis S, Barder HE, Evensen J, Haahr U, et al. Subjective quality of life in first-episode psychosis. A ten year follow-up study. Schizophr Res. 2016;172:23-8. 26. Grano N, Karjalainen M, Ranta K, Lindgren M, Roine M, Therman S. Community-oriented family-based intervention superior to standard treatment in improving depression, hopelessness and functioning among adolescents with any psychosis-risk symptoms. Psychiatry Res. 2016;237:9-16.-2727. Brewer WJ, Lambert TJ, Witt K, Dileo J, Duff C, Crlenjak C, et al. Intensive case management for high-risk patients with first-episode psychosis: service model and outcomes. Lancet Psychiatry. 2015;2:29-37.

The objective of this article was to provide a comprehensive review of the literature on neurobiology of the early stages of BD, with a special focus on the late prodromal stage and the period surrounding the first episode of mania. We also aimed to discuss the implications of emerging research findings in this field for investigation and clinical care.

Search strategy

A comprehensive literature search of computerized databases (PubMed, PsycINFO, Cochrane Library, and SciELO) was performed using the following terms: “bipolar disorder,” “mania,” “manic-depressive illness” cross-referenced with “prevention,” “early detection,” “early intervention,” “bipolar at risk,” “prodromal,” “preclinical,” “at risk mental states,” “clinical high risk,” “ultra-high risk,” “first episode of mania,” “biomarkers,” “brain-derived neurotrophic factor,” “inflammation,” “cytokines,” “oxidative stress.” Articles published from inception to December 2015 were retrieved. Selection of articles for inclusion in the review was based primarily on the information available in the study abstracts. The reference lists of the selected articles were also hand-searched for additional, potentially relevant citations. The exclusion criteria were articles written in languages other than English and studies of juvenile or pediatric BD (as we wished to focus on the adult phenotype of BD).

Clinical presentation of early stages

The gradual evolution of BD has been well recognized by individuals, their family members, and clinicians. In fact, there are convergent findings in the literature from extensive clinical observations regarding to the period of weeks, months, or even years during which mild, intermittent, and subthreshold mood symptoms are present before the onset of the first mood episode.2828. Fava GA, Kellner R. Prodromal symptoms in affective disorders. Am J Psychiatry. 1991;148:823-30.,2929. Beiser M, Erickson D, Fleming JA, Iacono WG. Establishing the onset of psychotic illness. Am J Psychiatry. 1993;150:1349-54. Several studies have recognized mood lability, major depressive episodes, subsyndromal manic symptoms, a diagnosis of a bipolar spectrum disorder (such as cyclothymia or BD not otherwise specified), and mood-congruent psychotic symptoms as precursors of BD.3030. Singh MK. Is there validity to the bipolar prodrome?J Clin Psychiatry. 2015;76:e655-6. 31. Rios AC, Noto MN, Rizzo LB, Mansur R, Martins FEJr, Grassi-Oliveira R, et al. Early stages of bipolar disorder: characterization and strategies for early intervention. Rev Bras Psiquiatr. 2015;37:343-9.-3232. Passos IC, Jansen K, Kapczinski F. Developmental staging models in bipolar disorder. Int J Bipolar Disord. 2015;3:33. On the other hand, in clinical practice, identification of a symptomatic high-risk BD phase is complicated by the complex nature of dimensions of this disorder, by potentially different symptom presentations in children and adolescents,55. Correll CU, Hauser M, Penzner JB, Auther AM, Kafantaris V, Saito E, et al. Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode. Bipolar Disord. 2014;16:478-92.,2121. Scott J. Bipolar disorder: from early identification to personalized treatment. Early Interv Psychiatry. 2011;5:89-90.,3333. Goetz M, Novak T, Vesela M, Hlavka Z, Brunovsky M, Povazan M, et al. Early stages of pediatric bipolar disorder: retrospective analysis of a Czech inpatient sample. Neuropsychiatr Dis Treat. 2015;11:2855-64. and by the blurred lines between the prodrome and the disease itself.3434. Noto MN, Noto C, Caribe AC, Miranda-Scippa A, Nunes SO, Chaves AC, et al. Clinical characteristics and influence of childhood trauma on the prodrome of bipolar disorder. Rev Bras Psiquiatr. 2015;37:280-8.

Retrospective and prospective studies have revealed a pattern of putative prodromal symptoms, of which mood lability/mood swings/cyclothymic features, depressive mood, racing thoughts, irritability, and physical agitation are most commonly reported.44. Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. 2014;16:493-504.,2121. Scott J. Bipolar disorder: from early identification to personalized treatment. Early Interv Psychiatry. 2011;5:89-90. Considering that the onset of first manic episode occurs mainly in adolescence and early adulthood, it can be assumed that mild, poorly differentiated, or nonspecific symptoms influence the earliest developmental stages of the individual.3535. Bellivier F, Golmard JL, Rietschel M, Schulze TG, Malafosse A, Preisig M, et al. Age at onset in bipolar I affective disorder: further evidence for three subgroups. Am J Psychiatry. 2003;160:999-1001.,3636. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).JAMA. 2003;289:3095-105. In fact, retrospective studies have shown that BD patients may report symptoms as early as 2 years of age, even though these manifestations are highly unspecific (such as sleep disorders or excessive crying).3737. Egeland JA, Hostetter AM, Pauls DL, Sussex JN. Prodromal symptoms before onset of manic-depressive disorder suggested by first hospital admission histories. J Am Acad Child Adolesc Psychiatry. 2000;39:1245-52. 38. Fergus EL, Miller RB, Luckenbaugh DA, Leverich GS, Findling RL, Speer AM, et al. Is there progression from irritability/dyscontrol to major depressive and manic symptoms? A retrospective community survey of parents of bipolar children. J Affect Disord. 2003;77:71-8.-3939. Rucklidge JJ. Retrospective parent report of psychiatric histories: do checklists reveal specific prodromal indicators for postpubertal-onset pediatric bipolar disorder?Bipolar Disord. 2008;10:56-66. Over time, with the progression of psychopathology across personal developmental phases (childhood, puberty, adolescence, etc.), there is a trend for symptoms to become more specific and more similar to BD.4040. Skjelstad DV, Malt UF, Holte A. Symptoms and signs of the initial prodrome of bipolar disorder: a systematic review. J Affect Disord. 2010;126:1-13. Accordingly, a 4-year follow-up study found that 38% of children and adolescents initially diagnosed with subsyndromal symptoms of BD (usually cyclothymia and BD not otherwise specified) and 25% of those diagnosed with type II BD were ultimately diagnosed with type I BD during the follow-up period.4141. Birmaher B, Axelson D, Goldstein B, Strober M, Gill MK, Hunt J, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry. 2009;166:795-804.

Study designs for the early stages of BD

Offspring studies

BD is a highly heritable disorder, with up to 85% of the variance in risk determined by genetic factors; hence, a positive family history is still the best predictive factor for development of the illness.1818. Scott J, Leboyer M, Hickie I, Berk M, Kapczinski F, Frank E, et al. Clinical staging in psychiatry: a cross-cutting model of diagnosis with heuristic and practical value. Br J Psychiatry. 2013;202:243-5.,2222. Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, Grof P, Andreazza A, et al. Immunological and neurotrophic markers of risk status and illness development in high-risk youth: understanding the neurobiological underpinnings of bipolar disorder. Int J Bipolar Disord. 2014;2:29.,2323. Mesman E, Nolen WA, Reichart CG, Wals M, Hillegers MH. The Dutch bipolar offspring study: 12-year follow-up. Am J Psychiatry. 2013;170:542-9. However, a family history does not merely predict an increased risk of BD. Meta-analyses have shown that, compared to other children, the offspring of a BD parent (OSBP) have an eight- to tenfold increase in lifetime risk of developing BD, but also a threefold lifetime risk of any severe mental disorder (e.g., psychosis) and one-in-two odds for any mental disorder.4242. Rasic D, Hajek T, Alda M, Uher R. Risk of mental illness in offspring of parents with schizophrenia, bipolar disorder, and major depressive disorder: a meta-analysis of family high-risk studies. Schizophr Bull. 2014;40:28-38. Thus, OSBP studies provide a reliable and valid means for identifying a sample of individuals at high risk of developing mental disorders, and can provide information on prodromal signs and symptoms of BD and rates of transition from “at-risk” state to clinical “caseness.”4343. Scott J. [Beyond psychosis: the challenge of early intervention in bipolar disorders].Rev Psiquiatr Salud Ment. 2012;5:1-4. Importantly, the study of OSBP is a useful “enrichment” strategy that may help identify the underlying pathophysiology and evolution of clinical stages of BD over time and access factors such as potential interactions between genetic liability, birth weight, and early-life stress.4444. Wals M, Reichart CG, Hillegers MH, Van Os J, Verhulst FC, Nolen WA, et al. Impact of birth weight and genetic liability on psychopathology in children of bipolar parents. J Am Acad Child Adolesc Psychiatry. 2003;42:1116-21.,4545. Hillegers MH, Burger H, Wals M, Reichart CG, Verhulst FC, Nolen WA, et al. Impact of stressful life events, familial loading and their interaction on the onset of mood disorders: study in a high-risk cohort of adolescent offspring of parents with bipolar disorder. Br J Psychiatry. 2004;185:97-101.

In addition, studies of OSBP can enhance our understanding of the clinical phenotypes of individuals at high risk of developing BD and demonstrate the heterotypic continuity of problems with a common developmental pattern, involving, e.g., anxiety problems in childhood, a first mood episode in early adolescence, and a (hypo)manic episode in late adolescence or early adulthood.2222. Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, Grof P, Andreazza A, et al. Immunological and neurotrophic markers of risk status and illness development in high-risk youth: understanding the neurobiological underpinnings of bipolar disorder. Int J Bipolar Disord. 2014;2:29.,2323. Mesman E, Nolen WA, Reichart CG, Wals M, Hillegers MH. The Dutch bipolar offspring study: 12-year follow-up. Am J Psychiatry. 2013;170:542-9. Prospective studies have the potential to clarify the illness trajectory by exposing the temporal relationship between childhood difficulties or non-mood problems and later affective pathology or development of BD. Questions as to whether non-mood pathology represents a risk syndrome or earlier manifestation of the disorder or whether it is a concurrent disorder in its own right may be answered by such studies of high-risk children. Furthermore, the longitudinal follow-up of affected and unaffected high-risk siblings from an early age allows exploration of clinical, biological, and environmental factors that may predict which high-risk family members ultimately develop BD.4646. Loftus J, Etain B, Scott J. What can we learn from offspring studies in bipolar disorder?Adv Psychiatr Treat. 2016;22:176-85.

However, when reviewing the findings on neurobiology and staging that derive from OSBP studies, it is important to consider differences in methodology.4747. Duffy A, Doucette S, Lewitzka U, Alda M, Hajek T, Grof P. Findings from bipolar offspring studies: methodology matters. Early Interv Psychiatry. 2011;5:181-91. There are often differences in the sampling or recruitment strategy employed (clinical/community; offspring of one affected parent/two affected parents), the assessments used (self/observer-rated), and the timeframe of assessment (cross-sectional/longitudinal; retrospective/prospective). The methods employed to recruit families into OSBP studies also vary widely, and include recruitment of families already involved in neurobiological and genetic research projects,4848. Nurnberger JIJr, McInnis M, Reich W, Kastelic E, Wilcox HC, Glowinski A, et al. A high-risk study of bipolar disorder. Childhood clinical phenotypes as precursors of major mood disorders. Arch Gen Psychiatry. 2011;68:1012-20. recruitment of all or some participants via self-referral and/or advertising campaigns,4949. Birmaher B, Axelson D, Goldstein B, Monk K, Kalas C, Obreja M, et al. Psychiatric disorders in preschool offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study (BIOS).Am J Psychiatry. 2010;167:321-30. recruitment from hospital settings and specialized clinics,5050. Henin A, Biederman J, Mick E, Sachs GS, Hirshfeld-Becker DR, Siegel RS, et al. Psychopathology in the offspring of parents with bipolar disorder: a controlled study. Biol Psychiatry. 2005;58:554-61. and from patient advocacy associations.4444. Wals M, Reichart CG, Hillegers MH, Van Os J, Verhulst FC, Nolen WA, et al. Impact of birth weight and genetic liability on psychopathology in children of bipolar parents. J Am Acad Child Adolesc Psychiatry. 2003;42:1116-21. Notably, higher rates of comorbidity are evident in studies that recruit via self-referral and families where the non-proband parent also had a non-affective psychiatric illness. Likewise, the nature of the control group also influences findings. For example, studies which included healthy children as controls demonstrated a major increase in a range of psychopathology in the OSBP, while studies using children of chronically medically ill parents (so-called positive controls) often show high levels of psychopathology in the comparison group as well as in the OSBP group.5151. Hammen C, Burge D, Burney E, Adrian C. Longitudinal study of diagnoses in children of women with unipolar and bipolar affective disorder. Arch Gen Psychiatry. 1990;47:1112-7. Finally, the use of pediatric or adult diagnostic criteria to identify BD, and the use of dimensional rather than categorical measures of psychopathology, may influence study findings.4646. Loftus J, Etain B, Scott J. What can we learn from offspring studies in bipolar disorder?Adv Psychiatr Treat. 2016;22:176-85. These issues are highly relevant to any comparisons of data regarding neurobiology of the stages of BD, as heterogeneity in OSBP clinical phenotypes or illness trajectories may obscure rather than clarify our understanding of clinicopathological boundaries across illness stages.

Retrospective designs

The majority of studies investigating the prodrome of BD have used retrospective designs.33. Correll CU, Olvet DM, Auther AM, Hauser M, Kishimoto T, Carrion RE, et al. The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. Bipolar Disord. 2014;16:505-22. These studies support the existence of a prolonged, symptomatic prodrome prior to the first episode of BD.5252. Bechdolf A, Ratheesh A, Wood SJ, Tecic T, Conus P, Nelson B, et al. Rationale and first results of developing at-risk (prodromal) criteria for bipolar disorder. Curr Pharm Des. 2012;18:358-75. Symptoms reported retrospectively during the prodromal phase include both mood (depressive symptoms, manic symptoms, mood lability, cyclothymia) and non-mood features (such as anxiety, sleep and concentration problems, and energy changes).5353. 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;16:455-70.

Retrospective studies of the BD prodrome have used a variety of methods to assess data from patients and caregivers, thus limiting comparison across studies.5252. Bechdolf A, Ratheesh A, Wood SJ, Tecic T, Conus P, Nelson B, et al. Rationale and first results of developing at-risk (prodromal) criteria for bipolar disorder. Curr Pharm Des. 2012;18:358-75. Most used either unstructured questionnaires or chart reviews, and failed to assess the onset pattern of the disorder and the symptom severity of the prodromal period, which limits validity.55. Correll CU, Hauser M, Penzner JB, Auther AM, Kafantaris V, Saito E, et al. Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode. Bipolar Disord. 2014;16:478-92. Furthermore, it remains unclear which person (i.e., the patient, a parent, teacher, or peer) is most likely to first notice the prodromal symptoms.55. Correll CU, Hauser M, Penzner JB, Auther AM, Kafantaris V, Saito E, et al. Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode. Bipolar Disord. 2014;16:478-92. Thus, studies that access information regarding prodromal symptoms only from the point of view of patients themselves may be less reliable. Finally, recall bias is another limitation that must be taken into account when analyzing findings on neurobiology derived from retrospective studies.5353. 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;16:455-70.

Prospective studies of first-episode mania

Prospective studies of first-episode mania are crucial to improving our understanding of the development, onset, and progression of BD. This strategy allows us to identify clinical correlates that might characterize patients at risk of poor medium- to long-term outcomes, and avoids the confounding effects of multiple episodes, morbidity, comorbidities, and treatment.5454. Chakrabarty T, Kozicky JM, Torres IJ, Lam RW, Yatham LN. Verbal memory impairment in new onset bipolar disorder: relationship with frontal and medial temporal morphology. World J Biol Psychiatry. 2015;16:249-60.,5555. Torres IJ, Kozicky J, Popuri S, Bond DJ, Honer WG, Lam RW, et al. 12-month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 2014;16:159-71. Additionally, this approach may help optimize treatment planning for the clinical, cognitive, and functional characteristics of patients identified as being at different, distinct stages of the illness.5656. Gignac A, McGirr A, Lam RW, Yatham LN. Recovery and recurrence following a first episode of mania: a systematic review and meta-analysis of prospectively characterized cohorts. J Clin Psychiatry. 2015;76:1241-8.

Different methodologies have been used in first-episode studies, and this must be taken into account when interpreting results from such investigations.5757. Daglas R, Yucel M, Cotton S, Allott K, Hetrick S, Berk M. Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. Int J Bipolar Disord. 2015;3:9. 58. Trotta A, Murray RM, MacCabe JH. Do premorbid and post-onset cognitive functioning differ between schizophrenia and bipolar disorder? A systematic review and meta-analysis. Psychol Med. 2015;45:381-94.-5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11. For instance, there is a lack of homogeneity regarding the definition of first mood episode. Follow-up studies have included patients with different mood states (mania, mixed states, or BD depression); included mixed samples of patients with BD and psychosis; or have defined first-episode onset as the first hospitalization.5757. Daglas R, Yucel M, Cotton S, Allott K, Hetrick S, Berk M. Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. Int J Bipolar Disord. 2015;3:9.,5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11. The mean age of the BD sample is another limitation in some studies. In our review of the literature, it is notable that most first-episode BD studies were conducted in adults6060. Lopez-Jaramillo C, Lopera-Vasquez J, Gallo A, Ospina-Duque J, Bell V, Torrent C, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12:557-67.,6161. Nehra R, Chakrabarti S, Pradhan BK, Khehra N. Comparison of cognitive functions between first- and multi-episode bipolar affective disorders. J Affect Disord. 2006;93:185-92. and very few included children or adolescents.6262. Torres IJ, DeFreitas VG, DeFreitas CM, Kauer-Sant'Anna M, Bond DJ, Honer WG, et al. Neurocognitive functioning in patients with bipolar I disorder recently recovered from a first manic episode. J Clin Psychiatry. 2010;71:1234-42.,6363. Strakowski SM, Adler CM, Cerullo M, Eliassen JC, Lamy M, Fleck DE, et al. Magnetic resonance imaging brain activation in first-episode bipolar mania during a response inhibition task. Early Interv Psychiatry. 2008;2:225-33. The nature of the control groups used in these first-episode studies is also a topic of some debate.5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11.,6464. Lee W, Bindman J, Ford T, Glozier N, Moran P, Stewart R, et al. Bias in psychiatric case-control studies: literature survey. Br J Psychiatry. 2007;190:204-9. Findings that emerge from studies comparing BD cases with healthy controls or probands to their relatives have shown consistent differences in regard to cognition. However, the magnitude of these differences in cognitive functioning itself differs according to the choice of control group. Overall, when compared to healthy controls, BD cases demonstrate more overt cognitive impairment, whereas smaller differences in cognitive performance have been observed when BD cases are compared to healthy relatives.5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11. This may point to methodological issues, or may represent a genuine link between a clinical phenotype and an inherited endophenotype.6565. Raust A, Daban C, Cochet B, Henry C, Bellivier F, Scott J. Neurocognitive performance as an endophenotype for bipolar disorder. Front Biosci (Elite Ed). 2014;6:89-103. However, disentangling these issues is complex, as even first-episode studies include many patients on polypharmacotherapy, and the possible triggering effect of these drugs has not been considered.5757. Daglas R, Yucel M, Cotton S, Allott K, Hetrick S, Berk M. Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. Int J Bipolar Disord. 2015;3:9.,5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11.

Prospective studies of individuals at clinical risk of BD

Prospective studies of individuals at risk of BD present a potentially reliable and valid approach to understanding the progression of BD psychopathology.44. Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. 2014;16:493-504.,6666. Ratheesh A, Cotton SM, Betts JK, Chanen A, Nelson B, Davey CG, et al. Prospective progression from high-prevalence disorders to bipolar disorder: exploring characteristics of pre-illness stages. J Affect Disord. 2015;183:45-8. Many studies use enrichment strategies to enhance the possibility of studying a sample in which a large proportion of subjects experience onset of BD. However, the disadvantage of this approach is that it may limit the universality of findings, due to lack of power or specificity for predicting BD as compared to onset of a range of mental disorders.5353. 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;16:455-70. High-risk prospective studies investigate individuals that are at specific risk of developing BD due to genetic loading or presence of early manifestations of psychiatric symptoms at a subclinical level,5353. 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;16:455-70. in the so-called close-in strategy.2121. Scott J. Bipolar disorder: from early identification to personalized treatment. Early Interv Psychiatry. 2011;5:89-90.

Research into the prodromal phase of BD has led to the assumption that individuals presenting at preclinical stages of BD may be identified. Initially, ultra-high risk (UHR) or bipolar at-risk (BAR) criteria for BD have been proposed, assuming that the initial phases of the disease may present with symptoms that are insufficient in severity, frequency, or duration. These criteria include: (a) subthreshold mania; (b) depression with cyclothymic features; or (c) depression associated with genetic risk for BD.6767. Bechdolf A, Nelson B, Cotton SM, Chanen A, Thompson A, Kettle J, et al. A preliminary evaluation of the validity of at-risk criteria for bipolar disorders in help-seeking adolescents and young adults. J Affect Disord. 2010;127:316-20. Recently, the BAR criteria were validated in a prospective study of adolescents and young adults. In the BAR group, 14.3% converted to first-episode hypomania/mania (as opposed to none in the control group) at 1-year follow-up, with subthreshold mania having the greatest predictive value.44. Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. 2014;16:493-504. In future, strategies to identify at-risk individuals will be partly dependent on the development of measurement scales with robust psychometric characteristics, such as the recently validated Bipolar Prodrome Symptom Interview and Scale-Prospective.33. Correll CU, Olvet DM, Auther AM, Hauser M, Kishimoto T, Carrion RE, et al. The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls. Bipolar Disord. 2014;16:505-22.

Neurobiology of the early stages of BD

Neuroimaging

Neuroimaging investigations of structural and functional brain abnormalities in individuals at genetic risk of BD offer several advantages: identifying brain abnormalities that potentially predate the onset of BD and are not confounded by factors such as illness duration or medication; identifying brain abnormalities that may confer risk for or protect against BD, to inform evaluation of risk of BD development and subsequent therapeutic intervention; and improving understanding of the developmental course of BD.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20. Furthermore, neuroimaging abnormalities found in individuals at high genetic risk may underlie the modest neurocognitive impairments (namely, executive function and working memory deficits) observed in relatives of patients with BD.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20.

A number of imaging studies in individuals at genetic risk for BD are available, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and structural magnetic resonance imaging (MRI) studies, which investigate grey- or white-matter volumes. Despite this large volume of published research, findings have been inconsistent, and no reliable structural or functional markers of genetic liability to BD have been identified.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20. An advantage of neuroimaging studies of young patients with BD is that they may help clarify neurodevelopmental aspects of the illness and identify biomarkers of disease onset and progression.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20. Brain imaging techniques such as MRI, PET, and DTI are being used increasingly for direct quantification of neural system abnormalities associated with BD and high risk of BD.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20.

Neuroimaging techniques are also some of the most powerful tools available for identification of endophenotypes. Identifying endophenotypic markers would help to confirm a likely diagnosis of BD; could allow clinicians and researchers to discriminate BD depression from unipolar depression; and, potentially, enable identification of at-risk individuals who will subsequently develop the illness, thus facilitating early intervention.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20.,6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84. Relevant findings in BD to date have centered on functional and structural neuroimaging studies, underlying core domains of the pathology in children with BD and those at high risk.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20.,6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84. As new protocols, techniques, and technologies emerge, there is the possibility of addressing important clinical questions, including the identification of treatment-relevant endophenotypes to create treatment response groupings to meet the long-term goal of rational treatment advances for BD.6868. Keener MT, Phillips ML. Neuroimaging in bipolar disorder: a critical review of current findings. Curr Psychiatry Rep. 2007;9:512-20.,6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84.

A recent meta-analysis showed that grey-matter loss may be a state-related factor for BD, suggesting that structural imaging may be a useful biomarker to distinguish individuals who will transition to BD from those who will not.6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84. However, prospective studies of grey-matter volume in high-risk individuals are needed to evaluate this finding.6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84. The same meta-analysis found that hyperactivation in the frontal and insular cortex is the neural substrate for the executive function impairments seen in high-risk individuals and patients with BD.6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84. The similarity between these findings in high-risk individuals and previous findings in patients with BD suggests that hyperactivation in these regions is a good candidate trait endophenotype for BD.6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84. However, further work is needed to determine how this relates to the affective disturbances and other clinical features that develop with onset of BD.6969. Fusar-Poli P, Howes O, Bechdol fA, Borgwardt S. Mapping vulnerability to bipolar disorder: a systematic review and meta-analysis of neuroimaging studies. J Psychiatry Neurosci. 2012;37:170-84.

To date, most studies of white-matter changes in BD have been conducted in older subjects and those with well-established disorders.7070. Lagopoulos J, Hermens DF, Hatton SN, Battisti RA, Tobias-Webb J, White D, et al. Microstructural white matter changes are correlated with the stage of psychiatric illness. Transl Psychiatry. 2013;3:e248. A recent study reported significant changes in major white-matter tracts in a large cohort of young patients in the early stages of BD.7070. Lagopoulos J, Hermens DF, Hatton SN, Battisti RA, Tobias-Webb J, White D, et al. Microstructural white matter changes are correlated with the stage of psychiatric illness. Transl Psychiatry. 2013;3:e248. Specifically, this study provided evidence of microstructural white-matter changes within the corpus callosum early in the course of illness.7070. Lagopoulos J, Hermens DF, Hatton SN, Battisti RA, Tobias-Webb J, White D, et al. Microstructural white matter changes are correlated with the stage of psychiatric illness. Transl Psychiatry. 2013;3:e248. The nature of these changes suggests an association with abnormalities in axon myelination.7070. Lagopoulos J, Hermens DF, Hatton SN, Battisti RA, Tobias-Webb J, White D, et al. Microstructural white matter changes are correlated with the stage of psychiatric illness. Transl Psychiatry. 2013;3:e248. Collectively, these results are consistent with the notion that BD is associated with discernable abnormalities in white-matter integrity, and that this is driven predominantly by the BD I phenotype.7070. Lagopoulos J, Hermens DF, Hatton SN, Battisti RA, Tobias-Webb J, White D, et al. Microstructural white matter changes are correlated with the stage of psychiatric illness. Transl Psychiatry. 2013;3:e248.

Another recent study that assessed white-matter microstructure and grey-matter volumes in a community sample of adolescents with BD found widespread alterations in white matter involving a number of tracts that continue to mature during adolescence.7171. Martinot JL, Mana S. [Neuroimaging of psychiatric and pedopsychiatric disorders].Med Sci (Paris). 2011;27:639-50. In addition, the authors observed that BD in adolescents is associated with structural connectivity alterations likely to affect the development of white-matter bundles and connected grey-matter areas involved in emotion regulation.7171. Martinot JL, Mana S. [Neuroimaging of psychiatric and pedopsychiatric disorders].Med Sci (Paris). 2011;27:639-50.

Since patients with BD have been reported to show hippocampal abnormalities, a recent systematic review of 25 studies analyzed hippocampal volume.7272. Otten M, Meeter M. Hippocampal structure and function in individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113-25. The results were consistent with decrease in hippocampal volume in four of 18 studies using adult samples and two of three samples using adolescents. Four studies revealed localized hippocampal deficits.7272. Otten M, Meeter M. Hippocampal structure and function in individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113-25. Meta-analysis revealed a significant but small effect with lower hippocampal volumes when comparing all BD patients vs. controls.7272. Otten M, Meeter M. Hippocampal structure and function in individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113-25. Lithium treatment was associated with larger hippocampal volumes across studies. Three functional studies were included and yielded contradictory evidence; the authors concluded that BD seems to feature a minor reduction in hippocampal volume, which may be more pronounced in early-onset BD and counteracted by a neuroprotective effect of lithium treatment.7272. Otten M, Meeter M. Hippocampal structure and function in individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113-25. However, how these structural abnormalities relate to functional deficits is largely unclear.7272. Otten M, Meeter M. Hippocampal structure and function in individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113-25. Given the paucity of functional neuroimaging studies and lack of congruence in their results, further investigation of hippocampal function in BD is recommended.7272. Otten M, Meeter M. Hippocampal structure and function in individuals with bipolar disorder: a systematic review. J Affect Disord. 2015;174:113-25.

The Systematic Treatment Optimization Program for Early Mania (STOP-BD) study used single-voxel proton MRS to assess hippocampal neurometabolite levels in patients with BD recruited within 3 months of recovery from first manic episode. In this study, glutamate plus glutamine (Glx) and N-acetyl aspartate levels were no different between BD patients and matched healthy subjects at baseline, and levels did not change differentially during the 1-year follow-up period in BD patients compared with controls. This suggests that patients in the early stage of BD did not experience alterations in hippocampal neurochemistry, and supports the importance of early interventions to arrest illness progression in BD.7373. Silveira LE, Bond DJ, MacMillan EL, Kozicky JM, Muralidharan K, Bucker J, et al. Hippocampal neurochemical markers in bipolar disorder patients following the first-manic episode: a prospective 12-month proton magnetic resonance spectroscopy study. Aust N Z J Psychiatry. 2016 Jan 20. pii: 0004867415623859. [Epub ahead of print]

In summary, translating knowledge of the neuroanatomy of BD into a diagnostic tool or test paradigm will require identifying the neural signature of predisposition for BD (potential cause) and separating it from the effects of long-standing illness and treatment (possible consequence of the disease process).7474. Hajek T, Bauer M, Simhandl C, Rybakowski J, O'Donovan C, Pfennig A, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014;44:507-17. Finally, structural neuroimaging studies focusing on volume could aid in the identification of individuals at risk of BD even before any behavioral manifestation, and further research into associations among genetic risk, illness burden, lithium treatment, and brain structure in BD could be useful.7474. Hajek T, Bauer M, Simhandl C, Rybakowski J, O'Donovan C, Pfennig A, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014;44:507-17.

Neurocognition

There is mounting evidence that individuals with BD experience neurocognitive deficits even in remission periods.6565. Raust A, Daban C, Cochet B, Henry C, Bellivier F, Scott J. Neurocognitive performance as an endophenotype for bipolar disorder. Front Biosci (Elite Ed). 2014;6:89-103.,7575. Bonnin CM, Reinares M, Martinez-Aran A, Balanza-Martinez V, Sole B, Torrent C, et al. Effects of functional remediation on neurocognitively impaired bipolar patients: enhancement of verbal memory. Psychol Med. 2016;46:291-301.,7676. Torrent C, Bonnin Cdel M, Martinez-Aran A, Valle J, Amann BL, Gonzalez-Pinto A, et al. Efficacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. Am J Psychiatry. 2013;170:852-9. This may be explained, in part, by the progressive course of illness involving relapses with increasing severity of residual symptoms, comorbidity with other psychiatric and medical conditions, and adverse effects of treatment. However, whether these cognitive deficits occur early in the course of BD or predate the onset of the diagnosable mood disorder is not yet clear.

Distinct methodologies have been used to investigate cognitive function in the premorbid stage of BD, both in general population studies (e.g., conscripts to national service or community-based cohorts) and in clinical high-risk or genetic studies of BD.5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11.,6666. Ratheesh A, Cotton SM, Betts JK, Chanen A, Nelson B, Davey CG, et al. Prospective progression from high-prevalence disorders to bipolar disorder: exploring characteristics of pre-illness stages. J Affect Disord. 2015;183:45-8. For instance, three “conscript” studies included young adults recruited from the armed forces and followed these individuals prospectively over long periods, but provided inconsistent or inconclusive findings.7777. Reichenberg A, Weiser M, Rabinowitz J, Caspi A, Schmeidler J, Mark M, et al. A population-based cohort study of premorbid intellectual, language, and behavioral functioning in patients with schizophrenia, schizoaffective disorder, and nonpsychotic bipolar disorder. Am J Psychiatry. 2002;159:2027-35. 78. Tiihonen J, Haukka J, Henriksson M, Cannon M, Kieseppa T, Laaksonen I, et al. Premorbid intellectual functioning in bipolar disorder and schizophrenia: results from a cohort study of male conscripts. Am J Psychiatry. 2005;162:1904-10.-7979. Zammit S, Allebeck P, David AS, Dalman C, Hemmingsson T, Lundberg I, et al. A longitudinal study of premorbid IQ Score and risk of developing schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses. Arch Gen Psychiatry. 2004;61:354-60. Zammit et al.7979. Zammit S, Allebeck P, David AS, Dalman C, Hemmingsson T, Lundberg I, et al. A longitudinal study of premorbid IQ Score and risk of developing schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses. Arch Gen Psychiatry. 2004;61:354-60. suggested that individuals who developed BD had cognitive performance comparable to that of healthy controls, while Tiihonen et al.7878. Tiihonen J, Haukka J, Henriksson M, Cannon M, Kieseppa T, Laaksonen I, et al. Premorbid intellectual functioning in bipolar disorder and schizophrenia: results from a cohort study of male conscripts. Am J Psychiatry. 2005;162:1904-10. showed that individuals who developed BD had superior performance in arithmetic but poorer visuospatial reasoning than healthy controls.

Another way to investigate neurocognitive functioning is to examine individuals at high risk of mood disorders/psychoses who are prospectively diagnosed as having BD. Using this methodology, Meyer et al. found comparable premorbid intelligence quotient (IQ) values between BD offspring and controls, while poorer executive function was observed among subjects who developed BD.8080. Meyer SE, Carlson GA, Wiggs EA, Martinez PE, Ronsaville DS, Klimes-Dougan B, et al. A prospective study of the association among impaired executive functioning, childhood attentional problems, and the development of bipolar disorder. Dev Psychopathol. 2004;16:461-76. In contrast, Olveta et al., in a follow-up study involving adolescents at high risk of developing psychoses, reported no differences in premorbid IQ or global neurocognitive scores between subjects who developed BD and those who did not transition to psychiatric illness.8181. Olvet DM, Stearns WH, McLaughlin D, Auther AM, Correll CU, Cornblatt BA. Comparing clinical and neurocognitive features of the schizophrenia prodrome to the bipolar prodrome. Schizophr Res. 2010;123:59-63. More recently, Ratheesh et al.6666. Ratheesh A, Cotton SM, Betts JK, Chanen A, Nelson B, Davey CG, et al. Prospective progression from high-prevalence disorders to bipolar disorder: exploring characteristics of pre-illness stages. J Affect Disord. 2015;183:45-8. investigated young people at UHR of psychoses during the prodromal phase of the illness and followed them prospectively for approximately 8 years. Most cognitive measures did not differ between subjects who developed BD and those who did not transition to psychoses or BD.8282. Duffy A, Hajek T, Alda M, Grof P, Milin R, MacQueen G. Neurocognitive functioning in the early stages of bipolar disorder: visual backward masking performance in high risk subjects. Eur Arch Psychiatry Clin Neurosci. 2009;259:263-9. Subjects also showed appropriate cognitive function (e.g., visual information processing) before the onset of BD.

Assessment of cognitive functioning from the first episode of mania is important to better understand whether cognitive deficits are already present at the early stages of illness or are progressive. To date, we have identified three meta-analyses that examined cognitive functioning in patients in first-episode mania.5757. Daglas R, Yucel M, Cotton S, Allott K, Hetrick S, Berk M. Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. Int J Bipolar Disord. 2015;3:9. 58. Trotta A, Murray RM, MacCabe JH. Do premorbid and post-onset cognitive functioning differ between schizophrenia and bipolar disorder? A systematic review and meta-analysis. Psychol Med. 2015;45:381-94.-5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11. Lee et al.5959. Lee RS, Hermens DF, Scott J, Redoblado-Hodge MA, Naismith SL, Lagopoulos J, et al. A meta-analysis of neuropsychological functioning in first-episode bipolar disorders. J Psychiatr Res. 2014;57:1-11. included 12 studies of cognition involving young adults (mean age, 28.2 years) with first-episode mania or mixed states, depression, or psychoses. Greater cognitive impairment (with a modest effect size) was found in patients compared to controls across eight domains, except for visual learning and memory. These cognitive dysfunctions were independent of current mood state, with the exception of response inhibition, which was found only in symptomatic patients. Similarly, Daglas et al.5757. Daglas R, Yucel M, Cotton S, Allott K, Hetrick S, Berk M. Cognitive impairment in first-episode mania: a systematic review of the evidence in the acute and remission phases of the illness. Int J Bipolar Disord. 2015;3:9. investigated the cognitive profiles of adults and adolescents during the acute phase of mania and the period following symptomatic recovery. The findings of this meta-analysis were inconclusive, although individual studies have previously reported cognitive dysfunctions in specific domains during the asymptomatic period. More recently, Trota et al.5858. Trotta A, Murray RM, MacCabe JH. Do premorbid and post-onset cognitive functioning differ between schizophrenia and bipolar disorder? A systematic review and meta-analysis. Psychol Med. 2015;45:381-94. reported data from a meta-analysis that compared global intellectual functioning measured before or following illness onset in psychiatric patients and controls. Interestingly, individuals with BD demonstrated poorer premorbid intellectual function than controls when function was measured retrospectively, but not when measured prospectively; BD cases also exhibited moderate cognitive impairment after onset of illness. A 1-year follow-up study in first-episode BD showed that cases differed from controls with regard to specific cognitive domains, such as processing speed, executive function, verbal and nonverbal memory, and working memory. Moreover, cognitive improvement (processing speed and executive function) was observed in patients after 1 year of follow-up, particularly in those without a history of substance abuse and who had discontinued antipsychotic treatment.5555. Torres IJ, Kozicky J, Popuri S, Bond DJ, Honer WG, Lam RW, et al. 12-month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 2014;16:159-71.

Comparing results from studies of first-episode mania to those of BD cases with multiple episodes, Lopez-Jaramillo et al.6060. Lopez-Jaramillo C, Lopera-Vasquez J, Gallo A, Ospina-Duque J, Bell V, Torrent C, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12:557-67. observed worse cognitive performance (attention, processing speed, and executive function) in euthymic patients who had experienced at least three manic episodes as compared with patients who had only one prior BD episode. Other researchers have also demonstrated that patients who have had multiple episodes are more likely to present with deficits in executive function and verbal memory than those at early stages of BD.6262. Torres IJ, DeFreitas VG, DeFreitas CM, Kauer-Sant'Anna M, Bond DJ, Honer WG, et al. Neurocognitive functioning in patients with bipolar I disorder recently recovered from a first manic episode. J Clin Psychiatry. 2010;71:1234-42.,8383. Hellvin T, Sundet K, Simonsen C, Aminoff SR, Lagerberg TV, Andreassen OA, et al. Neurocognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 2012;14:227-38. Furthermore, cognitive deficits may also limit long-term psychosocial functioning, which means that patients with greater cognitive impairment are more likely to experience poorer outcomes. In this regard, we previously reported progressive functional decline from the early through late stages of BD.8484. Rosa AR, Magalhaes PV, Czepielewski L, Sulzbach MV, Goi PD, Vieta E, et al. Clinical staging in bipolar disorder: focus on cognition and functioning. J Clin Psychiatry. 2014;75:e450-6. These findings are consistent with previous studies indicating an association between cognitive deficit and BD severity.6262. Torres IJ, DeFreitas VG, DeFreitas CM, Kauer-Sant'Anna M, Bond DJ, Honer WG, et al. Neurocognitive functioning in patients with bipolar I disorder recently recovered from a first manic episode. J Clin Psychiatry. 2010;71:1234-42.,8585. Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, et al. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord. 2006;93:105-15. The number of manic episodes is strongly associated with cognitive impairment,6060. Lopez-Jaramillo C, Lopera-Vasquez J, Gallo A, Ospina-Duque J, Bell V, Torrent C, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12:557-67.,8686. Kozicky JM, Torres IJ, Silveira LE, Bond DJ, Lam RW, Yatham LN. Cognitive change in the year after a first manic episode: association between clinical outcome and cognitive performance early in the course of bipolar I disorder. J Clin Psychiatry. 2014;75:e587-93. while other clinical features, such as subsyndromal depressive symptoms,7575. Bonnin CM, Reinares M, Martinez-Aran A, Balanza-Martinez V, Sole B, Torrent C, et al. Effects of functional remediation on neurocognitively impaired bipolar patients: enhancement of verbal memory. Psychol Med. 2016;46:291-301. illness duration,8787. Martinez-Aran A, Scott J, Colom F, Torrent C, Tabares-Seisdedos R, Daban C, et al. Treatment nonadherence and neurocognitive impairment in bipolar disorder. J Clin Psychiatry. 2009;70:1017-23. psychotic symptoms,8787. Martinez-Aran A, Scott J, Colom F, Torrent C, Tabares-Seisdedos R, Daban C, et al. Treatment nonadherence and neurocognitive impairment in bipolar disorder. J Clin Psychiatry. 2009;70:1017-23. number of hospitalizations,8585. Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, et al. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord. 2006;93:105-15. psychiatric comorbidities,5555. Torres IJ, Kozicky J, Popuri S, Bond DJ, Honer WG, Lam RW, et al. 12-month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 2014;16:159-71.,8787. Martinez-Aran A, Scott J, Colom F, Torrent C, Tabares-Seisdedos R, Daban C, et al. Treatment nonadherence and neurocognitive impairment in bipolar disorder. J Clin Psychiatry. 2009;70:1017-23. medications,66. Taylor M, Bressan RA, Pan Neto P, Brietzke E. Early intervention for bipolar disorder: current imperatives, future directions. Rev Bras Psiquiatr. 2011;33:s197-212.,5555. Torres IJ, Kozicky J, Popuri S, Bond DJ, Honer WG, Lam RW, et al. 12-month longitudinal cognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord. 2014;16:159-71. and adherence,8787. Martinez-Aran A, Scott J, Colom F, Torrent C, Tabares-Seisdedos R, Daban C, et al. Treatment nonadherence and neurocognitive impairment in bipolar disorder. J Clin Psychiatry. 2009;70:1017-23. have also been shown to correlate significantly with cognitive impairment.

In short, early intervention could play a crucial role in preventing illness progression (and any associated cognitive/functional decline) in BD. Primary prevention could be used to treat individuals at UHR of developing psychiatric disorders, as well as patients in stage I (more specific but still subsyndromal symptoms).8888. Berger GE, Wood SJ, Ross M, Hamer CA, Wellard RM, Pell G, et al. Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study. Curr Pharm Des. 2012;18:570-5. There is evidence supporting the neuroprotective benefits of early interventions for stage I patients, with the possibility of preserving cognitive and psychosocial functioning.7676. Torrent C, Bonnin Cdel M, Martinez-Aran A, Valle J, Amann BL, Gonzalez-Pinto A, et al. Efficacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. Am J Psychiatry. 2013;170:852-9.,8989. 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.,9090. Reinares M, Colom F, Rosa AR, Bonnin CM, Franco C, Sole B, et al. The impact of staging bipolar disorder on treatment outcome of family psychoeducation. J Affect Disord. 2010;123:81-6.

Biomarkers

As several different sets of symptoms and risk factors might be present prior to full-blown BD, a cluster of features including trait factors (such as genetic risk and personality traits) and state-related factors (such as subthreshold symptoms) might best capture the “at-risk” state for BD.44. Bechdolf A, Ratheesh A, Cotton SM, Nelson B, Chanen AM, Betts J, et al. The predictive validity of bipolar at-risk (prodromal) criteria in help-seeking adolescents and young adults: a prospective study. Bipolar Disord. 2014;16:493-504. Moreover, correlating these symptoms with prodromal biomarkers offers an exciting juncture whereby targeted interventions could be opportunistically employed to prevent neurodegenerative changes from accruing as the disease progresses.1111. Roda A, Chendo I, Kunz M. Biomarkers and staging of bipolar disorder: a systematic review. Trends Psychiatry Psychother. 2015;37:3-11.,9191. 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. Nevertheless, empirical data supporting the use of biomarkers for outcome prediction in prodromal stages are limited.9292. McGorry PD. Early intervention in psychosis: obvious, effective, overdue. J Nerv Ment Dis. 2015;203:310-8. One of the first studies, conducted by Padmos et al.,9393. Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry. 2008;65:395-407. identified a discriminating and coherent expression of 19 pro-inflammatory genes transcription in monocytes of patients with BD and in the offspring of BD parents. These results were in line with the work of Mesman et al.,2323. Mesman E, Nolen WA, Reichart CG, Wals M, Hillegers MH. The Dutch bipolar offspring study: 12-year follow-up. Am J Psychiatry. 2013;170:542-9. who conducted a longitudinal follow-up study and found that, during adolescence, offspring of BD parents demonstrated increased inflammatory gene expression in monocytes, high serum levels of pentraxin 3 (PTX3; a regulator of inflammatory response), but normal levels of the chemokine CCL2,2323. Mesman E, Nolen WA, Reichart CG, Wals M, Hillegers MH. The Dutch bipolar offspring study: 12-year follow-up. Am J Psychiatry. 2013;170:542-9. as well as decreased levels of brain-derived neurotrophic factor (BDNF). During young adulthood, monocyte activation remained, although to a lesser degree; serum PTX3 levels remained high; and signs of monocyte migration became apparent through increased CCL2 levels. In adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased, and both BDNF and S100B were increased. These abnormalities were independent of psychopathology state at all stages.

The identification of biological markers associated with clinical symptoms of imminent mania onset (in clinical high-risk individuals) might help increase the odds of early detection of BD and allow selection of subgroups for implementation of prevention strategies.55. Correll CU, Hauser M, Penzner JB, Auther AM, Kafantaris V, Saito E, et al. Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode. Bipolar Disord. 2014;16:478-92. To date, only preliminary data about biomarkers in at-risk states are available. These indicate that individuals at high risk of developing BD may have higher levels of lipid peroxidation as compared with healthy controls and lower levels compared with young people with syndromal BD.9494. Scola G, McNamara RK, Croarkin PE, Leffler JM, Cullen KR, Geske JR, et al. Lipid peroxidation biomarkers in adolescents with or at high-risk for bipolar disorder. J Affect Disord. 2016;192:176-83. In addition, small-scale studies have suggested that changes in sleep, circadian rhythm, and social rhythm regularity are altered in at-risk youths compared with age- and gender-matched healthy controls.9595. Alloy LB, Boland EM, Ng TH, Whitehouse WG, Abramson LY. Low social rhythm regularity predicts first onset of bipolar spectrum disorders among at-risk individuals with reward hypersensitivity. J Abnorm Psychol. 2015;124:944-52. 96. Zanini MA, Castro J, Cunha GR, Asevedo E, Pan PM, Bittencourt L, et al. Abnormalities in sleep patterns in individuals at risk for psychosis and bipolar disorder. Schizophr Res. 2015;169:262-7.-9797. Castro J, Zanini M, Goncalves Bda S, Coelho FM, Bressan R, Bittencourt L, et al. Circadian rest-activity rhythm in individuals at risk for psychosis and bipolar disorder. Schizophr Res. 2015;168:50-5. The predictive power of these biomarkers for transition to BD at follow-up is unknown.99. Brietzke E, Mansur RB, Soczynska JK, Kapczinski F, Bressan RA, McIntyre RS. Towards a multifactorial approach for prediction of bipolar disorder in at risk populations. J Affect Disord. 2012;140:82-91.

Conclusions

This review highlights not only the emerging evidence but also the critical gaps in our knowledge about the early stages of BD. One of these gaps is the urgent need to develop consensus-based criteria to define at-risk or clinical high-risk states. It is also important to harmonize recruitment criteria for offspring studies or, at least, to mandate reporting of the sampling strategy employed, thus allowing readers to compare the influence of recruitment on outcomes. The current use of disparate criteria makes if difficult to compare findings across studies and to generalize findings to other locations or to clinical practice. Incorporation of biomarkers into research on the early stages of BD is also a necessity, as clinical phenotypes alone are highly unlikely to have predictive validity for BD onset. However, research on biomarkers in psychiatry in general is still in its infancy and beset by methodological issues, including reproducibility, replication, validity, and integration concerns.9292. McGorry PD. Early intervention in psychosis: obvious, effective, overdue. J Nerv Ment Dis. 2015;203:310-8.,9898. Kraemer HC, Schultz SK, Arndt S. Biomarkers in psychiatry: methodological issues. Am J Geriatr Psychiatry. 2002;10:653-9.,9999. Scarr E, Millan MJ, Bahn S, Bertolino A, Turck CW, Kapur S, et al. Biomarkers for psychiatry: the journey from fantasy to fact, a report of the 2013 CINP think tank. Int J Neuropsychopharmacol. 2015;18:pyv042.

Another challenge in predicting outcomes is the need to develop and apply big-data bioinformatics platforms to analyze and integrate the volume of data available from large samples, multiple samples, and international multicenter studies.100100. McIntyre RS, Cha DS, Jerrell JM, Swardfager W, Kim RD, Costa LG, et al. Advancing biomarker research: utilizing 'Big Data' approaches for the characterization and prevention of bipolar disorder. Bipolar Disord. 2014;16:531-47. Bioinformatics tools allied to system biology paradigms may support more robust discoveries on the early stages of BD than any single approach on its own.101101. Alawieh A, Zaraket FA, Li JL, Mondello S, Nokkari A, Razafsha M, et al. Systems biology, bioinformatics, and biomarkers in neuropsychiatry. Front Neurosci. 2012;6:187.

Despite gaps in our knowledge, it is still vital to raise awareness among mental health professionals of the need for more timely and accurate diagnosis of BD, so as to enable recognition of the putative prodromes of BD as early as possible and, consequently, to minimize the use of antidepressant or psychostimulant monotherapies in at-risk individuals. This has been an important first step in promoting the philosophy of early intervention in psychosis, and is equally important for the field of mood disorders.2121. Scott J. Bipolar disorder: from early identification to personalized treatment. Early Interv Psychiatry. 2011;5:89-90.,3030. Singh MK. Is there validity to the bipolar prodrome?J Clin Psychiatry. 2015;76:e655-6.

Acknowledgements

EB has received research grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação de Amparo è Pesquisa do Estado de São Paulo (FAPESP), and has won a prize from L’Oréal/UNESCO/Academia Brasileira de Ciências para Mulheres na Ciência. ARR received support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). JS has received funding to visit academic centers in Brazil via the Science without Borders program; has received grant funding from the Medical Research Council (including for projects on bipolar II disorders, actigraphy, and cognitive-behavioral therapy for difficult-to-treat bipolar disorders), from the Research for Patient Benefit program (PB-PG-0609-16166: Early identification and intervention in young people at risk of mood disorders), and an NTW FSF grant (Trajectories of alcohol and substance use in early-onset mood disorders); and has received Independent Investigator grants via Newcastle University from AstraZeneca and Johnson & Johnson.

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Publication Dates

  • Publication in this collection
    11 Aug 2016
  • Date of issue
    Oct-Dec 2016

History

  • Received
    4 Apr 2016
  • Accepted
    9 May 2016
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