Bipolar Disorder: Emotional Dysregulation and

Pearls in Clinical Neuroscience

Bipolar Disorder: Emotional Dysregulation and Neuronal Vulnerability By Dan J. Stein, MD, PhD, Neil Horn, MB ChB, FRCPsych, Rajkumar Ramesar, PhD, and Jonathan Savitz, PhD

ABSTRACT

first manic episode had responded quickly to pharmacotherapy, each of her subsequent episodes had proved more resistant to treatment. Although she initially insisted on early discharge, during her psychotherapy she was gradually persuaded to stay until her symptoms were clearly improved. She was discharged on a combination of several agents in addition to lithium.

Bipolar disorder is clinically characterized by fluctuating affect, and neuropsychologically by impairment in executive functions. Such phenomena are consistent with the centrality of emotional dysregulation and impulsivity to bipolar disorder. They are also consistent with a key

COGNITIVE-AFFECTIVE NEUROSCIENCE

role for prefrontal-subcortical (striatal-thalamic) and associated limbic circuitry in its mediation.

Bipolar disorder is characterized clinically by fluctuating affect and neuropsychologically by impairment in executive functions.1-4 Such phenomena are consistent with the centrality of emotional dysregulation5,6 and impulsivity7,8 to bipolar disorder. While there is ongoing debate about the exact nature of such cognitive-affective dysfunction,5,6 it is consistent with a key role for prefrontal-subcortical (striatalthalamic) and associated limbic circuitry in the mediation of bipolar disorder. 9-11 Furthermore, there is growing data on the cellular mechanisms contributing to neuronal vulnerability in this mediating circuitry.12,13

Furthermore, there is growing data on the cellular mechanisms contributing to neuronal vulnerability in this mediating circuitry.

CASE REPORT Ursulla is a 24-year-old female who was admitted after presenting with her fourth manic episode in as many years. While lithium proved useful in maintaining a stable mood, she continued to have periods of hypomania. During such periods, she was less adherent to medication and more prone to use substances. While her

Dr. Stein is professor in and chair of the Department of Psychiatry and Mental Health at the University of Cape Town in South Africa, and is also on faculty at the Mount Sinai School of Medicine in New York City. He is the author of Philosophy of Psychopharmacology: Happy Pills, Smart Pills, and Pep Pills published by Cambridge University Press. Dr. Horn is senior lecturer in the Department of Psychiatry and Mental Health and Dr. Ramesar is professor in and chair of the Division of Human Genetics, both at University of Cape Town. Dr. Savitz is post-doctoral fellow in the Section on Neuroimaging in Mood and Anxiety Disorders in Mood and Anxiety Disorders Program at the National Institute of Mental Health in Bethesda, Maryland. Faculty Disclosures: Dr. Stein has received grant support/honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Lundbeck A/S, Orion, Pfizer, Pharmacia, Roche, Servier, Solvay, Sumitomo, Takeda, and Wyeth. Drs. Horn, Ramesar, and Savitz do not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Funding/Support: Dr. Stein receives support from the Medical Research Council of South Africa. Authors’ note: This case is based on an amalgam of the authors’ experience. CNS Spectr 14:3 © MBL Communications Inc.

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Neuroanatomy/Neurochemistry Functional imaging studies of bipolar disorder suggest dysfunction within subcortical (striatal-thalamic) and associated limbic regions, consistent with a model that diminished prefrontal modulation of such circuitry results in cognitive-affective dysregulation. 9 For example, euthymic individuals with bipolar disorder had increased striatal activity in response to potentially rewarding stimuli and decreased right dorsolateral prefrontal cortex activity in response to other emotionally salient stimuli (Figure 1),14 manic subjects had reduced ventrolateral prefrontal cortex regulation of amygdala response during emotion labeling (Figure 2), 15 and depressed bipolar subjects had an exaggerated increase in ventral prefrontal cortex during a Stroop task (Figure 3).16 Structural imaging studies11,17-19 show robust changes in various of these regions, albeit with some inconsistency across studies. Changes are consistently observable early in the course of the illness,20,21 indicating that structural abnormalities are not merely the sequelae of recurrent affective episodes or pharmacotherapy. Of particular note are the replicated findings of subcortical hyperintensity lesions on T2-weighted magnetic resonance imaging, at least partly consistent with an hypothesis of cellular vulnerability in bipolar disorder.12,13 Structural pathology is

also consistently found at postmortem in bipolar disorder; and includes abnormal neuronal size and reduced glial density in prefrontal cortices and subcortical nuclei.22 Magnetic resonance spectroscopy investigations have demonstrated abnormalities of membrane and second messenger metabolism, and of bioenergetics, in prefrontal cortex, striatum, and other regions. 10,23 This is consistent with a range of molecular findings suggesting that bipolar disorder is characterized by abnormalities in neuronal and synaptic plasticity. 12 The molecular basis of the neuronal vulnerability in bipolar disorder involves a range of cellular signaling cascades,12 and may be characterized by the inter-related processes of altered glutamatergic function, abnormal calcium influx, changed neurotrophin signaling, mitochondrial dysfunction, and oxidative stress.13,24-27 A key task for the future is to characterize changes in the cognitive-affective neuroscience of bipolar disorder over time, as it moves from a prodromal syndrome to a clinical disorder, and sometimes on to a resistant condition. 28 Various models have been put forward to help account for these changes; these include neuFIGURE 2.

Decreased activation of right lateral orbitofrontal cortex during an inhibition task was found during fMRI in patients with mania (bottom) compared with controls (top)15

FIGURE 1.

Euthymic bipolar individuals had increased activity in striatum in response to happy faces (left), and decreased activity in right dorsolateral prefrontal cortex in response to happy and neutral faces (right) during fMRI14

Hassel S, Almeida JRC, Kerr N, et al. Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: no associations with psychotropic medication load. Bipolar Disord Disord. 2008;10:916-927.

Foland LC, Altshuler LL, Bookheimer SY, et al. Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania. Psychiatry Research-Neuroimaging. 2008;162:27-37.

fMRI=functional magnetic resonance imaging.

fMRI=functional magnetic resonance imaging.

Stein DJ, Horn N, Ramesar R, Savitz J. CNS Spectr Spectr. Vol 14, No 3. 2009.

Stein DJ, Horn N, Ramesar R, Savitz J. CNS Spectr Spectr. Vol 14, No 3. 2009.

CNS Spectr 14:3 © MBL Communications Inc.

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Evolutionary Approaches Evolutionary theorists have considered the adaptive value of hypomania and associated features, as well as the possibility that mania represents a dysfunction in the relevant underlying psychobiological mechanisms. 50,51 They have argued that mood symptoms are particularly relevant to social hierarchy behaviors, such as dominance and submission. There is ongoing attention to the key question of how susceptibility alleles that predispose to common, harmful, heritable psychiatric disorders are able to persist.52

rosensitization 29 and allostatic load 30 theories. Translational approaches are likely to become increasingly relevant; animal models of bipolar disorder can focus on cognitive-affective deficits hypothesized to be central to this condition, or their mediating molecular mechanisms. 31-33 Gene expression studies34 may also contribute to elucidating pathogenesis.

Gene/Environment There is a large literature on both genetic and environmental contributors to bipolar disorder. 35-39 Although there is inconsistency across studies, findings are consistent with other work on the molecular basis of cellular vulnerability in bipolar disorder in pointing to the role of cellular signaling cascades.40,41 Gene-environment interactions are likely to play an important role in mediating susceptibility to bipolar disorder and its associated features. 42,43 Promising endophenotypes for bipolar disorder include certain executive impairments, 1-3,44,45 and perhaps neuroanatomical abnormalities. 20,46 There is growing research on the contribution of gene variants to imaging findings in bipolar disorder.47-49

CLINICAL IMPLICATIONS DSM-IV-TR Diagnosis There is ongoing debate about the optimal diagnostic criteria for bipolar disorder, and spectrum conditions.53-55 Clearly, emotional dysregulation and cellular vulnerability are not limited to bipolar disorder. Conversely, it may be useful to supplement the categorical criteria for bipolar disorder with dimensional measures of bipolar symptomatology.53,56 Our nosology may ultimately include biomarkers that contribute to diagnostic validity and clinical utility.57 Assessment/Evaluation Bipolar disorder is associated with significant morbidity.58,59 There are well-validated measures for screening and assessment of bipolar disorder, and its associated features.60-62 It is important to note that bipolar disorder is a systemic disease, and is frequently associated with a range of medical conditions, that deserve attention.63-65 Particular care is required in the assessment and evaluation of children and adolescents where bipolar disorder is part of the differential diagnosis.66,67

FIGURE 3.

Depressed bipolar patients had increased left caudal ventral prefrontal cortex activation compared with euthymic individuals while undertaking a Stroop task during fMRI16

Pharmacotherapy/Psychotherapy A focus on neuronal vulnerability, and its underlying mechanisms (eg, signaling cascades), may help explain how diverse agents, ultimately acting on common pathways, are effective in bipolar disorder. 12 Although expert guidelines and systematic reviews continue to emphasize the role of lithium, 68-71 various anticonvulsants and antipsychotics, and their combinations, are also effective.72-77 The optimal use of antidepressants for bipolar depression continues to be a matter of debate.78 Meanwhile, other agents are under active study.12,25,79-81

Blumberg HP, Leung HC, Skudlarski P, et al. A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry Psychiatry. 2003;60:601-609. fMRI=functional magnetic resonance imaging. Stein DJ, Horn N, Ramesar R, Savitz J. CNS Spectr Spectr. Vol 14, No 3. 2009.


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Psychotherapy may contribute to emotional regulation,82 and there is certainly an important evidence-base documenting the value of psychotherapy in the management of bipolar disorder, with enhanced long-term outcomes when added to pharmacotherapy.83-85 Psychoeducation may usefully address issues such as recognition of early signs, and improve adherence.86-89 There is also growing interest in the possibility of early intervention for bipolar disorder.90

15. Foland LC, Altshuler LL, Bookheimer SY, Eisenberger N, Townsend J, Thompson PM. Evidence for deficient modulation of amygdala response by prefrontal cortex in bipolar mania. Psychiatry Res. 2008;162:27-37. 16. Blumberg HP, Leung HC, Skudlarski P, et al. A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry Psychiatry. 2003;60:601-609. 17. McDonald C, Zanelli J, Rabe-Hesketh S, et al. Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry Psychiatry. 2004;56:411-417. 18. Kempton MJ, Geddes JR, Ettinger U, et al. Meta-analysis, database, and metaregression of 98 structural imaging studies in bipolar disorder. Arch Gen Psychiatry Psychiatry. 2008;65:1017-1032. 19. Konarski JZ, Mcintyre RS, Kennedy SH, et al. Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord. 2008;10:1-37. 20. Hajek T, Carrey N, Alda M. Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disord Disord. 2005;7:393-403. 21. Pfeifer JC, Welge J, Strakowski SM, Adler CM, DelBello MP. Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry Psychiatry. 2008;47:1289-1298. 22. Rajkowska G. Cell pathology in bipolar disorder. Bipolar Disord Disord. 2002;4:105-116. 23. Yildiz-Yesiloglu A, Ankerst DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry Psychiatry. 2006;30:969-995. 24. Quiroz JA, Gray NA, Kato T, et al. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology. Neuropsychopharmacology 2008;33:2551-2565. 25. Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008;11:851-876. 26. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry Psychiatry. 2005;10:900-919. 27. Zarate CA, Du J, Quiroz J, et al. Regulation of cellular plasticity cascades in the pathophysiology and treatment of mood disorders: role of the glutamatergic system. Ann N Y Acad Sci Sci. 2003;1003:273-291. 28. Berk M, Conus P, Lucas N, et al. Setting the stage: from prodrome to treatment resistance in bipolar disorder. Bipolar Disord. 2007;9:671-678. 29. Post RM. Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neurosci Biobehav Rev Rev. 2007;31:858-873. 30. Kapczinski F, Vieta E, Andreazza AC, et al. Allostatic load in bipolar disorder: Implications for pathophysiology and treatment. Neurosci Biobehav Rev Rev. 2008;32:675-692. 31. Machado-Vieira R, Kapczinski F, Soares JC. Perspectives for the development of animal models of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry Psychiatry. 2004;28:209-224. 32. Geyer MA. Developing translational animal models for symptoms of schizophrenia or bipolar mania. Neurotox Res. 2008;14:71-78. 33. Kato T, Kubota M, Kasahara T. Animal models of bipolar disorder. Neurosci Biobehav Rev Rev. 2007;31:832-842. 34. Elashoff M, Higgs BW, Yolken RH, et al. Meta-analysis of 12 genomic studies in bipolar disorder. J Mol Neurosci Neurosci. 2007;31:221-243. 35. Kato T. Molecular genetics of bipolar disorder and depression. Psychiatry Clin Neurosci. 2007;61:3-19. Neurosci 36. Serretti A, Mandelli L. The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions. Mol Psychiatry Psychiatry. 2008;13:742-771. 37. Etain B, Henry C, Bellivier F, et al. Beyond genetics: childhood affective trauma in bipolar disorder. Bipolar Disord Disord. 2008;10:867-876. 38. Alloy LB, Abramson LY, Urosevic S, Walshaw PD, Nusslock R, Neeren AM. The psychosocial context of bipolar disorder: environmental, cognitive, and developmental risk factors. Clin Psychol Rev Rev. 2005;25:1043-1075. 39. Post RM, Leverich GS. The role of psychosocial stress in the onset and progression of bipolar disorder and its comorbidities: the need for earlier and alternative modes of therapeutic intervention. Dev Psychopathol. 2006;18:1181-1211. 40. Burton PR, Clayton DG, Cardon LR, et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661-678 41. Sklar P, Smoller JW, Fan J, et al. Whole-genome association study of bipolar disorder. Mol Psychiatry Psychiatry. 2008;13:558-569. 42. Savitz J, Van Der Merwe L, Stein DJ, et al. Genotype and childhood sexual trauma moderate neurocognitive performance: a possible role for brain-derived neurotrophic factor and apolipoprotein E variants. Biol Psychiatry Psychiatry. 2007;62:391-399. 43. Savitz JB, Van Der Merwe L, Stein DJ, et al. Neuropsychological task performance in bipolar spectrum illness: genetics, alcohol abuse, medication and childhood trauma. Bipolar Disord Disord. 2008;10:49-494. 44. Savitz JB, Ramesar RS. Personality: is it a viable endophenotype for genetic studies of bipolar affective disorder? Bipolar Disord Disord. 2006;8:322-337.

CONCLUSION While mood fluctuations are normal, in bipolar disorder there is clearly dysregulation of the relevant psychobiological mechanisms. Advances in functional brain imaging have led to insights not only into the neurocircuitry underpinning normal emotion regulation,82 but also into the overlapping circuits involved in bipolar disorder. There is evidence of structural abnormalities in these circuits in bipolar disorder, and a growing understanding of the molecular mechanisms that may underpin these abnormalities. Although models of the psychobiology of bipolar disorder have many gaps, they provide a useful framework for approaching treatment and for planning future research. CNS

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