Neuroprogression in Bipolar Disorder
Bipolar Disorder (BD) is a neuropsychiatric illness that is the sixth leading cause of disability worldwide . BD is characterized by alternating manic and depressive mood episodes, with interspersed periods of euthymia that vary in length depending on biochemical, clinical and psychosocial factors implicated in age of illness onset, mood episode frequency and severity of clinical progression [2, 3]. Studies in which genetic susceptibility for BD is assessed report that the Brain Derived Neurotrophic Factor (BDNF) val66met polymorphism (val/met) is significantly involved in illness chronicity and neuroprogression, a more severe clinical course characterized by earlier age of illness onset (BD type I: ~11 yrs. earlier than those with val/val) frequent mood episodes (4 additional episodes per year), higher rate of medical comorbidities, neurocognitive impairment and functional decline [3-5]. In a biochemical sense, neuroprogression can be defined as the process through which the CNS reacts to repeated neurotoxic injury (i.e., inflammation and oxidative stress) . While BD clinical staging models   have been developed to assess neuroprogression and treatment outcomes, recent evidence-based efforts have been made to incorporate neuroinflammatory correlates as the high prevalence of medical comorbidity (i.e., cardiometabolic and endocrine disorders) suggests that shared mechanistic pathways mediated by inflammation may underlie BD neuroprogression.
In BD, mood episodes have been shown to correlate with elevated levels of pro-inflammatory cytokines IL-6, IL-10 and TNF-a – which have also been found abundantly in the orbitofrontal cortex in post-mortem studies of subjects with BD who completed suicide [8, 9]. In tandem with pro-inflammatory and oxidative stress upregulation, a significant decrease in anti-inflammatory cytokines and neurotrophins emerges during acute mood episodes and is related to the white matter hyperintensities that increase with number of manic episodes [3, 10]. Likewise, cardiometabolic and immunologic illnesses often emerge as a result of chronic pro-inflammatory upregulation, and are a marker of illness progression for BD .
BDNF is a protein essential for neuronal survival and synaptic functioning and has been shown to be significantly decreased during acute manic and depressive episodes, and chronically decreased during late stages [3, 8]. Similarly, BD carriers of the val/met polymorphism present significantly lower levels of serum BDNF compared to carriers of val/val variants, which translates to lower synaptic secretion and distribution of BDNF. Therefore, neuroanatomic correlates such as lower volumetric densities in the hippocampus [4, 11, 12], smaller bilateral anterior cingulate gyrus volumes , and reduced gray matter volume in the DLPFC , and larger ventricles  become pronounced in late stages of the illness. Congruently, subjects with BD tend to show pervasive impairments in verbal memory, selective attention and executive functioning , while impairments in verbal fluency are most often associated with depressive states, low serum BDNF levels and the val/met polymorphism [3, 13].
Some controversy remains in regard to neuroprogression, as emerging longitudinal studies  have found that some proposed correlates (i.e., neurocognitive impairment) remain stable regardless of mood episode frequency. Genetic endophenotypes (e.g., BDNF val/met polymorphism), medication type, and treatment adherence may partly modulate any fluctuations in neurocognitive functioning, as lithium is known to exert neuroprotective effects – primarily, by modulating BDNF regulation and anti-inflammatory cytokines [15, 16]. Similarly, residual symptoms tend to become unremitting during late stages of BD and may persistently burden baseline neurocognitive functioning . Because manifestations of BD are often complex and heterogeneous, future research efforts focused on the assessment of biochemical and neurocognitive correlates of neuroprogression may lead to further understanding the prognosis and treatment outcome for patients affected by this variant of BD.
Abstract: Longitudinal relationship between clinical course and neurocognitive impairments in bipolar disorder (2017)
Background: The aim of this study was to estimate the relationship between clinical course and trajectory of neurocognitive functioning during a follow-up period in a sample of euthymic bipolar patients. Methods: Fifty-one patients with BD performed two-neurocognitive assessment separated by a period of at least 48 months. The clinical course during the follow-up period was documented by: three measures 1) number of affective episodes, 2) time spent ill, and 3) mood instability. Results: Patients were followed-up for a mean period of 73.21 months. Neurocognitive performance tended to be stable throughout the follow-up. Performance in verbal memory and executive functions at the end of study were related with the number of hypo/manic episodes and time spent with hypo/manic symptoms during the followup. None of the clinical measures considered were related to changes in neurocognitive performance over the follow-up period. Limitations: The relatively small sample size limits the value of subgroup analysis. The study design does not rule out some risk of selection bias. Conclusions: Although there may be a positive relationship between number of episodes and neurocognitive deficits in patients with bipolar disorder, successive episodes do not seem to modify the trajectory of neurocognitive functioning over time. Theoretical implications of these findings are discussed.
Martino, D., Igoa, A., Marengo, E., Scápola, M. and Strejilevich, S. (2018). Longitudinal relationship between clinical course and neurocognitive impairments in bipolar disorder. Journal of Affective Disorders, 225, pp.250-255.
Other Media and Resources
Website – International Society for Bipolar Disorders
Website – International Bipolar Foundation
Documentary – Ride the Tiger: A Guide Through the Bipolar Brain (PBS)
Description (from PBS)
A one-hour documentary that tells the stories of individuals with bipolar disorder. Nearly 6 million Americans have been diagnosed with bipolar disorder and yet little is known about how the illness manifests itself in our brains. Ride the Tiger tells the stories of accomplished individuals who have been diagnosed with bipolar, and explores treatment options.
Webinar – Flavio Kapczinski on “Neuroprogression and immune activation in bipolar disorder” at the World Congress of Psychiatry 2017, Berlin.
Webinar – Aging Too Soon? Premature Brain and Biological Aging In Bipolar Disorder
With Dr. Lisa Eyler
Description (directly from IBPF)
People with bipolar disorder suffer from more age-related physical illnesses and live shorter lives than those without the disorder, leading to the idea that bipolar disorder is a condition that affects the whole body and involves an acceleration of the normal aging process. Immune and inflammatory pathways may be involved in the altered course of aging in bipolar disorder. In this talk, Dr. Eyler will review evidence for altered brain aging in BD and for changes in aging-related inflammatory pathways. She will present data from her own magnetic resonance imaging study of brain aging which used multiple measures of brain structural and functional integrity to create a “brain age” prediction for each participant. She will also present initial results from her ongoing longitudinal study of inflammation, mood, and cognition in BD. The implication of these findings for treatment and prognosis will be discussed.
Elshahawi, H. H., Essawi, H., Rabie, M. A., Mansour, M., Beshry, Z. A., & Mansour, A. N. (2011). Cognitive functions among euthymic bipolar I patients after a single manic episode versus recurrent episodes. Journal of Affective Disorders, 130(1-2), 180-191. doi:10.1016/j.jad.2010.10.027
Maletic, V., & Raison, C. (2014). Integrated Neurobiology of Bipolar Disorder. Frontiers in Psychiatry, 5. doi:10.3389/fpsyt.2014.00098
Muneer, A. (2016). Staging Models in Bipolar Disorder: A Systematic Review of the Literature. Clinical Psychopharmacology and Neuroscience, 14(2), 117-130. doi:10.9758/cpn.2016.14.2.117
Rheenen, T. E., Meyer, D., & Rossell, S. L. (2014). Pathways between neurocognition, social cognition and emotion regulation in bipolar disorder. Acta Psychiatrica Scandinavica, 130(5), 397-405. doi:10.1111/acps.12295
Solé, B., Jiménez, E., Torrent, C., Reinares, M., Bonnin, C. D., Torres, I., . . . Vieta, E. (2017). Cognitive Impairment in Bipolar Disorder: Treatment and Prevention Strategies. International Journal of Neuropsychopharmacology, 20(8), 670-680. doi:10.1093/ijnp/pyx032
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