Mechanisms of Illness Progression in the Recurrent Affective Disorders
ABSTRACT Along with genetic vulnerability, multiple environmental factors convey liability to illness progression, including: (1) distal and proximal stressors; (2) recurrence of episodes; and (3) comorbid cocaine abuse. Recurrence of each of these can increase responsivity (sensitize) to themselves and cross-sensitize to the two other factors and drive illness progression as seen clinically in increases in cycle acceleration, severity or duration of episodes, treatment refractoriness, disability, cognitive dysfunction, and premature death. Some mechanisms appear common to all three types of sensitization, such as decreases of brain-derived neuroprotective factor (BDNF) in hippocampus and blood, as well as increases in BDNF in the nucleus accumbens, suggesting the possibility that single treatments could ameliorate several of these factors at once. A potential example is N-acetylcysteine (NAC), which decreases bipolar affective illness severity (Berk et al. Biol Psychiatry 64:468–475, 2008) and cocaine reinstatement and craving (Baker et al. Ann N Y Acad Sci 1003:349–351, 2003; LaRowe et al. Am J Addict 15:105–110, 2006). Mechanisms of illness progression also involve epigenetic changes and add further rationale to the existing empirical clinical evidence of the importance of early recognition, treatment, and prevention of affective episodes. Adequate treatment could prevent or ameliorate both the increases in pathological factors and erosion of adaptive factors that propel illness exacerbation and treatment resistance. This view of the sensitization and cross-sensitization among stressors, episodes, and abused substances should lead to a fundamental re-conceptualization of the recurrent affective disorders not as benign, isolated episodes of “mental” illness, but as severe, potentially progressive and lethal medical disorders of brain and body that deserve careful life-long monitoring and treatment.
SourceAvailable from: Janusz Rybakowski[Show abstract] [Hide abstract]
ABSTRACT: Objective We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined.Method We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging.ResultsWe report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers.Conclusion Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of ‘early’- and ‘late’-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.Acta Psychiatrica Scandinavica 06/2014; 130(5). DOI:10.1111/acps.12305 · 5.55 Impact Factor
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ABSTRACT: INTRODUCTION: The understanding of the pathophysiology of bipolar disorder has steadily advanced in the past few years. Thereby, a focus on allostatic load and systemic changes has appeared, with the aim to understand illness progression. Amongst the peripheral markers, molecules that can be widely classified into neurotrophins, oxidadive stress markers, and inflammation markers have been elevated. OBJECTIVE: To describe recent findings regarding the systemic pathophysiology of bipolar disorder, with a special focus on Brazilian studies and to create a coherent view of the current knowledge in the field. METHOD: Narrative review of the literature regarding neurotrophins, oxidative stress, and inflammatory markers in bipolar disorder. RESULTS: A diverse body of evidence, based on both pre-clinical and clinical studies, reveals consistent systemic changes in bipolar disorder. The findings are particularly robust in patients after multiple episodes. Thereby, remarkable changes related to manic and depressive episodes were found in neurotrophins and oxidative damage to lipids. Regarding to immune system alterations, in particular pro-inflammatory states, the literature is less consistent. DISCUSSION: Systemic changes that link bipolar disorder to clinical comorbidity, cognitive dysfunction, disability and early mortality are becoming evident. In the near future, longitudinal studies with population-based samples and clinical trials incorporating biomarkers are needed to shed light upon the notion of a multisystem involvement in bipolar disorder.Revista de Psiquiatria Clínica 12/2011; 39(2):60-67. DOI:10.1590/S0101-60832012000200004 · 0.89 Impact Factor
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ABSTRACT: Stressful events promote a wide range of neurotransmitter and neuroendocrine changes, which likely serve in an adaptive capacity. However, with repeated stressor exposure, behavioral disturbances, such as anxiety and depression, may develop. Moreover, re-exposure to a stressor for some time following an initial aversive experience may instigate especially pronounced neurochemical variations that favor the emergence of depression and anxiety. These outcomes may stem from any number of neurobiological changes, but increasing attention has focused on the potential contribution of inflammatory factors, such as cytokines. Given the distinct differences in stressor responsiveness that have been reported between males and females, alongside a much higher rate of mood disorders in females, we sought to examine whether repeated exposure to stressors would differentially influence elevated plus-maze behavior in male and female CD-1 mice, and whether such changes would be paralleled by variations of pro-inflammatory mRNA cytokine expression within the prefrontal cortex (PFC) and the hippocampus. In males, the sensitization of interleukin (IL)-1β was evident in both brain regions in those mice that had initially been stressed and then 6 weeks later re-exposed to a stressor exhibiting higher IL-1β expression than did mice stressed on only a single occasion. Females demonstrated higher baseline expression of cytokine expression within the hippocampus, but neither a single exposure nor re-exposure stressor treatment produced significant cytokine elevations. In the PFC an acute stressor treatment increased IL-1R expression, but otherwise had little effect. In a plus-maze test, stressed male mice displayed markedly reduced latencies to the open arms that was evident in a test 6 weeks later irrespective of whether mice were re-exposed to a stressor, whereas in females this outcome was less evident. These studies are consistent with the perspective that female mice are relatively resilient toward stressor-induced cytokine elevations even though in humans females are generally more prone to developing mood disturbances.Neuroscience 09/2014; 277:239–249. DOI:10.1016/j.neuroscience.2014.07.007 · 3.33 Impact Factor