Pathophysiology of bipolar disorder
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Pathophysiology of Bipolar Disorder
Introduction to Bipolar Disorder Pathophysiology
Bipolar disorder (BD) is a complex and multifactorial mood disorder characterized by alternating episodes of mania and depression. The pathophysiology of BD involves a myriad of genetic, environmental, and neurobiological factors that interact in intricate ways to produce the clinical manifestations of the disorder.
Neurotransmitter Signaling and Brain Network Alterations
One of the core pathological alterations in BD is damage to the limbic network, which results in disrupted neurotransmitter signaling, particularly involving dopamine and serotonin. This damage is often mediated by immune-inflammatory processes affecting white matter connections within the limbic network. These disruptions lead to recurrent reconfigurations of intrinsic brain activity, manifesting as abnormal subcortical-cortical coupling and network activity changes. This dysbalance between networks, such as the sensorimotor, salience, and default-mode networks, contributes to the psychomotor, affective, and cognitive symptoms observed during manic and depressive phases of BD .
Genetic and Environmental Factors
The pathophysiology of BD is influenced by both genetic predispositions and environmental stressors. Genetic factors include defects in apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling pathways. Environmental factors, such as stress, interact with these genetic vulnerabilities, further complicating the disorder's pathophysiology. The stress-diathesis model and newer concepts like allostasis and hormesis provide frameworks for understanding how stress impacts BD development and progression 28.
Neuroplasticity and Chronobiology
Disturbed brain development and neuroplasticity are central to BD's pathophysiology. Chronobiological disruptions, including abnormalities in circadian rhythms, are also significant. These disruptions are linked to mitochondrial dysfunction, which affects cellular bioenergetics and oxidative stress pathways. Mitochondrial dysfunction is associated with abnormal Ca2+ levels, glutamate excitotoxicity, and imbalances in pro- and antiapoptotic proteins, leading to increased apoptosis and decreased ATP synthesis 269.
Role of Non-Coding RNAs
Recent research has highlighted the role of non-coding RNAs (ncRNAs) in BD. Dysregulated ncRNAs, including miRNAs, lncRNAs, and circRNAs, are enriched in neuron-related pathways such as GABAergic and glutamatergic synapses. These alterations provide insights into the molecular mechanisms underlying BD and suggest potential targets for novel therapeutic interventions .
Brain Regions and Functional Alterations
Imaging studies have identified several brain regions implicated in BD, including the anterior cingulate, amygdala, and prefrontal cortex. These regions are involved in mood regulation and are affected by disruptions in monoamine signaling and the hypothalamic-pituitary-adrenal (HPA) axis. The dynamic nature of compensatory processes in the brain and the interaction with pharmacologic treatments further complicate the understanding of BD's pathophysiology .
Pediatric Bipolar Disorder
In pediatric BD, marked state fluctuations, including rapid cycling and high rates of comorbid attention-deficit/hyperactivity disorder (ADHD), are prominent. Research on neural mechanisms underlying positive valence states and state regulation is crucial for understanding pediatric BD. Studies indicate that attention regulation plays a significant role in emotion regulation, which may be particularly relevant for the rapid mood changes observed in children with BD .
Conclusion
The pathophysiology of bipolar disorder is a multifaceted interplay of genetic, environmental, and neurobiological factors. Disruptions in neurotransmitter signaling, neuroplasticity, chronobiology, and mitochondrial function, along with the role of non-coding RNAs and specific brain regions, contribute to the complex clinical presentation of BD. Understanding these mechanisms is essential for developing targeted therapies and improving outcomes for individuals with BD.
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