Clinical meaning
Bipolar disorder is a chronic, episodic mood disorder characterized by alternating periods of mania (or hypomania) and major depression, with euthymic intervals between episodes. The neurobiology involves dysregulation across multiple neurotransmitter systems and neural circuits. Dopaminergic hyperactivity in the mesolimbic pathway is implicated in manic symptoms (euphoria, grandiosity, psychomotor agitation), while reduced serotonergic and noradrenergic transmission in prefrontal cortical circuits underlies depressive episodes. Glutamate excitotoxicity and impaired GABAergic inhibition contribute to mood instability and neuronal damage over time. Neuroimaging studies reveal decreased gray matter volume in the prefrontal cortex and anterior cingulate cortex (areas responsible for emotional regulation and executive function), enlarged amygdala with increased reactivity (contributing to emotional dysregulation), and disrupted white matter tracts connecting frontal and limbic structures. Mitochondrial dysfunction, oxidative stress, and neuroinflammation (elevated IL-6, TNF-alpha, and CRP during mood episodes) contribute to progressive neurodegeneration with successive episodes — the concept of 'neuroprogression.' The hypothalamic-pituitary-adrenal (HPA) axis shows dysregulation with elevated cortisol during both manic and depressive phases. Genetic heritability is approximately 80%, with polygenic contributions from CACNA1C (voltage-gated calcium channels), ANK3 (ankyrin G involved in axon initial segment function), and CLOCK genes (circadian rhythm regulation). Kindling theory proposes that initial episodes are often triggered by stressors, but successive episodes occur more spontaneously due to progressive limbic sensitization, emphasizing the importance of early and sustained pharmacotherapy.