Figure 2. Summary of recent research on neurobiological mechanisms of BD. Multiple biochemical pathways, not all of which are shown here, interact simultaneously to cause cellular damage. Mitochondrial dysfunction in BD pathophysiology is based on changes affecting oxidative phosphorylation, energy production, increased formation of ROS, mitochondrial DNA damage, membrane permeability, Ca+2 imbalance, and impairment in mitochondrial dynamics and mitophagy. These alterations can lead to increased apoptosis and NLRP3-inflammasome activation. However, this relationship may be bidirectional, wherein mitochondrial dysfunction can increase inflammatory factors, and inflammation can induce ROS production and mitochondrial dysfunction. Inflammation, also reported in BD, is responsible for the activation of enzymes indoleamine 2,3-dioxygenase and kynurenine 3-monooxygenase (KMO), leading to the skewing of the kynurenine metabolic balance toward increased neurotoxicity. Moreover, inflammatory mediators and stress mechanisms activate the HPA axis resulting in secretion of corticosteroids from the adrenal cortex. In BD, the negative feedback of cortisol to the hypothalamus and pituitary components is thought to be impaired, leading to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized, leading to increased activity of pro-inflammatory immune mediators and downregulation of neurotrophic factors such as the brain-derived neurotrophic factor. Besides, corticosteroids are secreted rhythmically, displaying ultradian and circadian patterns, and CLOCK-related genes directly regulate glucocorticoid receptor expression. Circadian rhythms also play a role in mitochondrial functioning by regulating biogenesis, fission/fusion, and mitophagy. These alterations could initiate a vicious cycle where multiple systems and mechanisms exacerbate and accelerate cellular damage, synaptic dysfunction, and impaired neurogenesis, resulting in progressive structural brain changes and cognitive decline thought to contribute to the neuroprogression of BD. 3-HK = 3-hydroxykynurenine; ACTH = adrenocorticotropic hormone; BD = bipolar disorder; BDNF = brain-derived neurotrophic factor; Ca = calcium; CRH = corticotropin releasing hormone; Fis-1 = mitochondrial fission 1 protein; FKBP51 = FK506-binding protein 51; GR = glucocorticoid receptor; HPA = hypothalamic-pituitary-adrenal; IDO = indoleamine 2,3-dioxygenase; IL = interleukin; KMO = kynurenine 3-monooxygenase; NMDA = N-methyl-D-aspartate; OXPHOS = mitochondrial oxidative phosphorylation; P = phosphorus; ROS = reactive oxygen species.