Chonnam Med J.  2016 Jan;52(1):18-37. 10.4068/cmj.2016.52.1.18.

The Neurobiology of Bipolar Disorder: An Integrated Approach

• Muneer A

• KMID: 2152653
• DOI: http://doi.org/10.4068/cmj.2016.52.1.18

Abstract

Bipolar disorder is a heterogeneous condition with myriad clinical manifestations and many comorbidities leading to severe disabilities in the biopsychosocial realm. The objective of this review article was to underline recent advances in knowledge regarding the neurobiology of bipolar disorder. A further aim was to draw attention to new therapeutic targets in the treatment of bipolar disorder. To accomplish these goals, an electronic search was undertaken of the PubMed database in August 2015 of literature published during the last 10 years on the pathophysiology of bipolar disorder. A wide-ranging evaluation of the existing work was done with search terms such as "mood disorders and biology," "bipolar disorder and HPA axis," "bipolar disorder and cytokines," "mood disorders and circadian rhythm," "bipolar disorder and oxidative stress," etc. This endeavor showed that bipolar disorder is a diverse condition sharing neurobiological mechanisms with major depressive disorder and psychotic spectrum disorders. There is convincing evidence of crosstalk between different biological systems that act in a deleterious manner causing expression of the disease in genetically predisposed individuals. Inflammatory mediators act in concert with oxidative stress to dysregulate hormonal, metabolic, and circadian homeostasis in precipitating and perpetuating the illness. Stress, whether biologically or psychologically mediated, is responsible for the initiation and progression of the diathesis. Bipolar spectrum disorders have a strong genetic component; severe life stresses acting through various paths cause the illness phenotype.

Keyword

Bipolar disorder; Circadian rhythm; Oxidative stress

MeSH Terms

Bipolar Disorder*
Circadian Rhythm
Comorbidity
Depressive Disorder, Major
Disease Susceptibility
Homeostasis
Neurobiology*
Oxidative Stress
Phenotype
Stress, Psychological

Figure

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  FIG. 1 The central role of glucocorticoid receptor in the biological functions of cortisol. Cortisol (CORT) enters the cytosol by passive diffusion and binds to the glucocorticoid receptor (GR) which is a dynamic multiprotein complex composed of an array of chaperones. These have inhibitory as well as facilitatory actions and induce conformational change, homodimerization and translocation of the glucocorticoid receptor. The GR homodimer shuttles to the nucleus where it binds to glucocorticoid response element (GRE) on the promoter region of the DNA resulting in gene expression. This attachment to the GRE is facilitated by steroid receptor coactivator-1 (SRC-1); the subsequent gene transcription plays diverse roles in physiological functioning. FKBP: FK506 binding protein, BAG 1: Bcl-2-associated gene product-1, PPID: petidylprolyl isomerase D.

• 

  FIG. 2 Pro and anti-inflammatory activities of IL-6. Anti-inflammatory activities of IL-6 include STAT3 dependent regeneration of cells and the induction of the hepatic acute phase response, mediated by membrane bound IL-6R (MB IL-6R). Pro-inflammatory activities of IL-6 via soluble IL-6R (sIL-6R) include recruitment of inflammatory cells and inhibition of regulatory T-cell differentiation. ADAM17 plays the key balancing role in determining the direction of IL-6 biological actions. ADAM17: a disintegrin and metalloproteinase 17, MNC: mononuclear cells, STAT3: signal transducer and activator of transcription 3.

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  FIG. 3 Development of psychiatric disorders as a consequence of prolonged SLS. When subjected to long lasting severe life stress (SLS) pathophysiological changes take place in the brain. NADPH oxidase (NOX) enzymes are induced, particularly NOX2 with ensuing increased generation of reactive oxygen species (ROS). The later enhance the release of glutamate (GLU) from neurons; prolonged glutamatergic discharge has such resultant effects as N-methyl D-aspartate (NMDA) receptor down regulation, loss of phenotype of inhibitory parvalbumin (PV) interneurons and apoptotic changes in the hippocampus. These alterations are similar to those seen in psychosis; the putative model of major psychiatric disorders described here is extrapolated from animal experiments carried out in rodents and primates.

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  FIG. 4 The kynurenine pathway of tryptophan metabolism. Tryptophan is the biochemical precursor for the production of serotonin. Activation of the enzyme indoleamine 2, 3 dioxygenase (IDO) by pro-inflammatory cytokines (PIC) and reactive oxidative species (ROS) metabolizes tryptophan into kynurenine (KYN) which can then be metabolized by kynurenine aminotransferase (KAT) into the neuroprotective kynurenic acid or by kynurenine mono-oxygenase (KMO) into the potentially neurotoxic 3-hydroxykynurenine and subsequently to quinolinic acid (QA).

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  FIG. 5 The relationship between mood regulation and the circadian system. The circadian clock affects several systems and pathways which are supposedly the cause of mood disorders. In the majority of patients there are shared aberrant connections which lead to dysregulated daily oscillations. Circadian gene mutations possibly make a person more susceptible to affective disturbances and these are worsened by environmental variations in the daily timetable. 5-HT: 5-hydroxytryptamine, DA: dopamine, HPA-axis: hypothalamic pituitary axis, NA: norepinephrine, SCN: supraschiasmatic nucleus.

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  FIG. 6 The integrative model of bipolar disorder pathophysiology. Dysfunctions in crucial bodily homeostatic systems acting in an orchestrated manner feed into one another leading to a progressively worsening course of bipolar disorder. The result is a persistent symptomatic state, treatment resistance, psychosocial functional deterioration and numerous physical complications. BD: bipolar disorder, HPA axis: hypothalamic-pituitary-adrenal axis, ROS: reactive oxygen species.

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