Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

Abstract

Bipolar disorder (BD) is a chronic and progressive psychiatric illness characterized by mood oscillations, with episodes of mania and depression. The impact of BD on patients can be devastating, with up to 15% of patients committing suicide. This disorder is associated with psychiatric and medical comorbidities and patients with a high risk of drug abuse, metabolic and endocrine disorders and vascular disease. Current knowledge of the pathophysiology and molecular mechanisms causing BD is still modest. With no clear biological markers available, early diagnosis is a great challenge to clinicians without previous knowledge of the longitudinal progress of illness. Moreover, despite recommendations from evidence-based guidelines, polypharmacy is still common in clinical treatment of BD, reflecting the gap between research and clinical practice. A major challenge in BD is the development of effective drugs with low toxicity for the patients. In this review article, we focus on the progress made and future challenges we face in determining the pathophysiology and molecular pathways involved in BD, such as circadian and metabolic perturbations, mitochondrial and endoplasmic reticulum (ER) dysfunction, autophagy and glutamatergic neurotransmission; which may lead to the development of new drugs.

Keywords: bipolar disorder; disease modeling; endoplasmic reticulum stress; glutamate; hyperexcitability; mitochondrial dysfunction; oxidative stress.

Figure 1

Integrated view of clinical and fundamental research interventions in bipolar disorder (BD). BD patients have neuropsychiatric symptoms and metabolic comorbidities that can be associated to mitochondrial dysfunction and low energetic status. Oxidative stress, endoplasmic reticulum (ER) stress, reduced autophagy and changes in glutamatergic neurotransmission are consequences of mitochondrial dysfunction and altered glucose metabolism contributing to the vulnerability of BD cells. Clinical and cellular features can be used to inform and validate cellular phenotypes useful in the construction of new research model systems (mouse models and induced pluripotent stem cells- iPSCs technology). Elucidation of pathways involved in BD pathology can lead to the development of novel therapies.

Figure 2

Mitochondrial dysfunction in BD. In BD cells, impaired oxidative phosphorylation results in a metabolic switch to glycolysis and lactate biosynthesis, with concomitant intracellular pH decrease. Decreased oxidative phosphorylation also causes an accumulation of reactive species (RS) and calcium in the mitochondria. Abbreviations: ER, endoplasmic reticulum; ETC, electron transport chain; TCA, tricarboxylic acid cycle; RS, reactive species.

Figure 3

Cellular response to ER stress. Accumulation of unfolded proteins in the ER lumen signal the unfolded protein response (UPR). The activated stress sensor proteins—protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) –signal different transduction pathways aiming at restoring cell homeostasis or committing the cell to death. Abbreviations: ERAD, endoplasmic reticulum-associated protein degradation; ER, endoplasmic reticulum.