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.

Dysregulation of glucose metabolism since young adulthood increases the risk of cardiovascular diseases in patients with bipolar disorder

“…In the present study, we found that BD patients with CVDs were characterized by glucose dysregulation since young adulthood and tended to have mania as their first episode. These results suggest that BD pathophysiology may be associated with dysfunctional regulation of both mood and glucose across the adulthood span and therefore supporting the “metabolic mood syndrome” hypothesis of BD [30]. Nevertheless, we should also note that the mania as a first episode was found to increase the risk for CVDs 4.69 times in the present analysis.…”

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

“…Current knowledge of BD's neurobiology and pathophysiology is still modest [8] and with no clear biological markers available, early diagnosis is presently a great challenge to clinicians.…”

“…Moreover, BD patients tend to have high rates of divorce, unemployment, drug abuse and crime as consequence of impaired social cognition, and its impact on patients can be devastating, with approximately 23% of patients with BD reported having suicide attempts [6]. Moreover, individuals with BD diagnosis have a high risk of medical comorbidities such as metabolic (diabetes, obesity and metabolic syndrome) and cardiovascular disorders [7].Current knowledge of BD's neurobiology and pathophysiology is still modest [8] and with no clear biological markers available, early diagnosis is presently a great challenge to clinicians.Pharmacological therapy is often the first-line treatment for BD, followed by psychological [9] and psychosocial interventions [10]. For maintenance pharmacological treatment the main goal is to prevent recurrences of mood episodes, using mood stabilizers (e.g.…”

“…The most replicated findings that show consistency with genome-wide association studies (GWAS), brain-imaging and post-mortem brain expression include abnormalities in endoplasmic reticulum (ER)-related stress responses, mitochondrial function and Ca 2+ signaling, which are often reversed in vitro with lithium. Furthermore, patient-derived cellular models also support that alterations in microRNAs (miRNAs), glia and immune cell signaling, cytoskeleton as well as oxidative stress, inflammasome activation, autophagy and apoptosis play a relevant role in BD pathophysiology [8,[19][20][21][22][23][24][25][26][27][28][29]. …”

<b><i>FKBP5</i></b> Gene Variants May Modulate Depressive Features in Bipolar Disorder

“…In addition, it is strictly correlated with several pathways implicated in neuronal function, synaptic plasticity, autophagy, and DNA methylation [22]. These pathways were also proven to be related to BPD [23-25]. FKBP5 genotypes are also associated with alterations in brain function and structure that affect behavior, particularly in brain regions associated with emotional processing, learning, memory, and inhibition (i.e., amygdala and hippocampus) [26, 27].…”