Second messengers and their importance for novel drug treatments of patients with bipolar disorder

Abstract

Second messenger systems, like the cyclic nucleotide, glycogen synthase kinase-3β, phosphoinositide, and arachidonic acid cascades, are involved in bipolar disorder (BD). We investigated their role on the development of novel therapeutic drugs using second messenger mechanisms. PubMed search and narrative review. We used all relevant keywords for each second messenger cascade combining it with BD and related terms and combined all with novel/innovative treatments/drugs. Our search produced 31 papers most were reviews, and focussed on the PI3K/AKT-GSK-3β/Nrf2–NF-ĸB pathways. Only two human randomized clinical trials were identified, of ebselen, an antioxidant, and celecoxib, a cyclooxygenase-2 inhibitor, both with poor unsatisfactory results. Despite the fact that all second messenger systems are involved in the pathophysiology of BD, there are few experiments with novel drugs using these mechanisms. These mechanisms are a neglected and potentially major opportunity to transform the treatment of bipolar illness.

Keywords:

• Bipolar disorder
• second messengers
• cyclic AMP
• inositol-3phosphate
• arachidonic acid
• drug discovery
• lithium

Author contributions

SNG and GS conceived and designed the review, FF, GDK, and GM carried out literature search and wrote substantial portions of the manuscript, FF, GM, and GDK wrote the first draft, SNG and GS supervised the manuscript. All authors read and approved the final version.

Disclosure statement

Until June 2021, Dr. SNG was an employee of Novartis Institutes for Biomedical Research (NIBR), Cambridge MA. All views expressed here are his own alone, and do not reflect those of his employers. GS, GDK, FF, and GM report no conflict of interests.