Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers

Abstract

Bipolar disorder afflicts approximately 1-3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele

“…This is not necessarily surprising, as these two agents are structurally highly dissimilar, and with the exception of GSK3 (glycogen synthase kinase 3), they have generally been found to target different molecules (reviewed by Gould et al 58 ). Unfortunately, GSK3 was not present on the Affymetrix gene chip arrays that were analyzed in this study, and as such, any common differential expression of this molecule could not be investigated.…”

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…4) regulates multiple cellular processes such as glycogen synthesis, gene transcription, events related to synaptic plasticity, apoptosis, and the circadian cycle. 180,182 In addition to lithium, serotonin and catecholamines, as well as a variety of other treatments known to have effects on mood including valproate, lamotrigine, antidepressants, antipsychotics, gonadal steroids, amphetamines, and electroconvulsive seizures, modulate GSK-3 either directly or indirectly within key areas of the brain implicated in BD. Thus, GSK-3 is situated at a nexus of multiple neurotransmitter and signaling cascades as well as neuroanatomic circuits putatively involved in BD.…”

Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling

“…GSK-3 consists of α and β isoforms and is a key kinase involved in the regulation of an array of transcription factors (reviewed in Grimes and Jope, 2001a). Increasing evidence suggests that lithium elicits its neuroprotective/neurotrophic effects primarily through inhibition of GSK-3 (Gould et al, 2004;Liang and Chuang, 2007). Besides direct inhibition, lithium has been shown to indirectly inhibit GSK-3 through phosphorylation of GSK-3α at Ser21 and GSK-3β at Ser9 by multiple mechanisms including the activation of PKA (Jope, 1999a), phosphatidylinositol 3-kinase (PI3-K)-dependent AKT (Chalecka-Franaszek and Chuang, 1999), protein kinase C (PKC) (Kirshenboim et al, 2004), as well as the involvement of GSK-3 autoregulation Liang and Chuang, 2007).…”

“…Besides direct inhibition, lithium has been shown to indirectly inhibit GSK-3 through phosphorylation of GSK-3α at Ser21 and GSK-3β at Ser9 by multiple mechanisms including the activation of PKA (Jope, 1999a), phosphatidylinositol 3-kinase (PI3-K)-dependent AKT (Chalecka-Franaszek and Chuang, 1999), protein kinase C (PKC) (Kirshenboim et al, 2004), as well as the involvement of GSK-3 autoregulation Liang and Chuang, 2007). GSK-3 inhibition is also likely involved in the anti-depressant and anti-manic effects of lithium observed in rodent models (Gould et al, 2004;Kaidanovich-Beilin et al, 2004;O'Brien et al, 2004).…”