Emerging therapeutic targets in bipolar mood disorder

Abstract

Bipolar mood disorder is a chronic, severe and life-threatening psychiatric illness, whose underlying pathophysiology is still obscure. Lithium is the mainstay of treatment for this illness, with robust acute antimanic and long-term prophylactic effects. Over the past decade, valproate has been another medication shown to have possibly similar mood-stabilising properties to lithium, in double-blind controlled trials. Nonetheless, among patients suffering from bipolar disorder, a substantial percentage appears to respond poorly to currently available pharmacological therapies, including lithium, valproate, carbamazepine and other newer compounds, clearly demonstrating that there is a substantial need for improved therapeutic agents. Very significant effort has been made in the past several years to elucidate the cellular mechanisms by which lithium and valproate produce their therapeutic effects. The available evidence points to a modulatory action of these compounds over multiple neural biochemical pathways and most investigations have found relevant actions of mood stabilisers on intracellular signal transduction mechanisms. Moreover, it has been shown in recent years that lithium and valproate lead to long-term changes in neural plasticity, with eventual neurotrophic and neuroprotective effects. Although these actions are not fully understood, stimulation of transcription factors and effects on gene expression are potentially involved. The search for the mechanisms of action of well-established mood-stabilisers has helped to reveal promising molecular targets to test novel therapeutic approaches. This review will examine the current investigations on the diverse biochemical and molecular pathways regulated by either lithium or valproate and highlight the potential cellular targets for the development of novel mood stabilisers.