Mood Stabilizers Target Cellular Plasticity and Resilience Cascades: Implications for the Development of Novel Therapeutics

Abstract

Bipolar disorder is a devastating disease with a lifetime incidence of about 1% in the general population. Suicide is the cause of death in 10 to 15% of patients and in addition to suicide, mood disorders are associated with many other harmful health effects. Mood stabilizers are medications used to treat bipolar disorder. In addition to their therapeutic effects for the treatment of acute manic episodes, mood stabilizers are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. The most established and investigated mood-stabilizing drugs are lithium and valproate but other anticonvulsants (such as carbamazepine and lamotrigine) and antipsychotics are also considered as mood stabilizers. Despite the efficacy of these diverse medications, their mechanisms of action remain, to a great extent, unknown. Lithium's inhibition of some enzymes, such as inositol monophosphatase and glycogen synthase kinase-3, probably results in its mood-stabilizing effects. Valproate may share its anticonvulsant target with its mood-stabilizing target or may act through other mechanisms. It has been shown that lithium, valproate, and/or carbamazepine regulate numerous factors involved in cell survival pathways, including cyclic adenine monophospate response element-binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen-activated protein kinases. These drugs have been suggested to have neurotrophic and neuroprotective properties that ameliorate impairments of cellular plasticity and resilience underlying the pathophysiology of mood disorders. This article also discusses approaches to develop novel treatments specifically for bipolar disorder.

Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol

“…53 By contrast, patients enrolled in this study had been in stable remission on average for more than a decade (minimum 3 years) and had received long-term documented lithium prophylaxis. The finding of normal NAA levels in our unique patient sample is conceptually consistent with the notion that lithium's beneficial effects may be due to its neurotrophic and neuroprotective properties 54,55 and fits well with an earlier report that described a lithium-induced increase in brain NAA. 21 To our knowledge, this is also the first study to describe a strong positive correlation between glutamate and NAA concentrations in the human hippocampus in vivo.…”

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

“…[9][10][11] Both medications have also been shown to have a number of other effects, including alterations to intracellular and neurotransmitter signaling in the brain. 12 The mechanisms by which these medications exert their effects, however, have yet to be completely determined. Further work is thus needed to understand which of these actions are essential for their efficacy in treating bipolar disorder.…”

Mitochondrially Mediated Plasticity in the Pathophysiology and Treatment of Bipolar Disorder

“…Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters (Bachmann et al, 2005;Schloesser et al, 2007). Most germane to the present discussion is the fact that it is now clear that mitochondria regulate not only long-term cell survival/cell death, but also immediate synaptic functionFboth of which are clearly very relevant for BPD.…”

“…In view of its major effects on BDNF, bcl-2 and GSK-3, it is not surprising that recent studies have investigated lithium's potential neuroprotective effects in a variety of preclinical paradigms, demonstrating robust neuroprotective properties against a variety of insults (reviewed by Bachmann et al, 2005;Chuang and Priller, 2006;Manji et al, 2000a;Schloesser et al, 2007).…”