The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis

Abstract

Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.

Fig. 1

Targets for lithium’s neuroprotective effects. Targets shown in orange are mainly pro-apoptotic proteins/receptors; lithium either significantly downregulates these proteins or decreases their expression. Anti-apoptotic proteins are showed in blue. Lithium increases their expression and/or levels, thus inducing neuroprotective and neurotrophic effects. Activation of brain neurotransmitter-coupled G-proteins induces PLC hydrolysis of PIP₂ to IP₃ and DAG (not shown), which activates PKC. IP₃ binds to the IP₃R, thus inducing the release of ER calcium stores. Increased intracellular calcium levels have been described in bipolar disorder and may increase the risk of apoptosis. The neuroprotective protein Bcl-2 downregulates ER calcium release through an IP₃R-dependent mechanism. The same effect is induced by lithium treatment, which also increases Bcl-2 levels. IP₃ is recycled by IMPase, another of lithium’s targets. Cellular signaling through Wnt glycoproteins and frizzled receptors result in GSK-3β inhibition, a critical cellular target and effector for diverse proteins. Inhibition of GSK-3β prevents β-catenin phosphorylation and stimulates its translocation to the nucleus, thus targeting transcription of specific genes activating neurotrophic effects and synaptogenesis. Activation of the BDNF receptor (Trk-B) activates the ERK/MAPK pathway, which inhibits GSK-3β and BAD. Activation of the ERK/MAPK pathway by BDNF increases the expression of nuclear CREB, which facilitates the expression of neurotrophic/neuroprotective proteins such as Bcl-2 and BDNF. BDNF also activates the PI3K pathway, which indirectly inhibits GSK-3β and BAD. Mitochondrial Bcl-2 and Bcl-xl also inhibit pro-apoptotic activation of BAD, as well as consequent mitochondrial increase of calcium influx and cytochrome C release. Bcl-2 = B-cell lymphoma-2; BDNF = brain-derived neurotrophic factor; Ca²⁺ = calcium; CREB = cAMP response element binding protein; Cyt C = cytochrome C; DAG = diacylglycerol; ER = endoplasmic reticulum; ERK = extracellular regulated kinase; GSK = glycogen-synthase kinase; IMPase = inositol monophosphatase; IP₃ = inositol 1,4,5-triphosphate 3; IP₃R = inositol 1,4,5-triphosphate 3 receptor; Mg²⁺ = magnesium; MAPK = mitogen activated protein kinase; NMDA = N-methyl D-aspartate; NT = neurotransmitter; PI3K = phosphatidylinositol-3 kinase; PIP₂ = phosphoinositide 4,5-biphosphate; PKC = protein kinase C; PLC = phospholipase C; PTP = permeability membrane pore; TrkB = tyrosine receptor kinase B.