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.

Cortical thickness, volume and surface area in patients with bipolar disorder types I and II

“…In accordance, the observed differences between patients and controls in the medial occipital areas become more pronounced when controlling for Li use. This is in agreement with other studies that found Li to be associated with increased cortical volumes [62][63][64] and could be related to neuroprotective mechanisms, as suggested for Li effects on hippocampal volumes.…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…24 Neurogenesis is responsible for the differentiation and survival of new neurons necessary to maintain the neural circuitry in the adult brain. 25 Much interest is now focused on the idea that BD may be caused by a decline in the action of neurotrophins, such as BDNF, which regulate this process of neurogenesis.…”

Marcadores periféricos e a fisiopatologia do transtorno bipolar

“…Uma variedade de agentes com propriedades antidepressivas é capaz de elevar a expressão de BDNF hipocampal, revertendo diminuições causadas por estresse; é possível que tal mudança seja uma via comum nos efeitos desses agentes 6 . O lítio é uma das substâncias que tem a propriedade de aumentar o BDNF e promover neuroproteção 35,36 . Corroborando esse mecanismo, dados clínicos sugerem que o uso de lítio esteja associado a uma menor chance para doença de Alzheimer 37 .…”