First, human studies showing evidence for neural cell atrophy and loss in BD are described, as well as lithium’s ability to reverse these pathological findings. Second, the potential roles of intracellular cascade systems in BD are described; these have been shown to directly regulate cell survival/death pathways and are directly targeted by lithium. Yucel et al. showed increased bilateral hippocampal volume after 2–4 years of lithium treatment in previously drug-naïve BD subjects (10). Also, a recent study using high-resolution volumetric MRI showed a direct therapeutic relevance of lithium neurotrophic effects in BD. It was observed that only lithium-responders showed increases in gray matter in the prefrontal areas (11). Third, the neurotrophic effects of lithium are described in preclinical models in vivo and in vitro and in clinical studies, demonstrating lithium’s clinical relevance not only in BD, but as a potential neurotrophic agent for use in several neurological disorders.
Although BD is not a typical neurodegenerative disorder, several postmortem morphometric and brain imaging studies [structural imaging and magnetic resonance spectroscopy (MRS)] have demonstrated the presence of neuronal/glial stress, atrophy, and death associated with the illness [reviewed in (2)].
Postmortem studies evaluating BD subjects matched to healthy controls have shown a significant decrease in brain volume in areas directly involved in mood regulation, mostly characterized by reduced number, density, and/or size of neurons and glial cells, with consistent evidence for the prefrontal and anterior cingulate cortices and amygdala [reviewed in (12, 13)]. For instance, Öngur and colleagues (14) described a significant decrease (41.2%) in glial cell density in the subgenual prefrontal cortex in BD subjects with a positive family history of mood disorders.
Changes in brain volume and structure, as well as altered energy parameters in specific brain areas related to mood regulation, have been described in neuroimaging studies evaluating individuals with BD. It has consistently been shown that there is decreased gray matter volume in diverse neural areas that regulate cognitive and emotional processing in BD, such as ventral/orbital/medial prefrontal cortex and amygdala [reviewed in (15, 16)]. In a seminal study, Drevets and colleagues (17) observed an approximate 40% reduction in subgenual prefrontal cortex volumes in familial mood disorder subjects. In addition, MRS studies showed regional abnormalities of N-acetyl-aspartate (NAA), choline, and myoinositol in BD, especially in the prefrontal and anterior cingulate cortices, hippocampus, and basal ganglia [reviewed in (18)]. These markers are related to the regulation of neurotrophic pathways (described elsewhere) and responded to lithium treatment (see next section), making them potential state-dependent markers. For instance, BD subjects showed abnormally high myoinositol levels in diverse brain areas during manic and depressive episodes; such levels were not observed during euthymia, in healthy controls, or after lithium treatment in BD subjects [reviewed in (19)].
Notably, while BD is not considered a classic neurodegenerative disorder based on the absence of gliosis (a marker of neurdegeneration), it has specific patterns of glial loss possibly associated with the decreased NAA and elevated choline levels described above in BD subjects (18, 20, 21). Furthermore, NAA synthesis occurs in the mitochondria, which are implicated in the altered cell energy regulation (e.g., decreased pH and increased lactate levels) described in the pathophysiology of BD (22, 23) (see “Mitochondrial and ER regulation of oxidative stress and apoptosis: a role for Bcl-2, IP3, and calcium”, p. 99); this has been hypothesized to be critical to the altered oxidative stress parameters, apoptosis, and disruption in gene expression that lead to loss of neurotrophic effects.
Lithium’s neurotrophic effects in BD: data from human studies
The most replicated finding from structural neuroimaging studies is an association between lithium treatment and increased gray matter volume in brain areas implicated in emotional processing and cognitive control, such as the anterior cingulate gyrus, amygdala, and hippocampus, which suggests that lithium has considerable neurotrophic effects (24, 25). One study found that patients with BD who were not treated with lithium had significantly reduced left anterior cingulate volumes compared to healthy volunteers and lithium-treated patients (26). Additional magnetic resonance imaging (MRI) studies examined the gray and white matter volumes of 12 untreated and 17 lithium-treated patients with BD and 46 healthy controls and found that total gray matter volumes were significantly increased in lithium-treated relative to untreated patients and healthy controls (27). Another study found that gray matter density was significantly greater in patients with BD relative to healthy controls in diffuse cortical regions (28). In an MRI study of the hippocampus conducted in 33 patients with BD (21 treated with lithium and 12 unmedicated) and 62 matched healthy controls, investigators found that total hippocampal volume was significantly greater in lithium-treated patients with BD compared with healthy controls (by 10%) and unmedicated patients (by 14%) (29).
As noted above, MRS studies have evaluated the potential effects of lithium treatment in BD subjects on abnormal concentrations of markers of neuronal integrity, including NAA and myoinositol (see also “Mitochondrial and ER regulation of oxidative stress and apoptosis: a role for Bcl-2, IP3, and calcium”, p. 99). Increased NAA levels were observed after four weeks of lithium treatment in different brain areas (30, 31), and decreased choline and myoinositol were reported after chronic lithium treatment in individuals with BD [(32), reviewed in (19)]. Despite some limitations, including the potential for a Type I or II error and negative findings in specific brain areas, human postmortem and imaging studies in BD suggest that neurotrophic effects play a critical role in lithium’s therapeutic effects.
Direct targets of lithium involving neuroprotection: potential relevance in the pathophysiology and treatment of BD
Glycogen synthase kinase 3 (GSK-3)
General aspects of GSK-3 and integration with other neurotrophic pathways
GSK-3 is a serine/threonine kinase that regulates diverse cellular processes and directly regulates cell apoptosis. Interest in GSK-3 as a target for BD drug development arose from findings that it is key to a number of central functions, such as glycogen synthesis, gene transcription, synaptic plasticity, apoptosis (cell death), cellular structure and resilience, and the circadian cycle (33); notably, all of these functions are significantly implicated in the pathophysiology of severe recurrent mood disorders. Indeed, Benedetti and colleagues (34) showed that a polymorphism in the GSK-3 gene was associated with earlier onset of BD.