Lithium and Neuropsychiatric Therapeutics: Neuroplasticity via Glycogen Synthase Kinase-3β, β-Catenin, and Neurotrophin Cascades

Abstract

Abstract. Mood disorders are not merely attributed to the functional defect of neurotransmission, but also are due to the structural impairment of neuroplasticity. Chronic stress decreases neurotrophin levels, precipitating or exacerbating depression; conversely, antidepressants increase expression of various neurotrophins (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor), thereby blocking or reversing structural and functional pathologies via promoting neurogenesis. Since the worldwide approval of lithium therapy in 1970, lithium has been used for its anti-manic, antidepressant, and anti-suicidal effects, yet the therapeutic mechanisms at the cellular level remain not-fully defined. During the last five years, multiple lines of evidence have shown that the mood stabilization and neurogenesis by lithium are due to the lithium-induced inhibition of glycogen synthase kinase-3β (GSK-3β), allowing accumulation of β-catenin and β-catenin-dependent gene transcriptional events. Altered levels of GSK-3β and β-catenin are associated with various neuropsychiatric and neurodegenerative diseases, while various classical neuropsychiatric drugs inhibit GSK-3β and up-regulate β-catenin expression. In addition, evidence has emerged that insulin-like growth factor-I enhances antidepression, antianxiety, memory, neurogenesis, and angiogenesis; antidepressants up-regulate expression of insulin-like growth factor-I, while insulin-like growth factor-I up-regulates brain-derived neurotrophic factor expression and its receptor TrkB level, as well as brain-derived neurotrophic factor-induced synaptic protein levels. More importantly, physical exercise and healthy diet raise transport of peripheral circulating insulin-like growth factor I into the brain, reinforcing the expression of neurotrophins (e.g., brain-derived neurotrophic factor) and the strength of cell survival signalings (e.g., phosphoinositide 3-kinase / Akt / GSK-3β pathway). This review will focus on the rapidly advancing new trends in the last five years about lithium, GSK-3β/ β-catenin, and neurotrophin cascades.

Comparing Augmentation with Non-Antidepressants over Sticking to Antidepressants after Treatment Failure in Depression: A Naturalistic Study

“…98 patients met criteria for assignment to one of the 4 treatment groups (phase II): 1) Lithium-augmentation (LiAugm), 2) switch of antidepressants (AD-Switch), 3) combination of antidepressants (AD-Comb), 4) augmentation with SGA (SGA-Augm). Criteria for enrolment into analysis were: patients had to have an adequate antidepressant monotherapeutic treatment in phase I according to duration (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) To assess the severity of depressive symptoms, clinician-rated and self-rating instruments were used at admission and at discharge (t1 and t2). Treatment groups were as heterogeneous as they normally appear in clinical practice.…”

“…A possible conclusion could be that patients who do not respond to substances with this mode of functioning do have a higher benefi t with medications of a diff erent mode of action. Possible explanations of superiority of Li-Augm compared to AD-Switch or AD-Comb include the diversity of pharmacological functioning: Lithium infl uences the neurotransmittersystem on the level of second messengers and gene-regulation [ 31 ] . Previous research has also focused on possible antidepressant eff ects of SGAs particularly on the multiple eff ects of those substances on diff erent neurotransmitters and their second messengers.…”

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

“…Lithium also increases Aktmediated phosphorylation of GSK3␤, which inhibits the activity of the enzyme. Altered levels of GSK3␤ and its target ␤-catenin are associated with various neuropsychiatric disorders and neuropsychiatric drugs (Wada, 2009). Moreover, GSK3␤ inhibitors have been shown to have antidepressant and anti-manic-like activity (Kaidanovich-Beilin et al, 2004;O'Brien et al, 2004;Gould et al, 2006).…”

AT1 Receptor Antagonism Is Proangiogenic in the Brain: BDNF a Novel Mediator

“…Glycogen synthase kinase-3b (GSK-3b) is a serine threonine kinase that plays a key role in gene expression regulation (Wada, 2009;Hur and Zhou, 2010). Recently, Li et al demonstrated the involvement of GSK-3b in the recovery after CNS ischemic insults (Li et al, 2011).…”