Mood stabilizer psychopharmacology

Abstract

Mood stabilizers represent a class of drugs that are efficacious in the treatment of bipolar disorder. The most established medications in this class are lithium, valproic acid, and carbamazepine. In addition to their therapeutic effects for treatment of acute manic episodes, these medications often are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. While important extracellular effects have not been excluded, most available evidence suggests that the therapeutically relevant targets of this class of medications are in the interior of cells. Herein we give a prospective of a rapidly evolving field, discussing common effects of mood stabilizers as well as effects that are unique to individual medications. Mood stabilizers have been shown to modulate the activity of enzymes, ion channels, arachidonic acid turnover, G protein coupled receptors and intracellular pathways involved in synaptic plasticity and neuroprotection. Understanding the therapeutic targets of mood stabilizers will undoubtedly lead to a better understanding of the pathophysiology of bipolar disorder and to the development of improved therapeutics for the treatment of this disease. Furthermore, the involvement of mood stabilizers in pathways operative in neuroprotection suggests that they may have utility in the treatment of classical neurodegenerative disorders.

Fig. 1

G proteins, cyclic AMP and phosphoinositol mediated signaling. G proteins are composed of G protein coupled receptor α, β, and γ subunits. These three subunits form a heterotrimer when the receptor to which they are coupled is not binding a ligand. Ligand binding to a particular receptor causes the subunits to dissociate from both each other and the receptor. GTP replaces GDP, allowing the activation of second messengers such as cyclic AMP and DAG/PI3. One of the effects of cAMP is activation of protein kinase A (PKA), an enzyme that phosphorylates many substrates including the cAMP response element binding protein (CREB). After activation this protein binds to the cAMP response element (CRE), a gene sequence found in the promoter of certain genes. Activation of other G proteins induces phospholipase C hydrolysis of phosphoinositide 4,5-bisphosphate (PIP₂) to diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP₃). DAG activates protein kinase C (PKC), an enzyme that has many effects including the activation of myristoylated alanine-rich C kinase substrate (MARKS). IP₃ binds to the IP₃ receptor that also functions as a calcium channel in the cell. This interaction results in the release of intracellular calcium reservoirs from the endoplasmic reticulum, initiating downstream effects such as activation of calmodulins and calmodulin-dependent protein kinases. IP₃ is recycled back to PIP₂ by the enzymes inositol monophosphate phosphatase (IMP) and inositol polyphosphatase phosphatase (IPPase); both of which are targets of lithium [68].

Fig. 2

Neurotrophins, the ERK MAP kinase signaling cascade, and GSK-3. Cell survival is dependent on neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor, and the expression of these factors can be induced by synaptic activity. The influence of neurotrophic factors on cell survival is mediated by activation of the MAP kinase cascade. Activation of neurotrophic factor receptors also referred to as Trks, results in activation of the MAP kinase cascade via several intermediate steps, including phosphorylation of the adaptor protein SHC and recruitment of the guanine nucleotide exchange factor Sos. This results in activation of the small guanosine triphosphate-binding protein Ras, which leads to activation of a cascade of serine/threonine kinases. This includes Raf, MAP kinase kinase (MEK), and MAP kinase (also referred to as extracellular response kinase, or ERK). One target of the MAP kinase cascade is RSK, which influences cell survival in at least two ways. RSK phosphorylates and inactivates the pro-apoptotic factor BAD. RSK also phosphorylates CREB and thereby increases the expression of the anti-apoptotic factor bcl-2 and BDNF. These mechanisms underlie many of the long-term effects of neurotrophins, including neurite outgrowth, cytoskeletal remodeling, and cell survival. Recent evidence suggests that lithium and VPA activate the ERK MAP kinase pathway. Lithium and VPA also appear to target GSK-3 and the Wnt signaling pathway. The function of GSK-3 in the Wnt signaling pathway – whereby Wnt glycoproteins interact with the frizzled family of receptors to stimulate the disheveled-mediated inactivation of GSK-3 and activation of the transcription factor β-catenin – is separate from the PI₃ kinase/AKT mediated inactivation of GSK-3. Lithium is a direct inhibitor of GSK-3; both lithium and VPA increase β-catenin levels.

Fig. 3

Lithium administration to rats protects against infarct size status-post middle cerebral artery occlusion, and suppresses the quinolinic acid induced excitotoxicity-induced striatal lesions in a rat models [168]. Figures are altered with permission from Wei et al. [181] and Nonaka and Chuang [182].