Anti-bipolar therapy: mechanism of action of lithium

Abstract

This review introduces the concepts that multiple actions of lithium are critical for its therapeutic effect, and that these complex effects stabilize neuronal activities, support neural plasticity, and provide neuroprotection. Three interacting systems appear most critical. (i) Modulation of neurotransmitters by lithium likely readjusts balances between excitatory and inhibitory activities, and decreased glutamatergic activity may contribute to neuroprotection.(ii) Lithium modulates signals impacting on the cytoskeleton, a dynamic system contributing to neural plasticity, at multiple levels, including glycogen synthase kinase-3␤, cyclic AMPdependent kinase, and protein kinase C, which may be critical for the neural plasticity involved in mood recovery and stabilization. (iii) Lithium adjusts signaling activities regulating second messengers, transcription factors, and gene expression. The outcome of these effects appears likely to result in limiting the magnitudes of fluctuations in activities, contributing to a stabilizing influence induced by lithium, and neuroprotective effects may be derived from its modulation of gene expression.Keywords: lithium; bipolar disorder; inositol; glutamate; cyclic AMP; AP-1 Recent research suggests that understanding how lithium works in the treatment of bipolar disorder requires a different way of thinking about drug action. The vast majority of drugs are designed, by evolution or synthesis, to interact with single proteins, such as a specific receptor or enzyme. However, it now seems likely that multiple sites affected by lithium contribute to its mood-stabilizing action. Thus, the therapeutic action of lithium in bipolar disorder appears not to result from an effect at a single target site, but rather as the culmination of an integrated re-orchestration of a complex concert of events which effectively adjusts neuronal activity at multiple levels. Numerous effects of lithium have been identified, and some of these may each provide a necessary, but individually insufficient, component of the therapeutic response. One of the current challenges is to distinguish those critical effects from the many known biochemical actions of lithium, many of which may have little discernible effect, contribute to side effects, or lead to toxicity. Another challenge is to integrate the multiple effects of lithium into a comprehensive picture of how neuronal function is modulated by lithium. In retrospect, considering the complexities of mood, it perhaps should not be surprising that mood stabilization by lithium is also a complex process involving multiple actions. It is also important to keep in mind that lithium has efficacy as an antimanic agent, as a prophylactic agent for mania and depression, as a relatively weak antidepressant, and as an augmenter of the effects of many antidepressants. These multiple therapeutic effects of lithium along with the complexities of mood disorders and the multiplicity of affected systems inherent in these illnesses suggest that it is unlikely that all these ...

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

“…The phosphorylation of cellular signaling proteins has been implicated in the pathophysiology of numerous neuropsychiatric diseases Jope, 1999;Konradi and Heckers, 2001;Lenox and Hahn, 2000;Maccioni et al, 2001). Indeed, the phosphorylated form of a protein is clearly of major biological interest; it often affects the function and/or subcellular distribution of enzymes, receptors, neurotransmitter transporters, ion channels, and transcription factors.…”

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

“…Moreover, the delayed onset of therapeutic action of lithium has led to the hypothesis that regulation of gene expression may be important for its mood stabilizing effects (Jope 1999;Li et al 2000). In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al 2000;Manji and Lenox 1999) NO .…”

“…ever, significant progress has been made over the past decade with cumulative evidence indicating that modulation of postreceptor signaling mechanisms in critical regions of the brain may be essential to the mood stabilizing properties of this agent (reviewed in Jope 1999;Li et al 2000;Manji and Lenox 1999).…”

“…Moreover, the delayed onset of therapeutic action of lithium has led to the hypothesis that regulation of gene expression may be important for its mood stabilizing effects (Jope 1999;Li et al 2000). In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al 2000;Manji and Lenox 1999), proapoptotic and antiapoptotic proteins (Chen and Chuang 1999), and synaptic secretory vesicle proteins (Cordeiro et al 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al 1998;Yuan et al 1998).…”

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

“…Further evidence for the involvement of PKC in bipolar disorders is derived from observations that lithium exerts significant effects on PKC in a number of cell systems, including central nervous system (CNS) (Manji et al 1993(Manji et al , 1995Manji and Lenox 1999). Therefore, it has been suggested by some investigators that PKC may be an important target for the action of mood stabilizers, such as lithium and valproate (Lenox and Manji 1998;Ikonomov and Manji 1999;Jope 1999).Although activation of PKC causes a variety of physiological responses, the steps involved between the activation of PKC and subsequent physiological responses are not known. One approach to examine the molecular steps between the activation of PKC and subsequent physiological responses is study of the substrates for PKC, which may help in understanding the downstream events.…”