Lithium pharmacodynamics and pharmacogenetics

Focus on inositol mono phosphatase (IMPase), inositol poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)

Alessandro Serretti, Antonio Drago, Diana De Ronchi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The mechanisms of lithium action are not known in detail. First messengers, second messengers, and gene expression all appear to be involved: the wide breadth of targets makes the lithium therapeutic path difficult to disentangle. In the present paper, we focused on the most direct biochemical lithium targets at therapeutic concentration, for which some pharmacogenetic finding is present (i.e. inositol mono phosphatase (IMPase), inositol polyphosphate-1-phosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)). They are all inhibited by lithium at therapeutic concentrations and are representative of the inositol depletion and of the GSK-3 beta based theories of lithium action. Then we surveyed gene variants on those targets that have been associated also with bipolar disorder. On the basis of the molecular characteristics of these proteins, we suggest a set of critical genetic variations. IMPase2, IPPase and GSK-3 beta gene appear to be good candidates for the analysis of lithium prophylactic efficacy and bipolar disorder phenotypes but the genetic association analysis conducted so far reported negative or not unequivocal finding. This may be due to the incomplete coverage of gene mutations in most studies or to the several actions that lithium is thought to perform and trigger in cell machinery, including receptors, calcium equilibrium, gene expression, activation of neuroprotective paths and other yet undetected or less considered mechanisms.

Original languageEnglish
Pages (from-to)1917-1948
Number of pages32
JournalCurrent Medicinal Chemistry
Volume16
Issue number15
DOIs
Publication statusPublished - 2009

Fingerprint

Pharmacodynamics
Pharmacogenetics
Inositol
Glycogen
Lithium
Phosphotransferases
Genes
Bipolar Disorder
Gene expression
Calcium-Sensing Receptors
Gene Expression
Phosphatases
Second Messenger Systems
myo-inositol-1 (or 4)-monophosphatase
Transcriptional Activation
Machinery
Therapeutics
Chemical activation
Association reactions
Phenotype

Keywords

  • Bipolar disorder
  • Candidate gene
  • Lithium
  • Pharmacogenetics
  • Psychopharmacology

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Lithium pharmacodynamics and pharmacogenetics : Focus on inositol mono phosphatase (IMPase), inositol poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta). / Serretti, Alessandro; Drago, Antonio; De Ronchi, Diana.

In: Current Medicinal Chemistry, Vol. 16, No. 15, 2009, p. 1917-1948.

Research output: Contribution to journalArticle

@article{20dea0f573af41818b31a3f124d89589,
title = "Lithium pharmacodynamics and pharmacogenetics: Focus on inositol mono phosphatase (IMPase), inositol poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)",
abstract = "The mechanisms of lithium action are not known in detail. First messengers, second messengers, and gene expression all appear to be involved: the wide breadth of targets makes the lithium therapeutic path difficult to disentangle. In the present paper, we focused on the most direct biochemical lithium targets at therapeutic concentration, for which some pharmacogenetic finding is present (i.e. inositol mono phosphatase (IMPase), inositol polyphosphate-1-phosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)). They are all inhibited by lithium at therapeutic concentrations and are representative of the inositol depletion and of the GSK-3 beta based theories of lithium action. Then we surveyed gene variants on those targets that have been associated also with bipolar disorder. On the basis of the molecular characteristics of these proteins, we suggest a set of critical genetic variations. IMPase2, IPPase and GSK-3 beta gene appear to be good candidates for the analysis of lithium prophylactic efficacy and bipolar disorder phenotypes but the genetic association analysis conducted so far reported negative or not unequivocal finding. This may be due to the incomplete coverage of gene mutations in most studies or to the several actions that lithium is thought to perform and trigger in cell machinery, including receptors, calcium equilibrium, gene expression, activation of neuroprotective paths and other yet undetected or less considered mechanisms.",
keywords = "Bipolar disorder, Candidate gene, Lithium, Pharmacogenetics, Psychopharmacology",
author = "Alessandro Serretti and Antonio Drago and {De Ronchi}, Diana",
year = "2009",
doi = "10.2174/092986709788186101",
language = "English",
volume = "16",
pages = "1917--1948",
journal = "Current Medicinal Chemistry",
issn = "0929-8673",
publisher = "Bentham Science Publishers B.V.",
number = "15",

}

TY - JOUR

T1 - Lithium pharmacodynamics and pharmacogenetics

T2 - Focus on inositol mono phosphatase (IMPase), inositol poliphosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)

AU - Serretti, Alessandro

AU - Drago, Antonio

AU - De Ronchi, Diana

PY - 2009

Y1 - 2009

N2 - The mechanisms of lithium action are not known in detail. First messengers, second messengers, and gene expression all appear to be involved: the wide breadth of targets makes the lithium therapeutic path difficult to disentangle. In the present paper, we focused on the most direct biochemical lithium targets at therapeutic concentration, for which some pharmacogenetic finding is present (i.e. inositol mono phosphatase (IMPase), inositol polyphosphate-1-phosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)). They are all inhibited by lithium at therapeutic concentrations and are representative of the inositol depletion and of the GSK-3 beta based theories of lithium action. Then we surveyed gene variants on those targets that have been associated also with bipolar disorder. On the basis of the molecular characteristics of these proteins, we suggest a set of critical genetic variations. IMPase2, IPPase and GSK-3 beta gene appear to be good candidates for the analysis of lithium prophylactic efficacy and bipolar disorder phenotypes but the genetic association analysis conducted so far reported negative or not unequivocal finding. This may be due to the incomplete coverage of gene mutations in most studies or to the several actions that lithium is thought to perform and trigger in cell machinery, including receptors, calcium equilibrium, gene expression, activation of neuroprotective paths and other yet undetected or less considered mechanisms.

AB - The mechanisms of lithium action are not known in detail. First messengers, second messengers, and gene expression all appear to be involved: the wide breadth of targets makes the lithium therapeutic path difficult to disentangle. In the present paper, we focused on the most direct biochemical lithium targets at therapeutic concentration, for which some pharmacogenetic finding is present (i.e. inositol mono phosphatase (IMPase), inositol polyphosphate-1-phosphatase (IPPase) and glycogen sinthase kinase 3 beta (GSK-3 beta)). They are all inhibited by lithium at therapeutic concentrations and are representative of the inositol depletion and of the GSK-3 beta based theories of lithium action. Then we surveyed gene variants on those targets that have been associated also with bipolar disorder. On the basis of the molecular characteristics of these proteins, we suggest a set of critical genetic variations. IMPase2, IPPase and GSK-3 beta gene appear to be good candidates for the analysis of lithium prophylactic efficacy and bipolar disorder phenotypes but the genetic association analysis conducted so far reported negative or not unequivocal finding. This may be due to the incomplete coverage of gene mutations in most studies or to the several actions that lithium is thought to perform and trigger in cell machinery, including receptors, calcium equilibrium, gene expression, activation of neuroprotective paths and other yet undetected or less considered mechanisms.

KW - Bipolar disorder

KW - Candidate gene

KW - Lithium

KW - Pharmacogenetics

KW - Psychopharmacology

UR - http://www.scopus.com/inward/record.url?scp=68449104276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68449104276&partnerID=8YFLogxK

U2 - 10.2174/092986709788186101

DO - 10.2174/092986709788186101

M3 - Article

VL - 16

SP - 1917

EP - 1948

JO - Current Medicinal Chemistry

JF - Current Medicinal Chemistry

SN - 0929-8673

IS - 15

ER -