Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers
Bipolar disorder afflicts approximately 1–3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical...
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| Veröffentlicht in: | Molecular psychiatry 2004-08, Vol.9 (8), p.734-755 |
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| creator | Gould, T D Quiroz, J A Singh, J Zarate, C A Manji, H K |
| description | Bipolar disorder afflicts approximately 1–3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness. |
| doi_str_mv | 10.1038/sj.mp.4001518 |
| format | Article |
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Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.</description><identifier>ISSN: 1359-4184</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/sj.mp.4001518</identifier><identifier>PMID: 15136794</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adenosine receptors ; Adenylate cyclase ; Adult and adolescent clinical studies ; Antimanic Agents - therapeutic use ; Antipsychotic Agents - therapeutic use ; Antipsychotics ; Arachidonic acid ; Behavioral Sciences ; Binding sites ; Biological and medical sciences ; Biological Psychology ; Bipolar disorder ; Bipolar Disorder - drug therapy ; Bipolar Disorder - genetics ; Bipolar Disorder - metabolism ; Bipolar disorders ; Carbamazepine ; Clinical trials ; Cyclic AMP ; Drug development ; Drugs ; Enzymes ; Enzymes - genetics ; feature-review ; Fundamental and applied biological sciences. Psychology ; Glycogen ; Glycogen synthase kinase 3 ; Histone deacetylase ; Humans ; Inositol polyphosphate ; Kinases ; Lithium ; Magnesium ; Medical sciences ; Medicine ; Medicine & Public Health ; Mental depression ; Models, Biological ; Molecular biophysics ; Mood ; Mood disorders ; myo-Inositol-1 (or 4)-monophosphatase ; Neurosciences ; Nucleotidase ; Pathophysiology ; Pharmacotherapy ; Phosphatase ; Phosphoglucomutase ; Protein kinase C ; Psychiatry ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; Psychotropic drugs ; Sodium channels ; Valproic acid</subject><ispartof>Molecular psychiatry, 2004-08, Vol.9 (8), p.734-755</ispartof><rights>Springer Nature Limited 2004</rights><rights>2004 INIST-CNRS</rights><rights>COPYRIGHT 2004 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2004</rights><rights>Nature Publishing Group 2004.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c588t-418ddfe4e3befb594ada8ec2e21a61905bd44c1fc0c0c40dddfce26b16322b093</citedby><cites>FETCH-LOGICAL-c588t-418ddfe4e3befb594ada8ec2e21a61905bd44c1fc0c0c40dddfce26b16322b093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.mp.4001518$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.mp.4001518$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16020423$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15136794$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gould, T D</creatorcontrib><creatorcontrib>Quiroz, J A</creatorcontrib><creatorcontrib>Singh, J</creatorcontrib><creatorcontrib>Zarate, C A</creatorcontrib><creatorcontrib>Manji, H K</creatorcontrib><title>Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>Bipolar disorder afflicts approximately 1–3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.</description><subject>Adenosine receptors</subject><subject>Adenylate cyclase</subject><subject>Adult and adolescent clinical studies</subject><subject>Antimanic Agents - therapeutic use</subject><subject>Antipsychotic Agents - therapeutic use</subject><subject>Antipsychotics</subject><subject>Arachidonic acid</subject><subject>Behavioral Sciences</subject><subject>Binding sites</subject><subject>Biological and medical sciences</subject><subject>Biological Psychology</subject><subject>Bipolar disorder</subject><subject>Bipolar Disorder - drug therapy</subject><subject>Bipolar Disorder - genetics</subject><subject>Bipolar Disorder - metabolism</subject><subject>Bipolar disorders</subject><subject>Carbamazepine</subject><subject>Clinical trials</subject><subject>Cyclic AMP</subject><subject>Drug development</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Enzymes - genetics</subject><subject>feature-review</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycogen</subject><subject>Glycogen synthase kinase 3</subject><subject>Histone deacetylase</subject><subject>Humans</subject><subject>Inositol polyphosphate</subject><subject>Kinases</subject><subject>Lithium</subject><subject>Magnesium</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental depression</subject><subject>Models, Biological</subject><subject>Molecular biophysics</subject><subject>Mood</subject><subject>Mood disorders</subject><subject>myo-Inositol-1 (or 4)-monophosphatase</subject><subject>Neurosciences</subject><subject>Nucleotidase</subject><subject>Pathophysiology</subject><subject>Pharmacotherapy</subject><subject>Phosphatase</subject><subject>Phosphoglucomutase</subject><subject>Protein kinase C</subject><subject>Psychiatry</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopathology. Psychiatry</subject><subject>Psychotropic drugs</subject><subject>Sodium channels</subject><subject>Valproic acid</subject><issn>1359-4184</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqF0s2L1TAQAPAiiruuHr1KUPTWZ5ImaeptWdYPWPCi55Im024ebVKTFtS7_7dTXuGBKJJDP-Y3zUw6RfGc0QOjlX6bj4dpPghKmWT6QXHJRK1KKWv9EO8r2ZSCaXFRPMn5iAaD8nFxgbZSdSMui1-3E6TBh4HA9xmSnyAsZiTLPSQzw7p4m0kfE-n8HEeTiPM5JgfpHfEh--F-wXCK05ZApjiCXTdlgiMWxvH0YBcfQyaxJ3ZNCTdAGR3Ji-n86H9Cyk-LR70ZMzzbr1fF1_e3X24-lnefP3y6ub4rrdR62VpxrgcBVQd9JxthnNFgOXBmFGuo7JwQlvWW4hLUIbbAVcdUxXlHm-qqeHP67pzitxXy0k4-b4WaAHHNrVK14I1W_4VM49nrmiJ89Qc8xjUFbKLlSkg87loLVC__qTjjAilHdDihwYzQ-tDHJRmLy8HkbQzQe3x_zbSWmitWYUJ5SrAp5pygb2f8gSb9aBltt-Fo87Gd5nYfDvQv9irWbgJ31vs0IHi9A5OtGftkgvX57BTlFAs9V5oxFAZI53b-vvNvR_bULQ</recordid><startdate>20040801</startdate><enddate>20040801</enddate><creator>Gould, T D</creator><creator>Quiroz, J A</creator><creator>Singh, J</creator><creator>Zarate, C A</creator><creator>Manji, H K</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20040801</creationdate><title>Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers</title><author>Gould, T D ; Quiroz, J A ; Singh, J ; Zarate, C A ; Manji, H K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c588t-418ddfe4e3befb594ada8ec2e21a61905bd44c1fc0c0c40dddfce26b16322b093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adenosine receptors</topic><topic>Adenylate cyclase</topic><topic>Adult and adolescent clinical studies</topic><topic>Antimanic Agents - therapeutic use</topic><topic>Antipsychotic Agents - therapeutic use</topic><topic>Antipsychotics</topic><topic>Arachidonic acid</topic><topic>Behavioral Sciences</topic><topic>Binding sites</topic><topic>Biological and medical sciences</topic><topic>Biological Psychology</topic><topic>Bipolar disorder</topic><topic>Bipolar Disorder - drug therapy</topic><topic>Bipolar Disorder - genetics</topic><topic>Bipolar Disorder - metabolism</topic><topic>Bipolar disorders</topic><topic>Carbamazepine</topic><topic>Clinical trials</topic><topic>Cyclic AMP</topic><topic>Drug development</topic><topic>Drugs</topic><topic>Enzymes</topic><topic>Enzymes - genetics</topic><topic>feature-review</topic><topic>Fundamental and applied biological sciences. 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Psychiatry</topic><topic>Psychotropic drugs</topic><topic>Sodium channels</topic><topic>Valproic acid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gould, T D</creatorcontrib><creatorcontrib>Quiroz, J A</creatorcontrib><creatorcontrib>Singh, J</creatorcontrib><creatorcontrib>Zarate, C A</creatorcontrib><creatorcontrib>Manji, H K</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gould, T D</au><au>Quiroz, J A</au><au>Singh, J</au><au>Zarate, C A</au><au>Manji, H K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><addtitle>Mol Psychiatry</addtitle><date>2004-08-01</date><risdate>2004</risdate><volume>9</volume><issue>8</issue><spage>734</spage><epage>755</epage><pages>734-755</pages><issn>1359-4184</issn><eissn>1476-5578</eissn><abstract>Bipolar disorder afflicts approximately 1–3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>15136794</pmid><doi>10.1038/sj.mp.4001518</doi><tpages>22</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular psychiatry, 2004-08, Vol.9 (8), p.734-755 |
| issn | 1359-4184 1476-5578 |
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| subjects | Adenosine receptors Adenylate cyclase Adult and adolescent clinical studies Antimanic Agents - therapeutic use Antipsychotic Agents - therapeutic use Antipsychotics Arachidonic acid Behavioral Sciences Binding sites Biological and medical sciences Biological Psychology Bipolar disorder Bipolar Disorder - drug therapy Bipolar Disorder - genetics Bipolar Disorder - metabolism Bipolar disorders Carbamazepine Clinical trials Cyclic AMP Drug development Drugs Enzymes Enzymes - genetics feature-review Fundamental and applied biological sciences. Psychology Glycogen Glycogen synthase kinase 3 Histone deacetylase Humans Inositol polyphosphate Kinases Lithium Magnesium Medical sciences Medicine Medicine & Public Health Mental depression Models, Biological Molecular biophysics Mood Mood disorders myo-Inositol-1 (or 4)-monophosphatase Neurosciences Nucleotidase Pathophysiology Pharmacotherapy Phosphatase Phosphoglucomutase Protein kinase C Psychiatry Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Psychotropic drugs Sodium channels Valproic acid |
| title | Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers |
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