Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania
OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled stud...
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creator | Allen, Michael H. Hirschfeld, Robert M. Wozniak, Patricia J. Baker, Ph.D., Jeffrey D. Bowden, Charles L. |
description | OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (≤55.0 g ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 g ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 g ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 g ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 g ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 g ml. |
doi_str_mv | 10.1176/appi.ajp.163.2.272 |
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A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (≤55.0 g ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 g ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 g ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 g ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 g ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 g ml.</description><identifier>ISSN: 0002-953X</identifier><identifier>EISSN: 1535-7228</identifier><identifier>DOI: 10.1176/appi.ajp.163.2.272</identifier><identifier>PMID: 16449481</identifier><identifier>CODEN: AJPSAO</identifier><language>eng</language><publisher>Washington, DC: American Psychiatric Publishing</publisher><subject>Acute Disease ; Adult ; Adult and adolescent clinical studies ; Analysis of Variance ; Antimanic Agents - administration & dosage ; Antimanic Agents - blood ; Antimanic Agents - therapeutic use ; Behavioral sciences ; Biological and medical sciences ; Bipolar disorder ; Bipolar Disorder - blood ; Bipolar Disorder - drug therapy ; Bipolar Disorder - psychology ; Clinical trials ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug therapy ; Female ; Groups ; Humans ; Linear Models ; Male ; Mania ; Manic depression ; Medical sciences ; Mood disorders ; Neuropharmacology ; Patients ; Pharmacology. Drug treatments ; Placebos ; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; Psychopharmacology ; Randomized Controlled Trials as Topic ; Regression analysis ; Treatment Outcome ; Valproic Acid - administration & dosage ; Valproic Acid - blood ; Valproic Acid - therapeutic use</subject><ispartof>The American journal of psychiatry, 2006-02, Vol.163 (2), p.272-275</ispartof><rights>2006 INIST-CNRS</rights><rights>Copyright American Psychiatric Association Feb 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a495t-df78bf96c99385bbaa3323664a85dea348e79536587ef197b48e1881d5ea63593</citedby><cites>FETCH-LOGICAL-a495t-df78bf96c99385bbaa3323664a85dea348e79536587ef197b48e1881d5ea63593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://psychiatryonline.org/doi/epdf/10.1176/appi.ajp.163.2.272$$EPDF$$P50$$Gappi$$H</linktopdf><linktohtml>$$Uhttps://psychiatryonline.org/doi/full/10.1176/appi.ajp.163.2.272$$EHTML$$P50$$Gappi$$H</linktohtml><link.rule.ids>314,780,784,2855,21626,21627,21628,27924,27925,77794,77799</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17474344$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16449481$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Allen, Michael H.</creatorcontrib><creatorcontrib>Hirschfeld, Robert M.</creatorcontrib><creatorcontrib>Wozniak, Patricia J.</creatorcontrib><creatorcontrib>Baker, Ph.D., Jeffrey D.</creatorcontrib><creatorcontrib>Bowden, Charles L.</creatorcontrib><title>Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania</title><title>The American journal of psychiatry</title><addtitle>Am J Psychiatry</addtitle><description>OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (≤55.0 g ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 g ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 g ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 g ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 g ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 g ml.</description><subject>Acute Disease</subject><subject>Adult</subject><subject>Adult and adolescent clinical studies</subject><subject>Analysis of Variance</subject><subject>Antimanic Agents - administration & dosage</subject><subject>Antimanic Agents - blood</subject><subject>Antimanic Agents - therapeutic use</subject><subject>Behavioral sciences</subject><subject>Biological and medical sciences</subject><subject>Bipolar disorder</subject><subject>Bipolar Disorder - blood</subject><subject>Bipolar Disorder - drug therapy</subject><subject>Bipolar Disorder - psychology</subject><subject>Clinical trials</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Groups</subject><subject>Humans</subject><subject>Linear Models</subject><subject>Male</subject><subject>Mania</subject><subject>Manic depression</subject><subject>Medical sciences</subject><subject>Mood disorders</subject><subject>Neuropharmacology</subject><subject>Patients</subject><subject>Pharmacology. Drug treatments</subject><subject>Placebos</subject><subject>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopathology. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Regression analysis</subject><subject>Treatment Outcome</subject><subject>Valproic Acid - administration & dosage</subject><subject>Valproic Acid - blood</subject><subject>Valproic Acid - therapeutic use</subject><issn>0002-953X</issn><issn>1535-7228</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtr3DAUhUVpaKZp_0AXRRTanR29ZS3DkD5gQqAvuhPXtkw1eCRXsgv999VkTANdJCsh8Z1z79FB6BUlNaVaXcI0-Rr2U00Vr1nNNHuCNlRyWWnGmqdoQwhhlZH8xzl6nvO-XAnX7Bk6p0oIIxq6QX7ng4OEP7sRZh9D_uknHAf8HcYpRZgd_uLScsDbGDoX5nQH4TkWQZ4K7jCEHt9Osz_AuLI799uNGQ8x4atuKRY3EDy8QGcDjNm9XM8L9O399dftx2p3--HT9mpXgTByrvpBN-1gVGcMb2TbAnDOuFICGtk74KJxukRSstFuoEa35YE2De2lA8Wl4Rfo3cm37P9rcXm2B587N44QXFyy1URzqql4FCzmzAhJC_jmP3AflxRKCMsYkcQorQvETlCXYs7JDXZK5U_SH0uJPdZlj3XZUpctdVlmS11F9Hp1XtqD6-8laz8FeLsCkDsYhwSh8_me00ILLo5ZLk_c3ZB_6z0w-i-8-66h</recordid><startdate>20060201</startdate><enddate>20060201</enddate><creator>Allen, Michael H.</creator><creator>Hirschfeld, Robert M.</creator><creator>Wozniak, Patricia J.</creator><creator>Baker, Ph.D., Jeffrey D.</creator><creator>Bowden, Charles L.</creator><general>American Psychiatric Publishing</general><general>American Psychiatric Association</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>K9.</scope><scope>NAPCQ</scope><scope>7TK</scope><scope>7X8</scope></search><sort><creationdate>20060201</creationdate><title>Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania</title><author>Allen, Michael H. ; Hirschfeld, Robert M. ; Wozniak, Patricia J. ; Baker, Ph.D., Jeffrey D. ; Bowden, Charles L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a495t-df78bf96c99385bbaa3323664a85dea348e79536587ef197b48e1881d5ea63593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Acute Disease</topic><topic>Adult</topic><topic>Adult and adolescent clinical studies</topic><topic>Analysis of Variance</topic><topic>Antimanic Agents - administration & dosage</topic><topic>Antimanic Agents - blood</topic><topic>Antimanic Agents - therapeutic use</topic><topic>Behavioral sciences</topic><topic>Biological and medical sciences</topic><topic>Bipolar disorder</topic><topic>Bipolar Disorder - blood</topic><topic>Bipolar Disorder - drug therapy</topic><topic>Bipolar Disorder - psychology</topic><topic>Clinical trials</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Administration Schedule</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Groups</topic><topic>Humans</topic><topic>Linear Models</topic><topic>Male</topic><topic>Mania</topic><topic>Manic depression</topic><topic>Medical sciences</topic><topic>Mood disorders</topic><topic>Neuropharmacology</topic><topic>Patients</topic><topic>Pharmacology. Drug treatments</topic><topic>Placebos</topic><topic>Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopathology. Psychiatry</topic><topic>Psychopharmacology</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Regression analysis</topic><topic>Treatment Outcome</topic><topic>Valproic Acid - administration & dosage</topic><topic>Valproic Acid - blood</topic><topic>Valproic Acid - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Allen, Michael H.</creatorcontrib><creatorcontrib>Hirschfeld, Robert M.</creatorcontrib><creatorcontrib>Wozniak, Patricia J.</creatorcontrib><creatorcontrib>Baker, Ph.D., Jeffrey D.</creatorcontrib><creatorcontrib>Bowden, Charles L.</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 Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The American journal of psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Allen, Michael H.</au><au>Hirschfeld, Robert M.</au><au>Wozniak, Patricia J.</au><au>Baker, Ph.D., Jeffrey D.</au><au>Bowden, Charles L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania</atitle><jtitle>The American journal of psychiatry</jtitle><addtitle>Am J Psychiatry</addtitle><date>2006-02-01</date><risdate>2006</risdate><volume>163</volume><issue>2</issue><spage>272</spage><epage>275</epage><pages>272-275</pages><issn>0002-953X</issn><eissn>1535-7228</eissn><coden>AJPSAO</coden><abstract>OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (≤55.0 g ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 g ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 g ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 g ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 g ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 g ml.</abstract><cop>Washington, DC</cop><pub>American Psychiatric Publishing</pub><pmid>16449481</pmid><doi>10.1176/appi.ajp.163.2.272</doi><tpages>4</tpages></addata></record> |
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source | MEDLINE; American Psychiatric Publishing Journals (1997-Present); EZB-FREE-00999 freely available EZB journals |
subjects | Acute Disease Adult Adult and adolescent clinical studies Analysis of Variance Antimanic Agents - administration & dosage Antimanic Agents - blood Antimanic Agents - therapeutic use Behavioral sciences Biological and medical sciences Bipolar disorder Bipolar Disorder - blood Bipolar Disorder - drug therapy Bipolar Disorder - psychology Clinical trials Dose-Response Relationship, Drug Drug Administration Schedule Drug therapy Female Groups Humans Linear Models Male Mania Manic depression Medical sciences Mood disorders Neuropharmacology Patients Pharmacology. Drug treatments Placebos Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Psychopharmacology Randomized Controlled Trials as Topic Regression analysis Treatment Outcome Valproic Acid - administration & dosage Valproic Acid - blood Valproic Acid - therapeutic use |
title | Linear Relationship of Valproate Serum Concentration to Response and Optimal Serum Levels for Acute Mania |
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