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S.01.02 Meta-analytic comparison of antipsychotics versus mood-stabilisers in mania
S175
Symposia
S.01. Advances in the treatment of bipolar disorder 18.01.011 Protein kinase C inhibitors in mania A. Yildiz 1 " D. 6ngii? , P.E Renshaw3 . 1Dokuz Eylul University, Psychiatry, Izmir, Turkey; 2 Harvard University McLean Hospital, Psychiatry, Belmont, USA; 3 University of Utah, Brain Imaging Center & Psychiatry, Salt Lake City, USA
Existing evidence suggests that two structurally dissimilar antimanic agents, lithium and va1proate, attenuate protein kinase C-PKC function in a therapeutically relevant time frame, whereas promanic psychostimulants activate PKC. PKC plays a major role in the regulation of neuronal excitability, neurotransmitter release, long-term alterations in gene expression and plasticity. Recently, two scientifically rigorous, placebo-controlled, randomized trials of a PKC inhibitor drug: tamoxifen in mania have been carried out. Both trials, which were carried out independently, indicate that tamoxifen has strong antimanic properies. In the first trial intentto-treat analysis of available measures on 66 subjects indicated that tamoxifen yielded a mean Young Mania rating Scale-YMRS decrease of5.84 points/week (0.73 CGI-Mania points/week) compared to a mean increase of 1.50 (YMRS) and 0.10 (CGI-Mania) points/week with placebo; both drug-placebo contrasts differed significantly (p < 0.001). The second study conducted at the NIMH with 16 manic patients reported a mean YMRS decrease of 18.3±4.29 points with tamoxifen compared to a mean increase of 4.67±4.08 YMRS points with placebo over 3 weeks. These two proof of concept trials on the role of 'PKC' in development and treatment of mania along with all the previous genomic, preclinical, and clinical work represents an example of thoughtful drug development and improved understanding of the pathophysiology of bipolar illness. This first target specific anti-manic treatment strategy via measurable effects of the disease or the test drug on the target: PKC may also lead to identification of a biomarker indicative of the disease state and potential treatment responders. References [1] Yildiz, A., Guleryuz, S., Ankerst, D.P., Ongiir, D., Renshaw, P.E, 2008 Protein kinase C inhibition in the treatment of mania: A double-blind, placebo-controlled trial of tamoxifen. Archives of General Psychiatry 65, 255-263. [2] Zarate, C.A. Jr., Singh, IB., Carlson, P.I, Quiroz, I, Jolkovsky, L., Luckenbaugh, D.A., Manji, H.K., 2007 Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disorders 9, 561-570. [3] Yildiz, A., Ongiir, D., Renshaw, P.E, 2009 Concomitant use of 10razepam with tamoxifen in bipolar mania clinical trials-Reply. Archives of General Psychiatry 66, 108-109.
18.01.021 Meta-analytic comparison of antipsychotics versus mood-stabilisers in mania
Vieta1 "
E. A. Yildiz2, IR. Baldessarini3 . 1 Clinical Institute of Neuroscience, Bipolar Disorders Progrom CIBERSAM, Barcelona, Spain; 2 Dokuz Eyliil University, Department of Psychiatry, Izmir, Turkey; 3Harvard Medical School, Department ofPsychiatry, Boston, USA Background: Treatment-recommendations for acute mania vary among experts, in part reflecting rapid innovation following decades of little progress, and uncertainty about relative efficacy and safety of specific treatments [1,2]. Accordingly, we undertook comprehensive meta-analyses of modem treatments for acute mania, based on meta-analyses of randomized controlled trials (RCTs). Objective: We conducted a meta-analytic review of placebocontrolled, monotherapy-RCTs in acute mania. Data Sources: We searched for relevant RCT reports, comparing experimental drug-monotherapy versus placebo for acute mania in standard computerized databases through August 2008, consulting investigators of identified trials for missing data when necessary. Study Selection: We identified abstracts of potential studies by key words (antipsychotic, anticonvulsant, antimanic, bipolar, mania, placebo), and read promising abstracts and reports. Data Extraction: Measures of efficacy, trial-design, samplesize, subject age and sex, history of manic/mixed episodes or presence of psychotic features, washout method, trial-duration, hospitalization, completion rates were pooled by meta-analyses. Data Synthesis: We included 14 active drug versus placebo comparisons from 46 trials involving 8858 manic/mixed patients. The following were indistinguishably (overlapping CIs) superior to placebo: aripiprazole, asenapine, carbamazepine, divalproex, haloperidol, lithium, olanzapine, quetiapine, risperidone, tamoxifen, and ziprasidone, and as did drug-classes (mood-stabilizers, modem antipsychotics, and PKC-inhibitors). Lamotrigine, topiramate and verapamil failed to separate from placebo. Conclusion: These analyses indicate similar short-term antimanic efficacy for various types of antimanic agents including antipsychotics and mood-stabilisers. Nevertheless, as more direct comparisons of specific alternatives are awaited, rational treatment-planning for manic patients requires consideration of individual clinical needs, expected benefits and risks. References [1] Vieta, E., Sanchez-Moreno, I, 2008 Acute and long-term treatment of mania. Dialogues Clin Neurosci. 10, 165-179. [2] Fountoulakis, K.N., Vieta, E., 2008 Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol. 11,999-1029.
Symposia
S.01. Advances in the treatment of bipolar disorder 18.01.011 Protein kinase C inhibitors in mania A. Yildiz 1 " D. 6ngii? , P.E Renshaw3 . 1Dokuz Eylul University, Psychiatry, Izmir, Turkey; 2 Harvard University McLean Hospital, Psychiatry, Belmont, USA; 3 University of Utah, Brain Imaging Center & Psychiatry, Salt Lake City, USA
Existing evidence suggests that two structurally dissimilar antimanic agents, lithium and va1proate, attenuate protein kinase C-PKC function in a therapeutically relevant time frame, whereas promanic psychostimulants activate PKC. PKC plays a major role in the regulation of neuronal excitability, neurotransmitter release, long-term alterations in gene expression and plasticity. Recently, two scientifically rigorous, placebo-controlled, randomized trials of a PKC inhibitor drug: tamoxifen in mania have been carried out. Both trials, which were carried out independently, indicate that tamoxifen has strong antimanic properies. In the first trial intentto-treat analysis of available measures on 66 subjects indicated that tamoxifen yielded a mean Young Mania rating Scale-YMRS decrease of5.84 points/week (0.73 CGI-Mania points/week) compared to a mean increase of 1.50 (YMRS) and 0.10 (CGI-Mania) points/week with placebo; both drug-placebo contrasts differed significantly (p < 0.001). The second study conducted at the NIMH with 16 manic patients reported a mean YMRS decrease of 18.3±4.29 points with tamoxifen compared to a mean increase of 4.67±4.08 YMRS points with placebo over 3 weeks. These two proof of concept trials on the role of 'PKC' in development and treatment of mania along with all the previous genomic, preclinical, and clinical work represents an example of thoughtful drug development and improved understanding of the pathophysiology of bipolar illness. This first target specific anti-manic treatment strategy via measurable effects of the disease or the test drug on the target: PKC may also lead to identification of a biomarker indicative of the disease state and potential treatment responders. References [1] Yildiz, A., Guleryuz, S., Ankerst, D.P., Ongiir, D., Renshaw, P.E, 2008 Protein kinase C inhibition in the treatment of mania: A double-blind, placebo-controlled trial of tamoxifen. Archives of General Psychiatry 65, 255-263. [2] Zarate, C.A. Jr., Singh, IB., Carlson, P.I, Quiroz, I, Jolkovsky, L., Luckenbaugh, D.A., Manji, H.K., 2007 Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disorders 9, 561-570. [3] Yildiz, A., Ongiir, D., Renshaw, P.E, 2009 Concomitant use of 10razepam with tamoxifen in bipolar mania clinical trials-Reply. Archives of General Psychiatry 66, 108-109.
18.01.021 Meta-analytic comparison of antipsychotics versus mood-stabilisers in mania
Vieta1 "
E. A. Yildiz2, IR. Baldessarini3 . 1 Clinical Institute of Neuroscience, Bipolar Disorders Progrom CIBERSAM, Barcelona, Spain; 2 Dokuz Eyliil University, Department of Psychiatry, Izmir, Turkey; 3Harvard Medical School, Department ofPsychiatry, Boston, USA Background: Treatment-recommendations for acute mania vary among experts, in part reflecting rapid innovation following decades of little progress, and uncertainty about relative efficacy and safety of specific treatments [1,2]. Accordingly, we undertook comprehensive meta-analyses of modem treatments for acute mania, based on meta-analyses of randomized controlled trials (RCTs). Objective: We conducted a meta-analytic review of placebocontrolled, monotherapy-RCTs in acute mania. Data Sources: We searched for relevant RCT reports, comparing experimental drug-monotherapy versus placebo for acute mania in standard computerized databases through August 2008, consulting investigators of identified trials for missing data when necessary. Study Selection: We identified abstracts of potential studies by key words (antipsychotic, anticonvulsant, antimanic, bipolar, mania, placebo), and read promising abstracts and reports. Data Extraction: Measures of efficacy, trial-design, samplesize, subject age and sex, history of manic/mixed episodes or presence of psychotic features, washout method, trial-duration, hospitalization, completion rates were pooled by meta-analyses. Data Synthesis: We included 14 active drug versus placebo comparisons from 46 trials involving 8858 manic/mixed patients. The following were indistinguishably (overlapping CIs) superior to placebo: aripiprazole, asenapine, carbamazepine, divalproex, haloperidol, lithium, olanzapine, quetiapine, risperidone, tamoxifen, and ziprasidone, and as did drug-classes (mood-stabilizers, modem antipsychotics, and PKC-inhibitors). Lamotrigine, topiramate and verapamil failed to separate from placebo. Conclusion: These analyses indicate similar short-term antimanic efficacy for various types of antimanic agents including antipsychotics and mood-stabilisers. Nevertheless, as more direct comparisons of specific alternatives are awaited, rational treatment-planning for manic patients requires consideration of individual clinical needs, expected benefits and risks. References [1] Vieta, E., Sanchez-Moreno, I, 2008 Acute and long-term treatment of mania. Dialogues Clin Neurosci. 10, 165-179. [2] Fountoulakis, K.N., Vieta, E., 2008 Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol. 11,999-1029.