Although lithium remains the treatment of choice for bipolar disorder, only 6O-80% of classic bipolar patients have a satisfactory clinical response. When the response rate of lithium is considered across the wide spectrum of bipolar disorders, it probably approaches 50%. A large subgroup of lithium-resistant manic patients are rapid cyclers, which is defined by Dunner and Fieve as 4 or more depressions and hypomanias or manias in a 12 month period. About 13-20% of bipolar patients become rapid cyclers and most are females. As many as 72-82% of rapid cyclers exhibit poor responses to lithium. Thus, a substantial percentage of poor response to lithium is accounted for on the basis of rapid cycling. Although controlled trials have demonstrated the efficacy of carbamazepine in the treatment of rapid-cycling bipolar disorder, the response to carbamazepine frequently deteriorates over time. Furthermore, its ability to autoinduce and heteroinduce drug metabolism complicates its routine use. These findings suggest substantial numbers of rapid cyclers become resistant to both carbamazepine and lithium and that additional mood stabilizers are needed. The acute and prophylactic efficacy of valproate in the management of the rapid-cycling bipolar disorder was recently reported by us. These open but prospective trials, as well as other positive reports of its efficacy in rapid cycling, indicate a need for controlled trials. We propose a modified random assignment, single center, 18 month, double- blind, parallel group comparison of valproate and lithium for the prophylactic outpatient management of hypomania/mania in 60 patients with rapid-cycling bipolar disorder. The primary objective of this study is to test the hypothesis that valproate monotherapy is more effective than lithium monotherapy in the prophylactic management of hypomania and mania. The primary efficacy variable for the study will be time to first hypomanic or manic relapse during maintenance monotherapy defined by Research Diagnostic Criteria. Secondary efficacy variables will be studied to further test the primary hypothesis: quality of life, total days hypomanic, total numbers hypomanic episodes, and severity of hypomanic episodes. Mean and worst score depression ratings during hypomanic and manic episodes will reflect the mixed quality of each individual episode. Data regarding antidepressant efficacy will be gathered including time to first depressive relapse, total days depressed, total number of depressed episodes, and mean and worst scores of depression severity. This study should provide novel data describing the safety and efficacy of valproate compared to lithium in a patient population with high public health significance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH050165-03
Application #
2392934
Study Section
Treatment Assessment Review Committee (TA)
Project Start
1995-04-01
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Wang, Zuowei; Kemp, David E; Chan, Philip K et al. (2011) Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. Int J Neuropsychopharmacol 14:131-42
Gao, Keming; Kemp, David E; Wang, Zuowei et al. (2010) Predictors of non-stabilization during the combination therapy of lithium and divalproex in rapid cycling bipolar disorder: a post-hoc analysis of two studies. Psychopharmacol Bull 43:23-38
Kemp, David E; Gao, Keming; Chan, Philip K et al. (2010) Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome. Bipolar Disord 12:404-13
Gao, K; Kemp, D E; Conroy, C et al. (2010) Comorbid anxiety and substance use disorders associated with a lower use of mood stabilisers in patients with rapid cycling bipolar disorder: a descriptive analysis of the cross-sectional data of 566 patients. Int J Clin Pract 64:336-44
Gao, Keming; Chan, Philip K; Verduin, Marcia L et al. (2010) Independent predictors for lifetime and recent substance use disorders in patients with rapid-cycling bipolar disorder: focus on anxiety disorders. Am J Addict 19:440-9
Kemp, David E; Gao, Keming; Ganocy, Stephen J et al. (2009) Medical and substance use comorbidity in bipolar disorder. J Affect Disord 116:64-9
Gao, Keming; Tolliver, Bryan K; Kemp, David E et al. (2009) Correlates of historical suicide attempt in rapid-cycling bipolar disorder: a cross-sectional assessment. J Clin Psychiatry 70:1032-40
Kemp, David E; Gao, Keming; Ganocy, Stephen J et al. (2009) A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and Co-occurring substance abuse or dependence. J Clin Psychiatry 70:113-21
Gao, Keming; Tolliver, Bryan K; Kemp, David E et al. (2008) Differential interactions between comorbid anxiety disorders and substance use disorder in rapid cycling bipolar I or II disorder. J Affect Disord 110:167-73
Gao, Keming; Verduin, Marcia L; Kemp, David E et al. (2008) Clinical correlates of patients with rapid-cycling bipolar disorder and a recent history of substance use disorder: a subtype comparison from baseline data of 2 randomized, placebo-controlled trials. J Clin Psychiatry 69:1057-63

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