Ignite Creation Date:
2024-05-05 @ 11:59 AM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00206778
Status:
COMPLETED
Last Update Posted:
2010-11-25
First Post:
2005-09-16
Brief Title:
Six Month Trial of Lamotrigine vs Sodium Valproate for Treatment of Mixed Mania
Sponsor:
Beth Israel Medical Center
Organization:
Beth Israel Medical Center
Study Overview
Official Title:
A Randomized Open-Label 6 Month Acute and Maintenance Trial of Lamotrigine vs Standard of Care Sodium Valproate Monotherapy for Treatment of Mixed Mania
Status:
COMPLETED
Status Verified Date:
2010-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
We are comparing the efficacy of Lamotrigine to that of Standard of Care Sodium Valproate for the treatment of Mixed Mania The study hypothesis is that Lamotrigine will be more efficative for treating mixed mania in patients with Bipolar Disorder
Detailed Description:
Mixed mania is a clinically distinct affective state which is likely to be more severe than classical euphoric mania and to have longer episode duration Mixed mania is associated with longer duration of illness suicidality and poor outcome McElroy et al 1995 Although at present there is no universally agreed on definition for mixed states 40-60 of patients in acute manic states also meet criteria for either major depression or dysphoria Dilsaver et al1999 Calabrese et al 1999 Secunda et al1985 Sporn and Sacks1997 Dilsaver at al 1999 in their factor analytic study of manic symptoms were able to differentiate dysphoric and depressed mania Patients with depressed mania 30 of all patients with mania were as manic as patients with euphoric mania and also met criteria for the Major depressive disorder Patients with dysphoric mania were less manic and less depressed but more irritable than both depressed and euphoric manic patients
At present there is no accepted treatment algorithms for mixed affective states including depressed and dysphoric mania in Dilsaver definition Currently used antimanic agents lorazepam typical antipsychotics olanzapine and mood stablizers lithium divlaproex sodium have little or no antidepressant activity Therefore treatment of mixed mania frequently results in emergence of bipolar depression that is often treatment-refractory Thus is an urgent need for effective treatment of mixed mania that will not result in bipolar depression
Lamotrigine is an anticonvulsant that prolongs the refractory phase of voltage sensitive channels an action that is associated with antimanic properties Hurly 2002 Sporn and Sacks 1997 Calabrese et al 1999 Normann et al 2002 Lamotrigine was postulated to decrease glutamate release by acting at voltage-sensitive sodium channel in their refractory phase stabilizing presynaptic neuronal membranes and inhibiting pathologic release of glutamate As abnormalities in glutamatergic system have been implicated in depression and NMDA receptor antagonists reverse anxiety or depression in various stress models lamotrigine could act as an antidepressant Thus lamotrigine has a potential to have both antimanic and antidepressant activity for refs see Sporn and Sacks 1997 and in theory should be uniquely effective for mixed mania Dilsaver et al 1999 Indeed clinical trials reviewed in detail by Hurley 2002 demonstrated that lamotrigine is somewhat effective an antimanic agent and has significant antidepressant activity in bipolar depression Lamotrigine was used in a combination with other agents or as monotherapy and the response rates for depressed mixed and rapid cycling states were similar ranging from 52 to 63 With slow dose titration 6 weeks side effects were few and the incidence of exfoliative dermatitis was 1 in 500 Of note although Sporn and Sachs 1997 reported a switch from depression to rapid cycling such incidences were few In our institution lamotrigine was effective for treatment of mixed mania and bipolar depression in patients receiving standard maintenance treatment for Bipolar Mood Disorder Lamotrigine did worsen agitation in two elderly patients with symptoms of irritable mania
Based on the above evidence it appears that lamotrigine either in combination with a proven antimanic agent or in monotherapy is uniquely suited to be the agent of choice for treatment of mixed mania Therefore we here propose a randomized open-label trial of lamotrigine vs standard of care sodium valpoate for treatment of mixed mania Within this framework the following are the studys hypotheses and objectives
HypothesisObjectives Objective One To compare the efficacy of the lamotrigine with sodium valproate standard of care for treatment of depressive symptoms of acute mania in patients with Bipolar Mood Disorder
Hypothesis One
Lamotrigine will be more effective than sodium valproate in treatment of depressive symptoms in acute mixed mania
Objective Two To compare the efficacy of the lamotrigine with that of sodium valproate for treatment of manic symptoms in acute mixed mania
Hypothesis Two
Lamotrigine and sodium valproate will be equally effective in treatment of manic symptoms in acute mixed mania as measured by the Young Mania Rating Scale scores
Objective Three To compare the efficacy of lamotrigine to that of sodium valproate in maintenance treatment of patients with bipolar mood disorder and a recent past episode of mixed mania
Hypothesis Three
iThe lamlotrigine will be more efficacious than sodium valproate in maintenance treatment of patients with bipolar mood disorder and a recent past episode of mixed mania
ii The lamotrigine patients will have lower relapse rate iii The lamotrigine patients will have lower rates of depression than patients treated with sodium valproate
Objective Four To compare the side effect profile of lamotrigine treatment of mixed mania to sodium valproate treatment of mixed mania in patients with bipolar mood disorder and a recent past episode of mixed mania
Hypothesis four
Lamotrigine acute treatment will result in comparable side effect profile with that of sodium valproate while lamotrigine maintenance treatment will be superior to that with sodium valproate
Methods We plan to study two eighteen-subject groups 36 subjects total of male and female study participants between ages 18 and 65 over a 1 12 year period The subjects will be enrolled from the inpatient units at the Beth Israel Medical Center and at the St Lukes-Roosevelt Hospital Center Continuum Health Partners and will be followed at the Center for Treatment of the Affective Disorders in the Department of Psychiatry at BIMC An independent evaluator Paul Teusink MD not affiliated with the study will determine capacity of consent We will select patients who would have had at least one prior manic episode and who meet inclusion and exclusion criteria for depressed acute mania Dilsaver et al 1999 The study criteria for an acute episode of irritable depressed mania will be a Young Mania Rating Scale YMRS score of at least 11 and the Hamilton Depression Rating Scale HDRS score of at least 18 with 72 hours prior to entering the study Patient could be randomized on study medication if shehe came to clinic on lamotrigine or Sodium valprole but shehe has low blood level of this drug
The study will have two phases
Phase 1 The Acute Phase Index medications schedule Following randomization during the first 8-week phase the index manic episode will be treated with either adjust lamotrigine or sodium valproate will be started at 25 mg po daily and will be increased biweekly until a maximal dose of 200 mgday Dose escalation schedule weeks 1-2 25 mg po qd week 3-4 25 mg po bid weeks 5-6 50 mg po bid weeks 7-8 100 mg po bid The dose could be decreased to as low as 50 mgday to reduce side effects other than rash The sodium valproate treatment will be initiated with a loading dose of 20 mgkg and the dose will be adjusted in 250 mgday increments to achieve a therapeutic level of 100-120 mcgkg
Concomitant medications schedule If a patient is receiving mood stabilizers such as lithium carbamazepine gabapentine trileptal lamotrigine or sodium valproate at the beginning of the study these medications will be discontinued in 72 hours informed consent is provided The following medications will not be permitted during the acute phase of the trial clozaril depot neuroleptics antipsychotic antidepressant and benzodiazepines other than lorazepam
Rescue medications Since neuroleptics and lorazepam will be liberally allowed for treatment of acute manic symptoms no rescue medications will be necessary in the acute phase
Crossover design for subjects with treatment failure If subjects condition deteriorates after randomization to lamotrigine or valporate subject will be crossed over to the other arm of the study ie those who failed sodium valproate will be treated with lamotrigine and vise versa and vise versa Subjects who will have failed the crossover switch will be removed from the study Deterioration will be defined as a three-point worsening in the patients YMRS score lasting more than 72 hours
Outcome measures The severity of illness will be measured with Young Mania Rating Scale MRS Hamilton Rating scale for depression and the CGI rating scale The primary outcome measures will be the YMRS total score change from baseline until the endpoint of Phase 1 The secondary outcome measures will be the HRSD total score change and the CGI score change from baseline until the Phase 1 endpoint Other secondary outcome measures will be the amount the incidences of seclusion and restraint the length of hospital stay and the medical indeces such as HgA1C weight changes and lipid profile
Phase 2 The Maintenance Phase If after two month of treatment patient improve on 50 compare to initial level of YMRS HDRS and YMRS11 HDRS18 patient will be transferred to the Maintenance Phase Index Medication Schedule
The acute phase will be followed by the 4 months maintenance phase In the maintenance phase all medications but lorazepam 4 mg day dose and lamotrigine or sodium valproate will be typed over for initial 4 weeks period In the last 3 month of the study the lamotrigine subjects will receive only lamotrigine monotherapy The dose will be adjusted by the study physicians as clinically necessary within the same dose range as in the Phase 1 The sodium valproate dose will be maintained to achieve a therapeutic level of 50-100 mcgml The subjects will be followed weekly for the first 5 weeks of the study For the rest of the study the subjects will be followed biweekly
Rescue medications schedule During the maintenance phase lorazepam will be tapered to a minimal dose that would allow nightly sleep of at least 8 hrs The dose adjustment will be done weekly according to the following dose reduction schedule 4 mg - 3 mg - 2 mg - 1 mg - 0 5 mg - 0 mg and will take up to five weeks depending on the initial dose
Outcome measures The primary outcome measures will be the number and the time to either manic or depressive episodes The secondary outcome measures will be an average change from baseline in YMRS HRSD and CGI scores from baseline until the endpoint of Phase 2 We will also evaluate medication side effects the need for adjunct lorazepam treatment the reasons for premature discontinuation the demographic data and the medical endpoints HgbA1C weight changes lipid profile We will use SPSS and appropriate statistical methods for statistical analysis
Study Population
The patient population will consist of psychiatric inpatients at the Beth Israel Medical Center and the St Lukes-Roosevelt Hospital Center who meet criteria for the DSM-IV diagnosis of Bipolar Mood Disorder I manic episode At present the patient ethnic and racial mix is 26 Hispanic 30 African American and 45 Caucasian The gender distribution is 46 male 54 female The inpatient payer mix is 26 Medicare and 50 Medicaid The average length of stay for the three units is 19 days for all patients and 26 days for patients without co-morbid substance use
In 1999-2001 inpatient units at the BIMC registered on average 1500 yearly admissions 1350 of them ages 17-65 Upon admission approximately 200 patients carried a diagnosis of Bipolar Mood Disorder I manic episode without comorbid substance abuse The inpatient units at Saint Lukes Roosevelt admit 100 manic patients yearly If the admission demographics remain unchanged for 2003 we expect that 40 patients per year will meet diagnostic inclusion criterion for the study Based on our previous experience with recruitment for research studies we expect that 30 of patients meeting the diagnostic criteria will also meet other inclusion and exclusion criteria will sign the inform consent and participate in the study Therefore we expect to recruit 36 patients per year and to complete the study accrual in 18 months We plan to complete the data analysis for the acute phase within one year
Inclusion Criteria
1 Males and females ages 18-65
2 Ability to sign an informed consent
3 Diagnosis of Bipolar Mood Disorder I manic episode
4 Mania Rating Scale MRS score of at least 11
5 HDRS score of at least 18
6 Global Assessment Scale GAS scores more than 60 Exclusion Criteria
1 Alcohol or substance abuse within the last 6 months 2 Current diagnosis of Obsessive-Compulsive Disorder 3 Current diagnosis of Schizophrenia or Schizoaffective Disorder 4 Previous adverse reaction or allergies to lamotrigine or sodium valproate
Study Design and Drug Regimens The study will be months open label parallel comparison with a blinded rater of combination therapy lamotrigine 25-200 mgdayflexible dosing and sodium valproate flexible dosing monotherapy for treatment of mixed mania in two groups of patients with Bipolar Mood Disorder I The study will have acute and maintenance phases Each group will consist of 18 subjects matched for age gender and education
Data Analysis
All patients who were randomly assigned to treatment groups and had at least one post-baseline assessment will be included in the efficacy analysis The primary time points will be the endpoints of Phases 1 and 2 ie the last available observation during Phases 1 and 2 The primary comparison will be between the lamotrigine sodium valproate groups The analysis of covariance model will be used to test differences between treatments at endpoint The model will include factors for treatment and baseline scores on MRS and HRDS as a covariate MRS scores at all time points will be analyzed jointly by means of repeated measures model HRDS scores will be analyzed in the same way as MRS scores Treatment over time will be used as a factor in the model Gehans generalized Wilcoxon test will be used to evaluate differences in time to discontinuation ref from Sachs and Van Elteren test will be used to evaluate differences in the CGI scores ref from Sachs
Scientific Relevance and Health Implications
The successful completion of this study will indicate that lamotrigine combination should be the preferred first-line treatment for mixed mania that should be continued as the preferred maintenance treatment for mixed mania
At present there is no accepted treatment algorithms for mixed affective states including depressed and dysphoric mania in Dilsaver definition Currently used antimanic agents lorazepam typical antipsychotics olanzapine and mood stablizers lithium divlaproex sodium have little or no antidepressant activity Therefore treatment of mixed mania frequently results in emergence of bipolar depression that is often treatment-refractory Thus is an urgent need for effective treatment of mixed mania that will not result in bipolar depression
Lamotrigine is an anticonvulsant that prolongs the refractory phase of voltage sensitive channels an action that is associated with antimanic properties Hurly 2002 Sporn and Sacks 1997 Calabrese et al 1999 Normann et al 2002 Lamotrigine was postulated to decrease glutamate release by acting at voltage-sensitive sodium channel in their refractory phase stabilizing presynaptic neuronal membranes and inhibiting pathologic release of glutamate As abnormalities in glutamatergic system have been implicated in depression and NMDA receptor antagonists reverse anxiety or depression in various stress models lamotrigine could act as an antidepressant Thus lamotrigine has a potential to have both antimanic and antidepressant activity for refs see Sporn and Sacks 1997 and in theory should be uniquely effective for mixed mania Dilsaver et al 1999 Indeed clinical trials reviewed in detail by Hurley 2002 demonstrated that lamotrigine is somewhat effective an antimanic agent and has significant antidepressant activity in bipolar depression Lamotrigine was used in a combination with other agents or as monotherapy and the response rates for depressed mixed and rapid cycling states were similar ranging from 52 to 63 With slow dose titration 6 weeks side effects were few and the incidence of exfoliative dermatitis was 1 in 500 Of note although Sporn and Sachs 1997 reported a switch from depression to rapid cycling such incidences were few In our institution lamotrigine was effective for treatment of mixed mania and bipolar depression in patients receiving standard maintenance treatment for Bipolar Mood Disorder Lamotrigine did worsen agitation in two elderly patients with symptoms of irritable mania
Based on the above evidence it appears that lamotrigine either in combination with a proven antimanic agent or in monotherapy is uniquely suited to be the agent of choice for treatment of mixed mania Therefore we here propose a randomized open-label trial of lamotrigine vs standard of care sodium valpoate for treatment of mixed mania Within this framework the following are the studys hypotheses and objectives
HypothesisObjectives Objective One To compare the efficacy of the lamotrigine with sodium valproate standard of care for treatment of depressive symptoms of acute mania in patients with Bipolar Mood Disorder
Hypothesis One
Lamotrigine will be more effective than sodium valproate in treatment of depressive symptoms in acute mixed mania
Objective Two To compare the efficacy of the lamotrigine with that of sodium valproate for treatment of manic symptoms in acute mixed mania
Hypothesis Two
Lamotrigine and sodium valproate will be equally effective in treatment of manic symptoms in acute mixed mania as measured by the Young Mania Rating Scale scores
Objective Three To compare the efficacy of lamotrigine to that of sodium valproate in maintenance treatment of patients with bipolar mood disorder and a recent past episode of mixed mania
Hypothesis Three
iThe lamlotrigine will be more efficacious than sodium valproate in maintenance treatment of patients with bipolar mood disorder and a recent past episode of mixed mania
ii The lamotrigine patients will have lower relapse rate iii The lamotrigine patients will have lower rates of depression than patients treated with sodium valproate
Objective Four To compare the side effect profile of lamotrigine treatment of mixed mania to sodium valproate treatment of mixed mania in patients with bipolar mood disorder and a recent past episode of mixed mania
Hypothesis four
Lamotrigine acute treatment will result in comparable side effect profile with that of sodium valproate while lamotrigine maintenance treatment will be superior to that with sodium valproate
Methods We plan to study two eighteen-subject groups 36 subjects total of male and female study participants between ages 18 and 65 over a 1 12 year period The subjects will be enrolled from the inpatient units at the Beth Israel Medical Center and at the St Lukes-Roosevelt Hospital Center Continuum Health Partners and will be followed at the Center for Treatment of the Affective Disorders in the Department of Psychiatry at BIMC An independent evaluator Paul Teusink MD not affiliated with the study will determine capacity of consent We will select patients who would have had at least one prior manic episode and who meet inclusion and exclusion criteria for depressed acute mania Dilsaver et al 1999 The study criteria for an acute episode of irritable depressed mania will be a Young Mania Rating Scale YMRS score of at least 11 and the Hamilton Depression Rating Scale HDRS score of at least 18 with 72 hours prior to entering the study Patient could be randomized on study medication if shehe came to clinic on lamotrigine or Sodium valprole but shehe has low blood level of this drug
The study will have two phases
Phase 1 The Acute Phase Index medications schedule Following randomization during the first 8-week phase the index manic episode will be treated with either adjust lamotrigine or sodium valproate will be started at 25 mg po daily and will be increased biweekly until a maximal dose of 200 mgday Dose escalation schedule weeks 1-2 25 mg po qd week 3-4 25 mg po bid weeks 5-6 50 mg po bid weeks 7-8 100 mg po bid The dose could be decreased to as low as 50 mgday to reduce side effects other than rash The sodium valproate treatment will be initiated with a loading dose of 20 mgkg and the dose will be adjusted in 250 mgday increments to achieve a therapeutic level of 100-120 mcgkg
Concomitant medications schedule If a patient is receiving mood stabilizers such as lithium carbamazepine gabapentine trileptal lamotrigine or sodium valproate at the beginning of the study these medications will be discontinued in 72 hours informed consent is provided The following medications will not be permitted during the acute phase of the trial clozaril depot neuroleptics antipsychotic antidepressant and benzodiazepines other than lorazepam
Rescue medications Since neuroleptics and lorazepam will be liberally allowed for treatment of acute manic symptoms no rescue medications will be necessary in the acute phase
Crossover design for subjects with treatment failure If subjects condition deteriorates after randomization to lamotrigine or valporate subject will be crossed over to the other arm of the study ie those who failed sodium valproate will be treated with lamotrigine and vise versa and vise versa Subjects who will have failed the crossover switch will be removed from the study Deterioration will be defined as a three-point worsening in the patients YMRS score lasting more than 72 hours
Outcome measures The severity of illness will be measured with Young Mania Rating Scale MRS Hamilton Rating scale for depression and the CGI rating scale The primary outcome measures will be the YMRS total score change from baseline until the endpoint of Phase 1 The secondary outcome measures will be the HRSD total score change and the CGI score change from baseline until the Phase 1 endpoint Other secondary outcome measures will be the amount the incidences of seclusion and restraint the length of hospital stay and the medical indeces such as HgA1C weight changes and lipid profile
Phase 2 The Maintenance Phase If after two month of treatment patient improve on 50 compare to initial level of YMRS HDRS and YMRS11 HDRS18 patient will be transferred to the Maintenance Phase Index Medication Schedule
The acute phase will be followed by the 4 months maintenance phase In the maintenance phase all medications but lorazepam 4 mg day dose and lamotrigine or sodium valproate will be typed over for initial 4 weeks period In the last 3 month of the study the lamotrigine subjects will receive only lamotrigine monotherapy The dose will be adjusted by the study physicians as clinically necessary within the same dose range as in the Phase 1 The sodium valproate dose will be maintained to achieve a therapeutic level of 50-100 mcgml The subjects will be followed weekly for the first 5 weeks of the study For the rest of the study the subjects will be followed biweekly
Rescue medications schedule During the maintenance phase lorazepam will be tapered to a minimal dose that would allow nightly sleep of at least 8 hrs The dose adjustment will be done weekly according to the following dose reduction schedule 4 mg - 3 mg - 2 mg - 1 mg - 0 5 mg - 0 mg and will take up to five weeks depending on the initial dose
Outcome measures The primary outcome measures will be the number and the time to either manic or depressive episodes The secondary outcome measures will be an average change from baseline in YMRS HRSD and CGI scores from baseline until the endpoint of Phase 2 We will also evaluate medication side effects the need for adjunct lorazepam treatment the reasons for premature discontinuation the demographic data and the medical endpoints HgbA1C weight changes lipid profile We will use SPSS and appropriate statistical methods for statistical analysis
Study Population
The patient population will consist of psychiatric inpatients at the Beth Israel Medical Center and the St Lukes-Roosevelt Hospital Center who meet criteria for the DSM-IV diagnosis of Bipolar Mood Disorder I manic episode At present the patient ethnic and racial mix is 26 Hispanic 30 African American and 45 Caucasian The gender distribution is 46 male 54 female The inpatient payer mix is 26 Medicare and 50 Medicaid The average length of stay for the three units is 19 days for all patients and 26 days for patients without co-morbid substance use
In 1999-2001 inpatient units at the BIMC registered on average 1500 yearly admissions 1350 of them ages 17-65 Upon admission approximately 200 patients carried a diagnosis of Bipolar Mood Disorder I manic episode without comorbid substance abuse The inpatient units at Saint Lukes Roosevelt admit 100 manic patients yearly If the admission demographics remain unchanged for 2003 we expect that 40 patients per year will meet diagnostic inclusion criterion for the study Based on our previous experience with recruitment for research studies we expect that 30 of patients meeting the diagnostic criteria will also meet other inclusion and exclusion criteria will sign the inform consent and participate in the study Therefore we expect to recruit 36 patients per year and to complete the study accrual in 18 months We plan to complete the data analysis for the acute phase within one year
Inclusion Criteria
1 Males and females ages 18-65
2 Ability to sign an informed consent
3 Diagnosis of Bipolar Mood Disorder I manic episode
4 Mania Rating Scale MRS score of at least 11
5 HDRS score of at least 18
6 Global Assessment Scale GAS scores more than 60 Exclusion Criteria
1 Alcohol or substance abuse within the last 6 months 2 Current diagnosis of Obsessive-Compulsive Disorder 3 Current diagnosis of Schizophrenia or Schizoaffective Disorder 4 Previous adverse reaction or allergies to lamotrigine or sodium valproate
Study Design and Drug Regimens The study will be months open label parallel comparison with a blinded rater of combination therapy lamotrigine 25-200 mgdayflexible dosing and sodium valproate flexible dosing monotherapy for treatment of mixed mania in two groups of patients with Bipolar Mood Disorder I The study will have acute and maintenance phases Each group will consist of 18 subjects matched for age gender and education
Data Analysis
All patients who were randomly assigned to treatment groups and had at least one post-baseline assessment will be included in the efficacy analysis The primary time points will be the endpoints of Phases 1 and 2 ie the last available observation during Phases 1 and 2 The primary comparison will be between the lamotrigine sodium valproate groups The analysis of covariance model will be used to test differences between treatments at endpoint The model will include factors for treatment and baseline scores on MRS and HRDS as a covariate MRS scores at all time points will be analyzed jointly by means of repeated measures model HRDS scores will be analyzed in the same way as MRS scores Treatment over time will be used as a factor in the model Gehans generalized Wilcoxon test will be used to evaluate differences in time to discontinuation ref from Sachs and Van Elteren test will be used to evaluate differences in the CGI scores ref from Sachs
Scientific Relevance and Health Implications
The successful completion of this study will indicate that lamotrigine combination should be the preferred first-line treatment for mixed mania that should be continued as the preferred maintenance treatment for mixed mania
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None