Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00146237
Status:
COMPLETED
Last Update Posted:
2009-11-25
First Post:
2005-09-06
Brief Title:
Phenytoin as an Augmentation for SSRI Failures
Sponsor:
Beersheva Mental Health Center
Organization:
Beersheva Mental Health Center
Study Overview
Official Title:
Phenytoin as an Augmentation for SSRI Failures A Controlled Study
Status:
COMPLETED
Status Verified Date:
2009-11
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:
About two-thirds of depressed patients respond to a standard course of serotonin specific reuptake inhibitor SSRIs within 3-4 weeks While some clinicians advise continued watchful waiting after this time or switch to a different reuptake-blocker based antidepressant result of such conservative strategies are usually disappointing For severe depression electroconvulsive therapy ECT is an option and for atypical depressions monoamine oxide inhibitors MAO inhibitors often give relief at this point A unique strategy with both theoretical and practical implications is lithium augmentation Fava et al 1994 Addition of lithium to SSRI failures at 3-4 weeks is consistently and sometimes dramatically found to be helpful This is considered true even by those authors who advocate use of lithium under usual circumstances only in bipolar patients
Lithium in recent years has been joined as a mood stabilizer by carbamazepine and valproate Phenytoin ignored for many years as a possible anticonvulsant mood stabilizer has been recently reported in double-blind controlled trials to be anti-manic Mishory et al 2000 and also prophylactic in BP disorder Mishory et al 2003
Data on mood stabilizers other than lithium as augmentors in SSRI failures are sparse Carbamazepine Steinacher et al 2002 and valproate Barbee et al 2002 have been used Given our recent preliminary results of phenytoins efficacy in unipolar depression Nemets et al 2005 and its analogy to lithium as a mood stabilizer it seems important to study phenytoin as a possible augmentation of SSRI failures
We have published a negative study previously of inositol as an augmentation of SSRI failures enrolling forty-two patients over two years Nemets et al 1999 Antidepressant failures are easier to recruit from referring physicians in our center than are untreated patients whom clinicians are reluctant to refer for new drug studies given the adequacy of standard treatment in 23 of them Thus we estimate that we could enroll 20 patients per year in such a study Survey of the literature of Li augmentation suggests that 40 phenytoin vs 40 placebo should give adequate power to detect a significant phenytoin effect if the phenytoin effect is similar to that of lithium
Lithium in recent years has been joined as a mood stabilizer by carbamazepine and valproate Phenytoin ignored for many years as a possible anticonvulsant mood stabilizer has been recently reported in double-blind controlled trials to be anti-manic Mishory et al 2000 and also prophylactic in BP disorder Mishory et al 2003
Data on mood stabilizers other than lithium as augmentors in SSRI failures are sparse Carbamazepine Steinacher et al 2002 and valproate Barbee et al 2002 have been used Given our recent preliminary results of phenytoins efficacy in unipolar depression Nemets et al 2005 and its analogy to lithium as a mood stabilizer it seems important to study phenytoin as a possible augmentation of SSRI failures
We have published a negative study previously of inositol as an augmentation of SSRI failures enrolling forty-two patients over two years Nemets et al 1999 Antidepressant failures are easier to recruit from referring physicians in our center than are untreated patients whom clinicians are reluctant to refer for new drug studies given the adequacy of standard treatment in 23 of them Thus we estimate that we could enroll 20 patients per year in such a study Survey of the literature of Li augmentation suggests that 40 phenytoin vs 40 placebo should give adequate power to detect a significant phenytoin effect if the phenytoin effect is similar to that of lithium
Detailed Description:
About two-thirds of depressed patients respond to a standard course of serotonin specific reuptake inhibitor SSRIs within 3-4 weeks While some clinicians advise continued watchful waiting after this time or switch to a different reuptake-blocker based antidepressant result of such conservative strategies are usually disappointing For severe depression electroconvulsive therapy ECT is an option and for atypical depressions monoamine oxide inhibitors MAO inhibitors often give relief at this point A unique strategy with both theoretical and practical implications is lithium augmentation Fava et al 1994 Addition of lithium to SSRI failures at 3-4 weeks is consistently and sometimes dramatically found to be helpful This is considered true even by those authors who advocate use of lithium under usual circumstances only in bipolar patients
Lithium in recent years has been joined as a mood stabilizer by carbamazepine and valproate Phenytoin ignored for many years as a possible anticonvulsant mood stabilizer has been recently reported in double-blind controlled trials to be anti-manic Mishory et al 2000 and also prophylactic in BP disorder Mishory et al 2003
Data on mood stabilizers other than lithium as augmentors in SSRI failures are sparse Carbamazepine Steinacher et al 2002 and valproate Barbee et al 2002 have been used Given our recent preliminary results of phenytoins efficacy in unipolar depression Nemets et al 2005 and its analogy to lithium as a mood stabilizer it seems important to study phenytoin as a possible augmentation of SSRI failures
We have published a negative study previously of inositol as an augmentation of SSRI failures enrolling forty-two patients over two years Nemets et al 1999 Antidepressant failures are easier to recruit from referring physicians in our center than are untreated patients whom clinicians are reluctant to refer for new drug studies given the adequacy of standard treatment in 23 of them Thus we estimate that we could enroll 20 patients per year in such a study Survey of the literature of Li augmentation suggests that 40 phenytoin vs 40 placebo should give adequate power to detect a significant phenytoin effect if the phenytoin effect is similar to that of lithium
The study has been approved by the Helsinki Committee and all patients must give written informed consent Patients will be evaluated for study if they meet DSM-IV criteria for major depression without psychotic features Patients can enter the study if they had at least 3 weeks of treatment with SSRI at clinically adequate doses 150mg fluvoxamine 20mg fluoxetine or 20mg paroxetine and still have a score of at least 18 on the Hamilton Depression Scale HDS on 24 item scale with at most mild improvement from onset of SSRI treatment Patients with alcohol or drug abuse or patients with unstable medical illnesses are excluded Design is parallel double-blind Patients continue SSRI treatment of the same medication and dose they received before entry They are randomly assigned to phenytoin or identical placebo capsules Patients will be rated on the HDRS weekly for four weeks after addition of phenytoin or placebo Patients who do not improve at least 1 unit on the GCI every two weeks will be dropped from the study for ethical reasons and referred to open treatment HDRS ratings are done weekly by an experienced psychiatrist BN blind to the treatment medication
Blood levels of phenytoin will be reported by the lab to the treating psychiatrist after dummy levels are assigned by the control psychiatrist to patients on placebo
All patients will be evaluated physically and EKG liver and kidney functions and blood cell count performed before entering the study
Special attention will be given to instruction of patients in dental hygiene and patients showing signs of gingival hyperplasia will be dropped Studies in epilepsy show that this side effect is surprisingly uncommon despite wide publicity No cases were seen in our previous short-term study or prophylactic study Mishory et al 2000 Mishory et al 2003 Nonlinear pharmacokinetics drug interactions and the consequent danger of toxicity will be handled by careful blood levels monitoring Patients with significant side effects or toxicity will be dropped from the study Patients with indications of hypersensitivity reactions morbilliform rash Stevens-Johnson syndrome systemic lupus erythematosus hepatic necrosis neutropenia and leukopenia red-cell aplasia agranulocytosis aplastic- or megalo- anemia or thrombocytopenia will be dropped from the study
Importance Almost one third of patients fail to respond to standard antidepressants Proof of efficacy of phenytoin augmentation in such cases would 1 be a useful addition to our clinical armamentarium 2 strengthen the theoretical profile of phenytoin as an antimanic antidepressant and mood stabilizing compound parallel to lithium and several other anticonvulsants 3 raise useful and heuristic ideas for mechanistic studies of phenytoins effects on mood
References
Barbee JG Jamhour NJ 2002 Lamotrigine as an augmentation agent in treatment-resistant depression J Clin Psychiatry 63737-741
Fava M Rosenbaum J McGrath P et al 1994 Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression Am J Psychiatry 151372-1374
Mishory A Yaroslavsky Y Bersudsky Y Belmaker RH 2000 Phenytoin as an antimanic anticonvulsant a controlled study American Journal of Psychiatry 157463-465
Mishory A Winokur M Bersudsky Y2003 Prophylactic effect of phenytoin in BP disorder a controlled study Bipolar Disorder 56464-7
Nemets B Stahal Z Belmaker RH 2002 Omega-3 fatty acid treatment of depressive breakthrough during unipolar maintenance American Journal of Psychiatry 159477-479
Nemets B Mishory A Levine J Belmaker RH 1999 Inositol addition does not improve depression in SSRI treatment failures Journal of Neural Transmission 106795-798
Nemets B Levine J 2005 Phenytoin is equivalent to fluoxetine in unipolar depression a controlled study 665586-90
Steinacher L Vandel P Zullino DF CB Eap Brawand-Amey M Baumann P 2002 Carbamazepine augmentation in depressive patients non-responding to citalopram a pharmacokinetic and clinical pilot study Eur Neuropsychopharmacol 12255-260
Lithium in recent years has been joined as a mood stabilizer by carbamazepine and valproate Phenytoin ignored for many years as a possible anticonvulsant mood stabilizer has been recently reported in double-blind controlled trials to be anti-manic Mishory et al 2000 and also prophylactic in BP disorder Mishory et al 2003
Data on mood stabilizers other than lithium as augmentors in SSRI failures are sparse Carbamazepine Steinacher et al 2002 and valproate Barbee et al 2002 have been used Given our recent preliminary results of phenytoins efficacy in unipolar depression Nemets et al 2005 and its analogy to lithium as a mood stabilizer it seems important to study phenytoin as a possible augmentation of SSRI failures
We have published a negative study previously of inositol as an augmentation of SSRI failures enrolling forty-two patients over two years Nemets et al 1999 Antidepressant failures are easier to recruit from referring physicians in our center than are untreated patients whom clinicians are reluctant to refer for new drug studies given the adequacy of standard treatment in 23 of them Thus we estimate that we could enroll 20 patients per year in such a study Survey of the literature of Li augmentation suggests that 40 phenytoin vs 40 placebo should give adequate power to detect a significant phenytoin effect if the phenytoin effect is similar to that of lithium
The study has been approved by the Helsinki Committee and all patients must give written informed consent Patients will be evaluated for study if they meet DSM-IV criteria for major depression without psychotic features Patients can enter the study if they had at least 3 weeks of treatment with SSRI at clinically adequate doses 150mg fluvoxamine 20mg fluoxetine or 20mg paroxetine and still have a score of at least 18 on the Hamilton Depression Scale HDS on 24 item scale with at most mild improvement from onset of SSRI treatment Patients with alcohol or drug abuse or patients with unstable medical illnesses are excluded Design is parallel double-blind Patients continue SSRI treatment of the same medication and dose they received before entry They are randomly assigned to phenytoin or identical placebo capsules Patients will be rated on the HDRS weekly for four weeks after addition of phenytoin or placebo Patients who do not improve at least 1 unit on the GCI every two weeks will be dropped from the study for ethical reasons and referred to open treatment HDRS ratings are done weekly by an experienced psychiatrist BN blind to the treatment medication
Blood levels of phenytoin will be reported by the lab to the treating psychiatrist after dummy levels are assigned by the control psychiatrist to patients on placebo
All patients will be evaluated physically and EKG liver and kidney functions and blood cell count performed before entering the study
Special attention will be given to instruction of patients in dental hygiene and patients showing signs of gingival hyperplasia will be dropped Studies in epilepsy show that this side effect is surprisingly uncommon despite wide publicity No cases were seen in our previous short-term study or prophylactic study Mishory et al 2000 Mishory et al 2003 Nonlinear pharmacokinetics drug interactions and the consequent danger of toxicity will be handled by careful blood levels monitoring Patients with significant side effects or toxicity will be dropped from the study Patients with indications of hypersensitivity reactions morbilliform rash Stevens-Johnson syndrome systemic lupus erythematosus hepatic necrosis neutropenia and leukopenia red-cell aplasia agranulocytosis aplastic- or megalo- anemia or thrombocytopenia will be dropped from the study
Importance Almost one third of patients fail to respond to standard antidepressants Proof of efficacy of phenytoin augmentation in such cases would 1 be a useful addition to our clinical armamentarium 2 strengthen the theoretical profile of phenytoin as an antimanic antidepressant and mood stabilizing compound parallel to lithium and several other anticonvulsants 3 raise useful and heuristic ideas for mechanistic studies of phenytoins effects on mood
References
Barbee JG Jamhour NJ 2002 Lamotrigine as an augmentation agent in treatment-resistant depression J Clin Psychiatry 63737-741
Fava M Rosenbaum J McGrath P et al 1994 Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression Am J Psychiatry 151372-1374
Mishory A Yaroslavsky Y Bersudsky Y Belmaker RH 2000 Phenytoin as an antimanic anticonvulsant a controlled study American Journal of Psychiatry 157463-465
Mishory A Winokur M Bersudsky Y2003 Prophylactic effect of phenytoin in BP disorder a controlled study Bipolar Disorder 56464-7
Nemets B Stahal Z Belmaker RH 2002 Omega-3 fatty acid treatment of depressive breakthrough during unipolar maintenance American Journal of Psychiatry 159477-479
Nemets B Mishory A Levine J Belmaker RH 1999 Inositol addition does not improve depression in SSRI treatment failures Journal of Neural Transmission 106795-798
Nemets B Levine J 2005 Phenytoin is equivalent to fluoxetine in unipolar depression a controlled study 665586-90
Steinacher L Vandel P Zullino DF CB Eap Brawand-Amey M Baumann P 2002 Carbamazepine augmentation in depressive patients non-responding to citalopram a pharmacokinetic and clinical pilot study Eur Neuropsychopharmacol 12255-260
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