Ignite Creation Date:
2024-05-06 @ 4:38 PM
Last Modification Date:
2024-10-26 @ 2:13 PM
Study NCT ID:
NCT05045378
Status:
RECRUITING
Last Update Posted:
2022-04-11
First Post:
2021-09-07
Brief Title:
Low-dose Ketamine Infusion Among Adolescents With Treatment-resistant Depression
Sponsor:
Taipei Veterans General Hospital Taiwan
Organization:
Taipei Veterans General Hospital Taiwan
Study Overview
Official Title:
Low-dose Ketamine Infusion Among Adolescents With Treatment-resistant Depression a Randomized Double-blind Placebo-control Study
Status:
RECRUITING
Status Verified Date:
2022-04
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:
In the past decades the prevalence of adolescent depression and suicide increased significantly in Taiwan and worldwide To date the suicide mortality is the second mortality cause in the adolescent and young adult population in Taiwan Previous studies reported that up to 40 of adolescents with major depressive disorder did not respond to at least two traditional antidepressants with the optimal dose and adequate duration Those patients would be considered the cases with treatment-resistant depression TRD which is related to the poor prognosis chronic depressive course higher suicidal risk severer cognitive dysfunction and greater family burdens However much less studies investigated the treatment strategy for adolescent TRD compared with that for adult TRD In this decade low-dose ketamine infusion has been proved as a rapid-acting antidepressant for adult patients with TRD In recent 5 years the investigators study team finished two randomized double-blind and placebo-control trials to support the rapid antidepressant and anti-suicidal effect in Taiwanese adult patients with TRD The investigators published several SCI studies about the investigators clinical findings and the underlying brain mechanisms In the following 4 years the investigators will conduct a new randomized double-blind and placebo-control trial in the adolescent TRD It will be the first clinical trial for ketamine effect in adolescent TRD worldwide The investigators will enroll 54 adolescents aged between 13 and 19 with TRD in four years The investigators hypothesize that low-dose ketamine will be effective and well tolerable for adolescents with TRD
Detailed Description:
1 Treatment-resistant depression TRD in adolescence
Major depressive disorder MDD in adolescents is characterized by a high risk of suicidality recurrence and chronicity and has been a topic of concern for decades in the fields of public health and clinical psychiatry Goodyer Dubicka et al 2007 Garber and Weersing 2010 The estimated prevalence of MDD is 8-20 in the adolescent population Yorbik Birmaher et al 2004 Thapar Collishaw et al 2012 Longitudinal studies on community-based and clinic-based population samples have suggested that 60-90 of adolescents reported to have depression achieve remission within a year moreover follow-up studies have indicated that 50 to 70 of patients who remit report subsequent depressive episodes within 5 years Dunn and Goodyer 2006 Thapar Collishaw et al 2012
Relevant studies have reported that adolescents with depression have less response to antidepressants and lower remission rates than adults with depression which may indicate a higher prevalence of TRD in adolescent population Michael and Crowley 2002 Kennard Silva et al 2009 Zhou Michael et al 2014 The Treatment for Adolescents with Depression Study TADS reported that the remission rate following 12-week antidepressant monotherapy or combination treatment using antidepressants and cognitive-behavioral therapy CBT was approximately 60 in adolescents with MDD which may indicate that at least one-third of adolescents with MDD did not respond to treatment or achieve remission after adequate antidepressant CBT or combined treatment Kennard Silva et al 2009 The Adolescent Depression Antidepressants and Psychotherapy Trial reported that only 57 of adolescents with depression exhibited moderate or substantial improvement after 28 weeks of SSRI or CBT treatment and that up to 20 demonstrated no improvement Goodyer Dubicka et al 2007 Furthermore Curry et al evaluated the predictors of response to fluoxetine treatment in adolescents with depression and reported that those with more psychiatric comorbidities including anxiety disorders attention deficit hyperactivity disorder ADHD and disruptive behavioral disorders were less likely to benefit from treatment than their counterparts Curry Rohde et al 2006 Hilton et al further investigated the efficacy of changing antidepressant treatment to another selective serotonin reuptake inhibitor SSRI or venlafaxine in adolescents with SSRI-resistant depression and determined that those who did not achieve remission exhibited increased anxiety ADHD and behavioral symptoms than those who did Hilton Rengasamy et al 2013
However current guidelines for TRD in adolescent patients with depression remain inadequate despite the high morbidity and severe impairment in these young patients Zhou Michael et al 2014 A recent meta-analysis showed that the overall response rate for the active treatments including the combination therapy with psychotherapy or second antidepressants augmentation therapy with lithiumatypical antipsychotics or the antidepressant-switching was only 46 among adolescent patients with TRD Approximately half of the adolescents who presented with TRD responded to active treatment which suggests that practitioners should remain persistent in managing these challenging cases Zhou Michael et al 2014 Treatment of Resistant Depression in Adolescents TORDIA study further suggested that the current clinical guidelines which recommend pursuing a given treatment strategy for at least 8-12 weeks may need to be revisited because their data support more vigorous intervention earlier in the course of treatment for nonresponding patients Emslie Mayes et al 2010
2 Suicide in adolescence
The suicide rates in the last half century increased by 60 worldwide it is estimated that by 2020 suicide would account more than 1 million deaths The WHO reports that Taiwan is one of the countries with the highest prevalence of suicide mortality 13100000 worldwide 2012 Fazel Wolf et al 2013 In Taiwan the prevalence of suicide mortality reached a peak in 2006 193100000 The Taiwan suicidal prevention program was implemented in 2005 and in the following years 20082011 the prevalence of suicide mortality declined gradually to 151100000 But the prevalence of suicide mortality rebounded up to 162100000 again in 2012 Cicinelli Pasqualetti et al 2003 More than suicide mortality and committed suicide the suicide attempt and suicide ideation also gained the clinical and public health attention and concerns in this decades 2012 Fazel Wolf et al 2013
Suicide among adolescents has gained substantial clinical attention in the psychiatric field in the recent decade and has become a major public health concern worldwide 2012 Fazel Wolf et al 2013 The US National Institute of Mental Health reported that suicide was the countrys third leading cause of mortality among adolescents and young adults aged 15 to 24 years 2012 Fazel Wolf et al 2013 In Taiwan the Ministry of Health and Welfare indicated that suicide was the second leading cause of mortality among adolescents and young adults accounting for the death of 71100000 adolescents and young adults Cicinelli Pasqualetti et al 2003
A Taiwan report in 2013 a nationally representative sample of 2835 college students demonstrated that a surprisingly high prevalence of college students about 12 of females and 9 of males had at least one time of attempted suicide in the preceding 12 months Chou Ko et al 2013 Previous studies have demonstrated that more than 70 of adolescents and young adults who attempt suicide or have suicidal ideation have psychiatric disorders including major depressive disorder bipolar disorder anxiety disorders disruptive behavior disorders and alcohol and substance use disorders Brent Perper et al 1994 Gould King et al 1998 Kelly Cornelius et al 2002 Hauser Galling et al 2013 Any form of suicide including suicide ideation suicide attempt and suicide mortality would cause a great amount of physical mental and financial loss and burden to the sufferers the family the community and the society Furthermore those suicide ideators and suicide attempters remain vulnerable to costly health and social problems in their later life
3 Low-dose ketamine infusion in adolescent depression
Based on the higher treatment resistance and the greater suicidal risk in adolescent depression increasing evidence suggests the potential therapeutic effect of low-dose ketamine infusion in adolescent patients with TRD although there was no any randomized double-blind placebo-control clinical trial to investigate this important clinical topic until now Ketamine is safe tolerable and commonly used in the pediatric anesthesia in the past decades Brewer Davidson et al 1972 Raju 1980 Green Klooster et al 2001 Koruk Mizrak et al 2010 In 2017 Dwyer et al reported the first case report study for the ketamine infusion as a treatment for adolescent depression Dwyer Beyer et al 2017 They described the personal history and clinical course of this case this patient was considered to be at high risk for suicide He had a history of three serious suicide attempts involving near-lethal antifreeze ingestion dextroamphetamine overdose and self-strangulation He presented as hopeless about the prospect of psychiatric improvement and complained of persistent thoughts of wanting to die The patient had failed multiple levels of care outpatient intensive outpatient and residential and multiple antidepressant medications with treatment informed by current practice parameters This patient received intravenous infusions of ketamine dosed at 05 mgkg over 40 minutes This patient received 3 infusions during the first week and weekly treatments thereafter resulting in 7 infusions over an 8-week hospitalization days 1 3 7 14 21 28 50 At 1 day after his first infusion he experienced a rapid reduction in his depressive symptoms 61 MADRS reduction 32 CDRS reduction suicidal ideation 88 SSI-5 reduction and hopelessness 57 BHS reduction The patient had an acute recovery with ketamine treatment as has been described in adults Figure 4 He tolerated all infusions well experiencing mild nausea and mild intrainfusion dissociative symptoms maximum CADSS of 7 of a possible 92 which returned to 0 by 80 minutes Dwyer Beyer et al 2017
This is a double-blind randomized-controlled trial of ketamine infusion to test whether 05mgkg ketamine infusion is a safe and effective add-on treatment for adolescents with TRD
Major depressive disorder MDD in adolescents is characterized by a high risk of suicidality recurrence and chronicity and has been a topic of concern for decades in the fields of public health and clinical psychiatry Goodyer Dubicka et al 2007 Garber and Weersing 2010 The estimated prevalence of MDD is 8-20 in the adolescent population Yorbik Birmaher et al 2004 Thapar Collishaw et al 2012 Longitudinal studies on community-based and clinic-based population samples have suggested that 60-90 of adolescents reported to have depression achieve remission within a year moreover follow-up studies have indicated that 50 to 70 of patients who remit report subsequent depressive episodes within 5 years Dunn and Goodyer 2006 Thapar Collishaw et al 2012
Relevant studies have reported that adolescents with depression have less response to antidepressants and lower remission rates than adults with depression which may indicate a higher prevalence of TRD in adolescent population Michael and Crowley 2002 Kennard Silva et al 2009 Zhou Michael et al 2014 The Treatment for Adolescents with Depression Study TADS reported that the remission rate following 12-week antidepressant monotherapy or combination treatment using antidepressants and cognitive-behavioral therapy CBT was approximately 60 in adolescents with MDD which may indicate that at least one-third of adolescents with MDD did not respond to treatment or achieve remission after adequate antidepressant CBT or combined treatment Kennard Silva et al 2009 The Adolescent Depression Antidepressants and Psychotherapy Trial reported that only 57 of adolescents with depression exhibited moderate or substantial improvement after 28 weeks of SSRI or CBT treatment and that up to 20 demonstrated no improvement Goodyer Dubicka et al 2007 Furthermore Curry et al evaluated the predictors of response to fluoxetine treatment in adolescents with depression and reported that those with more psychiatric comorbidities including anxiety disorders attention deficit hyperactivity disorder ADHD and disruptive behavioral disorders were less likely to benefit from treatment than their counterparts Curry Rohde et al 2006 Hilton et al further investigated the efficacy of changing antidepressant treatment to another selective serotonin reuptake inhibitor SSRI or venlafaxine in adolescents with SSRI-resistant depression and determined that those who did not achieve remission exhibited increased anxiety ADHD and behavioral symptoms than those who did Hilton Rengasamy et al 2013
However current guidelines for TRD in adolescent patients with depression remain inadequate despite the high morbidity and severe impairment in these young patients Zhou Michael et al 2014 A recent meta-analysis showed that the overall response rate for the active treatments including the combination therapy with psychotherapy or second antidepressants augmentation therapy with lithiumatypical antipsychotics or the antidepressant-switching was only 46 among adolescent patients with TRD Approximately half of the adolescents who presented with TRD responded to active treatment which suggests that practitioners should remain persistent in managing these challenging cases Zhou Michael et al 2014 Treatment of Resistant Depression in Adolescents TORDIA study further suggested that the current clinical guidelines which recommend pursuing a given treatment strategy for at least 8-12 weeks may need to be revisited because their data support more vigorous intervention earlier in the course of treatment for nonresponding patients Emslie Mayes et al 2010
2 Suicide in adolescence
The suicide rates in the last half century increased by 60 worldwide it is estimated that by 2020 suicide would account more than 1 million deaths The WHO reports that Taiwan is one of the countries with the highest prevalence of suicide mortality 13100000 worldwide 2012 Fazel Wolf et al 2013 In Taiwan the prevalence of suicide mortality reached a peak in 2006 193100000 The Taiwan suicidal prevention program was implemented in 2005 and in the following years 20082011 the prevalence of suicide mortality declined gradually to 151100000 But the prevalence of suicide mortality rebounded up to 162100000 again in 2012 Cicinelli Pasqualetti et al 2003 More than suicide mortality and committed suicide the suicide attempt and suicide ideation also gained the clinical and public health attention and concerns in this decades 2012 Fazel Wolf et al 2013
Suicide among adolescents has gained substantial clinical attention in the psychiatric field in the recent decade and has become a major public health concern worldwide 2012 Fazel Wolf et al 2013 The US National Institute of Mental Health reported that suicide was the countrys third leading cause of mortality among adolescents and young adults aged 15 to 24 years 2012 Fazel Wolf et al 2013 In Taiwan the Ministry of Health and Welfare indicated that suicide was the second leading cause of mortality among adolescents and young adults accounting for the death of 71100000 adolescents and young adults Cicinelli Pasqualetti et al 2003
A Taiwan report in 2013 a nationally representative sample of 2835 college students demonstrated that a surprisingly high prevalence of college students about 12 of females and 9 of males had at least one time of attempted suicide in the preceding 12 months Chou Ko et al 2013 Previous studies have demonstrated that more than 70 of adolescents and young adults who attempt suicide or have suicidal ideation have psychiatric disorders including major depressive disorder bipolar disorder anxiety disorders disruptive behavior disorders and alcohol and substance use disorders Brent Perper et al 1994 Gould King et al 1998 Kelly Cornelius et al 2002 Hauser Galling et al 2013 Any form of suicide including suicide ideation suicide attempt and suicide mortality would cause a great amount of physical mental and financial loss and burden to the sufferers the family the community and the society Furthermore those suicide ideators and suicide attempters remain vulnerable to costly health and social problems in their later life
3 Low-dose ketamine infusion in adolescent depression
Based on the higher treatment resistance and the greater suicidal risk in adolescent depression increasing evidence suggests the potential therapeutic effect of low-dose ketamine infusion in adolescent patients with TRD although there was no any randomized double-blind placebo-control clinical trial to investigate this important clinical topic until now Ketamine is safe tolerable and commonly used in the pediatric anesthesia in the past decades Brewer Davidson et al 1972 Raju 1980 Green Klooster et al 2001 Koruk Mizrak et al 2010 In 2017 Dwyer et al reported the first case report study for the ketamine infusion as a treatment for adolescent depression Dwyer Beyer et al 2017 They described the personal history and clinical course of this case this patient was considered to be at high risk for suicide He had a history of three serious suicide attempts involving near-lethal antifreeze ingestion dextroamphetamine overdose and self-strangulation He presented as hopeless about the prospect of psychiatric improvement and complained of persistent thoughts of wanting to die The patient had failed multiple levels of care outpatient intensive outpatient and residential and multiple antidepressant medications with treatment informed by current practice parameters This patient received intravenous infusions of ketamine dosed at 05 mgkg over 40 minutes This patient received 3 infusions during the first week and weekly treatments thereafter resulting in 7 infusions over an 8-week hospitalization days 1 3 7 14 21 28 50 At 1 day after his first infusion he experienced a rapid reduction in his depressive symptoms 61 MADRS reduction 32 CDRS reduction suicidal ideation 88 SSI-5 reduction and hopelessness 57 BHS reduction The patient had an acute recovery with ketamine treatment as has been described in adults Figure 4 He tolerated all infusions well experiencing mild nausea and mild intrainfusion dissociative symptoms maximum CADSS of 7 of a possible 92 which returned to 0 by 80 minutes Dwyer Beyer et al 2017
This is a double-blind randomized-controlled trial of ketamine infusion to test whether 05mgkg ketamine infusion is a safe and effective add-on treatment for adolescents with TRD
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None