Ignite Creation Date:
2024-10-26 @ 3:41 PM
Last Modification Date:
2024-10-26 @ 3:41 PM
Study NCT ID:
NCT06620276
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-25
Brief Title:
ACT_for Alcohol Use Disorder and Depression
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Acceptance and Commitment Therapy in Patients With Alcohol Use Disorder and Comorbid Treatment-Resistant Depression Who Are Undergoing Ketamine Intervention A Feasibility Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Alcohol use disorders AUDs and depressive disorders frequently coexist complicating the clinical management of patients suffering from them
Taken separately these two disorders have a significant prevalence in the population and a recent meta-analysis concluded that coexistence could reach 1 in 5 patients 208 This comorbidity represents a considerable challenge particularly in cases of treatment-resistant depression TRD where patients do not respond to conventional pharmacological interventions
Since alcohol can act as a powerful trigger for depressive symptoms and conversely a depressive state increases the risk of alcohol abuse the question of intervention sequence is also of clinical interest should priority be given to treating TRD AUD or both simultaneously This question raises a major issue for healthcare professionals as current conventional therapeutic approaches present limitations in the concomitant management of these complex disorders
Thus in certain clinical settings ketamine has emerged as a promising intervention to treat both TRD and AUD In fact ketamine has been shown to produce rapid but only transient antidepressant effects and is part of the possible treatment arsenal for TRD The potential of ketamine in the treatment of AUD has also been explored in recent studies with a few small randomized controlled trials In these trials the combination of ketamine with psychotherapy versus placebo was investigated as a means of alleviating AUD Ketamine was shown to increase abstinence rates time to relapse and decrease the number of heavy drinking days
Acceptance and Commitment Therapy ACT is a form of cognitive-behavioural therapy that emphasizes psychological flexibility and acceptance of difficult emotions and thoughts without judgment a type of psychotherapy particularly relevant to AUD Thus adding ACT to ketamine treatment could increase the duration of ketamines effect on depressive symptoms while reducing AUD
In view of this accumulated evidence of the potential benefit of ketamine and ACT adding acceptance and commitment therapy to ketamine appears to be a promising option for improving outcomes in patients diagnosed with TRD comorbid with AUD This study will not only verify the feasibility of this type of intervention in this particular patient population but also the preliminary effects on their alcohol consumption and depressive symptoms
Taken separately these two disorders have a significant prevalence in the population and a recent meta-analysis concluded that coexistence could reach 1 in 5 patients 208 This comorbidity represents a considerable challenge particularly in cases of treatment-resistant depression TRD where patients do not respond to conventional pharmacological interventions
Since alcohol can act as a powerful trigger for depressive symptoms and conversely a depressive state increases the risk of alcohol abuse the question of intervention sequence is also of clinical interest should priority be given to treating TRD AUD or both simultaneously This question raises a major issue for healthcare professionals as current conventional therapeutic approaches present limitations in the concomitant management of these complex disorders
Thus in certain clinical settings ketamine has emerged as a promising intervention to treat both TRD and AUD In fact ketamine has been shown to produce rapid but only transient antidepressant effects and is part of the possible treatment arsenal for TRD The potential of ketamine in the treatment of AUD has also been explored in recent studies with a few small randomized controlled trials In these trials the combination of ketamine with psychotherapy versus placebo was investigated as a means of alleviating AUD Ketamine was shown to increase abstinence rates time to relapse and decrease the number of heavy drinking days
Acceptance and Commitment Therapy ACT is a form of cognitive-behavioural therapy that emphasizes psychological flexibility and acceptance of difficult emotions and thoughts without judgment a type of psychotherapy particularly relevant to AUD Thus adding ACT to ketamine treatment could increase the duration of ketamines effect on depressive symptoms while reducing AUD
In view of this accumulated evidence of the potential benefit of ketamine and ACT adding acceptance and commitment therapy to ketamine appears to be a promising option for improving outcomes in patients diagnosed with TRD comorbid with AUD This study will not only verify the feasibility of this type of intervention in this particular patient population but also the preliminary effects on their alcohol consumption and depressive symptoms
Detailed Description:
Study rationale Acceptance and Commitment Therapy ACT has been proposed as a particularly well-suited form of psychotherapy to be added to ketamine for improving its rapid but short antidepressant action This is in part because of ketamines acute effect on psychological flexibility a crucial construct that is addressed with ACT
There has been extensive efforts to find effective strategies to enhance and sustain the therapeutic response of ketamine with most attempts using various pharmacotherapies-such as clonidine D-cycloserine lamotrigine lithium rapamycin and riluzole- which have yielded mostly disappointing results Consequently the most common approach to extending ketamine benefits has been to administer repeated doses although there is limited evidence supporting the long-term safety efficacy and practicality of this practice
Substantial evidence indicates that psychotherapy can enhance the effects of pharmacological treatments such as oral antidepressants and even help maintain their benefits after discontinuation While further research is required it is plausible to assume that similar benefits of adding psychotherapy could extend to ketamine particularly considering its potential neuroplastic effects
In view of the accumulated evidence the addition of ACT to a ketamine intervention appears as a promising option to improve the outcomes of patients diagnosed with AUD comorbid with TRD This study will not only verify the feasibility of adding psychotherapy to ketamine in this population but also the effect on their alcohol consumption and depressive symptoms
Background Alcohol Use Disorder AUD and depressive disorders frequently coexist and complicate the clinical management and treatment outcomes for patients It is estimated that around 1 in 10 people 104 in the USA is experiencing a major depressive disorder MDD in the course of a year while it goes up to 1 in 5 206 in the course of a lifetime As for AUD twelve month and lifetime prevalence are respectively 139 and 291 When these disorders coexist the prevalence is estimated as high as 208 as reported by a recent meta-analysis Research has also shown that individuals with AUD are approximately 23 times more likely to experience MDD within a given year
This comorbidity presents a formidable challenge particularly in cases of Treatment-Resistant Depression TRD a subset of MDD where patients do not respond to conventional pharmacological interventions In the United States it is estimated that out of 89 million adults receiving medication for MDD 28 million or 309 are grappling with TRD The economic impact is substantial with the total annual cost of medication-treated MDD reaching 927 billion nearly half of which-438 billion or 472-is attributable to TRD
The concomitance of TRD and AUD represents a major clinical challenge as alcohol can act as a powerful trigger for depressive symptoms and conversely a depressive state can increase the risk of alcohol abuse This creates a complex bidirectional relationship between the two disorders considerably complicating the assessment and clinical management of these concurrent disorders The question of intervention sequence is also of clinical interest should treatment of TRD AUD or both simultaneously be prioritized This question raises major challenges for health professionals as current conventional therapeutic approaches present limitations in the concomitant management of these complex disorders Traditional pharmacological treatments such as antidepressants may not be sufficiently effective or tolerated by some patients to treat these comorbid disorders As for standard psychotherapeutic approaches such as cognitive-behavioral therapy the heterogeneity of symptoms and diversity of issues often mean that the needs of individuals suffering from these comorbidities cannot be met comprehensively
In response to this challenge in selected clinical settings ketamine has emerged as a promising intervention for treating both AUD and depressive disorders Ketamine an NMDA receptor antagonist has been shown to produce rapid and substantial albeit short-lived ie 7 days antidepressant effects in individuals with TRD Furthermore ketamine potential in treating AUD has been explored in recent studies with randomized controlled trials emerging In such trials the combination of ketamine to psychotherapy as compared to a placebo is studied to alleviate AUD For instance individuals with AUD who received a ketamine infusion and motivational therapy had improved rates of abstinence prolonged time to relapse and fewer days of heavy drinking than individuals with AUD who received an infusion of midazolam considered as a placebo Another team also compared the use of ketamine with a relapse prevention-based psychological therapy to placebo and found that there was a significant increase in the number of days abstinent from alcohol
Considering the substantial but transient effect of ketamine on depressive symptomatology and its promising results in AUD patients a novel approach is to add a psychotherapeutic component to the ketamine treatment with the aim of enhancing and prolonging its effect Acceptance and Commitment Therapy ACT seems to be a particularly well-suited form of psychotherapy to be added to ketamine treatment Indeed ACT is a form of cognitive-behavioural therapy that emphasizes psychological flexibility and the acceptance of difficult emotions and thoughts without judgment ACT has been extensively studied in various psychopathologies including anxiety and depression demonstrating positive outcomes in multiple rigorous clinical trials and meta-analysis Growing evidence suggest that ACT may be an effective and even superior treatment for individuals with substance use disorders ACT encourages individuals to commit to behavior changes consistent with their values which can be particularly beneficial for those with AUD and comorbid TRD Ketamine has been shown to have an acute effect on psychological flexibility and the addition of ACTs focus on acceptance and value-driven behavior holds promise for improving the ketamines rapid and short antidepressant action and addressing the complex interplay of AUD and TRD
Standard treatment options
Alcohol Use Disorder AUD
In 2023 a committee of AUD specialists published the Canadian guideline with treatment recommendations for AUD As a strong recommendation they first proposed that all patients with AUD should be offered specialist-led psychosocial treatment interventions such as cognitive behavioral therapy or family-based therapy However both therapies were found to have small to medium beneficial impacts on AUD outcomes For pharmacotherapy as a complement to the psychosocial treatment naltrexone or acamprosate were recommended as first-line therapy Second-line options some of them being used as off-label therapies were also proposed namely gabapentin topiramate and disulfiram Of note these recommendations are in line with other reviews of AUD pharmacotherapy and other national guidelines namely American and Australian guidelines
However there are some limitations associated with the use of those treatment options Apart from safety concerns with common AE associated with treatments nausea dizziness and fatigue among others there is an ongoing debate among experts about the actual efficacy of the treatment options In fact naltrexone and acamprosate have an estimated number needed to treat to prevent a return to heavy drinking of 12 with modest differences found when comparing drugs with placebo contributing to their underutilization in AUD patients For instance in over 28000 Medicare beneficiaries hospitalized with a primary or secondary diagnosis of AUD it was found that only 07 of patients started pharmacotherapy within two days after discharge and 13 within 30 days Even among patients for whom AUD was the primary diagnosis after hospitalization only 23 started pharmacotherapy within two days of discharge
Treatment Resistant Depression TRD
Leading experts in TRD summarized in 2023 the options available to try and reach a favorable outcome in individuals who fail to respond to at least two adequate trials of psychotropics against depression First extending a current antidepressant trial could be a potential treatment plan A systematic review determined that up to 20 of patients who did not respond to their antidepressant in the first four weeks of treatment responded during the following four weeks from weeks five to eight and up to 10 during weeks nine to twelve Similarly there is some evidence albeit conflicting that switching antidepressants or combining antidepressants could benefit some patients especially if the change or addition involves a new mechanism of action To cite only one example of this option adding antidepressants with antagonism activity on the alpha-2 receptor ie mirtazapine trazodone to a selective serotonin reuptake inhibitor was superior to monotherapy in a meta-analysis
Other treatment modalities have also been studied including adding various pharmacological agents like second-generation antipsychotics and mood stabilizers In real-world settings most patients with TRD are prescribed multiple psychotropic medications often for extended periods with generally limited success For example a recent cohort study conducted over 12 months across various European countries involving 411 patients with TRD highlighted high rates of polypharmacy alongside modest clinical improvement-only about 30 showed a positive response after 6 to 12 months of consistent treatment The study also indicated a concerning level of therapeutic inertia where 60 of patients did not undergo any changes in their treatment plan despite ongoing poor outcomes
Electroconvulsive therapy ECT aside from the usual pharmacological approaches is considered one of the most empirically supported interventions for TRD However despite its effectiveness ECT is often hindered by significant barriers including societal stigma inconsistent access and notable side effects such as memory loss largely due to the need for general anesthesia during the procedure
Amid the current treatment challenges the rapid and robust antidepressant effects of subanesthetic doses of IV racemic ketamine-a distinctive N-methyl-D-aspartate NMDA receptor antagonist-have sparked considerable interest and optimism Meta-analyses suggest that nearly half of patients with treatment-resistant depression TRD experience a significant reduction in depressive symptoms over 50 within just hours to days following a single 40-minute IV ketamine infusion This promising efficacy has led many experts to regard subanesthetic ketamine as one of the most transformative advancements in psychiatric pharmacology in recent decades While impressive ketamines benefits typically fade within days or weeks
Given the evidence of ketamines beneficial effect the neuromodulation service of the CHUM began providing this treatment to patients with TRD in 2018 covering the whole province of Quebec Since then the neuromodulation service has created a state-of-the-art infrastructure for the ketamine service
There has been extensive efforts to find effective strategies to enhance and sustain the therapeutic response of ketamine with most attempts using various pharmacotherapies-such as clonidine D-cycloserine lamotrigine lithium rapamycin and riluzole- which have yielded mostly disappointing results Consequently the most common approach to extending ketamine benefits has been to administer repeated doses although there is limited evidence supporting the long-term safety efficacy and practicality of this practice
Substantial evidence indicates that psychotherapy can enhance the effects of pharmacological treatments such as oral antidepressants and even help maintain their benefits after discontinuation While further research is required it is plausible to assume that similar benefits of adding psychotherapy could extend to ketamine particularly considering its potential neuroplastic effects
In view of the accumulated evidence the addition of ACT to a ketamine intervention appears as a promising option to improve the outcomes of patients diagnosed with AUD comorbid with TRD This study will not only verify the feasibility of adding psychotherapy to ketamine in this population but also the effect on their alcohol consumption and depressive symptoms
Background Alcohol Use Disorder AUD and depressive disorders frequently coexist and complicate the clinical management and treatment outcomes for patients It is estimated that around 1 in 10 people 104 in the USA is experiencing a major depressive disorder MDD in the course of a year while it goes up to 1 in 5 206 in the course of a lifetime As for AUD twelve month and lifetime prevalence are respectively 139 and 291 When these disorders coexist the prevalence is estimated as high as 208 as reported by a recent meta-analysis Research has also shown that individuals with AUD are approximately 23 times more likely to experience MDD within a given year
This comorbidity presents a formidable challenge particularly in cases of Treatment-Resistant Depression TRD a subset of MDD where patients do not respond to conventional pharmacological interventions In the United States it is estimated that out of 89 million adults receiving medication for MDD 28 million or 309 are grappling with TRD The economic impact is substantial with the total annual cost of medication-treated MDD reaching 927 billion nearly half of which-438 billion or 472-is attributable to TRD
The concomitance of TRD and AUD represents a major clinical challenge as alcohol can act as a powerful trigger for depressive symptoms and conversely a depressive state can increase the risk of alcohol abuse This creates a complex bidirectional relationship between the two disorders considerably complicating the assessment and clinical management of these concurrent disorders The question of intervention sequence is also of clinical interest should treatment of TRD AUD or both simultaneously be prioritized This question raises major challenges for health professionals as current conventional therapeutic approaches present limitations in the concomitant management of these complex disorders Traditional pharmacological treatments such as antidepressants may not be sufficiently effective or tolerated by some patients to treat these comorbid disorders As for standard psychotherapeutic approaches such as cognitive-behavioral therapy the heterogeneity of symptoms and diversity of issues often mean that the needs of individuals suffering from these comorbidities cannot be met comprehensively
In response to this challenge in selected clinical settings ketamine has emerged as a promising intervention for treating both AUD and depressive disorders Ketamine an NMDA receptor antagonist has been shown to produce rapid and substantial albeit short-lived ie 7 days antidepressant effects in individuals with TRD Furthermore ketamine potential in treating AUD has been explored in recent studies with randomized controlled trials emerging In such trials the combination of ketamine to psychotherapy as compared to a placebo is studied to alleviate AUD For instance individuals with AUD who received a ketamine infusion and motivational therapy had improved rates of abstinence prolonged time to relapse and fewer days of heavy drinking than individuals with AUD who received an infusion of midazolam considered as a placebo Another team also compared the use of ketamine with a relapse prevention-based psychological therapy to placebo and found that there was a significant increase in the number of days abstinent from alcohol
Considering the substantial but transient effect of ketamine on depressive symptomatology and its promising results in AUD patients a novel approach is to add a psychotherapeutic component to the ketamine treatment with the aim of enhancing and prolonging its effect Acceptance and Commitment Therapy ACT seems to be a particularly well-suited form of psychotherapy to be added to ketamine treatment Indeed ACT is a form of cognitive-behavioural therapy that emphasizes psychological flexibility and the acceptance of difficult emotions and thoughts without judgment ACT has been extensively studied in various psychopathologies including anxiety and depression demonstrating positive outcomes in multiple rigorous clinical trials and meta-analysis Growing evidence suggest that ACT may be an effective and even superior treatment for individuals with substance use disorders ACT encourages individuals to commit to behavior changes consistent with their values which can be particularly beneficial for those with AUD and comorbid TRD Ketamine has been shown to have an acute effect on psychological flexibility and the addition of ACTs focus on acceptance and value-driven behavior holds promise for improving the ketamines rapid and short antidepressant action and addressing the complex interplay of AUD and TRD
Standard treatment options
Alcohol Use Disorder AUD
In 2023 a committee of AUD specialists published the Canadian guideline with treatment recommendations for AUD As a strong recommendation they first proposed that all patients with AUD should be offered specialist-led psychosocial treatment interventions such as cognitive behavioral therapy or family-based therapy However both therapies were found to have small to medium beneficial impacts on AUD outcomes For pharmacotherapy as a complement to the psychosocial treatment naltrexone or acamprosate were recommended as first-line therapy Second-line options some of them being used as off-label therapies were also proposed namely gabapentin topiramate and disulfiram Of note these recommendations are in line with other reviews of AUD pharmacotherapy and other national guidelines namely American and Australian guidelines
However there are some limitations associated with the use of those treatment options Apart from safety concerns with common AE associated with treatments nausea dizziness and fatigue among others there is an ongoing debate among experts about the actual efficacy of the treatment options In fact naltrexone and acamprosate have an estimated number needed to treat to prevent a return to heavy drinking of 12 with modest differences found when comparing drugs with placebo contributing to their underutilization in AUD patients For instance in over 28000 Medicare beneficiaries hospitalized with a primary or secondary diagnosis of AUD it was found that only 07 of patients started pharmacotherapy within two days after discharge and 13 within 30 days Even among patients for whom AUD was the primary diagnosis after hospitalization only 23 started pharmacotherapy within two days of discharge
Treatment Resistant Depression TRD
Leading experts in TRD summarized in 2023 the options available to try and reach a favorable outcome in individuals who fail to respond to at least two adequate trials of psychotropics against depression First extending a current antidepressant trial could be a potential treatment plan A systematic review determined that up to 20 of patients who did not respond to their antidepressant in the first four weeks of treatment responded during the following four weeks from weeks five to eight and up to 10 during weeks nine to twelve Similarly there is some evidence albeit conflicting that switching antidepressants or combining antidepressants could benefit some patients especially if the change or addition involves a new mechanism of action To cite only one example of this option adding antidepressants with antagonism activity on the alpha-2 receptor ie mirtazapine trazodone to a selective serotonin reuptake inhibitor was superior to monotherapy in a meta-analysis
Other treatment modalities have also been studied including adding various pharmacological agents like second-generation antipsychotics and mood stabilizers In real-world settings most patients with TRD are prescribed multiple psychotropic medications often for extended periods with generally limited success For example a recent cohort study conducted over 12 months across various European countries involving 411 patients with TRD highlighted high rates of polypharmacy alongside modest clinical improvement-only about 30 showed a positive response after 6 to 12 months of consistent treatment The study also indicated a concerning level of therapeutic inertia where 60 of patients did not undergo any changes in their treatment plan despite ongoing poor outcomes
Electroconvulsive therapy ECT aside from the usual pharmacological approaches is considered one of the most empirically supported interventions for TRD However despite its effectiveness ECT is often hindered by significant barriers including societal stigma inconsistent access and notable side effects such as memory loss largely due to the need for general anesthesia during the procedure
Amid the current treatment challenges the rapid and robust antidepressant effects of subanesthetic doses of IV racemic ketamine-a distinctive N-methyl-D-aspartate NMDA receptor antagonist-have sparked considerable interest and optimism Meta-analyses suggest that nearly half of patients with treatment-resistant depression TRD experience a significant reduction in depressive symptoms over 50 within just hours to days following a single 40-minute IV ketamine infusion This promising efficacy has led many experts to regard subanesthetic ketamine as one of the most transformative advancements in psychiatric pharmacology in recent decades While impressive ketamines benefits typically fade within days or weeks
Given the evidence of ketamines beneficial effect the neuromodulation service of the CHUM began providing this treatment to patients with TRD in 2018 covering the whole province of Quebec Since then the neuromodulation service has created a state-of-the-art infrastructure for the ketamine service
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