ACT_for Alcohol Use Disorder and Depression

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 (20.8%). 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 ketamine's 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.

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 ketamine's 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 (10.4%) in the USA is experiencing a major depressive disorder (MDD) in the course of a year, while it goes up to 1 in 5 (20.6%) in the course of a lifetime. As for AUD, twelve month and lifetime prevalence are respectively 13.9% and 29.1%. When these disorders coexist, the prevalence is estimated as high as 20.8%, as reported by a recent meta-analysis. Research has also shown that individuals with AUD are approximately 2.3 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 8.9 million adults receiving medication for MDD, 2.8 million, or 30.9%, are grappling with TRD. The economic impact is substantial, with the total annual cost of medication-treated MDD reaching $92.7 billion, nearly half of which-$43.8 billion or 47.2%-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 (i.e. 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 ACT's focus on acceptance and value-driven behavior holds promise for improving the ketamine's 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 28,000 Medicare beneficiaries hospitalized with a primary or secondary diagnosis of AUD, it was found that only 0.7% of patients started pharmacotherapy within two days after discharge and 1.3% within 30 days. Even among patients for whom AUD was the primary diagnosis after hospitalization, only 2.3% 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 (i.e., 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, ketamine's benefits typically fade within days or weeks.

Given the evidence of ketamine's 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.

Eligibility Criteria:
Inclusion Criteria:

Patients who satisfy the following inclusion and exclusion criteria of the study will be invited to enroll:

1. Have a diagnosis of treatment-resistant unipolar or bipolar depression (TRD) (defined as the failure to respond to at least two adequate trials of psychotropics with Level 1 evidence against bipolar or unipolar depression, according to Canadian national depression guidelines)
2. Have comorbid Alcohol Use Disorder (AUD) as diagnosed by a trained psychiatrist,
3. Have been accepted for treatment by IV ketamine for depression and AUD (Full inclusion and exclusion criteria are provided below. This includes solely clinical criteria, which will be verified by the clinical team at the CHUM neuromodulation ketamine clinic.)

Additional criteria :

* Provision of written informed consent after reading the patient information handout;
* Desire to engage in 8 weekly psychotherapy sessions;
* No changes to medications during treatment;
* Alcohol Use Disorder (AUD) as diagnosed by a trained psychiatrist, with an average daily ethanol consumption of at least a moderate risk according to the WHO risk level (Men:\&gt;40 to 60 g/day or\&gt;2.9 to 4.3 drinks/Women:\&gt;20 to 40 g/day or\&gt;1.4 to 2.9 drinks) (70, 71);
* Bipolar and unipolar depressive episode, current episode of depression (DSM-5) despite at least two adequate trials of psychotropics with Level 1 evidence against bipolar and unipolar depression (63, 64) as per the Montgomery-Asberg Depression Rating Scale (MADRS) ≥ 20 (83, 84);
* Age\&gt; 18-70 years old;
* No contraindication to ketamine
* Accept to abstain from consuming grapefruit juice (a potent 3A4 cytochrome inhibitor) on the day of the ketamine infusions as it may alter the metabolism of ketamine
* Accept to abstain from driving or operating heavy machinery

Exclusion Criteria:

Participants will be excluded if any of the following criteria are met:

* currently participating in other evidence-based psychotherapeutic intervention for mood disorders or substance abuse
* Are not able to commit to the study protocol secondary to professional/personal obligations
* Are non-English or non-French speaking.
* Other psychiatric comorbidity than MDD/TRD and AUD
* Prior or current substance abuse or dependence other than AUD (except for caffeine or nicotine dependence) and/or recent history (last 12 months) of cannabis abuse or dependence, as defined by DSM-5 criteria

  ○ In the context of its legalization, recreational use that does not meet criteria for a substance use disorder and/or is not deemed to be negatively impacting patients' physical and mental health will not justify the exclusion from the study just as it does not justify the exclusion from purely clinical treatment by ketamine
* The subject's depressive symptoms have previously demonstrated non-response to esketamine or ketamine in the current major depressive episode
* Known intellectual deficiency or autism spectrum disorder
* Unable to accommodate regular visits to the ketamine clinic at the CHUM
* Depression evaluated as secondary to stroke, cancer or other severe medical illnesses
* Known risk factors for intracranial hemorrhage, including previous significant trauma, known aneurysm, or previous neurosurgery
* Evidence of clinically relevant disease, e.g., uncontrolled hypertension, renal or hepatic impairment, significant coronary artery disease (myocardial infarct within a year prior to initial randomization), cerebrovascular disease, viral hepatitis B or C, acquired immunodeficiency syndrome
* Significant hearing impairment not improved with hearing aids and/or sound amplification or unwillingness to listen to music during treatment
* A positive toxicology screen for drugs that are not prescribed
* Unwilling or unable to hold benzodiazepines from the evening prior to the infusion of ketamine
* Unwilling or unable to hold alcohol for 24 hours prior to the infusion of ketamine
* Unwilling or unable to discontinue any narcotic beginning a minimum of 5 drug half-lives prior to infusion
* Unwilling or unable to discontinue memantine or lamotrigine (an NMDA antagonist) during infusions, beginning a minimum of 5 drug half-lives prior to infusions
* Pregnant, lactating, or of childbearing potential and not willing to use an approved method of contraception during the ketamine infusion, as per above

  ○ Female subjects of childbearing potential must have a negative urine pregnancy test at the beginning
* A clinical finding that is unstable or that, in the opinion of the treating clinician(s), would be negatively affected by, or would affect, the medication (e.g., diabetes mellitus, unstable angina)
* Liver function tests AST and ALT three times the upper normal limit at screening
* ECG results considered significantly abnormal as determined by the clinician(s)
* History of seizure disorder, except febrile convulsions
* Known history of intolerance or hypersensitivity to ketamine
* Acute psychotic symptoms, as judged by the initial clinical interview or reported by referring clinicians
* Any significant, recent, acute decline in exercise tolerance
* Uncorrected hypothyroidism or hyperthyroidism

  * Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 3 months prior to beginning infusions
  * Clinically significant deviation from the reference range in clinical laboratory test results as judged by the clinician(s).