At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial

This open-label (real-world evidence) paper (n=1247) argues that at-home sublingual ketamine (tablets for under the tongue) is both safe (only four patients dropped out) and effective (remission of 32% for depression and anxiety). Patients only spoke with a ‘guide’ (not a therapist) over video as the study was conducted during Covid. The results look promising, though the study sponsor (Mindbloom) has come under scrutiny recently.

Abstract

“Background At-home Ketamine-assisted therapy (KAT) with psychosocial support and remote monitoring through telehealth platforms addresses access barriers, including the COVID-19 pandemic. Large-scale evaluation of this approach is needed for questions regarding safety and effectiveness for depression and anxiety.

Methods In this prospective study, a large outpatient sample received KAT over four weeks through a telehealth provider. Symptoms were assessed using the Patient Health Questionnaire (PHQ-9) for depression, and the Generalized Anxiety Disorder scale (GAD-7) for anxiety. Demographics, adverse events, and patient-reported dissociation were also analyzed. Symptom trajectories were identified using Growth Mixture Modeling, along with outcome predictors.

Results A sample of 1247 completed treatment with sufficient data, 62.8 % reported a 50 % or greater improvement on the PHQ-9, d = 1.61, and 62.9 % on the GAD-7, d = 1.56. Remission rates were 32.6 % for PHQ-9 and 31.3 % for GAD-7, with 0.9 % deteriorating on the PHQ-9, and 0.6 % on the GAD-7. Four patients left treatment early due to side effects or clinician disqualification, and two more due to adverse events. Three patient subpopulations emerged, characterized by Improvement (79.3 %), Chronic (11.4 %), and Delayed Improvement (9.3 %) for PHQ-9 and GAD-7. Endorsing side effects at Session 2 was associated with delayed symptom improvement, and Chronic patients were more likely than the other two groups to report dissociation at Session 4.

Conclusion At-home KAT response and remission rates indicated rapid and significant antidepressant and anxiolytic effects. Rates were consistent with laboratory- and clinic-administered ketamine treatment. Patient screening and remote monitoring maintained low levels of adverse events. Future research should assess durability of effects.”

Authors: Thomas D. Hull, Matteo Malgaroli, Adam Gazzaley, Teddy J. Akiki, Alok Madan, Leonardo Vando, Kristin Arden, Jack Swain, Madeline Klotz & Casey Paleos

Summary

In this prospective study, a large outpatient sample received Ketamine-assisted therapy over four weeks through a telehealth provider. Symptoms were assessed using the Patient Health Questionnaire and the Generalized Anxiety Disorder scale.

1. Background

Anxiety and depression are leading causes of disability in the United States and are over-represented among minorities and the economically vulnerable. Lack of treatment availability is increasingly burdening healthcare systems with preventable mental and physical health concerns.

Research suggests that telemedicine does not diminish the effectiveness of evidence-based treatments in most cases, and the pandemic has increased patient and provider comfort with and utilization of telehealth.

Despite advances in access, mental health intervention is still limited by weak patient response to treatment and decreasing effects over time. New approaches are needed that expand access and improve outcomes.

Treatment utilizing compounds with dissociative or psychedelic properties has demonstrated rapid treatment effects for depression and anxiety, post-traumatic stress disorder (PTSD), substance-related disorders, end of life care, and other conditions. Ketamine, an N-methyl-D-aspartate receptor antagonist and glutamatergic modulator, is the only medication available for therapeutic use outside of a research setting.

Selection criteria for patients include allergies, heart health, urological health, and presence of any serious physical illnesses. Psychological criteria include trauma history, substance use history, and suicide history.

Ketamine treatment varies in the use of complementary behavioral intervention, with ketamine-infusion therapy typically denoting a medication-only treatment with support from the prescribing clinician as needed. Ketamine-assisted therapy utilized certified behavioral coaches to provide behavioral support in-between medication sessions.

This study evaluates sublingual ketamine treatment administered at-home with prescribing psychiatric clinician and behavioral coach support offered through a secure, HIPAA-compliant telehealth and remote monitoring platform. It also gathers and reports adverse events for a large patient population.

2.1. Setting

Data was collected as part of organizational quality assurance and program management processes for a service offering ketamine-assisted therapy (KAT) through a telemedicine platform. All patients and clinicians gave consent to the use of their data in a de-identified, aggregate format for research purposes.

2.2.1. Patients

Participants were individuals who presented with a chief complaint of anxiety or depression, were seeking treatment through the service, and scored 10 or higher on the PHQ-9 and/or GAD-7 at baseline.

Patients with ketamine allergy, ongoing alcohol or substance use dependence, history of opioid use disorder, active psychotic, manic or mixed symptoms, untreated high blood pressure, congestive heart failure or other serious cardiac problems, severe breathing problems, pregnancy, nursing, or currently trying to become pregnant were excluded.

2848 patient records were reviewed, and 1247 had two outcome measure completions sufficient for follow-up data analysis.

2.2.2. Clinicians and guides

The provider network had psychiatric training and prescription privileges, and 33 % of providers reported one or more additional certifications. The guides had prior behavioral coaching experience and/or relevant certifications.

Clinicians and patients met by video to determine suitability for and safety of the treatment. Individuals were sent a single 300 mg to 450 mg dose of sublingual, rapidly dissolving ketamine tablets. Ketamine dosing was developed based on bioavailability studies and clinical experience with sublingual administration. It was gradually adjusted up to 5 mg/kg based on clinician-observed levels of patient dissociation and to reduce risk of COVID-19 infection, while maintaining treatment safety and outcomes.

To prepare for treatment, patients review written and video materials on their web portal, meet with a specially trained “guide” by video, and have a peer monitor physically with them. The peer monitor is also trained to use the blood pressure cuff provided.

During medication sessions, patients hold ketamine tablets under the tongue or between the cheek and gums for 7 min, spit out all saliva, and lie down to listen to music. Patients meet with their prescribing clinician by video for 20 to 30 min after the first medication session, and with their guide by text daily after that. Guides assess ongoing tolerability of the medication and any adverse events, and provide time for the patient to reflect on their experience. The cost of a single ketamine infusion is between $193 and $250, so reducing the cost of out-of-pocket care is an important aim for increasing accessibility.

2.3.2. Assessments

Patients completed screening instruments for suicide, alcohol use, substance use, depression and anxiety symptoms at baseline and after two and four medication sessions, respectively.

The 9-item Patient Health Questionnaire was used to assess depression symptomatology. A score greater than or equal to 10 was considered clinically depressed.

Anxiety symptoms were assessed with a 7-item Generalized Anxiety Disorder questionnaire and a 5-item Columbia Suicide Severity Rating Scale. Individuals with positive indication of method, intent, or plan within the past month were provided appropriate referrals.

Alcohol use was assessed with the Alcohol Use Disorders Identification Test (AUDIT) and drug use with the DAST-10.

Side effects and adverse events were assessed through a self-report measure administered after session 2 and again after session 4, and were recorded in the electronic health record.

Dissociative symptoms were measured with a 3-item scale adapted from the Clinician Administered Dissociative States Scale and dropout was measured by the number of individuals who canceled ongoing treatment prior to Session 4.

2.4. Statistical analyses

Changes in symptoms from baseline to session 4 of treatment were monitored for patients meeting criteria for Depression and Anxiety. A response rate was defined as a 50 % or more reduction in symptom score on the respective measure.

We used Growth Mixture Modeling (GMM) in Mplus 8 to analyze outcome trajectories of anxiety and depression symptoms over the 4 weeks of treatment.

Patients’ baseline characteristics were nested into a conditional GMM and analyzed as trajectory predictors using 3-step multinomial logistic regression analyses. Missing values were iteratively imputed using the R package missForest.

3.1. Sample characteristics

Patients were between 19 and 76 years of age, and 54.6 % were women. 5.0 % had zipcodes in Center for Medicare and Medicaid Services classified rural areas.

3.2. Clinical outcomes

Suicide ideation was tracked for each cohort at each time point and remitted ideation was reviewed and escalated to the clinician as needed for safety.

Baseline severity scale score mean for the C-SSRS was 0.54, DAST-10 mean was 0.83, AUDIT mean was 3.54, and dissociation mean was 3.4 and 3.7 after session 2 and session 4, respectively.

Side effects were reported by 59 (4.7 %) patients after session 2, 27 (3.8 %) patients after session 4, and two were removed from treatment by the clinician due to noncompliance.

3.3. Trajectory patterns and predictors

Three classes of patients emerged, characterized by distinct patterns of GAD-7 and PHQ-9 scores over treatment. The modal group had lower baseline levels of PHQ-9 and GAD-7 scores, while the Chronic group had higher levels of symptoms that were maintained throughout treatment.

Logistic regression analyses indicated that Delayed Improvement patients experienced the least initial symptom reduction, and Chronic patients experienced more dissociation at Session 4 compared to the other groups.

4. Discussion

This study evaluated the real world safety and effectiveness of sublingual, at-home administration of ketamine-assisted therapy for depression and anxiety.

Baseline PHQ-9 and GAD-7 scores suggested this sample was predominantly in the moderately-severe category for depression and severe category for anxiety. Sublingual ketamine showed similar response and remission rates to those previously reported for ketamine in lab studies and real world effectiveness studies. The critical factor in achieving successful ketamine infusion therapy appears to be ongoing administration of treatment. Additional factors that may help to achieve this include the use of an at-home needle-free setting, psychosocial support, and a higher proportion of patients without a history of treatment resistance.

In this study, ketamine was associated with a reduction in anxiety symptoms. In addition, a higher proportion of men sought ketamine treatment than those who sought other forms of mental healthcare, suggesting that some aspect of ketamine therapy may be helpful in overcoming attitudinal and structural barriers for men.

KAT’s rapid, consistent, and large effects contrast with monoaminergic treatments, which can take up to 10 to 14 weeks to produce similar remission rates and have highly variable effect sizes. KAT’s large reductions in suicide ideation replicate those in more controlled settings.

While adverse events for psychotherapy are rare and mild, the adverse events for ketamine at-home therapy are remarkably low, which may account for the high treatment completion rates in this study.

There was strong evidence that experiencing greater dissociation at the end of treatment decreased the likelihood of symptom improvement for both depression and anxiety, and that experiencing side effects mid-treatment was also associated with delayed symptom improvement.

Acknowledgements

Although this study demonstrates the promising potential of KAT for treating anxiety and depression, there are limitations including the drop in symptom survey completions at week 4, which could bias the clinical outcomes reported after Session 4 upwards. This study found that trials offering incentives for measure completion artificially increase engagement, and that the lack of comparison or control group data for other types of ketamine treatment or non-ketamine therapies for depression and anxiety limits the claims that can be made from this study.

5. Conclusions

We found that 4 at-home sublingual KAT sessions over 4 weeks had large and persistent clinical effects for 62.8 % of depressed patients and 62.9 % of anxious patients, with very few adverse events.

CRediT authorship contribution statement

TDH, MM, LV, AM, AG, TJA, KA, MK, JS, CP designed and conducted the study.

Declaration of competing interest

LV, KA, JS, MK, AM, TDH, CP, TJA, and AG work for the service providing the data, and declare no competing interests.