Ketamine infusion for major depressive disorder in palliative care

Key points

• Treatments for major depression in people with life-limiting illness are limited
• A ketamine clinical trial for major depressive disorder in the palliative care setting may be feasible
• Ketamine infusions may be well-tolerated and may produce transient antidepressant effects over hours or days

Major depressive disorder impacts one in six people with advanced life-limiting illnesses, affecting their mood, interests, social interactions, and daily activities. It can worsen physical distress like pain and fatigue, hindering individuals’ abilities to make the most of their limited time.

Treatment options for people with major depressive disorder who have short life expectancies are limited. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist used as a dissociative anaesthetic, has shown rapid antidepressant effects at sub-anaesthetic doses in otherwise-well individuals with treatment-resistant depression.

In palliative care, ketamine might serve as a fast-acting antidepressant or a bridging intervention while waiting for traditional antidepressants to take effect. However, the safety, tolerability, and antidepressant efficacy of ultra-low-dose ketamine for major depressive disorder in people with advanced life-limiting illness remains uncertain.

The Subcutaneous ketamine infusion for major depressive disorder in the palliative care setting (SKIPMDD) study was a single-arm, open-label, phase II feasibility study. It was conducted to explore the potential of a future definitive trial using subcutaneous ketamine infusions for major depressive disorder in the palliative setting.

Adult study participants with major depressive disorder and advanced life-limiting illnesses were recruited from four palliative care services in Sydney, Australia. They received weekly subcutaneous ketamine infusions over two hours, with individual dose titration starting at 0.1mg/kg and reaching a maximum dose of 0.4mg/kg based on their responses.

The primary outcome assessed was feasibility, measured as the absolute numbers and proportions of participants who completed different study stages. Secondary outcomes assessed included: 

• Safety and tolerability using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
• Brief Psychiatric Rating Scale (BPRS) and Clinician Administered Dissociative States Scale (CADSS); and
• Antidepressant activity using Montgomery-Åsberg Depression Rating Scale (MADRS).

After baseline toxicity and depression assessments, participants were monitored for toxicity every 30 minutes during the 2-hour ketamine infusion and at two and four hours after infusion completion (Day 0). MADRS was reassessed four hours after each infusion completion.

Participants were further monitored for toxicity and anti-depressant activities using NCI CTCAE and MADRS scores on days 1, 3, and 7 of the week of ketamine administration (weeks 1-4). If no ketamine was given, they were also monitored on day 7 of each week until the end of week 8.

The feasibility criteria for a future definitive clinical trial were set a priori with an accrual rate of > 0.5 participants per month, and the proportion of treated participants with a positive response (≥ 50% reduction in baseline MADRS score) of > 10%.

Of 99 referrals, 10 participants received ketamine and were analysed for responses. The median Australia-modified Karnofsky Performance Status (AKPS) of participants was 40. Most participants had underlying malignancies (n = 9). Seven had pre-existing depression diagnoses, and four had a history of treatment-resistant depression. The accrual rate across sites was 0.54 participants per month, with attrition primarily due to clinical deterioration from underlying illnesses.

Feasibility barriers included clinical trial closure due to COVID-19 as well as  the challenges clinicians faced in screening, assessing and managing depression in rapidly deteriorating patients.

Safety assessments revealed mild increases in the prevalence of NCI CTCAE grade 2 somnolence (11% to 17%) and grade 1 headache (11% to 17%) during the 2-hour infusion. Systolic blood pressure increased slightly up to a median change of 16% (16mmHg) from baseline, which subsided within four hours after infusion completion. There was no other clinically relevant harm or intolerability found.

Five out of ten participants achieved a reduction of baseline depression score by 50% (positive response) during the week of infusion, but only two participants sustained this improvement on day 7 post-infusion. Most positive responses were achieved six hours after the infusion commencement at the ultra-low dose of 0.1mg/kg.

Nine of the ten participants had ≥ 50% reduction in baseline suicidal ideation during the intervention week with seven out of these nine participants having sustained improvement on day 7 post infusion.

Our study found that conducting a future definitive ketamine clinical trial for major depressive disorder in the palliative care setting may be feasible on addressing the identified feasibility barriers. Individual dose titration of subcutaneous ketamine infusions over two hours from 0.1mg/kg can be well-tolerated and produced transient antidepressant effects over hours to days.

You can help by raising awareness of depression in the palliative care setting, and by advocating for the implementation of strategies that improve the psychological care of people with major depressive disorders who have life-limiting illnesses when few treatment options are available.

If you are interested in participating in a clinical trial based on this study, please email us at paccsc@uts.edu.au

Read the full article: doi.org/10.1371/journal.pone.0290876

Dr Wei Lee is a palliative care physician based in the northern districts of Sydney. He is passionate about palliative care research and symptom management. He is a PhD candidate at University of Technology Sydney, exploring depression in end of life.