IV Ketamine for Resistant Depression in the Elderly: New Data

NEW ORLEANS ― Intravenous (IV) ketamine is effective for geriatric patients with treatment-resistant depression (TRD); the response rate was similar to that observed in younger adult patients, two new studies suggest.

“These were patients with depression who had not responded even to intensive therapies or procedures, and we found that after a 6-week ketamine infusion regimen, there was no difference in the response to the treatment between the treatment-resistant geriatric and nongeriatric patients,” study investigator Jonathan Kim, of Emory University, the first author of one of two studies presented here at the American Association for Geriatric Psychiatry (AAGP) 2023, told Medscape Medical News.

The findings are important because research on the effects of IV ketamine have not been well documented in geriatric patients, who have high rates of depression and TRD.

“There is a lack of data on IV ketamine in older adults with treatment-resistant depression, and there are some safety and tolerability concerns which may lead some older adults and their clinicians to be reluctant to pursue IV ketamine treatment,” study co-investigator Hanadi Ajam Oughli, MD, a health sciences assistant clinical professor in the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, told Medscape Medical News.

Nasal vs IV Administration

Ketamine has traditionally been used as an anesthetic that blocks N-methyl-D- aspartate (NMDA) glutamate receptors, Oughli and colleagues note.

In the treatment of TRD, an infusion of 0.5 mg/kg is typically administered over 40 minutes, producing a rapid antidepressant response. Recent research shows the drug reduces suicidality and improves mood and quality of life.

A more recent intranasal formulation of ketamine, esketamine, was approved by the US Food and Drug Administration for TRD in 2019, and some experts questioned its path to approval. In addition, the drug’s high cost and poor bioavailability in comparison with IV ketamine remains an issue, said Oughli.

In the previous TRANSFORM-3 study, a placebo-controlled randomized trial, there was no difference between esketamine, used in conjunction with an antidepressant, and placebo for geriatric patients.

To better understand the effects of IV ketamine in this patient population, Kim’s team conducted a retrospective chart review of 91 older patients with TRD who received IV ketamine treatment between October 2016 and August 2022.

Patients were divided into two groups ― those older than 60 years (n = 36; 44% women; mean age, 68.86) and those younger than 60 (n = 55; 49% women; mean age, 41.05). Participants in each age group received six ketamine infusions over 6 weeks.

Results showed that with regard to depression severity, as assessed using Beck Depression Inventory (BDI-II) scores, 27.8% of patients in the geriatric group had a 50% or greater improvement, vs 25.4% of those younger than 60.

The average BDI-II scores represented a significant improvement for both groups (P < .01), and the difference in scores between each group was not statistically significant (P = .973).

“It is important to note that our study was conducted in a real-world clinical setting with a treatment-resistant population; other clinical studies may not have such sick patients in their trials. Additional studies are therefore warranted to establish further treatment guidelines in this area,” Kim said.

Open-Label Trial Results

In the second study, Oughli and colleagues evaluated additional key outcomes in geriatric patients treated with IV ketamine as part of a larger open-label late-life trial on TRD.

The secondary analysis of the trial focused on 23 patients (mean age, 71.5 years) who had been initially treated with twice-a-week IV ketamine for 4 weeks.

After the first 4 weeks, patients who had experienced a partial response received an additional 4 weeks of once-weekly IV ketamine.

Overall, 48% of participants achieved a response, and 24% achieved remission of depressive symptoms following the first 4 weeks of twice-weekly treatment. This effect was maintained during the continuation phase of the study.

These findings are consistent with research in younger adults and demonstrate that twice-weekly infusions yield a more sustained antidepressant response than once-weekly infusions, the authors note.

The analysis also showed important increases in psychological well-being scores on the Scale for Suicidal Ideation, improved sleep quality, as measured by the Pittsburgh Sleep Quality Index, and overall psychological well-being, as shown on the NIH Toolbox Positive Affect on happiness/contentment and the NIH Toolbox General Life Satisfaction scales.

In a previous analysis, published in The American Journal of Geriatric Psychiatry, the researchers also evaluated cognitive function using the NIH Cognitive Battery, which showed that geriatric patients with TRD had significant improvements in a composite of executive functioning and fluid cognition during the 4-week acute treatment period of twice-weekly IV ketamine infusions (Cohen’s d = 0.61) and that those improvements were sustained in the continuation phase of once-weekly infusions for 4 more weeks.

Those results are consistent with ketamine’s known potential pro-cognitive effects in TRD, due to a putative antidepressant mechanism that rescues prefrontal circuit dysfunction through synaptogenesis, the researchers note.

Oughli said that in both analyses, patients tolerated ketamine well, and there were no serious adverse events.

“Adverse events, including hypertension, dissociated effects, and cravings, were rare and did not prevent the continued use of IV ketamine by older adults. We were able to use clonidine to help manage blood pressure changes seen during the infusions,” she noted.

“These findings are very promising and will need to be confirmed and extended in a larger randomized controlled trial.”

Unsettling for Some Older Patients

Commenting on the findings for Medscape Medical News, George Grossman, MD, of the Chambers-Grundy Center for Transformative Neuroscience at School of Integrated Health Sciences, in Las Vegas, Nevada, noted that in his experience, IV ketamine treatment can be unsettling for some older geriatric patients, such as those in their 80s.

“Particularly with some of my older patients, the kind of psychotomimetic properties of ketamine and the out-of-body experiences [with the initial treatment] can be frightening,” he said. “They may be willing to try, but I’ve had more than one patient quit after one treatment because they became so frightened.”

However, the dire nature of TRD and failure to respond to multiple medications and combinations and other strategies may prompt patients to try ketamine as a measure with at least some potential, he noted.

“But there is a high bar for acceptance, especially on the part of older adults and their families, more than for younger people,” he said.

The investigators have disclosed no relevant financial relationships. Grossberg has received consulting fees from Acadia, Avanir, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Otsuka, Roche, and Takeda

American Association for Geriatric Psychiatry (AAGP) 2023: Abstract NR-34. Presented March 5, 2023.

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