Summary: A new study reports ketamine may be a safe and effective method of treating depression in older people. The University of New South Wales study reveals ketamine was well tolerated by those with depression, and repeated treatments led to a higher likelihood of remission.
Source: University of New South Wales.
Australian researchers have completed the world’s first randomised control trial (RCT) assessing the efficacy and safety of ketamine as a treatment for depression in elderly patients.
The results, published in the latest American Journal of Geriatric Psychiatry, provide preliminary evidence suggesting ketamine’s effectiveness as an antidepressant when delivered in repeated intravenous doses.
Led by a team of researchers from UNSW Sydney and Black Dog Institute, the trial tested different doses of ketamine amongst 16 older age participants (aged over 60 years) who had treatment-resistant depression, administered at Wesley Hospital.
“These findings take us a big step forward as we begin to fully understand the potential and limitations of ketamine’s antidepressant qualities,” said lead author UNSW Professor Colleen Loo, who is based at Black Dog Institute.
“Not only was ketamine well-tolerated by participants, with none experiencing severe or problematic side effects, but giving the treatment by a simple subcutaneous injection (a small injection under the skin) was also shown to be an acceptable method for administering the drug in a safe and effective way.”
Participants received increasing doses of ketamine over a period of five weeks, with doses optimised for each individual participant using a new dose-titration approach developed by Professor Loo’s Sydney research team and collaborators.
As part of the double-blind, placebo-controlled trial, an active control treatment which causes sedation similar to ketamine, was used to substitute for one of the treatment sessions. Researchers monitored for mood and other side-effects after each treatment session.
Following the RCT, participants also received 12 ketamine treatments in an open-label phase to investigate the effectiveness of multiple doses of ketamine.
By the six-month follow up, 43 percent of participants (7 of 14) who completed the RCT had remitted, with five remitting at amounts below the commonly-used dose of 0.5 mg/kg. Repeated treatments also resulted in a higher likelihood of remission or a longer time to relapse, with an overall response and remission rate of 68.8 percent for the patients receiving ketamine treatment.
“Elderly patients with severe depression face additional barriers when seeking treatment for the condition. Many medications may cause more side effects or have lower efficacy as the brain ages,” said co-author Dr Duncan George from UNSW Sydney. “Older people are also more likely to have co-morbidities like neurodegenerative disorders and chronic pain, which can cause further complications due to ketamine’s reported side effects. “Our results indicate a dose-titration method may be particularly useful for older patients, as the best dose was selected for each individual person to maximise ketamine’s benefits while minimising its adverse side effects.”
Previous studies into ketamine treatments for older people with depression – which are limited to just five case reports – show mixed success, with findings limited by small sample sizes.
More broadly, little is known about ketamine’s potential side effects at different doses, which include cognitive and dissociative effects, elevated blood pressure and heart rate, liver inflammation and urinary problems.
“These results are a promising early piece of the puzzle, but the risks of ketamine use are still not wholly understood. Future studies with greater sample sizes are needed to formally assess ketamine’s side effects, such as its impact on liver function,” Professor Loo added.
The study was a collaboration between UNSW Sydney, Black Dog Institute, Royal North Shore Hospital, The Wesley Hospital Kogarah, the Dementia Collaborative Research Centre and the University of Otago.
Professor Loo will build on these promising results as part of her current work directing the world’s largest trial of ketamine to treat depression, which is now recruiting participants.
Source: Gabrielle Dunlevy – University of New South Wales
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Original Research: Abstract for “Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression” by Duncan George, M.B.B.S., Verònica Gálvez, M.D., Donel Martin, Ph.D., Divya Kumar, B.Med., John Leyden, M.B.B.S., Dusan Hadzi-Pavlovic, B.S.C., Simon Harper, M.B.B.S., Henry Brodaty, D.Sc., Paul Glue, M.D., Rohan Taylor, M.B.B.S., Philip B. Mitchell, M.D., and olleen K. Loo, M.D. in American Journal of Geriatric Psychiatry. Published online June 13 2017 doi:10.1016/j.jagp.2017.06.007
Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression
To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment.
In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months.
Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse.
Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505).
“Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression” by Duncan George, M.B.B.S., Verònica Gálvez, M.D., Donel Martin, Ph.D., Divya Kumar, B.Med., John Leyden, M.B.B.S., Dusan Hadzi-Pavlovic, B.S.C., Simon Harper, M.B.B.S., Henry Brodaty, D.Sc., Paul Glue, M.D., Rohan Taylor, M.B.B.S., Philip B. Mitchell, M.D., and olleen K. Loo, M.D. in American Journal of Geriatric Psychiatry. Published online June 13 2017 doi:10.1016/j.jagp.2017.06.007