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Ketamine is increasingly being used as an off-label treatment for depression, but researchers have found it might not provide any long term benefits. Depression has been recognised by the World Health Organization (WHO) as a leading cause of disability globally, with about one in six adults reporting moderate to severe depressive symptoms in the UK. Previous studies have suggested about a third of people with depression do not respond well to conventional antidepressants which mostly target the hormones serotonin, dopamine and noradrenaline. One recent study found some antidepressants can cause changes in blood pressure and trigger weight gain in the first eight weeks. Other side-effects include loss of appetite, a low sex drive and mood swings, according to the NHS. Anaesthetic ketamine given in low doses is one alternative - but evidence to support using the drug for depression is limited. “Our initial hypothesis was that repeated ketamine infusions for people hospitalised with depression would improve mood outcomes. However, we found this not to be the case,” Declan McLoughlin, professor of psychiatry at Trinity College Dublin and consultant psychiatrist at St Patrick’s Mental Health Services said. Researchers from Trinity College Dublin, St Patrick’s Mental Health Services, Queen’s University Belfast, Ireland, investigated the use of twice-weekly ketamine infusions as an add-on treatment for inpatients with serious depression. Ketamine works by blocking the action of a chemical in the nervous system that is important in creating persistent pain. This reduces the amplification of the messages sent to the brain that tell you that you are in a lot of pain, according to the NHS. Single infusions of ketamine have also been reported to produce rapid antidepressant effects, but these disappear within days. However, study authors expected repeated ketamine infusions to have a more sustained benefit. The randomised trial was developed to assess antidepressant safety, cost-effectiveness, and quality of life during and after serial ketamine infusions when compared to a psychoactive comparison drug midazolam. Trial participants were randomised to receive up to eight infusions of either ketamine or midazolam, given over four weeks and then followed up after six months. However, researchers found there was no significant difference between the two groups. “Under rigorous clinical trial conditions, adjunctive ketamine provided no additional benefit to routine inpatient care during the initial treatment phase or the six-month follow-up period. Previous estimates of ketamine’s antidepressant efficacy may have been overstated, highlighting the need for recalibrated expectations in clinical practice,” Professor McLoughlin said. Study authors noted that despite their best efforts to keep the trial patients and researchers blinded about the randomised treatment, the vast majority of patients correctly guessed the treatment allocation. Lead author of the study, Dr Ana Jelovac, Trinity College Dublin, said: “Our trial highlights the importance of reporting the success, or lack thereof, of blinding in clinical trials. Especially in clinical trials of therapies where maintaining the blind is difficult, e.g. ketamine, psychedelics, brain stimulation therapies. Such problems can lead to enhanced placebo effects and skewed trial results that can over-inflate real treatment effects.”
