How Can We Take Advantage of Ketamine’s “Window of Opportunity?”

At the turn of the century, researchers first identified that the psychedelic ketamine, used widely as a horse sedative and stupor-inducing street drug, could have rapid acting antidepressant effects.

This surprising finding initiated years of research, culminating in the US Food and Drug Administration’s licensing of a ketamine-based nasal spray for depression, the Janssen branded drug Spravato® (Esketamine) in 2019.

At the British Neuroscience Association’s 2021 Festival of Neuroscience, an entire session was devoted to the discussion of new research working towards understanding ketamine’s mechanism of action and its potential use as a treatment for alcohol use disorder.

“Ketamine has these [antidepressant] effects particularly in treatment-resistant populations,” explained session co-chair and University of Bristol Professor Emma Robinson. “The effects are rapid, and interestingly, they are sustained.” Whilst most side-effects of a ketamine high wear off within a few hours, users have reported antidepressant effects lasting days and even weeks.

How ketamine changes the brain

The session presented both pre-clinical and clinical research that aimed to tease out the mechanisms underpinning ketamine's "mysterious" antidepressant effects.

Robinson presented work that characterized how ketamine alters reward pathways in the brain. “The working hypothesis is that ketamine has an acute initial effect as a rapidly-acting antidepressant, working in regions such as the prefrontal cortex,” she said.

This leads to what Robinson called a “downstream neuroadaptation” – a longer-lasting alteration in the brain that may involve changes to neuronal circuitry known as synaptic plasticity in the prefrontal cortex. Robinson focused on one important symptom of major depressive disorder in her research – loss of pleasure in previously enjoyable activities. This symptom poorly treated by frontline serotonin-selective reuptake inhibitors (SSRIs) that are usually prescribed by clinicians.

Robinson reviewed research data that explored reward behaviors in rodent models of depression. Mice given traditional SSRI  antidepressants showed more interest in subsequent reward activities, whilst mice given ketamine showed no change.

Interestingly, Robinson showed additional data that compared mice given ketamine to those given a specific SSRI, venlafaxine. The mice on ketamine showed more positive responses to previously learned negative experiences, an effect that was not shown by mice given the SSRI.

Robinson outlined her team’s theory about these findings: “We think that acute antidepressants and cognitive behavioral therapy can positively bias new, but only new memories, and this takes time,” she said. “Ketamine, because it can modify these previously learned negatively-biased memories, has an immediate effect.”

This raises further questions – will the antidepressant effects of ketamine, which is only capable of altering memories of prior experiences – wear off more quickly than SSRIs? More research is clearly required, especially in humans.

KARE through ketamine

An example of this much-needed research was provided by Professor Celia Morgan of the University of Exeter, who presented preliminary data from her team’s KARE (Ketamine for the reduction of Alcoholic RElapse) trial.

This work investigated the ability of ketamine to improve outcomes for people with alcohol use disorder (AUD) and whether any such improvement would be boosted using psychological therapy. The trials divided 96 participants into four groups – one allocated ketamine plus AUD-tailored therapy, one given ketamine plus an alcohol education program and two groups given these psychological interventions alongside a placebo.

Whilst the participants had been required to sustain a period of sobriety prior to the study, they had histories of severe alcohol abuse, with each of the four groups averaging over 120 units per week at their heaviest drinking point over the previous year.

Morgan’s study showed that three months after the groups completed their regimen, which included three doses of ketamine for the trial group, they began to diverge in their abstinence.

After six months, the latest timepoint shown in Morgan’s data, the groups had significantly different outcomes:

• Patients given ketamine and therapy were most likely to remain abstinent
• This was followed by those given ketamine and an alcohol education program
• Followed by those given placebo and therapy
• Patients given placebo and alcohol education were most likely to have relapsed

 

This raised several practical questions for how ketamine-based interventions might work. Responding to a question from Technology Networks during the session, Morgan said that ketamine research may have “missed a trick” in not combining ketamine with therapy in trials, an approach which is more common in research using psilocybin.

Whilst the exact reason why ketamine "opens up" the brain to reconsolidation of negative memories remains elusive, session co-chair Vasileia Kotoula, a student researcher at King’s College London, said that research should aim to make the most of the “window of opportunity” that opens after ketamine infusion: “We should be paying more attention to this, and I am sure there will be more studies that combine ketamine and psychotherapy to just advantage of this opportunity that ketamine gives us,” she said at the session’s conclusion. 

This article is partly based on research findings that are yet to be peer-reviewed. Results are therefore regarded as preliminary and should be interpreted as such. Find out about the role of the peer review process in research here. For further information, please contact the cited source.