A University of Otago-led clinical trial has tested an oral form of ketamine therapy for treatment-resistant depression that has fewer side effects whilst also reducing the risk of abusing the powerful, tightly-regulated anaesthetic.
Working in collaboration with New Zealand’s Douglas Pharmaceuticals, researchers have conducted a trial of ketamine in an extended-release tablet form. The study, published in Nature Medicine, involved 168 adults for whom regular anti-depressant therapy repeatedly failed. They either took a range of oral doses of ketamine or a placebo for 12 weeks.
Professor Paul Glue, Otago’s Hazel Buckland Chair in Psychological Medicine, says the highest dose of ketamine – 180mg – showed significant improvement in depressive symptoms, compared with patients who received placebo.
“Ketamine can be given by injection or nasal spray, but these methods can leave people feeling spaced out, sedated, and increases their blood pressure. This study shows the extended-release ketamine tablets are safe and effective, and overall, tolerability was good, with participants reporting minimal side effects,” he says.
Douglas Pharmaceuticals is now seeking the interest of partners to complete registrational clinical trials and prepare for commercialisation of the tablets.
“We have found there are many people, here in New Zealand and around the world, who have treatment-resistant depression, and who have no or very little chance of accessing ketamine. Because most doses of this tablet formulation can be taken at home, this is potentially a much cheaper and convenient option for these patients compared with weekly clinic visits for ketamine injections or nasal sprays.”
Ketamine has been used legally by doctors in New Zealand since the 1970s for sedation and pain relief, but it has been classified as an illegal drug for recreational use since the 1980s.
Professor Glue says having the drug in a tablet form reduces the risk of abuse as the manufacturing process makes them difficult to manipulate.
Using the old anaesthesia drug ketamine to pull people out of the depths of severe depression has gone from fringe idea to widespread use in just a few years. Sparked by promising studies and stories of lives transformed, clinics offering intravenous infusions of ketamine have popped up in the US. Some also offer a newer, more expensive, nasal spray version.
But major questions remain about who ketamine can help, why some people get tremendous relief within days or weeks while others don’t, and the costs and benefits of different ways of delivering the drug.
New findings just came out from a study that seeks to answer some of those questions. They add more evidence about the power of IV ketamine to help some of the most severely ill people with depression or bipolar disorder who haven’t gotten relief from other treatments, including many who have frequent suicidal thoughts.
Called Bio-K, the study involved 74 people treated at four clinics in Michigan, Maryland and Minnesota. After just three infusions of ketamine over 11 days, 52% of participants saw their severe depression ease so much they achieved remission. Another 15% responded somewhat.
Half of those who had thought often of suicide before receiving ketamine experienced a dramatic drop in those impulses. The results are published in the Journal of Affective Disorders.
“These participants are very representative of the sickest patients we see, with more than 80% reporting suicidality that would have excluded them from other depression treatment studies,” said University of Michigan Health psychiatrist and study leader Sagar Parikh, MD.
“As in other studies of ketamine, the initial response to treatment was a strong predictor of who would do well,” he added. “Two-thirds of those who responded after one infusion went on to achieve remission, while those who hadn’t responded measurably after two infusions were unlikely to start to respond after an additional one.”
Who responds and why?
What’s the difference between them and those who responded? That’s a key focus of Bio-K, which is funded by donors to the U-M Eisenberg Family Depression Center.
A third of all Bio-K participants didn’t respond to ketamine by the end of the three infusions provided under the study, leaving them to cope with one more failure in a series of attempted treatments.
The team’s in-depth interviews with some of these non-responders show how difficult that can be, as the team reported in a paper last year.
By studying molecules in blood samples from the study’s participants, the Bio-K team hopes to find biomarkers that could predict who is most likely to get relief from ketamine, and who should try other options.
The study is evaluating cell signaling proteins, inflammatory markers and molecules that can indicate rates of cell metabolism in mitochondria. Early results from those analyses should be available in the next year.
From research to clinical use
In the meantime, the strength of the response in Bio-K participants helped fuel the founding of an IV ketamine clinic at University of Michigan Health, says Parikh, who oversees the clinic.
U-M now accepts referrals from providers across the region who have patients with treatment-resistant depression and need another option after trying at least four medications.
Patients come to the main U-M medical campus around eight times during the span of a month for infusions under the care of psychiatrists, anaesthesiologists and other clinicians.
Parikh and his colleagues even wrote a guide for other hospitals on how best to set up and run such a clinic.
A newer version
Meanwhile, the nasal spray form of ketamine, called esketamine and sold under the name Spravato, has captured attention in recent years for its potential to ease disabling and life threatening symptoms without requiring an IV.
The spray involves a form of the drug manufactured by a pharmaceutical company in a way that isolates just one variety of the ketamine molecule, which allowed the company to seek a specific FDA approval.
Parikh notes that U-M was one of the sites for the original small study that led to Spravato’s approval by the FDA, and another larger study sponsored by Janssen, the drug’s manufacturer, that recently concluded. In addition to serving as the local principal investigator for these studies, Parikh also briefly served as a consultant to the company.
Based on the experience in these studies, U-M hopes to start offering Spravato alongside IV ketamine on a clinical basis. Even though it’s not given through an intravenous drip, the nasal spray still requires careful observation of patients under the FDA’s approval conditions.
IV vs nasal spray
Even as researchers search for biomarkers to predict ketamine response, clinicians find themselves with a conundrum: Which patients should start with IV ketamine, and which with Spravato? And how do the two compare head to head in actual response to treatment?
That’s what researchers at Yale University, U-M and their colleagues will soon try to find out, through a new study just funded by the federal Patient-Centered Outcomes Research Institute.
The study, which will begin enrolling up to 400 people at six sites nationwide later this year, will randomly assign people with treatment resistant depression to either the IV or nasal spray form of the drug. They’ll then receive that treatment for about four weeks, and have their symptoms monitored during treatment and for months afterward.
Such a head-to-head study might help inform insurers that haven’t yet started covering one or both forms of ketamine, Parikh noted.
More about the Bio-K results
In the meantime, the treatment response results from the Bio-K study and other studies can help more patients and clinicians understand the impact of IV ketamine.
Although Bio-K accepted people who were suicidal, which many antidepressant medication studies do not, it did not include people who use cannabis or those who have an active substance use disorder, schizophrenia or psychosis. But participants had to have failed to respond to at least two antidepressant or mood stabilising medications after at least eight weeks, or failed to respond to six sessions of ECT, the treatment based on electric stimulation of the brain that has been seen as the last resort for many patients.
The study found that it did not matter if they got their infusions slowly over 100 minutes or in a standard session of 40 minutes.
At the start of the study, the average score of participants on a standard depression scale called MADRS was 28; that average dropped to 11 at 24 hours after the third infusion. A score of 10 or below is considered depression free, or remission, and a drop in score of at least 50% of the total score is considered response. In all, 67% achieved what is considered response, and 52% reached remission.
Rapid-acting antidepressants, including ketamine, scopolamine and psilocybin, have been found to have immediate and lasting positive effects on mood in patients with major depressive disorder but how these effects arise is unknown. New research led by the University of Bristol and published in Science Translational Medicine explored their neuropsychological effects and found that all three of these drugs can modulate affective biases associated with learning and memory.
Negative affective biases are a core feature of major depressive disorder. Affective biases occur when emotions alter how the brain processes information and negative affective biases are thought to contribute to the development and continuation of depressed mood.
The research team used an affective bias test, based on an associative learning task, to investigate the effects of rapid-acting antidepressants (RAADs) in rats.
They found that all the treatments were able to reduce negative affective biases associated with past experiences but there were additional characteristics of the dissociative anaesthetic, ketamine, and the serotonergic psychedelic, investigational COMP360 psilocybin (Compass Pathways’ proprietary formulation of synthetic psilocybin), which could explain why the effects of a single treatment can be long-lasting.
The findings suggest that these sustained effects are due to adaptive changes in the brain circuits which control affective biases, and these can influence how past experiences are remembered.
The effects at low doses were very specific to affective bias modulation and were localised to the prefrontal cortex of the brain, a region known to play an important role in mood.
Emma Robinson, Professor of Psychopharmacology in the School of Physiology, Pharmacology & Neuroscience at Bristol, and lead author, said: “Using a behavioural task we showed that drugs that are believed to have rapid and sustained benefits in depressed patients, specifically modulate affective biases associated with past experiences, something which we think is really important for understanding why they can improve a patient’s mood so quickly.
“We also found differences in how ketamine, scopolamine and COMP360 psilocybin interact with these neuropsychological mechanisms which may explain why the effects of a single treatment in human patients can be long-lasting, days (ketamine) to months (psilocybin).
“By using an animal model, we have been able to investigate these important interactions with learning and memory processes and neural plasticity and propose a two-stage model that may explain the effects we observe.”
In the task, each animal learnt to associate a specific digging material with a food reward under either treatment or control conditions.
The treatment condition is designed to generate a change in the animal’s affective state and a choice test is used to quantify the affective bias this generates.
Acute treatment with the RAADs ketamine, scopolamine, or psilocybin prevented the retrieval of the negative affective bias induced in this model.
However, the most exciting finding was at 24 hours after treatment when low, but not high, doses of ketamine and psilocybin led to a re-learning effect where the negatively biased memory was retrieved with a more positive affective valence.
Only psilocybin, but not ketamine or scopolamine treatment also positively biased new experiences.
Exploring in more detail the re-learning effects of ketamine in the studies, the researchers found they were protein synthesis-dependent, localised to the medial prefrontal cortex and could be modulated by cue-reactivation, consistent with their predictions of experience-dependent neural plasticity.
The study’s findings propose a neuropsychological mechanism that may explain both the immediate and sustained effects of RAADs, potentially linking their effects on neural plasticity with mood.
Over the years, studies have demonstrated the psychoactive drug ketamine’s effect on depression, providing profound and fast relief to many people. But these studies have a critical flaw: participants usually can tell whether they have been given ketamine or a placebo. Even in blinded trials in which participants are not told which they received, ketamine’s oftentimes trippy effects are a dead giveaway.
In a new study published in Nature Mental Health, Stanford Medicine researchers devised a clever workaround to hide the psychedelic, or dissociative, properties of the anesthetic first developed in 1962. They recruited 40 participants with moderate to severe depression who were also scheduled for routine surgery, then administered a single infusion of ketamine (0.5 mg kg−1) or placebo (saline) during usual anaesthesia.
All researchers and clinicians involved in the trial also were blinded to which treatment patients received. The treatments were revealed two weeks later.
The researchers were amazed to find that both groups experienced the large improvement in depression symptoms usually seen with ketamine.
“I was very surprised to see this result, especially having talked to some of those patients who said ‘My life is changed, I’ve never felt this way before,’ but they were in the placebo group,” said Boris Heifets, MD, PhD, assistant professor of anaesthesiology, perioperative and pain medicine, and senior author.
Just one day after treatment, both the ketamine and placebo groups’ scores on the Montgomery-Åsberg depression rating scale (MADRS) dropped, on average, by half. Their scores stayed roughly the same throughout the two-week follow-up.
“To put that into perspective, that brings them down to a category of mild depression from what had been debilitating levels of depression,” said Theresa Lii, MD, a postdoctoral scholar in the Heifets lab and lead author of the study.
What does it all mean?
The researchers concede that their study, having taken an unexpected turn, raises more questions than it answers.
“Now all the interpretations happen,” said Alan Schatzberg, MD, a co-author of the study. “It’s like looking at a Picasso painting.”
The researchers determined that it was unlikely the surgeries and general anaesthesia account for the improvements because studies have found that depression generally does not change after surgery; sometimes, it worsens.
A more likely interpretation, the researchers said, is that participants’ positive expectations may play a key role in ketamine’s effectiveness.
At their last follow-up visit, participants were asked to guess which intervention they had received. About a quarter said they didn’t know. Of those who ventured a guess, more than 60% guessed ketamine.
Their guesses did not correlate with their treatment – confirmation of effective blinding – but rather with how much better they felt.
A low-cost version of ketamine to treat severe depression has performed strongly in a placebo-controlled double-blind trial. Results published in the British Journal of Psychiatry showed that more than one in five participants achieved total remission from their symptoms after a month of bi-weekly injections, while a third had their symptoms improve by at least 50%.
“For people with treatment-resistant depression – so those who have not benefitted from different modes of talk-therapy, commonly prescribed antidepressants, or electroconvulsive therapy – 20 per cent remission is actually quite good,” lead researcher Professor Colleen Loo says.
“We found that in this trial, ketamine was clearly better than the placebo – with 20 per cent reporting they no longer had clinical depression compared with only 2 per cent in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field which only had past smaller trials that compared ketamine with placebo.”
How the trial worked
The researchers, led by UNSW Sydney and the affiliated Black Dog Institute, recruited 179 people with treatment-resistant depression. All were given an injection of either a generic form of ketamine that is already widely available in Australia as a drug for anaesthesia and sedation – or placebo. Participants received two injections a week in a clinic where they were monitored for around two hours while acute dissociative and sedative effects wore off, usually within the first hour. The treatment ran for a month and participants were asked to assess their mood at the end of the trial and one month later.
In this double-blind trial, a placebo was chosen that also causes sedation, to improve treatment masking. Midazolam is a sedative normally administered before a general anaesthetic, while in many previous studies the placebo was saline.
“Because there are no subjective effects from the saline, in previous studies it became obvious which people were receiving the ketamine and which people received placebo,” Prof Loo says.
“In using midazolam – which is not a treatment for depression, but does make you feel a bit woozy and out of it – you have much less chance of knowing whether you have received ketamine, which has similar acute effects.”
Other features of the recent trial that set it apart from past studies included accepting people into the trial who had previously received electroconvulsive therapy (ECT).
“People are recommended ECT treatment for their depression when all other treatments have been ineffective,” Prof. Loo says.
“Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not.”
Another difference about this trial was that the drug was delivered subcutaneously (injected into the skin) rather than by drip, thus greatly reducing time and medical complexity. The study is also the largest in the world to date that compares generic ketamine with placebo in treating severe depression.
Much more affordable
Apart from the positive results, one of the standout benefits of using generic ketamine for treatment-resistant depression is that it is much cheaper than the patented S-ketamine nasal spray currently in use in Australia. Where S-ketamine costs about AUS$800 (R9 600) per dose, the generic ketamine is a mere fraction of that, costing as little as AUS$5 (R60), depending on the supplier and whether the hospital buys it wholesale. On top of the cost for the drug, patients need to pay for the medical care they receive to ensure their experience is safe – which at Black Dog Institute clinics, comes to AUS$350 (R4200) per session.
“With the S-ketamine nasal spray, you are out of pocket by about AUS$1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you’re paying around AUS$300-350 for the treatment including the drug cost,” Prof Loo says.
She adds that for both S-ketamine and generic ketamine treatments, the positive effects often wear off after a few days to weeks, so ongoing treatment may be required, depending on someone’s clinical situation. But the prohibitive costs of the drug and procedure make this an unsustainable proposition for most.
The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.
Ketamine, an established anaesthetic and increasingly popular antidepressant, dramatically reorganises activity in the brain, as if a switch had been flipped on its active circuits, according to a new study published in a Nature Neuroscience paper.
Researchers observed greatly altered patterns of neuronal activity in the cerebral cortex of animal models after ketamine administration – normally active neurons were silenced while another set that were normally quiet suddenly sprang to action.
This ketamine-induced activity switch in key brain regions tied to depression may impact our understanding of ketamine’s treatment effects and future research in the field of neuropsychiatry.
“Our surprising results reveal two distinct populations of cortical neurons, one engaged in normal awake brain function, the other linked to the ketamine-induced brain state,” said the co-lead and co-senior author Joseph Cichon, MD, PhD, an assistant professor at the University of Pennsylvania. “It’s possible that this new network induced by ketamine enables dreams, hypnosis, or some type of unconscious state. And if that is determined to be true, this could also signal that it is the place where ketamine’s therapeutic effects take place.”
Anaesthesiologists routinely deliver anesthetic drugs before surgeries to reversibly alter activity in the brain so that it enters its unconscious state. Since its synthesis in the 1960s, ketamine has been a mainstay in anaesthesia practice because of its reliable physiological effects and safety profile. One of ketamine’s signature characteristics is that it maintains some activity states across the surface of the brain (the cortex). This contrasts with most anaesthetics, which work by totally suppressing brain activity. It is these preserved neuronal activities that are thought to be important for ketamine’s antidepressant effects in key brain areas related to depression. But, to date, how ketamine exerts these clinical effects remains mysterious.
In their new study, the researchers analysed mouse behaviours before and after they were administered ketamine, comparing them to control mice who received placebo saline. One key observation was that those given ketamine, within minutes of injection, exhibited behavioural changes consistent with what is seen in humans on the drug, including reduced mobility, impaired responses to sensory stimuli, which are collectively termed “dissociation.”
“We were hoping to pinpoint exactly what parts of the brain circuit ketamine affects when it’s administered so that we might open the door to better study of it and, down the road, more beneficial therapeutic use of it,” said co-lead and co-senior author Alex Proekt, MD, PhD, an associate professor at Penn.
Two-photon microscopy was used to image cortical brain tissue before and after ketamine treatment. By following individual neurons and their activity, they found that ketamine turned on silent cells and turned off previously active neurons.
The neuronal activity observed was traced to ketamine’s ability to block the activity of synaptic receptors called NMDA receptors and ion channels called HCN channels. The researchers found that they could recreate ketamine’s effects without the medications by simply inhibiting these specific receptors and channels in the cortex. The scientists showed that ketamine weakens several sets of inhibitory cortical neurons that normally suppress other neurons. This allowed the normally quiet neurons, the ones usually being suppressed when ketamine wasn’t present, to become active.
The study showed that this dropout in inhibition was necessary for the activity switch in excitatory neurons – the neurons forming communication highways, and the main target of commonly prescribed antidepressant medications. More work will need to be undertaken to determine whether the ketamine-driven effects in excitatory and inhibitory neurons are the ones behind ketamine’s rapid antidepressant effects.
“While our study directly pertains to basic neuroscience, it does point at the greater potential of ketamine as a quick-acting antidepressant, among other applications,” said co-author Max Kelz, MD, PhD. “Further research is needed to fully explore this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric illnesses.”
The commonly used anaesthetic ketamine, which is also increasingly prescribed for the relief of depression symptoms, has created concern over whether it poses an addiction risk.
University of Geneva (UNIGE) researchers found that ketamine triggers an increase in dopamine in mice’s brains, and that it also inhibits a specific receptor that precludes the progression to addiction. These results can be found in the journal Nature.
For the past ten years or so, ketamine has also been prescribed to treat the depressive symptoms of people who are resistant to conventional treatments. Its action has the advantage of a swift onset, acting within hours of the first dose, whereas traditional antidepressants take several weeks to act. Although its prescription is increasing for this type of treatment, this substance is still widely debated within the scientific community.
”Some people believe that ketamine presents a strong addictive risk if taken for a long time, others do not. The whole point of our research was to try to provide some answers,” explained Professor Christian Lüscher.
Brief reward system stimulation The UNIGE researchers allowed mice to self-administer doses of ketamine. ”The drugs intensely stimulate the reward system in the brain, which leads to an increase in dopamine levels. The first step was to observe whether this mechanism was also at work when taking ketamine,” explained Yue Li, a Postdoctoral Scholar in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine.
The scientists found that dopamine levels increased with each dose and induced a positive reinforcement in the mice, which motivated them to repeat the self-administration. ”However, unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug,” said Dr Li.
A drug that leaves no ‘mark’ Probing the mechanism behind this phenomenon, the researchers discovered that ketamine triggered an increase in dopamine by inhibiting a molecule called NMDA receptor in the reward centre of the rodent brain. Dopamine then binds to another receptor (called the D2 receptor), which acts as a rapid brake on the increase in dopamine. The researchers also confirmed that the action of the NMDA receptor is necessary to modify the communication between the nerve cells that underlie the behavioural change leading to addiction. Ketamine’s inhibition of the NMDA receptor makes this modification impossible.
”The consequence of this dual action of ketamine is that it does not induce the synaptic plasticity that addictive drugs do and that persists in the brain after the substance has worn off. It is this memorization of the product in the reward system – absent in the case of ketamine – that drives the repetition of consumption,” explained Prof Lüscher. “Therefore, the addictive risk of ketamine appears to be zero in rodents. Is this also the case in humans? Could this risk vary according to the individual? Our study provides a solid framework for debating access to its therapeutic use,” concludes Christian Lüscher.
Researchers have identified the fast-acting dissociative anaesthetic ketamine has significant potential as a treatment for mental health conditions. First manufactured more than 50 years ago, ketamine is often used in veterinary and emergency medicine. It also has a history of being an illicit party drug.
In a recent study published in the British Journal of Psychiatry, the research team found ketamine to have significant anti-depressant and anti-suicidal effects. They also found evidence that even more benefits.
Led by Psychology Professor Dr Zach Walsh and doctoral student Joey Rootman, the research team arrived at this conclusion after analysing more than 150 worldwide studies on the effects of sub-anaesthetic ketamine doses for the treatment of mental illness.
“We found strong evidence that indicates ketamine provides rapid and robust anti-depressant and anti-suicidal effects, but the effects were relatively short-lived,” explained Rootman. “However, repeated dosing appeared to have the potential to increase the duration of positive effects.”
The study also provides limited evidence to suggest a possible use for ketamine in the treatment of other disorders, such as eating disorders, problematic substance use, post-traumatic stress and anxiety.
“What our research provides is an up-to-date overview and synthesis of where the knowledge on ketamine is at right now,” said Rootman. “Our results signal that ketamine may indeed have a broader spectrum of potential applications in psychiatric treatment—and that tells us that more investigation is needed.”
This study serves as a foundation for fellow researchers looking to design ketamine-related projects and offers valuable data for clinicians considering using ketamine with their patients.
The results also help to satisfy the public’s appetite for information on innovative and emerging psychiatric treatments, said Dr Walsh, explaining that the review provides a relatively compact document with evidence regarding which ketamine treatments may be helpful for diverse diagnoses.
With many people experiencing mental health disorders, Dr Walsh said that “the reality is that existing treatments don’t work for everyone. As a result, many Canadians are curious about new approaches to help with these serious conditions.”
Overall, while Dr Walsh acknowledges research into other treatment areas is just beginning, he finds the preliminary evidence encouraging.
“We need a lot more information on how these interventions could work – for example, administering the drug is only a part of treatment. We need to figure out what amount and type of psychotherapy would best compliment the drug intervention to really maximise potential benefits,” he explained. “With that being said, it is a truly exciting time for ketamine research. If it can deliver the relief that early evidence suggests it can, this could be among the most significant developments in mental health treatment in decades.”
New research with low doses of the anaesthetic ketamine, recently approved by the FDA for use as an antidepressant, shows the drug could provide longer-lasting relief.
Depression is often treated with selective serotonin reuptake inhibitors, or SSRIs, but they can take six weeks before symptom relief begins, and in up to 30% of people they are ineffective.
For the past two decades, however, psychiatrists have been using low doses of ketamine, normally a veterinary anaesthetic, to treat patients whose depression has not responded to other treatments. It also has hallucinogenic effects and is sometimes abused as a street drug. Its use in psychiatry was long considered “off label,” but in 2019 the U.S. Food and Drug Administration approved a nasal spray version for use as an antidepressant, followed in 2020 by expanding the approval to include patients with depression who are having suicidal thoughts or have recently tried to take their own lives or otherwise harm themselves.
The approval opened up new possibilities as well as new lines of research that may change the way psychiatrists think about depression. Dr Benjamin Brody, an assistant professor of clinical psychiatry at Cornell University is heading a programme exploring ketamine to treat the condition. “What’s so exciting about ketamine is not only that it works for people whose symptoms are not responding to traditional treatments, but it also works much more rapidly — in days or even hours,” says Dr. Brody, who developed the protocol before the spray was approved, and still prefers infusions because they allow him to tailor each dose to a patient’s weight (while the spray only comes in two pre-set doses). “For some people, ketamine really does provide almost immediate relief. That’s wonderful and very gratifying to see.”
One problem with ketamine, however, is that its positive effects wear off within weeks or months. “Another major issue,” says Dr. Brody, “is that we have so little information on the long-term effects, or what type of treatment patients will need to remain well.”
Dr Conor Liston, associate professor of neuroscience in the Feil Family Brain and Mind Research Institute, is exploring the question of how ketamine works in the long term to create more synapses in a region of the brain called the medial prefrontal cortex. The new connections seem temporary, but if they could be augmented with another treatment, a person might be permanently cured of depression.
For a study published last year in Science, Dr. Liston and his team worked with mice that exhibited depression-like behavior, as determined by their reaction to a stressful situation. A mouse that freezes more than it attempts to wriggle free, known as “motivated escape behaviour”, displays an important feature of depression. “Mice are not people, and many symptoms that we think of as core to depression — sadness, hopelessness — are hard or probably even impossible to imagine modelling in a mouse,” said Dr Liston. “But there are some things we can measure.”
Dr Liston examined the mice’s brains before administering ketamine. As predicted, lacking motivated escape behaviour was correlated with lost synapses in the medial prefrontal cortex. Just hours after one dose, the mice no longer exhibited that ‘depressed’ behaviour and their brains showed that synapses had regrown. But just like humans, depressive symptoms returned days later and the new synapses had disappeared.
Interestingly, the reduction in depressive behaviour occurred before the new synapses appeared, meaning they could not have caused the immediate relief. However, the new synapses were apparently necessary for maintaining the antidepressant effects long after the ketamine dose. If those synapses were eliminated, the mice quickly became depressed again. “We think that some kind of intervention aimed at boosting the restoration of those synapses or enhancing their survival over time could be useful for augmenting ketamine’s antidepressant effects,” said Dr. Liston, adding that it could be another drug or an intervention as simple as exercise or improved sleep, two known factors in synapse survival.
Dr Liston noted that his team’s work is just a first step and more basic science needs to be done before work involving human subjects.
