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A low-cost version of ketamine to treat severe depression has performed strongly in a double-blind trial that compared it with placebo.
In research published today in the British Journal of Psychiatry, researchers led by UNSW Sydney and the affiliated Black Dog Institute found 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 per cent. The study was a collaboration between six academic clinical mood disorder units in Australia and one in New Zealand and was funded by the Australian National Health and Medical Research Council (NHMRC).
“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 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.
As a double-blind trial, neither participants nor researchers administering the drug were aware which patients received generic ketamine or placebo, to ensure psychological biases were minimised. Importantly, 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 $800 per dose, the generic ketamine is a mere fraction of that, costing as little as $5, 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 $350 per session.
“With the S-ketamine nasal spray, you are out of pocket by about $1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you’re paying around $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 Australians.
“This is why we’re applying for a Medicare item number to fund this treatment now, because it’s such a powerful treatment.
“And if you consider that many of these people might spend many months in hospital, or be unable to work and are often quite suicidal, it’s quite cost effective when you see how incredibly quickly and powerfully it works. We’ve seen people go back to work, or study, or leave hospital because of this treatment in a matter of weeks.”
The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.
Chronic pain often leads to depression, which increases suffering and is clinically challenging to treat. Now, for the first time, researchers have uncovered the underlying mechanism that drives those depressive systems, according to a study published in The Journal of Clinical Investigation.
The mechanism acts to cause hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for the treatment of chronic pain-induced depression, say Lingyong Li, Ph.D., and Kimberley Tolias, Ph.D., co-leaders of the research.
“Chronic pain is a major, unmet health issue that impacts the quality of life,” said Li, an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Unfortunately, patients suffering from chronic pain have limited effective treatment options.”
The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild the cytoskeletons of cells. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons.
This higher spine density increased the number of connections and the strength of those connections between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model by using an antagonist of Tiam1, relieved the mice of depression and diminished hypersensitivity of the neurons.
The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 in the ACC was activated in two mouse models of chronic pain with depressive or anxiety-like behaviours compared to controls.
To show that Tiam1 in the ACC modulates chronic pain-induced depressive-like behaviors, the researchers used molecular scissors to delete Tiam1 from the forebrain excitatory neurons of the mice. These mice were viable and fertile and displayed no gross alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive- or anxiety-like behaviors in five tests that gauge depression or anxiety.
When researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons specifically mediates chronic pain-induced depressive-like behaviors.
Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is alterations in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus and the amygdala. Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior — they saw a significant increase in dendritic spine density and signs of increased cytoskeleton building. This was accompanied by increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.
These maladaptive changes were not seen in the Tiam1-knockout mice.
Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated the chronic pain-induced depressive-like behaviors, without reducing the chronic pain hypersensitivity itself. The inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitudes.
Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without decreasing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent, maladaptive synaptic plasticity in the mouse ACC neurons.
“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said.
Ketamine therapy has a swift short-term effect on reducing symptoms of depression and suicidal thoughts, according to a review of all the available evidence.
A systematic review led by the University of Exeter and funded by the Medical Research Council analysed evidence from 83 published research papers. The strongest evidence emerged around the use of ketamine to treat both major depression and bipolar depression. Symptoms were reduced as swiftly as one to four hours after a single treatment, and lasted up to two weeks. Some evidence suggested that repeated treatment may prolong the effects, however more high-quality research is needed to determine by how long
Similarly, single or multiple doses of ketamine resulted in moderate to large reductions in suicidal thoughts. This improvement was seen as early as four hours following ketamine treatment and lasted on average three days, and up to a week
.
Lead author Merve Mollaahmetoglu, of the University of Exeter, said: “Our research is the most comprehensive review of the growing body of evidence on the therapeutic effects of ketamine to date. Our findings suggest that ketamine may be useful in providing rapid relief from depression and suicidal thoughts, creating a window of opportunity for further therapeutic interventions to be effective. It’s important to note that this review examined ketamine administration in carefully controlled clinical settings where any risks of ketamine can be safely managed.
For other psychiatric disorders, including anxiety disorders, post-traumatic stress disorders and obsessive-compulsive disorders, there is early evidence to suggest the potential benefit of ketamine treatment. Moreover, for individuals with substance use disorders, ketamine treatment led to short-term reductions in craving, consumption and withdrawal symptoms.
Published in the British Journal of Psychiatry Open, the review synthesises the evidence from a growing field of research into the potential benefits of ketamine for conditions for which there are limited effective treatments. The review included 33 systematic reviews, 29 randomised control trials, and 21 observational studies.
Ketamine’s effects on depressive symptoms and suicidal thoughts are supported by numerous systematic reviews and meta-analyses, which provide an exhaustive overview of research in a given topic. These are considered to have the highest strength of evidence compared to other types of studies, increasing confidence in the evidence for ketamine’s antidepressant and anti-suicidal effects.
However, ketamine’s therapeutic effects for psychiatric conditions other than depression and suicidal thoughts are based on small number of studies that did not randomise people into different treatment arms. These effects require replication in larger randomised placebo-controlled trials, which are considered as gold standard.
The authors noted a number of difficulties in the research field, which they recommend that future studies should seek to address. One factor is the bias created because participants realise they have been given ketamine, rather than a saline solution. Senior author Professor Celia Morgan, of the University of Exeter, said: “We’re finding that ketamine may have promising benefits for conditions that are notoriously hard to treat in clinic. We now need bigger and better-designed trials to test these benefits. For example, due to ketamine’s unique subjective effects participants may be able to tell whether they have been given ketamine or a saline solution as the placebo, potentially creating an expectation about the effects of the drug. This effect may be better controlled by having active placebo-controlled trials, where the control group receives another drug with psychoactive properties.”
A number of questions remain unanswered in the research field, including the optimal dose, route of administration and number of doses of ketamine treatment. There is also a need for further research on the added and interactive benefit of psychotherapy alongside ketamine treatment.
Additionally, the importance of ketamine’s acute subjective effects in its therapeutic benefits has not been fully explored. More research is also needed on how to optimise participants’ preparation for ketamine treatment and the setting in which ketamine treatment is delivered.
The research involved collaboration with the University of British Columbia, and received support from the Society for the Study of Addiction. The paper is entitled ‘Ketamine for the treatment of mental health and substance use disorders: a comprehensive systematic review’, and is published in the British Journal of Psychiatry Open.