Ketamine is a safe drug and will revolutionalise the treatment of depression
First UK study of ketamine for people with severe depression
03 Apr 14
The first UK study of the use of ketamine intravenous infusions in people with treatment-resistant depression has been carried out in an NHS clinic by researchers at Oxford Health NHS Foundation Trust and the University of Oxford.
‘Ketamine is a promising new antidepressant which works in a different way to existing antidepressants. We wanted to see whether it would be safe if given repeatedly, and whether it would be practical in an NHS setting. We especially wanted to check that repeated infusions didn’t cause cognitive problems,’ explains principal investigator Dr Rupert McShane, a consultant psychiatrist at Oxford Health and a researcher in Oxford University’s Department of Psychiatry.
The researchers confirmed that ketamine has a rapid antidepressant effect in some patients with severe depression who have not responded to other treatments. These are patients suffering from severe depression which may have lasted years despite multiple antidepressants and talking therapies. Although many patients relapsed within a day or two, 29% had benefit which lasted at least three weeks and 15% took over two months to relapse.
Ketamine did not cause cognitive or bladder side effects when given on up to six occasions, although some people did experience other side effects such as anxiety during the infusion or being sick. The team have now given over 400 infusions to 45 patients and are exploring ways to maintain the effect. They report their findings in the Journal of Psychopharmacology. The study was funded by National Institute for Health Research (NIHR) Research for Patient Benefit Programme.
We’ve seen remarkable changes in people who’ve had severe depression for many years
Dr Rupert McShane
Dr McShane, also of the Radcliffe Department of Medicine at the University, says: ‘We’ve seen remarkable changes in people who’ve had severe depression for many years that no other treatment has touched. It’s very moving to witness. Patients often comment that that the flow of their thinking seems suddenly freer. For some, even a brief experience of response helps them to realise that they can get better and this gives hope.’
In treatment-resistant depression, electroconvulsive therapy (ECT) is sometimes considered. Although ECT is effective, this benefit has to be balanced against the risk of memory loss. There is a need for developing more treatment options.
In the past few years, small randomised controlled trials have consistently shown that a single infusion of ketamine has a substantial and rapid antidepressant effect in some patients with treatment-resistant depression who have been taken off other antidepressants. In those single dose studies, patients typically, though not always, relapse within a week.
In the Oxford study, 28 patients with treatment-resistant depression were treated over three weeks. They received either three or six ketamine infusions lasting 40 minutes in the recovery room of a routine ECT clinic at the Warneford hospital, part of Oxford Health NHS Foundation Trust. Memory tests were carried out a few days after the final infusion. Patients reported their mood symptoms daily via text or email.
The antidepressant response sometimes took a second ketamine infusion to become apparent. Three days after the last infusion, the depression scores had halved in 29% of the patients. In those that responded to the treatment, the duration of benefit varied widely, lasting between 25 days and eight months (median 2.3 months).
The ketamine did not cause memory or bladder problems. Some patients became anxious during the infusions and some did not complete the course because they did not feel they were benefiting. A few were sick and one fainted. The patients were severely depressed and episodes of suicidal behaviour (such as had occurred before the infusions) also occurred during the study, but suicidal ideas diminished overall.
Most patients experienced some short-lived ‘dissociative’ effects from the ketamine – their perceptions might be distorted slightly, they felt disconnected from their body – but these only occurred while the drug was being infused and were not connected to the antidepressant effect. They did not feel euphoric with the treatment.
The ECT clinic worked well as the setting for the ketamine treatment because all the necessary facilities and experienced staff were already in place and the treatment could be incorporated into the twice weekly clinic routine.
Ketamine is a licensed medical drug and is very widely used as an anaesthetic and in pain relief. It is also used as a recreational drug or drug of abuse, and is to be reclassified as a Class B banned substance by the Home Office. However, the doses used are very different. When used on the street at a level of several grams a day, severe bladder problems occur and cognitive function is impaired. The dose used in this study was no more than 80 mg (80 thousandths of a gram) every week in the controlled and closely monitored setting of an NHS hospital.
The team has now treated 45 patients in total. Of these, nine (20%) have benefited to the point where it was thought worthwhile to have further intermittent ketamine treatments. Of these nine, four are currently continuing ketamine treatment, one is in remission (is not currently depressed) without treatment, and four relapsed and have gone on to other treatment. As with its use for chronic pain, there has been no evidence of addiction when given regularly over up to two years.
‘Intravenous ketamine is an inexpensive drug which has a dramatic, but often short-term, effect in some patients whose lives are blighted by chronic severe depression,’ says Dr McShane.
He adds: ‘We now need to build up clinical experience with ketamine in a small number of carefully monitored patients. By trying different infusion regimes and adding other licensed drugs, we hope to find simple ways to prolong its dramatic effect.’
Serial infusions of low-dose ketamine for major depression
- Keith G Rasmussen1
- Timothy W Lineberry1
- Christine W Galardy1
- Simon Kung1
- Maria I Lapid1
- Brian A Palmer1
- Matthew J Ritter2
- Kathryn M Schak1
- Christopher L Sola1
- Allison J Hanson1
- Mark A Frye1
1Department of Psychiatry and Psychology, Mayo Clinic, Rochester, USA
2Department of Anesthesiology, Mayo Clinic, Rochester, USA
- Keith G Rasmussen, Department of Psychiatry, Mayo Clinic, Rochester, MN 55905, USA. Email: [email protected]
Abstract
Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients. Side effects during the infusions have been common. It is not known whether serial infusions or lower infusion rates result in greater efficacy.
Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given. Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions.
Results: Five of 10 patients achieved remission status. There were no significant increases on the BPRS or YMRS. Two of the remitting patients sustained their improvement throughout the four week follow-up period.
Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care. Serial ketamine infusions appear to be more effective than a single infusion. Further research to test relapse prevention strategies with continuation ketamine infusions is indicated.
Intranasal Ketamine Promising For Treatment-Resistant Major Depression
Results from a newly published study indicate that intranasal ketamine spray can produce a rapid and sustained antidepressant effect within 24 hours, and was well tolerated in a small group of patients with treatment-resistant major depressive disorder.
This is the first study to show benefits with an intranasal formulation of ketamine. Previous research has indicated that intravenous ketamine may have a role in helping patients with major depressive disorder and suicidal ideation.
The study was published online in the Biological Psychiatry on April 2.
In a double-blind, crossover study, the researchers randomized 20 patients with major depressive disorder to ketamine (a single 50 mg dose) or saline. Change in depression severity was measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included changes in self-reports of depression, anxiety, the durability of response, as well as the proportion of responders. Eight patients met response criteria to ketamine within 24 hours versus one on saline, out of 18 patients completing two treatment days with ketamine or saline.
Ketamine, one of the most common NMDA receptor antagonists. (Photo credit: Wikipedia)
In the study, ketamine was found to be safe with minimal dissociative effects or changes noted in blood pressure or heart rate. The intranasal route for drug delivery has been of interest to investigators because it is non-invasive, and may offer rapid absorption and delivery. In addition, the ease of administration may potentially improve compliance.
“We found intranasal ketamine to be well tolerated with few side effects,” said Kyle Lapidus, MD, PhD, Assistant Professor of Psychiatry, at the Icahn School of Medicine at Mount Sinai.
ball-and-stick model of (R)-ketamine (Photo credit: Wikipedia)
Ketamine, an FDA-approved anesthetic which is an NMDA receptor antagonist, has been used in animals and humans for many decades. Ketamine has also been a drug of abuse and can lead to adverse psychiatric or cognitive problems when abused. In low doses, ketamine has already shown promise in providing rapid relief of depression, with tolerable side effects.
“One of the primary effects of ketamine in the brain is to block the NMDA [N-methyl-d-aspartate] glutamate receptor,” said James W. Murrough, MD, principal investigator of the study, and Assistant Professor of Psychiatry and Neuroscience, and Associate Director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai. “There is an urgent clinical need for new treatments for depression with novel mechanisms of action. With further research and development, this could lay the groundwork for using NMDA targeted treatments for major depressive disorder.”
“What we have here is a proof of concept study,” stated co-author Dr. Dennis S. Charney, the Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and President for Academic Affairs for the Mount Sinai Health System, and a world expert on the neurobiology and treatment of mood disorders, “and we consider the results very promising. We hope to see this line of research further developed so that we have more treatments to offer patients with severe, difficult-to-treat major depressive disorder.”
Ketamine, which acts by blocking the NMDA receptor, has a more rapid effect in alleviating symptoms of depression (within hours) compared to more standard medications such as SSRIs which take many weeks to months to begin to have effects. In fact, serial ketamine infusions have shown promise compared to the effect of a single dose of ketamine for treatment-resistant depression. Overall, medications such as SSRIs may only be moderately effective, leaving up to a third of depressed patients resistant to medical therapy.
“Currently, there is an important unmet need for additional antidepressant options,” Lapidus explained. “Many patients fail to respond to many medication treatments and even if response is achieved, there often is a long delay in treatment efficacy.”
“Although more research is needed to confirm the antidepressant effects and to determine how to extend this potential benefit, our findings suggest that intranasal ketamine can have antidepressant properties and limited side effects even when given in addition to other ongoing antidepressant medications,” added Lapidus.
Lapidus explained that they noted these effects in both a highly treatment-resistant population and in subjects with fewer antidepressant failures.
Whether ketamine holds promise for use in the emergency department as a “rescue medication” to alleviate the symptoms of depression has intrigued both researchers and the public.
“Our research provides a proof of concept for intranasal ketamine in depression. In this context, it remains too early to advocate treatment clinically in any setting.” said Lapidus.
Lapidus believes that additional research is required before clear clinical recommendations can be formulated. But he also felt that there was clear promise for the utility of the approach in the near future.
“Our findings suggest that intranasal ketamine may be easily and rapidly administered and previous studies have included administration of ketamine in emergency rooms as well as other contexts,” explained Lapidus. “Providing medication via an intranasal route could also reduce the level of support services needed relative to an intravenous infusion.”
Whether intranasal ketamine can be a game change in the management of depression as rescue or even longer term therapy will likely be debated from this study.
“A growing body of evidence continues to support a possible role for ketamine as a rapid-acting antidepressant. A specific role in acute symptom exacerbations has not been directly addressed in our study, but rapid-action could potentially have increased utility in such situations,” said Lapidus.
“It is difficult to completely predict the long-term implications of our research. Our recent study of intranasal ketamine in depression builds on previous findings with intravenous ketamine from our group at Mount Sinai and others including work by Drs. Dennis Charney, James Murrough, Dan Iosifescu, Sanjay Mathew, and Carlos Zarate”.
