Rupert McShane, chair of the ECT and Related Treatments Committee at the Royal College of Psychiatrists, outlines why a monitoring system for ketamine and esketamine is needed
News earlier this year that an advisory committee to the US Food and Drugs Administration has endorsed a new drug, esketamine, for treatment resistant depression has prompted much excitement on both sides of the Atlantic.
Given that 1 in 6 adults in England have taken an antidepressant in the past year and a third are treatment resistant, the interest in esketamine—a form of ketamine—is understandable.
Ketamine-based therapies offer new hope for the millions of patients worldwide who don’t respond to conventional drugs. But, without wishing to be a killjoy, we need to think hard about exactly how we monitor the use of esketamine and ketamine before it becomes widespread, as now seems likely.
Ketamine is a licensed painkiller and anaesthetic. It is already widely used off label for depression, intravenously, orally, or intramuscularly, in over 200 ketamine clinics in the US. We do not know the optimal dosing schedule, or even the best route of administration. There are almost no data on long term safety of repeated use.
Esketamine is one of the two mirror-image molecules in ketamine. It has been developed as a nasal spray for patients with depression which is resistant to at least two other antidepressants. The US licence for esketamine is based on a clearly defined and researched, clinic-based, dosing schedule: twice weekly for a month, then weekly or fortnightly. The available one-year safety data for esketamine are, as far as they go, reassuring.
The European Medicines Agency and the UK drugs regulator will make a decision in November on licensing esketamine—if approved it would become available through private clinics. And early next year, the National Institute for Health and Care Excellence is scheduled to decide on whether to approve it for NHS use.
But no one is pretending that this is a miracle drug. Firstly, we do not know how use of licensed esketamine will play out in the real world. It is good that, unusually for an antidepressant, longer term data are available before it comes to market. But the reality is that data on patients with rigorously defined illness, treated within a rigid phase 3 trial protocol, only tell us a partial story about real world use. Symptoms of depression which are resistant to treatment occur in many other psychiatric and physical illnesses, and also in patients whose unhappiness has been incorrectly diagnosed as depression. It is inevitable that esketamine will gradually get used in these situations. At the moment, a conventional post-marketing monitoring registry is tracking intranasal esketamine in the US. This will help restrict it to licensed use, prevent abuse of esketamine and help define the less common side-effects.
So far, so good. But this ignores the other side of the story: ketamine.
Conventional post marketing monitoring of licensed esketamine is not enough. Off-label ketamine must also be monitored through the same system.
Tolerance is also an acknowledged possibility with esketamine as well as ketamine. The advantage of licensed intranasal esketamine is that there is a defined top dose of 84mg weekly. This is a good way to stop dose-creep with long-term use. The same cannot be said of ketamine which has no ‘top dose’. This situation may well drive patients who feel they need a higher dose of esketamine but cannot get it to switch to a doctor who will provide ketamine at a more flexible dose or route.
There will be other strong drivers for switching too: cost, availability of esketamine on NHS, the desire to control one’s own treatment rather than be bound by rigid clinical protocols.
These same factors will also stimulate patients to by-pass esketamine altogether. An unknown number—possibly the majority—will start by seeking out cheaper off-label ketamine or pursue the unwise strategy of self-treatment with street ketamine.
So, we need a multi-drug monitoring system, which tracks both esketamine and ketamine. This should be tightly linked to clinical care and dispensing, like the system for clozapine. Every dose of ketamine or esketamine taken by patients should be logged. Patients should control access to their data but will find that few doctors are willing to prescribe if they, the doctors, are not given access to the information. People who self-treat should also be able to self-monitor through the same system.
The MHRA, NICE, NHSE, DHSC, pharma, Royal Colleges, NHS and private providers need to thrash out how this could work. The problem doesn’t clearly lie with any one agency. But if we ignore ketamine because its use is off-label, or ‘out of scope’, or because there isn’t a precedent for multi-drug monitoring, or because it’s difficult to see how to fund it, we risk descent into overuse, backlash and stigma.
So far the evidence suggests that patients stand to benefit from ketamine-related drugs. We need wide access with strong monitoring—which must include ketamine as well as esketamine—to ensure that this is not just a flash in the pan.
Rupert McShane is a consultant psychiatrist who works at Oxford Health NHS Foundation Trust
Competing interests: Rupert McShane has participated in advisory boards for Janssen Pharmaceuticals, which is part of Johnson & Johnson and is an investigator on esketamine trials. He runs ketamine clinics in Oxford Health NHS Foundation Trust.