Is use of ketamine for treating depression a step too far?
While it seems esketamine has potential as a treatment for depression, there are doubts about how to use it safely and rationally
Dependence is a key concern around esketamine treatment. Urging caution and a need for public debate, a British expert observed that “we need to not let the genie get out of the bottle”
A new drug for treating depression has been approved in the US by the Federal Drug Administration (FDA). The same drug is now undergoing evaluation by the European Medicines Agency. So why do I feel uneasy about ketamine?
Routinely used as an anaesthetic agent, ketamine has had a chequered history. It has been used in veterinary medicine as a horse tranquilliser, and is a drug of abuse with the street name Special K. Its main attraction as a recreational drug is that it makes users feel they are disassociating from reality.
Ketamine has its supporters. Prof Brendan Kelly, professor of psychiatry at Trinity College Dublin, says “while there is not yet sufficient evidence for routine use, ketamine is one of the most promising areas in depression research at the moment”.
A trial of ketamine currently under way in his department is looking to see whether the drug can prevent future depressive episodes in people who have recently recovered from depression. Researchers are looking at using intravenous ketamine in a very select group of patients.
Trials elsewhere have shown a large therapeutic benefit, including a reduction in suicidal thoughts, in people given a slow intravenous administration of ketamine. However, the effects were transient, with patients returning to their baseline severity within a few weeks. Because patients may experience sedation, confusion and dissociation they have to be closely monitored during and after administration.
So far, so logical.
But the FDA approval in March of esketamine – part of the ketamine molecule – in the form of a nasal spray for the treatment of resistant depression is, in my opinion, a step too far.
We need a lot more research on the potential for abuse of the nasal spray before we put medication, so closely related to a drug with an established reputation as a party drug, on the market.
Normally two adequate and well-controlled trials is the threshold for new drug approval. Some experts argue, however, that the FDA moved forward in this case with just one.
Esketamine can reportedly lift a patient’s mood within 24 hours of use. This puts it into a different league from current antidepressants which can take four weeks or so to work. Its licence states it must be taken in conjunction with another oral antidepressant. While traditional drugs focus on increasing serotonin levels in the brain, esketamine targets glutamate, a chemical linked with learning and memory.
So while it seems esketamine has potential as a useful treatment for depression there are major doubts about how to use the drug safely and rationally, and uncertainty over what point should it be slotted into the current antidepressant armamentarium.
There is concern that seeking a European licence for esketamine as a third-line option, after two other antidepressant drugs have not worked for a patient, may not be appropriate.
According to pharmaceutical company Janssen studies have shown that treatment with esketamine nasal spray plus a newly initiated oral antidepressant was associated with a rapid reduction of depressive symptoms, improving in as early as two days. A long-term safety study was also positive.
But dependence is the key concern. Urging caution and a need for public debate, a British expert observed that “we need to not let the genie get out of the bottle”.
He is right to be cautious. I have written before of problems with the painkiller Lyrica – in 2016 and in 2017. As an anticonvulsant it was not expected to induce dependence; however the experience of some patients has been far from pleasant. They describe in some detail the real and persistent difficulty of coming off the drug, suggesting its potential for inducing dependency is greater than first estimated.
There is undoubtedly an unmet need when it comes to treating resistant depression. Whether a nasal spray with the potential for abuse is the solution must be a matter of doubt.