A bright hope has suddenly appeared in depression therapy: the ‘party’ drug, ketamine. Known best as a horse tranquilliser, it is also used as an anaesthetic in hospitals.
But ketamine can cause soaring highs and is used illegally, with potentially nightmarish results; the drug is addictive and can trigger psychosis.
Recently, leading depression experts lined up at a London briefing to explain how an engineered version of the drug, called esketamine, promises a breakthrough in providing fast-acting help to sufferers of treatment-resistant depression.
This severe form of depression carries a very high risk of suicide. Around a third of those affected will attempt to kill themselves at some point, according to Dutch research published last year.
At the briefing, the experts declared that while conventional SSRI antidepressants can take weeks or months to take effect, esketamine, a ketamine-type nasal spray, may bring enduring benefits within hours.
More than four in ten British health professionals who take money from drug companies don’t disclose those payments or say where the money came from, according to the latest figures.
This made headlines in UK national newspapers and The BMJ. Myriad internet news sites then swept the excitement around the world.
Newspapers reported Professor Allan Young, director of the Centre for Affective Disorders at the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, telling the briefing: ‘We haven’t had anything really new for 50 or 60 years. What’s particularly exciting is the arrival of a new type of treatment; and that’s ketamine.
‘It’s got a different pharmacology. It’s not just the same old steam engine. It seems to work in a different way and it seems to work more quickly.’
Dr Carlos Zarate, head of experimental therapeutics at the U.S. National Institute of Mental Health, who conducted the first clinical trial of ketamine for depression in 2006, added his authoritative voice, saying: ‘Ketamine is now the prototype of the future generation of antidepressants that will have rapid robust effects within a few hours.’
The third expert, Dr Rupert McShane, a consultant psychiatrist and associate professor at the University of Oxford, who runs the UK’s only experimental ketamine clinic for depression, was quoted saying that although there were safety concerns about the drug, ‘Ketamine, in my experience, and esketamine, according to the data, are potent and potentially transformative antidepressants’.
DOES FUNDING BIAS RESEARCH?
What was not made clear in reports of the briefing is that Professor Young, Dr McShane and Dr Zarate have conflicts of interest that could potentially compromise their independence as advocates of ketamine and esketamine.
A document issued at the briefing acknowledged that Dr McShane and Professor Young have links with Janssen-Cilag, the maker of esketamine, have been paid by Janssen and have conducted trials for it that bolstered claims for esketamine’s usefulness.
Such links are far from uncommon nowadays. However, they are an increasing concern because studies show that when research is funded by drug makers, it is significantly more likely to reach positive conclusions about effectiveness and safety of the funders’ drugs.
The need for transparency is paramount when the drug involved may cause serious side-effects and potential addiction. And even more so when the drug is expensive: esketamine costs an estimated £29,000 to treat a patient for a year.
Janssen, a subsidiary of the U.S. multinational Johnson & Johnson (for which Professor Young says he is a consultant), is lobbying UK and European authorities to have esketamine approved for depression.
Dr Zarate may consequently profit from this. He holds patents entitling him to receive royalties on future sales of ketamine-type drugs for severe depression.
Professor Young, who is ‘ranked as one of the world’s leading scientific minds in the field of psychiatry’ according to the King’s College London website, has made few previous public disclosures of his links with Janssen-Cilag.
He features frequently in briefings hosted by the Science Media Centre in London, a charity that fosters communication between scientists and journalists, and while the recent briefing set out his potential conflict of interest, he has not listed Janssen in his income disclosures on Disclosure UK.
This online register was set up in 2016 by the drug companies’ official body, The Association of British Pharmaceutical Industry (ABPI) to create transparency, by enabling healthcare professionals to show payments and hospitality received from drug companies.
In his ABPI income disclosures for 2016, 2017 and 2018, Professor Young declares receipt of £14,700 from three other companies. From 2016-2017 Professor Young was the principal investigator on a research contract for £163,635 from Janssen. As the grant was paid to King’s College London rather than to Professor Young he was not required to declare it as personal income.
DOCTORS ALLOWED TO KEEP SILENT
Under the ABPI’s interpretation of data protection rules, he doesn’t actually have to disclose any payments: individual healthcare professionals can require that information on their payments be withheld — without having to provide a reason why.
The British Association for Psychopharmacology, of which Professor Young is president, received £22,000 in sponsorship last year from Janssen and had Dr Zarate as the guest speaker at its recent annual conference.
By contrast, Dr McShane’s links with Janssen are comparatively easy to discern.
In several journal papers, he lists himself as a principal investigator for Janssen’s trials of esketamine, and as a consultant to the company.
His ABPI voluntary disclosure shows he received £8,937 in fees and expenses from Janssen in 2018. Such transparency matters, for while drug company funding is vital to the creation of new drugs, UK health professionals, regulators and the public need to be able to fathom whether an expert opinion is potentially biased.
This need not be deliberate or done in a corrupt way, but the fact is that evidence shows drug company links can influence expert opinion in ways that may be so subtle as to be subliminal.
For example, a review in 2017 by the highly respected Cochrane group concluded that clinical trials tend to find more favourable outcomes about a drug company’s products if the company sponsors the trial. Moreover, an editorial in The BMJ last year warned that it is becoming increasingly difficult to untangle the links between drug companies and trial research: ‘Without more transparency, we risk undermining the integrity of some of medicine’s most influential research.’
But as Dr Ben Goldacre, the best-selling author of Bad Science and campaigner for research transparency, told Good Health, we are often on a cleft stick because we rely on drug company funds to research new therapies. ‘How are you going to get ‘completely independent researchers’ on any topic?’ he asks. ‘Who else is going to pay for that? Rightly or wrongly, the reality is that all companies pay for the research on their own products.’
Dr Goldacre’s solution is that we should legally require all potential financial conflicts of interest to be declared fully on an easily accessible database (see box).
‘Unfortunately, such conflicts are commonly not disclosed,’ he says. ‘This could be fixed by the medical profession taking a stand, by policy makers passing clear rules on disclosure, and by professional bodies penalising offenders.’
PATIENTS MISS OUT ON WHOLE PICTURE
The need for complete transparency is paramount with a drug as controversial as ketamine.
The potential side-effects, which include hallucinations, dizziness, anxiety, psychosis and blood pressure surges, mean patients can be given the drug only under supervision in a clinic room — and kept there for two hours after each weekly dose, while being monitored by staff trained to deal with hallucinatory, cardiac and respiratory problems.
Another concern is that scientists disagree on how the drug might work.
In February, Professor Young wrote a paper in the journal PeerJ which suggests that ketamine may work against resistant depression by inhibiting areas of the brain associated with troublesome emotions and memories (he declared in the journal that he had no competing interests).
However, Alan Schatzberg, an eminent professor of psychiatry at Stanford University in the U.S., published a study last year showing that ketamine works by activating the brain’s opioid receptors — as do drugs such as morphine and heroin — which is what can also make such drugs addictive.
When Professor Schatzberg’s team introduced a drug that blocked these opioid receptors from working, ketamine’s effects stopped. This suggests a high risk of becoming addicted to ketamine-type drugs and subsequently suffering withdrawal pains.
During several years of trials sponsored by Janssen, six people administered esketamine died, as opposed to none on placebos. Three deaths were suicides.
The U.S. medicine-licensing authority, the Food and Drug Administration (FDA), said it was difficult to consider the deaths as drug-related. However, Professor Schatzberg says the deaths look similar to the way addicts kill themselves during withdrawal from opioids. Two suicides had occurred within three weeks of the patients stopping treatment.
‘To me, these deaths are related to going off the drug,’ Professor Schatzberg argues.
Dr McShane is also concerned about the potential for addiction. ‘Because ketamine makes you feel better so quickly, when you relapse you want to take it again,’ he told reporters in March.
‘When the dosage and frequency get too high, that’s when it becomes toxic. It is possible that people will end up treating themselves with ketamine obtained illegally.’ (He is also emphatic that the drug’s use must be closely monitored.)
Critics also claim that ketamine-type drugs have actually failed to prove their effectiveness in treating depression. In two out of three short-term trials sponsored by Janssen, esketamine proved little or no better than a placebo at alleviating depressive symptoms.
Dr McShane’s own Janssen-sponsored trial on 138 older patients was not conclusive and showed the drug to be of benefit only when the pool of patients in the trial was narrowed to the under-75s.
When esketamine was licensed in the U.S. by the FDA in March, this was on the basis only of clinical trials funded and conducted by Janssen, rather than any conducted independently.
Meanwhile, separate clinical pilot-projects of ketamine for depression in Australia and New Zealand, not funded by Janssen, were abandoned last year amid concerns about dangerous side-effects and lack of effectiveness.
WHY THIS MATTERS TO YOU
In Britain, esketamine could be given the go-ahead for depression under the brand name Spravato as soon as November. It is currently being considered by the UK drug regulator, the Medicines and Healthcare products Regulatory Agency (MHRA).
However, some worry that ketamine could prove a case of history disastrously repeating itself. Widespread withdrawal problems associated with conventional SSRI antidepressants — as highlighted by Good Health — have finally been acknowledged officially by UK bodies such as the Royal College of Psychiatrists. Could the medical authorities soon be adding a drug with similar dangers?
Dr James Davies, a lecturer in psychotherapy at Roehampton University and spokesman for the Council for Evidence-Based Psychiatry, which raises awareness about the harm that can be caused by psychiatric drugs, told Good Health: ‘We are deeply concerned about the proposed approval of esketamine. It works via an opioid mechanism and is likely to cause serious problems of addiction and withdrawal.
‘No one should forget the troubled history of psychiatric medication, where supposedly safe and effective medicines turn out to be addictive and damaging when used long term. We urge the MHRA to deny this drug a licence at least until long-term trials on safety and efficacy have been completed.’
Professor Young and Dr Zarate had not responded to the Mail’s requests for comment before going to press.
Dr McShane pointed out that in all discussions with journalists, he highlights his potential conflicts of interest. A spokesman for Janssen said: ‘We actively encourage the healthcare professionals we work with to disclose payments that they have received from both Janssen and the wider industry.’