The illegal, hallucinogenic ‘party’ drug ketamine is addictive, physically perilous and known to increase the risk of suicide.
Now a pharmaceutical version, called esketamine (brand name Spravato), is set to be approved as a wonder cure for people with depression so severe it may drive them to suicide.
This has prompted protests from experts who argue that the tests on esketamine have been inadequate and that even in those tests, involving some 1,600 people, esketamine was associated with six deaths.
Ketamine is legally used as a horse tranquilliser and an anaesthetic in emergency departments and battlefields because it rapidly induces a trance-like state (called dissociation), while providing pain relief, sedation, and memory loss.
Back in 2006, evidence emerged that ketamine might improve symptoms of depression in some patients.
But ketamine was long out of patent, meaning anyone could produce it, and so had no potential for profit-making. Since then, the drug-maker Janssen has altered the drug’s molecule, which makes it lucratively patentable.
Last month, a European Union regulator unexpectedly recommended approval for esketamine to be used as a depression drug across the EU.
The news prompted warnings by leading experts and scathing attacks in the medical journal The Lancet.
In September, Public Health England published a landmark report warning of the addictiveness of prescribed drugs for depression and other common psychiatric problems.
It found that nearly 12 million people are on at least one drug such as an antidepressant or benzodiazepine that is potentially addictive.
Many of these drugs were said to be safe when introduced, but this was based on studies lasting a few months rather than comprehensive tests lasting years. Now experts fear this will happen with esketamine.
MPs on the All-Party Parliamentary Group (APPG) for Prescribed Drug Dependence believed that UK approval for the drug was to be discussed this month by the drug-safety watchdog, the Medicines and Healthcare products Regulatory Agency.
The APPG repeatedly wrote to the agency asking about this meeting, so it could present its objections, but heard nothing.
Instead, last month, the APPG learned that Janssen had sent an application for European-wide approval to the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, the EU regulator, and that this has now been granted provisional approval.
The company sent the CHMP trial evidence showing esketamine nasal spray, given in combination with antidepressant pills to people with treatment-resistant depression, ‘achieved superior improvement in depression symptoms, and sustained improvement in their symptoms over time compared to adults who received a placebo and an oral antidepressant’.
Patients are considered to have treatment-resistant depression if they’ve not responded to at least two different antidepressants.
Janssen says depression affects approximately 40 million people across Europe with about a third not responding to currently available treatments. Janssen’s ﬁve trials apparently showed a reduction in depressive symptoms within two days.
Approximately half of the treated patients ended the trial with few, if any, symptoms of depression, Janssen told the CHMP. So why are some experts so concerned? They argue that esketamine has dangerous side-effects and its benefits remain unproven.
Ketamine is also addictive and studies show that stopping it after regular use can trigger withdrawal symptoms, including anxiety, depression, shaking, sweating and palpitations and craving.
Known side-effects include a rapid pulse and high blood pressure, nausea, vertigo, anxiety, feeling drunk and disassociation. It can also cause nightmares and induce a schizophrenic-like state in otherwise healthy people.
No one even knows for sure how esketamine works for depression. Janssen says it may improve links between brain cells.
There are also concerns that the evidence submitted to the European regulator involved trials led by employees of Janssen.
‘It is not unusual for trials to be conducted by company employees, but for all of the trials presented as evidence to be done this way is unusual and worrying,’ argues Dr James Davies, who lectures in psychology at the University of Roehampton, and is co-founder of the Council for Evidence-based Psychiatry.
‘Some of these trials showed esketamine to have no benefit over placebo, while a couple showed a very minor short-term benefit.
‘This can be explained by the fact that people quickly work out they’re on the real drug — thanks to its mental effects — which makes them think it must be working,’ he adds.
‘These trials therefore fail to show a clinically significant benefit. Setting this alongside the potential harms, it is baffling why esketamine is being considered for public use.’
However, in March, esketamine was approved for use by the Food and Drug Administration (FDA) in the U.S. in patients with treatment-resistant depression, sparking fears it may subsequently be approved in the UK.
In August, the APPG wrote to the UK regulator, asking whether there was a deadline for it to submit evidence for consideration. The Medicines and Healthcare products Regulatory Agency (MHRA) said it would respond fully within 18 days, but it didn’t.
In October, the APPG’s chair, Sir Oliver Letwin MP, wrote to the UK regulator outlining his objections to esketamine as a drug likely to cause ‘dependence, addiction and withdrawal’.
He asked the agency not to approve esketamine, ‘at least until long-term trials have taken place and the long-term risks are fully understood’.
Instead, Janssen announced that esketamine had won provisional Europe-wide approval.
Since then, 12 UK mental-health experts have written to the MHRA warning that six patients involved in esketamine trials have died, which ‘may well be consistent with a severe withdrawal reaction from the medication, which is known to occur in other medications such as antidepressants and opiates’.
In a separate letter, Joanna Moncrieff, a professor of critical and social psychiatry at University College London, warned the MHRA: ‘The evidence for the benefits of esketamine is not strong.’
Members of the UK support group, Let’s Talk Withdrawal, which represents people badly affected by antidepressants, antipsychotics and benzodiazepines, have also written to the MHRA seeking longer-term studies before the drug is licensed in the UK.
In October, the trial evidence for esketamine was dismissed in two scathing attacks in The Lancet. Erick Turner, a senior U.S. psychiatrist, argued that the trials had not tested patients with ‘treatment-resistant’ depression, but those with less intense depression.
He warned: ‘Clinicians might find esketamine demonstrates less efficacy among real-world patients.’
In another paper, Dr Ioana Cristea, an assistant professor of brain and behaviour sciences at the University of Pavia in Italy, warns the U.S. approval was based on only three Janssen-sponsored clinical trials.
Normally, the FDA requires two positive trials to license a drug, ‘each convincing on its own’. Dr Cristea points out that the FDA dropped this requirement. President Trump had by then tweeted urging esketamine’s adoption. (The White House has refused to explain the President’s involvement.)
‘One short-term trial demonstrated significant benefits over placebo, whereas two others found no difference,’ Dr Cristea writes. ‘The European Medicines Agency should carefully consider whether the existing evidence for esketamine is sufficient to warrant approval.’
On top of this are concerns about the drug’s cost. In the U.S. it costs more than £25,000 to treat one patient for a year. Last month, the CHMP, (part of the the European regulator), recommended the European Commission approve the drug.
The Commission normally makes its final decision 67 days after the CHMP has issued a positive recommendation.
A spokeswoman for the MHRA told Good Health that under EU rules: ‘During the 67-day period, if member states raise important new questions of a scientific or technical nature which have not been dealt with in the opinion, the procedure will be referred back for further examination.’
The MHRA is normally responsible for issuing new drugs licenses for use in the UK. However, the European regulator EMA can also licence drugs — and the drug in question can then be used across all of Europe, including the UK.
Will the MHRA raise objections? It says it cannot comment on ‘ongoing procedures,’ and refused to confirm or deny if it could veto EMA decisions.
Head of neuroscience at Janssen, Dr Husseini Manji, said they are pleased with CHMP’s recommendation: ‘For decades there have been no new treatment options for patients with treatment-resistant depression. Esketamine represents a new way to manage this.’