Beating the blues

C&I Issue 6, 2017

British experts are calling for the illegal recreational drug ketamine to be responsibly introduced as a treatment for depression when other treatments have failed. The paper, in The Lancet Psychiatry (I. Singh et al, 2017, 4( 5), 419), claims that given ‘the impressive antidepressant effects’ observed, off-label use of the drug, which is currently approved as an anaesthetic, can be ethical.

‘Ketamine has been hailed as the most important advance in the treatment of depression of the past 50 years,’ write the authors, led by researchers at Oxford University.

The authors’ conclusions follow encouraging findings from several drug studies, including one led by Oxford researchers who found that 42% of patients who had exhausted all other antidepressant treatment options responded to ketamine. The scientist leading the study, Rupert McShane, a consultant psychiatrist at Oxford Health NHS Foundation Trust, says: ‘I have seen ketamine work where nothing has helped before.’

Alongside the roll out, the experts also call for clinical guidelines, with treatment in specialist centres and formally tracked in national registries. This would help pick up any safety or abuse problems from longer-term use and help narrow down the optimal dose and treatment frequency.

‘Our approach balances the potential harms of ketamine use for treatment-resistant depression, such as its misuse potential, with a focus on reporting structures that promote the broad benefits of clinical innovation and the ethical judgement of the clinician,’ notes lead author, Ilina Singh from the Oxford department of psychiatry.

Inadequate responses
In the UK alone, there are nearly 2m people living with depression. Many look to the multitude of antidepressants available to treat the condition, designed to increase certain chemicals in the brain, such as serotonin. But approximately two-thirds of patients fail to achieve an adequate response to first-line drugs, and as many as one-third see no beneficial effect after trying several types of antidepressants. Patients that fall into the latter group are known as having treatment-resistant depression, believed to number 158,000 people in the UK. 

These less than spectacular response rates have raised question marks over traditional antidepressants, further compounded by a study in 2010 which claimed antidepressants were no more effective that placebo for most depressed patients. This has since been corroborated by other scientific reviews, while clinical trial data suggest only a quarter of patient improvement is attributable to the specific effects of the drugs.

Furthermore, traditional antidepressants can take six to 12 weeks before any response is seen, while having some nasty side effects, from dizziness to headaches and nausea, and in extreme cases seizures, irregular heartbeat, suicidal thoughts and unconsciousness.    

Stephen Buckley, head of information at UK mental health charity Mind, says managing depression can be complicated. ‘We still do not know the exact causes behind depression, and when it comes to treatments there is no one-size-fits-all approach. Patients need access to a range of treatments so they can determine what works best for them.’ Psychiatrist Steven Levine is a proponent of ketamine as a treatment for depression and has founded several private Ketamine Treatment Centres in the US to provide this option to patients. He says that, while current antidepressants do help many people, they are ‘very imprecise, imperfect tools’.

According to Gin Malhi, psychiatry professor at the University of Sydney, ‘there is an ever-present need for the development of novel antidepressant treatments that are effective and act rapidly, and this partly accounts for the resurgence of interest in ketamine.’ In a 2016 paper in the British Journal of Psychiatry (G. Malhi  et al, 2016, 2(3), e5) the authors write that: ‘Given the poor state of new drug development in mood disorders, it is important that a potential opportunity to better understand depression and possibly develop new medications for its treatment is not squandered.’

Ketamine has a place
Ketamine was first discovered in the 1960s and later approved as an anaesthetic in humans, while also being used to treat chronic pain and as an animal tranquiliser. But the dissociative effects of the drug soon led to its introduction to the party scene where it has garnered a reputation – nicknamed ‘Special K’ – and, in the UK, a Class B drug designation.

Trying to shake-off the recreational party drug image and focus on the medical benefits has been a struggle, but an increasing number of studies suggest real potential in treating depression. According to Levine, ketamine studies have shown response rates anywhere from 25% to over 80%, with patients feeling considerably better within a day of treatment. Indeed, private clinics such as Levine’s have been popping up in the US as doctors move to offer ‘off-label’ ketamine to patients with depression, and numerous patients quoted in the media have claimed that ketamine has changed their lives.

However, McShane stresses that the doses used in trials and clinics are much lower than that used recreationally. The patient’s in McShane’s trials, for instance, received iv drip infusions of 0.5mg/kg, while on the street doses can be equivalent to 25mg/kg.   

The exact mechanisms of how ketamine works in treating depression are still being clarified but the drug itself is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors are the gates in nerve cells that allow the neurotransmitter glutamate to pass through to communicate messages between brain cells. Ketamine blocks these receptors and thereby glutamate. It’s believed that changing the glutamate levels and communication between nerve cells creates the dissociative ‘awe’ effect, which changes the sense of reality. It’s this that may ‘fragment’ the depressive thoughts.

However, there are now suggestions that the antidepressant effects may not be through the NMDA receptor, after chemicals mimicking ketamine’s NMDA receptor antagonism failed to generate the same effect as the drug. Now considerations are moving to ketamine’s metabolites and their mechanism of action, including activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which studies suggest has a role in depression. Meanwhile, Levine says another likely action is that ketamine appears to increase levels of the growth factor brain-derived neurotrophic factor (BDNF), which helps to repair damaged or poorly functioning connections in the brain.         

These mechanisms of action are different to the current antidepressants. The second-generation antidepressants are known as selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), which work on the monoamine neurotransmitter systems focusing on serotonin, noradrenaline and/or dopamine to increase these chemicals in the brain. Given that people with depression don’t tend to have low levels of these chemicals, some scientists have suggested these drugs may not have the right target, which could explain the low efficacy rates.

Controversy abounds

The use of ketamine as a potential depression treatment remains controversial. Experts point to basic questions over how ketamine works and how to achieve an enduring response. Allan Young, chair of the psychopharmacology special committee at the Royal College of Psychiatrists, welcomes the ‘preliminary data’, but he says any benefits and harms will need to be continually appraised. ‘Despite clinical trials showing rapid improvement in mood after ketamine infusion, there are still significant gaps in our knowledge about dosage levels, treatment protocols and the effectiveness and safety of long-term use,’ he says. ‘Before ketamine can be recommended for use in clinical practice, extensive research is required to understand how to optimally use ketamine for treating depression.’ This is echoed by the American Psychiatric Association, which earlier in 2017 published a report in JAMA Psychiatry (G. Sanacora et al, 2017, 74(4), 399) concluding there were still many safety and efficacy gaps, particularly the long-term impact, and urged further research.

It’s for this reason that McShane and his Oxford colleagues suggest in The Lancet paper that any roll-out should be through specialist centres and tracked through national registries. Concerns have been raised about bladder inflammation, which has been seen in people who have taken the drug recreationally, and questions remain about other long-term effects including cognitive impairment, as well as the potential for abuse. Tracking treatment would give rise to any issues, McShane says. ‘Getting the right level of oversight is important; not enough, and we risk overuse and an inevitable backlash; too much, and we leave patients in misery unnecessarily.’

The fear McShane has is the prevalence of ketamine clinics with limited clinical checks when these issues haven’t been answered. In the US alone, more than 100 clinics have been set up in the past two years, he says. In response, however, Levine says there are still many questions around US Food and Drug Administration (FDA) approved antidepressants. ‘In fact, in some ways we know more about ketamine and the basic science around its proposed mechanisms than we do for SSRIs.’

He adds that there has yet to be a study of ketamine for depression that has not worked. But he also notes treatment should be restricted to carefully monitored medical settings. ‘There is a great unmet need in the treatment of depression. We will be contributing to a worldwide patient registry that will gather data from thousands of patients to help answer some of these remaining questions.’

Meanwhile, the science is moving apace. Indeed, a licensed and approved ketamine treatment could be available in the next couple of years. Pharma giant Janssen currently has an intranasal product in Phase 3 trials. The S-enantiomer of ketamine, known as esketamine, received FDA Breakthrough Therapy Designation for treatment-resistant depression in 2013, which expedites development and review of the drug. Studies have shown esketamine improves treatment-resistant depression compared with placebo and Janssen plans to file for marketing authorisation in this indication in 2018.

Ketamine might be shrouded in questions, but the psychiatric community is cautiously optimistic that the drug could provide a much-needed new treatment option for depression. As Gin Malhi and colleagues wrote in the British Journal of Psychiatry in 2016 (G. Malhi et al, 2016, 2(3), pe5): ‘Whilst ketamine cannot yet be endorsed as an antidepressant for general use on the basis of current evidence, it should not be dismissed completely.’

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