Monday, 16 May 2016

Ketamine: painkiller, party drug – and possibly next-generation antidepressant

Keith Laws, School of Life and Medical Sciences
Ecstasy, methylenedioxy-methamphetamine or MDMA, is well known as a recreational drug today, but its first use was as a therapeutic aid for couples attending marriage guidance counselling. LSD, the potent psychedelic popularised by the counter-cultural movements of the 1960s onwards, and psilocybin, found in hallucinogenic mushrooms, have also been studied for their potential in treating post-traumatic stress, depression, and alcoholism.

Strict drugs laws make it difficult to research these psychoactive drugs, and clinical research typically lags behind the bold claims of advocates. Ketamine is another drug with a recent history of recreational use, but as it has a longstanding legal pharmaceutical use as an anaesthetic, it is available for research and has in recent years been examined for its anti-depressant effects.

Ketamine, originally called CI-581, was first synthesised in 1962 and patented for use as an anaesthetic in humans and animals four years later. The drug was used as a battlefield anaesthetic by US forces during the Vietnam War, and is commonly used by vets as an animal tranquilliser.

On August 3, 1964, Edward Domino administered the first intravenous subanesthetic dose of ketamine to a human, remarking: “I gradually increased the dose from no effect, to conscious but ‘spaced out’, and finally to enough for general anesthesia. Our findings were remarkable!”

From the beginning, clinicians noted that many who were given ketamine described strange experiences such as the feeling of floating in space and something akin to an out-of-body experience – described by today’s recreational users as the “K-hole”.

But in the past few years, ketamine has been reborn as an antidepressant. Trials consistently show that it reduces the symptoms of depression, often in the 10-20% who have failed to respond to other drug treatments, and in emergency situations, where ketamine can rapidly reduce suicidal thinking possibly for up to three months. Ketamine has also proved to be a safe, effective and crucially, a rapid way to potentially reduce fear, depression, pain and suffering in the terminally ill.

Our own meta-analysis of 21 published trials into antidepressant uses for ketamine leaves no doubt as to the drug’s efficacy as a rapid antidepressant, with consistent reports of considerable effects on tackling depressive symptoms. In people diagnosed with major depression, the benefit occurs within four hours following a single dose of the drug. A comparable pattern of responsiveness has also been found for people diagnosed with bipolar depression. By contrast, conventional antidepressants and psychotherapy may take weeks or months to produce any effect.

Such findings have led to ketamine being described as “arguably the most important discovery in half a century”. Despite its promise as an anti-depressant, ketamine as a treatment has been slow to take off and met with scepticism. A new study published in Nature now offers hope that the unpleasant side effects and hallucinogenic effects of ketamine may be bypassed as the team of researchers from the US have tried to pinpoint the underlying mechanism by which ketamine relieves depression.

SSRI antidepressants such as Prozac bring unwelcome side effects. Michiel1972, CC BY-SA

Bypassing side effects

Ketamine belongs to a class of drugs that block cellular receptors for the neurotransmitter glutamate, an important chemical that is the brain’s chief means of activating neurons. Until now, it was proposed that ketamine’s antidepressant effects were produced by blocking N-methyl-D-aspartic acid (NMDA) glutamate receptors. However, questions about the mechanisms underpinning ketamine’s anti-depressive effects remained unanswered. NMDA is largely involved in associative memory and learning, so the link with depression was unclear. Additionally, the beneficial effects of ketamine appear to persist long after the drug has been excreted from the body.

This study suggests that a chemical byproduct the body creates while breaking down ketamine may underpin its rapid antidepressant effect. The authors found that this byproduct, or metabolite, called (2R,6R)-hydroxynorketamine, is responsible for reversing depression-like behaviours in mice. But they found it didn’t elicit the anaesthetic, dissociative psychological effects, nor the damage to the bladder that is associated with ketamine use.

If this study’s outcomes can be repeated in human subjects, it would mean a massive expansion of the potential uses for the drug, particularly as a treatment for depression. Because the effects of ketamine are relatively short-lived, concerns about side effects, building up a tolerance to the drug, and safety have so far proved a barrier to administering repeated doses of ketamine. This new study goes some way towards addressing those concerns.

The prospect of using ketamine or a derivative of it as an anti-depressant is fascinating, especially comparing its effects to psychotherapy or those of common SSRIs antidepressants such as Prozac which can take weeks before antidepressant effects begin to take hold (and even increase depressive symptoms in the short term).

But we should not race too far ahead. At present, the antidepressant effects of ketamine have not been examined beyond a two-week window, and this partly reflects the issue of side effects. Until these wrinkles are ironed out, there’s still more work to do before ketamine could emerge as a truly viable mainstream treatment for depression.

The Conversation
Keith Laws, Professor of Cognitive Neuropsychology, University of Hertfordshire
This article was originally published on The Conversation. Read the original article.

Thursday, 5 May 2016

Crime on the Home Front: from "brides in the bath" to consorting with Australians

“Your wife is not going on as she ought to. She stops out all night and has sold up most of your things. She has left the baby by itself, and the poor little thing cries all day. I have seen her out with Australians.”

So went a letter received by one Private Henry Canham, serving in France during the First World War. Returning on leave, he learnt that his wife had contracted a venereal disease from an officer, and promptly shot her dead with his service revolver.

The upheaval of war had a huge effect on life on the Home Front as well as on those serving on the front lines. The presence of large numbers of soldiers in the country’s capital had – according to vocal public figures at the time – the potential to spread moral turpitude and disrupt family life. But the soldiers themselves were also a magnet for criminal activity – including robbery, assault, and even murder.

New research by Dr Andrew Maunder (School of Humanities) has unearthed some of the nefarious goings on of that period.

You can read more about these cases on the Everyday Lives in War blog. Find out what happened to Private Henry Canham, and learn about the grisly fate of Canadian soldier Alfred Williams. And of course ‘normal’ criminal activity carried on as usual – as the infamous case of the Brides in the Bath will reveal…


Dr Andrew Maunder is Head of English Literature & Creative Writing, and Reader in Victorian Studies at the University of Hertfordshire. He is part of the Everyday Lives in War centre – one of five First World War engagement centres funded by the Arts and Humanities Research Council. His latest book, British Theatre and the Great War, 1914-1919 is published by Palgrave Macmillan.

Tuesday, 3 May 2016

What are delusions – and how best can we treat them?

John Done, School of Life and Medical Sciences
From believing that clouds are alien spaceships to thinking that MI6 agents are following you in unmarked cars, delusions are the hallmark of severe mental illness. Even psychologists and psychiatrists who work with delusional patients remain puzzled about why someone can possibly hold such beliefs when the evidence is clearly contradictory. And if we can’t really understand them, how are we supposed to help?

For example, could it be that delusions are really just extreme perceptual illusions – the cloud really looks like a spaceship? In this case, the explanation would be completely rational. Or does a delusional belief result from a breakdown in rationality, whereby the person has the correct evidence but draws the wrong conclusions?

How to understand delusions has been the subject of a lot of psychological research. One standard approach is to use tests which assess cognitive skills such as perception or reasoning. Perception tests might investigate whether the person with the spaceship delusion was more sensitive than non-deluded people to illusions or seeing meaningful patterns as opposed to random dots.

But such tests have been poor at shedding light on why such bizarre beliefs can be held with such conviction. For starters, these tests have not managed to reliably distinguish between deluded and non-deluded people. Nor do they explain why someone with sensitive perception sees just spacecraft and only in clouds rather than in other curvy forms – such as some buildings and hills – too.

Cloud or spaceship? Jonathan Pincas/Flickr, CC BY-SA

Based on my own research studying delusional patients, I think the logic of this psychological testing approach is misplaced. Each delusion is very specific such that the breakdown in a patient’s belief system is peculiar to some, but not all beliefs. So we need methods that unpick these specific disturbed beliefs, focusing more on the particular content and how this changes with a change of perspective.

Socratic questioning

I think we can capture a wealth of knowledge about the breakdown of beliefs through semi-structured interviews – getting the deluded patient to evaluate the veracity of their own delusional beliefs as well as assessing them when expressed by another person, such as the interviewer. Here’s an example from the clinic.

AM (a deluded patient) holds a belief that he has robots in his head that are controlling him with GPS. When asked “How convinced are you that this is true?”, AM reported that he was “110% sure” and was unwavering in his certainty (“I am not crazy and never have been”). However, when this same belief was presented from a third person perspective “I (the psychologist) meet you in the White Horse pub and during our conversation I tell you I have robots in my head controlling me with GPS. How convinced would you be that this belief of mine is true?” AM replied, “I would want to know more”. When asked “Would there be some doubt?” AM replied, “Yes … I’d be unsure”.

I knew this patient had a turbulent romantic relationship, but this was not the subject of any delusion so I continued presenting another belief I claimed to hold: that my wife was having affairs with several men. To this, AM reflected, “I’d be unsure … It’s a difficult one this one, because I have a girlfriend … and I do worry about if she’s cheating, but I know she isn’t … You get to know a person.”

Could Socratic questioning help people with psychosis get better faster? Pressmaster/Shutterstock

What can we make of AM’s answers? His rationality is rock bottom when deliberating about his own delusion but doubt creeps in when this same belief becomes that of another person. We then observe what seems like a near perfectly rational stance when talking about my made-up concerns regarding my wife. This clearly shows that we can’t just treat patients with a delusion as irrational or being exactly the same as some other person with delusions. But AM may be unusual so we have to examine a larger group of patients to see how commonly this pattern occurs and then what it might signify regarding treatment options.

Our challenge as research psychologists is to develop systematic approaches to capture different levels of rationality (or irrationality). This is not straightforward as it requires transforming quite woolly philosophical concepts about rationality into a measure that can be rated.

Semi-structured interviews could also help us provide “belief maps”, showing where rationality is intact as opposed to broken down. In this way, we can be more systematic about the initial clinical state and measure recovery of rationality during the course of therapy – by looking only in areas where there was a problem to begin with.

For people with a first episode of a psychosis, the treatments recommended by NICE include both anti-psychotic medication and psychological therapy. But in the last 15 years we have come to realise that the earlier the intervention – even detecting those at risk for psychosis – can have substantial long-term benefits and even be preventive. But putting all such people on anti-psychotic medication is fraught with problems and so the treatment guidelines for at risk patients is therapy only.

As noted in a recent paper in the British Journal of Psychiatry, however, “Treatments for schizophrenia have reached a plateau. There has been no major breakthrough in the past decade.” Through my method of interviewing, patients reveal to themselves the erroneous logic they routinely use. This is far more powerful than having a psychologist lecturing about it, and may ultimately make it easier to change thinking patterns and behaviour. Building such third-person perspectives into actual therapy needs to be investigated.

The Conversation
John Done, Research fellow of Psychology, University of Hertfordshire
This article was originally published on The Conversation. Read the original article.