Tag Archives: psychosis

Trendy Psychiatric Research: A need to sanitise hubris and bad faith?

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An article in the Times by Dorothy Bishop explores some of the problems in biomedical research which arise from the obsession with high-impact journals and expensive grants.

monopoly boardHer critique is especially apt in the case of the physical basis of mental illness, in which researchers seeking fame and fortune must master the storytelling arts of simplicity, metaphor and metonymy. Those seeking H-impact & lucre must stay “on message” and above all, never stray into the chaos of imperfect methods and noisy data.

 

http://www.timeshighereducation.co.uk/comment/opinion/the-big-grants-the-big-papers-are-we-missing-something/2017894.article#pq=M87JTT

Bishop concludes with a warning, that the relentless focus on publishing in prestigious journals encourages…

1. Over-claiming the significance of research findings.

2. Leaving important, but contradictory results unpublished.

Hubris is the orientation of the former, bad faith the foundation of the latter.

“…what changes everything is the fact that in bad faith it is from myself that I am hiding the truth“. http://www.philosophymagazine.com/others/MO_Sartre_BadFaith.html

Why NMDA drugs keep failing in schizophrenia.

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nmda receptor

The NMDA receptor. Glutamate and glycine are required for NMDA receptor activation. Activation involves the opening of a channel allowing calcium and sodium ions to flow into the neuron. Recent attempts to translate NMDA pharmacology into the clinic have focussed on the glycine site.

Twenty years ago it all looked so promising. The model was as follows: Learning and memory were clearly being driven by activity at the glutamate NMDA receptor. Boost the NMDA receptor by pharmacological means, and perhaps intellectual performance could be improved above baseline. The hope was that an NMDA enhancer might work in schizophrenia, which many had come to regard as a disorder of cognition. Yet the story has not played out as anticipated. The latest generation of NMDA enhancers, like their predecessors, has failed in schizophrenia [link]. And it is looking increasingly likely that the basic model [boost NMDA -> boost intellectual functioning] was overtly simplistic.

long term potentiation

Long Term Potentiation (LTP) is induced by NMDA receptor activation. The mechanism of early-phase LTP involves the enhancement of AMPA receptor conductances and insertion of new AMPA receptors into the post-synaptic membrane.

An recent review article by Collingridge and colleagues is worthy of study. Back in 1983, Collingridge had shown that activation of the glutamate NMDA receptor was the initial catalyst for the process of LTP (long-term-potentiation). At that time glutamate was only just gaining entry to the neurotransmitter club, whereas LTP [a process in which excitatory synapses become and remain stronger] had achieved fame ten years earlier as a likely substrate for learning and memory in nervous systems.

The discovery of NMDA-dependent LTP, as the phenomena came to be known, was the stimulus for an enormous, worldwide research effort into glutamate neurobiology. Since then, our knowledge of NMDA receptors has advanced, to the point where the complexity can be overwhelming [figure below]. But the medicines have not materialised. The biology appears to be several orders more complex than the model. Is that why the drugs have failed? In any case, the model [boost NMDA -> boost intellectual functioning] can now be safely abandoned with little risk of missing a major therapeutic breakthrough.

Intracellular modulation of NMDA receptors

Sites of intracellular modulation of NMDARs. Schematic representation of the distribution of selected posttranslational regulatory sites on the intracellular C-terminal domains of NMDAR subunits. Properties such as channel gating, receptor desensitisation and receptor shuttling are modulated by phosphorylation at key residues. Collingridge et al 2013

POSTSCRIPT

Recently the NIMH (National Institute of Mental Health], the main funder of mental health research in the world, announced that they would no longer support clinical trials of new drugs unless there was a clear mechanistic advance at the same time:

“a positive result will require not only that an intervention ameliorated a symptom, but that it had a demonstrable effect on a target, such as a neural pathway implicated in the disorder or a key cognitive operation.”

The NMDA receptor story calls the logic of this approach into question. That story is the archetypal case in which a mechanism was clearly defined, and well supported after decades of preclinical research. Indeed the mechanism [the model] had become so appealing that many were reluctant to abandon it, even as it was becoming obvious that the therapeutics were not going to work. An overhaul of drug discovery in psychiatry is needed, but it will require to be more realistic than solving mechanism and efficacy problems concurrently. Pulling back the bureaucracy, the inflated costs and the micromanagement could be a more fruitful intervention.

Is CBT really ineffective for schizophrenia? – 2 rounds: Marquis of Queensbery Rules

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CBT-for-Psychosis-Final-Poster399x282In the UK the National Institute of Clinical & Health Excellence (NICE) has recommended that the treatment of psychosis should include cognitive behavioural therapy (CBT). As a result CBT has been ‘rolled out’ for people suffering schizophrenia and other psychotic disorders.

But the efficacy of CBT in schizophrenia has been challenged. A recent paper in the British Journal of Psychiatry has argued that the returns of CBT are small, and if the highest standards of the clinical trial are applied, any benefits disappear into nothingness. Not surprisingly – given the stakes – there has been a robust counter argument in favour of CBT for schizophrenia.

Ahead of a forthcoming Maudsley debate, the protagonists have made their case in a ‘head to head’ article published in the British Medical Journal [available here]. This is the preamble to the main event, a tag-match involving two rounds of ‘live action’, between…

in the Blue corner: CBT critics

Peter McKenna, Research Psychiatrist, Barcelona &                                                         Keith Laws, Professor of Cognitive Neuropsychology, University of Hertfordshire

& in the red corner: CBT defenders

David Kingdon, Professor of Mental Health Care Delivery, University of Southampton Peter Kinderman, Professor of Clinical Psychology, University of Liverpool

(& your match referee: Professor Sir Robin Murray FRS)                                                                    

Psychosis Research. Where have we been & where are we going?

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phenotype and genotype

The Institute of Psychiatry at The Maudsley is the largest centre for psychiatric research in Europe. Recently a group of leading researchers were tasked with summarising an area of research as it pertains to psychosis and psychopharmacology.

The outcome was a series of short lectures, delivered to a lively audience of psychiatrists, mental health workers and psychologists at The Maudsley. The lecture slides and audio are now available below and constitute a unique training resource for those who treat patients.

1. Sir Robin Murray,
“Psychosis research: Deconstructing the dogma“
2. David Taylor,
“Current Psychopharmacology: Facts & Fiction“
3. Oliver Howes,
“How can we Treat psychosis better?“
4. Marta DiForti,
“An idiot's guide to psychiatric genetics“
5. Sameer Jauhar,
“Ten psychosis papers to read before you die!”
6. Paul Morrison,
“Future antipsychotics“

 

Cannabis, schizophrenia & psychosis: The current evidence

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http://georgefrench.co.uk/projects/paintings.html

1.0 Introduction

Cannabis is the most widely used illicit drug in the world. Various preparations are available including traditional hash resin and marijuana as well as more potent products such as sinsemilla. The latter product caused some alarm in the media although this has now probably been superseded by concern over the so-called “legal highs”, a range of substances, which can be purchased on-line, that includes stimulants as well as synthetic cannabinoids such as “spice”, containing HU-210, JWH-018 etc1. The main worry regarding the recreational use of cannabinoids (herbal or synthetic) is the risk to the users mental health, specifically the risk of psychotic illness2 .

It has long been known that, in some users, cannabis/THC intoxication can elicit an acute paranoid psychosis3. This is beyond doubt, appearing in the ancient Chinese and Indian medical texts, the writings of Baudelaire and Moreau from the nineteenth century and latterly, in formal laboratory-based or community based experimental studies4-8 There is also little doubt that cannabis use can worsen the course of a pre-existing chronic psychotic disorder, with a recurrence or worsening of positive symptoms (hallucinations and delusions) and further hospitalization being the usual outcome measures9-14. And it is now clear from numerous studies that schizophrenic patients who have a history of cannabis use go through their first psychotic breakdown at an earlier age, compared to those who did not use the drug15-23, (by 2.7 years on average24). This is not merely a statistical point because the earlier a psychosis emerges the worse the outcome25. Where there has been some controversy is around the issue of whether cannabis can actually cause schizophrenia in the first place26.

2.1 Cannabis use & schizophrenia

Epidemiological surveys conducted in numerous countries, since the late 1980s, have been consistent in showing an association between cannabis use and psychotic symptoms/schizophrenia27-37. But an association is not the same as causation. Alternative explanations, at least in theory, are reverse causality (i.e. that people with an existing psychosis are more likely to use cannabis, perhaps as self-medication) and confounding (e.g. cannabis is merely a marker for a 'true' causative agent, perhaps the use of another drug such as amphetamine)38.

Regarding the issue of reverse causality, in longitudinal follow-up studies, where the temporal relationship between cannabis-use and schizophrenia can be assessed with some confidence, the most common finding is that cannabis-use predates the onset of mental illness38 39. Regarding confounding, all of the longitudinal studies to date have made allowances, by incorporating factors such as amphetamine-use into the statistical model3839. The general finding is that the incorporation of other factors reduces the strength of the association between cannabis and schizophrenia, but that the association remains (and remains statistically significant)38. It is possible that residual confounding persists, and that an unknown factor 'drives' the relationship – but there are no suggestions as to what this unknown factor could be26.


2.2 Cannabis & Schizophrenia: The strength of the relationship.

The strength of the association between cannabis and schizophrenia is best framed in terms of an odds-ratio. Overall, taking an average of the recent studies, it has been found that cannabis-use approximately doubles the odds of developing schizophrenia40-42.Importantly however, there appears to be a dose-response relationship, in that the more extensive the use of cannabis the higher the risk. The Swedish conscript study showed this clearly. For those men that had taken cannabis on over 50 occasions, the odds of developing a schizophrenic illness increased from x2 (in those who endorsed ever having taken cannabis) to x728. A recent study from DiForti & colleagues also found a clear relationship between the frequency of cannabis use and the chances of developing a psychotic illness43.


2.3 Cannabis is a component risk factor for schizophrenia.

It has been pointed out repeatedly, that the use of cannabis is neither necessary nor sufficient for the development of schizophrenia. People can develop schizophrenia having never taken cannabis, and millions of people worldwide have used cannabis without developing a major mental illness. But the same can be said for cigarettes and lung cancer (where the risk is much higher). It is perhaps more useful to consider cannabis-use as a (component) risk-factor for major mental illness, in the same way that there are risk-factors for cardiovascular disease, such as high fat diets etc39.


2.4.1 Interactions between cannabis-use & other risk factors for schizophrenia

A major theme has been to clarify which additional factors interact with cannabis to confer risk. Some studies have investigated the interaction between cannabis and known environmental risk factors (such as being brought up in an urban versus a rural setting, or having a history of maltreatment in childhood)44. In general a supra-additive (synergistic) effect has been observed between cannabis-use and these other risk factors45-49.


2.4.2 Cannabis-use and susceptibility genes

It is suspected that particular genetic variants modulate the risk of cannabis for users in terms of psychosis outcomes. Polymorphic variation in dopamine components, and the enzyme AKT1 have attracted the most support. Initial work implicated an interaction between cannabis and a functional polymorphism in the gene for catechol-O-methyltransferase (COMT)50, and this interaction received support in laboratory-based and community-based experimental studies8 51. However two further epidemiological studies have been negative52 53.

More recently two independent groups have observed an interaction between cannabis and polymorphic variation at rs2494732 in the gene for the intracellular enzyme AKT1, which is an intermediate between neurotrophin receptors and mRNA translation within dendritic spines. Both studies found that, in conjunction with cannabis-use, CC carriers were twice as likely as TT carriers to develop a psychotic disorder54 55.


2.5 The age of cannabis onset

The risk of cannabis in terms of adverse mental health outcomes probably depends on the age when the subject begins to use cannabis. There appears to be a higher risk for use that emerges in early/mid adolescence compared to use that begins in adulthood29 56 57 An appealing explanation is that cannabis impacts upon the developing neural networks. Some animal studies, but not all58, support the idea that the sustained adverse consequences of CB1 agonists on cognition and social interaction arise if the drug is administered during maturation as opposed to adulthood59-61 Certainly, and perhaps to an even greater extent in higher primates, there is a massive re-organization of the nervous system in adolescence. In humans, the reorganization of synapses occurs in parallel with the development of abstract reasoning, and the emergence of social, philosophical, political and lifestyle attitudes62. The implication is that cannabis has the ability to disrupt the unfolding of the highest faculties of the nervous system, increasing the chances of future involvement with mental health services. The long-term impact of cannabis on IQ also appears to be age dependent. And again it is the adolescent period that appears to constitute a window of vulnerability63.


2.6 The type of cannabis

Recent epidemiological studies have begun to explore the nuances of the cannabis-schizophrenia relationship in more detail. One question in particular is whether sinsemilla [high THC: negligible CBD64] constitutes a higher risk (for mental health) than traditional cannabis products. This appears to be the case. A study from South London showed that patients in the midst of their first psychotic breakdown and healthy matched controls were equally likely to endorse ever having taken cannabis, but that patients were about x7 more likely than their peers to have used sinsemilla43. The higher the frequency of sinsemilla use, the higher the risk. Sinsemilla is largely devoid of cannabidiol (CBD), which can pharmacologically antagonize some of the effects of THC65, and may have anti-psychotic properties in its own right66, suggesting that the risk of sinsemilla might be partly accounted for by the absence of CBD rather than by elevated THC alone67. It has been argued that users of sinsemilla might self-titrate their intake of THC, much in the same way that spirit drinkers consume less volume of fluid than beer drinkers, however if the critical factor is the ratio of THC: CBD, then self-titration might be less important. Two epidemiological studies have shown that the relative absence of CBD in cannabis products is associated with more positive psychotic symptoms68 69. This is in agreement with laboratory-based studies in healthy controls in which doses of the two cannabinoids can be tightly controlled70 71.


2.7 Heavy use of cannabis & cannabis Addiction

The South London study also showed that there are a significant proportion of people who used cannabis (including sinsemilla) every day43. Many psychiatrists in clinical practice will encounter people who freely admit to having used cannabis, all-day, every-day, beginning immediately on waking. Some initial reports have suggested that sinsemilla is more addictive than traditional forms of cannabis, and similar to the case with psychosis, the relative absence of CBD may be a factor72. Studies are now beginning to explore whether CBD has efficacy against cannabis dependence.

It is now clear that cannabis dependence exists as a phenomenon73, and there is little doubt that a cannabis withdrawal syndrome exists, characterized by cravings, nervousness, insomnia, nightmares, irritability and abdominal pain74 75 Not surprisingly, people who experience the most severe withdrawals are much more likely to relapse and begin taking cannabis again74. People who are addicted to cannabis suffer poorer mental health generally compared to non-dependent users, with elevated rates of mood disorders as well as psychotic disorders76 77.


2.8 An acute cannabis-psychosis is a marker for the emergence of schizophrenia

People who experience an acute psychotic episode following cannabis, to the extent that treatment is needed, are at high risk of going on to develop a chronic psychotic disorder78.In a recent study from Finland (n=18,478), 46% [95% CI, 35-57%] of people who had been hospitalized for cannabis induced psychosis developed schizophrenia over the next 8 years, compared to 30% [95% CI, 14-46%] who had been hospitalized because of amphetamine induced psychosis79. This suggests that acute-psychotic experiences following cannabis are perhaps not as benign as was once believed.


3.0 Summary

There is little doubt that some people run into problems with cannabis, as is the same for any recreational substance. The worry in regard to cannabis is that many young people are putting their long-term mental health at risk by using the drug.

Early, heavy and dependent patterns of use clearly amplify any inherent risk of cannabis per-se. Sinsemilla appears to be more habit-forming than traditional forms of cannabis, and the evidence that it constitutes an elevated risk for psychosis is now fairly robust.There may well be SNPs that determine how risky cannabis is [in terms of psychosis outcome] for a particular individual. Currently variation in the gene for AKT1 is the most convincing, although COMT has not been discounted. Small-scale genetic studies can be revealing but carry the danger of false positives, and at the present time, there is no genetic test that can be used clinically to estimate the risk of cannabis-addiction or cannabis-psychosis for a particular individual.

But what we can say with some confidence is that the following patterns of cannabis-use put any individual at risk – particularly if the personality and mind are still maturing; 1.Everyday (dependent) use and 2.The use of high potency products. Finally, a history of acute cannabis-induced psychosis must be regarded as a red flag, warning against further use.


references on request.