Next-generation, evidence-based healthcare management

barnsleyfernHealthcare delivery is at last beginning to adopt mathematical and engineering principles [link]. There is an awareness, especially in the USA, that the leadership of an inherently chaotic system requires a professional mathematical sensibility, infinitely more sophisticated than the tired mix of power-point, polished-comportment, faux-bonhomie, affected-positivity and sloganeering.

Complex systems are made up of many components. A decision which impacts upon one component in a healthcare system may affect other components, and indeed the whole system, in a way which was not predicted at the outset. Quite often a decision aimed at conservation can actually end up leaking resource as unforeseen consequences on the whole system emerge.

Mathematical modelling of complex systems, such as a healthcare trust, can provide insight into how the change in one component affects other parts of the system. With a deeper analysis of the system, decisions can be taken with less uncertainty over downstream consequences.

Healthcare delivery services and their administrative and managerial supports are recognised as complex adaptive systems. Adaption signifies that the system learns from feedback and moves, overtime, ever closer towards an optimal configuration. Systems differ in their adaptiveness, however. Some evolve, almost effortlessly, towards an optimal configuration, but others appear to move chaotically from one state to another. The perception is that healthcare delivery in the UK typifies the latter.

Mathematical modelling is the ideal method for guiding healthcare delivery systems towards an optimal configuration. It is suggested that the optimal configuration of a healthcare system is aligned with the principle of utilitarianism;

Maximal well-being for a maximal number, at minimal cost.

Phenomenolgy: Freedom from psychological oppression.

Phenomenology is the philosophical root of biological psychiatry. Two aspects are essential: Firstly, phenomenology is description, using plain, unambiguous language, of events that arise in consciousness. Secondly, the describing attempts to divest itself of all of all pre-existing ideology and theory.


This attempt, to get at conscious events without the framework of any ideology whatsoever, is what is known as the phenomenological method, as first described by the philosopher Edmund Husserl.

Phenomenology arose in response to totalising, repressive, idealogically-laden accounts of consciousness, namely psychoanalysis [psychologism], the new religion – the displacement of one set of priests for another – and behavioural psychology [empiricism] the conceptualisation of conscious life as robot, consciousness as machine.

Phenomenology would morph into existentialism, structuralism and ultimately deconstructionism – the final annihilation of the foundation of all ideological positions, a freeing from the limitations of all possible psychologies, an escape  from all totalising theory.

But behaviourism would fight back as cognitive psychology – an intellectual whimper. That fight back reveals itself as nothing more than an age-old grasp for power, another priesthood [secular & cosmopolitan this time] with the urge to define, to control and to trap consciousness within an ideology. The latest manifestation of the drive to confine consciousness within the linguistic framework of the day.

Phenomenology is a pure, cleansing water, devoid of all restrictions, limitations and theory, untainted by desire for power, with no need for faith, no need for belief, no shackles. As such it is the ideal anarchic antidote to all totalising psychologies.

Cannabidiol (CBD) softens the effect of THC (again).

DataRemixed-Logo45Congratulations to Dave Nutt, Val Curran and their colleagues at Imperial and UCL. Following on from their groundbreaking studies of MDMA on channel 4, they have now repeated the same format with cannabis.

Running live psychopharmacology studies on television is not for the faint hearted, but it offers a unique way to impart public health knowledge in a way which is lively and captures the imagination. And the visual element works well.

The personal testimony of Jon Snow and the other participants was particularly revealing. The channel 4 experiments on cannabis demonstrated that CBD can inhibit the tendency for THC to produce paranoid thinking, a finding that was in complete agreement with two previous studies at the Institute of Psychiatry a few years back.

1. Does CBD inhibit THC?
2. Cannabidiol inhibits THC-elicited paranoid symptoms

All the evidence points in the same direction, skunk cannabis [high THC, zero CBD] is more hazardous for mental health than traditional cannabis [equivalent CBD & THC]. The community-based studies in psychiatric clinics and the experimental studies in the lab are in complete agreement on this point [link]. CBD softens the effect of THC again and again.

Holding up Psychiatric Progress – the new Bureaucrats.

Psychiatric research ultimately aims at improving the wellbeing of those who suffer from mental illness. In its purest form, the momentum for this effort comes from a desire to relieve the inner crisis of another person, rather than for personal glory or for trumpeting the ‘impact’ of a particular university in the international market. It is irrelevant where a genuine breakthrough occurs, or who achieves it, if the collective desire is to enhance our technical ability to relieve mental suffering in our fellow man.

orson welles 1962

The momentum of psychiatric research is being stalled by the amount of paperwork required to satisfy the plethora of new bureaucrats employed in paperwork governance.

And yet the natural flow of this altruistic endeavour is being stymied by an ever-growing, self-serving uber-bureaucracy within British Universities. Research looking for better treatments, which would once have been up and running within a month or so, is now required to jump through numerous, seemingly arbitrary, local hoops.

In the UK, the new bureaucracies have tagged themselves onto the longstanding [and highly commendable] ethics process. But whereas the ethics committee rightly puts the patient and patient safety above all, these new regulatory bodies have little concern with the patient or with medical science. Their only concern is governance of the paperwork – wrong form, wrong version number, needs additional sign off etc. – driven perhaps by the fear of an inspection by another bureaucratic body, higher up the bureaucratic food-chain, and so on.

The new bureaucrats show their mastery of the arts of pedantry in those cases where the researchers believe that the protocol could benefit from a subtle amendment; for example, a request to roll out the availability of a promising new treatment to a wider geographic area. But at this juncture the uninitiated young researcher should prepare for interminable delay, much cross-checking of documents, submissions, gentle scoldings and re-submissions! Eventually, hopefully that happy day will come, [ideally before the end of their university contract or the drug-expiry date], when the paperwork has met the stringent demands of the local apparatchiks, and can finally be presented for a re-hearing at the ethics committee proper – who usually pass it that same day without fuss.

The real sadness is that the University bureaucrats recoil instinctively from the creative solution, the quick-fix, even if it is aimed at “helping to speed up the development of new treatments“, to borrow the typical phraseology from the ever-expanding media office [another growth area in our Universities and hospitals]. It is also of little use in explaining to the bureaucrat that experimental therapeutics proceeds in a trial and error fashion, and that flexibility is to be desired in the interests of progress, as evidenced by the history of clinical psychopharmacology [and medicine as a whole]. The naivety is the hope of working together with the bureaucrat, to find a quick solution. But the bureaucrat cannot move away from procedure. The bureaucrat is inflexible at all times, in all situations, by definition.

So the new reality is that paperwork governance has become more powerful than the medical science it was originally set up to support. Reform is needed, mainly for the sake of those patients who continue to suffer from psychiatric disorders and who don’t get better with existing treatments. The stalling of progress in psychiatric therapeutics, the stalling of hope, not on grounds of concern for participants or because of technical risk, but rather on arbitrary, locally-set, self-serving bureaucratic grounds, is an affront to those patients – and has reached the threshold of being an ethical issue in itself.

Oscar Wilde — ‘The bureaucracy is expanding to meet the needs of the expanding bureaucracy.’

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

A recent 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 impact & lucre must stay “on message” and above all, never stray into the chaos of imperfect methods and noisy data.

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“.

Why NMDA drugs keep failing in schizophrenia.

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


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.

Modafinil to boost academic performance: Effective, Addictive, Cheating?

Originally marketed as a wake-promoting agent, modafinil is a prescription drug that is said to boost cognition in healthy subjects. As such it’s use has spread amongst college students cramming for dreaded examinations. Anecdotal reports are of enhanced focus, clarity of thought and intellectual stamina; attractive properties for those hoping to secure a competitive edge for themselves.

But how do the pro-cognitive effects of modafinil stack up in proper scientific studies? Is modafinil addictive? And what ethical stance should be taken on the use of performance-enhancing agents in academic life?

Does modafinil enhance cognitive performance?

The first laboratory-based study of modafinil (single dose 100 or 200mg) in 2003 showed that it had clear pro-cognitive properties. Since then a further six studies have been in agreement, with performance enhancements in the domains of working memory, cognitive flexibility and planning.

A recent and elegant study carried out in Cambridge involving 64 healthy participants between the ages of 19-36 is illustrative [Muller et al 2012]. Participants were randomly allocated to receive modafinil (200mg) or placebo under experimental conditions, two hours ahead of a cognitive challenge. In addition to the usual measures of memory performance, task enjoyment was rated.

Performance in planning/problem solving under modafinil v placebo

The modafinil group achieved success with fewer choices in a task requiring cognitive planning. Performance enhancement was most apparent at the highest level of difficulty. Error bars are SEM.
From: Muller et al Neuropharmacology 64 (2013) 490-495.

The main findings were that the modafinil group out-performed the placebo group on tests of working memory, planning and pattern recognition memory. These improvements were more prominent as the cognitive tasks became more difficult.

And for the first time, it was shown that modafinil boosted enjoyment during the testing.

The authors postulated that the enjoyment could have arisen from the sense of satisfaction at task mastery or instead be the result of heightened motivation as a direct effect of the drug – surely now a topic for further study.

Is modafinil addictive?

The behavioural pharmacology of modafinil appears to stem from inhibition of the dopamine re-uptake transporter (DAT), akin to the mechanism of the classic [and addictive] stimulants, cocaine and amphetamine. However modafinil is a relatively weak inhibitor of DAT.

raclopride PET following modafinil

PET images of the human brain showing that compared to placebo, modafinil reduces raclopride binding in the striatum. The reduction in raclopride binding is indicative of dopamine release. Volkow et al (2009) JAMA 2009 301:1148-54

There are a number of behavioural differences between modafinil and the classical stimulants. Perhaps most notably, modafinil has a very low propensity for abuse (Wisor 2013). Indeed there was some hope that modafinil might actually constitute a treatment for cocaine/amphetamine addiction, but the findings to date in clinical trials have been disappointing.

Does the use of modafinil for exam revision constitute cheating?

Modafinil certainly confers a cognitive advantage, at least in the short term. And the downside in terms of addiction appears to be negligible, despite the pharmacological similarities of modafinil to ‘hard drugs’ such as cocaine and amphetamine.

The differences in cognitve performance under modafinil may be slight, and only apparent as the demands of the task increase. But isn’t this similar to the highest levels of sport, in which performance enhancing substances confer a critical edge as the competition reaches a climax.

The ethics of ‘smart drugs’ is complex [unlike the pharmacological questions above, which in contrast, can be settled by experiment, as well as reason]. One could argue that personal choice is all that matters. Surely the individual student should make their own judgement on whether to use, or abstain from, cognitive enhancers?  But is it only a personal matter? A decision to use smart drugs has a potential impact on the competition, the rest of the field. Is the use of modafinil, and the like, nothing other than cheating?