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?

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

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)                                                                    

Calcium dynamics & psychiatric illness.

calcium transientsThe alpha subunit of the L-type calcium channel (CaV1.2) is encoded by the gene CACNA1C. An apparently obscure protein, CaV1.2 has risen to prominence in the last five years.

Several large scale genome-wide association (GWAS) studies are in agreement that variation in CACNA1C is associated with bipolar disorder and schizophrenia. Additionally, mutations in CACNA1C are a direct cause of autism. As a consequence, Ca2+ signalling has begun to receive attention amongst psychiatrists.

A recent review by Michael Berridge is the ideal introduction to Ca2+ dynamics. Calcium does not only enter cells via channels. There are intracellular stores, which can be stimulated to release Ca2+ into the cytosol. Neurotransmitters such as serotonin, noradrenaline and glutamate can invoke the release of Ca2+  from intracellular stores by way of an intermediate 2nd messenger pathway, the phosphatidylinositol 4,5 biphosphate (PIP2) system. Berridge is best known for having deciphered the foundations of the PIP2 system in the 1980′s and as such he is an authoratative guide for the relevance of calcium signalling to psychiatric disorders.

The full paper is available here.

History repeats. Revelation ends up as show-business


The dorsolateral prefrontal cortex (DLPFC) and frontal eye fields (FEF) are larger in people who spend more time playing video games.

An elegant new study has revealed that video game enthusiasts have an enlarged (left) dorsolateral prefrontal cortex [DLPFC]. This is the region of the brain which is believed to organise and plan mental activity, the central executive. It appears that we can choose to expand our central executive by practice, much in the same way that a muscle responds to repetitive exercise.

But is there really anything new? The brain is plastic at multiple levels. Synapses and circuits are moulded by the environmental information which they process. For instance the part of the brain which processes music is known to enlarge in people who develop musical expertise. Cortical thickness is not predestined. Instead, the cortex is a dynamic structure upon which an impoverished (or enriched) environment will impact. The brain/mind assembles it’s world and is assembled by the world – essentially a Hegelian insight.

The findings from this new study should caution those repeated efforts to reveal something about psychiatric patients on the basis of the size/thickness of their prefrontal cortices. There are many variables, aside from psychiatric diagnostic status [itself an art rather than a science], which determine the size/thickness of the cortex. The irony of course is that such a trivial, mindless pastime as playing video games can enlarge the physical correlate of what is usually regarded as a higher mental faculty.

The full paper can be read here.

Zapping the Blues: The effectiveness of magnetic and electrical stimulation for treatment-resistant depression.

Blake glad day

Treatment-resistant depression (TRD) affects 1-3% of the population. Recently Holtzheimer & Mayberg reviewed the effectiveness of a range of new and promising techniques based on direct neural stimulation. The list includes Transcranial magnetic stimulation, Transcranial direct current stimulation, Magnetic seizure therapy, Vagus nerve stimulation and Deep brain stimulation.

The prototype of course is ECT (electroconvulsive therapy), which is a highly effective treatment for melancholic depression, but suffers from the effects of a negative historical portrayal. The authors present a balanced and elegant appraisal of the current state of affairs for the new techniques which can be read here in full. The summary points are as follows…

Transcranial magnetic stimulation (TCMS)

- FDA (US food & drug administration) approved.

- Uses rapidly alternating magnetic fields to induce current in the underlying cortex.

- 10 to 30 treatment sessions over 2-6 weeks.

- Controlled trials have been positive.

- Response rates in TRD: 20-40%.

- Remission rates in TRD: 10-20%.

- Repeated courses may maintain initial benefits.

Transcranial direct current stimulation

- Delivers a low-intensity direct current to the underlying cortex.

- 5 times per week treatments for several weeks.

- Fewer side effects than TCMS?

- Antidepressant effects claimed from a small number of open and controlled studies.

- Response, remission & relapse rates are unclear.

Magnetic seizure therapy

- Seizures are induced using a transcranial magnetic stimulation device.

- Antidepressant effects from a small number of open studies.

- Claims for less side-effects than ECT, but may be less effective.

Vagus nerve stimulation

- FDA (US food & drug administration) approved.

- Electrical stimulation to the left vagus nerve through an implanted pulse generator.

- Open-label response rates in TRD: 30-40%.

- Open-label remission rates in TRD: 15-17%.

- No evidence for efficacy in a large controlled study.

- Simple surgical procedure.

Deep brain stimulation.

- Precise neurosurgical implantation of electrodes using stereotactic techniques.

- Remission rates in TRD: 40-60%.

- Relapse in remitted patients is uncommon.

- Complex surgical procedure.

Holtzheimer & Mayberg conclude, “Neuromodulation for depression is at an exciting and promising stage of development, and continued well-conducted research will help clarify and realize its potential“.


Ketamine for resistant depression: Outstanding promise, outstanding issues.

Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it's powerful antidepressant properties (Berman et al 2000; Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it's beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism

Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).