Calcium dynamics & psychiatric illness.

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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

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DLPFC

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.

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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.

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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).

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“