Tag Archives: fMRI

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“

 

BD or not BD?

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The Bipolar Spectrum: can brain scans resolve diagnostic uncertainty?

The concept of manic-depression was extended some years back to cover less extreme manifestations characterised by hypomania (Bipolar II), as well as the classical form, defined by mania (Bipolar I). But other forms (perhaps less dramatic, though still a cause of much suffering) also exist.

These ‘softer’ forms of bipolar illness appear to blur into unipolar depression and perhaps also with the category which has been termed, borderline personality disorder. Although there has been a trend to view psychiatric disorders as points on a spectrum, rather than as discrete, encapsulated diagnoses, many psychiatrists would hesitate to equate borderline personality disorder and bipolar illness. Ultimately the matter will be resolved when we fully grasp the underlying neurobiology of affective disorders.

A new paper from researchers based in Sydney provides an authoritative and balanced account of the current state of our knowledge. The authors elegantly summarise the functional MRI literature across the hypothesised spectrum. One feature appears to be common across the various disorders – limbic hyperactivity. Perhaps this is not so surprising as the limbic system is the ‘seat’ of emotion, and all the various disorders/forms are characterised by emotional upset.

But there also appear to be differences. For example, the orbitofrontal cortex (a higher centre, which ‘dampens’ and regulates emotion) appears to be underactive in bipolar I, but not in unipolar depression nor in borderline personality disorder.

Further work will be needed before clear-cut conclusions can be drawn. The authors conclude…”Eventually, as the respective signatures of personality-based emotional dysregulation and bipolar mood dysregulation become increasingly crisp, we may be able to use functional neural profile to assist in clarifying diagnosis or treatment options in clinically muddy presentations, although a great deal of work will need to be done before imaging will be sufficiently robust to be used in this manner.”

The full paper can be read here:

http://www.expert-reviews.com/doi/pdfplus/10.1586/ern.12.126

 

New insights into how antidepressants work.

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fMRI scan.

It is well established that antidepressants take at least 2 weeks to shift a depressed mood. A new study from researchers at Oxford, reveals that the drug is working behind the scenes, much earlier than this.

People with depression are known to show an exaggerated response to pictures of human faces that are expressing fear. The response can be observed using functional MRI brain scanning. The part of the brain which lights up is their own 'fear processor', the amygdala. The usual interpretation is that the depressed patient's fear system is unduly sensitive to anything from the outside world which signifies fear. And human faces elicit the most robust response.

Previous work had shown that standard SSRI antidepressants can dampen down the hyperactive amygdala, and return it's function to normal. What was unknown was whether the effect on the amygdala or the effect on mood came first.

The Oxford researchers have now shown that SSRI antidepressants dampen down the amygdala at least 1 week before the patient experiences a shift in their mood. They compared 3 groups of people: depressed patients who had been randomised to receive escitalopram (10mg); depressed patients who had been randomised to placebo; and a group of healthy controls. A week after being randomised to active drug or placebo, the depressed patients were given an fMRI scan.

The main finding was that the patients who had been taking escitalopram for a week had normal amygdala responses to pictures of fearful human faces. In contrast, the patients on placebo showed the characteristic hyperactive response in the amygdala on the right hand-side of their brains (see scan above). Notably, 1 week was too early for any antidepressant effect – Treated and untreated patients were equally depressed at this stage.

This is an important finding, which shows that SSRI antidepressants affect how the brain processes emotional information before the patient feels an improvement in their mood.

Further studies are planned. One key goal will be to assess if the degree of amygdala dampening at 1 week can distinguish between patients who ultimately get better from those who will remain depressed. The technology might even be used in selecting the 'best' type of antidepressant drug for a particular patient, rather than having to adopt a 'wait and see' approach.

The full paper can be read here

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488813/