Tag Archives: major depressive disorder

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“

 

Natural antidepressants & new brain cells

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New Brain Cells

In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.

hippocampus from nieuwenhuys et al

The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.

Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.

 

Natural Antidepressants

There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.

curcumin

Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.

A new paper from researchers at King's College London provides an excellent summary of work in this area. The full paper can be read here.

 

Complementary Treatments for Depression

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Exercise, meditation and nutritional supplements in depression: Helpful or not?

Since 1965 it has been clear from clinical trials that antidepressant medications are effective in major depression. However many patients are not keen to take tablets, expressing a wish for more 'natural' forms of treatment. Numerous alternative treatments have been advocated, but is there any evidence that any of these work? Here we briefly review the case for physical exercise, meditation (or mindfulness, as it is now known) and several nutritional supplements.

Alternative treatments as a group can often be criticised because they do not subject themselves to rigorous trials, as is the case with conventional treatments (pharmacological or psychological). This criticism is valid. Indeed it is only within the last 60 years that conventional medicine itself has demanded clear demonstrations of efficacy before a treatment can be licensed for a particular illness. The randomised, double-blind control trial (RCT) is the gold standard by which efficacy is judged. Until recently, very few alternative treatments were subjected to the strict demands of the RCT. But this is changing.

Is physical exercise beneficial in depression?

There is now good evidence that a programme of physical exercise is an effective treatment for depression. Researchers in Brazil conducted a metanalysis in which the results from 10 separate trials were pooled to give an overall finding. (Metanalysis is a powerful method for deciding whether a treatment works. All available trials are scrutinised, and those with no control group or no randomised allocation to drug or placebo are usually excluded on the grounds of being poor quality studies).

stretching exercisesThe main finding from the Brazilian study was that moderate exercise (3 times per week) was effective in reducing depressive symptoms. Those patients who were older, and those with milder depression derived the most benefit. It made no difference whether the exercise programme involved strength-training or aerobic training, although the authors showed a preference for aerobic training. The authors concluded:

“The present meta-analysis concluded that physical exercise, mainly aerobic training, improves the response to depression treatment. However, the efficacy of exercise in the treatment of depression was influenced by age and severity of symptoms“.

The full paper can be read here.

Meditation (Mindfulness)

Mindfulness is a currently fashionable psychological approach for the treatment of depression, which has its roots in eastern meditation techniques. The various traditional schools of meditation differ in flavour, but all centre on the idea of mastering an unruly and restless mind. Mindfulness training involves short sessions in which the aim is to direct consciousness towards full immersion in the activity at hand, rather than on the mind's incessant chatter. But does it work?

meditation candle

A recent review from the US attempted to tackle this question. However the authors were unable to reach a definitive conclusion. At present there are not enough studies, of sufficient quality, to yield an answer. They point out that further (and more robust) trials are needed, but they regard mindfulness as a promising approach to depression. They remark:

“Regardless of the various limitations present in the available literature, findings to date have consistently demonstrated that training focused on improving attention, awareness, acceptance, and compassion may facilitate more flexible and adaptive responses to stress“.

The full paper can be read here.

Nutritional Supplements

Vitamin deficiencies (especially B-vitamins) can cause neuropsychiatric disorders, although this is very rarely seen now in developed countries. But the idea of supplementation is to provide additional quantities of a specific nutrient in an effort to obtain a therapeutic effect. Three nutrients in particular have attracted attention as possible treatments for depression: folic acid, S-adenosylmethionine (SAM-e) and omega-3 fatty acids. A recent Canadian paper has reviewed the evidence.

nutritional supplements

Omega-3 fatty acids (fish oils) have been shown to possess antidepressant properties in a metanalysis of 16 trials. SAM-e has also been shown to be effective in a metanalysis of 7 trials. The evidence in support of folic acid has been more limited. One of two trials was positive and further work is needed. The authors conclude:

“Physicians should consider screening for and treating folate deficiency but the benefits of folate supplementation remain unclear. Limited evidence supports the use of omega-3 fatty acids and S-adenosylmethionine, but further research is required“.

The full paper can be read here

 

 

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