Depression treatment: ketamine and biological effects

Along with talking therapies, pharmacological approaches are often used to tackle depression. Selective serotonin reuptake inhibitors (SSRI's) are often a first choice for depression treatment, and while they work well for many people with depression, oftentimes they don't. When they are effective, SSRI's typically take weeks to kick in (an interesting recent paper has suggested a possible reason why).

But other drugs are being used to fight depression. Although ketamine is known as a drug of abuse, it is also used for a number of medical purposes, including as an anaesthetic. However, at sub-anaesthetic doses, ketamine may also have antidepressant effects. For psychiatrists and their patients, the exciting aspect of ketamine is that it has a positive effect in many patients who do not respond to other antidepressants, and this alleviation of depression has been evident within a matter of hours rather than weeks. The downside is that this positive effect may not persist for much longer than a week, so repeated doses may be required to maintain the effect.

What may be driving the effect of ketamine? It has been suggested that brain-derived neurotrophic factor (or BDNF for short) may play a role in depression. BDNF is used in the maintenance and function of neurons, but chronic stress may reduce BDNF levels, and this could act as a mechanism through which long-term stress leads to depression. Previous evidence has indicated that ketamine treatment can increase BDNF in people whose depression is alleviated by the drug. However, this previous study just looked a single dose.

A recent study from our group looked at multiple doses of ketamine, to examine whether multiple doses would lead to comparable effects on depression, and also on BDNF. Patients were recruited who had failed to respond to first-line pharmacological therapy-even after the time it would take to show an effect these classic antidepressants, they were still depressed. Ketamine was administered under controlled conditions, with doctors supervising patients for a sufficient length of time to ensure patients would be protected from any potential adverse effects. Patients reported on their levels of depression before and after three doses of ketamine, and blood samples were taken at these times to assess patient's levels of BDNF.

We defined a clinical response in depression severity as a 50% or more reduction in scores on the Hamilton Depression Rating Scale, a widely used scale for quantifying depression severity. Ketamine significantly improved depressive symptoms in a majority of patients, both after two hours and one week later, and this was the case after each dose. (It should be noted however that not all patients continued with a second or third dose).

As had previously been shown, BDNF was reduced in those suffering from depression at baseline compared to healthy controls. Ketamine increased BDNF at one week after the first dose in those patients whose depression was alleviated by ketamine. However, this rise in BDNF did not occur after a second or third dose. So, although ketamine was keeping depression levels down for most of these patients, BDNF was not showing a persistent increase that mirrored this. The results, in this case, did not seem to support the idea that changes in BDNF goes hand-in-hand with an alleviation of depression.

As a comparison, we also looked at depression levels and BDNF in response to electroconvulsive therapy* (ECT), which is also used to treat depression in people who have not seen improvement after first-line treatment. Again, ECT was administered under controlled conditions, with patients being monitored for any side effects. Similar to ketamine, ECT reduced depression in the patient group. ECT did not increase BDNF at a one-week follow-up, although previous evidence has suggested that BDNF may be increased one month post-ECT.

Future research may tell us more about how ketamine has the rapid impact that it does upon depression. Understanding these mechanisms in greater depth may ultimately allow for treatments which target these mechanisms more specifically, thus minimising the risk of side effects.

Allen, A.P., Naughton, M., Clarke, G., Dowling, J., Walsh, A., Ismail, F., Shorten, G., Scott, L., McLoughlin, D., Cryan, J.F., Dinan, T.G. (in press). Serum BDNF as a peripheral biomarker of treatment-resistant depression and the rapid antidepressant response: A comparison of ketamine and ECT. Journal of Affective Disorders. doi: 10.1016/j.jad.2015.06.033

*I should note here that although ECT has had a very negative portrayal in some classic films, ECT as it is administered today is not only effective, but is also not the painful experience one might see in a film, as patients are prepared by being given an anaesthetic and muscle relaxant before the procedure. Nonetheless, like other treatments for depression, it is still associated with the risk of side effects.

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