Last week’s announcement that a UK company won US approval for device-based treatment of depression is excellent news for taking academic findings into a clinical setting
Mood disorders such as depression are devastating to sufferers, and hugely costly to treat. The most severe form of depression, often called clinical depression or major depressive disorder (MDD), increases the person’s likelihood of suicide and contributes significantly to a person’s disability-adjusted life years (DALYs), a measure of quality of life taking into account periods of incapacity. The healthcare burden of MDD is large in most countries, especially when the person requires a stay in hospital. Putting these factors together, it’s clear we need to develop effective treatments to combat depression.
The mechanisms of depressive disorders are not well understood, and it seems likely that there is no single cause. Most modern therapies use drugs that target neurotransmitters – the chemicals that carry signals between neurons. For example, the class of drugs known as SSRIs, or selective serotonin reuptake inhibitors, prevent the neurotransmitter serotonin from being reabsorbed by a neuron; this means that more serotonin is available to wash around between the nerve cells, and is more likely to activate cells in the brain networks that area affected in MDD.
But SSRIs and other drugs are not a pharmacological ‘free lunch’. Drug treatments for depression are ineffective for many people, cause side-effects, and may lose their therapeutic effect over time. For these reasons, many researchers are searching for alternative treatments for MDD that overcome these problems, and are more effective or less unpleasant. One potential treatment involves the use of pulses of magnetic energy over the head to target the brain’s mood circuits. This technique, called transcranial magnetic stimulation (TMS), may potentially address some of the problems of pharmaceutical treatments, but we still don’t know exactly how it works, or how effective it will be in treating MDD.
Some of these mysteries may be close to a solution however, with last week’s news that a company based in West Wales was granted approval by the US Food and Drug Administration to enter the USA market for device-based treatment of MDD. The approval of the Magstim Company’s Rapid2 stimulator means that the stimulator can be used as a treatment option in adult sufferers of MDD who have not responded to other therapy- or drug-based treatments. Magstim’s products have long been used in universities and research centres to probe and modulate brain function, and approval of these devices for clinical use marks an important milestone in translational neuroscience - the idea of taking academic findings into the clinic.
TMS works by sending pulses of magnetic energy across the skull. These magnetic fields induce electric currents to flow in small patches of the brain of around one square centimetre, which in turn causes the neurons in that area to activate - these events take place over fractions of a second. For reasons that are not well understood, spacing out trains of these magnetic pulses leads to more durable effects, lasting for an hour or more after the stimulation - this is known as repetitive TMS, or rTMS. Repeated sessions of rTMS, given every day for several days, exploit the brain’s plasticity to change brain activity for many months. This gives neuroscientists a way to reorganise (never ‘rewire’) small brain circuits.
rTMS treatment for MDD targets the prefrontal cortex, usually in a spot a few centimetres above the corner of the left eye, called the dorsolateral prefrontal cortex (or DLPFC). The cells in this area connect to networks that project throughout the brain, and rTMS has both enhancing and inhibiting effects on distant brain regions. The full extent of these hubs and networks are poorly understood, but it seems clear that modulating the activity of the prefrontal cortex releases neurotransmitters deep in the ancient structures of the midbrain, in particular the caudate nucleus. In turn, these structures regulate our basic motivations and emotions. So by indirectly stimulating these regions, rTMS seems to correct the low mood and listlessness of MDD in some people.
Is rTMS the future of depression treatment? The treatment certainly looks promising, with increased remittance rates and seemingly few side-effects. Baseline depression scores may be reduced by up to a third according to some studies, although other studies are more cautious. It seems that longer courses of treatment, lasting several weeks, have greater effects - this suggests an additive effect of rTMS on the brain over time. However the uncertainties over the mechanisms of rTMS in MDD mean that neurologists will find it difficult to personalise treatment for an individual patient. The number of parameters involved in rTMS, such as the number of pulses to deliver, or the intensity of each pulse, make it difficult to specify precisely the dose required for a patient. Precision is also a problem in locating the exact target in prefrontal cortex for stimulation - each person’s brain folds in its own way, and missing the DLPFC even by a centimetre can mean the difference between a person being a ‘responder’ or a ‘non-responder’, in the stark language of psychiatry. Moreover, the physical sensation of rTMS, which can feel like a woodpecker tapping the head, makes it difficult to create a placebo condition for use in clinical trials.
rTMS is currently approved for use only in the USA, and only in a restricted group of patients. However it is likely that, with further research into improvements in efficacy and in understanding the mechanisms of the technique, we will see increasing use of rTMS as a treatment for this burdensome disorder. The entry of Magstim into this market offers clinicians a new avenue for people who may be running out of drug-based options, and marks an important milestone in taking knowledge gained in research and making use of it for the benefit of many.
This article was written by Nick Davis, for theguardian.com on Monday 18th May 2015 07.00 Europe/Londonguardian.co.uk © Guardian News and Media Limited 2010