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Stimulating Approaches to Depression

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By Paul B. Fitzgerald

New forms of brain stimulation are offering hope to a substantial group of depressed patients who don’t get better with standard medical and psychological treatments.

Jamie is a 33-year-old married mother of two who has suffered recurrent episodes of depression since the age of 16. Initially these episodes would respond slowly to psychotherapy and anti­depressant medications like fluoxetine (Prosac) and venlafaxine (Effexor). These act by increasing brain chemicals like serotonin and noradrenaline. The depression would resolve only to return a year or two later, requiring an increased dose of medication or a change of medication.

However, over the past 2 years her depression has not gone away. Her psychiatrist has tried increasing medication doses, changing antidepressants, combining antidepressants and even adding antipsychotic medications – all to no avail. Jamie has become increasingly desperate and despairing, and less able to be distracted from her thoughts of suicide.

Her psychiatrist, also increasingly concerned, feels the only option now is electroconvulsive therapy (ECT). Jamie and her family, whose views on this have been formed mainly by films such as One Flew over the Cuckoo’s Nest, are horrified at the thought.

This scenario and ones like it are surprisingly common. Depression affects almost one of five Australians throughout their life and about 6–7% every year. Many of these patients get better with medication and psychotherapy but many don’t: almost one-third won’t get better over a couple of years of treatment, with many of these having persistent symptoms over many years.

ECT is the only well-established treatment for treatment-resistant depression. However, its use is limited by the requirement for multiple general anaesthetics, memory-related side-effects and substantial community stigma and opposition to the treatment.

For this reason there has been a substantial focus in recent years on developing alternative approaches to the treatment of depression. Many of these have exploited growing knowledge about the brain processes involved in depression, with an extensive number of brain imaging studies identifying a series of brain regions that are abnormally active in patients with depression: some overactive and some underactive.

Another focus of research has been the development of a series of new ways of directly modulating brain activity. Here, neuroscientists are increasingly developing methods using electricity, magnetic fields and even ultrasound and near-infrared light to potentially change brain activity. These methods are being adapted to the potential treatment of disorders such as depression, markedly broadening the scope of treatment options.

The therapy that is currently most advanced is a technique known as repetitive transcranial magnetic stimulation (rTMS), which involves the repeated application of a strong pulsed magnetic field to a focal area of the brain. When a time-variable magnetic field is applied to material that conducts electricity, such as the nerve cells of the brain, a current is induced. If the magnetic field is of sufficient strength it will directly trigger the firing of a group of nerve cells under the stimulation coil. By repeatedly making nerve cells fire, the activity of a local brain region and the strength of its connections to other brain regions can be altered.

Psychiatrists interested in this technique initially identified the left dorsolateral prefrontal cortex as a likely therapeutic target. This region, at the front of the brain, is underactive in depressed patients and is connected to most other brain regions linked to depression. Studies conducted over a 15-year period using a type of rTMS that increases brain activity have consistently demonstrated antidepressant effects. This has led to approval of the technique for clinical use in Canada, the US and throughout Europe. The first publically funded clinical rTMS service in Australia commenced operation at the Alfred Hospital in Melbourne in 2012.

Despite increasing clinical use of rTMS in depression, considerable research remains underway into this technique. Trials are being conducted to test whether coils that stimulate deeper in the brain will have greater benefits, while other research aims to try and identify which patients are most likely to respond to rTMS treatment. Studies are also evaluating the therapeutic use of rTMS across a number of other disorders including schizophrenia, autism, addiction and Parkinson’s disease.

A second brain stimulation approach to the treatment of depression harks back to the 1870s when German doctors pioneered the use of various low voltage electrical stimulation therapeutic approaches. Forms of non-convulsive electrical stimulation were somewhat revitalised in the mid-20th century, but again fell from favour as the psychopharmacological revolution in psychiatry got underway.

Over the past 10 years, transcranial direct current stimulation (tDCS) has become the focus of intensive interest and research. This technique involves the stimulation of brain regions with low amplitude (1–2 mA) current passed directly between an anode and cathode placed at relevant points on the scalp. Studies have shown an increase in brain activity under the positive electrode and the opposite under the negative electrode. Early studies indicate that anodal stimulation of the left prefrontal cortex has antidepressant activity, although large multi-site and longer-term studies are clearly required.

Interestingly, the beneficial effects of tDCS may not be limited to mood disorders. Research has consistently shown the capacity of tDCS to temporarily improve cognitive functions, such as specific types of memory. Studies are underway to translate these findings into a therapeutic approach for dis­orders characterised by cognitive dysfunction, such as schizophrenia, Parkinson’s disease and head injury.

A third novel brain stimulation approach is more invasive but still has some potential advantages over traditional ECT. Magnetic seizure therapy (MST), like ECT, involves the deliberate induction of a modified seizure under general anaesthetic. During MST, the seizure is produced by stimulating the brain with a strong magnetic field using a modified rTMS machine (unlike ECT, which uses an electrical current to achieve the same goal).

The potential advantages of magnetic rather than electrical stimulation are significant. When an electrical current is applied to the head, a considerable proportion of the current passes around the head as the resistance of the skull produces widespread and non-focal stimulation. In contrast, a magnetic stimulus passes into the brain without resistance and can be applied much more precisely. This means there is no direct stimulation of deep brain structures involved in memory, and hence there is a more benign side-effect profile for MST – while ECT can induce memory-related side-effects, these don’t seem to occur with MST. Although MST does appear to have anti­depressant effects, studies still need to establish whether these are of the same magnitude to those achieved with ECT.

The most invasive of all forms of novel brain stimulation involve some form of operative procedure to implant stimulating electrodes. During vagal nerve stimulation, a device similar to a pacemaker stimulates electrodes connected to the vagus nerve in the neck. Signals passing back into the brain through the vagal nerve seem to have the capacity to produce some antidepressant effects, although the magnitude of these is quite modest and this has limited clinical uptake.

A second approach, only really explored to a very limited degree so far, involves the stimulation of the brain through arrays of electrodes placed on the brain surface.

Going beyond this, deep brain stimulation (DBS) involves the implantation of stimulating electrodes directly into relevant areas of the brain. DBS approaches have been used for disorders such as Parkinson’s disease, where stimulation of basal ganglia structures can modify movement symptoms.

Studies investigating the use of DBS in depression have targeted several regions identified by brain imaging experiments or used in past psychosurgical approaches to psychiatric disorders. A small but consistent series of studies has supported the therapeutic use of DBS targeted to white matter adjacent to the subgenual anterior cingulate, and other studies are probing the use of DBS applied to the nucleus accumbens or ventral striatum.

Due to their invasive nature, DBS approaches are likely to be restricted to the most severely unwell and non-responsive of patients. One potential advantage is that if patients respond to treatment, the application of DBS is ongoing and relapse rates in follow-up studies to date seem low.

Despite the range of these approaches, they are just the first wave of methods under development. Researchers are currently developing or investigating methods of brain stimulation that involve the use of low intensity magnetic fields, ultrasound, near infra-red light and even light stimulation of genetically modified neurones (optogenetics).

Laboratory studies have already established that neurones may be stimulated with a number of these technologies. For example, ultrasound appears to stimulate neuronal activity by opening specific chemical channels on nerve membrane at levels of ultrasound stimulation that do not heat tissue.

It is unclear how low intensity magnetic fields interact with neuronal tissue, but nerve cells do contain small amounts of metals that are potentially manipulable by magnetic fields.

Optogenetics uses viral vectors to insert light-sensitive proteins into nerve cell membranes. When these nerve cells are exposed to specific frequencies of light, the proteins open pathways in nerve membranes, causing nerve cells to fire. Optogenetic applications have been developed in animal models, although there will be considerable challenges translating this research into human applications.

Other new approaches proposed involve the activation of brain regions by stimulating other aspects of the nervous system, such as branches of the vagal or trigeminal nerves or the caloric system in the inner ear. These nerves can be stimulated as they are close to the surface of the skin, and stimulation sends signals back into the brain and can potentially modulate brain activity.

Presumably only a very limited number of all of these techniques will ultimately make their way through development and clinical trials into widespread use. This process will be dependent on the science but also a range of commercial and clinical realities. For example, the progress of the development of tDCS is likely to be hindered by the lack of patent protection and hence commercial investment in this technique currently, an issue that slowed the development of rTMS. Clinical uptake of some of these techniques will require the development of new clinical infrastructure, the cost of which may also be limiting.

A final challenge and opportunity lies in the clinical difficulties found in comprehensively establishing the effectiveness of any antidepressant strategy. Most depression researchers now see it as a heterogeneous syndrome that is probably made up of a number of different types of depression. This variability is likely to have contributed to the difficulties faced in anti­depressant drug development, with response rates to medications often quite limited and not much greater than placebo.

Evaluating these new brain stimulation methods in a similar unsophisticated manner is also likely to be problematic. However, if researchers can combine the development of these techniques with improved understanding of the brain dynamics involved in depression and the effects of brain stimulation on brain networks in patients, they will be better able to target treatment and individualise treatment approaches.

So where does all this leave Jamie? She currently has few more options unless she lives in one of the places where rTMS is becoming available. However, over the coming years, patients like Jamie are likely to have the option of exploring non-invasive techniques like rTMS and tDCS quite early in their illness, and certainly when there are signs that medication is not producing a response.

The choice of the type of treatment and its method of application may well be personalised using brain imaging methods such as functional magnetic resonance imaging. If she does not respond to these, MST or some derivative of it may be a safe and effective alternative to ECT. If she remains depressed and struck in her illness she may have the option of DBS and related approaches.

Hopefully these developments will mean that the burden of suffering produced by depression and related illnesses will be progressively ameliorated over the coming years.

Paul B. Fitzgerald is a Professor of Psychiatry at Monash University and The Alfred Hospital in Melbourne. He has been utilising new brain stimulation approaches to study and treat psychiatric disorders for 15 years.