Clinical trials of game-like software designed to re-programme the brain and tackle some of the most intractable symptoms of schizophrenia could usher in a new way to treat a range of neurological diseases
Despite effective pharmacological treatments for the positive symptoms of schizophrenia such as hallucinations or delusions, many people with the disease remain debilitated by negative symptoms like social withdrawal and apathy.
Effective drug treatments for negative symptoms – which can make it hard for patients to live independently of supportive care – have proved elusive. Now, however, help may be at hand in the form of game-like software that trains schizophrenic patients to overcome these cognitive and social deficits.
Effective drug treatments for negative symptoms of schizophrenia … have proved elusive
Many of us will be familiar with the brain-training programmes sold for games consoles, and the underlying principles are the same in the use of software to treat schizophrenia and other central nervous system diseases.
The premise relies on the concept of 'brain plasticity', which holds that the brain can change its circuitry through learning, practice or experience at any stage in a human's lifespan, from infancy through to older age – in both health and pathological disease states.
Training using software can exert structural, functional and chemical changes – at every level of organisation in the brain, according to Dr Henry Mahncke, chief operating officer of Brain Plasticity Inc (BPI), the company developing the schizophrenia treatment software.
“What we've learned in the past 30 years is that learning new skills or facts leads to changes in the brain at the molecular level all the way up to very high levels of organisation, for example how areas of the brain are interconnected,” he says.
Seeking FDA approval
BPI was formed to develop clinical applications of brain-training programmes and recently initiated clinical trials in the hope of securing a first in the brain-training sector: approval by the FDA as a medical device.
The company is focusing initially on schizophrenia because it has become clear that cognitive elements are a core component of the disease, and not a by-product of the positive symptoms or secondary to the drugs used to control them as was thought previously.
“If a patient's positive symptoms are controlled with antipsychotic medications, it often becomes apparent that the cognitive elements are the main determinant of overall outcome,” according to Mahncke.
If these are addressed, living independently, making friends and holding down a job, for example, become much more attainable, providing a dramatic increase in the patient's quality of life.
Mahncke believes that the brains of schizophrenics are compromised in their processing of information – a bit like a radio that is slightly out of tune with a station so the sound is affected by static – affecting patients' attention, memory and decision-making.
“We're trying to build a set of exercises based on our understanding of brain plasticity that will be appealing for schizophrenia patients and help them improve the quality of that information processing.”
For example, one element of BPI's software is an exercise that trains patients to process auditory information by playing two short sounds and asking the subject to identify which came first, which is a fairly hard task for a patient with the processing impairment seen in schizophrenia. The software adapts to the patient's progress so the task becomes progressively harder, with the sounds played more closely together and harder to discriminate.
Independent academic investigators at the University of California San Francisco (UCSF), as well as Duke and Columbia Universities, carried out pilot studies that provided initial indications that the training software was having a positive effect on patients.
Using IQ tests as an analogy, Mahncke notes that a typical schizophrenic would have a score of around 70 and according to the pilot study results could hope to gain a 10-point improvement, in some cases maintained for six months after the training period ended.
We're trying to build a set of exercises … that will be appealing for schizophrenia patients …
“That's a substantial and clinically significant improvement, though at the same time it is clear that we are not returning patients to normality,” he points out.
The subjects underwent around 40 hours of training over two months in the pilots, and BPI wants to see if longer-term training can provide additional benefits.
To that end, the company approached the National Institutes of Health for funding to carry out a larger multi-site study involving 150 patients at a dozen sites around the US and making use of recognised endpoints for cognition as well as functional measures of a person's ability to carry out everyday tasks that are the same as those used in pharmaceutical studies.
That trial – Cognitive Adaptive E-treatment in Schizophrenia-diagnosed Adults (e-CAeSAR) – has just got underway thanks to a $3m grant and, depending on patient enrolment rates, could complete in 18-24 months with results available in 2014. Each subject would receive around six months of training according to the protocol.
Rather than being delivered over a set period, perhaps more realistically this type of training could become part of a schizophrenic patient's routine life “in much the same way as someone might go to the gym to stay fit”, he suggests.
A lot is riding on the outcome of the study programme. There are many organisations proffering brain-training programmes in the marketplace, but opinion is divided as to whether they confer any meaningful and/or long-lasting benefit in terms of cognitive enhancement.
For example, a 2010 study in Nature (Vol. 465, 775–778) using subjects split into three different test groups found that regular computer-based training improved the performance of subjects on the tasks they practiced. The researchers found, however, that the gains were not transferrable to other untrained tasks, even if they were cognitively closely related.
Critics of the study have pointed out that the training in the study was fairly light and the participants were young, healthy people with robust cognitive function, but the findings nevertheless cast a shadow on the brain-training sector that has been hard to shake off.
For that reason, BPI is keen to rise above the debate on the back of hard data, and also to follow a recognised clinical development and regulatory pathway to get its software accepted as a prescribable medical device by the authorities and medical profession.
The technology would fit into patient care alongside drug therapy and the psychiatry and support teams, while being free of the adverse reactions and drug interaction issues that plague pharmacological therapies for schizophrenia.
The software is browser-based and can be carried out on any PC connected to the internet so could be delivered in clinics, doctors' surgeries or the patients' own homes.
BPI is a medical spin-off of Post Science, a company that focuses its attention on programmes to help maintain cognitive function in normal ageing, and schizophrenia is just one of the neurological applications that the company hopes to address with its technology.
“We have data already in healthy ageing that have suggested that this type of training reduces the risk of developing depressive symptoms,” notes Mahncke.
The technology would fit into patient care alongside drug therapy and the psychiatry team
“That's not to say we can treat depression quite yet, but does suggest we can arrest the process that leads it to occur in older adults, and that warrants further study.”
Among earlier-stage research projects ongoing at BPI in this area are attempts to delay Alzheimer's and Parkinson's progression, ameliorating attention-deficit hyperactivity disorder (ADHD) in children, remediation of patients suffering brain trauma, and treatment of anxiety and depressive disorders.
“All these conditions are linked by problems in brain organisation, and once we understand the problems I see no reason why we cannot design programmes to address them,” he adds.
“I think the future is wide open for this type of intervention.”
Phil Taylor is a freelance journalist specialising in the pharmaceutical industry.