Mind games

C&I Issue 9, 2014

Mental illness is a tricky subject, in more ways than one. While there are many chemical treatments – such as anti-psychotic drugs – there are currently no chemical tests to diagnose a condition such as depression.

But that is changing. Although the causes of mental illness are still not understood, researchers have found biomarkers that could help to diagnose conditions such as depression, schizophrenia and bipolar disorder.

This could lead to faster, more accurate diagnosis, ensuring that sufferers receive earlier, better targeted treatment. It could also help to remove some of the stigma associated with mental disorder.

The current method [of diagnosis] is interview-based, where we ask patients how they feel,’ says Sabine Bahn, head of the Cambridge Centre for Neuropsychiatric Research (CCNR) at Cambridge University, UK. ‘This hasn’t changed in 100 years.’

US company Myriad Genetics is working to commercialise tests based on patents held by CCNR. It says the first two – for bipolar disorder and schizophrenia – could be launched in the ‘mid term’ – not sooner than three years.

The tests rely on identifying 10-20 protein ‘biomarkers’ in the blood. These have been narrowed down using a number of ‘proteomics’ techniques, including mass spectrometry, glycoprotein profiling and analyte assay screening.

‘These approaches use technology that already has a track record of approval with the US Food & Drug Administration (FDA),’ says Bahn.

Bahn was earlier involved in the pan-European SchizDX project, whose aim was to develop a test for schizophrenia. The research was actually commercialised as VeriPsych, but later withdrawn from the market – because it was too expensive and not specific enough: it could distinguish schizophrenia from control patients.
Bahn stresses that tests will not lead to a simple yes/no diagnosis, like a pregnancy test. Instead, they may indicate that a patient is suffering from a particular condition – or may move from a ‘prodromal’ – early stage – condition to more serious mental disorder.

‘It’s an aid to a diagnosis,’ she says. ‘The main objective is to diagnose patients earlier, because we know this improves outcome.’

The most likely use for such a test would be in GPs’ surgeries – in combination with a patient questionnaire.

Further down the line, test results could also help psychiatrists to improve their treatments. For example, people with bipolar disorder often have depressive symptoms – but treating them with antidepressants can make their symptoms worse.

‘For this reason, a test for underlying bipolar disorder would be very useful,’ says Bahn.

Another positive use of such a test would be to offer reassurance to patients: many stop taking their medication if they feel it is not working. A chemical test could provide ‘proof’ that a particular medication is having an effect. It would also give doctors a chance to monitor the effect of a particular therapy – such as exercise, counselling or drug dosage.

Perhaps most significantly, a chemical test would ‘medicalise’ mental disorders – accounting for them in terms of altered protein levels in the blood. ‘Putting mental illness on such as biological basis could help to de-stigmatise it,’ says Bahn.

Platelet link

Blood platelets – which assist in the clotting process – might also be crucial in diagnosing depression. Researchers at the Medical University of Vienna, Austria, led by Lukas Pezawas, have devised a test that links levels of a neurotransmitter in blood platelets with a ‘depression network’ in the brain.

Serotonin transporter (SERT) is a protein that regulates levels of the neurotransmitter serotonin – often referred to as the ‘happiness hormone’ – in the brain. SERT is also the target for a number of antidepressant drugs.

‘SERT has been studied extensively in the brain,’ says Pezawas. ‘When you block it, serotonin increases in the brain and works as an antidepressant.’

But SERT is not only found in the brain. Large amounts also sit in the intestines, and in the blood – where it helps to regulate serotonin levels. By measuring the speed at which serotonin is transported into blood platelets – and taking MRI scans of the brain – Pezawas was able to demonstrate a link between the two.

‘We found a strong correlation between the take-up of serotonin and the activation of the depression network,’ he says.

The test links the speed of serotonin uptake in blood platelets with the activation of a depression network in the brain – called the default mode network (DMN). The DMN is usually suppressed during complex thought processes. However, patients with depression find it difficult to suppress it – meaning they are less able to concentrate, and more likely to ‘think in circles’.

Testing was carried out on 48 people, who had no history of mental disorders. They performed a series of specific mental tasks, which activated particular areas of the brain. But despite finding a correlation, Pezawas says that a usable blood test is some way off. Apart from the fact that it uses MRI scanning – which is too expensive and time-consuming for general clinical use – the study only gives a statistical link between serotonin in blood platelets and brain activation.

‘At the moment, it’s a proof of principle,’ says Pezawas. ‘It’s not been used on single patients.’

He says there are currently too many variants for the test to be applied to a single person.

‘SERT is acting as a pump,’ he says. ‘Sometimes the pump works faster, sometimes it is slower.’

He is convinced of the benefits of a blood test – not least because it would offer an objective way of assessing treatment.

‘You’d be able to measure an effect without asking the patient’s opinion – that’s why lots of people are doing experiments on biomarkers,’ he says.

Despite the obvious benefits of a chemical test for depression, neither Bahn nor Pezawas sees it as a replacement for traditional treatment – but as a complement to it.

‘A test will never be a substitute for talking to a patient, but it would provide useful additional information diagnosis and therapy in future,’ he says.

Alzheimer’s test

Meanwhile, UK researchers have identified a set of proteins in the blood that could help to predict the likelihood of developing Alzheimer’s disease.

This could lead to a blood test that determines which people with memory problems – known as mild cognitive impairment (MCI) – are likely to progress to Alzheimer’s disease.

‘The conversion rate from MCI to Alzheimer’s is about 20% per year. If we can identify people who are more likely to convert in the next year, they could be included in clinical trials,’ says Simon Lovestone, professor of psychiatry at Oxford University, UK, who led the research while at King’s College London.

Lovestone says that many Alzheimer’s drug trials fail because by the time patients start taking a drug they are too far advanced with the disease to respond to treatment.

‘A simple blood test could help us identify patients at a much earlier stage to take part in clinical trials, and hopefully develop treatments which could prevent progression of the disease,’ he says.

The progression from MCI to Alzheimer’s can currently be predicted: but it is done using either brain scans, which is expensive, or analysis of cerobro-spinal fluid from a lumbar puncture, which is invasive. Lovestone says that a blood test would be far cheaper and less invasive.

The researchers, from King’s College London and Proteome Sciences, used data from three international studies, analysing blood samples from more than 1000 individuals. They identified 26 proteins associated with brain shrinkage, in either MCI or Alzheimer’s (Alzheimer’s and Dementia, doi: 10.1016/j.jalz.2014.05.1749).

A second series of tests, to determine which proteins could predict the progress from MCI to Alzheimer’s, identified a combination of 10 proteins. The test has an accuracy of 87%, say the researchers.

It has taken nearly 10 years to identify the 10 proteins – although Lovestone says there is ‘nothing remarkable’ about them. He says there is more work to do in refining and validating the test, but he is hopeful that one could be ready ‘in a few years’.

Lovestone stresses that the test is geared towards people with MCI symptoms: it is not intended as a ‘screening’ test for people with no symptoms. This means it might also be used by doctors in ‘memory clinics’ – but the test would need further refinement in this case.

‘This would need much more work, to demonstrate that the test is repeatable,’ says Lovestone.

Tests like these, to help doctors diagnose mental disorders, would undoubtedly speed up diagnosis and improve treatment for sufferers. But conditions like ‘depression’ and ‘schizophrenia’ are actually very broad terms – making an understanding of them very difficult. ‘The term ‘schizophrenia’ is a bit like ‘fever’ – there is no known cause,’ says Bahn.

So perhaps these simple chemical tests – when they are ready – will help to cut through the complexity of these conditions, and bring early relief to people who suffer from them.

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