Rebecca Wright was 23 and just starting grad school when she first thought about how to end her life.
She had been diagnosed with depression six years earlier, and had no reason to suspect the diagnosis might be wrong. “I felt confused and very alone,” she remembered. “At the time I identified myself as depressed. It’s a household term. People use the word and talk about it, so it wasn’t hard to think, ‘Well this must be depression.’ But as well as sheer numb exhaustion, I would have periods where every cell in my body seemed to be zapping with electricity.”
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As she found out later, Wright had been misdiagnosed for years with unipolar depression when in fact she had bipolar disorder—a fundamentally different disease with a significantly different treatment regimen. It’s a tragically common mix-up made by many doctors, with 40 percent of all bipolar patients initially misdiagnosed this way. According to surveys, the average time until a correct diagnosis is reached is over 13 years. These misdiagnoses can be a contributing factor in suicide.
“People don’t realize how physical the symptoms are,” Wright said. “It’s simply horrifying to feel like this and have no idea why.”
However, an increasing number of scientists believe they can detect bipolar and other mental illnesses faster and more accurately than ever, and even predict them before patients develop symptoms.
The solution, these scientists say, is to screen for mental illness the same way you screen for glucose levels in diabetics, check for liver diseases such as cirrhosis or monitor cholesterol: with a blood test. But are such tests sufficient to diagnose diseases as complex as mental illnesses?
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For over a decade, scientists from California to Cambridge have been trying to develop diagnostic blood tests for mental illnesses. They find the idea of a lab test for disorders such as bipolar, schizophrenia, and depression tantalizing, as right now all are diagnosed entirely through standardized questionnaires checking for various symptoms. It has been suggested that identifying and screening for biological traces of these diseases could reduce misdiagnosis and the risk of patients being prescribed the wrong medications. These scientists see blood tests as both a way of improving patient welfare and an exciting business opportunity.
Professor Sabine Bahn is a psychiatrist who runs the Cambridge Centre for Neuropsychiatric Research. Five years ago, her research group developed the basis for the world’s first blood test for schizophrenia. The test was brought to market under the name VeriPsych through her spin-off company Psynova Neurotech and a Texas based biomarker laboratory called Rules-Based Medicine.
These scientists see blood tests as both a way of improving patient welfare and an exciting business opportunity
In November, her lab announced the discovery of a similar blood test for bipolar disorder, a unique fingerprint of 20 molecules called biomarkers which Bahn believes could be used to assist doctors in diagnosing the disease in patients aged between 18 and 35.
The particular quantities of these biomarkers are able to predict bipolar patients from healthy individuals with 90 percent accuracy, and 84 percent accuracy at distinguishing bipolar from unipolar patients, according to Bahn’s test. Perhaps most importantly, they appear capable of predicting the onset of bipolar disorder in individuals who were thought to be at risk of developing the disease, but had yet to display symptoms.
The potential social implications of such a test are wide-ranging. “There’s a lot of concern over people in highly stressful and dangerous jobs which also comprise a lot of responsibility,” said Dr. Flavio Kapczinski, one of the world’s leading bipolar researchers. “Airplane pilots or soldiers who have the propensity to develop bipolar or schizophrenia may be a risk to their colleagues and those in their care. The stress or traumatic nature of their professions could prove to be a trigger for the onset of the disease, with the potential for a lot of harm. If blood tests can be used as part of the screening process when hiring individuals, to detect whether they could be at risk, we may be able to prevent a lot of suffering.”
However, for this test to succeed it would have to forge new ground. While the VeriPsych schizophrenia test was brought to market in 2010 and was ordered by 30 clinical centres across the US, it was withdrawn three years later, after being acquired by the pharmaceutical company Myriad Genetics in 2011.
Myriad’s Chief Medical Officer Richard Wenstrup said that the decision to pull the VeriPsych test in 2013 was mainly because clinicians were more interested in having a test which could differentially diagnose schizophrenia from other mental illnesses such as bipolar, while the VeriPsych test could only detect schizophrenics from healthy individuals. As of 2016, the company says the test remains on hold while such options are being explored.
As a result, so far no blood tests for mental illnesses have managed to gain a permanent foothold in the clinic.
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Like many bipolar sufferers, Wright describes her childhood behaviour and feelings as fluctuating and volatile.
“As a child I was often angry and irritable at the drop of a hat,” she said. “I would be happy one second but then the slightest thing would make me angry. As a teenager, I was often very sad. I would cope by cutting myself which meant I was mistakenly diagnosed with depression at 17 and prescribed medication.”
Misdiagnosis often occurs due to these early similarities between the two diseases.
“There’s a delay between the first symptoms which occur between five and ten and the full-blown appearance of bipolar disorder which usually only happens in adulthood,” Kapczinski explains. “Until these signs occur, bipolar can appear almost identical to depression in the eyes of a doctor.”
Wright was eventually given a correct diagnosis. But those years of consuming drugs designed for a different disease led her to develop symptoms known as hypomania. Unless treated this can develop into severe mania or depressive episodes, the latter of which is linked to a much greater risk of suicide.
“Because the studies done at the moment are only based on a few hundred individuals, it’s not enough to be able to say that the test can be applied to the clinic.”
“A hypomanic episode feels as if I have static in my brain, as if I can’t hold on to a thought,” she said. “Adrenaline would surge through my chest. This makes completing any higher-level task really difficult, and almost painful, because it’s simply so difficult to think.”
Struggling to understand what was wrong, and attempting to deal with the demands of exams and assignments amid worsening symptoms, she began self-medicating with alcohol and slipped into a dangerous pattern of isolation. Now 26, she has been hospitalized five times in the past three years for suicidal ideations and forced to quit graduate school.
“I felt as though I was in a deep, dark abyss. So deep down that no one could possibly hear my cries,” she said. “People would ask me, ‘Why didn’t you call me? Why didn’t you ask me for help?’ But it wasn’t physically possible. All I was capable of was lying in bed and either sleeping or thinking of ways in which I could end it all.”
Like so many bipolar patients, Wright’s problems could have been helped by a much earlier, correct diagnosis. But with just a list of symptoms to guide them, many of which overlap between conditions, identifying the correct psychiatric disorder can be a minefield for doctors. Bipolar patients sometimes experience delusions which can lead to a schizophrenia misdiagnosis, while the intense negative mood episodes can be mistaken for depression.
Coming to the correct diagnosis depends heavily both on the doctor’s ability to ask the right questions and the patient’s ability and willingness to provide detailed and accurate answers. As a result, even after extensive enquiry, specialists may still fail to detect signs of both the distinct manic and depressive mood episodes which make it clear that the patient is bipolar.
“The crucial signs can be highly emotional memories which mental health patients may not want to talk about readily,” Bahn says. “It can take a long time to build up the necessary trust for them to confide in you.”
Bahn and other scientists around the world have been inspired to try and change the field by screening blood samples from hundreds of schizophrenia and bipolar patients, with the aim of detecting biomarkers, or subtle biological differences underpinning the behavioural and physical symptoms of these disorders which are different to healthy individuals.
But just how much can we trust the biomarkers that are found?
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In the aftermath of the VeriPsych schizophrenia test becoming commercially available, Psychiatric Times ran an article titled “Blood Tests for Schizophrenia and Depression: Not Ready for Prime Time.”
Five years on, most of the industry holds the same view. While Michael Maes, a psychiatrist who has researched depression for the past three decades, finds Bahn’s proposed blood test for bipolar disorder interesting, he doesn’t believe enough is known for it to be developed into a product.
In particular, in December, researchers at the Mayo Clinic reported a series of new biomarkers for bipolar disorder. However none of these overlapped with the biomarker panel Bahn’s group had reported a month earlier. Maes believes this comes to the heart of one of the main issues with blood-based biomarkers for psychiatric disorders: reproducibility.
The Bahn Laboratory. Image: Cambridge Neuroscience
“When you measure the levels of these molecules in the blood, you’re looking for a pattern of differences between bipolar patients and healthy or depressed individuals,” he says. “But in any person these molecules have a very small variability between one day and the next. And between any two people there’s a huge variability. Most of the inflammatory molecules which make up these tests have a huge variance across the population of bipolar patients. And because the studies done at the moment are only based on a few hundred individuals, it’s not enough to be able to say that the test can be applied to the clinic.”
Maes feels that the way to develop a reproducible diagnostic test for bipolar and other mental illnesses in future, is to combine the search for biomarkers in the blood with key differences seen in neuroimaging, genetics and epigenomics—the study of how environmental factors such as stress or life traumas can alter our genes, with potentially far-reaching consequences.
Such an initiative is currently underway in the US, led by the National Institute of Mental Health. The researchers heading this project believe that if it succeeds, it will reinvent psychiatry, but it will take time. Despite advances in DNA sequencing and functional imaging, Maes says that finding a way to identify and combine biomarkers from all these different fields is still a decade away.
But even if the ultimate diagnostic test is eventually developed by combining analysis of proteins in the blood with imaging, genetics, and behavioural information, it will not help bipolar patients live with and manage their disorder. However, obtaining a correct diagnosis can go a long way to helping them deal with it without undue suffering.
Wright knows the pain caused by undiagnosed bipolar disorder. But ten years on from her initial misdiagnosis with unipolar depression, she has now been able to find a combination of treatments which keep her suicidal urges under control. She returned to work, finding a job as a secretary and legal research assistant for an attorney in her home town. One day she hopes to re-apply to graduate school. But there are still ups and downs.
“It has taken years for me to figure out how to live in the world successfully with my disease,” she says. “Even now, when I have a depressive episode, even though the medications I take have reduced their frequency to a day or two once in a blue moon, I still sleep all day and communicate with no one. I’m in a stable place now though and I hope to lead to a productive life.”
