Currently, mental disorders are diagnosed by analysis of behavior and reports from the patient on their own thoughts. This way of diagnosing disease can be difficult, subjective and messy, particularly with regard to symptom overlaps between disorders. It also necessitates waiting until the disorder is fully manifest before the diagnosis can be made. Moreover, these disorders are heterogeneous, with wide variation in the abnormal behaviors within a given disorder, and very likely wide variation in genetic and environmental causes of the disorder. These are the reasons why we need biomarkers – objective, quantifiable, molecular signatures of each disease, and each type of disorder within a given disease category. It would be ideal to have a test that could be done on serum as is done for high cholesterol, which raises the concern for cardiovascular disease. Other possible sources of biomarkers could be urine or even fecal samples, all of which are non-invasive tests. MRI is another non-invasiv test of interest, but is very expensive. Taking samples of cerebral spinal fluid is both invasive and expensive, but is of course more relevant for the brain than are serum and urine.
A new paper from a multi-national collaboration provides what may be a first step towards “Identification of a biological signature for schizophrenia in serum”. While this title of the paper overstates the case, some progress towards this goal is reported. The authors measured the concentrations of 181 proteins and small molecules in serum taken from newly diagnosed schizophrenia (Sz) patients as well as serum from patients with major depressive disorder (MDD), bipolar disorder (BPD) and Asperger syndrome (AS). In one large group of Sz samples, they found that the levels of 34 molecules could be used to define or separate Sz from control serum – with high sensitivity (detect most of the Sz subjects) and high specificity (identify Sz subjects without mistakenly identifying controls as Sz). However, when they used this 34 molecular “signature” on 4 other groups of Sz subjects, they were able to separate only 60-75% of Sz subjects from controls. The sensitivity and specificity in comparing Sz against BPD was 86 and 78% (respectively). Comparing Sz against MDD was 87 and 94%. Comparing Sz against AS was 96 and 96%. Thus, the 34 molecular signature was extremely useful in deciding between Sz and AS, very good between Sz and MDD, and quite good between Sz and BPD, but not as good comparing Sz and controls. Since it can be difficult, at least at the outset, to make a differential diagonsis between Sz and BPD based on behavior, this molecular approach may be helpful in that case.
So what are these 34 molecules? Can they tell us something useful about Sz? Many of these molecules have been implicated in acute and chronic inflammatory conditions, and as I emphasize in my book, there are many other connections between inflammation and Sz, autism and MDD .
A puzzling aspect of this work is why the investigators started with only 181 proteins and small molecules when it is technically possible to assay several thousand molecules in serum. However, a strength in this work is that they were able to obtain samples from newly diagnosed Sz subjects, before they were taking medications. This is not the case in prior publications of this type. This is the case for a Chinese paper. However, the latter paper used a global metabolic method (far broader and unbiased compared to the new paper) to look for changes in Sz serum. They reported evidence suggesting upregulated fatty acid metabolism in Sz. The authors of both of these papers suggest Sz has a metabolic component.
What about biomarkers for autism? There have been several molecular analyses of urine from ASD children that found differences from controls. One from Tony Persico and colleagues in Rome particularly caught my eye. They reported that a molecule called p-cresol is significantly higher in young autistic children (particularly females) compared to controls. This is intriguing because this molecule is produced by particular species of gut bacteria, and the composition of gastrointestinal bacterial species differs between ASD and control children. This is discussed in more detail in some of my prior posts.