The Challenges of Identifying Biomarkers of Psychiatric Illness

There is minimal overlap in neurologic variations among individuals with severe psychiatric conditions such as schizophrenia spectrum disorders and bipolar disorder.

Minimal overlap was found in neurologic variation among individuals with severe psychiatric conditions such as schizophrenia-spectrum disorders and bipolar disorder, according to a study published in JAMA Psychiatry.

One of the challenges of treating patients with clinically heterogeneous conditions such as schizophrenia and bipolar disorder is the focus in research on the “average” patient. Researchers sought to find objective biomarkers in brain structure that might alleviate the diagnostic reliance on typical external symptoms, as patients’ actual experiences vary widely.

The authors recruited participants as part of the Thematically Organized Psychosis study between 2004 and 2012 in the Oslo, Norway, area. Patients (n=218) between 18 and 65 years of age who had IQs >70 and had not experienced major head trauma were included, with diagnoses established according to the Structured Clinical Interview for DSM-IV Axis I Disorders. This included 163 instances of pure schizophrenia and 190 instances of bipolar disorder. Healthy controls (n=256) were randomly sampled from Norwegian registries. All participants underwent magnetic resonance imaging.

Although healthy individuals did not vary significantly from the normative model of the brain, patients with bipolar disorder or a schizophrenia spectrum disorder exhibited reduced volume in different areas, including the cerebellum. The nature of these deviations varied substantially among patients, preventing the identification of reliable biomarkers.

Frontal regions, the cerebellum, and the temporal cortex had reduced cortical volume in patients with schizophrenia compared with those with a healthy lifespan trajectory. This finding was less pronounced in an average patient with bipolar disorder and was primarily present in the cerebellar regions.

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The authors noted a minor relationship between drug misuse and reduced gray matter volume in patients with schizophrenia but were not able to infer the extent to which drug use may have confounded results.

Investigators concluded that, “group-level differences disguised biological heterogeneity and interindividual differences among patients with the same diagnosis. This finding suggests that the idea of the average patient is a noninformative construct in psychiatry that falls apart when mapping abnormalities at the level of the individual patient.”


Wolfers T, Doan NT, Kaufmann T, et al. Mapping the heterogeneous phenotype of schizophrenia and bipolar disorder using normative models. JAMA Psychiatry. 2018;75:1146-1155.