Researchers have reported new evidence bearing on their multi-year effort to identify clinically useful markers of high risk for the onset of psychosis in young people.

A first episode of psychosis (FEP) is typically preceded by a “prodrome,” a period characterized by precursor or attenuated psychotic symptoms as well as signs of functional impairment. Those with prodromal symptoms are considered to be at high risk for developing full-blown psychotic disorder—and in many cases, a diagnosis of schizophrenia, although psychotic symptoms do occur in other disorders including bipolar disorder and major depression. Between one in three and one in four youths at high risk for psychosis goes on to develop psychotic disorder. In addition to clinical signs, having a parent with a history of psychosis is also an important factor in assessing an individual’s risk.

Patrick D. McGorry, M.D., Ph.D., a professor of Youth Mental Health at the University of Melbourne, Australia, and founder of the Orygen Youth Mental Health Foundation and Headspace clinics in Australia, has won worldwide recognition for his work in seeking to characterize people at high risk for psychosis, as well as his efforts to treat those with prodromal symptoms in the effort to prevent progression to psychosis, schizophrenia, and other psychotic disorders. Dr. McGorry is the 2015 winner of the BBRF Lieber Prize for outstanding schizophrenia research, and was a 1998 BBRF Distinguished Investigator.

Dr. McGorry and colleagues in recent years have developed and tested criteria for a risk class called “ultra-high risk” (UHR) for psychosis onset in young people. UHR criteria were introduced to prospectively identify the prodromal period, and also to try to unravel heterogeneity within the ultra-high risk population. “Recognizing the prodrome of a first psychotic episode prospectively creates the opportunity of intervention, which could delay, ameliorate or even prevent onset,” they said. “Valid criteria and a reliable methodology for identifying possible prodromes are needed.”

In a new study published in Biological Psychiatry: Global Open Science, Dr. McGorry, Dr. Naomi R. Wray, and doctoral candidate Lauren Barker, report on their efforts to analyze white blood cell patterns in UHR youth as a possible predictor of their response to psychosocial therapy delivered over a period of 6 months. The team also included Barnaby Nelson, Ph.D., 2015 BBRF Baer Prize winner, 2015 BBRF Independent Investigator, and 2008 BBRF Young Investigator.

Data from 91 youths were analyzed. All had been part of a clinical trial conducted by the team called STEP (Staged Treatment in Early Psychosis) which tested the effectiveness of a sequential intervention strategy for preventing psychosis in adolescents and young people who met criteria for UHR status. Their average age was about 17. During the trial, participants received psychosocial therapy and were assessed for remission of UHR status after 6 weeks and then at 6 months from the trial’s start.

Among the 91 youths analyzed in the new study, 31 “remitted” their UHR status, i.e., no longer met the criteria of being at ultra-high risk for psychosis, by the 6-month assessment. The question explored in the new study was whether blood samples collected at the beginning of the STEP trial (“baseline”) contained evidence of patterns in comparative levels of different white blood cell types that correlated with (and therefore might be taken to have “predicted”) remission of UHR status after 6 months of treatment.

As noted by the team, past research has supplied ample evidence suggesting inflammation and immune dysfunction have contributing roles in the underlying mechanisms of schizophrenia and psychosis. They cite “increasing evidence” that lymphocytes—including T cells, B cells, and natural killer (NK) cells that defend the body against infections, viruses, and cancer—may be helpful in identifying potential white blood cell-based markers of disease.

Lymphocytes are part of the acquired, or “adaptive” immune system, while other white blood cell types, including neutrophils, monocytes, and eosinophils, are part of the “innate” immune system (or work across both systems). In the current study, the team sought to break down the total amount of white blood cells into the relative proportion belonging to each of the different white blood cell types to see if levels of any particular white blood cell type are relevant for remission of UHR status.

Measurements were made on the basis of whole blood samples obtained from the STEP trial participants, which had been subjected to analysis of methylation patterns. This is a way of studying genome modifications, but can also be used to infer relative proportions of various cell types within tissues, or in this case, peripheral blood.

After the data were adjusted to reflect demographic variables such as age, sex and ancestry, lymphocyte proportions were tested for association with remission status. The team found that those who remitted from UHR status after the 6-month treatment window “had significantly lower proportions of lymphocytes”—as measured at baseline, when the trial began. This association was even stronger after corrections for other factors including childhood trauma, depression symptom score, and whether or not a participant had a psychiatric diagnosis when the trial began (about half did).

It was not possible, given the method used in the study, to determine if the decrease in lymphocyte proportions was being driven by one or more particular lymphocyte subtypes. Attempts were also made to determine whether white blood cell-type proportions at baseline correlated with when during the 6 months of the STEP trial each of the 31 remitters actually achieved that status. The team found that lymphocytes tended toward lower proportions in remitters at both steps of the assessment process (at 6 weeks and 6 months) relative to non-remitters. It remains possible that proportions of various subtypes of lymphocytes may have relevance to “time to remission,” but this was not possible to assess using this study’s dataset.

As for the significance of their main finding—that lymphocyte proportions were lower in future remitters—it was impossible for the researchers to determine in this study whether that relationship was influenced at all (or if so to what degree) by the psychosocial treatment given during the STEP clinical trial. It’s possible that this association of white blood cell proportions with future remission may have been caused by other unmeasured factors, or that it may have been a function of biological differences present in the remitters even before they entered the trial.

In efforts to validate the current finding, future studies should recruit a much larger and more diverse sample of young people with UHR status, the team said. They might also try to determine if the association of white blood cells with remission does indeed predict a response to treatment “or, if it may predict the course of attenuated psychotic symptoms regardless of whether treatment is received.”