Years of imaging studies have revealed to researchers that schizophrenia, bipolar disorder, and depression are accompanied by structural changes in the brain. But it has been hard work to establish how these changes relate to symptom types and severity, what their timing is relative to illness onset, and how they may be implicated in illness causation and progression. It is also not known why some people with bipolar disorder and schizophrenia show marked brain alterations, while others with the same diagnoses do not.

Tomas Hajek, M.D., Ph.D., a 2015 BBRF Independent Investigator and 2007 Young Investigator at Dalhousie University in Halifax, Nova Scotia, has led two research teams that have recently published studies relevant to these questions. In Schizophrenia Bulletin, he and colleagues reported that obesity is a risk factor for accelerated aging of the brain, which they found to be correlated in some patients with more severe negative symptoms and lower functioning in the 1- to 2-year period following a first episode of psychosis (FEP). Separately, in Molecular Psychiatry, Dr. Hajek and a large international team reported that comorbid obesity may explain why certain brain-structure alterations are more pronounced in some individuals with bipolar disorder.

The psychosis study followed upon prior results Dr. Hajek and colleagues had obtained which demonstrated that obesity was associated with advanced brain age and reduced volume of the brain's cerebellum in individuals who had experienced a first psychotic episode. One objective in the new study was to establish whether obesity was contributing to observed brain changes in the FEP patients or perhaps had a role in causing them.

Dr. Hajek's focus on FEP reflects his belief that studying people early in the course of illness is particularly relevant for early intervention and for prevention of long-term negative outcomes.

One relatively new measure of the impact of psychosis and schizophrenia on the brain is to calculate the "biological age" of the brain in patients, and to compare that age with the individual's chronological age (i.e., time since birth).

In the Schizophrenia Bulletin study, structural magnetic resonance imaging scans (sMRI) were collected in 183 FEP patients during their initial hospitalization for psychosis as well as in 155 healthy controls. A second set of scans was made 1 to 2 years after the first. An additional sample of 504 healthy controls received sMRI scans, results of which were fed into a machine-learning computer program and used to train software designed to calculate the brain's effective biological age.

“We were most interested to find out whether any of the factors we assessed at the time of the initial scan would allow us to predict brain age when we performed the second scan, 1 to 2 years later,” said Dr. Hajek.

The study revealed that participants with FEP had a higher initial biological brain age compared with controls—3.4 years older, on average. But these same patients and controls showed similar annual rates of brain aging during the average 1.6-year interval separating the first brain scan in the study from the second. This is good news for patients, the researchers say. At the same time, one factor measured at the time of the first scan did predict faster brain aging in the next 1 to 2 years in FEP participants: body mass index (BMI), a measure of obesity.

Brain aging between the scans grew more rapid at the rate of one month per year, on average, for each additional point on the BMI scale. In those FEP participants in whom brain aging was accelerated, negative symptoms also tended to worsen. (Negative symptoms in schizophrenia, which have a great impact on potential for recovery, include flattened emotions, reduced motivation, difficulty speaking, and a disinclination to socialize or seek pleasure.)

"We do not understand the origins of neurostructural alterations that we observe in FEP and currently have no means of alleviating or preventing them," Dr. Hajek and colleagues noted. Yet their findings, they say, do reveal that obesity contributes to brain alterations in FEP, and that this relates to severity of negative symptoms. This evidence, they advise, emphasizes the need to improve weight monitoring and management in FEP patients and to better integrate medical care and psychiatric care. The findings also suggest the future possibility that improved treatments for newly diagnosed psychosis patients might be developed based upon targeting factors in the brain which underly the obesity-brain age association.

A similar conclusion was reached in the study by Dr. Hajek and a different team, studying obesity and brain changes in patients with bipolar disorder. That study showed that higher BMI scores may account, at least in part, for one of the most often-noted brain changes seen in people with bipolar disorder: enlargement of the ventricles. The ventricles are four interconnected cavities in the brain in which vital cerebrospinal fluid is produced.

"The fact that a significant part of the association between bipolar disorder and ventricular volume was related to higher BMI," the team noted, "raises the possibility that targeting BMI could lower the extent of ventricular expansion in bipolar disorder patients."

Dr. Hajek said that jointly the two studies "suggest that obesity is relevant for the presence and progression of brain changes and related adverse mental health outcomes, and that future studies should explore the impact of weight-management on brain health and clinical outcomes in patients with major psychiatric disorders."

In addition to Dr. Hajek, members of the team on the bipolar disorder paper included: Paul Thompson, Ph.D., 2017 BBRF Distinguished Investigator; Lakshmi Yatham, MBBS, FRCPC, 2018 BBRF Colvin Prize winner, 2003 and 1999 Independent Investigator and 1996 Young Investigator; Martin Alda, M.D., 2003, 1999 BBRF Independent Investigator; Lisa Eyler, Ph.D., 2001 BBRF Young Investigator; Janice Fullerton, Ph.D., 2007 BBRF Young Investigator; Colm McDonald, M.D., Ph.D., 2009 BBRF Independent Investigator, 2002 Young Investigator; Roel Ophoff, Ph.D., 2016 BBRF Distinguished Investigator, 2008 Independent Investigator, 2005 and 2002 Young Investigator; Jonathan Savitz, Ph.D., 2015 and 2009 BBRF Young Investigator; Dan J. Stein, Ph.D., FRCPC, 1991 BBRF Young Investigator; and Eduard Vieta, M.D., Ph.D., 2012 BBRF Colvin Prize winner.