What changes occur in the brain after a young person has a first episode of psychosis (FEP)?

The question is of great interest because brain changes following a first episode can provide valuable insights into disease mechanisms. Such knowledge may also suggest potential biological targets for slowing or even preventing disease progression, and for diagnosing the illness. The same potential benefits apply to young FEP patients who receive other diagnoses involving psychosis, including schizophrenia and forms of major depression and bipolar disorder in which psychotic symptoms occur.

Continuing with their past research, a team co-led by BBRF Scientific Council member Akira Sawa, M.D., of Johns Hopkins University, explored levels of 10 key metabolites in the brain, comparing levels in FEP patients and healthy controls, over a 4-year period. Metabolites are molecules generated as a result of biological processes—in this case in the brain. The team used a technology called magnetic resonance spectroscopy (MRS) to measure levels of the 10 metabolites in five brain regions implicated in psychosis. In this study, the MRS device operated at a high electric-field intensity to deliver especially precise and well-resolved measurements of the targeted metabolites.

In addition to serving on the BBRF Scientific Council, Dr. Sawa has received BBRF grants in 2011 (Distinguished Investigator) and 2004 and 2002 (Young Investigator). Five other BBRF grant recipients were members of the team, including the last author of the team’s paper appearing in Molecular Psychiatry, Kun Yang, Ph.D., a 2019 BBRF Young Investigator.

Thirty-eight patients with first-episode psychosis were compared in the study with 48 healthy controls. The FEP patients had experienced their first psychotic episode within the prior 2 years. The typical patient was about 23 years old; 25 were Black and 27 were male; all were taking medications for psychosis. Twenty-one of the participants were diagnosed with schizophrenia or a related disorder; 10 had bipolar disorder with psychosis, 4 had major depression with psychotic features; and 3 had psychosis that did not conform to these diagnostic categories. These 38 individuals all received MRS scans at the outset of the study, as did all of the control participants. The typical participant across both groups received a follow-up MRS brain scan about 2 years after their initial scan.

After the closing of the 4-year period during which follow-up scans were made, the team was able to arrive at three notable findings after analyzing the data. One molecule of interest was glutamate, which plays an important role in energy production in the brain. Past studies have noted a reduction in glutamate in psychosis patients, including FEP patients. The current study showed a decline in glutamate levels over time, in a brain area called the anterior cingulate cortex (ACC). Importantly, this decline occurred in both FEP patients and healthy controls, although in patients the rate of decline was faster—perhaps directly related to the pathology process in psychosis.

A second finding concerned GABA (an inhibitory neurotransmitter), NAA (essential for synthesis of the myelin sheaths that protect neural connections), myoinositol (highly enriched in astrocytes), choline (key in building cell membranes), and creatine (involved in energy production). Each of these molecules showed a decline in FEP patients, but only in the ACC—not in the other four brain areas probed. A third finding was that levels of the molecule glutathione in all five of the brain regions examined were stable over time, in both patients and controls.

In discussing the significance of these findings, the team said it was notable that the most significant changes over time in metabolite levels occurred only in the ACC. Recent structural brain imaging has reported progressive structural changes of the ACC in schizophrenia, they pointed out. The dorsal segment of the ACC is important in the brain’s salience network, which the team notes has been proposed as a locus of changes giving rise to psychotic symptoms. “Progressive changes in key nodes of the salience network have reportedly been related to poor prognosis in schizophrenia,” they added. In the team’s view, their data “support the notion that the dorsal ACC may be a ‘hotbed’ for longitudinal changes of brain metabolites in early-stage psychosis.”

The lack of change in levels of glutathione over time in both patients and controls was also deemed potentially important. Glutathione is a key antioxidant in the central nervous system and is needed to protect against oxidative damage. Numerous past studies have reported abnormal glutathione levels in the brains of patients with psychosis. It has been suggested that oxidative stress in the brain is associated with early-stage psychosis, and may even precede its onset. Such stress is thought to be especially severe in a subset of psychosis patients who are most resistant to treatment.

A 2022 study by Drs. Sawa, Yang and Johns Hopkins colleagues reported significantly lower glutathione levels in treatment-resistant psychosis patients compared to healthy controls during baseline visits. The current study showed that glutathione levels remained stable in both patients and controls relative to baseline levels, over time, in contrast to the observed longitudinal changes in levels of other brain metabolites. Together, the team says, these two findings imply glutathione’s possible utility as a biomarker. If glutathione levels are below the normal range at the onset of the disease, it could indicate the patient might be more likely to fail to respond to antipsychotic treatments. At the same time, it might also suggest the value of exploring whether such patients would stand to benefit from treatments aiming to reduce oxidative stress.

With possible implications for both diagnosis and future therapies, the study, in the view of the authors, provides “an important foundation for future projects that investigate the relationship between dynamic changes in brain metabolites” and their impacts on psychosis symptoms, across diagnostic categories.

Dr. Sawa says that the team’s MRS studies are continuing. “By combining MRS findings with clinical observations over time (regarding, for instance, treatment resistance and relapse/remission), the information becomes even more powerful in translation.” In one current study, the team has used MRS to study functional deterioration in the brain after relapse of psychotic disorders.

The research team also included: Nicola G. Cascella, M.D., 2000 BBRF Young Investigator; Jennifer M. Coughlin, M.D., 2013 BBRF Young Investigator; Frederick C. Nucifora Jr., D.O., Ph.D., 2013 and 2010 BBRF Young Investigator; and Thomas W. Sedlak. M.D., Ph.D., 2006 BBRF Young Investigator.