The continuing search for more effective schizophrenia treatments is directly related to efforts by researchers to more precisely understand mechanisms underlying major symptoms such as psychosis and cognitive dysfunction, as well as patients’ varying response to antipsychotic medicines. (An estimated 30% of first-episode psychosis and recently diagnosed schizophrenia patients do not respond adequately to antipsychotics.)

Research performed by a team led by 2017 BBRF Young Investigator Deepak K. Sarpal, M.D., of the University of Pittsburgh School of Medicine, is relevant to the biology of both symptoms and treatment response. The new findings, reported in the journal Neuropsychopharmacology, concern how alterations in glutamate (Glu) and GABA, the brain’s principal excitatory and inhibitory neurotransmitters, contribute to fundamental processes thought to be perturbed in schizophrenia.

Glu and GABA can also be considered metabolites, since they are products of metabolic processes and are created naturally within brain cells. Other metabolites, important for understanding cell health and integrity, were also measured in the study. These include those indicating the interaction between neurons and support cells called astroglia, which also affects the balance between neural excitation and inhibition.

Studying brain changes in schizophrenia is tricky. Various departures from normal brain biology are related to the underlying pathology, but medicines also change the brain and likely have an impact on some or all of these factors. A classic example is evidence that imbalance in the Glu versus GABA systems is a “core mechanism” of schizophrenia and related disorders (sometimes collectively called schizophrenia spectrum disorders, or SSDs). But drugs that target the D2 dopamine receptor—and this includes all the first- and second-generation antipsychotics, which are typically prescribed for schizophrenia—“likely exert downstream effects,” Dr. Sarpal and colleagues note. Among these effects, they perturb the very glutamate and GABA systems underlying schizophrenia symptoms and the response to medications. In particular, this Glu-GABA impact is seen in circuits connecting the cortex and striatum and the cortex and the thalamus. The thalamus integrates and relays sensory and motor information. The striatum is involved in motor, sensory, and cognitive processes.

Some clues about the biology underlying schizophrenia and psychosis have been generated by magnetic resonance spectroscopic imaging (MRSI). MRSI has repeatedly revealed Glu system abnormalities in the cortex and in subcortical regions such as caudate and thalamus, and there is emerging evidence of GABA alterations, too. Studies looking at first-episode psychosis patients over time have shown that elevated levels of Glu in the striatum normalize in those who respond to antipsychotics and that this correlates with symptom improvement. Sophisticated imaging studies have linked Glu levels to dopamine system dysfunction and response to medication.

Dr. Sarpal and colleagues took advantage of a leap forward in technology: they used ultra-high-field MRSI to measure Glu, GABA, and 12 other metabolites in a cohort of 29 young adults with early schizophrenia/SSD and in a matched comparison group of 91 healthy young adults. The typical participant in both groups was 23-24 years old; all but 6 of the SSD patients were male; the control group was evenly divided among males and females.

The high-powered MSRI scan sequence is capable of much finer resolution of the various targeted metabolites, across multiple parts of the brain, than prior versions of MRSI. The team’s focus was on metabolites in the subcortical areas implicated in early psychotic illness, notably the thalamus and caudate (the latter is a part of the striatum).

Early-stage patients recruited for the study were being treated at Pittsburg’s Western Psychiatric Hospital, and all had moderate-to-severe psychosis. All participants were imaged with MRSI at the start of the study; SSD patients were imaged again after 8 weeks of antipsychotic therapy.

The most important evidence generated by the study was an indication of “asymmetric disruptions” in key subcortical areas in Glu, GABA and other metabolites. The team refers to “a pattern of lateralized Glu and GABA dysregulation,” with higher glutamate and Glx seen in the right side of the striatum. (Glx is a combined measure of glutamate and glutamine, the latter synthesized in astrocytes from glutamate as part of the glutamine-glutamate recycling loop.) The team also observed elevated levels of GABA in the brain’s right hemisphere and reduced levels of GABA in the left hemisphere, in both the caudate and the thalamus. Glx was elevated in the thalamus in the left hemisphere, along with “disrupted Glu-GABA coupling.” The latter refers to an imbalance in Glu and GABA that would indicate dysfunction in a mechanism that normally helps regulate the balance between neural excitation and inhibition.

The meaning or implications of these and other key findings in the study are subject to interpretation. The team felt it was particularly significant that altered glutamate metabolism in early SSD patients was “lateralized,” i.e., different on the two sides of the brain. Overall, they propose that their data supports “a shift in emphasis” from past research focusing on an isolated imbalance of neurotransmitters in the schizophrenia brain, and toward a model of dysfunction in the metabolic coordination of neurons and glial cells in circuits connecting the cortex and the striatum.

The specific kind of coordination referred to, called astroglial-neuronal balance, concerns vital functional and metabolic cooperation between astrocytes (a type of glial cell) and pairs of neurons that maintains homeostasis, synaptic transmission, and overall health in the central nervous system.

The “baseline metabolite profile” of patients gleaned from the study “reveals a striking hemispheric dissociation [i.e., lack of coordination] that may reflect different stages of a shared pathological process,” the team said, although the “left-hemisphere predominance of the findings raises the possibility” of a left-brain “neurodegenerative-like process in early-phase schizophrenia spectrum disorder. This would be consistent with large-scale neuroimaging data that has indicated left-predominant structural and synaptic pathology in schizophrenia, they noted.

The patient cohort in the study was small and comparable studies involving many more patients and with a higher fraction of females are essential in validating the findings. Also, baseline imaging in this study was performed after early treatment with antipsychotics had begun, which might distort the results to some degree.

Broadly, the team believes its data support “an asymmetric disruption of astroglial-neuronal balance in subcortical circuits in early-phase schizophrenia, with distinct metabolic trajectories characterizing treatment response.” The ongoing aim of the team’s research is to clarify how metabolic signatures relate to dopamine signaling, network dysconnectivity, and clinical outcomes, they said.

The team also included Beatriz Luna, Ph.D., 1997 BBRF Young Investigator.