Novel approach confirms dysfunctional energy production in schizophrenia

By Eleanor McDermid, Senior medwireNews Reporter

A method of directly assessing creatine kinase (CK) in the brain provides “direct and compelling” evidence for abnormal bioenergetics in the brains of patients with schizophrenia, say the study authors.

The team led by Fei Du (McLean Hospital, Belmont, Massachusetts, USA) used 31P magnetization transfer spectroscopy to measure the reaction rate of CK, an enzyme that, in the brain, is crucial for maintaining stable adenosine triphosphate (ATP) levels during changes in neuronal activity.

“This approach examines specific biological processes directly involved in bioenergetics, as opposed to generic glucose or oxygen metabolic rates available through other methods such as positron emission tomography,” Du et al comment in JAMA Psychiatry.

They studied 26 patients with chronic schizophrenia or schizoaffective disorder and 26 age- and gender-matched controls, and found a significant 22% reduction in the CK forward rate constant in the former versus the latter group. The reduction was present in both schizophrenia and schizoaffective disorder patients.

This finding “suggests that the machinery of energy metabolism is dysfunctional in [schizophrenia],” they say. “Therefore, ATP availability might be compromised, especially at times of high demand, such as during brain activation.”

The reduced reaction rate did not result in altered levels of substrate or product; the ratios of metabolites to ATP were similar in patients and controls, except for a 12% reduction in the ratio of phosphodiester to β-ATP in the patients.

In addition, schizophrenia patients had a significant 0.03-unit reduction in intracellular pH, “suggesting a relative increase in the contribution of glycolysis to ATP synthesis, with resultant buildup of lactic acid.”

The researchers say that this pH change could account for about a third of the reduction in the CK reaction rate. With other possible contributors, such as ADP, only likely to account for a very small proportion of the change, most of the remaining two-thirds of the reduction is probably caused by changes in CK concentration or molecular structure, they believe.

This is consistent with findings from postmortem studies, they add, and “together, this is a picture of an underlying failure of energy production” in schizophrenia.

Given that energy use in the brain mostly drives glutamatergic neurotransmitter cycling, “bioenergetic abnormalities in [schizophrenia] are likely to have implications for neuronal and circuit activity,” says the team.

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