Schizophrenia: a disorder of broken brain bioenergetics

Henkel, Nicholas; Wu, Xiajoun; O’Donovan, Sinead M.; Devine, Emily; Jiron, Jessica M; Rowland, Laura M.; Sarnyai, Zoltán; Ramsey, Amy J.; Wen, Zhexing; Hahn, Margaret; McCullumsmith, Robert E.

doi:10.1038/s41380-022-01494-x

Cited by 36 publications

(33 citation statements)

References 199 publications

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“…Modules with a divergent pattern included those enriched for glucose homeostasis, mitochondria, and inflammatory response. These results are consistent with prior literature on dysregulation of energy metabolism in SCZ and complex actions of APDs on these pathways [20,21], as well as potential modulation of neuroinflammatory response and activation states of microglia [22,23].…”

Section: Discussionsupporting

confidence: 92%

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

et al. 2023

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Recent postmortem transcriptomic studies of schizophrenia (SCZ) have shown hundreds of differentially expressed genes. However, the extent to which these gene expression changes reflect antipsychotic drug (APD) exposure remains uncertain. We compared differential gene expression in the prefrontal cortex of SCZ patients who tested positive for APDs at the time of death with SCZ patients who did not. APD exposure was associated with numerous changes in the brain transcriptome, especially among SCZ patients on atypical APDs. Brain transcriptome data from macaques chronically treated with APDs showed that APDs affect the expression of many functionally relevant genes, some of which show expression changes in the same directions as those observed in SCZ. Co-expression modules enriched for synaptic function showed convergent patterns between SCZ and some of the APD effects, while those associated with inflammation and glucose metabolism exhibited predominantly divergent patterns between SCZ and APD effects. In contrast, major cell-type shifts inferred in SCZ were primarily unaffected by APD use. These results show that APDs may confound SCZ-associated gene expression changes in postmortem brain tissue. Disentangling these effects will help identify causal genes and improve our neurobiological understanding of SCZ.

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Section: Discussionsupporting

confidence: 92%

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

et al. 2023

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“…Furthermore, proteins associated with the glycolytic pathway have been linked to schizophrenia in the past [ 35 ], which supports the notion that metabolic abnormalities could be inherent to at least a subgroup of schizophrenia patients. Recent studies have also suggested that schizophrenia may be a consequence of bioenergetic pathway abnormalities in the brain, indicating potential novel treatment opportunities [ 36 , 37 ]. Regarding the role of CD36 in the brain, its functions include regulating myelin and amyloid debris clearance by microglia and reducing neuroinflammation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic model development for schizophrenia based on peripheral blood mononuclear cell subtype-specific expression of metabolic markers

et al. 2022

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A significant proportion of the personal and economic burden of schizophrenia can be attributed to the late diagnosis or misdiagnosis of the disorder. A novel, objective diagnostic approaches could facilitate the early detection and treatment of schizophrenia and improve patient outcomes. In the present study, we aimed to identify robust schizophrenia-specific blood biomarkers, with the goal of developing an accurate diagnostic model. The levels of selected serum and peripheral blood mononuclear cell (PBMC) markers relevant to metabolic and immune function were measured in healthy controls (n = 26) and recent-onset schizophrenia patients (n = 36) using multiplexed immunoassays and flow cytometry. Analysis of covariance revealed significant upregulation of insulin receptor (IR) and fatty acid translocase (CD36) levels in T helper cells (F = 10.75, P = 0.002, Q = 0.024 and F = 21.58, P = 2.8 × 10−5, Q = 0.0004, respectively), as well as downregulation of glucose transporter 1 (GLUT1) expression in monocytes (F = 21.46, P = 2.9 × 10−5, Q = 0.0004). The most robust predictors, monocyte GLUT1 and T helper cell CD36, were used to develop a diagnostic model, which showed a leave-one-out cross-validated area under the receiver operating characteristic curve (AUC) of 0.78 (95% CI: 0.66–0.92). The diagnostic model was validated in two independent datasets. The model was able to distinguish first-onset, drug-naïve schizophrenia patients (n = 34) from healthy controls (n = 39) with an AUC of 0.75 (95% CI: 0.64–0.86), and also differentiated schizophrenia patients (n = 22) from patients with other neuropsychiatric conditions, including bipolar disorder, major depressive disorder and autism spectrum disorder (n = 68), with an AUC of 0.83 (95% CI: 0.75–0.92). These findings indicate that PBMC-derived biomarkers have the potential to support an accurate and objective differential diagnosis of schizophrenia.

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“…Effective glucose metabolism maintains global excitatory neural network function [ 54 ]. Therefore, low availability of energy substrates can reduce synaptic function and lead to neural network instability [ 55 ], as is the case with the glucose hypometabolism that the discussed neurological conditions share.…”

Section: Clinical Evidence Of the Ketogenic Diet In Neurological Cond...mentioning

confidence: 99%

“…Neuroleptic medications treat positive symptoms, but they have not been able to improve cognition, nor do they target pathophysiological mechanisms thought to underlie these deficits. Furthermore, antipsychotic use is frequently associated with motor and metabolic side effects [ 54 ]. Therefore, research is additionally focusing on both interventional strategies targeting brain dysfunction and the potential role of systemic metabolic dysfunction.…”

Section: Schizophrenia Metabolism Inflammation and Neuronal Targetsmentioning

confidence: 99%

“…It is thought that the mechanism of KD bypassing glucose hypometabolism in patients with SZ helps increase oxygen consumption, improves ATP energy metabolism, and induces brain-derived neurotrophic factor to improve cognition [ 3 , 54 , 79 ]. In a postmortem analysis study by Sullivan et al [ 80 ] investigating the brains of mouse models of SZ, the authors reported a 19%–22% decrease in glucose transporter expression, GLUT1 and GLUT3, and in glycolytic genes.…”

Section: Ketogenic Diets and Symptoms In Schizophreniamentioning

confidence: 99%

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The Role of Ketogenic Metabolic Therapy on the Brain in Serious Mental Illness: A Review

Dalai

Ford

2022

J Psychiatry Brain Sci

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In search of interventions targeting brain dysfunction and underlying cognitive impairment in schizophrenia, we look at the brain and beyond to the potential role of dysfunctional systemic metabolism on neural network instability and insulin resistance in serious mental illness. We note that disrupted insulin and cerebral glucose metabolism are seen even in medication-naïve first-episode schizophrenia, suggesting that people with schizophrenia are at risk for Type 2 diabetes and cardiovascular disease, resulting in a shortened life span. Although glucose is the brain’s default fuel, ketones are a more efficient fuel for the brain. We highlight evidence that a ketogenic diet can improve both the metabolic and neural stability profiles. Specifically, a ketogenic diet improves mitochondrial metabolism, neurotransmitter function, oxidative stress/inflammation, while also increasing neural network stability and cognitive function. To reverse the neurodegenerative process, increasing the brain’s access to ketone bodies may be needed. We describe evidence that metabolic, neuroprotective, and neurochemical benefits of a ketogenic diet potentially provide symptomatic relief to people with schizophrenia while also improving their cardiovascular or metabolic health. We review evidence for KD side effects and note that although high in fat it improves various cardiovascular and metabolic risk markers in overweight/obese individuals. We conclude by calling for controlled clinical trials to confirm or refute the findings from anecdotal and case reports to address the potential beneficial effects of the ketogenic diet in people with serious mental illness.

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Schizophrenia: a disorder of broken brain bioenergetics

Cited by 36 publications

References 199 publications

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

Diagnostic model development for schizophrenia based on peripheral blood mononuclear cell subtype-specific expression of metabolic markers

The Role of Ketogenic Metabolic Therapy on the Brain in Serious Mental Illness: A Review

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