Alterations in gamma-band auditory steady-state response (ASSR) are the most robust finding of abnormal neural oscillations in patients with first-episode (FES) and chronic schizophrenia. Gamma-band ASSRs may indicate GABAergic interneuron dysfunction. Nevertheless, it is unknown whether abnormal gamma-band ASSRs are present before the onset of psychosis. Subjects were 15 ultra-high-risk (UHR) individuals, 13 FES patients, and 21 healthy control (HC) subjects. We performed electroencephalogram recordings and measured ASSRs in each group as they were presented with click trains at 20, 30, and 40 Hz. We then conducted time-frequency analyses and calculated intertrial phase coherence and event-related spectral perturbation. The time course of gamma-band ASSRs showed significantly different features among groups. Compared with the HC group, the UHR group was characterized by intact early-latency (0-100 ms) and reduced late-latency (300-500 ms) ASSRs. In contrast, both early- and late-latency ASSRs were significantly reduced in the FES group. Gamma-band ASSRs were correlated with clinical symptoms and attentional functioning in FES (|rs| > 0.70). These results suggest differential alterations of gamma-band ASSRs between UHR and FES groups. The late-latency ASSR alteration may represent a biomarker for early detection of psychosis, while the early-latency ASSR abnormality may develop through the onset of psychosis.

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Recent reviews and meta-analyses suggest that reducing the duration of untreated psychosis leads to better symptomatic and functional outcome in patients with psychotic disorder. Early intervention attenuates the symptoms of individuals at clinical high-risk (HR) for psychosis and may delay or prevent their transition to psychosis. Identifying biological markers in the early stages of psychotic disorder is an important step toward elucidating the pathophysiology, improving prediction of the transition to psychosis, and introducing targeted early intervention for help-seeking individuals aiming for better outcome. Mismatch negativity (MMN) is a component of event-related potentials that reflects preattentive auditory sensory memory and is a promising biomarker candidate for schizophrenia. Reduced MMN amplitude is a robust finding in patients with chronic schizophrenia. Recent reports have shown that people in the early stages of psychotic disorder exhibit attenuation of MMN amplitude. MMN in response to duration deviants and in response to frequency deviants reveals different patterns of deficits. These findings suggest that MMN may be useful for identifying clinical stages of psychosis and for predicting the risk of development. MMN may also be a “translatable” biomarker since it reflects N-methyl-d-aspartte receptor function, which plays a fundamental role in schizophrenia pathophysiology. Furthermore, MMN-like responses can be recorded in animals such as mice and rats. This article reviews MMN studies conducted on individuals with HR for psychosis, first-episode psychosis, recent-onset psychosis, and on animals. Based on the findings, the authors discuss the potential of MMN as a clinical biomarker for early intervention for help-seeking individuals in the early stages of psychotic disorder, and as a translatable neurophysiological marker for the preclinical assessment of pharmacological agents used in animal models that mimic early stages of the disorder.

Few biomarkers have been known that can easily measure clinical conditions in mental illnesses such as schizophrenia. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) is a new method that can measure ionized and low-molecular-weight metabolites. To explore global metabolomic alterations that characterize the onset of schizophrenia and identify biomarkers, we profiled the relative and absolute concentrations of the plasma metabolites from 30 patients with first-episode schizophrenia (FESZ, four drug-naïve samples), 38 healthy controls and 15 individuals with autism spectrum disorders using CE-TOFMS. Five metabolites had robust changes (increased creatine and decreased betaine, nonanoic acid, benzoic acid and perillic acid) in two independent sample sets. Altered levels of these metabolites are consistent with well-known hypotheses regarding abnormalities of the homocysteine metabolism, creatine kinase-emia and oxidative stress. Although it should be considered that most patients with FESZ received medication, these metabolites are candidate biomarkers to improve the determination of diagnosis, severity and clinical stages, especially for FESZ.

Previous studies have shown glutamatergic dysfunction and γ-aminobutyric acid (GABA)-ergic dysfunction in schizophrenia. Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) dysfunction and GABA-ergic dysfunction interact with each other and lead to alterations in excitatory/inhibitory balance. The NMDAR and GABAergic-interneuron functions may be indexed by mismatch negativity (MMN) and auditory steady-state gamma-band response (ASSR), respectively. However, no previous studies have tested the hypothesis of an abnormal association between MMN and gamma-band ASSR in the same patients to identify the in vivo evidence of NMDAR-GABA association during the early stages of psychosis. Participants were individuals with recent-onset schizophrenia (ROSZ; N = 21), ultra-high risk (UHR; N = 27), and healthy controls (HCs; N = 24). The MMN amplitude was significantly impaired in ROSZ (p = 0.001, d = 1.20) and UHR (p = 0.003, d = 1.01) compared with HCs. The intertrial phase coherence (ITC) index of gamma-band ASSR was significantly reduced in ROSZ compared with HCs (p < 0.001, d = –1.27) and UHR (p = 0.032, d = –0.75). The event-related spectral perturbation (ERSP) index of gamma-band ASSR was significantly smaller in ROSZ compared with HCs (p < 0.001, d = −1.21). The MMN amplitude was significantly correlated with the ITC in ROSZ (r = −0.69, p < 0.001). These findings provide the first in vivo evidence that an abnormal association of the electrophysiological indices of NMDAR and GABA dysfunctions may be present in recent-onset schizophrenia.