Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model.

Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.

Association between mismatch negativity and voxel-based brain volume in schizophrenia.

OBJECTIVE: This study aimed to investigate the association between mismatch negativity (MMN) and volumes of several brain regions measured using a semi-automated method in patients with schizophrenia and healthy controls. METHODS: MMN in response to duration deviants and magnetic resonance imaging were acquired from 36 schizophrenia patients and 14 healthy controls. FreeSurfer was used for volumetric analysis. MMN amplitudes, brain volumes and their association were compared between schizophrenia and controls. Correlation analysis and multiple linear regression analysis were used to examine the correlated variables of MMN. RESULTS: MMN amplitude was significantly lower in the schizophrenia group. In schizophrenia, MMN was positively correlated with age and negatively correlated with left hippocampal and right pars opercularis volumes. The association between left hippocampal volume and MMN in schizophrenia remained significant after controlling for potential confounders. CONCLUSIONS: Smaller hippocampal volume may play a role in the abnormal manifestation of MMN in schizophrenia. SIGNIFICANCE: The significant association between MMN and left hippocampal volume may suggest unique neurobiological contribution of hippocampus in auditory processing in schizophrenia.

Auditory event-related potential of subjects with suspected pre-psychotic state and first-episode psychosis.

BACKGROUND: Recent schizophrenia research exploring the complicated pathogenesis of schizophrenia has focused on the subjects with at-risk mental states in order to exclude the influence of confounding factors. This study explores 3 sets of auditory-related event potentials in subjects with different risk levels of psychosis. METHODS: Subjects were recruited from the SOPRES study in Taiwan. P50 and N100 using an auditory paired-click paradigm and duration MMN were assessed on 32 first-episode psychosis (FEP), 30 ultra-high risk (UHR), 37 E-BARS (early/broad at-risk mental states) participants and 56 controls. RESULTS: MMN was correlated with neither P50 nor N100, whereas many parameters of the latter two were intercorrelated with each other. Compared to healthy controls, MMNs were significantly lower in all 3 clinical groups (E-BARS, UHR and FEP). A gradient of sensory-gating deficits, manifested by increased P50 ratios (S2/S1) and decreased N100 differences, across different levels of clinical severity was suggested by a linear trend. For the UHR subjects, P50 gating ratio, N100 gating ratio, N100 difference, and N100S2 amplitude might be potential indicators to discriminate converters from non-converters. CONCLUSIONS: By including subjects with E-BARS, our results provide new insight regarding pre-attentive auditory event-related potential in subjects across different risk levels of psychotic disorders. Impaired deviance detection shown by MMNs already exists in people at a pre-psychotic state regardless of clinical severity, while sensory-gating deficits shown by P50/N100 varies depending on the risk levels in prodromal period. Further longitudinal research exploring the relationship between ERPs and subjects with a suspected pre-psychotic state is needed.

Impaired flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives: the effect of genetic loading.

We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia.