Dose-tapering trajectories in patients with remitted psychosis undergoing guided antipsychotic reduction to reach minimum effective dose.

BACKGROUND: Patients with remitted psychosis wish to reduce antipsychotic doses yet facing increased risks of relapse. Examining dose-tapering processes may provide insights to re-evaluate the risk-to-benefit balance. We aimed to depict and subgroup tapering trajectories, and explore factors associated with different dose-reduction patterns. METHODS: A 2-year open-label randomized prospective comparative trial from August 2017 to September 2022 in Taiwan. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomizing a proportion to conduct guided dose reduction. We depicted the trajectories of individual patients and named subgroups based on dose-tapering patterns. Predictors of baseline characteristics for designated subgroups were examined by logistic regression analysis; changes in outcomes were compared by paired t-test. RESULTS: Fifty-one patients undergoing guided dose reduction, 18 (35.3%) reduced 4 steps consecutively (sequential reducers, SR), 14 (27.5%) reduced 1 to 3 steps (modest reducers, MR), 3 (5.9%) re-escalated to previous level (alert reducers, AR), 7 (13.7%) returned to baseline level (baseline returners, BR), 6 (11.7%) relapsed (failed reducers, FR) and 3 (5.9%) withdrew without relapse (early exits, EE). Patients with a history of relapse assumed a conservative dose-tapering pace; only the SR subgroup exhibited significant improvements in functioning and quality of life while failing to identify variables for predicting who would become SR or FR. CONCLUSIONS: Guided dose reduction comprises dynamic processes with differences between individual trajectories. The proposed naming of dose-tapering patterns/subgroups provides a framework depicting patients undergoing dose-tapering. Longer-term observation and more flexible tapering approaches are anticipated to reveal favorable outcomes.

Guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis: a 2-year randomized controlled trial with a naturalistic cohort.

BACKGROUND: Patients with remitted psychosis face a dilemma between the wish to discontinue antipsychotics and the risk of relapse. We test if an operationalized guided-dose-reduction algorithm can help reach a lower effective dose without increased risks of relapse. METHODS: A 2-year open-label randomized prospective comparative cohort trial from Aug 2017 to Sep 2022. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomized 2:1 into guided dose reduction group (GDR) v. maintenance treatment group (MT1), together with a group of naturalistic maintenance controls (MT2). We observed if the relapse rates would be different between 3 groups, to what extent the dose could be reduced, and if GDR patients could have improved functioning and quality of life. RESULTS: A total of 96 patients, comprised 51, 24, and 21 patients in GDR, MT1, and MT2 groups, respectively. During follow-up, 14 patients (14.6%) relapsed, including 6, 4, and 4 from GDR, MT1, and MT2, statistically no difference between groups. In total, 74.5% of GDR patients could stay well under a lower dose, including 18 patients (35.3%) conducting 4 consecutive dose-tapering and staying well after reducing 58.5% of their baseline dose. The GDR group exhibited improved clinical outcomes and endorsed better quality of life. CONCLUSIONS: GDR is a feasible approach as the majority of patients had a chance to taper antipsychotics to certain extents. Still, 25.5% of GDR patients could not successfully decrease any dose, including 11.8% experienced relapse, a risk comparable to their maintenance counterparts.

The plasma level of complement component 4A decreases with aripiprazole treatment in patients with early psychosis.

The complement component 4 (C4) gene has been reported to be significantly associated with schizophrenia, and C4A RNA expression was found to increase in postmortem brains of schizophrenia patients. This study aimed to examine the plasma levels of C4A and C4B proteins in patients with early psychosis and their changes following aripiprazole treatment. We recruited 45 patients, including 17 patients with ultra-high-risk and 28 patients with first-episode psychosis, and 45 age-matched and sex-matched controls. All patients received aripiprazole treatment for 4 weeks. Each patient received symptom evaluation before and after the treatment period. We measured the plasma levels of C4A and C4B in the pretreatment and posttreatment stages of patients and controls using an enzyme-linked immunosorbent assay. We found no significant differences in C4A and C4B levels between patients and controls, but the C4A level decreased significantly with aripiprazole treatment. Multivariate analysis showed that the decrease rate of C4A was significantly associated with the treatment response of the positive symptom dimension. In summary, we found that the plasma level of C4A decreased with aripiprazole treatment, and the decrease rate was associated with the treatment response of the positive dimension in patients with early psychosis. This mechanism deserves further clarification.

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.

Neurodevelopmental model of schizophrenia revisited: similarity in individual deviation and idiosyncrasy from the normative model of whole-brain white matter tracts and shared brain-cognition covariation with ADHD and ASD.

The neurodevelopmental model of schizophrenia is supported by multi-level impairments shared among schizophrenia and neurodevelopmental disorders. Despite schizophrenia and typical neurodevelopmental disorders, i.e., autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), as disorders of brain dysconnectivity, no study has ever elucidated whether whole-brain white matter (WM) tracts integrity alterations overlap or diverge between these three disorders. Moreover, whether the linked dimensions of cognition and brain metrics per the Research Domain Criteria framework cut across diagnostic boundaries remains unknown. We aimed to map deviations from normative ranges of whole-brain major WM tracts for individual patients to investigate the similarity and differences among schizophrenia (281 patients subgrouped into the first-episode, subchronic and chronic phases), ASD (175 patients), and ADHD (279 patients). Sex-specific WM tract normative development was modeled from diffusion spectrum imaging of 626 typically developing controls (5-40 years). There were three significant findings. First, the patterns of deviation and idiosyncrasy of WM tracts were similar between schizophrenia and ADHD alongside ASD, particularly at the earlier stages of schizophrenia relative to chronic stages. Second, using the WM deviation patterns as features, schizophrenia cannot be separated from neurodevelopmental disorders in the unsupervised machine learning algorithm. Lastly, the canonical correlation analysis showed schizophrenia, ADHD, and ASD shared linked cognitive dimensions driven by WM deviations. Together, our results provide new insights into the neurodevelopmental facet of schizophrenia and its brain basis. Individual's WM deviations may contribute to diverse arrays of cognitive function along a continuum with phenotypic expressions from typical neurodevelopmental disorders to schizophrenia.

Niacin skin flush and membrane polyunsaturated fatty acids in schizophrenia from the acute state to partial remission: a dynamic relationship.

Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

Detection of advanced brain aging in schizophrenia and its structural underpinning by using normative brain age metrics.

Conceptualizing mental disorders as deviations from normative functioning provides a statistical perspective for understanding the individual heterogeneity underlying psychiatric disorders. To broaden the understanding of the idiosyncrasy of brain aging in schizophrenia, we introduced an imaging-derived brain age paradigm combined with normative modeling as novel brain age metrics. We constructed brain age models based on GM, WM, and their combination (multimodality) features of 482 normal participants. The normalized predicted age difference (nPAD) was estimated in 147 individuals with schizophrenia and their 130 demographically matched controls through normative models of brain age metrics and compared between the groups. Regression analyses were also performed to investigate the associations of nPAD with illness duration, onset age, symptom severity, and intelligence quotient. Finally, regional contributions to advanced brain aging in schizophrenia were investigated. The results showed that the individuals exhibited significantly higher nPAD (P < 0.001), indicating advanced normative brain age than the normal controls in GM, WM, and multimodality models. The nPAD measure based on WM was positively associated with the negative symptom score (P = 0.009), and negatively associated with the intelligence quotient (P = 0.039) and onset age (P = 0.006). The imaging features that contributed to nPAD mostly involved the prefrontal, temporal, and parietal lobes, especially the precuneus and uncinate fasciculus. This study demonstrates that normative brain age metrics could detect advanced brain aging and associated clinical and neuroanatomical features in schizophrenia. The proposed nPAD measures may be useful to investigate aberrant brain aging in mental disorders and their brain-phenotype relationships.

Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Discontinuing Antipsychotic Medication After Remission from First-Episode Psychosis: A Survey of Psychiatrists' Attitudes in Taiwan.

Background: Patients in remission after first-episode psychosis are inclined to discontinue antipsychotic treatment, which may lead to higher risk of relapse and unfavorable outcomes. Paradoxically, also there are evidences suggesting that certain patients may stay well in drug-free condition. Psychiatrists' views towards this dilemma might affect their approaches to these patients, and discrepant attitudes are noted between Western and Asian clinicians. This study aimed to examine psychiatrists' attitudes about discontinuing antipsychotic medications after remission from first-episode psychosis. Methods: Psychiatrists were recruited for this study using convenience sampling. A cross-sectional survey was conducted using a set of questionnaires comprising nine items for attitudes toward medication discontinuation, six vignettes for probing psychiatrists' practice in designated clinical scenarios, and a list of criteria that may affect their responses. Results: Responses were provided by 118 psychiatrists, two-thirds men, mean age 39.8 ± 10.1 years and mean experience 12.7 ± 9.7 years. Half of the participants endorsed that fewer than 20% of the remitted patients should stop medication completely; the majority advised that an observation period of 1 year or longer is necessary while discontinuing medication. The majority would not initiate discussion with patients about discontinuing medication. Responding to two case vignettes, those who endorsed that more patients could stop antipsychotics were also more inclined to discuss it with patients, but not consistently in response to the other four case vignettes. Taiwan psychiatrists expressed a wide range of decision-making considerations for discontinuing antipsychotics. Conclusion: The majority of Taiwan psychiatrists thought it was not feasible to stop medications completely but were willing to consider this option. Once being presented with actual clinical scenarios, many participants hesitated to discontinue antipsychotic medications for various reasons. The proactive attitude of psychiatrists towards conducting clinical trials to test the feasibility of medication discontinuation may help to provide better reference for this clinical dilemma.

Identifying dopamine supersensitivity through a randomized controlled study of switching to aripiprazole from other antipsychotic agents in patients with schizophrenia.

BACKGROUND: Aripiprazole has been reported to worsen psychotic symptoms when switching from other antipsychotics, possibly due to dopamine supersensitivity psychosis. OBJECTIVE: This study aimed to explore the predictors and possible underlying mechanisms of aripiprazole-related psychotic exacerbation. METHODS: We conducted an 8-week, open-label, randomized controlled study from October 2007 to September 2009, assigning patients with a primary diagnosis of schizophrenia or schizoaffective disorder to switch from other antipsychotics to aripiprazole with 2-week dual administration, and then to taper off the original agents in fast (n = 38, within 1 week) or slow (n = 41, within 4 weeks) strategies. Positive and Negative Syndrome Scale (PANSS) was examined at day 0, 7, 14, 28, 56. Aripiprazole-related exacerbation (ARE) was defined positive as a 2-point increase in delusion/hallucination dimension score within 28 days compared with baseline. Baseline demographic, clinical and intervention-related variables were compared between the ARE+ and ARE- groups. RESULTS: Of the 79 randomized patients, 21 fulfilled the criteria of ARE+ , and 46 were classified as ARE-. Fourteen patients in the ARE+ group had worsening psychotic symptoms in the first and second weeks. Compared with the ARE- group, the ARE+ group had a higher baseline chlorpromazine equivalent dose (405.8 ± 225.8 mg vs 268.1 ± 165.4 mg, p = 0.007) and was associated with prescription of first-generation antipsychotics (p = 0.038). CONCLUSIONS: A higher dose of original antipsychotics and prescription of first-generation antipsychotics may be associated with a higher risk of ARE. The underlying mechanism might be covert dopamine supersensitivity psychosis. These findings may help to identify high-risk patients and guide appropriate treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT00545467.

Protocol of guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis based on pragmatic design.

AIMS: Patients with psychosis intend to discontinue antipsychotic treatment for various reasons. As antipsychotic discontinuation involves a high risk of relapse, maintenance treatment is recommended by mainstream opinion even when remission is attained. To optimize the risk-to-benefit ratio of long-term antipsychotic treatment, we proposed an operationalized guided dose-reduction algorithm to serve as an intermediate approach as to achieve the lowest effective antipsychotic dose and better functioning for patients with remitted psychosis. METHODS: Outpatients with a history of schizophrenia-related psychotic disorders currently under stable medications and symptoms are eligible to register in this protocol. Patients intending for dose reduction are randomized into 2:1, guided dose reduction group (GDR) versus maintenance treatment group (MTG1). Eligible patients who do not intend to reduce antipsychotics serve as naturalistic maintenance controls (MTG2). The GDR patients reduce no more than 25% of their baseline antipsychotic dose, with at least a 6-month stabilization period before reducing another 25% of their last dose. The timing of the next dose reduction will be determined by shared decision-making with the patient. Following a dose reduction, the patients will receive three consecutive monthly monitoring; otherwise, they receive treatment as usual. DISCUSSION: By employing this pragmatic-based protocol, patients are empowered to evaluate their readiness for next dose reduction attempt. We would like to test in real-world situations if stable patients can reduce antipsychotics not at the expense of an increased risk of relapse, so as to optimize the balance between risk-to-benefit ratios of long-term antipsychotic treatment.

Impaired response to sleep deprivation in heterozygous Disc1 mutant mice.

OBJECTIVES: Sleep/circadian rhythm disturbances are environmental stress factors that might interact with genetic risk factors and contribute to the pathogenesis of psychiatric disorders. METHODS: In this study, the multiple-platform method was used to induce sleep deprivation (SD). We evaluated the impact of 72-hour SD in behavioural, anatomical, and biochemical aspects in heterozygous Disc1 mutant (Disc1 Het) mice, an animal model of schizophrenia. RESULTS: The sleep pattern and circadian activity were not altered in Disc1 Het mice. Yet, we observed differential responses to SD stress between genotypes. Increased microglial density and reduced neuronal proliferative activity were found in the dentate gyrus, a neurogenic niche, in Het-SD mice. Notably, SD-induced Bdnf mRNA elevations were evident in both WT and Het mice, while only in WT-SD mice did we observe increased BDNF protein expression. Our results suggested an SD-induced physical response featured by the elevation of BDNF protein expression to counteract the harmful influences of SD and sufficient DISC1 is required in this process. CONCLUSIONS: The present study proposes that sleep disturbance could be pathogenic especially in genetically predisposed subjects who fail to cope with the stress. Potential therapeutic strategies for psychiatric disorders targeting the mRNA translation machinery could be considered.

Follow-up of subjects labelled with putative pre-psychotic states: Viewed from a transdiagnostic clinical high-at-risk mental state (CHARMS) paradigm.

BACKGROUND: Follow-up of subjects with putative pre-psychotic states is essential to clarify the transition process to psychosis, while "non-converters" also deserve clinical attention as many may evolve into other psychiatric disorders with diverse outcomes. This study aimed to examine help-seeking individuals who have been labelled at clinical high-risk state but not converting to full-blown psychosis during first two years of follow-up. METHODS: A retrospective observational cohort study of help-seeking subjects was conducted by reviewing medical records of participants in a previous early psychosis study at the study hospital between 2006 and 2020. We portrayed those who developed first episode psychosis after first 2-year follow-up in detail, and provided sketches of clinical macrophenotypes other than psychosis emerging from subjects among different risk groups. RESULTS: Among 132 eligible subjects, data of 98 (74.2%) were available for detailed evaluation. Of these, 15 transitioned to first-episode psychosis (11.4%) with time to psychosis from 2 to 11 years, 11 had anxiety spectrum (8.3%), 11 had depressive spectrum (8.3%), 10 had obsessive compulsive (7.6%), 5 had bipolar spectrum disorders (3.8%), 13 had predominantly schizotypal (9.8%) and 4 had other personality traits (3%), and 13 had problems attributable to adjustment or developmental issues (9.8%). CONCLUSION: Various diagnoses, either full- or sub-threshold, appropriately describe the diverse clinical phenomenology of a cohort presenting with non-specific and/or subthreshold psychotic symptoms. The clinical high-at-risk mental state (CHARMS) paradigm provides a reasonable transdiagnostic approach for orienting clinicians' attention toward young subjects seeking mental health help at an early stage of illness to potentially pluripotent trajectories.

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations.

People with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10-6). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.

Challenging the Minimum Effective Antipsychotic Dose During Maintenance: Implications From 10-Year Follow-Up of First Episode Psychosis.

Background: Contradictory messages regarding the necessity of long-term antipsychotic treatment after first episode psychosis arouse deliberations in clinical practice. We explored if there is an alternative beyond the dichotomy of maintenance treatment and discontinuation of medications. Methods: We conducted a retrospective observational study by reviewing medical records at the study hospital of a cohort of patients since their participation in an early psychosis study starting from 2006, with special interests in patients able to maintain good functioning under treatment with a low antipsychotic dose. Results: Of the 81 patients with first-episode psychosis, 55 patients (67.9%) had follow-up information for longer than 5 years. The majority (n = 46, 83.6%) had non-affective psychosis, 20 patients (36.4%) had full-time employment/education by the time of their latest visit; among them, 15 patients received dosage of antipsychotics no more than the minimum effective dose [chlorpromazine equivalent (CPZE) dose, 200 mg/day]. Besides, 10 of 55 patients (18.2%) only received very low dose antipsychotics (CPZE < 50 mg/day) during maintenance, which was significantly correlated to good functioning. Being male, having a history of hospitalization, and being on clozapine therapy were correlated to poorer functioning. Antipsychotic-free status was achieved only in two non-psychotic patients. Conclusions: A substantial proportion of patients could achieve good functioning under low-dose antipsychotic maintenance after first-episode psychosis, even if they could not completely withdraw antipsychotics in the long term. Optimizing the balance between preventing relapse and preserving functioning by fine-tuning antipsychotic dosage during maintenance is a challenge warranting more clinical attention.

P50, N100, and P200 Auditory Sensory Gating Deficits in Schizophrenia Patients.

BACKGROUND: Sensory gating describes neurological processes of filtering out redundant or unnecessary stimuli during information processing, and sensory gating deficits may contribute to the symptoms of schizophrenia. Among the three components of auditory event-related potentials reflecting sensory gating, P50 implies pre-attentional filtering of sensory information and N100/P200 reflects attention triggering and allocation processes. Although diminished P50 gating has been extensively documented in patients with schizophrenia, previous studies on N100 were inconclusive, and P200 has been rarely examined. This study aimed to investigate whether patients with schizophrenia have P50, N100, and P200 gating deficits compared with control subjects. METHODS: Control subjects and clinically stable schizophrenia patients were recruited. The mid-latency auditory evoked responses, comprising P50, N100, and P200, were measured using the auditory-paired click paradigm without manipulation of attention. Sensory gating parameters included S1 amplitude, S2 amplitude, amplitude difference (S1-S2), and gating ratio (S2/S1). We also evaluated schizophrenia patients with PANSS to be correlated with sensory gating indices. RESULTS: One hundred four patients and 102 control subjects were examined. Compared to the control group, schizophrenia patients had significant sensory gating deficits in P50, N100, and P200, reflected by larger gating ratios and smaller amplitude differences. Further analysis revealed that the S2 amplitude of P50 was larger, while the S1 amplitude of N100/P200 was smaller, in schizophrenia patients than in the controls. We found no correlations between sensory gating indices and schizophrenia positive or negative symptom clusters. However, we found a negative correlation between the P200 S2 amplitude and Bell's emotional discomfort factor/Wallwork's depressed factor. CONCLUSION: Till date, this study has the largest sample size to analyze P50, N100, and P200 collectively by adopting the passive auditory paired-click paradigm without distractors. With covariates controlled for possible confounds, such as age, education, smoking amount and retained pairs, we found that schizophrenia patients had significant sensory gating deficits in P50-N100-P200. The schizophrenia patients had demonstrated a unique pattern of sensory gating deficits, including repetition suppression deficits in P50 and stimulus registration deficits in N100/200. These results suggest that sensory gating is a pervasive cognitive abnormality in schizophrenia patients that is not limited to the pre-attentive phase of information processing. Since P200 exhibited a large effect size and did not require additional time during recruitment, future studies of P50-N100-P200 collectively are highly recommended.

Abnormally low prolactin levels in schizophrenia patients after switching to aripiprazole in a randomized trial: a biomarker for rebound in psychotic symptoms?

BACKGROUND: Switching to aripiprazole from other antipsychotics can avoid antipsychotic-induced hyperprolactinemia but may result in an abnormally low prolactin level. This study aimed to assess whether the aripiprazole-induced abnormally low prolactin level was a biomarker for subsequent rebound of positive symptoms in schizophrenia patients. METHODS: Participants were 63 patients in an 8-week trial of switching to aripiprazole, in which preswitching antipsychotics were maintained for the first 2 weeks and aripiprazole was fixed at 15 mg orally throughout the trial. A prolactin level of < 3.7 ng/ml was defined as abnormally low, and an increase of two or more points in the positive subscore of the Positive and Negative Syndrome Scale at two adjacent ratings was defined as a psychotic rebound. RESULTS: Among 63 patients, 25 (39.7%) had an abnormally low prolactin level and 21 (33.3%) had a psychotic rebound after switching to aripiprazole. In patients with abnormally low prolactin levels, 48.0% of them had a rebound in psychotic symptoms, whereas in those without abnormally low prolactin levels 23.7% did so. Multivariable logistic regression analysis with adjustment for sex, early age at onset, and preswitching medications revealed that abnormally low prolactin levels were associated with psychotic rebound (adjusted odds ratio = 3.55, 95% confidence interval = 1.02, 12.5). Furthermore, there was concurrency between the trend of the cumulative proportion of patients having an abnormally low prolactin level and that of the cumulative proportion of patients having a rebound in psychotic symptoms. CONCLUSIONS: An abnormally low prolactin level after switching to aripiprazole in schizophrenia patients was a potential warning sign of a psychotic rebound. Hence, monitoring of prolactin levels after switching to aripiprazole may help avoid such rebound in schizophrenia. TRIAL REGISTRATION: NCT00545467 ; Date of registration: 17/10/2007.

Generalization of diffusion magnetic resonance imaging-based brain age prediction model through transfer learning.

Brain age prediction models using diffusion magnetic resonance imaging (dMRI) and machine learning techniques enable individual assessment of brain aging status in healthy people and patients with brain disorders. However, dMRI data are notorious for high intersite variability, prohibiting direct application of a model to the datasets obtained from other sites. In this study, we generalized the dMRI-based brain age model to different dMRI datasets acquired under different imaging conditions. Specifically, we adopted a transfer learning approach to achieve domain adaptation. To evaluate the performance of transferred models, brain age prediction models were constructed using a large dMRI dataset as the source domain, and the models were transferred to three target domains with distinct acquisition scenarios. The experiments were performed to investigate (1) the tuning data size needed to achieve satisfactory performance for brain age prediction, (2) the feature types suitable for different dMRI acquisition scenarios, and (3) performance of the transfer learning approach compared with the statistical covariate approach. By tuning the models with relatively small data size and certain feature types, optimal transferred models were obtained with significantly improved prediction performance in all three target cohorts (p â€‹< â€‹0.001). The mean absolute error of the predicted age was reduced from 13.89 to 4.78 years in Cohort 1, 8.34 to 5.35 years in Cohort 2, and 8.74 to 5.64 years in Cohort 3. The test-retest reliability of the transferred model was verified using dMRI data acquired at two timepoints (intraclass correlation coefficient â€‹= â€‹0.950). Clinical sensitivity of the brain age prediction model was investigated by estimating the brain age in patients with schizophrenia. The prediction made by the transferred model was not significantly different from that made by the reference model. Both models predicted significant brain aging in patients with schizophrenia as compared with healthy controls (p â€‹< â€‹0.001); the predicted age difference of the transferred model was 4.63 and 0.26 years for patients and controls, respectively, and that of the reference model was 4.39 and -0.09 years, respectively. In conclusion, transfer learning approach is an efficient way to generalize the dMRI-based brain age prediction model. Appropriate transfer learning approach and suitable tuning data size should be chosen according to different dMRI acquisition scenarios.

Clinical implications of oxidative stress in schizophrenia: Acute relapse and chronic stable phase.

Several studies have suggested a higher oxidative stress in schizophrenia. However, the implications of oxidative stress on clinical symptoms remain unclear. This study aimed to investigate the platelet oxidative stress in different stages of schizophrenia (i.e., chronic stable and acute relapse) in order to clarify the clinical implications of oxidative stress and the treatment effects. We recruited 43 chronic stable patients with schizophrenia and 48 non-psychiatric controls. Platelets were collected for measuring the levels of nitric oxide (NO), lipid peroxidation (LPO), and glutathione (GSH) and the activity of GSH peroxidase (GPx) and superoxide dismutase (SOD). The levels and activity were compared between patients and controls and were examined for their relationship with clinical severity. Further, we evaluated the changes of levels and activity before and after treatment in an independent sample with acute relapse (N = 19). Patients with chronic stable schizophrenia had lower SOD activity compared to non-psychiatric controls. In chronic stable patients, NO level was positively correlated with positive and disorganized symptoms, while the GPx activity were negatively correlated with excitement. In patients with acute relapse, the levels and activity were not different before and after four weeks of antipsychotic treatment, but LPO level was negatively correlated with pretreatment disorganized symptoms. The change of LPO can also predict the change of disorganized symptoms and negative symptoms. Our findings suggest that platelet SOD was lower in chronic stable schizophrenia. Platelet LPO may be associated with less disorganized symptoms in acute relapse patients and better treatment response.