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Gamma oscillations are essential for brain communication. The 40 Hz neural oscillation deficits in schizophrenia impair left frontotemporal connectivity and information communication, causing auditory hallucinations. Transcranial alternating current stimulation is thought to enhance connectivity between different brain regions by modulating brain oscillations. In this work, we applied a frontal-temporal-parietal 40 Hz-tACS stimulation strategy for treating auditory hallucinations and further explored the effect of tACS on functional connectivity of brain networks. 32 schizophrenia patients with refractory auditory hallucinations received 20daily 20-min, 40 Hz, 1 mA sessions of active or sham tACS on weekdays for 4 consecutive weeks, followed by a 2-week follow-up period without stimulation. Auditory hallucination symptom scores and 64-channel electroencephalograms were measured at baseline, week2, week4 and follow-up. For clinical symptom score, we observed a significant interaction between group and time for auditory hallucinations symptoms (F(3,90) = 26.964, p < 0.001), and subsequent analysis showed that the 40Hz-tACS group had a higher symptom reduction rate than the sham group at week4 (p = 0.036) and follow-up (p = 0.047). Multiple comparisons of corrected EEG results showed that the 40Hz-tACS group had higher functional connectivity in the right frontal to parietal (F (1,30) = 7.24, p = 0.012) and right frontal to occipital (F (1,30) = 7.98, p = 0.008) than the sham group at week4. Further, functional brain network controllability outcomes showed that the 40Hz-tACS group had increased average controllability (F (1,30) = 6.26, p = 0.018) and decreased modality controllability (F (1,30) = 6.50, p = 0.016) in the right frontal lobe compared to the sham group. Our polit study indicates that 40Hz-tACS combined with medicine may be an effective treatment for targeting symptoms specific to auditory hallucinations and altering functional connectivity and controllability at the network level.

Treatment-resistant schizophrenia (TRS) affects up to one in three individuals with schizophrenia and is associated with a significant clinical, social, and economic burden. Different from treatment-responsive forms, TRS appears to involve other biological mechanisms extending beyond dopaminergic dysfunctions. This review outlines current knowledge on the molecular and cellular basis of TRS, focusing on alterations in glutamate signaling, imbalances between excitatory and inhibitory activity, disruptions in D-amino acid metabolism, and evidence of neuroinflammation, oxidative stress, and mitochondrial or endoplasmic reticulum dysfunction. Data from genomics, proteomics, metabolomics, preclinical models, and postmortem studies suggest that TRS may have a peculiar neurobiological substrate. Further, multimodal brain imaging studies reveal differences in brain structure, white matter integrity, and network connectivity when compared to treatment-responsive individuals. Altogether, these findings support a shift from the traditional dopamine hypothesis toward a more comprehensive model that includes multiple immune, metabolic, and synaptic factors. Understanding the possible interplay of these complex mechanisms may lead to the identification of potential biomarkers that may help to predict antipsychotic response, as well as the development of more targeted treatments. Early recognition and a deeper biological insight into TRS are essential for improving care and guiding personalized therapeutic strategies.

\"Many schizophrenics experience their condition as one of radical incarceration, mind-altering medications, isolation, and dehumanization. At a time when the treatment of choice is anti-psychotic medication, world-renowned psychoanalyst Christopher Bollas shows that schizophrenics can be helped by much more humane treatments, and explains that they have a chance to survive and even reverse the process if they have someone to talk with them regularly and for a sustained period soon after they show signs of imminent breakdown. In this sensitive and evocative narrative, Bollas draws on his personal experiences working with schizophrenics since the 1960s. He offers his interpretation of how schizophrenia develops, typically in the teen years, as an adaptation during the difficult transition to adulthood.\"-- Provided by publisher.

Background A subset of patients with schizophrenia do not respond sufficiently to conventional antipsychotic treatment and often have a more complex clinical course, including high rates of sleep disturbances, which can contribute to further worsening of symptoms. However, sleep disturbances are often overlooked in clinical psychiatric settings, and non-pharmacological treatment options are not initiated. Cognitive behavioral therapy for insomnia (CBT-I) has been shown to effectively ameliorate sleep disturbances in schizophrenia but is yet to be assessed in treatment-resistant schizophrenia. In the present study, we aim to investigate the efficacy of CBT-I versus standard cognitive behavioral therapy (CBT), an active control intervention. Methods Sixty patients diagnosed with treatment-resistant schizophrenia and comorbid sleep disturbance will be included in this randomized intervention study. Included patients will be randomized to 8–10 sessions of psychotherapy with either CBT-I (active intervention) or regular CBT (active control) following baseline. At baseline and 12-week follow-up, patients will be assessed with clinical interviews (Positive and Negative Syndrome Scale), self-reported measures (e.g., Insomnia Severity Index), and polysomnography. The 24-week follow-up will include the same assessments apart from polysomnography. The active intervention group will receive an individual course of treatment with CBT-I focused on the patients’ sleep patterns, while the active control group will receive an individual course of treatment with standard cognitive behavioral therapy (CBT) focused on patients’ psychopathology. It is hypothesized that while both groups will show improvements on central outcome measures, CBT-I will show greater improvements in sleep disturbances. Further, it is hypothesized that the improvement in sleep disturbances will correlate with an improvement in positive symptoms. Lastly, it is anticipated that the CBT-I group will show objective improvements in sleep architecture, such as sleep latency, wake after sleep onset, sleep efficiency, and total sleep time, compared to the CBT group. Discussion Should CBT-I prove efficacious in improving sleep disturbances in treatment-resistant schizophrenia, it would provide an avenue for a cost-beneficial, short-term, and implementable non-pharmacological treatment of a severe comorbidity in complex schizophrenia patients. Potential issues pertaining to the completion of the study are discussed. Trial registration ClinicalTrials.gov NCT06749444. Registered on December 27, 2024.

Abstract Insufficient or lack of response to antipsychotic medications in some patients with schizophrenia is a major challenge in psychiatry, but the underlying mechanisms remain unclear. Two seemingly unrelated observations, cerebral white matter and N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been linked to treatment-resistant schizophrenia (TRS). As NMDARs are critical to axonal myelination and signal transduction, we hypothesized that NMDAR antibody (Ab), when present in schizophrenia, may impair NMDAR functions and white matter microstructures, contributing to TRS. In this study, 50 patients with TRS, 45 patients with nontreatment-resistant schizophrenia (NTRS), 53 patients with schizophrenia at treatment initiation schizophrenia (TIS), and 90 healthy controls were enrolled. Serum NMDAR Ab levels and white matter diffusion tensor imaging fractional anisotropy (FA) were assessed. The white matter specificity effects by NMDAR Ab were assessed by comparing with effects on cortical and subcortical gray matter. Serum NMDAR Ab levels of the TRS were significantly higher than those of the NTRS (P = .035). In patients with TRS, higher NMDAR Ab levels were significantly associated with reduced whole-brain average FA (r = −.37; P = .026), with the strongest effect at the genu of corpus callosum (r = −.50; P = .0021, significant after correction for multiple comparisons). Conversely, there was no significant correlation between whole-brain or regional cortical thickness or any subcortical gray matter structural volume and NMDAR Ab levels in TRS. Our finding highlights a potential NMDAR mechanism on white matter microstructure impairment in schizophrenia that may contribute to their treatment resistance to antipsychotic medications.

The ClozaGene Study is a nationwide cohort of adults who have been treated with clozapine. While clozapine is indicated in the management of treatment-resistant schizophrenia, it is associated with a considerable adverse drug reaction (ADR) burden, and not all patients achieve adequate symptomatic response. The current study focuses on self-reported experiences of clozapine use and response, clozapine-associated ADRs, and mental health comorbidity. A total of 1021 participants (41.0% female; aged 46.2 ± 10.6 years [range 18-66]) were recruited via a mail-out based on prescriptions for clozapine. Participants completed a self-report questionnaire. Most participants (90.1%, n = 912) were living with schizophrenia while 41.5% reported a lifetime diagnosis of depression, 15.6% bipolar disorder, and 8.1% schizoaffective disorder. Clozapine was currently prescribed to 944 (92.5%) participants and 37.8% of these participants self-reported currently taking additional antipsychotic medication. Nearly 3 quarters of participants living with schizophrenia reported that clozapine helped control their schizophrenia symptoms moderately to very well. The most commonly reported ADRs were sialorrhea (80.3%), weight gain (71.0%), constipation (56.9%), and sedation (52.8%). The prevalence of clozapine cessation due to clozapine-induced myocarditis and neutropenia was 1% and 0.4%, respectively. Our findings highlight the high rate of psychotic and metabolic symptoms and ADRs among adults prescribed clozapine in the general Australian population. Future genomic analyses will focus on identifying genetic variants influencing clozapine treatment response and side effects.