Harvey PD, Kaul I, Chataverdi S
… +6 more, Patel T, Claxton A, Sauder C, Harvey CD, Brannan SK, Horan WP
Schizophr Res
· 2026 Aug · PMID 42019313
·
Publisher ↗
BACKGROUND: Negative symptoms may worsen with age in schizophrenia. Behavioral manifestations of avolition include reduced physical activity, suggesting a linkage with sedentary behavior. We used active and passive digit...BACKGROUND: Negative symptoms may worsen with age in schizophrenia. Behavioral manifestations of avolition include reduced physical activity, suggesting a linkage with sedentary behavior. We used active and passive digital phenotyping to examine treatment related changes in a 12-month open label trial with xanomeline/trospium chloride. Activities were characterized by Ecological Momentary Assessment (EMA) reports of physical activity and step counts collected with actigraphy. METHODS: Participants were 312 male and female outpatients with schizophrenia (167 age 45 or older). They answered EMA surveys 3 times per day, 7 days per week, one week per month. On EMA survey days, participants wore an actigraph. EMAs queried location, social context, positive affect (PA), and activities. EMA-measured activities were characterized as recumbent, seated, standing, and moving. RESULTS: Participants who were adherent to both EMA and Actigraphy answered 33,657 EMA surveys and provided 7957 participant-days of actigraphy. At baseline, older participants had lower step counts, (p < .001), more recumbent and seated activities (both p < .001) and fewer standing and moving activities (both p < .01). There were treatment-related reductions in sedentary activities and increases in standing and moving, (p < .001. Steps increased over 12 months, p < .001. Momentary PA increased over time and was associated changes in steps, p < .001; increased step counts correlated with decreased sedentary activities and increased standing and moving, p < .001. IMPLICATIONS: Despite age-related baseline differences in sedentary behavior, treatment-related benefits were equivalent. These data suggest that reduced physical activity can be treated, possibly improving health outcomes. Substantial correlations between EMA-reported activities and step counts support the validity of EMA assessment of activities.
Schizophr Res
· 2026 Aug · PMID 42000633
·
Publisher ↗
BACKGROUND: Negative symptoms of schizophrenia are highly disabling and remain insufficiently responsive to pharmacological treatment. High-definition transcranial direct current stimulation (HD-tDCS) targeting the left...BACKGROUND: Negative symptoms of schizophrenia are highly disabling and remain insufficiently responsive to pharmacological treatment. High-definition transcranial direct current stimulation (HD-tDCS) targeting the left dorsolateral prefrontal cortex (DLPFC) may improve these symptoms, but its neurophysiological correlates remain unclear. METHODS: This study was a secondary fNIRS analysis of a randomized, double- blind, sham-controlled trial. Sixty clinically stable patients with schizophrenia and predominant negative symptoms received active or sham online HD-tDCS over the left DLPFC while performing a two-back working memory task. Functional near-infrared spectroscopy was used to assess prefrontal activation during the two-back task and verbal fluency task (VFT), as well as resting-state functional connectivity. Graph- theoretical analyses quantified global efficiency (Eg) and local efficiency (Eloc). Negative symptoms were assessed using the PANSS factor score for negative symptoms (FSNS) and the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: Active HD-tDCS was associated with significantly greater increases in left DLPFC activation during both the two-back task and VFT compared with sham stimulation. Resting-state Eg and Eloc did not differ significantly between groups. Changes in task-evoked fNIRS signals were not significantly correlated with improvements in negative symptoms. However, lower resting-state Eloc was significantly associated with greater negative symptom severity. CONCLUSIONS: Online HD-tDCS enhanced task-evoked left DLPFC activation in schizophrenia, but these changes were not directly related to clinical improvement. Resting-state local efficiency may better reflect the severity of negative symptoms than task-based activation, suggesting a potential role for intrinsic prefrontal network organization in schizophrenia.
Janssen H, van den Berg KC, Keijsers GPJ
… +1 more, Marcelis MC
Schizophr Res
· 2026 Aug · PMID 42000632
·
Publisher ↗
BACKGROUND: Emotional Mental Imagery (eMI) may contribute to the development and persistence of auditory verbal hallucinations (AVHs), particularly through imagery appraisals. However, empirical evidence from large clini...BACKGROUND: Emotional Mental Imagery (eMI) may contribute to the development and persistence of auditory verbal hallucinations (AVHs), particularly through imagery appraisals. However, empirical evidence from large clinical samples is limited. The present study examined associations between seven characteristics of eMI (i.e., frequency, quality (liveliness, compellingness), and appraisals (encapsulated beliefs and metacognitions)) and AVH severity, exploring whether levels of depression and anxiety mediate this association. METHODS: 107 individuals with subclinical (psychotic-like experiences) and clinical psychosis and current AVHs completed cross-sectional questionnaires on eMI, AVH severity, and the level of depression and anxiety. A multiple regression analysis was applied to test the association between seven aspects of eMI and AVH severity. Exploratory mediation analyses using the PROCESS macro for SPSS were applied. RESULTS: eMI characteristics were positively associated with the severity of AVHs in individuals with subclinical and clinical psychosis (η= 0.239, p < .001). Lower positive encapsulated beliefs (η= 0.072, p = .007) and higher negative metacognitions (η = 0.077, p = .005) were associated with more severe AVHs. The remaining five imagery characteristics failed to show significant associations with AVH severity. A significant indirect effect was found for negative metacognitions (η= 0.059, 99%CI [0.04, 0.36]) on AVH severity via depression levels. Indirect pathways via anxiety did not reach statistical significance. DISCUSSION: Imagery appraisals seem important in relation to AVH severity across the psychosis spectrum, potentially via a mediating role of depression levels. Future studies are needed to further examine the underlying cognitive processes driving this association.
Prettyman GE, Kales E, Didier P
… +15 more, Savage C, Levinson T, Rosenbaum S, de Moraes Leme LFV, Kable JW, Moore TM, Satterthwaite TD, Davatzikos C, Shinohara RT, Elliott MA, Kohler CG, Gur RC, Gur RE, Calkins ME, Wolf DH
Schizophr Res
· 2026 Aug · PMID 41996963
·
Publisher ↗
BACKGROUND: Youth at risk for psychosis based on subthreshold positive symptoms (PS) show elevated negative symptoms such as amotivation, associated with disability and increased risk of psychotic transition. Intrinsic m...BACKGROUND: Youth at risk for psychosis based on subthreshold positive symptoms (PS) show elevated negative symptoms such as amotivation, associated with disability and increased risk of psychotic transition. Intrinsic motivation (IM), the desire to obtain internal satisfactions such as mastery or curiosity, is more impaired in psychosis than extrinsic motivation (EM), the desire to obtain external rewards. However, the neural mechanisms underlying IM impairment in PS have scarcely been studied, and never with measures designed for this purpose. METHODS: We applied a novel fMRI fractal memory task that leveraged distinct feedback conditions designed to engage IM and EM processes, along with self-reported IM and EM, in adolescents and young adults with PS (n = 95) and healthy controls (CT, n = 31). RESULTS: We hypothesized that IM would generate reinforcement signals in the ventral striatum (VS), a core motivation region, as individuals internally evaluated their performance relative to their expectations. We further hypothesized that reduced VS activation would relate dimensionally to lower self-reported IM across both PS and CT groups. Consistent with these hypotheses, VS and related motivation circuitry preferentially activated to higher confidence task choices and to reward prediction error during performance feedback. VS activation during task choices related selectively to IM but not EM. CONCLUSIONS: Our findings highlight the role of VS in encoding self-generated reinforcement signals, and demonstrate a selective relationship between VS activation and IM. Understanding the link between VS dysfunction and impaired IM will facilitate therapeutic advances to remediate IM deficits in those at risk for psychosis.
Schizophr Res
· 2026 Aug · PMID 41996962
·
Publisher ↗
In people with schizophrenia, anhedonia is commonly conceptualized using the notion of an "emotion paradox." This "emotion paradox" refers to relatively preserved positive affect during immediate exposure to pleasant sti...In people with schizophrenia, anhedonia is commonly conceptualized using the notion of an "emotion paradox." This "emotion paradox" refers to relatively preserved positive affect during immediate exposure to pleasant stimuli despite reduced pleasure on non-current self-reports and lower engagement in pleasurable activities. Across levels of analysis, case-control studies have converged in suggesting impairments in representational and evaluative processes involved in anticipating, maintaining, and translating reward into motivated behavior, rather than a uniform incapacity to experience pleasure in the moment. In this critical perspective, we argue that the "emotion paradox" framework remains valuable but requires refinement. We review evidence that normatively pleasant situations may elicit co-occurring negative affect, affective ambivalence, and reduced positivity offset, each of which may weaken the motivational impact of reward. We further argue that momentary positive affect is not uniform across schizophrenia samples but may vary with overall negative symptom severity. Moreover, we show how measures labeled as "momentary" differ in their reliance on bottom-up and top-down information sources when individuals report emotional experience. These methodological differences may create method-specific artifacts that mimic a dissociation between intact laboratory responding and impaired non-current affective self-reports. We conclude that case-control approaches may obscure meaningful heterogeneity and that understanding anhedonia in schizophrenia requires greater attention to negative affective dynamics, dimensional accounts of negative symptoms, and impaired representational processes.
Miller CR, Taylor SF, Breier A
… +2 more, Vohs JL, Burton CZ
Schizophr Res
· 2026 Aug · PMID 41996961
·
Publisher ↗
OBJECTIVE: Improving outcomes for individuals with first-episode psychosis (FEP) benefits from rapid and accurate symptom assessment, yet few measures exist that can be used in 'real world' clinical settings. We evaluate...OBJECTIVE: Improving outcomes for individuals with first-episode psychosis (FEP) benefits from rapid and accurate symptom assessment, yet few measures exist that can be used in 'real world' clinical settings. We evaluated the psychometric properties of a clinician-administered symptom measure, the COMPASS-10, and a briefer conceptually-derived 6-item version (the COMPASS-6), including factor structure, convergent validity, and internal consistency. PARTICIPANTS AND METHODS: Data were gathered from individuals with FEP treated through coordinated specialty care (CSC) clinics as part of the Early Psychosis Intervention Network (EPINET) (N = 3187; age M = 21.4, SD = 4.02; 54.7% male; 43.5% White, 30% Black/African American) in the United States. We used confirmatory factor analysis to evaluate three-factor (positive, negative, and affective symptoms) and two-factor models (positive and negative symptoms) for the COMPASS-10 and COMPASS-6, respectively. Internal consistencies were calculated using McDonald's omega statistic. Convergent validity was assessed via correlations with the Modified Colorado Symptom Index (MCSI). RESULTS: Fit statistics showed that the three-factor models for the COMPASS-10 and the two-factor model for the COMPASS-6 had generally acceptable fit parameters, with the COMPASS-6 having the best fit indices. Both measures had good internal consistency, and both measures had small to medium correlations with the MCSI. CONCLUSIONS: Findings from a large clinical sample of individuals with FEP supported the psychometric properties of the COMPASS-10 and COMPASS-6 scales with individuals with FEP in largely community settings, demonstrating adequate support for the hypothesized factor structures, as well as good internal consistency and convergent validity with another measure of psychopathology.
BACKGROUND: Psychosis results from a complex interaction between genetic vulnerability and environmental risk factors, including perinatal stress, which may influence neurodevelopment and endocrine function. Dysregulatio...BACKGROUND: Psychosis results from a complex interaction between genetic vulnerability and environmental risk factors, including perinatal stress, which may influence neurodevelopment and endocrine function. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and prolactin secretion has been linked to cognitive impairment and symptom severity in early psychosis. This study examined whether perinatal stress moderates the associations between hormonal alterations and cognitive performance or clinical symptoms. METHODS: Fifty-one outpatients with early psychosis (<3 years since onset) and 50 healthy controls were assessed. Cognitive performance was evaluated using the MATRICS Consensus Cognitive Battery and additional tasks. Perinatal stress exposure was determined through clinical interviews and medical records. Hormonal measures included fasting plasma prolactin, morning salivary cortisol, and the dexamethasone suppression test ratio (DSTR; 0.25 mg). Multiple linear regression models tested main and interaction effects between perinatal stress and hormonal variables on cognitive domains and symptom severity, adjusting for relevant covariates. RESULTS: Perinatal stress significantly moderated associations between prolactin levels and several cognitive domains. Higher prolactin was associated with poorer processing speed, verbal memory, visual memory, and social cognition, particularly among individuals without perinatal stress. DSTR also interacted with perinatal stress in predicting executive functioning: higher DSTR was linked to worse Stroop performance mainly in those without perinatal stress. Additionally, elevated morning cortisol was associated with greater negative symptom severity among individuals with perinatal stress. CONCLUSIONS: Perinatal stress modifies the relationship between hormonal dysregulation and cognitive and clinical outcomes in early psychosis, highlighting the relevance of early-life stress in shaping endocrine and neurocognitive trajectories.
BACKGROUND: The exposome is strongly linked to psychosis risk and may affect cognition in first-episode psychosis (FEP). Studying FEP patients and their unaffected siblings provides a framework to explore this relationsh...BACKGROUND: The exposome is strongly linked to psychosis risk and may affect cognition in first-episode psychosis (FEP). Studying FEP patients and their unaffected siblings provides a framework to explore this relationship. This study examined whether environmental risk, measured by the Maudsley Environmental Risk Score (ERS), is associated with sex differences in cognitive performance in FEP patients and their unaffected siblings. METHODS: 72 individuals with FEP (43 males and 29 females) and 98 siblings (33 males and 65 females) from the PAFIP and PAFIP-FAMILIAS cohorts were assessed. Participants completed sociodemographic, clinical, and neuropsychological assessments covering verbal memory, visual memory (VisM), processing speed (PS), executive functions, motor dexterity (MD), attention, theory of mind (ToM) and Global Cognitive Functioning (GCF). ERS was calculated using data on ethnicity, urbanicity, cannabis use, childhood adversity, paternal age, and obstetric complications. Group comparisons were conducted by linear mixed-effects and regression models. RESULTS: Across both sex groups, individuals with FEP showed poorer cognitive performance than their unaffected siblings. After correction for multiple comparisons, males with FEP showed significantly lower MD than brothers. In females, lower performance in PS, VisM, and GCF was observed in patients compared with sisters. Adjustment for ERS did not substantially change these differences. CONCLUSIONS: These findings suggest that cognitive differences between individuals with FEP and their unaffected siblings may follow sex-specific patterns. These differences persisted after accounting for cumulative environmental exposure as measured by the ERS, indicating that environmental factors captured by this index may not fully explain cognitive disparities within familial-risk contexts.
Cognitive impairment associated with schizophrenia (CIAS) is a fundamental symptom of the disorder, which significantly affects individuals' daily functioning and overall quality of life. Currently available antipsychoti...Cognitive impairment associated with schizophrenia (CIAS) is a fundamental symptom of the disorder, which significantly affects individuals' daily functioning and overall quality of life. Currently available antipsychotic drugs have little beneficial effect on CIAS, so there remains a significant unmet need to continue development of novel treatment options. Typical assessment of CIAS relies on performance based cognitive tests which have limitations in both application and interpretation. The interview-based Schizophrenia Cognition Rating Scale (SCoRS) was originally designed to facilitate the measurement of CIAS and related functioning as viewed by patients, informants, and interviewers, and has the potential to provide a measure of clinically meaningful changes in cognitive impairment and related functional capacity. This study used confirmatory factor analysis (CFA) to assess the structural validity of the SCoRS Interviewer total score, together with known-groups validity assessment. Using data from a clinical trial of iclepertin in adult patients with schizophrenia, we explored the dimensionality of the SCoRS using various CFA models including single factor, four correlated factor, and bifactor models. Three external reference anchors were used to assess known-groups validity, based on clinician and study partner ratings of disease severity over time. We found that the models support the essential unidimensionality of the SCoRS, while the known-group validity analysis showed that the SCoRS interviewer total score was able to discriminate between severity groups, which supports its use for measuring CIAS in both clinical research and real-world clinical practice.
Our previous study demonstrated that the niacin flush response and pathway biomarkers could differentiate schizophrenia patients from healthy controls. Whether these biomarkers also distinguish schizophrenia from bipolar...Our previous study demonstrated that the niacin flush response and pathway biomarkers could differentiate schizophrenia patients from healthy controls. Whether these biomarkers also distinguish schizophrenia from bipolar disorder remains unclear. This study aimed to develop and validate predictive models to differentiate schizophrenia, bipolar disorder, and healthy controls. Independent training and validation sets were established for schizophrenia and healthy controls, and model performance was further evaluated in distinguishing schizophrenia from bipolar disorder. We recruited 223 schizophrenia patients, 62 bipolar disorder patients, and 162 healthy controls in Taiwan. Logistic regression was used to construct prediction models. The prediction model demonstrated high discriminative performance in differentiating individuals with schizophrenia from healthy controls, achieving an AUC of 0.97 in the training set and 0.92 in the validation set. Furthermore, the model effectively distinguished schizophrenia from bipolar disorder, with an AUC of 0.96, and 0.91 for cross-validated results. Niacin flush response and GPR109A were the most significant for differentiating schizophrenia patients from healthy controls, while EP2, PGE2, and GPR109A were key for schizophrenia and bipolar disorder classification. Principal component and partial least squares-discriminant analyses confirmed separation among different groups. Shapley Additive Explanation value analysis demonstrated divergent feature importance of biomarkers, indicating differential regulation of the niacin flush pathway in schizophrenia and bipolar patients. We externally validated that biomarkers from the niacin flush pathway were good candidates for distinguishing schizophrenia patients from healthy controls, while EP2, PGE2, and GPR109A may further aid in differentiating schizophrenia from bipolar disorder, potentially reflecting their distinct etiological underpinnings.
Kamp D, Riesbeck M, Lowe A
… +16 more, Weide K, Bechdolf A, Leopold K, Brockhaus-Dumke A, Klos B, Hurlemann R, Wasserthal S, Muthesius A, Kambeitz J, Klingberg S, Hölz L, Hellmich M, Rosenberger KD, Sadura S, Meyer-Lindenberg A, Wölwer W
OBJECTIVE: Cognitive remediation therapy (CRT) is an evidence-based behavioral intervention that enhances functional outcomes in schizophrenia patients by improving cognition. However, not all patients benefit equally fr...OBJECTIVE: Cognitive remediation therapy (CRT) is an evidence-based behavioral intervention that enhances functional outcomes in schizophrenia patients by improving cognition. However, not all patients benefit equally from CRT, and predictors of real-world functional improvement are poorly understood. This study aimed to identify patient-related baseline predictors of functional improvement by evaluating two distinct CRT approaches targeting different types of cognition: social cognition (Integrated Social Cognition and Social Skills Training, ISST) and neurocognition (Neurocognitive Remediation Therapy, NCRT). METHODS: This secondary analysis used data from a large, multicenter randomized controlled trial. Participants with schizophrenia (N = 174) were randomly assigned to ISST or NCRT for six months. Multiple linear regression analyses were performed to determine whether baseline demographic, cognitive, clinical, or functional characteristics predicted changes in real-world functioning, as measured by the Social and Occupational Functioning Assessment Scale. RESULTS: The Digit Symbol Substitution Test was the strongest and most consistent predictor of functional improvement. Lower baseline functioning also predicted greater gains, although only in multivariable models. Domain-specific predictors were identified for each intervention: better affect recognition predicted better outcomes in ISST, whereas verbal memory did so in NCRT. CONCLUSION: The CRT approaches studied here appear to be most effective for individuals with a more preserved baseline level of cognitive performance, especially in terms of processing speed. These findings support the use of brief cognitive assessments to guide CRT implementation and suggest that tailoring interventions to individual cognitive profiles may enhance treatment efficacy.
BACKGROUND: Negative cognitive schemas about the self and others are prevalent in schizophrenia-spectrum disorders (SSDs) and are associated with symptom severity. Recent conceptualizations of recovery emphasize function...BACKGROUND: Negative cognitive schemas about the self and others are prevalent in schizophrenia-spectrum disorders (SSDs) and are associated with symptom severity. Recent conceptualizations of recovery emphasize functional and personal outcomes in addition to symptoms. The current study examined the effects of schemas on domains of symptoms, functioning, and personal recovery. METHODS: 71 individuals diagnosed with SSDs were included in the present study. Data presented in this study were collected as part of the baseline assessment for a clinical trial evaluating remotely delivered cognitive behavioural therapy for psychosis. Participants completed measures of core schemas, symptom severity, psychosocial functioning, and personal recovery. RESULTS: Cognitive schemas accounted for significant variance in personal recovery (65%), symptom severity (27%), and psychosocial functioning (18%). Negative-self schemas were associated with poorer social functioning, lower personal recovery, and greater overall symptom severity (ps = 0.034-0.036; BH-adjusted ps = 0.073). Positive-other schemas were associated with greater social functioning (p = .018; BH-adjusted p = .072) and personal recovery (p and BH-adjusted p < .001). Positive-self schemas were associated with greater personal recovery (p and BH-adjusted p < .001). Associations between schemas and personal recovery largely persisted after the influence of the other recovery domains was accounted for (ps < 0.001-0.062). CONCLUSION: Cognitive schemas demonstrated associations with symptoms, psychosocial functioning, and personal recovery in individuals with SSDs, with negative-self evaluations in particular showing trend-level associations across all three domains. Greater personal recovery was associated with higher positive self- and other-evaluations, independent of symptom severity and functioning, underscoring their relevance for recovery-oriented interventions.
Ku BS, Arrant EJ, Yuan QE
… +12 more, Aberizk KM, Addington JM, Bearden CE, Cadenhead KS, Cannon TD, Carrión RE, Keshavan MS, Mathalon DH, Perkins DO, Stone WS, Woods SW, Walker EF
Schizophr Res
· 2026 Jul · PMID 41955767
·
Full text
OBJECTIVE: Hippocampal volume (HV) reductions are a nonspecific marker of psychiatric vulnerability, including risk for psychosis. However, the behavioral and contextual factors that shape this association remain poorly...OBJECTIVE: Hippocampal volume (HV) reductions are a nonspecific marker of psychiatric vulnerability, including risk for psychosis. However, the behavioral and contextual factors that shape this association remain poorly understood. This study examined whether social withdrawal, a behavioral risk factor for psychosis, is associated with HV in adolescents, and whether neighborhood residential stability moderates this relationship. METHODS: Participants included 166 youth at clinical high risk for psychosis (CHR-P) and 41 healthy comparisons (ages 12-19, 40.1% female, 51.2% White non-Hispanic) from the North American Prodrome Longitudinal Study Phase 2. Clinicians assessed social withdrawal via the Premorbid Adjustment Scale. We derived residential stability measures from the 2010-2014 5-year American Community Survey estimates. Using linear mixed-effects models, we tested cross-sectional associations between bilateral HV and social withdrawal. Follow-up models tested the interaction between social withdrawal and neighborhood residential stability. RESULTS: Greater social withdrawal was associated with reduced bilateral HV in both univariable (left: β = -0.180, 95% CI = -0.316 to -0.044; right: β = -0.189, 95% CI = -0.317 to -0.060) and multivariable models (left: β = -0.169, 95% CI = -0.313 to -0.026; right: β = -0.154, 95% CI = -0.296 to -0.012). Notably, this association was moderated by neighborhood residential stability (left: interaction β = 0.217, 95% CI = 0.064 to 0.370; right: interaction β = 0.191, 95% CI = 0.048 to 0.333). CONCLUSIONS: Social withdrawal may reflect neurodevelopmental vulnerability in adolescence, and neighborhood stability may buffer this risk. These findings underscore the value of integrating both behavioral and contextual factors into early risk detection and intervention efforts.
BACKGROUND: Previous studies have demonstrated the potential of transcranial alternating current stimulation (tACS) to modulate auditory verbal hallucinations (AVH) in patients with schizophrenia (SZ) by regulating neura...BACKGROUND: Previous studies have demonstrated the potential of transcranial alternating current stimulation (tACS) to modulate auditory verbal hallucinations (AVH) in patients with schizophrenia (SZ) by regulating neural oscillations. However, the therapeutic efficacy of tACS for treatment-refractory AVH (TRAVH) remains elusive. This study aimed to investigate the efficacy and safety of adjunctive tACS to stable antipsychotic medication for TRAVH in patients with SZ. METHODS: A 6-week, randomized (1:1), double-blind, sham-controlled clinical trial was conducted, consisting of a 4-week tACS add-on treatment phase and a 2-week follow-up phase. All participants met the diagnostic criteria for treatment-resistant schizophrenia (TRS) with moderate AVH and were randomly assigned to either the active 40 Hz tACS group or the sham tACS group. The study employed tACS with the left dorsolateral prefrontal cortex (DLPFC) and left temporo-parietal junction (TPJ) serving as stimulation electrodes and the Cz as the return electrode. Each session lasted 20 min, administered once daily, five days a week, for a total of four weeks. The primary outcome was the change in scores on the Auditory Hallucination subscale of the Psychotic Symptom Rating Scale (PSYRATS-AH). Repeated-measures analysis of variance (RM-ANOVA) and analysis of covariance (ANCOVA) were used to assess the therapeutic effect of tACS on AVH. RESULTS: A total of 92 patients were screened, and 39 participants (active group: n = 20; sham group: n = 19) completed the 6-week study. RM-ANOVA revealed a significant time × group interaction for PSYRATS-AH scores at week 6 (P = 0.033) between the two groups, a finding further validated by ANCOVA (P = 0.044). In the active tACS group, improvements in PSYRATS-AH scores at week 2 significantly predicted improvements at week 6 (P = 0.032). No serious adverse events (SAEs) were reported throughout the 6-week trial. CONCLUSIONS: This study suggests that 40 Hz tACS targeting the left DLPFC and left. TPJ is a potentially effective intervention for ameliorating TRAVH in patients with TRS, with a tentative effect on AVH controllability. Additionally, tACS was well tolerated by all participants.