Advancements and Future Directions in Prevention Based on Evaluation for Individuals With Clinical High Risk of Psychosis: Insights From the SHARP Study

Abstract

Introduction

The concept of clinical high risk (CHR) for psychosis has been a prominent topic in mental health research for around 3 decades.¹ During this time, there has been a notable shift in focus toward developing novel diagnostic and intervention techniques aimed at intercepting psychosis at its earliest identifiable stages.² Researchers have increasingly recognized the paramount importance of preventive measures preceding functional rehabilitation post-onset.³ However, the task of preventing psychosis presents a complex and challenging endeavor. It requires not only a comprehensive understanding of the onset process but also insights into the multitude of objective factors that contribute to its progression. At the crux of this challenge lies the necessity for 2 fundamental components: the establishment of high-quality cohorts^4–6 and the identification of viable biological targets.^7–9 These prerequisites serve as the cornerstone for the development of targeted and effective interventions. High-quality cohorts provide researchers with robust datasets necessary for elucidating the intricate pathways leading to psychosis onset, while the identification of biological targets offers promising avenues for intervention strategies.

The History of SHARP’s Development

The inception of the Shanghai At Risk for Psychosis (SHARP) cohort dates back to 2010 when, under the guidance of Professor Larry Seidman and others from North American Prodrome Longitudinal Study (NAPLS) consortium, the SHARP cohort initiated its pioneering efforts to identify individuals at CHR in mainland China. From 2010 to 2012, the primary focus of SHARP was to introduce and implement the Structured Interview for Psychosis-Risk Syndromes (SIPS) for CHR identification,¹⁰ followed by an epidemiological survey to assess the feasibility of CHR criteria within Chinese psychiatric clinical practices, revealing an incidence rate of 4.2% among first-visit help-seeking population.¹¹ Continuing its trajectory, from 2012 to 2014, the SHARP project delved into exploring the trajectory of CHR individuals, revealing conversion rates over 2 years similar to those observed in non-Chinese cohorts like the NAPLS-1, ranging between 25% and 30%.^12,13 During this phase, emphasis was placed on evaluating symptomatology^14,15 and cognitive characteristics.^16,17

From 2014 to 2016, the SHARP project embarked on comprehensive biological characterization, encompassing analyses of blood samples (genetic¹⁸ and biochemical markers^19,20), saliva (oral microbiota),²¹ brain imaging (structural,²² resting-state,²³ diffusion tensor imaging,²⁴ etc.), electrophysiology (electroencephalography (EEG) and electrocardiogram (ECG)),²⁵ eye movements,²⁶ and niacin skin response testing.²⁷ Progressing further from 2016 to 2020, the SHARP project aimed to delineate biological markers in the disease progression, construct predictive models (such as SIPS-RC²⁸ (risk calculator) and SHARP-RC²⁹), and endeavor toward risk prediction.³⁰ Concurrently, the Shanghai Mental Health Center established specialized outpatient clinics for individuals at risk of psychosis, transitioning toward clinical applications.

In 2021, the SHARP project shifted its focus to evaluation-based prevention, initiating a series of clinical trials, including assessments of real-world effectiveness of antipsychotic (AP) medications (Clinicaltrials.gov identifier NCT04010864),³¹ Specific Memory Attention Resource and Training (SMART) application (Chinese Clinical Trial Registry identifier ChiCTR2000031741),³² Decreasing risk of psychosis by sulforaphane (Clinicaltrials.gov identifier NCT03932136),³³ and personalized transcranial magnetic stimulation (TMS) over parieto-hippocampal network.³⁴ These endeavors aim to optimize early prevention outcomes for CHR individuals. Based on the aforementioned research initiatives, the project team synthesized non-pharmacological intervention techniques tailored to illness-related characteristics, fostering precision in early prevention strategies.

Characteristics of the SHARP CHR Population

In the SHARP study, inclusion criteria involved individuals aged 14–45 years who fulfilled diagnostic criteria for 1 of 3 psychosis-risk syndromes: attenuated positive symptom syndrome (APSS), brief intermittent psychotic syndrome (BIPS), or genetic risk and deterioration syndrome (GRDS). These diagnoses were established using the Structural Interview for Prodromal Syndromes (SIPS) interview. The proportion of GRDS (about 10%) and BIPS (about 1%) cases was relatively small, compared to the predominant APSS cases (about 80%–90%). Exclusion criteria encompassed a current or lifetime occurrence of a psychotic episode, symptomatology that could be attributed more fittingly to nonpsychotic disorders or substance abuse, prior use of psychotropic medication regardless of dosage, ongoing or historical use of psychoactive substances (such as methamphetamine), presence of neurological or endocrine disorders, lack of proficiency in Mandarin, and an inability to comprehend or provide informed consent. In the SHARP cohort, the CHR population is predominantly Han Chinese, comprising over 95% of the sample, with a balanced gender ratio. The average age is approximately 18 years old, and individuals have received an average of around 10 years of education. The majority of the CHR individuals come from a background of being in school, with common presenting complaints including school refusal, peer relationship issues, and significant decline in academic performance. By the end of 2023, there were more than 1700 individuals recruited in the SHARP cohort who met the criteria for being at CHR.

One notable difference between the SHARP dataset and other international CHR cohorts, such as the NAPLS, is the conversion rate. The SHARP dataset showed a relatively high conversion rate between 25% and 30%, compared to NAPLS-2 and NAPLS-3, where the conversion rate was below 20% (approximately 10%–20%).^35,36 This discrepancy in conversion rates may be related to differences in baseline clinical and cognitive features between the Chinese and American samples, as well as variations in the inclusion and exclusion criteria used in each study. Additionally, the SHARP cohort represents a relatively pure population of CHR for psychosis, as individuals with a history of substance abuse were strictly excluded, which may also contribute to the observed differences in conversion rates compared to NAPLS.

APs Have Suboptimal Efficacy for Preventing Conversion

The SHARP research team conducted a series of inquiries into the use of AP medication in CHR individuals, examining its effectiveness in preventing conversion. APs represent the frontline treatment for individuals experiencing their initial episode of psychosis and are often the preferred choice of clinicians. Consequently, there is a prevailing assumption in some circles that APs could be effective in preventing psychosis onset in CHR individuals.^37,38 The team investigated the usage of APs among 717 CHR patients within the SHARP cohort and observed AP’s real-world preventive efficacy.³⁹ The findings revealed a high utilization rate of APs, reaching 68.6%. However, among those who received AP treatment, the conversion rate to psychosis stood at 27.0%, compared to 10.9% for those who did not receive AP treatment. Stratifying the survival analysis based on the severity of baseline positive symptoms, the project team addressed the significant confounding factor. Significant reductions in conversion rates were observed only among CHR individuals with low-level baseline positive symptoms who did not receive AP treatment, while individuals who received AP treatment, regardless of the severity of symptoms, exhibited higher conversion rates, hinting at the absence of preventive benefits from AP usage.⁴⁰ Simple stratification based on the severity of symptoms as a criterion for AP use may not be feasible. Moreover, concerns regarding AP’s adverse effects in adolescents were highlighted.

Further analysis explored the timing of AP usage in CHR and First Episode Psychosis (FEP).⁴¹ Results indicated higher remission rates among patients initiating AP treatment during FEP compared to those initiating treatment during the CHR phase. Reasons for widespread AP usage without preventive efficacy were also examined,⁴² revealing that clinicians and CHR individuals primarily sought to control positive symptoms. However, it is important to note that while APs may effectively control positive symptoms, the progression to psychosis is more strongly correlated with factors such as negative symptoms and overall functional status. This suggests that while APs may alleviate symptoms, they may not address the underlying risk of psychosis conversion, potentially leading to an artificial deflation of conversion rates. We proposed that only a small subset of CHR individuals (13%) might benefit from AP usage, specifically those meeting the criteria of the “three TEN rules”⁴⁰: a higher score for positive symptoms (>10 total score of positive symptoms in SIPS), a lower score for negative symptoms (<10), and a higher score for general symptoms (>10) at baseline. As mentioned above, the conventional practice among clinicians of using APs for preventing psychosis onset reveals shortcomings.⁴³ However, in the process of exploring the more suitable use of AP in CHR subtypes,⁴⁴ the prototype of a Prevention Based on Evaluation (PBE) model has gradually emerged, primarily utilizing behavioral characterization in its initial stages. Subsequently, the SHARP team began incorporating biological features into the PBE model, exploring a more comprehensive approach to early prevention targeted at the main pathogenic factors. The PBE refers to a prevention approach that utilizes systematic evaluation and assessment of psychiatric symptoms, cognitive functioning, neuroimaging, electrophysiology, biochemical markers, genetic factors, and other relevant biological and psychosocial variables to inform targeted preventive interventions.

PBE for Non-Pharmacological Intervention

The PBE model serves as a transitional approach between symptom-based and etiology-based model. The PBE model refers to conducting targeted interventions aimed at reversing observed “abnormalities” identified through assessment and detection. Here, “abnormalities” do not necessarily correspond to symptomatic diagnostic classifications, nor do they always indicate the primary etiological features. In contrast to current symptom-based diagnostic and therapeutic model, the high degree of heterogeneity impedes precise diagnosis and treatment. Taking CHR individuals as an example, where less than one-third progress to FEP, it implies that at least this subset of CHR requires a distinct preventive approach from the rest. Moreover, within this subset progressing to FEP, there exists further heterogeneity, with diverse leading factors contributing to progression. While an etiology-based diagnostic and therapeutic model appears ideal, it remains unachievable presently, primarily due to the multifactorial nature of psychosis etiology, which varies across different stages and is challenging to pinpoint definitively at any given point in time. Therefore, at present, the team considers PBE as a feasible transitional approach. It involves targeted non-pharmacological interventions based on identified issues, aiming to achieve a balance between preventive efficacy and safety.

In the following sections, we present 3 examples of PBE initiatives conducted by the SHARP team.

Implementing Nutritional Supplementation Interventions Based on Niacin Skin Response Blunting

The team explored whether there exist rapid and effective tests to detect the levels of inflammation balance or oxidative stress in CHR individuals.^45,46 This inquiry aligns with the key function of nutrients, which is to regulate the balance of immune inflammation and oxidative stress levels in patients. One of the important functions of nutrients in regulating inflammatory and oxidative processes⁴⁷ is to maintain a balance between pro-inflammatory and anti-inflammatory signals, as well as manage oxidative stress levels in the body. Unsaturated fatty acids, such as omega-3 fatty acids, play a critical role in this process by serving as precursors for anti-inflammatory mediators and influencing the expression of genes involved in inflammation and oxidative stress responses.⁴⁸ This underscores the importance of nutritional interventions in CHR individuals as a means to modulate these physiological processes.⁴⁹

The nutritional intervention research in CHR individuals has been fraught with hope and disappointment. From the 2010 year, a randomized, double-blind, placebo-controlled (RCT) study by Amminger et al suggesting that polyunsaturated fatty acids (PUFAs) could prevent psychotic episodes,⁵⁰ to the 2017 year multicenter RCT study by McGorry et al reporting negative results for PUFAs prevention,⁵¹ there has been ongoing controversy surrounding nutritional interventions. The crux of the matter lies in the fact that the efficacy of nutritional interventions may not be as significant, or may only be effective for a subset of CHR individuals.⁵² Our team initially conducted a systematic review of nutritional interventions for psychosis,⁵³ identified 2 intervention strategies: PUFAs and sulforaphane (SFN).

The next critical question was how to identify a CHR subgroup that might respond effectively to nutritional interventions. In 2015, the team was fortunate to collaborate with Professor Jeffrey Yao, commencing the testing of niacin skin response in the Chinese population under his guidance. The team discovered that niacin skin response blunting is a biomarker for schizophrenia,⁵⁴ with a small fraction of FEP patients exhibiting blunted responses.⁵⁵ These patients with a blunted phenotype showed pronounced negative symptoms and cognitive impairment,⁵⁶ correlated with inflammation imbalance.⁵⁷ The team also conducted niacin skin response testing in the CHR population,²⁷ finding that CHR individuals with blunting had a higher risk of conversion. To standardize and facilitate the clinical application of this test, the team developed corresponding niacin response testing equipment, aiding clinicians in conducting niacin tests more conveniently.⁵⁸ Based on this testing, the team initiated 2 interventional trials. One is a multicenter RCT involving 300 CHR subjects. The study duration includes a 52-week intervention period and an additional 1-year follow-up.³³ The nutritional trials have completed baseline enrollment of 290 CHR individuals as of the end of March 2024. It is anticipated that all baseline enrollments will be completed by April, with follow-up scheduled to conclude for all participants by June 2025. The other trial is an open-label trial of PUFAs intervention in the real world. CHR individuals with niacin skin response blunting are recommended to use PUFAs soft capsules; dosage: 4 g/day, administered orally twice daily; duration: 6 months. Clinical trials are ongoing, and the team aims to establish a PBE model for serving the CHR population through niacin testing—nutritional intervention, particularly for the subset of CHR individuals with inflammation imbalance/oxidative stress.^45,46

For individuals with blunted niacin response among CHR individuals, we recommend the following interventions: daily oral intake of 4 g of omega-3 polyunsaturated fatty acids (each capsule containing 500 mg, with omega-3 proportion above 90%) or sulforaphane will be delivered as its precursor glucoraphanin along with a conversion enzyme, myrosinase, which converts glucoraphanin to sulforaphane in the body. The dosage is 6 active tablets (411 μmol glucoraphanin) per day. The intervention duration with omega-3 polyunsaturated fatty acids or sulforaphane is 52 consecutive weeks.

Implementing Precision TMS Interventions Based on Cognitive and Brain Functional Abnormal Characteristics

The SHARP project extensively evaluated cognitive function in CHR individuals,^59,60 identifying visuospatial learning (VSL) performance as a key predictor of psychosis development.^17,61 Longitudinal studies consistently revealed VSL impairments preceding psychosis onset, notably observed through the BVMT-R.⁶² Across different studies such as NAPLS,⁶³ CHR individuals who later converted to psychosis consistently exhibited poorer BVMT-R performance compared to non-converting CHR individuals, underscoring the significance of VSL deficits in psychosis development.

VSL performance involves both visuospatial and memory functions, and both components may be impaired in individuals undergoing CHR. Extensive research has already elucidated the impairment in the memory component,⁶⁴ which represents a more general cognitive function. However, the relationship between the visuospatial component and the mechanism of psychosis conversion warrants further explanation. The visuospatial component plays a crucial role in spatial orientation, navigation, and environmental perception, all of which are fundamental aspects of psychotic symptoms such as auditory hallucinations and primary delusions. Disruptions in visuospatial processing may lead to difficulties in interpreting spatial relationships and navigating complex environments, which could contribute to the emergence of fully psychosis. Additionally, abnormalities in visuospatial memory have been linked to alterations in brain structure and connectivity, particularly within the hippocampal and parietal regions, which are implicated in the pathophysiology of psychosis. Therefore, impairments in both the visuospatial and memory components may contribute synergistically to the risk of psychosis conversion. These findings suggest that targeting VSL deficits could serve as a valuable strategy for early intervention in psychosis.

Drawing on nearly 2 decades of expertise in the field of brain stimulation, the SHARP team explored the potential of TMS technology to enhance VSL function in CHR population. Our study⁶⁵ has shown that TMS effects are more pronounced in adolescent populations compared to adults and the elderly, making CHR individuals, who are mostly adolescents, potentially suitable candidates for early TMS intervention. Focusing on the specific cognitive domain of VSL during the early CHR stage, the team aimed to develop network-based TMS treatments targeting VSL as part of their PBE model. Pioneering studies⁶⁶ in healthy volunteers have demonstrated the efficacy of targeting memory-related networks with precise TMS, resulting in improved associative and visuospatial memory performance. Investigating the potential of precise TMS targeting the parieto-hippocampal network to enhance VSL and prevent or delay the onset of psychosis is of significant interest.

Following this, a proof-of-concept, randomized, sham-controlled clinical trial was conducted by our team,³⁴ wherein CHR patients underwent precise, personalized TMS targeting the network between the left inferior parietal lobule and the left hippocampus, supported by evidence indicating the critical role of this network in episodic memory retrieval and spatial navigation, suggesting its potential relevance for enhancing visuospatial memory.⁶⁶ An accelerated TMS protocol comprising 10 sessions of 20 Hz TMS treatments within 2 days was employed to enhance the TMS effect. Utilizing a novel network-based TMS strategy targeting the left parieto-hippocampal connectivity associated with VSL, significant improvements in BVMT-R were observed exclusively following active-TMS treatment, not sham TMS. This effect was specific to BVMT-R among the 8 neurocognitive tasks. The active-TMS subgroup exhibited a conversion rate of 6.7%, significantly lower than the sham-TMS subgroup’s rate of 28.0%. These results indicate that the left parieto-hippocampal TMS protocol can selectively enhance VSL performance in CHR individuals, offering a potential avenue for preventing psychosis. This is another PBE model for serving the CHR population through left parieto-hippocampal TMS protocol intervention, particularly targeting the subset of CHR individuals with impaired VSL abilities/brain functional connectivity abnormalities, to achieve precise preventive effects.

Currently, we are also exploring the utility of BVMT-R performance in identifying CHR individuals who may benefit from precision TMS treatments. Through ongoing research, we aim to determine whether specific patterns or thresholds of BVMT-R performance can help guide the selection of CHR patients for targeted TMS interventions. This endeavor involves leveraging advanced imaging analysis techniques. In the imaging analysis of BVMT-R testing in CHR individuals, the graphical representations typically depict their performance in visuospatial memory tasks. These graphics may include charts illustrating the visual patterns recalled or reproduced by CHR participants across different trials. The content of these graphics may encompass aspects such as the accuracy of their drawings, the arrangement and organization of visual stimuli, as well as any errors or omissions during the memory recall process. Through machine learning analysis of these recall graphics, researchers can assess CHR individuals’ performance in visuospatial memory tasks to provide more nuanced assessments of cognitive functioning, thereby facilitating the personalized and optimized application of TMS therapies in CHR populations.

The personalized aspects of the TMS intervention encompass several factors: Firstly, all participants underwent MRI scanning before receiving TMS treatment. Secondly, to identify the personalized optimal TMS target over the left inferior parietal lobule (IPL), we utilized the same spherical IPL mask as in the study by Wang et al.⁶⁶ with a 15 mm radius centered at the MNI coordinate (x = −47, y = −68, and z = 36). Thirdly, a personalized TMS target was identified as the voxel within the IPL mask showing the local maximum functional connectivity with the left hippocampus. Lastly, we recorded the MNI coordinate of this voxel for each participant. The individual structural images were then registered to the MNI space, and we localized the target with its MNI coordinate using the LOCALITE TMS Navigator.

In line with PBE model, we have identified visuospatial memory as a crucial cognitive function in CHR individuals. Early impairment in visuospatial memory poses an increased risk of conversion to psychosis. Utilizing a novel network-based TMS strategy targeting left parieto-hippocampal connectivity, we have demonstrated the ability to enhance visuospatial memory function, thereby reducing the risk of psychosis onset. Additionally, considering that the majority of CHR individuals are adolescents, the safety of TMS application in this population is paramount. Based on our clinical experience, we have found the use of TMS in adolescents to be safe, with no reports of severe adverse events and fewer adverse reactions compared to adult and elderly populations. Notably, even in our experiments utilizing high-frequency (20 Hz) TMS, no severe adverse events have been observed in adolescents.

Implementing Cognitive Behavioral Therapy for Psychotic Symptoms Based on Symptomatology and Impaired Insight Characteristics

In the early identification of CHR individuals, the SIPS assessment serves as a crucial tool, not only for determining whether individuals meet CHR criteria but also for collecting various symptomatological characteristics, which are valuable for guiding subsequent treatment, particularly psychological therapy. Traditionally, clinicians have been hesitant to apply psychological therapy to psychotic symptoms in China. Consequently, in the early stages of the SHARP project, very few CHR individuals received psychological therapy. However, with an increased understanding of the CHR concept among domestic clinicians, it has been gradually recognized that insight is a key indicator distinguishing CHR from FEP. Specifically, when CHR individuals retain some insight into their experienced psychotic symptoms, these symptoms are considered “attenuated.” Conversely, when CHR individuals lose insight into their psychotic symptoms, it is deemed to have reached the severity of psychosis. Insight emerges as the most crucial symptomatological feature in the conversion from CHR to FEP. Concurrently, our team conducted comprehensive investigations into both cognitive insight (using the Beck Cognitive Insight Scale (BCIS)) and clinical insight (using the Schedule for Assessment of Insight (SAI)) in CHR individuals.⁶⁷ The results revealed that CHR individuals exhibit impaired cognitive insight, characterized by lower self-reflectiveness,⁶⁸ which subsequently affects clinical insight. Our study further explored cognitive and clinical insight and their relationship across groups with varying severity of positive symptoms, from the premorbid to the early psychosis stages.

For CHR individuals with impaired insight, targeted psychological interventions aimed at improving cognitive insight may prove beneficial in maintaining good clinical insight. Impaired insight refers to CHR individuals’ diminished awareness or understanding of the attenuated positive symptoms they are experiencing. This is assessed using the BCIS and SAI. Currently, we lack a universally applicable threshold for distinguishing between levels of insight, thus relying on group-level differences. This approach not only has the potential to delay or prevent the progression from the pre-morbid stage to a fully psychotic episode but also to shorten the duration of untreated psychosis, thereby promoting functional recovery. To address these challenges, our team has initiated collaboration with the Psychology Interventions Clinic for Outpatients with Psychosis (PICuP) to introduce Cognitive Behavioral Therapy for Psychotic Symptoms (CBTp) for CHR individuals. Initially, our team conducted a systematic review to evaluate the effectiveness of CBTp in CHR populations.⁶⁹ The findings suggest that while the evidence for CBTp’s impact on functioning, depression, quality of life, and distress reduction is modest, there is support for its potential to significantly reduce transition rates and attenuated psychotic symptoms over various time frames. Subsequently, our team translated “Cognitive Behavioural Therapy for Psychotic Symptoms: A Therapist’s Manual”⁷⁰ into Chinese to better equip clinical psychologists in serving CHR individuals. Additionally, with guidance from the PICuP team, a 2-year training program for domestic psychological counselors was completed, focusing on a PBE model that integrates symptomatology and insight assessment to deliver targeted CBTp interventions for CHR individuals. Our team is now preparing for an RCT trial to further validate the efficacy of CBTp for CHR individuals.

Summary

The 3 examples of PBE model implemented by SHARP team offer innovative approaches to early intervention in psychosis. By targeting specific deficiencies identified through the niacin skin response, tailored dietary interventions aim to rebalance inflammatory and oxidative stress levels; Utilizing neurocognitive markers, such as VSL deficits, precise TMS treatments target brain networks associated with cognitive impairments, offering a noninvasive method to enhance cognitive function; Informed by symptomatology and impaired insight characteristics, CBTp interventions specifically address attenuated psychotic symptoms in CHR individuals with insight deficits. These PBE models offer several advantages: (1) Targeted Intervention: each model identifies specific markers or characteristics associated with psychosis risk, allowing for targeted interventions tailored to individual needs. (2) Multidisciplinary Approach: these models integrate insights from various disciplines, including psychiatry, psychology, and neuroscience, fostering a holistic understanding of psychosis risk and treatment. (3) Clinical Utility: the implementation of these models provides clinicians with practical tools and strategies for early intervention in psychosis, offering new avenues for preventive care in the Chinese context. Overall, these PBE models represent promising approaches to psychosis prevention, offering new insights and strategies for addressing psychosis risk in China and potentially improving outcomes for individuals at risk of developing psychosis.

Future Directions

In the realm of future endeavors, the SHARP team is poised to embark on an ambitious expansion of its CHR sample size. By December 31, 2023, the SHARP CHR cohort had already surpassed 1800 individuals, with a steady annual increase of 100–150 new cases. As the sample size continues to grow, so too will the demands of follow-up assessments. As of now, the CHR individual with the longest follow-up has been tracked for 13 years. The team consistently conducts annual face-to-face long-term follow-ups for all CHR cases enrolled previously, aiming to maintain a loss-to-follow-up rate below 20%. This comprehensive approach aims to glean insights into CHR outcomes, including progression to FEP, other Axis I disorders, and social functional outcomes, employing dynamic, multi-time-point assessments to deepen our understanding of the psychosis trajectory.

Furthermore, the team is committed to advancing the “Evaluation” aspect through technological innovation and enhancement. This involves harnessing new techniques such as oral microbiome analysis,²¹ EEG,^25,71 ECG,^72,73 eye-tracking,⁷⁴ fundus photography, functional near-infrared spectroscopy,^75,76 and natural language processing analysis⁷⁷ to guide precision prevention efforts. Development of portable, wearable psychiatric devices is underway to capture long-term behavioral and biological features, exploit objective markers, and integrate AI technologies to construct comprehensive, cross-modal, and temporal evaluation techniques and models for enhanced accuracy and breadth.

Lastly, in the realm of “Prevention,” significant strides will be made in expanding the repertoire and precision of non-pharmacological treatments, closely integrating evaluation techniques’ findings. This involves the development of technologies spanning nutritional intervention, neural modulation, and digital therapeutics to address clinical issues specific to CHR individuals, fostering a closed-loop prevention model. Moreover, recognizing that the preventive target audience may extend beyond clinical confines, the SHARP team is exploring avenues to transition from solely medical services to broader public outreach, thereby realizing the goal of disease prevention at its inception.

While our current PBE strategies primarily rely on group-level findings, we recognize the importance of moving toward precision prevention and tailoring interventions for each individual in clinical practice. Precision prevention offers the opportunity to address the unique risk factors and needs of each individual, maximizing the effectiveness of interventions and minimizing unnecessary interventions for those at lower risk. By adopting precision prevention approaches, we can capitalize on advances in personalized medicine and predictive modeling to identify specific risk profiles and tailor interventions accordingly. This may involve integrating genetic, neurobiological, and environmental data to develop personalized risk profiles and treatment plans. Additionally, leveraging technology such as machine learning algorithms can enhance our ability to predict individual outcomes and tailor interventions accordingly. Incorporating precision prevention into clinical practice not only enhances treatment efficacy but also promotes patient engagement and satisfaction by addressing their unique needs and preferences. Moving forward, our focus will be on further exploring and implementing individualized strategies to optimize prevention efforts in the CHR population.

Acknowledgments

For the purpose of commemorate, Prof. Larry J. Seidman, passed away on September 2017., Prof. Jeffrey Yao passed away on March, 2018. They were founder and core member of this study. The authors have declared that there are no conflicts of interest in relation to the subject of this study.

Funding

This study was supported by the Ministry of Science and Technology of China, National Key R&D Program of China (2023YFC2506800) and National Natural Science Foundation of China (82171544, 82371505, 82151314, 82101623, and 82101582), Clinical Research Plan of SHDC (SHDC2022CRD026, SHDC2020CR4066, SHDC12022113).

References