Bo Liu

Major depressive disorder (MDD) remains a significant global health challenge, with substantial limitations inherent in current pharmacotherapeutic and psychotherapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe, effective, and non-invasive neuromodulation therapy, particularly for treatment-resistant depression (TRD). However, conventional rTMS is limited by long treatment duration and variable interindividual efficacy. This expert opinion examines recent advances in rTMS optimization strategies aimed at overcoming these limitations. Key areas of progress include the development of novel stimulation protocols such as theta-burst stimulation (TBS); accelerated regimens and priming TMS; the use of magnetic resonance imaging (MRI)-guided TMS; and the integration of closed-loop systems using real-time electroencephalography (EEG) or functional near-infrared spectroscopy (fNIRS) feedback. Additionally, technological innovations, including robot-assisted TMS and wearable devices, promise to enhance targeting accuracy and treatment accessibility. Despite these developments, significant challenges impede clinical translation, including the high cost of personalized protocols, insufficient standardization and validation of novel approaches, and technical barriers to closed-loop implementation. Future efforts should focus on cost reduction, large-scale randomized controlled trials, biomarker development, and device portability. Ultimately, optimized rTMS shows significant potential to become a more efficient, precise, and accessible cornerstone of depression therapy.

Major depressive disorder (MDD) is one of the most prevalent mental disorders, yet its pathogenesis remains incompletely understood. Accumulating evidence indicates that MDD is closely associated with gut microbiota dysbiosis, with bidirectional communication along the microbiota-gut-brain axis playing a pivotal role in disease development. The gut microbiota and its metabolites exert dual influences on MDD, contributing to its pathophysiology while also offering promising therapeutic targets. In recent years, the prevalence of depression, especially in adolescents, has shown a sharp upward trend, increasing the risk of suicide in this population. However, few studies have systematically reviewed the link between gut dysbiosis and MDD in adolescents. This review summarizes current evidence on structural and functional alterations of the gut microbiota in adolescent MDD and explores the underlying mechanisms mediated by the microbiota-gut-brain axis. Furthermore, we also discuss the therapeutic potential of microbiota-targeted interventions, including dietary modification, probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation. Future research should aim to characterize specific microbial alterations in adolescent MDD and clarify the mechanisms underlying gut-brain interactions, thereby advancing the clinical translation of microbiota-targeted therapeutics for adolescent depression.

Background: Emerging research suggests virtual reality (VR) techniques hold promise for mitigating cognitive decline in patients with mild cognitive impairment (MCI). Furthermore, accumulating evidence indicates that gut dysbiosis is a key factor associated with cognitive impairment. This study aims to determine whether a novel virtual reality-integrated multi-modal intervention can beneficially modulate the brain-gut axis in individuals with MCI. Methods: This study is a randomized single-blind controlled trial that will include 66 older adults with MCI from the community. Eligible participants will be randomly assigned in a 1:1 ratio to the intervention group or the waitlist group. The intervention group will complete 36 sessions (three sessions per week for 12 weeks) consisting of virtual reality cognitive training (VRCT), traditional cognitive training (TCT), and physical exercise (PE). The control group will not receive any intervention during the study period. The primary outcome is the change in a memory-weighted cognitive composite score. Exploratory outcomes: mechanistic changes along the brain-gut axis, including: (1) Changes in gut microbiota alpha/beta diversity and composition assessed by 16S rRNA gene sequencing, (2) Changes in resting-state brain activity and functional connectivity assessed by fMRI. Outcome measures will be assessed at three or four time points: baseline, mid-intervention (Week 6), post-intervention (Week 12), and at a 12-week follow-up (Week 24). Expected outcomes: We hypothesize that, relative to the waitlist control, the intervention group will demonstrate concurrent improvements in cognitive performance and a shift in gut microbiota composition toward a more favorable profile, thereby providing preliminary evidence for modulation of the brain-gut axis. Clinical trial registration: [ www.chictr.org.cn ], identifier [ChiCTR2400093397].

Background: Schizophrenia is a severe mental disorder affecting approximately 1% of the global population, characterized by three core symptom domains: positive symptoms, negative symptoms, and cognitive dysfunction. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising intervention for both positive and negative symptoms in schizophrenia. However, its therapeutic potential for cognitive dysfunction remains inconclusive. Methods: This randomized, double-blind, sham-controlled trial will enroll 70 medication-stable patients meeting DSM-5 criteria for schizophrenia. Participants will be randomly allocated (1:1) to receive either active or sham augmented intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC). The treatment protocol consists of 600 pulses per session, three sessions per day, for 10 consecutive weekdays. Clinical symptoms will be evaluated with the Positive and Negative Syndrome Scale (PANSS), cognitive function will be assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and neural activity will be measured via functional near-infrared spectroscopy (fNIRS) during a semantic verbal fluency task. All patients will be assessed at baseline and post-intervention. Ethics and dissemination: The trial protocol complies with the principles of the Declaration of Helsinki and has been approved by the Ethics Committee of Zigong Mental Health Center (approval number: 20250802). The findings of this trial will be published and made publicly accessible in a peer-reviewed journal. Discussion: This study aims to provide strong evidence supporting the therapeutic potential of augmented iTBS for improving cognitive functioning in schizophrenia, offering a potential new treatment option for patients with schizophrenia. Clinical Trial Registration: https://www.chictr.org.cn/index.html , identifier ChiCTR2500107943.

Introduction: Anhedonia, a core negative symptom of schizophrenia, refers to the inability to experience pleasure from normally enjoyable activities. It significantly worsens prognosis and remains poorly addressed by current treatments. In recent years, repetitive transcranial magnetic stimulation (rTMS) has shown potential in treating anhedonia in depression and other disorders; however, its application to anhedonia in schizophrenia remains underexplored. This study aimed to evaluate the efficacy of rTMS targeting the dorsomedial prefrontal cortex (DMPFC) on anhedonia in patients with schizophrenia, and to explore its correlation with cognitive function and prefrontal activity. Methods: The present study is a randomized controlled trial that will include 82 patients with schizophrenia who meet DSM-5 diagnostic criteria and have a score of ≥12 on the Snaith-Hamilton Pleasure Scale (SHAPS). Eligible participants will be randomly allocated in a 1:1 ratio to either active or sham rTMS stimulation groups. The active group will receive a high-frequency rTMS intervention using an intermittent theta-burst stimulation (iTBS) protocol (20 trains x 10 pulses at 5 Hz, with an intensity of 90% of resting motor threshold) administered twice daily for 15 days. The sham group will receive a sham-stimulation regimen with the same parameters. All participants will be assessed using both the SHAPS and the Scale for the Assessment of Negative Symptoms (SANS) at three time points: baseline (T0), immediately post-treatment (T1), and 4-week follow-up (T2). In addition, the Wisconsin Card Sorting Test (WCST) and the dynamics of prefrontal oxygenated hemoglobin (Δoxy-Hb) monitored by functional near-infrared spectroscopy (fNIRS), will be assessed at T0, T1, and T2. Ethics and dissemination: The trial protocol complies with the principles of the Declaration of Helsinki and has been approved by the Ethics Committee of Zigong Mental Health Center (approval number: 20250801). The findings of this trial will be published and made publicly accessible in a peer-reviewed journal. Discussion: If the iTBS protocols targeting the DMPFC lead to positive changes in anhedonia symptoms in patients with schizophrenia, this would provide a new intervention strategy for negative symptoms. Furthermore, leveraging neuroimaging evidence from such studies could help optimize rTMS target selection and overall treatment strategies. Trial registration: ChiCTR2500107965.

Attention‐deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that begins in childhood and can persist into adolescence and adulthood. Stimulants, particularly methylphenidate and amphetamines, are the first‐line treatments for ADHD in children and adolescents. While the potential for stimulants to induce psychosis‐like or mania‐like symptoms in children has been recognized for decades, there have been no reported cases of increased recall of negative memories associated with methylphenidate. Here, we present a rare case in which an initial dose of 18 mg of Methylphenidate Hydrochloride Extended‐Release Tablets led to increased recall of negative life events in a 6‐year‐old child with ADHD. Interestingly, the symptom resolved spontaneously the following day without discontinuing the medication, suggesting that it was an adaptive response rather than a toxic reaction.

Rationale: Lithium carbonate, a mood stabilizer, is most commonly used for the treatment and prevention of mania and bipolar disorder. Common renal side effects include polyuria and polydipsia. However, when combined with other psychotropic medications that have sedative properties, lithium may increase the risk of nocturnal enuresis. Patient concerns: A 12-year-old girl experienced recurrent major depressive episodes with psychotic symptoms. Her clinical presentation was complex, including depressed mood, irritability, suicidal ideation or behavior, and partial psychotic features. During treatment, she frequently reported polydipsia, polyuria, and nocturnal enuresis. Diagnoses: Based on the International Classification of Diseases, 10th Edition, the patient was diagnosed with major depressive disorder with psychotic symptoms (F32.3) and enuresis not due to a physical disorder (F98.0). Interventions: In addition to receiving antidepressants, antipsychotics, benzodiazepines, and modified electroconvulsive therapy, she was also intermittently treated with lithium carbonate extended-release tablets, with a maximum daily dose of 1.2 g. No pathophysiological abnormalities were identified through imaging examinations in relation to her nocturnal enuresis. After suspecting a link between her enuresis and lithium, her nocturnal enuresis resolved following the discontinuation of lithium carbonate extended-release tablets. Outcomes: During the 4-month follow-up, the patient remained free of nocturnal enuresis, while her depressive and psychotic symptoms significantly subsided. Lessons: Psychiatrists should be aware of the possibility of lithium-induced nocturnal enuresis when polyuria and polydipsia emerge during lithium treatment, particularly in children and adolescents receiving concomitant psychotropic medications with sedative properties.

Rationale: Zolpidem, a non-benzodiazepine sedative-hypnotic, is considered safer for the treatment of insomnia compared to benzodiazepines. However, in recent years, there have been growing reports of Zolpidem dependence, addiction, and withdrawal symptoms. We reported a case of Zolpidem addiction and successful detoxification, reviewed similar cases in the literature, and proposed a potential mechanism underlying Zolpidem addiction. Patient concerns: The patient was a 46-year-old Tibetan woman who had been using Zolpidem intermittently to treat insomnia for at least 8 years. She was overweight, with a BMI of 28.04 kg/m², and had hypertension, diabetes, a 20-year smoking history, and several years of alcohol abuse, often seeking instant gratification. She voluntarily increased both the dosage and frequency of Zolpidem, experiencing euphoria, anxiolysis, and increased appetite at higher doses, which led her to gradually escalate her dosage to 280 mg per day in divided doses. However, upon stopping Zolpidem, she experienced withdrawal symptoms, including insomnia, tension, and palpitations. Diagnoses: She was diagnosed with a combination of hypnotic use disorder, anxiety disorder, hypertension, and diabetes. Interventions: She underwent diazepam replacement therapy, along with antianxiety medications and mindfulness-based cognitive therapy, to address Zolpidem addiction. Outcomes: After 13 days of inpatient treatment, the patient successfully quit Zolpidem. During a 3-month follow-up, she returned to work and remained free from Zolpidem use. Lessons: We speculate that Zolpidem addiction is likely linked to the drug’s euphoric effects and certain patient characteristics, such as sensation-seeking behavior. A comprehensive approach, involving both pharmacological and psychological interventions, is essential for an effective detoxification strategy for Zolpidem addiction.

Liu, Bo, Minlan Yuan, Mei Yang, Hongru Zhu, and Wei Zhang. The effect of high-altitude hypoxia on neuropsychiatric functions. High Alt Med Biol 00:000–000, 2023. Background: In recent years, there has been a growing popularity in engaging in activities at high altitudes, such as hiking and work. However, these high-altitude environments pose risks of hypoxia, which can lead to various acute or chronic cerebral diseases. These conditions include common neurological diseases such as acute mountain sickness (AMS), high-altitude cerebral edema, and altitude-related cerebrovascular diseases, as well as psychiatric disorders such as anxiety, depression, and psychosis. However, reviews of altitude-related neuropsychiatric conditions and their potential mechanisms are rare. Methods: We conducted searches on PubMed and Google Scholar, exploring existing literature encompassing preclinical and clinical studies. Our aim was to summarize the prevalent neuropsychiatric diseases induced by altitude hypoxia, the potential pathophysiological mechanisms, as well as the available pharmacological and nonpharmacological strategies for prevention and intervention. Results: The development of altitude-related cerebral diseases may arise from various pathogenic processes, including neurovascular alterations associated with hypoxia, cytotoxic responses, activation of reactive oxygen species, and dysregulation of the expression of hypoxia inducible factor-1 and nuclear factor erythroid 2-related factor 2. Furthermore, the interplay between hypoxia-induced neurological and psychiatric changes is believed to play a role in the progression of brain damage. Conclusions: While there is some evidence pointing to pathophysiological changes in hypoxia-induced brain damage, the precise mechanisms responsible for neuropsychiatric alterations remain elusive. Currently, the range of prevention and intervention strategies available is primarily focused on addressing AMS, with a preference for prevention rather than treatment.