Treatment-resistant Schizophrenia Research Articles

Prevalence of treatment-resistant schizophrenia among people with early psychosis and its clinical and demographic correlates.

The prevalence of treatment-resistant schizophrenia (TRS) among people with first-episode schizophrenia (FES) has been sub-optimally researched in Australia and internationally. We evaluated the prevalence of TRS among a cohort of FES patients and compared their sociodemographic and clinical characteristics to those with FES who were treatment responsive. Over 2 years, we collated demographic, clinical and treatment-related data of all patients with ICD-10 (International Classification of Diseases, Tenth revision) diagnosis of schizophrenia who were active in October 2020 at four early psychosis intervention services (EPIS) in Western Australia. We used a modified version of Suzuki et al. criteria to diagnose TRS. The data were analysed utilising descriptive statistics, the Mann-Whitney U test, Student's t-test and the False-Discovery Rate method. The prevalence of TRS among the 167 patients diagnosed with FES was 41.3%, and the rates did not differ significantly between the services (p = 0.955). Those in the TRS group were less independent (p = 0.011), had more prolonged unemployment (p = 0.014) and were more likely to be on disability pension (p = 0.011) compared to the treatment responsive group. Furthermore, they had greater severity of symptoms (p = 0.002), longer duration of psychiatric symptoms (p = 0.019), more hospitalisations (p = 0.002) and longer cumulative admission durations (p = 0.002). Our study revealed that treatment resistance to antipsychotics is prevalent among people with FES managed at EPIS. Notably, it establishes an association between TRS and heightened clinical severity and psychosocial and treatment burden. These findings highlight the imperative for early detection of treatment resistance and timely and specialised interventions for this condition in mental health services.

Immunoinflammatory features and cognitive function in treatment-resistant schizophrenia: unraveling distinct patterns in clozapine-resistant patients.

Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients and 84 healthy controls were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score (p = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients (p < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t = 2.075, p = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = - 0.327, t = - 2.109, p = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients (p < 0.05). Clozapine‑resistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.

Developing a validated methodology for identifying clozapine treatment periods in electronic health records

BackgroundClozapine is the only recommended antipsychotic medication for individuals diagnosed with treatment-resistant schizophrenia. Unfortunately, its wider use is hindered by several possible adverse effects, some of which are rare but potentially life threatening. As such, there is a growing interest in studying clozapine use and safety in routinely collected healthcare data. However, previous attempts to characterise clozapine treatment have had low accuracy.AimTo develop a methodology for identifying clozapine treatment dates by combining several data sources and implement this on a large clinical database.MethodsNon-identifiable electronic health records from a large mental health provider in London and a linked database from a national clozapine blood monitoring service were used to obtain information regarding patients' clozapine treatment status, blood tests and pharmacy dispensing records. A rule-based algorithm was developed to determine the dates of starting and stopping treatment based on these data, and more than 10% of the outcomes were validated by manual review of de-identified case note text.ResultsA total of 3,212 possible clozapine treatment periods were identified, of which 425 (13.2%) were excluded due to insufficient data to verify clozapine administration. Of the 2,787 treatments remaining, 1,902 (68.2%) had an identified start-date. On evaluation, the algorithm identified treatments with 96.4% accuracy; start dates were 96.2% accurate within 15 days, and end dates were 85.1% accurate within 30 days.ConclusionsThe algorithm produced a reliable database of clozapine treatment periods. Beyond underpinning future observational clozapine studies, we envisage it will facilitate similar implementations on additional large clinical databases worldwide.

Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition

Predictors of functioning in treatment-resistant schizophrenia: the role of negative symptoms and neurocognition

Characteristics and causes of reported clozapine-related medication errors: analysis of the Ministry of Health database in Saudi Arabia.

Clozapine has shown great efficacy in treating treatment-resistant schizophrenia, but it is associated with a variety of medication- related safety problems. Despite this, there remains a lack of research on medication errors (MEs) associated with its use. To characterize the nature and contributory factors of clozapine-related MEs reported from government hospitals and primary care centres in Saudi Arabia (SA). A cross-sectional analysis was carried out on MEs related to clozapine use reported to the General Administration of Pharmaceutical Care at the Ministry of Health (MOH) in Saudi Arabia between 2018 and 2022. The data were analysed descriptively to examine the nature and contributory factors of MEs. A total of 1,165 MEs were reported. The majority of reported errors involved patients aged > 18 years old, with 72.2% (n = 841) being male. The central region was found to report errors more frequently (32.3%, n = 376). Pharmacists were reported to detect errors most frequently (59.6%, n = 695). MEs most often occurred in the prescribing stage (77.8%, n = 906), with "missing prescription information" (30.1%, n = 351) being the most frequent finding. The most frequent contributing factor was the lack of policy (33.1%, n = 351). The majority of errors did not reach the patients (92.3%, n = 1,075), and those that did reach patients rarely resulted in harm (0.3%, n = 2). This study identified areas for improvement which could expedite the development of remedial interventions to reduce the risk of errors.

Predictors of clozapine efficacy in treatment-resistant schizophrenia: A cross-sectional analysis of sociodemographic, clinical, biochemical, and electrophysiological EEG changes

Predictors of clozapine efficacy in treatment-resistant schizophrenia: A cross-sectional analysis of sociodemographic, clinical, biochemical, and electrophysiological EEG changes

Impact of clozapine once-daily versus multiple-daily dosing regimen on relapse in patients with treatment-resistant schizophrenia:A1-year retrospective cohort study.

Clozapine, the standard treatment for treatment-resistant schizophrenia (TRS), is generally recommended in a multiple-daily dosing regimen. However, it is commonly administered once daily in clinical practice. Few studies have compared the longitudinal clinical outcomes of these two dosing regimens. To investigate the effect of once-daily versus multiple-daily dosing regimens of clozapine on relapse in patients with TRS. This retrospective cohort study included patients with TRS who commenced treatment with clozapine during hospitalization and were discharged between April 2012 and January 2022 from a tertiary psychiatric hospital in Japan. Relapse, defined as a psychiatric exacerbation requiring re-hospitalization within the first-year post-discharge, was analyzed. Multivariable Cox proportional hazards regression analysis compared the relapse risk between once-daily and multiple-daily dosing regimens. A subgroup analysis was conducted to examine the potential interactions between dosing regimen and dose category (low versus high dose). Among 179 patients, 107 (59.8%) received clozapine once daily. No significant difference in the relapse risk was observed between once-daily and multiple-daily dosing regimens (adjusted hazard ratio [aHR]: 1.16; 95% confidence interval [CI]: 0.68-1.99; p = 0.58). However, in patients receiving high doses of clozapine (> 300mg/day), multiple-daily dosing increased the relapse risk compared to once-daily dosing (aHR: 2.23; 95% CI: 1.00-4.97; p = 0.049). Once-daily clozapine dosing may not be associated with an increasedrelapse risk. The increased relapse risk in high-dose multiple-daily dosing may be confounded by unmeasured non-adherence. Further randomized controlled trials are required to validate these findings.

Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals.

Clozapine-induced inflammation, such as myocarditis and pneumonia, can occur during initial titration and can be fatal. Fever is often the first sign of severe inflammation, and early detection and prevention are essential. Few studies have investigated the effects of clozapine titration speed and concomitant medication use on the risk of clozapine-induced inflammation. We evaluated the risk factors for clozapine-associated fever, including titration speed, concomitant medication use, gender and obesity, and their impact on the risk of fever and the fever onset date. We conducted a case-control study. The medical records of 539 Japanese participants with treatment-resistant schizophrenia at 21 hospitals in Japan who received clozapine for the first time between 2010 and 2022 were retrospectively investigated. Of these, 512 individuals were included in the analysis. Individuals were divided into three groups according to the titration rate recommended by international guidelines for East Asians: the faster titration group, the slower titration group and the ultra-slower titration group. The use of concomitant medications (such as antipsychotics, mood stabilisers, hypnotics and anxiolytics) at clozapine initiation was comprehensively investigated. Logistic regression analysis was performed to identify the explanatory variables for the risk of a fever of 37.5°C or higher lasting at least 2 days. Fever risk significantly increased with faster titration, male gender and concomitant use of valproic acid or quetiapine. No increased fever risk was detected with the use of other concomitant drugs, such as olanzapine, lithium or orexin receptor antagonists. Fever onset occurred significantly earlier with faster titration. Multivariate analysis identified obesity as being a factor that accelerated fever onset. A faster titration speed and concomitant treatment with valproic acid and quetiapine at clozapine initiation increased the risk of clozapine-associated fever. Clinicians should titrate clozapine with caution and consider both the titration speed and concomitant medications.

Development and initial evaluation of a clinical prediction model for risk of treatment resistance in first-episode psychosis: Schizophrenia Prediction of Resistance to Treatment (SPIRIT).

A clinical tool to estimate the risk of treatment-resistant schizophrenia (TRS) in people with first-episode psychosis (FEP) would inform early detection of TRS and overcome the delay of up to 5 years in starting TRS medication. To develop and evaluate a model that could predict the risk of TRS in routine clinical practice. We used data from two UK-based FEP cohorts (GAP and AESOP-10) to develop and internally validate a prognostic model that supports identification of patients at high-risk of TRS soon after FEP diagnosis. Using sociodemographic and clinical predictors, a model for predicting risk of TRS was developed based on penalised logistic regression, with missing data handled using multiple imputation. Internal validation was undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. Interviews and focus groups with clinicians were conducted to establish clinically relevant risk thresholds and understand the acceptability and perceived utility of the model. We included seven factors in the prediction model that are predominantly assessed in clinical practice in patients with FEP. The model predicted treatment resistance among the 1081 patients with reasonable accuracy; the model's C-statistic was 0.727 (95% CI 0.723-0.732) prior to shrinkage and 0.687 after adjustment for optimism. Calibration was good (expected/observed ratio: 0.999; calibration-in-the-large: 0.000584) after adjustment for optimism. We developed and internally validated a prediction model with reasonably good predictive metrics. Clinicians, patients and carers were involved in the development process. External validation of the tool is needed followed by co-design methodology to support implementation in early intervention services.

Impacts of exposure to and subsequent discontinuation of clozapine on tripartite synaptic transmission.

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but its discontinuation leads to discontinuation syndrome/catatonia complicated by benzodiazepine-resistance and rhabdomyolysis. This study determined time-dependent effects of exposure and subsequent discontinuation of clozapine on expression of connexin43, 5-HT receptors, intracellular L-β-aminoisobutyrate (L-BAIBA) and 2nd-messengers and signalling of AMPK, PP2A and Akt in cultured astrocytes and rat frontal cortex. Intracellular L-BAIBA levels increased during clozapine exposure but immediately recovered after discontinuation. Both exposure to clozapine and L-BAIBA increased connexin43 and signalling of AMPK/Akt time-dependently, but reduced PP2A signalling, 5-HT receptor expression and IP3 level. These changes recovered within 2 weeks after discontinuation, while 5-HT receptors and IP3 transiently increased during the recovery process. L-BAIBA activated AMPK signalling, leading to attenuated PP2A signalling. Astroglial D-serine release was increased by clozapine exposure but continued to increase within 1 week after discontinuation via activation of IP3 receptor function. Clozapine discontinuation restored PP2A signalling due to decreased L-BAIBA, increased 5-HT receptor expression via probably enhanced 5-HT receptor recycling, but increased astroglial D-serine release persisted by transiently activated IP3 receptors via transiently increased IP3 level. Decreased L-BAIBA caused by clozapine discontinuation is, at least partially, involved in the transiently increased 5-HT receptor and astroglial D-serine release.

Distinct alterations in probabilistic reversal learning across at-risk mental state, first episode psychosis and persistent schizophrenia

We used a probabilistic reversal learning task to examine prediction error-driven belief updating in three clinical groups with psychosis or psychosis-like symptoms. Study 1 compared people with at-risk mental state and first episode psychosis (FEP) to matched controls. Study 2 compared people diagnosed with treatment-resistant schizophrenia (TRS) to matched controls. The design replicated our previous work showing ketamine-related perturbations in how meta-level confidence maintained behavioural policy. We applied the same computational modelling analysis here, in order to compare the pharmacological model to three groups at different stages of psychosis. Accuracy was reduced in FEP, reflecting increased tendencies to shift strategy following probabilistic errors. The TRS group also showed a greater tendency to shift choice strategies though accuracy levels were not significantly reduced. Applying the previously-used computational modelling approach, we observed that only the TRS group showed altered confidence-based modulation of responding, previously observed under ketamine administration. Overall, our behavioural findings demonstrated resemblance between clinical groups (FEP and TRS) and ketamine in terms of a reduction in stabilisation of responding in a noisy environment. The computational analysis suggested that TRS, but not FEP, replicates ketamine effects but we consider the computational findings preliminary given limitations in performance of the model.

Negative symptoms in treatment-resistant schizophrenia and its relationship with functioning

BackgroundRecent operational criteria for treatment-resistant schizophrenia (TRS) recognized positive and negative symptoms. TRS patients may have heterogeneity in negative symptoms, but empirical data were lacking. We aimed to characterize TRS patients based on negative symptoms using cluster analysis, and to examine between-cluster differences in social functioning. MethodsWe administered the Clinical Assessment Interview of Negative symptoms (CAINS), Brief Negative Symptom Scale (BNSS), the Positive and Negative Syndrome Scale (PANSS) and the Social and Occupational Functional Assessment (SOFAS to 126 TRS outpatients. All patients also completed the Temporal Experience of Pleasure Scale (TEPS), the Emotion Expressivity Scale (EES), and the Social Functional Scale (SFS). A two-stage hierarchical cluster analysis was performed with the CAINS, TEPS and EES as clustering variables. We validated the clusters using ANOVAs to compare group differences in the BNSS, PANSS, SOFAS and SFS. ResultsClustering indices supported a 3-cluster solution. Clusters 1 (n = 46) and 3 (n = 16) exhibited higher CAINS scores than Cluster 2 (n = 64), and were negative-symptom TRS subtypes. Cluster 1 reported lower TEPS than Cluster 3; but Cluster 3 reported lower EES than Cluster 1. Upon validation, Clusters 1 and 3 exhibited higher BNSS scores than Cluster 2, but only Cluster 1 exhibited lower SOFAS and higher PANSS general symptoms than Cluster 2. Both Clusters 1 and 3 had higher self-report functioning than Cluster 2. ConclusionWe provided evidence for heterogeneity of negative symptoms in TRS. Negative symptoms can characterize TRS patients and predict functional outcome.

Multimodal prediction of the need of clozapine in treatment resistant schizophrenia; a pilot study in first-episode psychosis

As many as one third of the patients diagnosed with schizophrenia do not respond to first-line antipsychotic medication. This group may benefit from the atypical antipsychotic medication clozapine, but initiation of treatment is often delayed, which may worsen prognosis. Predicting which patients do not respond to traditional antipsychotic medication at the onset of symptoms would provide fast-tracked treatment for this group of patients. We collected data from patient records of 38 first-episode psychosis patients, of whom seven did not respond to traditional antipsychotic medications. We used clinical data including medical records, voxel-based morphometry MRI data and inter-subject correlation fMRI data, obtained during movie viewing, to predict future treatment resistance. Using a neural network model, we correctly predicted future treatment resistance in six of the seven treatment resistance patients and 25 of 31 patients who did not require clozapine treatment. Prediction improved significantly when using imaging data in tandem with clinical data. The accuracy of the neural network model was significantly higher than the accuracy of a support vector machine algorithm. These results support the notion that treatment resistant schizophrenia could represent a separate entity of psychotic disorders, characterized by morphological and functional changes in the brain which could represent biomarkers detectable at early onset of symptoms.

Plasma neurofilament light protein is differentially associated with age in individuals with treatment-resistant schizophrenia and bipolar affective disorder compared to controls

Accelerated brain ageing has been observed in multiple psychiatric disorders. This study examined whether relationships between age and plasma neurofilament light (NfL) protein differed in individuals with psychiatric disorders (major depressive disorder (n = 42), bipolar affective disorder (n = 121), treatment-resistant schizophrenia (TRS, n = 82)) compared to two healthy control (HC) groups (n = 1,926 and n = 59). Compared to two independent HC samples, individuals with TRS demonstrated a stronger positive relationship between age and NfL levels. Individuals with BPAD had a stronger negative relationship between age and NfL levels compared to the large normative HC cohort, but not locally-acquired HCs. These findings show that plasma NfL levels are differentially associated with age in individuals with TRS and BPAD compared to healthy individuals.

Treatment-Resistant Schizophrenia: Evaluation and Management.

Treatment-Resistant Schizophrenia: Evaluation and Management.

Attitude and knowledge about electroconvulsive therapy among trainee doctors and psychiatrists: A survey before and after a training session

Abstract: BACKGROUND: Electroconvulsive therapy (ECT) is a safe and effective treatment in psychiatry, but its use is decreasing. AIM: It was intended to evaluate the attitude and knowledge among psychiatric trainees and psychiatrists and any change following a training session on ECT. MATERIALS AND METHODS: A survey was conducted in a teaching psychiatric hospital before and after a training session on ECT using questionnaires on attitude, knowledge, and clinical scenarios for prescribing ECT. RESULTS: This study suggested that the majority of trainees and psychiatrists had positive attitudes and appreciable knowledge base regarding ECT. There were uncertainties in a few areas, such as ECT for treatment-resistant depression without risk of self or others, treatment-resistant schizophrenia, patients with no mental capacity, and those who refuse to consent. The change following the training session was more prominent in prescribing scenarios. In other areas, the change was marginal, probably because of the ceiling effect. CONCLUSIONS: While psychiatrists and trainees maintain positive attitude and appreciable knowledge about ECT, it is essential to remain aware of recent advances and guidelines about ECT through training to continue prescribing it appropriately.

Use of Clozapine in persons with a history of seizures: A retrospective study

BackgroundSeizures are considered to be one of the dreaded side effects of clozapine, and due to this, the use of clozapine is avoided in patients with treatment-resistant schizophrenia. Resultantly, there is little information about the use of clozapine among patients with seizure disorder. AimTo assess the safety of clozapine in patients with history of seizures in their lifetime before starting clozapine and receiving clozapine for the management of psychotic disorders. ResultsOut of the 958 patients, 35 (3.65 %) had a history of at least one seizure episode before starting clozapine, with a mean of 5.06 (SD: 7.23; Median: 3.00) seizures before starting clozapine. The mean duration between the last seizure and the starting of clozapine was 123.75 (SD: 124.99; Median: 84) months, with nine patients having an episode of seizure in the previous 12 months and 15 patients being seizure-free for more than ten years. About one-fourth (25.7 %; nine out of 35) of the patients had recurrence of seizure while receiving clozapine for a mean duration of about five years. When the recurrence of seizure after starting clozapine was evaluated in patients receiving antiepileptics along with clozapine, the incidence of at least one seizure was 26.67 % (4 out of 15), and among those not receiving antiepileptics, the incidence of at least one seizure was 25 % (5 out of 20). The dose of clozapine at which seizure was noted ranged from 12.5 mg to 600 mg/day with a mean of 236.25 (SD: 169.04; Median: 162.5) mg/day. In none of the patients, clozapine had to be stopped due to the continuation of seizures. ConclusionAbout one-fourth of the patients with history of an episode of seizure have recurrence of seizure while receiving clozapine. The demographic and clinical variables do not differ between those who develop and who do not develop seizures after starting clozapine, including concomitant use of antiepileptics.

Clozapine levels and outcomes in Serbian patients with treatment-resistant psychotic disorders previously treated without measuring clozapine levels (CLOSER)

Clozapine remains the only pharmacological treatment option for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of clozapine is recommended, although evidence for the therapeutic range of 350–600 ng/ml is limited. In various countries including Serbia, TDM of clozapine is not routinely performed.This study evaluated the distribution of clozapine levels and their relationship with clinical outcomes in Serbian patients who had not undergone prior TDM. 140 Patients with treatment-resistant schizophrenia and schizo-affective disorder were enrolled. Clozapine levels were measured by dried blood spot (DBS) analysis. Side effects were evaluated by GASS-c, severity of symptoms and functional impairment with WHODAS, CGI-S and GAF.Of the patients, 51.2% had subtherapeutic levels, 24.8% were in the therapeutic window, and 24% had supratherapeutic levels. Clozapine levels showed no association with side effects and a weak positive association with symptom severity and functional impairment. No serious side effects were observed in patients with clozapine levels surpassing 1000 ng/ml (n = 8).Based on these findings, we propose that the upper limit of the therapeutic range should not be regarded as an absolute barrier, and guidelines should allow for a personalized approach when prescribing clozapine.

Analysis of clinical studies on clozapine from 2012-2022.

Clozapine has been considered the "gold standard" in the treatment of schizophrenia for many years. Clozapine has a superior effect, particularly in the treatment of negative symptoms and suicidal behaviour. However, due to its numerous adverse reactions, clozapine is mainly used for treatment-resistant schizophrenia. The aim of this paperis to analyze the results of clinical studies on clozapine from 2012-2022. PubMed was used as the database. Sixty-four studies were included and categorised by topic. The pharmacokinetic properties of clozapine tablets and a clozapine suspension solution did not differ markedly. Clozapine was superior to olanzapine and risperidone in reducing aggression and depression. A long-term study showed that metabolic parameters changed comparably with olanzapine and clozapine after 8 years. Risperidone and ziprasidone can be used as an alternative to clozapine. Scopolamine, atropine drops, and metoclopramide are effective in the treatment of clozapine-induced hypersalivation. Eight drugs, including liraglutide, exenatide, metformin, and orlistat, are potentially effective in the treatment of clozapine-induced weight gain. Ziprasidone, haloperidol, and aripiprazole showed a positive effect on symptoms when added to clozapine. No investigated drug was superior to clozapine for the treatment of schizophrenia. Ziprasidone and risperidone can also be used well for the treatment of schizophrenia. In the treatment of clozapine-induced hypersalivation and weight gain, some drugs proved to be effective.

Non-invasive brain stimulation for treatment-resistant schizophrenia: protocol of a systematic review and network meta-analysis

BackgroundNon-invasive brain stimulation (NIBS) is a promising intervention for treatment-resistant schizophrenia. However, there are multiple available techniques and a comprehensive synthesis of evidence is lacking. Thus, we will conduct a systematic review and network meta-analysis to investigate the comparative efficacy and safety of NIBS techniques as an add-on to antipsychotics for treatment-resistant schizophrenia.MethodsWe will include single- and double-blind randomized-controlled trials (RCT) comparing any NIBS technique with each other or with a control intervention as an add-on to antipsychotics in adult patients with treatment-resistant schizophrenia. We will exclude studies focusing on predominant negative symptoms, maintenance treatment, and single sessions. The primary outcome will be a change in overall symptoms, and secondary outcomes will be a change in symptom domains, cognitive performance, quality of life, functioning, response, dropouts, and side effects. We will search for eligible studies in previous reviews, multiple electronic databases and clinical trial registries from inception onwards. At least two independent reviewers will perform the study selection, data extraction, and risk of bias assessment. We will measure the treatment differences using standardized mean difference (SMD) and odds ratio (OR) for continuous and dichotomous outcomes, respectively. We will conduct pairwise and network meta-analysis within a frequentist framework using a random-effects model, except for rare event outcomes where we will use a fixed-effects Mantel–Haenszel method. We will investigate potential sources of heterogeneity in subgroup analyses. Reporting bias will be assessed with funnel plots and the Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) tool. The certainty in the evidence will be evaluated using the Confidence in Network Meta-analysis (CINeMA) approach.DiscussionOur network meta-analysis would provide an up-to-date synthesis of the evidence from all available RCTs on the comparative efficacy and safety of NIBS for treatment-resistant schizophrenia. This information could guide evidence-based clinical practice and improve the outcomes of patients.Systematic review registrationPROSPERO-ID CRD42023410645.