Treatment-refractory Schizophrenia Research Articles

Correction to "Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia".

Correction to "Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia".

Effect of propranolol on pharmacokinetics of clozapine in schizophrenic patients: a meta-analysis.

Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. The SMDs with 95% CIs of AUC0-12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = - 0.05, 95% CI [- 0.25, 0.15], p = 0.63). The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions.

Association of cytokines levels, psychopathology and cognition among CR-TRS patients with metabolic syndrome

Clozapine-resistant treatment-refractory schizophrenia (CR-TRS) patients face significant clinical challenges. While links between metabolic syndrome (MetS) and inflammatory cytokines in schizophrenia have been established, the relationship between MetS and cytokine levels in CR-TRS patients remains unexplored. This study aimed to investigate the relationship between cytokines levels, clinical symptoms and cognitive impairments in CR-TRS patients, both with and without MetS. The study included 69 CR-TRS patients (31with MetS and 38 without MetS) and 84 healthy controls. The levels of IL-2, IL-6, TNF-α and routine biochemical parameters were measured. Psychopathological symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. We found that CR-TRS patients with MetS displayed lower cognitive function scores compared to those without MetS, even when accounting for potential confounders. TNF-α levels were significantly higher in CRTRS patients with MetS compared to those without MetS, demonstrating substantial pathophysiological potential for CR-TRS patients with MetS via receiver operating characteristic curve (ROC). In CR-TRS patients without MetS, IL-2 independently contributed to the total score and general psychopathology subscore of PANSS. Additionally, IL-6 exhibited an independent contribution to the positive subscore of PANSS. In terms of cognition function, IL-6 independently contributed to the delayed memory of RBANS in CR-TRS patients without MetS. TNF-α could potentially serve as a predictive marker for distinguishing between CR-TRS patients with/without MetS, while IL-2 and IL-6 could independently contribute to psychopathological symptoms or cognitive function in CRTRS patients without MetS. Our study provided insights into the potential interplay between cytokines, clinical symptoms and cognitive impairments in CR-TRS patients with/without MetS.

Case series and Literature review – Clozapine Induced Transient Myocarditis. Clinical characteristics and outcomes

Introduction Clozapine is a second-generation atypical antipsychotic medication used in patients with treatment-refractory schizophrenia. Its use is limited due to its associated adverse effects, including myocarditis. These adverse effects may have variable presentations, such as myocarditis transient or persistent, and a generalized inflammatory process. Thus, clinical monitoring to inform accurate diagnosis is essential to avoid unnecessary discontinuation of clozapine, leading to psychiatric decompensation.ObjectivesTo review clinical features of clozapine induced Myocarditis and accurately identify signs and symptoms attributed to be most specific for myocarditis and determine at what stage clozapine should be discontinued.Methods We conducted a literature review on PubMed, MeSH, google scholar and Mount Sinai’s Levy Library using keywords, clozapine, drug related side effects, adverse reaction, myocarditis, treatment resistant schizophrenia. Review of two cases series was done.Results A review of 15 articles that addressed the cardiac complications of clozapine was performed. This review provides a base on variable clinical characteristics and outcomes of clozapine –induced Myocarditis. It showed patients who had myocarditis ruled out, demonstrated high prevalence of systemic signs of inflammation such as fever, malaise, tachycardia and elevated c-reactive protein. However, despite clozapine maintenance in most, this systemic response subsided without any intervention. A nonspecific inflammatory response is common when initiating clozapine, this inflammatory “clozapine storm’ occurs within the first month of initiation and is not necessarily predictive of myocarditis. These patients were monitored closely. Those confirmed with clozapine- induced myocarditis using echocardiography and cardiac magnetic resonance imaging were managed with dose reduction, laboratory monitoring, vital signs check, with early initiation of beta-blockers without discontinuation of clozapine, with improvement in their laboratory results and vital signs. Those with progressive clinical signs of myocarditis required immediate cessation of clozapine.Conclusions We are proposing a critical need for a multidisciplinary team of psychiatrists, cardiologists and pharmacists collaborating to prevent premature termination of clozapine in cases of treatment-refractory schizophrenia. Our cases showed middle aged patients with treatment - refractory schizophrenia, presenting with symptoms suggestive of clozapine induced- myocarditis, few weeks after initiation. Clozapine was continued with close monitoring, as symptoms resolved. Though clozapine is associated with myocarditis, with proper knowledge on guidelines for monitoring patients, it can mitigate unnecessary discontinuation of clozapine in those patients.Disclosure of InterestNone Declared

Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia.

Previous electroencephalography (EEG) studies have indicated altered brain oscillatory α-band activity in schizophrenia, and treatment with repetitive transcranial magnetic stimulation (rTMS) using individualized α-frequency has shown therapeutic effects. Magnetic resonance imaging-based neuronavigation methods allow stimulation of a specific cortical region and improve targeting of rTMS; therefore, we sought to study the efficacy of navigated, individual α-peak-frequency-guided rTMS (αTMS) on treatment-refractory schizophrenia. We recruited medication-refractory male patients with schizophrenia or schizoaffective disorder in this doubleblind, sham-controlled study. We randomized patients to a 3-week course of either active αTMS or sham stimulation applied to the left dorsolateral prefrontal cortex (DLPFC). We assessed participants with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) at baseline and after treatment. We conducted a follow-up assessment with the PANSS 3 months after intervention. We included 44 patients. After treatment, we observed a significantly higher PANSS total score (p = 0.029), PANSS general psychopathology score (p = 0.027) and PANSS 5-factor model cognitive-disorganized factor score (p = 0.011) in the αTMS group than the sham group. In addition, the CGI-Improvement score was significantly higher among those who received αTMS compared with sham stimulation (p = 0.048). The limited number of study participants included only male patients. Depression was not formally evaluated. Navigated αTMS to the left DLPFC reduced total, general psychopathological, and cognitive-disorganized symptoms of schizophrenia. These results provide evidence for the therapeutic efficacy of individual α-peak-frequency-guided rTMS in treatment-refractory schizophrenia. NCT01941251; ClinicalTrials.gov.

(151) Considerations in Continuing Clozapine in an Aging Medically Ill Patient with Treatment Refractory Schizophrenia: A Case Report

(151) Considerations in Continuing Clozapine in an Aging Medically Ill Patient with Treatment Refractory Schizophrenia: A Case Report

A brief history of clozapine in China with a look forward

Clozapine was first manufactured in China in 1976. Clozapine is currently used not only for treatment-refractory schizophrenia (TRS), but also continues to be used in the treatment of patients with non-TRS and other mental disorders; moreover, low-dose clozapine is also used in sedative-hypnotic therapy and in combination with other drugs. There is need for studies in China using various titrations and assessing their risk for myocarditis and aspiration pneumonia. The Chinese clozapine package insert will also greatly benefit from these changes.

Postsurgical morbidity and mortality favorably informs deep brain stimulation for new indications including schizophrenia and schizoaffective disorder.

Deep brain stimulation (DBS) shows promise for new indications like treatment-refractory schizophrenia in early clinical trials. In the first DBS clinical trial for treatment refractory schizophrenia, despite promising results in treating psychosis, one of the eight subjects experienced both a symptomatic hemorrhage and an infection requiring device removal. Now, ethical concerns about higher surgical risk in schizophrenia/schizoaffective disorder (SZ/SAD) are impacting clinical trial progress. However, insufficient cases preclude conclusions regarding DBS risk in SZ/SAD. Therefore, we directly compare adverse surgical outcomes for all surgical procedures between SZ/SAD and Parkinson's disease (PD) cases to infer relative surgical risk relevant to gauging DBS risks in subjects with SZ/SAD. In the primary analysis, we used browser-based statistical analysis software, TriNetX Live (trinetx.com TriNetX LLC, Cambridge, MA), for Measures of Association using the Z-test. Postsurgical morbidity and mortality after matching for ethnicity, over 39 risk factors, and 19 CPT 1003143 coded surgical procedures from over 35,000 electronic medical records, over 19 years, from 48 United States health care organizations (HCOs) through the TriNetX Research Network™. TriNetXis a global, federated, web-based health research network providing access and statistical analysis of aggregate counts of deidentified EMR data. Diagnoses were based on ICD-10 codes. In the final analysis, logistic regression was used to determine relative frequencies of outcomes among 21 diagnostic groups/cohorts being treated with or considered for DBS and 3 control cohorts. Postsurgical mortality was 1.01-4.11% lower in SZ/SAD compared to the matched PD cohort at 1 month and 1 year after any surgery, while morbidity was 1.91-2.73% higher and associated with postsurgical noncompliance with medical treatment. Hemorrhages and infections were not increased. Across the 21 cohorts compared, PD and SZ/SAD were among eight cohorts with fewer surgeries, nine cohorts with higher postsurgical morbidity, and fifteen cohorts within the control-group range for 1-month postsurgical mortality. Given that the subjects with SZ or SAD, along with most other diagnostic groups examined, had lower postsurgical mortality than PD subjects, it is reasonable to apply existing ethical and clinical guidelines to identify appropriate surgical candidates for inclusion of these patient populations in DBS clinical trials.

Verbal and visual learning ability in patients with treatment-resistant schizophrenia: A 1-year follow-up study

ObjectiveIn the general population, repeated cognitive testing produces learning effects with potential for improved test performance. It is currently unclear whether the same effect of repeated cognitive testing on cognition pertains to people living with schizophrenia, a condition often associated with significant cognitive impairments. This study aims to evaluate learning ability in people with schizophrenia and—considering the evidence that antipsychotic medication can additionally impair cognitive performance—explore the potential impact of anticholinergic burden on verbal and visual learning. MethodThe study included 86 patients with schizophrenia, treated with clozapine, who had persisting negative symptoms. They were assessed at baseline, weeks 8, 24 and 52 using Positive and Negative Syndrome Scale, Hopkins Verbal Learning Test–Revised (HVLT-R) and Brief Visuospatial Memory Test-R (BVMT-R). ResultsThere were no significant improvements in verbal or visual learning across all measurements. Neither the clozapine/norclozapine ratio nor anticholinergic cognitive burden significantly predicted participants' total learning. Premorbid IQ was significantly associated with verbal learning on the HVLT-R. ConclusionsThese findings advance our understanding of cognitive performance in people with schizophrenia and demonstrate limited learning performance in individuals with treatment-refractory schizophrenia.

Myocarditis induced by clozapine and COVID-19 infection: a case report

IntroductionClozapine is the only available treatment for refractory schizophrenia and is rarely associated with the development of myocarditis. Usually, the onset of symptoms occurs within the first month of treatment. The symptoms of myocarditis include fever, flu-like symptoms, fatigue, and dyspnea, symptoms that overlap with the COVID-19 infection. Coronavirus has been associated with cardiovascular complications, including myocarditis. It is not known whether clozapine increases the risk of developing viral myocarditis in patients with COVID-19 infection.ObjectivesReport a case of myocarditis in a patient treated with clozapine, who also had a history of COVID-19 infection.MethodsCollection of clinical information and review of the literature.ResultsA 24-year-old man was admitted following severe psychotic symptoms that have been developing for the past several months. He presented with disorganized speech and behavior, paranoid delusions, thought alienation, auditory hallucinations, and blunted affect. He had no known medical co-morbidity, but he had tested positive for COVID-19 the month before admission. The lab and imaging tests and the electrocardiogram (EKG) were normal. He was diagnosed with schizophrenia and after treatment failure with three antipsychotics, the patient was started on clozapine, with symptom improvement. Two weeks after clozapine initiation, he started flu-like symptoms, fever, chest pain, and tachycardia. Lab tests showed leukocytosis (12 400 cells/uL), elevated inflammatory markers (C-reactive protein 143,30 mg/L) and cardiac biomarkers (troponin I 12.139 ng/mL, NT-proBNP 9321 pg/ml). The evaluation for viruses, including SARS-CoV-2, was negative. The EKG revealed ST-segment elevations and a transthoracic echocardiogram showed systolic dysfunction (left ventricular ejection fraction was 37%). Cardiac magnetic resonance confirmed severe left ventricular dysfunction and diffuse myocardial edema. The patient’s symptoms resolved following the discontinuation of clozapine and supportive therapies. Troponin and EKG normalized over the following 7 days. By this time, the patient tested positive for COVID-19.ConclusionsThe temporal relationship with the initiation of clozapine supports the diagnosis of clozapine-associated myocarditis. However, the COVID-19 infection may have played a part in the emergence of cardiac alterations. We hypothesize that the co-occurrence of COVID-19 and clozapine treatment may act synergically as both factors increase the risk of developing myocarditis. However, further studies are needed to evaluate the relationship between these factors. While clinicians should stay alert for the risk of clozapine-associated myocarditis, the overall risk is low, and given the effectiveness of clozapine, as well as the absence of other evidence-based treatments, people with refractory schizophrenia should be given a monitored trial of clozapine, regardless of their COVID-19 status.Disclosure of InterestNone Declared

Clozapine levels and therapeutic response: using individual patient meta-analysis data for a ROC Curve analysis

IntroductionClozapine has been well established as the most efficacious medication for treatment refractory schizophrenia. Optimising the benefit during clozapine trial is an important clinical consideration. Therapeutic drug monitoring of clozapine plasma or serum levels has formed a critical part of this. Though there is no agreed standardised therapeutic range, advice traditionally recommends a clozapine level of >350ng/mL in order to effect best response. Most studies analysing the relationship between treatment response and clozapine level are older, have small sample sizes, and do not consider whether additional factors might assist in determining optimal clozapine level for response.ObjectivesWe conducted a systematic review of PubMed, PsycInfo and Embase for studies that provided individual participant level data on clozapine levels and response.MethodsThis data was analysed using Receiver Operating Characteristic (ROC) curves to determine the prediction performance of serum clozapine levels for treatment response.ResultsWe were able to include data on 294 individual participants. ROC analysis yielded an area under the curve (AUC) of 0.612. The clozapine level at the optimal Youden index was 372ng/mL, and at this level there was response sensitivity of 57.3%, and specificity of 65.7%. The interquartile range for treatment response was 223ng/mL – 558ng/mL. There was no improvement in ROC performance with mixed models including patient sex, age or length of trial.ConclusionsClozapine dose should be optimised based on clozapine therapeutic levels. We found that a range between 250 – 550ng/mL could be recommended, while noting that a level of >350ng/mL is most optimal for response.Disclosure of InterestNone Declared

Treatment resistant psychosis in children and adolescents and clozapine: Nuances.

With proliferation in research on high-risk psychosis spectrum diseases, it is crucial to distinguish a prodrome or psychosis-like episode in children and adolescents from true psychosis. The limited role of psychopharmacology in such circumstances is well-documented, underlining the difficulties in diagnosing treatment resistance. To add to the confusion is emerging data on the head-to-head comparison trials for treatment-resistant and treatment-refractory schizophrenia. Clozapine, the gold-standard drug for resistant schizophrenia and other psychotic psychopathology, lacks FDA or manufacturer guidelines for use in the pediatric population. Possibly due to developmental pharmacokinetic (PK) considerations, clozapine-related side effects are more commonly seen in children than adults. Despite evidence of an increased risk for seizures and hematological problems in children, clozapine is widely used off-label. Clozapine reduces the severity of resistant childhood schizophrenia, aggression, suicidality, and severe non-psychotic illness. There is inconsistent prescribing, administration, and monitoring of clozapine, and limited database evidence-backed guidelines. Despite the overwhelming efficacy, problems remain regarding unambiguous indications of use and risk-benefits assessments. This article reviews the nuances in the diagnosis of treatment resistance psychosis in childhood and adolescents and its management, in particular highlighting the evidence base for clozapine in this population group.

Clozapine: Dose, Sex, Ethnicity, Smoking Habit, Age, Body Weight, and Plasma Clozapine and N-Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients. This study aimed to audit the plasma clozapine and N-desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit. The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017. There were 371,610 samples (48,098 patients, 32,855 male). Ethnicity was recorded for 763 Afro-Caribbean, 536 Asian, and 7940 White patients. Males were prescribed significantly higher median doses than females but attained significantly lower median plasma clozapine and norclozapine concentrations. Asian and Afro-Caribbean males were prescribed significantly lower and higher median doses, respectively, than White males but attained significantly higher and lower median plasma clozapine and norclozapine concentrations, respectively. Data from 78,431 samples (23,516 patients) were analyzed using a linear mixed model. The predicted dose to attain a predose plasma clozapine concentration of 0.35 mg/L in a nonsmoking White male aged 40 years, with weight of 70 kg, and plasma clozapine-norclozapine ratio of 1.32 was 344 mg/d (95% confidence interval, 227-526 mg/d). The predicted dose was 33% higher and 20% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. In all cases, the predicted dose was increased by 36% in smokers and decreased by 22% in females. Research is needed to further investigate the complex relationships between dose, sex, ethnicity, plasma clozapine and norclozapine concentrations, and clinical outcome such as weight gain.

C-L Psychiatrists Bring Expertise to End-of-Life Care

C-L Psychiatrists Bring Expertise to End-of-Life Care

Therapeutic monitoring of plasma clozapine andN-desmethylclozapine (norclozapine): practical considerations

SUMMARYClozapine dose assessment in treatment-refractory schizophrenia is complicated. There is a narrow margin between an effective and a potentially toxic dose and wide inter-individual variation in clozapine metabolic capacity. Moreover, factors such as changes in smoking habit, infection/inflammation, co-prescription of certain drugs, notably fluvoxamine, and age alter the dose requirement within individuals. Therapeutic drug monitoring (TDM) of plasma clozapine andN-desmethylclozapine (norclozapine) can help assess adherence, guide dosage and guard against toxicity. This article gives an overview of clozapine pharmacokinetics and factors affecting clozapine dose requirements. It then outlines the procedures and processes of clozapine TDM, from taking the blood sample for laboratory assay or point-of-contact (finger-prick) testing (POCT) to interpreting and acting on the results.

Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial

BackgroundAlthough clozapine is an effective option for treatment-resistant schizophrenia (TRS), there are still 1/3 to 1/2 of TRS patients who do not respond to clozapine. The main purpose of this randomized, double-blind, placebo-controlled trial was to explore the amisulpride augmentation efficacy on the psychopathological symptoms and cognitive function of clozapine-resistant treatment-refractory schizophrenia (CTRS) patients.MethodsA total of 80 patients were recruited and randomly assigned to receive initial clozapine plus amisulpride (amisulpride group) or clozapine plus placebo (placebo group). Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Clinical Global Impression (CGI) scale scores, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Treatment Emergent Symptom Scale (TESS), laboratory measurements, and electrocardiograms (ECG) were performed at baseline, at week 6, and week 12.ResultsCompared with the placebo group, amisulpride group had a lower PANSS total score, positive subscore, and general psychopathology subscore at week 6 and week 12 (PBonferroni < 0.01). Furthermore, compared with the placebo group, the amisulpride group showed an improved RBANS language score at week 12 (PBonferroni < 0.001). Amisulpride group had a higher treatment response rate (P = 0.04), lower scores of CGI severity and CGI efficacy at week 6 and week 12 than placebo group (PBonferroni < 0.05). There were no differences between the groups in body mass index (BMI), corrected QT (QTc) intervals, and laboratory measurements. This study demonstrates that amisulpride augmentation therapy can safely improve the psychiatric symptoms and cognitive performance of CTRS patients.ConclusionThis study indicates that amisulpride augmentation therapy has important clinical significance for treating CTRS to improve clinical symptoms and cognitive function with tolerability and safety.Trial registration Clinicaltrials.gov identifier- NCT03652974. Registered August 31, 2018, https://clinicaltrials.gov/ct2/show/NCT03652974

55.3 Clozapine: Practical Applications for the Child and Adolescent Psychiatrist

Clozapine is widely accepted as an effective treatment option for treatment-refractory schizophrenia and schizoaffective disorder. However, minimal literature exists for the use of clozapine in the pediatric population. In cases of early-onset psychosis, it is important that prescribers appropriately utilize clozapine when treating youth with treatment-refractory psychosis.

Generation of two human induced pluripotent stem cell lines from peripheral blood mononuclear cells of clozapine-tolerant and clozapine-induced myocarditis patients with treatment-resistant schizophrenia

Clozapine has superior efficacy in the treatment of refractory schizophrenia; however, use of clozapine is limited due to severe side effects, including myocarditis. Using non-integrative Sendai virus, we generated induced pluripotent stem cell lines from peripheral blood mononuclear cells of two patients with refractory schizophrenia, one clozapine-tolerant and one clozapine-induced myocarditis. Both cell lines exhibited a normal karyotype and pluripotency was validated by flow cytometry, immunofluorescence and their ability to differentiate into the three germ layers. These lines can be used to generate 2D and 3D patient-specific human cellular models to identify the mechanism by which clozapine induces myocardial inflammation.

Convergent lines of evidence supporting involvement of NFKB1 in schizophrenia

ObjectivesNFKB1 was associated with treatment-refractory schizophrenia (SZ) and response to antipsychotics; however, the underlying mechanisms through which NFKB1 confers its risk for SZ are largely unknown. We aimed to investigate the potential role of NFKB1 in SZ. MethodsIn the present study, we investigated the association of the risk SNP rs230529 of NFKB1 with gray matter density and with NFKB1 mRNA levels in various human brain regions. The spatiotemporal expression pattern of NFKB1 in human brains was explored. We constructed a miRNA-NFKB1-target gene regulatory network and analyzed its druggability through targeting NFKB1 for SZ treatment. ResultsNFKB1 showed the highest expression levels in the cerebellum, in which these levels were stratified by genotypes of rs230529. Interestingly, the allelic state of rs230529 was significantly associated with regional gray matter density in multiple brain regions (including the cerebellum), which also differed between patients with schizophrenia and controls. Furthermore, regulatory targets of NFKB1 were enriched among SZ susceptibility genes. A substantial proportion of NFKB1 target genes were subject to combinatorial regulation by NFKB1 and miRNAs, constituting a hybrid NFKB1-miRNA-gene regulatory network. Some components of this network showed expression changes relevant to both the disease and the treatment. Finally, we detected the dynamic changes of NFKB1-miR-155-5p-GSK3B and NFKB1-miR-155-5p/let-7a-5p-IL6 networks in course of the treatment of SZ. ConclusionTaken together, our findings support the involvement of NFKB1-mediated dysregulation in the development of SZ.

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment‑resistantschizophrenia.

RationaleThough numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ’s efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ’s unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning.ObjectiveIn a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2’), which demonstrates utility as a proxy measure for elements of DA functioning.MethodsParticipants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2’ in relation to CLZ response (% reduction of psychotic symptoms).ResultsWe first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2’ across CLZ treatment.ConclusionOverall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00213-022-06138-0.