This case report discusses a 25-year-old Middle Eastern female with a 14-year history of schizophrenia, managed as an inpatient for nearly eight years. Initially referred to a psychiatrist at age 12, with one-year-long concerns about preoccupation with the idea of having a serious illness, depressed mood, decreased appetite, social withdrawal, and aggression, she underwent multiple admissions, various medication combinations, and electroconvulsive therapy but remained resistant to treatment until clozapine monotherapy was initiated in 2023. After starting clozapine, improvements were noted in speech, communication, and eye contact, though negative symptoms and bouts of aggression persisted. This case highlights the efficacy of clozapine monotherapy in managing treatment-resistant schizophrenia after years of ineffective polypharmacy treatment. The importance of clozapine in treating treatment-resistant schizophrenia cannot be understated. Despite its efficacy, clozapine is often underutilised globally due to concerns about adverse effects and the need for blood monitoring, leading to the overuse of antipsychotic polypharmacy. This polypharmacy is associated with higher adverse event rates, increased costs, and uncertain long-term safety. This case report demonstrates the successful management of treatment-resistant schizophrenia with clozapine monotherapy. The patient\'s significant improvement supports the need to prioritise clozapine, highlighting its benefits over polypharmacy and advocating for its broader use to enhance patient outcomes.

The contribution of anticholinergic burden to cognitive function in patients with treatment resistant schizophrenia (TRS) is uncertain. This case-control study aims to comprehensively examine the association between treatment resistance and cognitive functions and the contribution of anticholinergic burden in patients with schizophrenia. Anticholinergic burden of all patients was calculated using the Anticholinergic Cognitive Burden scale. Exploratory Factor Analysis of 11 cognitive assessments identified four cognitive domains: verbal memory, attention and general cognitive functions, visual memory and processing speed, and executive function. Two structural equation models (SEM) examined the relationship of TRS and these cognitive functions with, and without considering anticholinergic burden. A total of 288 participants were included (TRS N=111, non-TRS N=177). Patients with TRS performed poorer than the non-TRS group only in the executive function domain. Anticholinergic burden contributed significantly to the attention and general cognitive functions, visual memory and processing speed, and executive function. The impact of TRS on executive function was no longer significant after adding anticholinergic burden to the SEM. Results suggested that anticholinergic burden contributes to a wide range of cognitive function impairment in patients with schizophrenia and is likely to be part of the apparent differences of cognitive function between TRS and non-TRS.

BACKGROUND: Around 30 % of schizophrenia patients do not respond sufficiently to conventional antipsychotic treatment. Glutamate and γ-aminobutyric acid (GABA) may be implicated in treatment resistant (TR) patients. Some data indicate that TR patients show increased glutamate levels compared to responders, but findings are inconclusive and limited in the early disease stage. Furthermore, the two neurotransmitters have rarely been assessed in conjunction. We therefore aimed to investigate the role of GABA+ and glutamate in first episode TR patients and explore whether these neurometabolites could be potential predictive markers for TR schizophrenia.
METHODS: We used proton magnetic resonance spectroscopy (MRS) to assess glutamate + glutamine (Glx) and GABA including macromolecules (GABA+) in the anterior cingulate cortex (ACC) of 58 first episode psychosis patients. At six months follow-up treatment response was determined and in a subgroup of 33 patients a follow-up MRS scan was acquired.
RESULTS: Glx and GABA+ levels were not significantly different between TR patients and responders at baseline and the levels did not change at six months follow-up. The groups differed in voxel fractions, which could have influenced our results even though we corrected for these differences.
CONCLUSIONS: Our findings do not provide evidence that ACC Glx or GABA+ levels are potential biomarkers for TR in first episode psychosis. Future research needs to take in to account voxel fractions and report potential differences. Comparison with previous literature suggests that illness duration, clozapine responsiveness and medication effects may partly explain the heterogeneous results on Glx and GABA+ levels in TR.

Mesial temporal sclerosis (MTS) is one of the most common causes of treatment-resistant epilepsy, especially temporal lobe epilepsy (TLE). Various psychiatric symptoms are common with temporal lobe epilepsy. However, the least established symptoms were psychotic symptoms. Furthermore, treatment-resistant schizophrenia is a significant proportion of schizophrenia patients who have failed treatment with at least two different antipsychotics, resulting in poor outcomes and a significant negative impact on the patient\'s life. In our case report, psychotic symptoms and abnormal behaviors were explained by schizophrenia for more than 17 years in a 32-year-old female, while the diagnosis of temporal lobe epilepsy with mesial temporal sclerosis was missed, resulting in incomplete treatment, which led to a deterioration of her quality of life for years. This case aims to shed light on TLE rare manifestations and to discuss the proper investigations and treatment that might increase the quality of life of these patients. Underlining the necessity for more research in treatment-resistant schizophrenia, this unusual case underscores the importance of exploring the underlying biological, psychological, and social risk factors. It also emphasizes the need to focus additional attention on formulating proper investigation strategies for the susceptible patient population.

BACKGROUND: This study aimed to conduct a systematic review and meta-analysis on cognitive performances of patients with treatment-resistant schizophrenia (TRS) after clozapine treatment and to examine the potential effect of follow-up duration and clozapine dosage.
METHODS: Five electronic databases were searched and studies were included if treatment-resistant schizophrenia patients were treated with clozapine and with baseline and follow-up cognitive functions assessments. Cognitive measures were categorised into six domains based on DSM-5-TR. Random-effect model analysis was used to pool the effect estimates. Moderator effects of clozapine dosage, follow up duration, duration of illness, age, years of education and change in positive symptoms severity were examined with meta-regression.
RESULTS: Nineteen articles were included with 50 cognitive measures reported. Systematic review found inconsistent results. Twelve cognitive measures were included for meta-analysis and found overall improvement of cognitive performances after clozapine treatment SMD = 0.11 [95 % CI 0.02, 0.20] (p = 0.021). Patients with younger age, more years of education and improvements in positive symptoms are more likely to improve in cognitive performances. Subgroup analysis found significant improvement in studies with follow-up periods of 6-months or longer but not for studies with shorter follow-up periods.
CONCLUSIONS: Clozapine may improve some domains of cognitive function, particularly over a longer period. However, the overall inconsistent results suggest that more studies with larger sample size and standard cognitive function assessments would be needed to enhance our understanding of the impact of clozapine on the cognitive functions in the TRS patients.

Clozapine has unique effectiveness in treatment-resistant schizophrenia and is known to cause immunological side-effects. A transient spike in neutrophils commonly occurs in the first weeks of clozapine therapy. There is contradictory evidence in the literature as to whether neutrophil changes with clozapine are linked to treatment response.
The current study aims to further examine the neutrophil changes in response to clozapine and explore any association between neutrophil trajectory and treatment response.
A retrospective cohort study of patients undergoing their first treatment with clozapine and continuing for at least 2 years identified 425 patients (69% male/31% female). Neutrophil counts at baseline, 3 weeks and 1 month were obtained predominantly by linkage with data from the clozapine monitoring service. Clinical Global Impression- Severity (CGI-S) was rated from case notes at the time of clozapine initiation and at 2 years. Latent class growth analysis (LCGA) was performed to define distinct trajectories of neutrophil changes during the first month of treatment. Logistic regression was then conducted to investigate for association between the trajectory of neutrophil count changes in month 1 and clinical response at 2 years as well as between baseline neutrophil count and response.
Of the original cohort, 397 (93%) patients had useable neutrophil data during the first 6 weeks of clozapine treatment. LCGA revealed significant differences in neutrophil trajectories with a three-class model being the most parsimonious. The classes had similar trajectory profiles but differed primarily on overall neutrophil count: with low, high-normal and high neutrophil classes, comprising 52%, 40% and 8% of the sample respectively. Membership of the high-normal group was associated with significantly increased odds of a positive response to clozapine, as compared to the low neutrophil group [Odds ratio (OR) = 2.10, p-value = 0.002; 95% confidence interval (95% CI) = 1.31-3.36]. Baseline neutrophil count was a predictor of response to clozapine at 2 years, with counts of ≥5 × 109/l significantly associated with positive response (OR = 1.60, p-value = 0.03; 95% CI = 1.03-2.49).
Our data are consistent with the hypothesis that patients with low-level inflammation, reflected in a high-normal neutrophil count, are more likely to respond to clozapine, raising the possibility that clozapine exerts its superior efficacy via immune mechanisms.

Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50-80 nm at a distance of 20-40 nm creating \"nanocolumns\" within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor\'s interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.

People who are diagnosed with treatment resistant schizophrenia (TRS) are likely to have clozapine as a therapeutic management option. There is a high prevalence of metabolic syndrome in patients receiving clozapine. To mitigate against this, monitoring of weight, waist circumference, lipid profile, glycated haemoglobin (HbA1c), fasting blood glucose (FBG) and blood pressure (BP) is recommended. The aims of this study were to examine the prevalence of metabolic syndrome and whether any variables were correlated with its development, and to highlight any opportunities for the pharmacist to offer support. This study was conducted in an urban hospital and its associated Clozapine Clinic in Cork, Ireland. A retrospective audit assessed the prevalence of metabolic syndrome using the International Diabetes Federation (IDF) criteria. Patients were eligible for inclusion if they were aged 18 years or more, registered with the Clozapine Clinic, and had the capacity to provide informed consent. All data were entered into Microsoft® Excel ® (Microsoft Corporation) and further statistical analysis was undertaken using R, t-tests, Fisher\'s Exact Test and Mann-Whitney U tests as appropriate, and p ≤ 0.05 was considered statistically significant. Of 145 patients (32% female; mean age (SD) 45.3 (±11.7) years; 86.2% living independently/in family home), nearly two thirds (n = 86, 59.3%) were diagnosed with metabolic syndrome. The mean age of participants with metabolic syndrome was 44.4 years (SD = 10.8), similar to the 46.6 years (SD = 12.8) for those without. Variables that were identified to be statistically significantly associated with metabolic syndrome included waist circumference, weight, triglycerides, high density lipoprotein-cholesterol (HDL-C), BP, FBG and HbA1c. The high incidence of metabolic syndrome in this patient population highlights the need for continued physical health monitoring of these patients to ameliorate the risk of developing metabolic syndrome.

Schizophrenia (SZ) is a serious mental disorder that is typically treated with antipsychotic medication. Treatment-resistant schizophrenia (TRS) is the condition where symptoms remain after pharmacological intervention, resulting in long-lasting functional and social impairments. As the identification and treatment of a TRS patient requires previous failed treatments, early mechanisms of detection are needed in order to quicken the access to effective therapy, as well as improve treatment adherence. In this study, we aim to find a microRNA (miRNA) signature for TRS, as well as to shed some light on the molecular pathways potentially involved in this severe condition. To do this, we compared the blood miRNAs of schizophrenia patients that respond to medication and TRS patients, thus obtaining a 16-miRNA TRS profile. Then, we assessed the ability of this signature to separate responders and TRS patients using hierarchical clustering, observing that most of them are grouped correctly (~70% accuracy). We also conducted a network, pathway analysis, and bibliography search to spot molecular pathways potentially altered in TRS. We found that the response to stress seems to be a key factor in TRS and that proteins p53, SIRT1, MDM2, and TRIM28 could be the potential mediators of such responses. Finally, we suggest a molecular pathway potentially regulated by the miRNAs of the TRS profile.

Various studies have investigated the relationship between genetic polymorphisms of antipsychotic drug-metabolizing agents and drug response. DNA methylation is a form of epigenetic modification that regulates gene expression. Few studies have analyzed the relationship between genome-wide methylation patterns and treatment resistance schizophrenia. The primary aim of this pilot study is to investigate the association between treatment resistance status and genome-wide DNA methylation in schizophrenia patients. Treatment resistance status was determined for 109 patients with schizophrenia. Treatment resistance was the primary outcome variable in a model, including methylation status of white blood cells using the Illumina 450 array. The genome-wide DNA methylation levels in 109 Schizophrenia subjects did not show that DNA methylation sties were associated with resistance status. From our study, it is evident the importance of continuing to investigate the relationship between DNA methylation and antipsychotic response to personalize treatment in schizophrenia. Future studies require larger prescription databases to build on the results presented in this pilot study.