Treatment-resistant schizophrenia (TRS) presents considerable challenges in contemporary psychiatric practice due to inadequate response to conventional antipsychotic treatments. Paliperidone, the primary active metabolite of risperidone, particularly in its long-acting injectable (LAI) form, has emerged as a promising option for TRS due to its consistent medication delivery, reducing symptom exacerbation and relapse associated with oral dosing fluctuations. This case report presents the clinical journey of a 42-year-old female diagnosed with schizophrenia at age 15. Despite numerous hospital admissions and trials of various oral and injectable antipsychotics, including clozapine and electroconvulsive therapy (ECT), her symptoms persisted. During her last admission, her condition showed minimal improvement despite extensive pharmacological interventions. Introducing paliperidone LAI while tapering off other antipsychotics led to significant improvements within four weeks. The patient exhibited reduced hallucinatory behaviour, delusions, and disorganized behaviour. Follow-up assessments confirmed sustained progress, with the patient showing increased engagement in daily activities and reduced irritability and suspiciousness. This case underscores the potential efficacy of paliperidone LAI in managing TRS. The patient\'s notable improvement highlights the importance of personalized treatment plans and continuous monitoring in complex psychiatric conditions. Its favourable safety and tolerability profile further supports its use as a long-term treatment option for TRS, potentially leading to enhanced patient compliance and overall quality of life. The significant symptomatic relief and functional improvement observed advocate for the consideration of paliperidone LAI as a promising therapeutic option for TRS, with the potential to be considered in the future among the first-line treatments for TRS.

BACKGROUND: Concern about clozapine-associated neutropenia contributes to clozapine\'s underutilization and racial disparities in access. People with African ancestry are more likely to have lower normative absolute neutrophil counts (ANC), associated with the Duffy null genetic polymorphism. Recent data on clozapine-associated neutropenia in the US are lacking.
METHODS: Patients prescribed clozapine in the Johns Hopkins Medicine electronic medical record (EMR) between 2013 and 2023 were identified. Duffy null Associated Neutrophil Count (DANC) was assigned if there were two ANC\'s < 2000 cells/μL, >30 days apart, before starting clozapine. Rates of neutropenia, timing of first neutropenia, and demographic differences were explored.
RESULTS: 974 received clozapine and had ANC\'s available, with 63.9 % male, 51.1 % White, and 39 % Black. 287 were presumed to start clozapine during the study period, and were 62.4 % male, 46 % White, and 44.9 % Black. No patients developed severe neutropenia. 59 (6.1 %) developed mild or moderate neutropenia. 19 (6.6 %) new starts had presumed DANC, and none developed neutropenia. 11 of 16 presumed new starts who developed neutropenia did so within eight months. No demographic differences were found between groups for presumed new starts. For non-new starts, where DANC assignment was not possible, Black patients were more likely than White patients to develop neutropenia (OR 3.48, 95 % CI [1.65, 7.73]).
CONCLUSIONS: To our knowledge, this is the first observational study of clozapine-associated neutropenia in the US in the past decade, and it includes a substantial proportion of Black patients. ANC monitoring requirements may be too strict, contributing to clozapine underutilization.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.

Some patients with schizophrenia fail to respond to standard antipsychotics and are considered treatment-resistant. In these cases, clozapine is the only antipsychotic with proven efficacy, but its use is complicated by severe adverse effects, complex monitoring requirements, and non-response. Variation within the CYP450 enzymes CYP1A2, CYP2D6, CYP3A4, and CYP2C19 has been linked to the differential metabolism of antipsychotics. Testing for CYP450 single nucleotide polymorphisms may be a useful predictor of treatment resistance and could inform pharmacogenetic recommendations to identify potential treatment non-responders. Nonetheless, it remains uncertain whether differential antipsychotic metabolism is directly related to treatment efficacy. This comprehensive narrative review endeavours to delve into the molecular and genetic basis of schizophrenia, and discuss the current treatments available. In particular, we aim to examine the aetiology of treatment resistance in schizophrenia through available literature and discuss current challenges within the field.

BACKGROUND: Schizophrenia is a debilitating psychiatric disorder with diverse cognitive impairments. Insulin-like growth factor binding protein 1 (IGFBP-1), a ubiquitous negative regulator of IGF signaling, crosses the blood-brain barrier after peripheral synthesis. Given the crucial role of IGF signaling in cognitive function, we reasoned that altered serum IGFBP-1 concentrations might be associated with cognitive impairments in schizophrenia. To test this hypothesis, we examined the relationship between serum IGFBP-1 levels and cognitive performance in both medicated and treatment-resistant schizophrenia (TRS) patients.
METHODS: Serum IGFBP-1 was measured in 31 TRS patients, 49 chronic medicated schizophrenia (CMS) patients, and 53 healthy controls. Clinical symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS) and cognitive functions using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
RESULTS: Both TRS and CMS patients exhibited cognitive deficits compared to healthy controls (p < 0.05). Serum IGFBP-1 concentration differed significantly among groups (F=36.805, p < 0.001) and post hoc tests demonstrated significantly higher concentrations in both schizophrenia groups compared to controls (p < 0.001). Further, serum IGFBP-1 concentration was higher in the TRS group than the CMS group (p = 0.048). Correlation analysis identified a significant relationship between serum IGFBP-1 and attention in the TRS group (r = 0.411, p = 0.021), immediate memory in the CMS group (r = -0.417, p = 0.003), and RBANS total score in the CMS group (r = -0.368, p = 0.009). Multiple regression analysis adjusting for confounding factors revealed that serum IGFBP-1 was independently associated with attention in TRS patients (p = 0.016, 95 %CI. 0.002-0.015) and immediate memory in CMS patients (p = 0.022, 95 %CI-0.012 to -0.001).
CONCLUSIONS: Elevated serum IGFBP-1 concentration may serve as a predictive biomarker for distinct cognitive deficits in TRS and CMS patients. Further investigations are warranted.

BACKGROUND: 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.
OBJECTIVE: To investigate the effect of once-daily versus multiple-daily dosing regimens of clozapine on relapse in patients with TRS.
METHODS: 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).
RESULTS: 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 (> 300 mg/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).
CONCLUSIONS: Once-daily clozapine dosing may not be associated with an increased relapse 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.

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.

BACKGROUND: Recent 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.
METHODS: We 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.
RESULTS: Clustering 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.
CONCLUSIONS: We provided evidence for heterogeneity of negative symptoms in TRS. Negative symptoms can characterize TRS patients and predict functional outcome.

Control groups used in randomised controlled trials investigating psychological interventions for depression and anxiety disorders have effects of their own. This has never been investigated for schizophrenia, in particular treatment-resistant schizophrenia. This systematic review and meta-analysis aimed to examine how control groups in randomised controlled trials on psychological interventions for treatment-resistant schizophrenia behave in their effects on general symptomatology. In a search of various databases until July 2023, 31 eligible studies with 3125 participants were found whose control groups were assigned to four categories: active, inactive, treatment as usual and waitlist. The analyses showed that psychological interventions had a greater effect on symptom reduction to all control groups combined. When separating the control groups, only compared to TAU and waitlist controls the psychological interventions were superior. The difference was larger when less active control groups (e.g. waitlist - or treatment as usual control groups) were used. All control groups were associated with an improvement in symptoms from pre- to post-measurement point, with the greatest improvement observed in the inactive control group. The results are preliminary, but they suggest that the choice of the control group has a considerable impact on study effects as it has been shown in other psychiatric diagnoses.

UNASSIGNED: The impact of obtaining second-opinion consultations on diagnoses of schizophrenia spectrum disorders was evaluated.
UNASSIGNED: A retrospective chart review was conducted for 177 patients referred to a psychosis consultation service at an academic medical center from January 1, 2017, to October 1, 2023; these consultations aimed to clarify a diagnosis of psychosis. Diagnoses made before and after consultations were compared, and treatment recommendations resulting from the consultation visit were summarized.
UNASSIGNED: Among patients without a preconsultation diagnosis of schizophrenia, 28% (N=28 of 100) received a postconsultation diagnosis of schizophrenia. Among 62 patients with a postconsultation diagnosis of treatment-resistant schizophrenia (TRS), 56% (N=35) received this diagnosis only after consultation. Nearly all of these patients were advised to begin taking clozapine, and electroconvulsive therapy was less commonly recommended.
UNASSIGNED: Expert consultation facilitates timely identification and optimal treatment of schizophrenia and its more severe subtype, TRS.