Clozapine (CLO) is an atypical antipsychotic drug often used for treatment of pharmacoresistant schizophrenia. Therapeutic drug monitoring (TDM) is highly recommended in CLO therapy as optimal therapeutic range is narrow, high interindividual variability in plasma concentration exists and there is a significant risk of adverse drug reactions. TDM is traditionally based on venous blood sampling, which may be burdensome for patients and limits frequent monitoring. Dried blood spot (DBS) sampling represents a minimally invasive alternative, offering advantages in cost, stability, and ease of sample handling. This study aimed to characterize the relationship between CLO concentrations measured in DBS and serum. A total of 20 patient samples were collected, and CLO concentrations were determined in both matrices using an LC-MS method. Chromatographic separation was achieved on a Kinetex C18 column with gradient elution, and detection was performed using positive ionization on a maXis impact qTOF MS. Method optimization focused on sampling devices and extraction conditions. The method for determination of CLO in the DBS was validated accordingly to EMA guidelines. A strong correlation was observed between DBS and serum concentrations (r = 0.90, 95% CI 0.76-0.96). The effect of haematocrit was also evaluated. Our findings indicate that DBS sampling is a feasible alternative for CLO monitoring in clinical practice. However, due to systematic differences between matrices, and influence of haematocrit on agreement of concentrations DBS and serum, appropriate conversion for accurate interpretation is required, which should be validated in larger patient cohorts.

BACKGROUND:Borderline personality disorder (BPD) is characterized by emotional dysregulation and high rates of suicidal and self-harming behavior, while effective treatments remain limited. This study evaluated short- and long-term effects of right dorsolateral prefrontal cortex (DLPFC) rTMS in a double-blind, sham-controlled design, accounting for concurrent treatment and trauma history. METHODS:Thirty women with BPD and recent nonsuicidal self-injury or suicidal behavior underwent 15 sessions of active or sham 10-Hz rTMS targeting the right DLPFC over three weeks. Outcomes were assessed at baseline, post-treatment, and three- and six-month follow-up. Primary analyses compared longitudinal trajectories between groups using linear mixed-effects models. RESULTS:No significant Group × Time interactions were observed for primary outcomes, indicating no evidence of differential longitudinal change between active and sham stimulation. Exploratory within-group analyses showed reduced self-reported depressive symptoms in the active group at post-treatment (β = -0.58), with borderline-significant reductions at three and six months; medication adjustment yielded a significant effect at three months (β = -0.78), but not six months (β = -0.62). Impulsivity decreased in the sham group at three (β = -0.58) and six months (β = -0.59). Self-harming and suicidal behavior decreased in both groups at three and six months. Dissociation decreased in the sham group at three months (β = -0.53). CONCLUSION:No evidence of superior longitudinal effects of active versus sham rTMS was observed. Exploratory within-group findings warrant further investigation but do not establish stimulation-specific efficacy. Larger sham-controlled trials are needed to determine the efficacy and durability of rTMS in BPD.

OBJECTIVE:To analyse the use of antipsychotics for first-episode of psychosis (FEP) and relapsed schizophrenia, and the impact of predominant symptoms on decision making. METHODS:A survey among 150 European psychiatrists was conducted using computer-assisted web interviewing to assess preferred medications, switching, dose adjustments, and maintenance therapy in acute FEP and relapse settings. RESULTS:Negative or affective symptoms were reported as prevalent in 55% of FEP and 59% of relapsed schizophrenia cases, indicating significant unmet treatment needs. Olanzapine and risperidone were the most commonly prescribed antipsychotics for FEP, with treatment choices influenced by symptom profiles. Long-acting injectables (LAIs) were prescribed to 28% of FEP patients, with notable variation across countries (15-43%; p < 0.05). During hospitalisation, 41% of patients required therapy adjustments, while discharge decisions were driven by drug tolerability and symptom severity. For relapsed patients, non-adherence was identified as the primary cause of relapse (71%), and olanzapine, risperidone, and aripiprazole were the most prescribed treatments. Post-discharge adjustments for relapsed patients focused on adherence and long-term treatment goals. CONCLUSION:Despite the prevalence of negative or affective symptoms in FEP and relapsed patients, traditional antipsychotics remain the most prescribed treatments. Non-adherence and variability in LAI usage highlight the need for improved symptom-specific approaches and standardised LAI protocols.

This study aimed to develop a robust methodology for quantifying cortisol decay in segmented human hair and to establish accurate retrospective estimates of initial cortisol levels. Two independent probabilistic approaches were employed: i) a Bayesian multilevel analysis across 37 individuals with 3-6 hair segments each and ii) a Bayesian repeated sampling approach in a single individual with 10 segments collected over eight months. All hair segments were analyzed for cortisol concentration using liquid chromatography-mass spectrometry with on-line solid phase extraction. Both approaches demonstrated an exponential decay pattern of cortisol in hair, with estimated decay constants (k) of 0.16 (95 % Credible interval: 0.10-0.22) and 0.11 (95 % Credible interval: 0.06-0.15), respectively. A correction factor was introduced to significantly enhance the accuracy of initial cortisol level estimation, enabling more reliable comparisons with reference intervals obtained from proximal hair segments. This innovative method has the potential to significantly improve long-term cortisol monitoring and advance clinical research especially in psychiatry and endocrinology.

Mayerová, Michaela MD, PhD; Maslaňáková, Helena MSc; Ustohal, Libor MD; Horská, Kateřina PharmDr, PhD Author Information

Ústav farmakologie a toxikologie, Farmaceutická fakulta Masarykovy univerzity

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

INTRODUCTION:The rate of pharmacoresistance among in patients diagnosed with schizophrenia is around 30%. Clozapineis the drug of choice for these patients; however, an adequate response to treatment doesn't always occur. One of the possible augmentation approaches, specifically for non-adherent patients, is the administration of long-acting parenteral antipsychotics. Our goal was to evaluate previous experiences of administering a combination of the atypical antipsychotic clozapine and long-acting injectable antipsychotics to pharmacoresistant patients at the Department of Psychiatry the Czech Republic and to assess the safety and effectiveness of such administration. METHODS:A retrospective evaluation of patient case studies was conducted for those who were hospitalized in the Ward for the therapy of Psychotic disorders between 2016 and 2020 and had a medication history of combining clozapine and depot antipsychotics. RESULTS:Over half of the patients had no illness relapses during the observed period. The clinical manifestation of adverse effects from combination therapy appears low in our patient sample, primarily involving mild and pharmacologically manageable side effects (tachycardia). Only one of the cases recorded neutropenia, which led to discontinuation of clozapine; the patient was maintained on long-acting injectable antipsychotics medication. CONCLUSION:From our findings, it can be inferred that augmenting clozapine with depot antipsychotics is a potential therapeutic intervention that pharmacoresistant patients could benefit from. However, it is essential to emphasize that this therapeutic approach should only be administered after carefully considering the patient's existing treatment. It should be strictly individualized based on the treating physician's or clinical pharmacist's sufficient professional experience.

The aim of this pilot study was to find whether the dysregulation of neuroendocrine biomarker signaling pathways in the first episode of non-affective psychosis is a predictive factor of treatment outcome. Patients with the first episode of non-affective psychosis (N = 29) were examined at admission, at discharge, and at follow-up (N = 23). The biomarkers included serum aldosterone, cortisol, free thyroxine, thyroid stimulating hormone, and prolactin. We revealed lower baseline aldosterone and higher baseline cortisol concentrations in patients with very good outcome compared to those with good outcome after one year. We failed to reveal any significant association between treatment outcome and neurohumoral biomarkers in the whole sample at 1-year follow-up. However, baseline aldosterone concentrations negatively correlated with total PANSS scores at the discharge. Lower baseline aldosterone and higher baseline cortisol concentrations have the potential to predict a more favorable outcome for patients with the first episode of psychosis.

IntroductionPatients with schizophrenia have difficulties in cognitive and affective mentalizing which is manifested by excessive (‘overmentalizing’) or defective (‘undermentalizing’) attribution of mental states. As most of the tests does not differentiate between ‘overmentalizing’ and ‘undermentalizing’, it is not yet clear how are these deficits reflected in mentalizing network in schizophrenia.ObjectivesInvestigate how is cognitive and affective ‘overmentalizing’ and ‘undermentalizing’ reflected in mentalizing network in schizophrenia.MethodsWe recruited 30 schizophrenia patients and 30 healthy controls who underwent fMRI session while they completed ‘Social situations assessment task’ consisting of 90 stories with 30 questions on affective, 30 on cognitive mental states and 30 control memory questions and 4 possible answers: no mentalizing, undermentalizing, appropriate mentalizing, overmentalizng (for control condition 1 correct and 3 incorrect).ResultsOn a behavioral level, we found increased no mentalizing and undermentalizing and decreased mentalizing in patients, but no difference in overmentalizing between groups. For fMRI results, patients showed lesser recruitment of dorsomedial prefrontal cortex and temporal poles (with right superior temporal sulcus) only during appropriate mentalizing in both affective and cognitive conditions. However, ventromedial prefrontal cortex and precuneus showed increased pattern of activation across all mentalizing levels in healthy controls compared to schizophrenia, but suppressed activation in appropriate cognitive mentalizing corresponding to the level of a schizophrenia group.ConclusionsSchizophrenia patients show different pattern of mentalizing compared to healthy control that can be associated with specific activity mentalizing brain network.DisclosureNo significant relationships.

Background: Schizophrenia is a severe and often difficult to treat psychiatric illness. In many patients, negative symptoms dominate the clinical picture. Meta-analysis has suggested moderate, but significant effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on these symptoms. For treatment of depression a much shorter protocol - intermittent theta burst stimulation (iTBS) - has shown to be non-inferior to conventional high-frequency rTMS. This randomized, sham-controlled, rater-blinded clinical trial assesses the effects of conventional HF-rTMS as well as of iTBS of the left dorsolateral prefrontal cortex in comparison with sham. Methods: The study will be conducted at two psychiatric university hospitals in Germany and at two in the Czech Republic. Assuming an effect size of 0.64 to be detected with a power of 80%, the calculated sample size is 90 patients. Primary outcome will be the difference in the Scale for the Assessment of Negative Symptoms (SANS) score between each active arm and the sham arm at end of treatment. In addition, the trial investigates effects on depressive symptoms, cognitive performance and cigarette smoking. Recording magnetic resonance imaging (MRI) and electroencephalography (EEG) data will serve to assess whether treatment success can be predicted by neural markers and is related to specific neurobiological changes. Discussion: This is a clinical trial directly comparing 10 Hz-rTMS and iTBS in a sham-controlled manner in treating negative symptoms of schizophrenia. If successful, this would present an interesting treatment option for a chronic and severe condition that can be applied at most psychiatric hospitals and only takes up a few minutes per day.

Sverak, Tomas PhD; Mayerova, Michaela MD, PhD; Obdrzalkova, Marie MD; Ustohal, Libor MD, PhD Author Information

Objective Patients with schizophrenia are at higher risk of cardiovascular (CVS) related mortality. Close attention is being paid to the clinical utility of readily available CVS markers. Methods A pilot one-year longitudinal study in inpatients with first-episode psychosis (FEP) was carried out to determine markers of inflammation and endothelial dysfunction (monocyte- and neutrophil-to-lymphocyte ratios) and basal blood pressure, pulse, and derived hemodynamic parameters (PP: pulse pressure; RPP: rate pressure product; and MAP: mean arterial pressure). Results After one year, PP and RPP increased, as did systolic blood pressure and heart rate. Systolic blood pressure, PP, total white blood cells, and neutrophils correlated with weight gain. After one year, correlations between monocyte-to-lymphocyte ratio and RPP and MAP were observed. Conclusion Our study indicates worsening CVS health over the first year of treatment and emphasises the importance of early monitoring of CVS status using easily accessible parameters to prevent CVS-related mortality.

OBJECTIVES:Repetitive transcranial magnetic stimulation (rTMS) is an innovative method in the treatment of borderline personality disorder (BPD). We hypothesized that prefrontal rTMS in patients with BPD leads to improved BPD symptoms and that these effects are associated with brain connectivity changes. METHODS:Fourteen patients with BPD received 15 sessions of individually navigated prefrontal rTMS over the right dorsolateral prefrontal cortex. Clinical effects were measured by the Borderline Symptom List 23, UPPS-P, the Difficulties in Emotion Regulation Scale (DERS), the Zung Self-Rating Anxiety Scale (SAS), and the Montgomery and Åsberg Depression Rating Scale (MADRS). Effects of rTMS on brain connectivity were observed with a seed correlation analysis on resting-state fMRI and with a beta series correlation analysis on Go/No Go tasks during fMRI. Assessments were made before and immediately after the treatment. RESULTS:The assessments after rTMS showed significant reductions in two subscales of UPPS-P, and in DERS, SAS, and MADRS. The brain connectivity analysis revealed significant decreases in amygdala and insula connectivity with nodes of the posterior default mode network (pDMN; precuneus, posterior cingulate cortex, parietal lobules). Connectivity changes were observed both in the resting state and during inhibition. The decrease of amygdala-pDMN connectivity was positively correlated with reduced depression and lack of premeditation after rTMS. CONCLUSIONS:Despite the study limitations (open single-arm study in a small sample), our findings suggest a possible neural mechanism of rTMS effect in BPD, reduced amygdala connectivity with the pDMN network, which was positively associated with symptom reduction.

Článek shrnuje některé nežádoucí účinky při léčbě antipsychotiky, které nejsou v praxi časté, ačkoliv jde o léčbu běžně užívanými antipsychotiky. Výběr z literatury je doplněn kazuistikami pacientů z naší praxe. Zaměřili jsem se na trombózy a anticholinergní deliria a doplnili ostatními. Příčiny a okolnosti rozvoje vedlejších účinků jsou doplněny klinickým managementem těchto situací.