Infections associated with clozapine: a pharmacovigilance study using VigiBase®.

Introduction: Clozapine is primarily reserved for treatment-resistant schizophrenia due to safety concerns associated with its use. Infections have been reported with clozapine, which may lead to elevated serum levels of the drug. However, the existing literature on this topic is limited. Therefore, we conducted a study using VigiBase® to investigate the potential over-reporting of infections associated with clozapine, to explore the presence of dose-dependency, and to investigate the underlying mechanism. Methods: Disproportionality analyses were performed using VigiBase to assess the association between clozapine and all types of infections, the association between clozapine-associated infections and neutropenia, the association between clozapine-associated infections and agranulocytosis, the dose-effect relationship between clozapine and infections, and the interaction between clozapine and the main strong CYP450 inhibitors using reports carried out until 11 April 2023. Results: A statistically significant signal of infections was observed with clozapine, as indicated by an information component of 0.43 [95% CI: (0.41-0.45)]. The most commonly reported infections were respiratory and gastrointestinal in nature. Neutropenia showed weaker association with clozapine-associated reports of infections compared to other clozapine-associated reports [X2 (1, N = 204,073) = 454; p < 0.005], while agranulocytosis demonstrated a stronger association with clozapine-associated reports of infections [X2 (1, N = 204,073) = 56; p < 0.005]. No evidence of dose-dependency was observed. Among the 17 tested CYP inhibitors, significant drug-drug interactions were found with clarithromycin, metronidazole, valproic acid, lansoprazole, omeprazole, amiodarone, and esomeprazole. Discussion: Our study revealed a significant safety signal between clozapine use and infections, predominantly respiratory and gastrointestinal infections. The co-administration of clozapine with valproic acid or proton pump inhibitors may potentially contribute to an increased risk of infection. Further vigilance is warranted in clinical practice, and consideration of therapeutic drug monitoring of clozapine in cases involving concomitant use of these drugs or in the presence of infections may be beneficial.

Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase®.

BACKGROUND: Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database. METHODS: We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report. RESULTS: Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75-10.77) and leukaemia (aROR 3.54, 95% CI 2.97-4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2-9.9) for malignant lymphoma and 2.5 years (IQR 0.6-7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association. CONCLUSIONS: Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

Does the Beck Cognitive Insight Scale predict change in delusional beliefs?

OBJECTIVES: The Beck Cognitive Insight Scale (BCIS) is composed of two subscales, self-reflectiveness and self-certainty, assessing reflectiveness and openness to feedback, and mental flexibility. Delusions have previously been associated with low cognitive insight. The aim of this study was to determine whether changes in BCIS scores predict changes in delusional beliefs. METHODS: The study is a secondary analysis of a previously published randomized controlled trial. All participants had a psychotic disorder diagnosis and received treatment as usual, with half of them also receiving the cognitive restructuring intervention 'Michael's game'. Participants were assessed at three different times: at baseline (T1), at 3 months (T2), and at 9 months (T3). Cognitive insight was measured with the BCIS, belief flexibility with the Maudsley assessment of delusions schedule (MADS), and psychotic symptoms with the Brief Psychiatric Rating Scale (BPRS). RESULTS: A total of 172 participants took part in the trial. After using generalized estimating equation (GEE) modelling, we observed (1) significant main effects of BCIS self-certainty and Time and (2) significant Time × BCIS self-certainty and Time × treatment group interaction effects on belief flexibility. Improvements in self-certainty (i.e., decrease in scores) were associated with more changes in conviction over time, more accommodation, improved ability in ignoring or rejecting a hypothetical contradiction and increased use of verification of facts. Medication and BPRS total scores were controlled for in the GEE analyses at their baseline values. CONCLUSIONS: Overall improvement in BCIS self-certainty scores over time predicted better treatment outcomes as assessed with MADS items. PRACTITIONER POINTS: Treatments for patients with psychosis should focus on improving cognitive insight as this seems to improve overall treatment outcomes and recovery. The Beck Cognitive Insight Scale can be used to measure changes during treatment and can predict treatment outcomes.

Does Change over Time in Delusional Beliefs as Measured with PDI Predict Change over Time in Belief Flexibility Measured with MADS?

Delusional beliefs and their behavioral consequences are predominant symptoms in patients with psychosis and play an important role in the treatment. Delusional beliefs are a multidimensional concept which can be divided into three components: distress, preoccupation and conviction of delusions. These can be measured using Peters delusions inventory (PDI-21). We question, whether changes in delusional beliefs over time during treatment measured with the PDI-21 can predict changes in belief flexibility measured with the Maudsley assessment of delusions schedule (MADS). We used a group of patients from a randomized controlled trial for a cognitive intervention for psychosis or psychotic symptoms. Aside standard treatment for psychosis, half of the patients took part in a group treatment "Michael's game". Patients were assessed at baseline (T1), at 3 months (T2), and at 9 months (T3). We measured delusional beliefs using PDI-21 and belief flexibility with the MADS. One hundred seventy-two patients were included in the analysis. We measured a main effect of PDI-21scores on belief flexibility measured with MADS. PDI-21 Conviction scores predicted outcomes for all measured MADS items. Increasing PDI Distress and Preoccupation scores were predictors for being more likely to dismiss beliefs and change conviction. Time itself was a predictor for changing conviction and being able to plan a behavioral experiment. Overall the changes in PDI scores predicted outcomes for belief flexibility measured with MADS items. The PDI-21 could be a simple and effective way to measure progress in treatment on delusional beliefs.

High-Frequency Neuronavigated rTMS in Auditory Verbal Hallucinations: A Pilot Double-Blind Controlled Study in Patients With Schizophrenia.

INTRODUCTION: Despite extensive testing, the efficacy of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of temporo-parietal targets for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia is still controversial, but promising results have been reported with both high-frequency and neuronavigated rTMS. Here, we report a double-blind sham-controlled study to assess the efficacy of high-frequency (20 Hz) rTMS applied over a precise anatomical site in the left temporal region using neuronavigation. METHODS: Fifty-nine of 74 randomized patients with schizophrenia or schizoaffective disorders (DSM-IV R) were treated with rTMS or sham treatment and fully evaluated over 4 weeks. The rTMS target was determined by morphological MRI at the crossing between the projection of the ascending branch of the left lateral sulcus and the superior temporal sulcus (STS). RESULTS: The primary outcome was response to treatment, defined as a 30% decrease of the Auditory Hallucinations Rating Scale (AHRS) frequency item, observed at 2 successive evaluations. While there was no difference in primary outcome between the treatment groups, the percentages of patients showing a decrease of more than 30% of AHRS score (secondary outcome) did differ between the active (34.6%) and sham groups (9.1%) (P = .016) at day 14. DISCUSSION: This controlled study reports negative results on the primary outcome but demonstrates a transient effect of 20 Hz rTMS guided by neuronavigation and targeted on an accurate anatomical site for the treatment of AVHs in schizophrenia patients.

Network modeling of resting state connectivity points towards the bottom up theories of schizophrenia.

The dysconnectivity theory of schizophrenia proposes that schizophrenia symptoms arise from abnormalities in neuronal synchrony. Resting-state Functional Connectivity (FC) techniques allow us to highlight synchronization of large-scale networks, the Resting-state Networks (RNs). A large body of work suggests that disruption of RN synchronization could give rise to specific schizophrenia symptoms. The present study aimed to explore within- and between-network FC strength of 34 RNs in 29 patients suffering from schizophrenia, and their relationships with schizophrenia symptoms. Resting-state data were analyzed using independent component analysis and dual-regression techniques. Our results showed that both within-RN and between-RN FC were disrupted in patients with schizophrenia, with a global trend toward weaker FC. This decrease affected more particularly visual, auditory and crossmodal binding networks. These alterations were correlated with negative symptoms, positive symptoms and hallucinations, indicating abnormalities in visual processing and crossmodal binding in schizophrenia. Moreover, we stressed an anomalous synchronization between a visual network and a network thought to be engaged in mental imaging processes, correlated with delusions and hallucinations. Altogether, our results supported the assumption that some schizophrenia symptoms may be related to low-order sensory alterations impacting higher-order cognitive processes, i.e. the "bottom-up" hypothesis of schizophrenia symptoms.

Functional deficit of the medial prefrontal cortex during emotional sentence attribution in schizophrenia.

BACKGROUND: Functional brain imaging research has already demonstrated that patients with schizophrenia had difficulties with emotion processing, namely in facial emotion perception and emotional prosody. However, the moderating effect of social context and the boundary of perceptual categories of emotion attribution remain unclear. This study investigated the neural bases of emotional sentence attribution in schizophrenia. METHODS: Twenty-one schizophrenia patients and 25 healthy subjects underwent an event-related functional magnetic resonance imaging paradigm including two tasks: one to classify sentences according to their emotional content, and the other to classify neutral sentences according to their grammatical person. RESULTS: First, patients showed longer response times as compared to controls only during the emotion attribution task. Second, patients with schizophrenia showed reduction of activation in bilateral auditory areas irrespective of the presence of emotions. Lastly, during emotional sentences attribution, patients displayed less activation than controls in the medial prefrontal cortex (mPFC). CONCLUSIONS: We suggest that the functional abnormality observed in the mPFC during the emotion attribution task could provide a biological basis for social cognition deficits in patients with schizophrenia.

Reducing Delusional Conviction through a Cognitive-Based Group Training Game: A Multicentre Randomized Controlled Trial.

OBJECTIVE: "Michael's game" (MG) is a card game targeting the ability to generate alternative hypotheses to explain a given experience. The main objective was to evaluate the effect of MG on delusional conviction as measured by the primary study outcome: the change in scores on the conviction subscale of the Peters delusions inventory (PDI-21). Other variables of interest were the change in scores on the distress and preoccupation subscales of the PDI-21, the brief psychiatric rating scale, the Beck cognitive insight scale, and belief flexibility assessed with the Maudsley assessment of delusions schedule (MADS). METHODS: We performed a parallel, assessor-blinded, randomized controlled superiority trial comparing treatment as usual plus participation in MG with treatment as usual plus being on a waiting list (TAU) in a sample of adult outpatients with psychotic disorders and persistent positive psychotic symptoms at inclusion. RESULTS: The 172 participants were randomized, with 86 included in each study arm. Assessments were performed at inclusion (T1: baseline), at 3 months (T2: post-treatment), and at 6 months after the second assessment (T3: follow-up). At T2, a positive treatment effect was observed on the primary outcome, the PDI-21 conviction subscale (p = 0.005). At T3, a sustained effect was observed for the conviction subscale (p = 0.002). Further effects were also observed at T3 on the PDI-21 distress (p = 0.002) and preoccupation subscales (p = 0.001), as well as on one of the MADS measures of belief flexibility ("anything against the belief") (p = 0.001). CONCLUSION: The study demonstrated some significant beneficial effect of MG.

Functional and structural brain asymmetries in patients with schizophrenia and bipolar disorders.

OBJECTIVES: This study aimed to compare the functional and gray matter asymmetries in patients with schizophrenia (SZ), patients with bipolar disorders (BD), and healthy controls (HCs) to test whether decreased leftward functional hemispheric lateralization and gray matter volume asymmetry could mark the boundary between schizophrenia and bipolar disorder. METHODS: A total of 31 right-handed SZ and 20 right-handed BD underwent a session of functional MRI with a speech listening paradigm. Participants were matched with HCs for gender, age, and education. Functional laterality indices (FLI) and gray matter volume asymmetry indices (GVAI) were computed from the individual functional language network. Correlations between the FLI and GVAI indices were also examined. RESULTS: SZ exhibited significantly decreased leftward functional hemispheric lateralization whereas BD did not. The GVAIs did not differ significantly between SZ and HCs or between BD and HCs. There were positive correlations between GVAIs and FLIs in all groups. CONCLUSIONS: Loss of laterality for language comprehension with retention of gray matter volume asymmetry indicates that gray matter loss alone will not account for the pathophysiology of schizophrenia. Impaired leftward functional hemispheric lateralization for language but not gray matter volume asymmetry can be considered a biomarker of SZ.

Social cognition in schizophrenic patients: the effect of semantic content and emotional prosody in the comprehension of emotional discourse.

BACKGROUND: The recognition of the emotion expressed during conversation relies on the integration of both semantic processing and decoding of emotional prosody. The integration of both types of elements is necessary for social interaction. No study has investigated how these processes are impaired in patients with schizophrenia during the comprehension of an emotional speech. Since patients with schizophrenia have difficulty in daily interactions, it would be of great interest to investigate how these processes are impaired. We tested the hypothesis that patients present lesser performances regarding both semantic and emotional prosodic processes during emotional speech comprehension compared with healthy participants. METHODS: The paradigm is based on sentences built with emotional (anger, happiness, or sadness) semantic content uttered with or without congruent emotional prosody. The study participants had to decide with which of the emotional categories each sentence corresponded. RESULTS: Patients performed significantly worse than their matched controls, even in the presence of emotional prosody, showing that their ability to understand emotional semantic content was impaired. Although prosody improved performances in both groups, it benefited the patients more than the controls. CONCLUSION: Patients exhibited both impaired semantic and emotional prosodic comprehensions. However, they took greater advantage of emotional prosody adjunction than healthy participants. Consequently, focusing on emotional prosody during carrying may improve social communication.

Functional and white matter abnormalities in the language network in patients with schizophrenia: a combined study with diffusion tensor imaging and functional magnetic resonance imaging.

BACKGROUND: Schizophrenia is a mental disorder characterized by functional abnormalities in the language network. Anatomical white matter (WM) abnormalities (volume and integrity) have also been reported for this pathology. Nevertheless, few studies have investigated anatomo-functional relationships in schizophrenia, and none has focused on the language comprehension network in relation to various diffusion parameters. We hypothesized that the WM abnormalities that are reflected by several diffusion parameters underlie functional deficits in the language network. METHODS: Eighteen DSM-IV patients with schizophrenia and 18 healthy controls without any significant differences in sex, age, or level of education were included. First, functional brain activation within the language network was estimated. Then, using diffusion tensor imaging, fractional anisotropy (FA), radial diffusivity (RD), and mean diffusivity (MD) values were extracted within WM regions adjacent to this network and their anatomo-functional relationships were investigated. RESULTS: Compared with healthy participants, both functional and diffusion deficits were observed in patients with schizophrenia. Primarily, an altered diffusion-functional relationship was observed in patients in the left middle temporal region: functional activations were positively correlated with FA, but were negatively correlated with RD. CONCLUSIONS: Our findings indicate a close relationship between diffusion and functional deficits in patients with schizophrenia, suggesting that WM integrity disturbance might be one cause of functional alterations in the language network in patients with schizophrenia. Thus, the present multimodal study improves our understanding of the pathophysiology of schizophrenia.

Functional hemispheric lateralization for language in patients with schizophrenia.

BACKGROUND: It is widely reported that patients with schizophrenia exhibit decreased hemispheric lateralization. However, no study has evaluated relationships between the hemispheric anatomical and functional asymmetry in language areas. The present study aimed to determine whether decreased leftward hemispheric lateralization could be related to asymmetry of the grey matter volume in patients with schizophrenia. This investigation was the first to use a functional index of laterality to analyze the global functional network specifically involved in the language task. METHODS: Twenty-seven right-handed patients with schizophrenia and 54 right-handed control subjects underwent a session of a functional magnetic resonance imaging (fMRI) with a speech listening paradigm. Functional laterality indices (FLI) were calculated (Wilke, M. and Lidzba, K., 2007. LI-tool: a new toolbox to assess lateralization in functional MR-data. J Neurosci Methods. 163, 128-136). The indices of asymmetry in the volume of grey matter (GVAIs) were computed from the functional language network. RESULTS: Patients with schizophrenia exhibited significantly decreased leftward hemispheric lateralization. There was a positive correlation between GVAIs and FLIs in healthy subjects, while no such correlation was seen in patients with schizophrenia. DISCUSSION: This study reports for the first time a significant relationship between the anatomical and functional asymmetry in healthy subjects, but not in patients with schizophrenia. While decreased leftward functional lateralization for language was observed in patients with schizophrenia compared to the control group, this functional abnormality was not related to asymmetry in the volume of grey matter.

Links among resting-state default-mode network, salience network, and symptomatology in schizophrenia.

Neuroimaging data support the idea that schizophrenia is a brain disorder with altered brain structure and function. New resting-state functional connectivity techniques allow us to highlight synchronization of large-scale networks, such as the default-mode network (DMN) and salience network (SN). A large body of work suggests that disruption of these networks could give rise to specific schizophrenia symptoms. We examined the intra-network connectivity strength and gray matter content (GMC) of DMN and SN in 26 schizophrenia patients using resting-state functional magnetic resonance imaging and voxel-based morphometry. Resting-state data were analyzed with independent component analysis and dual-regression techniques. We reported reduced functional connectivity within both DMN and SN in patients with schizophrenia. Concerning the DMN, patients showed weaker connectivity in a cluster located in the right paracingulate cortex. Moreover, patients showed decreased GMC in this cluster. With regard to the SN, patients showed reduced connectivity in the left and right striatum. Decreased connectivity in the paracingulate cortex was correlated with difficulties in abstract thinking. The connectivity decrease in the left striatum was correlated with delusion and depression scores. Correlation between the connectivity of DMN frontal regions and difficulties in abstract thinking emphasizes the link between negative symptoms and the likely alteration of the frontal medial cortex in schizophrenia. Correlation between the connectivity of SN striatal regions and delusions supports the aberrant salience hypothesis. This work provides new insights into dysfunctional brain organization in schizophrenia and its contribution to specific schizophrenia symptoms.

Distinct episodic verbal memory profiles in schizophrenia.

According to some authors, episodic memory impairment may be a feature shared by all schizophrenic patients, whereas others argue in favor of the mnesic heterogeneity. Our aims were to determine whether patients can be grouped based on according to their mnesic performances. The California Verbal Learning Test (CVLT), an episodic verbal learning test, was compared in 61 schizophrenic patients and 61 matched healthy subjects. The 32 indices were calculated using CVLT Scoring Software. This process allowed us to describe patients' episodic processes in detail (encoding, storage, retrieval). We isolated one group with normative data, another showed impairment of both encoding and retrieval processes, and in the last one, only encoding process was impaired. As schizophrenia is heterogeneous with regard to episodic memory, impairments should not be considered as a common core to the various forms of the illness and it would be fruitful to systematically assess episodic processes in detail to take into account individual abilities and challenges.

Meaningfulness and global-local processing in schizophrenia.

The present work aimed to study the influence of the meaningfulness of stimuli during global-local processing in schizophrenia. Study participants were asked to determine whether pairs of compound stimuli (global forms composed of local forms) were identical or not. Both global and local forms represented either objects or non-objects. Results indicated that when identification processes were useful for performing the task, similar global-local response patterns were observed in patients and controls. However, patients were more affected than controls when an object was present at a distractor level, particularly when this information came from the local level. These results are discussed in terms of the conjunction of executive and visuospatial deficits and underscore the importance of meaningful identification in the visual perception of schizophrenia patients, given its central role in day-to-day situations.

Functional deficit in the medial prefrontal cortex during a language comprehension task in patients with schizophrenia.

OBJECTIVE: We and others have observed that patients with schizophrenia commonly presented a reduced left recruitment in language semantic brain regions. However, most studies include patients with leftward and rightward lateralizations for language. We investigated whether a cohort comprised purely of patients with typical lateralization (leftward) presented a reduced left recruitment in semantic regions during a language comprehension task. The goal was to reduce the inter-subject variability and thus improve the resolution for studying functional abnormalities in the language network. METHODS: Twenty-three patients with schizophrenia (DSM-IV) were matched with healthy subjects in age, sex, level of education and handedness. All patients exhibited leftward lateralization for language. Functional MRI was performed as subjects listened to a story comprising characters and social interactions. Functional MRI signal variations were analyzed individually and compared among groups. RESULTS: Although no differences were observed in the recruitment of the semantic language network, patients with schizophrenia presented significantly lower signal variations compared to controls in the medial part of the left superior frontal gyrus (MF1) (x=-6, y=58, z=20; Z(score)=5.6; p<0.001 uncorrected). This region corresponded to the Theory of Mind (ToM) network. Only 5 of the 23 patients (21.7%) and 21 of the 23 (91.3%) control subjects demonstrated a positive signal variation in this area. CONCLUSIONS: A left functional deficit was observed in a core region of the ToM network in patients with schizophrenia and typical lateralizations for language. This functional defect could represent a neural basis for impaired social interaction and communication in patients with schizophrenia.

Stability of functional language lateralization over time in schizophrenia patients.

BACKGROUND: Cross-sectional functional imaging studies have shown a reduced leftward language lateralization in schizophrenic patients. An unanswered question is whether this reduced leftward lateralization is stable over time or is modified over the course of the illness. METHODS: Ten right-handed (RH) patients (DSM-IV) and 10 RH controls were matched one-to-one for sex, age, and level of education. The subjects underwent two separate fMRI sessions while engaged in a story listening task, 21 months apart. After each session, story comprehension (task performance) was assessed through a 12-item questionnaire. The stability of the decreased asymmetry indices in the semantic region of interest (LANG) was investigated with an ANOVA to compare groups and sessions. In order to test the evolution of functional asymmetry indices at an individual level, a linear correlation between both fMRI session asymmetry indices was calculated in all subjects. Correlations between asymmetry indices and the severity of psychotic symptoms or task performances were computed. RESULTS: The asymmetry indices of the LANG were significantly reduced in patients as compared to controls and strongly correlated between sessions. Values of asymmetry indices were unrelated to either psychotic symptoms or task performances. CONCLUSIONS: This reduced leftward lateralization for language did not vary over time and was not influenced by the psychosis severity or the task performances. This result reinforces the hypothesis that schizophrenia is characterized by a particular organization of language.