Building a neurocognitive profile of suicidal risk in severe mental disorders.

BACKGROUND: Research on the influence of neurocognitive factors on suicide risk, regardless of the diagnosis, is inconsistent. Recently, suicide risk studies propose applying a trans-diagnostic framework in line with the launch of the Research Domain Criteria Cognitive Systems model. In the present study, we highlight the extent of cognitive impairment using a standardized battery in a psychiatric sample stratified for different degrees of suicidal risk. We also differentiate in our sample various neurocognitive profiles associated with different levels of risk. MATERIALS AND METHODS: We divided a sample of 106 subjects into three groups stratified by suicide risk level: Suicide Attempt (SA), Suicidal Ideation (SI), Patient Controls (PC) and Healthy Controls (HC). We conducted a multivariate Analysis of Variance (MANOVA) for each cognitive domain measured through the standardized battery MATRICS Consensus Cognitive Battery (MCCB). RESULTS: We found that the group of patients performed worse than the group of healthy controls on most domains; social cognition was impaired in the suicide risk groups compared both to HC and PC. Patients in the SA group performed worse than those in the SI group. CONCLUSION: Social cognition impairment may play a crucial role in suicidality among individuals diagnosed with serious mental illness as it is involved in both SI and SA; noteworthy, it is more compromised in the SA group fitting as a marker of risk severity.

Psychiatric emergencies during, after, and before the COVID-19 lockdown: what happened to our patients? A naturalistic observational study.

BACKGROUND: Despite concerns on mental health problems related to lockdowns, recent reports revealed a reduction in psychiatric admissions in Emergency Departments (ED) during the lockdown period compared with the previous year in several countries. Most of the existing studies focused on the first lockdown not considering the different phases of the COVID-19 crisis. The present study aimed to analyze differences in ED admission for psychiatric consultation during three different phases of the COVID-19 health crisis in Italy. METHODS: Information on ED admission for psychiatric consultations were retrospectively collected at the ED of the Santo Spirito Hospital in Rome (Italy), and compared between the three periods: the lockdown (March-June 2020) and the post-lockdown period (June 2020-June 2021) compared to the pre-lockdown (January 2019-March 2020). Multinomial logistic regression was used to assess the risk of accessing ED for psychiatric consultation before, during, after the lockdown. RESULTS: Three thousand and eight hundred seventy-one ED psychiatric consultations were collected. A significant reduction of psychiatric consultations in ED during the lockdown period and the post-lockdown (H 762,45; p < 0.001) was documented. Multinomial logistic regression analysis showed that compared to pre-lockdown during the lockdown and post-lockdown patients were more likely to be men (RRR 1.52; 95% CI 1.10-2.12) and more often diagnosed with non-severe mental illnesses (nSMI) (relative risk ratio [RRR] 1.53, 95% CI 1.10-2.15; and 1.72, 95% CI 1.42-2.08); during the lockdown, patients were also more often diagnosed with alcohol/substance abuse (A&S) (RRR 1.70; 95% CI 1.10-2.65). CONCLUSIONS: several changes in the clinical characteristics of psychiatric consultations during and after the lockdown emerged from the present study; nSMI and A&S abuse patients were more likely to present at the ED in the lockdown and post-lockdown periods while SMI patients appeared to be less likely. These may inform clinicians and future preventive strategies among community mental health services.

Gender, age at onset, and duration of being ill as predictors for the long-term course and outcome of schizophrenia: an international multicenter study.

BACKGROUND: The aim of the current study was to explore the effect of gender, age at onset, and duration on the long-term course of schizophrenia. METHODS: Twenty-nine centers from 25 countries representing all continents participated in the study that included 2358 patients aged 37.21 ± 11.87 years with a DSM-IV or DSM-5 diagnosis of schizophrenia; the Positive and Negative Syndrome Scale as well as relevant clinicodemographic data were gathered. Analysis of variance and analysis of covariance were used, and the methodology corrected for the presence of potentially confounding effects. RESULTS: There was a 3-year later age at onset for females (P < .001) and lower rates of negative symptoms (P < .01) and higher depression/anxiety measures (P < .05) at some stages. The age at onset manifested a distribution with a single peak for both genders with a tendency of patients with younger onset having slower advancement through illness stages (P = .001). No significant effects were found concerning duration of illness. DISCUSSION: Our results confirmed a later onset and a possibly more benign course and outcome in females. Age at onset manifested a single peak in both genders, and surprisingly, earlier onset was related to a slower progression of the illness. No effect of duration has been detected. These results are partially in accord with the literature, but they also differ as a consequence of the different starting point of our methodology (a novel staging model), which in our opinion precluded the impact of confounding effects. Future research should focus on the therapeutic policy and implications of these results in more representative samples.

Unveiling the Burden of Interactions Among Clinical Risk Factors for 1-Year Mortality in Hospitalized Older Patients.

Background: Hospitalized older patients are particularly exposed to adverse health outcomes. Objective: In this study, we aimed at investigating the prognostic interactions between disability in basic activities of daily living (BADL), cognitive impairment, low handgrip strength, anticholinergic cognitive burden (ACB), and depression on 1-year mortality. Setting and Subjects: Our series consisted of 503 older patients discharged from acute care hospitals. Methods: Disability in at least one BADL, ACB, depression, cognitive impairment, and low handgrip strength was considered in the analysis. One-year mortality was investigated by Cox regression analysis and prognostic interactions among study variables were assessed by survival tree analysis. Results: Basic activities of daily living disability, ACB, cognitive impairment, and low handgrip strength were significantly associated with 1-year mortality. Survival tree analysis showed that patients with BADL disability and high ACB carried the highest risk of poor survival [hazard ratio (HR): 16.48 (2.63-74.72)], followed by patients with BADL disability and low ACB (HR: 8.43, 95% CI: 1.85-38.87). Patients with cognitive impairment and no BADL disability were characterized by a lower but still significant risk of mortality (HR: 6.61, 95% CI: 1.51-28.97) and those with high ACB scores and good cognitive and functional performance (HR: 5.28, 95% CI: 1.13-24.55). Conclusion: Basic activities of daily living dependency, cognitive impairment, and ACB score were the three main predictors of 1-year mortality among patients discharged from acute care hospitals; the interaction between BADL dependency and ACB score was found to significantly affect survival. Early identification of such high-risk patients may help tailor targeted interventions to counteract their detrimental effects on prognosis.

Design and methodology of the chronic kidney disease as a dysmetabolic determinant of disability among older people (CKD-3D) study: a multicenter cohort observational study.

BACKGROUND: Chronic kidney disease (CKD) is a common condition in older people and represents a global health issue since it increases the risk of associated comorbidities and all-cause mortality. Furthermore, older people with reduced renal function might be at higher risk for developing functional limitation and disability. Moreover, the current creatinine-based measures of renal function are influenced by several factors in older population. The aims of the CKD-3D project are to perform an observational study to expand the knowledge about CKD-disability relationship and to investigate the use of novel biomarkers of kidney function. METHODS: An observational, multicenter, prospective cohort study will be conducted in 75 + old patients consecutively admitted to acute care wards of geriatric medicine at participating hospitals. The study planned to enroll 440 patients undergoing clinical and laboratory evaluations at baseline and after 12 months. Face-to-face follow-up at 6 months and telephone follow-up at 3 and 9 months will be carried out. Comprehensive Geriatric Assessment (CGA) and the measurement of Cystatin C, Beta-Trace Protein and Beta2-Microglobulin levels will be included. DISCUSSION: This study will provide useful information to prevent CKD-related disability by collecting real-life data over 1-year period. The combined approach of CGA and the investigation of innovative existing biomarkers will make it possible to develop new recommendations and guidelines for a patient-centered approach. It is believed that such a study may lead to an improvement of knowledge on CKD in elderly patients and may also have implications in daily clinical practice and in decision-making process.

Modeling psychological function in patients with schizophrenia with the PANSS: an international multi-center study.

BACKGROUND: The aim of the current study was to explore the changing interrelationships among clinical variables through the stages of schizophrenia in order to assemble a comprehensive and meaningful disease model. METHODS: Twenty-nine centers from 25 countries participated and included 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Multiple linear regression analysis and visual inspection of plots were performed. RESULTS: The results suggest that with progression stages, there are changing correlations among Positive and Negative Syndrome Scale factors at each stage and each factor correlates with all the others in that particular stage, in which this factor is dominant. This internal structure further supports the validity of an already proposed four stages model, with positive symptoms dominating the first stage, excitement/hostility the second, depression the third, and neurocognitive decline the last stage. CONCLUSIONS: The current study investigated the mental organization and functioning in patients with schizophrenia in relation to different stages of illness progression. It revealed two distinct "cores" of schizophrenia, the "Positive" and the "Negative," while neurocognitive decline escalates during the later stages. Future research should focus on the therapeutic implications of such a model. Stopping the progress of the illness could demand to stop the succession of stages. This could be achieved not only by both halting the triggering effect of positive and negative symptoms, but also by stopping the sensitization effect on the neural pathways responsible for the development of hostility, excitement, anxiety, and depression as well as the deleterious effect on neural networks responsible for neurocognition.

Relationship between aberrant salience and positive emotion misrecognition in acute relapse of schizophrenia.

INTRODUCTION: Aberrant salience is the incorrect assignment of salience or significance to innocuous stimuli, and been hypothesized to be a central mechanism in the development of psychosis. In addition to aberrant salience, social-cognitive models of psychosis suggest that the way people process information about the self is important in all stages of psychosis. The aim of the present study is to explore the relationship between aberrant salience and emotion processing in schizophrenia patients with psychotic relapse. METHODS: A sample of 42 patients with relapse was recruited. Aberrant salience was measured with the Aberrant Salience Inventory (ASI). Assessment of social cognition was carried out using the Facial Emotion Identification Test (FEIT). Partial correlations were controlled for possible confounding variables. RESULTS: The ASI factors "increase in meaning" and "heightened cognition" positively correlated with impaired recognition of positive emotions, and ASI total score inversely correlated to time to response to task. Most of incorrect answers corresponded to misclassification of positive emotions. CONCLUSION: Our findings show that there is evidence for a relationship between aberrant salience and emotion processing during a psychotic episode; we propose that aberrant salience and alterations in emotion processing trigger the loss of modulating feedback from the external world to produce a self-referential mental state.

The Complex Relationship Among Formal Thought Disorders, Neurocognition, and Functioning in Nonacutely Ill Schizophrenia Patients.

The aims of the present study were to 1) evaluate clinical differences between patients suffering from schizophrenia (SZ) with mild versus moderate/severe formal thought disorder (FTD); 2) explore relationships between dimensions of FTD, neuropsychological domains, and global functioning; and 3) compare clinical dimensions of FTD in early and late SZ. One hundred thirty-six individuals with schizophrenia were recruited and evaluated during a nonacute phase of illness. FTD was assessed with the Thought, Language, and Communication Scale. Partial correlations, t-tests, and stepwise regression were undertaken to address the study aims. Patients with moderate/severe FTD performed worse than those with mild FTD for processing speed, reasoning and problem solving, and social cognition, and demonstrated poorer global functioning. Early SZ did not differ from late SZ in terms of negative FTD and difficulty in abstract thinking (DAT). Negative FTD was correlated with reasoning and problem solving; DAT was correlated with social cognition. All clinical dimensions of FTD, regardless of neurocognitive impairment, accounted for a significant amount of variance in global functioning. FTD predicted global functioning, regardless of neurocognitive factors. Due to their stability in different phases of the course of the disease and their strong relationship with other core variables, Neg-FTD and DAT should be investigated as an intermediate phenotype of the illness.

Staging of Schizophrenia With the Use of PANSS: An International Multi-Center Study.

INTRODUCTION: A specific clinically relevant staging model for schizophrenia has not yet been developed. The aim of the current study was to evaluate the factor structure of the PANSS and develop such a staging method. METHODS: Twenty-nine centers from 25 countries contributed 2358 patients aged 37.21 ± 11.87 years with schizophrenia. Analysis of covariance, Exploratory Factor Analysis, Discriminant Function Analysis, and inspection of resultant plots were performed. RESULTS: Exploratory Factor Analysis returned 5 factors explaining 59% of the variance (positive, negative, excitement/hostility, depression/anxiety, and neurocognition). The staging model included 4 main stages with substages that were predominantly characterized by a single domain of symptoms (stage 1: positive; stages 2a and 2b: excitement/hostility; stage 3a and 3b: depression/anxiety; stage 4a and 4b: neurocognition). There were no differences between sexes. The Discriminant Function Analysis developed an algorithm that correctly classified >85% of patients. DISCUSSION: This study elaborates a 5-factor solution and a clinical staging method for patients with schizophrenia. It is the largest study to address these issues among patients who are more likely to remain affiliated with mental health services for prolonged periods of time.

The clinical correlates of suicidal ideation in Parkinson's disease.

INTRODUCTION: Suicidal ideation is increased in Parkinson's disease (PD) patients. The possible relationship between parkinsonian motor and non-motor symptoms and suicidal ideation in PD is unknown. The aim of the study was to evaluate suicidal ideation in patients with PD in a controlled study specifically designed to identify the clinical correlates of PD suicidal ideation. METHODS: We consecutively enrolled 100 patients with PD, 76 patients with psoriasis and 80 healthy subjects. Motor symptoms and complications were evaluated by using the International Parkinson and Movement Disorder Society-Unified Parkinson's Disease Rating Scale. Non-motor symptoms were evaluated by means of the Non-Motor Symptoms assessment scale for PD. All patients also underwent a psychiatric evaluation that included the administration of the Columbia-Suicide Severity Rating Scale. RESULTS: Suicidal ideation was present in 31% of PD patients, 16% of patients with psoriasis and 2% of healthy controls. PD patients showing suicidal ideation have more frequent motor complications, more severe non-motor symptoms and a higher perceived disability than patients without suicidal ideation. Suicidal ideation correlated with the presence of motor complications as well as with non-motor symptom severity, perceived disability severity and the presence of psychiatric disorders. CONCLUSIONS: Our findings showed that suicidal ideation is increased in PD patients compared with healthy controls and patients with psoriasis and that several clinical PD features, including motor complications and non-motor symptoms, are associated with suicidal ideation in PD. The results suggest a multi-factorial origin of PD suicidal ideation.

Lifestyle Interventions and Prevention of Suicide.

Over the past years, there has been a growing interest in the association between lifestyle psychosocial interventions, severe mental illness, and suicide risk. Patients with severe mental disorders have higher mortality rates, poor health states, and higher suicide risk compared to the general population. Lifestyle behaviors are amenable to change through the adoption of specific psychosocial interventions, and several approaches have been promoted. The current article provides a comprehensive review of the literature on lifestyle interventions, mental health, and suicide risk in the general population and in patients with psychiatric disorders. For this purpose, we investigated lifestyle behaviors and lifestyle interventions in three different age groups: adolescents, young adults, and the elderly. Several lifestyle behaviors including cigarette smoking, alcohol use, and sedentary lifestyle are associated with suicide risk in all age groups. In adolescents, growing attention has emerged on the association between suicide risk and internet addiction, cyberbullying and scholastic and family difficulties. In adults, psychiatric symptoms, substance and alcohol abuse, weight, and occupational difficulties seems to have a significant role in suicide risk. Finally, in the elderly, the presence of an organic disease and poor social support are associated with an increased risk of suicide attempt. Several factors may explain the association between lifestyle behaviors and suicide. First, many studies have reported that some lifestyle behaviors and its consequences (sedentary lifestyle, cigarette smoking underweight, obesity) are associated with cardiometabolic risk factors and with poor mental health. Second, several lifestyle behaviors may encourage social isolation, limiting the development of social networks, and remove individuals from social interactions; increasing their risk of mental health problems and suicide.

Suicidal ideation, perceived disability, hopelessness and affective temperaments in patients affected by Parkinson's disease.

BACKGROUND: Previous studies investigating the risk of suicide in patients with Parkinson's disease (PD) have reported conflicting results. This study evaluated suicide risk in PD and investigated the relationship between suicide risk and perceived disability, hopelessness and affective temperaments in PD. METHODS: One-hundred and twenty PD patients were consecutively enrolled. The diagnosis of PD was based on clinical criteria. All patients underwent a psychiatric evaluation that included the administration of the Columbia-Suicide Severity Rating Scale, the Italian Perceived Disability Scale, the Beck Hopelessness Inventory and the TEMPS-A questionnaire. The results were compared with those of a control group of 91 patients affected by another chronic disease, ie, open angle glaucoma. RESULTS: Parkinson's disease patients had higher suicidal ideation, higher perceived disability and lower hyperthymia than the control group. In PD, higher perceived disability was associated with higher current and lifetime suicidal ideation, lower hyperthymia, older age and higher scores on negative temperaments. Suicidal ideation, negative temperaments and hopelessness were risk factors for perceived disability, while hyperthymia was a protective factor for perceived disability. DISCUSSION: Patients with PD have an increased risk of suicidal ideation. Increased suicidal ideation in PD is associated with the increased perceived disability. A psychiatric assessment that includes the investigation of suicide risk and perceived disability is recommended in patients with PD.

Long-Acting Injectable Second-Generation Antipsychotics Improve Negative Symptoms and Suicidal Ideation in Recent Diagnosed Schizophrenia Patients: A 1-Year Follow-up Pilot Study.

Long-acting injectable second-generation antipsychotics (LAI-SGA) are typically used to maintain treatment adherence in patients with chronic schizophrenia. Recent research suggests that they may also provide an effective treatment strategy for patients with early-phase disease. The aim of this study is to evaluate clinical and psychosocial outcomes among recent and long-term diagnosed schizophrenia outpatients treated with LAI-SGA during a follow-up period of 12 months. Stable schizophrenia patients receiving LAI-SGA with 5 or less years of illness duration (n = 10) were compared to those with more than 5 years of illness duration (n = 15). Clinical data was assessed through the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF), the Columbia Suicide Severity Rating Scale (C-SSRS), the Recovery Style Questionnaire (RSQ), and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) Managing Emotion branch. Recently diagnosed patients showed greater improvement versus patients diagnosed for more than 5 years in adjusted mean GAF score, in PANSS factor score for negative and depressive symptoms, and in severity and intensity of suicidal ideation. Our preliminary findings support the hypothesis that LAI-SGA may influence the course of the illness if administered at the early phase of the illness. However, replicate studies are needed, possibly with larger samples.

Suicide Prevention in Schizophrenia: Do Long-Acting Injectable Antipsychotics (LAIs) have a Role?

Suicide risk is a major cause of death among patients with schizophrenia. Death by suicide has been reported in approximately 5% of schizophrenia patients although this figure appears to be an underestimate of the problem. A number of risk factors are routinely reported as associated with suicide risk among these patients, some of which are modifiable by targeted therapeutic strategies. Clozapine is the only compound that gathered evidence as an effective treatment for reducing suicide risk in schizophrenia. Long-Acting Injectable Antipsychotics (LAIs) have a range of advantages in terms of efficacy, safety and tolerability in the treatment of schizophrenia, and one area of interest is whether LAI-treatment may decrease suicidality by indirectly acting on a range of risk factors for suicide specific to schizophrenia patients. This background encouraged the present review of research pertaining to LAIs in relation to modifiable risk factors for suicide in schizophrenia. We viewed our task as gathering, speculating and critically appraising the available research relevant to the topic, with the aim of formulating a hypothesis to be tested with further research.

Anomalous self-experiences and their relationship with symptoms, neuro-cognition, and functioning in at-risk adolescents and young adults.

Empirical and theoretical studies support the notion that anomalous self-experience (ASE) may constitute a phenotypic aspect of vulnerability to schizophrenia, but there are no studies examining the relationship of ASE with other clinical risk factors in a sample of ultra-high risk (UHR) subjects. The aim of the present study was to explore the relationship between ASE, prodromal symptoms, neurocognition, and global functioning in a sample of 45 UHR adolescents and young adults (age range 15-25years) at first contact with Public Mental Health Services. Prodromal symptoms and global functioning were assessed through the SIPS interview. ASE was evaluated through the Examination of Anomalous Self-Experience (EASE); for neurocognition, we utilized a battery of tests examining seven cognitive domains as recommended by the Measurement And Treatment Research to Improve Cognition in Schizophrenia. In the UHR group, higher levels in two domains of the EASE (stream of consciousness and self-awareness) were found in comparison with help-seeking subjects. Correlational analysis corrected for possible confounding variables showed a strong association (p>0.001) between higher EASE scores and global functioning. A principal factor analysis with Varimax rotation yielded a two-factor solution, jointly accounting for 70.58% of the total variance in the UHR sample. The first factor was comprised of SOPS domains, while the second was comprised of EASE-total, EASE-10, and GAF variables. Our findings provide support for the notion that disorders of self-experience are present early in schizophrenia and are related to global functioning. As such, they may constitute a potential marker of risk supplementing the UHR approach.

White matter microstructure in ultra-high risk and first episode schizophrenia: A prospective study.

There is increasing evidence of white matter (WM) pathology in schizophrenia, but its role at the very early stage of the disorder remains unclear. In an exploration of WM microstructure in ultra-high risk (UHR) subjects and first episode schizophrenia (FES), 34 FES, 27 UHR and 26 healthy control (HC) subjects underwent a magnetic resonance imaging (MRI) tract based spatial statistics (TBSS) investigation. Whole brain fractional anisotropy (FA), mean diffusivity (MD), radial (RD) and axial diffusivity (AD) values were extracted. UHR subjects who later developed psychosis showed lower FA compared with HC in the corpus callosum (CC), the left superior and inferior longitudinal fasciculus, the left inferior fronto-occipital fasciculs (IFO), and the forceps; RD was significantly higher in the CC, the forceps, the anterior thalamic radiation bilaterally, and the cingulum bundle. FES, compared to HC, showed a significant FA reduction of the CC, the superior and inferior longitudinal fasciculi bilaterally, the IFO bilaterally, the corona radiate bilaterally, and the forceps; while RD was found to be significantly increased in the left superior longitudinal fasciculus. UHR who later developed psychosis had WM abnormalities affecting brain pathways that are crucial for intra- and inter-hemispheric connections.

Xanthurenic Acid Activates mGlu2/3 Metabotropic Glutamate Receptors and is a Potential Trait Marker for Schizophrenia.

The kynurenine pathway of tryptophan metabolism has been implicated in the pathophysiology of psychiatric disorders, including schizophrenia. We report here that the kynurenine metabolite, xanturenic acid (XA), interacts with, and activates mGlu2 and mGlu3 metabotropic glutamate receptors in heterologous expression systems. However, the molecular nature of this interaction is unknown, and our data cannot exclude that XA acts primarily on other targets, such as the vesicular glutamate transporter, in the CNS. Systemic administration of XA in mice produced antipsychotic-like effects in the MK-801-induced model of hyperactivity. This effect required the presence of mGlu2 receptors and was abrogated by the preferential mGlu2/3 receptor antagonist, LY341495. Because the mGlu2 receptor is a potential drug target in the treatment of schizophrenia, we decided to measure serum levels of XA and other kynurenine metabolites in patients affected by schizophrenia. Serum XA levels were largely reduced in a large cohort of patients affected by schizophrenia, and, in patients with first-episode schizophrenia, levels remained low after 12 months of antipsychotic medication. As opposed to other kynurenine metabolites, XA levels were also significantly reduced in first-degree relatives of patients affected by schizophrenia. We suggest that lowered serum XA levels might represent a novel trait marker for schizophrenia.

Impairment of left ventricular function early in treatment with clozapine: a preliminary study.

This preliminary prospective study evaluated cardiac status in 15 treatment-resistant schizophrenia patients (aged 18-55 years) without evidence of cardiovascular disease. Patients underwent clinical assessment, blood tests, ECG, and echocardiography before and during clozapine treatment for 4 weeks as doses increased from 25 to 100 mg/day. Serum concentrations of high-sensitivity C-reactive protein, troponin-I, brain natriuretic peptide, and clozapine+norclozapine were assayed at week 3; ECG and echocardiography were repeated at week 4. At moderate serum drug concentrations (124 ng/ml), the heart rate increased by 10% and high-sensitivity C-reactive protein levels were slightly elevated, but troponin-I and brain natriuretic peptide levels were not elevated. Echocardiographic indices indicated declining left ventricular (LV) diastolic and systolic function in 60-80% of participants, with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index by 16-24% in 60-80% of participants and a decrease in the E/A ratio by 29% in 73% of participants - all uncorrelated with drug concentrations. Early treatment with moderate doses of clozapine was associated with subclinical but substantial decreases in LV functioning in surprisingly high proportions of participants. Studies with more participants, higher drug doses, and long-term follow-up are needed to confirm and determine the course of the observed abnormalities and to evaluate their relationship with rare clinical cardiotoxicity associated with clozapine.