Mounting evidence points towards a crucial role of the kynurenine pathway (KP) in the altered gut-brain axis (GBA) balance in severe mental illness (SMI, namely depression, bipolar disorder, and schizophrenia) and cardiometabolic comorbidities. Preliminary evidence shows that serotonergic psychedelics and their analogues may hold therapeutic potential in addressing the altered KP in the dysregulated GBA in SMI and comorbidities. In fact, aside from their effects on mood, psychedelics elicit therapeutic improvement in preclinical models of obesity, metabolic syndrome, and vascular inflammation, which are highly comorbid with SMI. Here, we review the literature on the therapeutic modulation of the KP in the dysregulated GBA in SMI and comorbidities, and the potential application of psychedelics to address the altered KP in the brain and systemic dysfunction underlying SMI and comorbidities. Psychedelics might therapeutically modulate the KP in the altered GBA in SMI and comorbidities either directly, via altering the metabolic pathway by influencing the rate-limiting enzymes of the KP and affecting the levels of available tryptophan, or indirectly, by affecting the gut microbiome, gut metabolome, metabolism, and the immune system. Despite promising preliminary evidence, the mechanisms and outcomes of the KP modulation with psychedelics in SMI and systemic comorbidities remain largely unknown and require further investigation. Several concerns are discussed surrounding the potential side effects of this approach in specific cohorts of individuals with SMI and systemic comorbidities.

The application of machine learning in health care often necessitates the use of hierarchical codes such as the International Classification of Diseases (ICD) and Anatomical Therapeutic Chemical (ATC) systems. These codes classify diseases and medications, respectively, thereby forming extensive data dimensions. Unsupervised feature selection tackles the "curse of dimensionality" and helps to improve the accuracy and performance of supervised learning models by reducing the number of irrelevant or redundant features and avoiding overfitting. Techniques for unsupervised feature selection, such as filter, wrapper, and embedded methods, are implemented to select the most important features with the most intrinsic information. However, they face challenges due to the sheer volume of ICD and ATC codes and the hierarchical structures of these systems.

The objective of this study was to compare several unsupervised feature selection methods for ICD and ATC code databases of patients with coronary artery disease in different aspects of performance and complexity and select the best set of features representing these patients.

We compared several unsupervised feature selection methods for 2 ICD and 1 ATC code databases of 51,506 patients with coronary artery disease in Alberta, Canada. Specifically, we used the Laplacian score, unsupervised feature selection for multicluster data, autoencoder-inspired unsupervised feature selection, principal feature analysis, and concrete autoencoders with and without ICD or ATC tree weight adjustment to select the 100 best features from over 9000 ICD and 2000 ATC codes. We assessed the selected features based on their ability to reconstruct the initial feature space and predict 90-day mortality following discharge. We also compared the complexity of the selected features by mean code level in the ICD or ATC tree and the interpretability of the features in the mortality prediction task using Shapley analysis.

In feature space reconstruction and mortality prediction, the concrete autoencoder-based methods outperformed other techniques. Particularly, a weight-adjusted concrete autoencoder variant demonstrated improved reconstruction accuracy and significant predictive performance enhancement, confirmed by DeLong and McNemar tests (P<.05). Concrete autoencoders preferred more general codes, and they consistently reconstructed all features accurately. Additionally, features selected by weight-adjusted concrete autoencoders yielded higher Shapley values in mortality prediction than most alternatives.

This study scrutinized 5 feature selection methods in ICD and ATC code data sets in an unsupervised context. Our findings underscore the superiority of the concrete autoencoder method in selecting salient features that represent the entire data set, offering a potential asset for subsequent machine learning research. We also present a novel weight adjustment approach for the concrete autoencoders specifically tailored for ICD and ATC code data sets to enhance the generalizability and interpretability of the selected features.

Background and Objectives: Schizophrenia, a debilitating mental illness, is often associated with significant physical health risks. Many second-generation antipsychotics increase the risk of metabolic syndrome and cardiovascular disease. Community pharmacists are highly accessible and could play a role in monitoring cardiometabolic adverse drug events in people with schizophrenia. However, it remains uncertain whether mental health professionals perceive this as valuable. This study aimed to explore the opinions of mental healthcare professionals regarding the role of community pharmacists in reducing the incidence of cardiometabolic adverse events in people with schizophrenia and their integration into a multidisciplinary mental health team. Materials and Methods: Qualitative semi-structured interviews were conducted with Australian psychiatrists, mental health nurses and mental health pharmacists. Transcription of the interviews underwent thematic analysis using an inductive approach. Results: Eleven mental healthcare professionals from metropolitan and regional areas across Australia were interviewed, leading to the identification of five overarching themes. These themes encompassed the following aspects: the benefits of community pharmacists' involvement in managing cardiometabolic adverse drug events in people with schizophrenia, improving communication pathways with community pharmacists, defining roles and responsibilities for monitoring cardiometabolic parameters and managing adverse cardiometabolic drug events, fostering collaboration between community pharmacists and mental health care professionals, and recognising the acceptance of community pharmacists' integration within a multidisciplinary team. Mental health professionals believed that community pharmacists could play a role in reducing the incidence of cardiometabolic adverse events in schizophrenia. However, they underscored the need for enhanced communication and collaboration pathways with other healthcare professionals, emphasised the importance of more comprehensive mental health first aid training, and identified potential barriers for community pharmacists such as remuneration, workload, and staff resources. Conclusions: Mental health professionals acknowledged the benefits of incorporating community pharmacists into multidisciplinary teams as a strategy to reduce the incidence of adverse events among individuals with schizophrenia. They recognise the competence of community pharmacists in monitoring cardiometabolic adverse events. However, these professionals have also highlighted specific perceived barriers to the complete integration of community pharmacists within these teams. Notably, there are concerns related to remuneration, staff resources, time constraints, acceptance by other healthcare professionals and patients, and the need for improved communication pathways. Addressing these barriers and providing targeted training could facilitate the valuable inclusion of community pharmacists in the comprehensive care of people with schizophrenia.

Psychiatric disorders are associated with cardiometabolic diseases, partly due to adverse drug effects with individual risk variabilities. Risperidone and sertraline are widely used for youths. Although they may be exposed to anthropometric changes, few data about this population exist. We evaluated the correlation between several blood parameters and body changes in a very small group of drug-naïve adolescents who had started risperidone or sertraline. We examined weight, waist circumference (WC), WC/height ratio and body mass index (BMI) at baseline (T0) and after at least three months of therapy (T1), and blood glucose and lipid profiles at T0. Here, we show significant increases in several anthropometric parameters in both groups, a negative correlation between HDL and ΔWC in the risperidone group and positive correlations between insulin and ΔBMI and between HOMA-IR and ΔBMI in the sertraline group. Despite the sample size, these results are important because it is difficult to study adolescents who are long-term-compliant with psychotropic drugs. This pilot study supports the importance of future large-scale investigations to understand the metabolic risk profiles of psychotropic drugs, their individual vulnerabilities and their underlying mechanisms. Simultaneous guideline-based psychiatric and metabolic interventions should be part of daily practice.

The aim of this study was to assess the risk of readmission in patients with severe mental disorders, compare it between patients using different types of antipsychotics and determine risk factors for psychiatric readmission.

Medical records of a non-concurrent cohort of 625 patients with severe mental disorders (such as psychoses and severe mood disorders) who were first discharged from January to December 2012 (entry into the cohort), with longitudinal follow-up until December 2017 constitute the sample. Descriptive statistical analysis of characteristics of study sample was performed. The risk factors for readmission were assessed using Cox regression.

Males represented 51.5% of the cohort, and 75.6% of the patients had no partner. Most patients (89.9%) lived with relatives, and 64.7% did not complete elementary school. Only 17.1% used more than one antipsychotic, 34.2% did not adhere to the treatment, and 13.9% discontinued the medication due to unavailability in public pharmacies. There was a need to change the antipsychotic due to the lack of therapeutic response (11.2% of the patients) and adverse reactions to the antipsychotic (5.3% of the patients). Cox regression showed that the risk of readmission was increased by 25.0% (RR, 1.25; 95% CI, 1.03-1.52) when used typical antipsychotics, compared to those who used atypical ones, and by 92.0% (RR, 1.92; 95% CI, 1.63-2.27) when patients did not adhere to maintenance treatment compared to those who adhered.

Use of atypical antipsychotics and adherence to treatment were associated with a lower risk of psychiatric readmissions.

clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused.

to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic.

a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia", "side effects", "agranulocytosis", "TRS", or "bipolar affective disorder (BAF)" for the last ten years.

clinical trials on adults with acute symptoms of schizophrenia or related disorders.

we selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection.

we considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) a CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with the proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Individuals diagnosed with schizophrenia or bipolar disorder have a life expectancy 15-20 years shorter than that in the general population. The rate of unnatural deaths, such as suicide and accidents, is high for these patients. Despite this increased proportion of unnatural deaths, physical conditions account for approximately 70% of deaths in patients with either schizophrenia or bipolar disorder, with cardiovascular disease contributing 17.4% and 22.0% to the reduction in overall life expectancy in men and women, respectively. Risk factors for cardiovascular disease, such as smoking, unhealthy diet and lack of exercise, are common in these patients, and lifestyle interventions have been shown to have small effects. Pharmacological interventions to reduce risk factors for cardiovascular disease have been proven to be effective. Treatment with antipsychotic drugs is associated with reduced mortality but also with an increased risk of weight gain, dyslipidaemia and diabetes mellitus. These patients have higher risks of both myocardial infarction and stroke but a lower risk of undergoing interventional procedures compared with the general population. Data indicate a negative attitude from clinicians working outside the mental health fields towards patients with severe mental illness. Education might be a possible method to decrease the negative attitudes towards these patients, thereby improving their rates of diagnosis and treatment.

Drug-induced QT prolongation is associated with higher cardiovascular mortality.

We conducted a protocol-based comprehensive review of antidepressant-induced QT prolongation in people with mental disorders.

Based on findings from 47 published randomized controlled trials (RCTs), 3 unpublished RCTs, 14 observational studies, 662 case reports of torsades de pointes, and 168 cases of QT prolongation, we conclude that all antidepressants should be used only with licensed doses, and that all patients receiving antidepressants require monitoring of QT prolongation and clinical symptoms of cardiac arrhythmias. Large observational studies suggest increased mortality associated with all antidepressants (RR = 1.62, 95% CI: 1.60-1.63, number of adults: 1,716,552), high doses of tricyclic antidepressants (OR = 2.11, 85% CI 1.10-4.22), selective serotonin reuptake inhibitors (OR = 2.78, 95% CI: 1.24-6.24), venlafaxine (OR = 3.73, 95% CI: 1.33-10.45, number of adults: 4,040), and nortriptyline (OR = 4.60, 95% CI: 1.20-18.40, number of adults: 5,298).

Evidence regarding the risk of QT prolongation in children is sparse.

This case report highlights the rare occurrence of postpartum psychosis in the setting of peripartum cardiomyopathy, which can have rare presentations like arrhythmias and pulmonary edema; and the challenges one should anticipate while managing these conditions together. Caution is advised whenever antipsychotic drugs are to be administered to a patient with a cardiac condition as these drugs potentially increase the risk of arrhythmias and sudden death.

A 35 year old grand multiparous woman who was 1 week into puerperium was admitted with severe difficulty in breathing at rest, chest congestion and pain. She also had easy fatigability, orthopnea, paroxysmal nocturnal dyspnea, edema, tachycardia, tachypnea, irregularly irregular heart rate with a pulse deficit, elevated jugular venous pressure, cardiomegaly, hepatomegaly and pulmonary crepitations. On the sixth day while improving on standard drugs for heart failure, she developed bizarre behavior and confusion. She also had auditory, visual and olfactory hallucinations; violence to the baby and the husband; and refusal to feed and take medication. There was no altered sensorium and the vital signs were normal. She was diagnosed with puerperal psychosis during the management of peripartum cardiomyopathy.

In the rare occurrence of puerperal psychosis in the course of management of peripartum cardiomyopathy one must be acutely aware of the risk of sudden cardiac death occasioned by use of antipsychotics, either directly or due to arrhythmias. Continuous electrocardiogram (ECG) monitoring or use of alternative management modalities is thus highly advised.

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.

Cardiac mortality among patients diagnosed with mental disorders is higher compared to the general population. Some authors suggest that cardiovascular risk is related to intrinsic factors specific to psychiatric disease. Nevertheless, the interpretation of these results is limited by the concomitant prescription of antipsychotics which have a cardiovascular effect. Studies evaluating the hemodynamic and electrocardiographic profile of drug naïve or drug-free patients suffering from mental disorders remain few.

The aims of this work were to study the electrocardiographic and hemodynamic profile of drug naïve or drug-free patients with mental disorders and to determine clinical and biological factors associated with any electrocardiographic abnormalities.

It was a descriptive and evaluative cross-sectional study. We enrolled drug naïve or drug-free patients for at least two months. All subjects were inpatients and had at admission clinical, biological and electrocardiographic evaluation.

Forty-four percent of the sample had asymptomatic electrocardiographic abnormalities. These subjects had lower serum thyroid hormone levels compared to healthy group (P=0.066). Hemodynamic profile showed that 12% of the population had orthostatic hypotension.

Electrocardiographic and hemodynamic abnormalities are common among drug-free or drug naïve patients diagnosed with psychotic disorders. The association of electrocardiographic abnormalities with low levels of thyroxin requires more investigation.

Psychiatric patients have a greater risk of premature mortality, predominantly due to cardiovascular diseases (CVDs). Convincing evidence shows that psychiatric conditions are characterized by an increased risk of metabolic syndrome (MetS), a clustering of cardiovascular risk factors including dyslipidemia, abdominal obesity, hypertension, and hyperglycemia. This increased risk is present for a range of psychiatric conditions, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, anxiety disorder, attention-deficit/hyperactivity disorder (ADHD), and posttraumatic stress disorder (PTSD). There is some evidence for a dose-response association with the severity and duration of symptoms and for a bidirectional longitudinal impact between psychiatric disorders and MetS. Associations generally seem stronger with abdominal obesity and dyslipidemia dysregulations than with hypertension. Contributing mechanisms are an unhealthy lifestyle and a poor adherence to medical regimen, which are prevalent among psychiatric patients. Specific psychotropic medications have also shown a profound impact in increasing MetS dysregulations. Finally, pleiotropy in genetic vulnerability and pathophysiological mechanisms, such as those leading to the increased central and peripheral activation of immunometabolic or endocrine systems, plays a role in both MetS and psychiatric disorder development. The excess risk of MetS and its unfavorable somatic health consequences justifies a high priority for future research, prevention, close monitoring, and treatment to reduce MetS in the vulnerable psychiatric patient.

Patients with schizophrenia have higher mortality and shortened life expectancy than the general population, and cardiovascular disease (CVD) accounts for up to 50% cases of early mortality in schizophrenia. We determined risk factors, particularly pathophysiological changes, for early circulatory mortality in schizophrenia. In this multi-institutional, nested, case-control study, we enrolled consecutive inpatients with schizophrenia admitted to three psychiatric hospitals in the northern Taiwan. Seventy-nine patients who died of CVD before 65 years of age were identified as cases through record linkage, and 158 controls were randomly selected in a 2:1 ratio through risk-set density sampling, after matching for age (±2 years), sex, and index admission (±3 years). Data were obtained through medical record reviews. At the time of death, the mean age of the patients was 47.5 years (standard deviation = 10.3). Conditional logistic regression revealed that the duration of antipsychotic treatment was significantly associated with a lower risk of early circulatory mortality, and leukocyte counts at index hospitalization were significantly associated with a higher risk. Systemic inflammation may be a risk factor for early circulatory mortality in schizophrenia, but antipsychotic treatment, in particular typical antipsychotic treatment, could be a protective factor.

Drug-induced QT prolongation is associated with higher risk of cardiac arrhythmias and cardiovascular mortality. We investigated the effects of atypical antipsychotic drugs on QT interval in children and adults with mental disorders.

We conducted random-effects direct frequentist meta-analyses of aggregate data from randomized controlled trials (RCT) and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to October 2017 identified studies that examined aripiprazole, quetiapine, risperidone, olanzapine, ziprasidone and brexpiprazole.

Low quality evidence suggests that aripiprazole (four meta-analyses and twelve RCTs), brexpiprazole (one systematic review and four RCTs) or olanzapine (five meta-analyses and twenty RCTs) do not increase QT interval. Low quality evidence suggests that ziprasidone (five meta-analyses and 11 RCTs) increases QT interval and the rates of QT prolongation while risperidone (four meta-analyses, 70 RCTs) and quetiapine (two meta-analyses and seven RCTs) are associated with QT prolongation and greater odds of torsades de pointes ventricular tachycardia especially in cases of drug overdose.

The main conclusion of our study is that in people with mental disorders and under treatment with atypical antipsychotic drugs, in order to avoid QT prolongation and reduce the risk of ventricular tachycardia clinicians may recommend aripiprazole, brexpiprazole or olanzapine in licensed doses. Long-term comparative safety needs to be established.

Several lines of evidence suggest that a functional variant of the brain-derived neurotrophic factor gene (BDNF Val66Met) correlates with a number of eating disorders. Studies have also shown that the BDNF Val66Met polymorphism was associated with weight gain in patients with schizophrenia on long-term antipsychotic treatment. This study aimed to determine whether there was a relationship between the BDNF Val66Met polymorphism and BMI values in patients with chronic schizophrenia. We compared 308 Han Chinese patients with schizophrenia on long-term antipsychotic medication with 304 healthy normal controls on BDNF polymorphism. Body weight and BMI were measured before breakfast on the day blood samples were taken. The symptomatology of schizophrenia was assessed using the Positive and Negative Syndrome Scale. The results showed that the BDNF Val66Met polymorphism was associated with the BMI value, with genotype having a strong effect on the mean BMI value in male but not in female patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment.

A search in the SciELO and PubMed databases showed few studies on human immunodeficiency virus (HIV) positive individuals in long-term care institutions (LTCIs), thus prompting the present study. The aim of this study was to ascertain whether there were any HIV-positive individuals in LTCIs for the elderly.

Cross-sectional study in which the Hospital Infection Control Committee (HICC) of a 405-bed LTCI was consulted.

The medical records of 405 individuals interned in the LTCI who had been tested for HIV infection were requested for analysis of the following variables: [1] age and gender; [2] length of stay at LTCI (months); [3] causes and diagnoses on admission to LTCI according to International Classification of Diseases, 10th edition; [4] date of HIV diagnosis; [5] seropositivity for syphilis and hepatitis B and C viruses; [6] medications used at last prescription in medical file; and [7] mean CD4 lymphocyte count based on: total lymphocyte count/6 and total lymphocyte count x 0.8 x 0.2 or 0.3.

Four men were HIV-positive, with mean age 71.2 ± 8.6 years, LTCI stay 74.2 ± 38.1 months and length of HIV diagnosis 24.5 ± 17 months (confirmed by HICC standard screening). Three had stroke sequelae; one, dementia syndrome; two, seropositivity for syphilis; two, hepatitis B and one, hepatitis C. The main drugs used were lamivudine, zidovudine, lopinavir, ritonavir, levothyroxine, omeprazole, ranitidine, lactulose and risperidone. The estimated CD4 count was 341 ± 237/mm3.

HIV-positive individuals are present in LTCIs, diagnosable through serological screening and treatable with antiretroviral drugs.

Excessive weight gain, glucose intolerance, and dyslipidemia are well-known physical side effects of the metabolic syndrome commonly associated with atypical antipsychotic (AAP) treatment. We review these side effects of AAPs and their monitoring and management strategies.

A literature search was conducted to identify articles published on the prevalence, monitoring, and management of cardiometabolic side effects of AAPs.

Comparative risk of AAPs on weight gain, hyperlipidemia, glucose intolerance, and QT interval corrected for heart rate prolongation varies across the AAPs currently available. Likewise, pharmacologic and nonpharmacologic options investigated for management of these side effects, and monitoring those at appropriate intervals, differ based on the clinical condition and risk factors identified.

Atypical antipsychotics in general have little difference among them in short-term efficacy; however, the prevalence of their physical side effects substantially distinguishes them. It is of importance that clinicians carefully select AAPs bearing in mind the presence of risk factors, initiating patients directly on AAPs with a low risk of cardiometabolic side effects, and monitoring and managing those side effects at appropriate intervals.

Ventricular repolarization is a complex electrical phenomenon which represents a crucial stage in electrical cardiac activity. It is expressed on the surface electrocardiogram by the interval between the start of the QRS complex and the end of the T wave or U wave (QT). Several physiological, pathological and iatrogenic factors can influence ventricular repolarization. It has been demonstrated that small perturbations in this process can be a potential trigger of malignant arrhythmias, therefore the analysis of ventricular repolarization represents an interesting tool to implement risk stratification of arrhythmic events in different clinical settings. The aim of this review is to critically revise the traditional methods of static analysis of ventricular repolarization as well as those for dynamic evaluation, their prognostic significance and the possible application in daily clinical practice.

People with schizophrenia have 2- to 5-fold higher risk of type 2 diabetes than the general population. The traditional risk factors for type 2 diabetes, especially obesity, poor diet, and sedentary lifestyle, are common in people with schizophrenia already early in the course of illness. People with schizophrenia also often have low socioeconomic status and income, which affects their possibilities to make healthy lifestyle choices. Antipsychotic medications increase the risk of type 2 diabetes both directly by affecting insulin sensitivity and indirectly by causing weight gain. Lifestyle modification interventions for prevention of diabetes should be an integral part of treatment of patients with schizophrenia. In the treatment of type 2 diabetes in patients with schizophrenia, communication and collaboration between medical care and psychiatric treatment providers are essential.

Ventricular repolarization is a complex electrical phenomenon which represents a crucial stage in electrical cardiac activity. It is expressed on the surface electrocardiogram by the interval between the start of the QRS complex and the end of the T wave or U wave (QT). Several physiological, pathological and iatrogenic factors can influence ventricular repolarization. It has been demonstrated that small perturbations in this process can be a potential trigger of malignant arrhythmias, therefore the analysis of ventricular repolarization represents an interesting tool to implement risk stratification of arrhythmic events in different clinical settings. The aim of this review is to critically revise the traditional methods of static analysis of ventricular repolarization as well as those for dynamic evaluation, their prognostic significance and the possible application in daily clinical practice.

Data from observational studies have raised concerns about the safety of treatment with antipsychotic agents (APs) in elderly patients with dementia, but this area has been insufficiently investigated. We performed a head-to-head comparison of the risk of major adverse cardiovascular events and noncardiovascular mortality associated with individual APs (ziprasidone, olanzapine, risperidone, quetiapine, levomepromazine, chlorprothixen, flupentixol, and haloperidol) in Danish treatment-naïve patients aged ≥70 years.

We followed all treatment-naïve Danish citizens aged ≥70 years that initiated treatment with APs for the first time between 1997 and 2011 (n=91 774, mean age 82±7 years, 35 474 [39%] were men). Incidence rate ratios associated with use of different APs were assessed by multivariable time-dependent Poisson regression models. For the first 30 days of treatment, compared with risperidone, incidence rate ratios of major adverse cardiovascular events were higher with use of levomepromazine (3.80, 95% CI 3.43 to 4.21) and haloperidol (1.85, 95% CI 1.67 to 2.05) and lower for treatment with flupentixol (0.54, 95% CI 0.45 to 0.66), ziprasidone (0.31, 95% CI 0.10 to 0.97), chlorprothixen (0.76, 95% CI 0.61 to 0.95), and quetiapine (0.68, 95% CI 0.58 to 0.80). Relationships were generally similar for long-term treatment. The majority of agents were associated with higher risks among patients with cardiovascular disease compared with patients without cardiovascular disease (P for interaction <0.0001). Similar results were observed for noncardiovascular mortality, although differences in associations between patients with and without cardiovascular disease were small.

Our study suggested some diversity in risks associated with individual APs but no systematic difference between first- and second-generation APs. Randomized placebo-controlled studies are warranted to confirm our findings and to identify the safest agents.