Severe mental illness: cardiovascular risk assessment and management.

Patients with severe mental illness (SMI) including schizophrenia and bipolar disorder die on average 15-20 years earlier than the general population often due to sudden death that, in most cases, is caused by cardiovascular disease. This state-of-the-art review aims to address the complex association between SMI and cardiovascular risk, explore disparities in cardiovascular care pathways, describe how to adequately predict cardiovascular outcomes, and propose targeted interventions to improve cardiovascular health in patients with SMI. These patients have an adverse cardiovascular risk factor profile due to an interplay between biological factors such as chronic inflammation, patient factors such as excessive smoking, and healthcare system factors such as stigma and discrimination. Several disparities in cardiovascular care pathways have been demonstrated in patients with SMI, resulting in a 47% lower likelihood of undergoing invasive coronary procedures and substantially lower rates of prescribed standard secondary prevention medications compared with the general population. Although early cardiovascular risk prediction is important, conventional risk prediction models do not accurately predict long-term cardiovascular outcomes as cardiovascular disease and mortality are only partly driven by traditional risk factors in this patient group. As such, SMI-specific risk prediction models and clinical tools such as the electrocardiogram and echocardiogram are necessary when assessing and managing cardiovascular risk associated with SMI. In conclusion, there is a necessity for differentiated cardiovascular care in patients with SMI. By addressing factors involved in the excess cardiovascular risk, reconsidering risk stratification approaches, and implementing multidisciplinary care models, clinicians can take steps towards improving cardiovascular health and long-term outcomes in patients with SMI.

Peripheral artery disease in patients with schizophrenia as compared to controls.

BACKGROUND: Patients with schizophrenia have an increased prevalence of risk factors for peripheral artery disease (PAD) and is expected to have an increased prevalence of PAD. PAD can be detected utilizing toe-brachial index (TBI) which screens for vascular pathology proximal to the toes. METHODS: Using a cross-sectional design, we defined the subpopulations: (1) Patients diagnosed with schizophrenia less than 2 years before inclusion (SCZ < 2), (2) Psychiatric healthy controls matched to subpopulation 1 on sex, age, and smoking status, and (3) Patients diagnosed with schizophrenia 10 or more years before inclusion (SCZ ≥ 10). TBI was calculated by dividing toe pressures by systolic brachial blood pressure, and PAD was defined by TBI < 0.70. Logistic regression analysis with PAD as outcome and sex, age, smoking status, BMI, skin temperature, diagnosis of schizophrenia, and comorbidities as explanatory variables was conducted. RESULTS: PAD was present in 26.2% of patients diagnosed with SCZ < 2 (17 of 65) and in 18.5% of psychiatric healthy controls (12 of 65) with no statistically significant difference in prevalence rates (p = 0.29). PAD was present in 22.0% of patients diagnosed with SCZ ≥ 10 (31 of 141). In logistic regression, patients diagnosed with SCZ < 2 had an increased odds of PAD with psychiatric healthy controls as reference (Odds ratio = 2.80, 95% confidence interval 1.09-7.23, p = 0.03). The analysis was adjusted for age, sex, smoking status, BMI and comorbidities such as hypertension, diabetes and heart disease. CONCLUSIONS: This study did not find statistically significant increased prevalence rates of PAD in patients with schizophrenia even though patients with SCZ were compared to psychiatric healthy controls using TBI. Utilizing logistic regression PAD was associated with schizophrenia diagnosis within the last 2 years, age and skin temperature. As PAD is initially asymptomatic, screening could be relevant in patients with schizophrenia if other risk factors are prevalent. Further large-scale multicenter studies are warranted to investigate schizophrenia as a potential risk factor for PAD. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02885792.

Cardiovascular autonomic reflex tests using a handheld device in the diagnosis of cardiovascular autonomic neuropathy in patients with schizophrenia.

Study objective: This study investigated whether schizophrenia and the duration of schizophrenia were associated with cardiovascular autonomic neuropathy (CAN) by using heart rate variability (HRV) as a marker. Design: Cross-sectional study. Setting: The examinations were conducted at the Centre for Psychosis Research and at the Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark. Participants: 240 patients with first-episode and chronic schizophrenia and 180 controls. Interventions: CAN was assessed by the cardiovascular reflex tests (CARTs): HR, RS ratio, E:I ratio, and VM using a handheld device. Main outcome measures: One abnormal CART was interpreted as borderline CAN and ≥2 abnormal CARTs established definitive CAN. Borderline CAN and definitive CAN together was categorized as overall CAN. Analyses were adjusted for age, sex, smoking, overweight, and hypercholesterolemia. Results: A total of 240 patients with schizophrenia (median age 42.5 [28.8, 52.3], 42.9 % women) and 180 controls (median age 45.8 [24.0, 60.1], 47.8 % women) were included, with 50.8 % of patients with schizophrenia having overall CAN compared to 27.2 % among controls. Dividing patients into patients with first-episode and chronic schizophrenia, 32.9 % vs 10 % (p < 0.001) and 59.1 % vs 41 % (p < 0.001) had overall CAN compared with controls, respectively. Schizophrenia was significantly associated with overall CAN (OR, 2.80; 95%CI, 1.75-4.50), with an OR of 2.31 (95%CI, 1.14-4.68) for first-episode schizophrenia and an OR of 2.97 (95%CI, 1.81-4.87) for chronic schizophrenia. Conclusion: It was demonstrated that a diagnosis of schizophrenia was associated with CAN. Patients with chronic schizophrenia had a significantly higher prevalence of CAN compared to patients with first-episode schizophrenia, suggesting an association between the duration of schizophrenia and CAN.

Mental health among patients with non-Hodgkin lymphoma: A Danish nationwide study of psychotropic drug use in 8750 patients and 43 750 matched comparators.

Psychological distress following cancer diagnosis may lead to mental health complications including depression and anxiety. Non-Hodgkin lymphomas (NHLs) include indolent and aggressive subtypes for which treatment and prognosis differ widely. Incident use of psychotropic drugs (PDs-antidepressants, antipsychotics, and anxiolytics) and its correlation to lymphoma types can give insights into the psychological distress these patients endure. In this prospective matched cohort study, we used nationwide population-based registries to investigate the cumulative risk of PD use in NHL patients compared to a sex- and age-matched cohort from the Danish background population. In addition, contact patterns to psychiatric departments and incident intentional self-harm or completed suicide were explored. In total, 8750 NHL patients and 43 750 matched comparators were included (median age 68; male:female ratio 1.6). Median follow-up was 7.1 years. Two-year cumulative risk of PD use was higher in NHL patients (16.4%) as compared to the matched comparators (5.1%, p < .01); patients with aggressive NHL subtypes had the highest incidence. Prescription rates were higher in the first years after diagnosis but approached the rate of the matched population 5 years into survivorship in aggressive NHLs, whereas patients with indolent subtypes continued to be at higher risk. NHL patients had a slightly higher two-year risk of suicide/intentional self-harm (0.3%) as compared to the matched comparators (0.2%, p = .01). These results demonstrate that mental health complications among NHL patients are frequent. Routine assessment for symptoms of depression and anxiety should be consider as part of standard follow-up of NHL patients.

Psychotropic Drug Use in Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS): A Danish Nationwide Matched Cohort Study of 2404 AML and 1307 MDS Patients.

INTRODUCTION: The diagnosis of a life-threatening disease can lead to depression and anxiety resulting in pharmacological treatment. However, use of psychotropic drugs (antidepressants, anxiolytics, and antipsychotics) in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) is undetermined. METHODS: Prescription of psychotropic drugs in Danish AML and MDS patients was compared to a cohort matched on age, sex, and country of origin from the Danish background population using national population-based registries. RESULTS: In total, 2404 AML patients (median age 69 years) and 1307 MDS patients (median age 75 years) were included and each matched to five comparators from the background population. Two-year cumulative incidences showed that AML (20.6%) and MDS (21.2%) patients had a high risk of redemption of a psychotropic drug prescription compared to the background population (7.0% and 7.9%). High age, low educational level, and Charlson Comorbidity Index score ≥1 was associated with a higher risk in AML and MDS patients. Furthermore, non-curative treatment intent and performance status in AML patients, and high risk MDS were associated with elevated risk of psychotropic drug prescription. CONCLUSION: In conclusion, diagnoses of AML and MDS were associated with a higher rate of psychotropic drugs prescription compared to the background population.

Hepatic steatosis in patients with schizophrenia: a clinical cross-sectional study.

OBJECTIVE: With hepatic steatosis (HS) being an established risk factor for CVD in the general population, it may also be a predictor of CVD in patients with schizophrenia. The aim of the present study was to investigate if time since schizophrenia diagnosis, body mass index (BMI), sex, metabolic syndrome, alcohol use, smoking, alanine transaminase (ALT), and body fat percentage (as measured by bioelectrical impedance) were associated with HS, determined by computed tomography (CT), in a population of patients diagnosed with schizophrenia. METHODS: Moderate to severe HS (40 CT Hounsfield units as threshold) was determined utilizing non-contrast enhanced CT. The association between the explanatory variables and outcome of HS was assessed using multivariable logistic regression. RESULTS: In the present study, 145 patients diagnosed with schizophrenia (mean age 42.2 years (SD ± 13.8)) were included, with 88 (60.7%) being male. On average, patients had been diagnosed for 14.8 (SD ± 10.7) years. A total of 31 (21.4%) patients had HS as determined by CT. The presence of HS was associated with ALT (OR 1.06, 95% CI (1.02-1.10) per 1 U/L increase), and the presence of metabolic syndrome (OR 62.89, 95% CI (2.03-1949.55)). The presence of HS was not associated with BMI, body fat percentage or time since diagnosis in the multivariable analysis. CONCLUSION: Higher ALT and the presence of metabolic syndrome were associated with HS in patients with schizophrenia utilizing multivariable analysis. The findings suggest that risk factors for HS are similar in both the general population and in patients with schizophrenia.

Coronary artery calcium in patients with schizophrenia.

BACKGROUND: Coronary heart disease (CHD) is a major cause of increased mortality rates in patients with schizophrenia. Moreover, coronary artery calcium (CAC) score is associated with CHD. We hypothesized that patients with schizophrenia have more CAC than the general population and aimed to investigate the CAC score in patients with schizophrenia compared to norms based on the general population. Additionally, this study investigated if age, sex, diabetes, dyslipidemia and smoking were associated with the CAC score. METHODS: In a cross-sectional study, 163 patients with schizophrenia underwent cardiac computed tomography, and the CAC score was measured and compared to norms by classifying the CAC scores in relation to the age- and gender matched norm 50th, 75th and 90th percentiles. Logistic and linear regression were carried out to investigate explanatory variables for the presence and extent of CAC, respectively. RESULTS: A total of 127 (77.9%) patients had a CAC score below or equal to the matched 50th, 20 (12.3%) above the 75th and nine (5.5%) above the 90th percentile. Male sex (P < 0.05), age (P < 0.001) and smoking (P < 0.05) were associated with the presence of CAC while age (P < 0.001) and diabetes (P < 0.01) were associated with the extent of CAC. CONCLUSIONS: The amount of CAC in patients with schizophrenia follows norm percentiles, and variables associated with the CAC score are similar in patients with schizophrenia and the general population. These findings indicate that the CAC score may not be sufficient to detect the risk of CHD in patients with schizophrenia. Future studies should explore other measures of subclinical CHD, including measures of peripheral atherosclerosis or cardiac autonomic neuropathy to improve early detection and intervention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02885792 , September 1, 2016.

Risk of hospitalization and hip fracture associated with psychotropic polypharmacy in patients with dementia: A nationwide register-based study.

OBJECTIVE: To investigate the association of benzodiazepines and antidepressants on the risk of hospitalization and hip fracture in patients with dementia initiating antipsychotic drug treatment. METHODS: A register-based retrospective cohort study using data on all incident dementia cases (≥65 years) initiating antipsychotic treatment as monotherapy or in combination with benzodiazepines and/or antidepressants in Denmark from 2000 to 2015. The outcomes of interest were all-cause hospitalization and hip fracture. Cox proportional hazards models with adjustment for multiple variables were used to investigate risk of hospitalization and hip fracture within 180 days. RESULTS: The risk of all-cause hospitalization during 180-days follow-up was significantly increased by 55% (adjusted HR: 1.55, 95% CI: 1.29-1.86, p < 0.0001), when antipsychotic use was combined with benzodiazepines, when compared to antipsychotic monotherapy. The association between the combination of antipsychotics and benzodiazepines with the risk of hip fracture did not reach statistical significance (adjusted HR: 1.50, 95% CI: 0.99-2.26, p = 0.0534). CONCLUSIONS: The observed increased risk of all-cause hospitalization and hip fracture may indicate increased drug-related adverse events. Thus, careful and regular monitoring is needed to assess response to treatment and decrease the risk of adverse events, when antipsychotics are combined with BZDs, albeit confounding cannot be fully excluded within the current design.

Cardiovascular disease in patients with severe mental illness.

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.

Transcranial pulsed electromagnetic fields for treatment-resistant depression: A multicenter 8-week single-arm cohort study.

BACKGROUND: The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression. METHODS: A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group. RESULTS: In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D17) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D6), respectively, 51 and 16% obtained remission, defined as HAM-D6 ≤ 4. CONCLUSIONS: The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.

Why are somatic diseases in bipolar disorder insufficiently treated?

BACKGROUND: Somatic diseases, including cardiovascular, respiratory, and cancer diseases, are the main contributors to a shortened life expectancy of 10-20 years in patients with bipolar disorder as compared to the general population. In the general population an increase in survival has been observed over the last decades, primarily due to the advances in primary prophylaxis, medical treatment and progress in early detection and monitoring of somatic diseases. In this narrative review, we discuss the existing literature on treatment and outcomes of cardiovascular, respiratory, and cancer diseases in patients with bipolar disorder, and put this in the context of findings in studies on patients diagnosed with other severe mental disorders. MAIN BODY: The existing literature suggests that patients with bipolar disorder receive fewer or delayed medical interventions, when admitted with severe somatic diseases, compared to those not diagnosed with bipolar disorder. Cardiovascular disease is the most investigated disease regarding outcomes in patients with severe mental illness, and novel findings indicate that the increased mortality following cardiac events in these patients can be reduced if they are intensively treated with secondary prophylactic cardiac intervention. Elderly patients diagnosed with mental disorders and cancer experience a delay in receiving specific cancer treatment. No studies have investigated treatment outcomes in patients with severe mental disease and respiratory diseases. CONCLUSION: It is surprising and of major concern that patients with bipolar disorder have not benefitted from the significant improvement that has taken place over time over time of somatic treatments in general, especially in countries with equal and free access to healthcare services. Therefore, no matter whether this situation is a result of a negative attitude from health care providers to patients with mental illness, the result of the patient's lack of awareness of their physical illness or the results of other factors, further attention including research on developing strategies for improving the management of somatic diseases in patients with bipolar disorder is needed.

The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study.

OBJECTIVE: To investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression. METHOD: A randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3 g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome. RESULTS: A total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p = 0.88). All findings regarding secondary outcomes were statistically or clinically insignificant. LIMITATIONS: The study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo. CONCLUSIONS: Based on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.

Neuroleptic malignant syndrome-an 11-year longitudinal case-control study.

OBJECTIVE: To describe patients with neuroleptic malignant syndrome (NMS), to establish occurrence of NMS, to investigate risk factors of NMS, and to investigate mortality associated with NMS. METHOD: We conducted a longitudinal register linkage case-control study of NMS. RESULT: In health care registers covering the period from 1996 to 2007, we identified, among 224 372 patients with organic, psychotic, affective, or neurotic diagnosis, 83 patients with NMS, equivalent to an occurrence of 0.04%. Treatment with second-generation antipsychotics (SGAs) in the 3 months preceding admission increased the NMS risk (OR 4.66; 95% CI 1.96 to 11.10) and also first-generation antipsychotics (FGAs) of high potency (OR 23.41; 95% CI 5.29 to 103.61) and mid potency (OR 4.81; 95% CI 1.96 to 11.79), and depot antipsychotics (OR 4.53; 95% CI 1.60 to 12.80). Benzodiazepines (BDZs) also increased the risk of NMS (OR 3.43; 95% CI 1.68 to 12.80). NMS was associated with an increased mortality (HR 1.88; 95% CI 1.19 to 2.98) in patients, compared with sex-, age-, and diagnosis-matched control subjects, but no significant difference in mortality between patients and control subjects was observed after the initial 30 days (P = 0.27). CONCLUSIONS: The occurrence of NMS is low, and the prediction of NMS is difficult. Previous treatment with FGAs, SGAs, and BDZs was identified as a risk factor for developing NMS. NMS increased mortality within 30 days after NMS.

Characteristics and predictors of long-term institutionalization in patients with schizophrenia.

BACKGROUND: Patients with schizophrenia requiring long-term institutionalization represent those with the worst outcome, leading to personal costs for patients and relatives and constituting a large economical burden for society. AIM: To identify characteristics and predictors of outcome of institutionalized patients with schizophrenia. METHOD: One-year follow-up cohort study, utilizing the Danish national registers, of all institutionalized and non-institutionalized patients with schizophrenia in Denmark with an ICD-10 lifetime diagnosis of schizophrenia (F20.0-F20.9) since 1969 and alive at the index date of January 1st 2006 (total number 22,395). RESULTS: Compared with non-institutionalized patients, institutionalized patients (n=2188; 9.8%) had earlier onset of schizophrenia and lower scholastic achievements, were more often diagnosed with a hebephrenic subtype (odds ratio (OR), 2.34; 95% confidence interval (CI), 1.95-2.80; p<0.001), received higher dosages of antipsychotics, more antipsychotic polypharmacy and more concomitant medications, and had more substance misuse and early retirement pension. In a logistic regression model adjusted for sex and age, institutionalized patients with schizophrenia had an increased risk of type II diabetes (AOR, 1.22; CI, 1.01-1.42; p<0.001), but the mean age of onset of type II diabetes did not differ. The mean patient age was higher in the institutionalized group (62.7 vs. 58.7 years; p=0.027), which was mainly driven by absence of death from suicide in the institutionalized group. Multivariate predictors of institutionalization included hebephrenic subtype, a diagnosis of epilepsy, early retirement pension, male sex, a greater proportion of prior hospitalization, and substance misuse. CONCLUSIONS: Institutionalized patients with schizophrenia had a more complex and worse outcome of the disorder, except for less suicide, illustrated by lower scholastic achievement, receiving higher dosages of antipsychotic medications, more concomitant medications and more prior bed-days.