Lipid-modifying agents and risk of all-cause, natural and suicide mortality in schizophrenia: nationwide cohort study.

BACKGROUND: Individuals with schizophrenia face high mortality risks. The effects of lipid-modifying agents on this risk remain understudied. AIM: This study was conducted to investigate the effects of lipid-modifying agents on mortality risk in people with schizophrenia. METHOD: This nationwide cohort study collected the data of people with schizophrenia from Taiwan's National Health Insurance Research Database for the period between 1 January 2001 and 31 December 2019. Multivariable Cox proportional hazards regression with a time-dependent model was used to estimate the hazard ratio for mortality associated with each lipid-modifying agent. RESULTS: This study included 110 300 people with schizophrenia. Of them, 22 528 died (19 754 from natural causes and 1606 from suicide) during the study period, as confirmed using data from Taiwan's national mortality database. The use of lipid-modifying agents was associated with reduced risks of all-cause (adjusted hazard ratio [aHR]:0.37; P < 0.001) and natural (aHR:0.37; P < 0.001) mortality during a 5-year period. Among the lipid-modifying agents, statins and fibrates were associated with reduced risks of all-cause mortality (aHRs:0.37 and 0.39, respectively; P < 0.001 for both) and natural mortality (aHRs: 0.37 and 0.42, respectively; P < 0.001 for both). Notably, although our univariate analysis indicated an association between the use of lipid-modifying agents and a reduced risk of suicide mortality, the multivariate analysis revealed no significant association. CONCLUSIONS: Lipid-modifying agents, particularly statins and fibrates, reduce the risk of mortality in people with schizophrenia. Appropriate use of lipid-modifying agents may bridge the mortality gap between these individuals and the general population.

Sex-specific risk profiles for suicide mortality in bipolar disorder: incidence, healthcare utilization and comorbidity.

BACKGROUND: Evidence on sex-specific incidence and comorbidity risk factors of suicide among patients with bipolar disorder is scarce. This study investigated the sex-specific risk profiles for suicide among the bipolar disorder population in terms of incidence, healthcare utilization and comorbidity. METHODS: Using data from the Taiwan National Health Insurance Research Database between 1 January 2000 and 31 December 2016, this nationwide cohort study included patients with bipolar disorder (N = 46 490) and individuals representative of the general population (N = 185 960) matched by age and sex at a 1:4 ratio. Mortality rate ratios (MRRs) of suicide were calculated between suicide rates of bipolar disorder cohort and general population. In addition, a nested case-control study (1428 cases died by suicide and 5710 living controls) was conducted in the bipolar disorder cohort to examine the sex-specific risk of healthcare utilization and comorbidities. RESULTS: Suicide risk was considerably higher in the cohort (MRR = 21.9) than in the general population, especially among women (MRR = 35.6). Sex-stratified analyses revealed distinct healthcare utilization patterns and physical comorbidity risk profiles between the sexes. Although female patients who died by suicide had higher risks of nonhypertensive cardiovascular disease, pneumonia, chronic kidney disease, peptic ulcer, irritable bowel syndrome, and sepsis compared to their living counterparts, male patients who died by suicide had higher risks of chronic kidney disease and sepsis compared to the living controls. CONCLUSIONS: Patients with bipolar disorder who died by suicide had sex-specific risk profiles in incidence and physical comorbidities. Identifying these modifiable risk factors may guide interventions for suicide risk reduction.

Mood stabilizers and risk of all-cause, natural, and suicide mortality in bipolar disorder: A nationwide cohort study.

OBJECTIVES: People with bipolar disorder have an elevated risk of mortality. This study evaluated associations between the use of mood stabilizers and the risks of all-cause mortality, suicide, and natural mortality in a national cohort of people with bipolar disorder. METHODS: In this nationwide cohort study, we used data from January 1, 2000, to December 31, 2016, collected from Taiwan's National Health Insurance Research Database and included 25,787 patients with bipolar disorder. Of these patients, 4000 died during the study period (including 760 and 2947 from suicide and natural causes, respectively). Each standardized mortality ratio (SMR) was calculated as the ratio of observed mortality in the bipolar cohort to the number of expected deaths in the general population. Multivariable Cox proportional hazards regression with a time-dependent model was performed to estimate the hazard ratio (HR) of each mood stabilizer with each mortality outcome. RESULTS: The SMRs of all-cause mortality, suicide, and natural mortality in the bipolar disorder cohort were 5.26, 26.02, and 4.68, respectively. The use of mood stabilizers was significantly associated with decreased risks of all-cause mortality (adjusted HR [aHR] = 0.58, p< 0.001), suicide (aHR = 0.60, p < 0.001), and natural mortality (aHR = 0.55, p < 0.001) within a 5-year follow-up period after index admission. Among the individual mood stabilizers, lithium was associated with the lowest risks of all-cause mortality (aHR = 0.38, p < 0.001), suicide (aHR = 0.39, p < 0.001), and natural mortality (aHR = 0.37, p < 0.001). CONCLUSION: In addition to having protective effects against suicide and all-cause mortality, mood stabilizers also exert a substantial protective effect against natural mortality, with lithium associated with the lowest risk of mortality.

Cardioprotective potential of lithium and role of fractalkine in euthymic patients with bipolar disorder.

OBJECTIVE: Over a half century, lithium has been used as the first-line medication to treat bipolar disorder. Emerging clinical and laboratory studies suggest that lithium may exhibit cardioprotective effects in addition to neuroprotective actions. Fractalkine (CX3CL1) is a unique chemokine associated with the pathogenesis of mood disorders and cardiovascular diseases. Herein we aimed to ascertain whether lithium treatment is associated with favorable cardiac structure and function in relation to the reduced CX3CL1 among patients with bipolar disorder. METHODS: We recruited 100 euthymic patients with bipolar I disorder aged over 20 years to undergo echocardiographic study and measurement of plasma CX3CL1. Associations between lithium treatment, cardiac structure and function and peripheral CX3CL1 were analyzed according to the cardiovascular risk. The high cardiovascular risk was defined as (1) age ⩾ 45 years in men or ⩾ 55 years in women or (2) presence of concurrent cardiometabolic diseases. RESULTS: In the high cardiovascular risk group (n = 61), patients who received lithium as the maintenance treatment had significantly lower mean values of left ventricular internal diameters at end-diastole (Cohen's d = 0.65, p = 0.001) and end-systole (Cohen's d = 0.60, p = 0.004), higher mean values of mitral valve E/A ratio (Cohen's d = 0.51, p = 0.019) and superior performance of global longitudinal strain (Cohen's d = 0.51, p = 0.037) than those without lithium treatment. In addition, mean plasma levels of CX3CL1 in the high cardiovascular risk group were significantly lower among patients with lithium therapy compared with those without lithium treatment (p = 0.029). Multiple regression models showed that the association between lithium treatment and mitral value E/A ratio was contributed by CX3CL1. CONCLUSION: Data from this largest sample size study of the association between lithium treatment and echocardiographic measures suggest that lithium may protect cardiac structure and function in patients with bipolar disorder. Reduction of CX3CL1 may mediate the cardioprotective effects of lithium.

Prevalence and 5-year trend of incidence for medical illnesses after the diagnosis of bipolar disorder: A nationwide cohort study.

OBJECTIVE: Medical comorbidities are prevalent in patients with bipolar disorder. Evaluating longitudinal trends of the incidence of medical illnesses enables implementation of early prevention strategies to reduce the high mortality rate in this at-risk population. However, the incidence risks of medical illnesses in the early stages of bipolar disorder remain unclear. This study investigated the incidence and 5-year trend of medical illnesses following bipolar disorder diagnosis. METHODS: We identified 11,884 patients aged 13-40 years who were newly diagnosed as having bipolar disorder during 1996-2012 and 47,536 age- and sex-matched controls (1:4 ratio) who represented the general population from Taiwan's National Health Insurance Research Database. We estimated the prevalence and incidence of individual medical illnesses yearly across the first 5 years after the index date. The adjusted incidence rate ratio was calculated to compare the occurrence of specific medical illnesses each year between the bipolar disorder group and control group using the Poisson regression model. RESULTS: Apart from the prevalence, the adjusted incidence rate ratios of most medical illnesses were >1.00 across the first 5-year period after bipolar disorder diagnosis. Cerebrovascular diseases, ischaemic heart disease, congestive heart failure, other forms of heart disease, renal disease and human immunodeficiency virus infection exhibited the highest adjusted incidence rate ratios during the first year. Except for that of renal disease, the 5-year trends of the adjusted incidence rate ratios decreased for cerebrovascular diseases, cardiovascular diseases (e.g. ischaemic heart disease, other forms of heart disease, and vein and lymphatic disease), gastrointestinal diseases (e.g. chronic hepatic disease and ulcer disease) and communicable diseases (e.g. human immunodeficiency virus infection, upper respiratory tract infection and pneumonia). CONCLUSION: Incidence risks of medical illnesses are increased in the first year after bipolar disorder diagnosis. Clinicians must carefully evaluate medical illnesses during this period because the mortality rates from medical illnesses are particularly high in people with bipolar disorder.

Lithium Treatment Improves Cardiac Dysfunction in Rats Deprived of Rapid Eye Movement Sleep.

Rapid eye movement (REM) sleep deprivation triggers mania and induces cardiac fibrosis. Beyond neuroprotection, lithium has cardioprotective potential and antifibrotic activity. This study investigated whether lithium improved REM sleep deprivation-induced cardiac dysfunction and evaluated the potential mechanisms. Transthoracic echocardiography, histopathological analysis, and Western blot analysis were performed in control and REM sleep-deprived rats with or without lithium treatment (LiCl of 1 mmol/kg/day administered by oral gavage for 4 weeks) in vivo and in isolated ventricular preparations. The results revealed that REM sleep-deprived rats exhibited impaired contractility and greater fibrosis than control and lithium-treated REM sleep-deprived rats. Western blot analysis showed that REM sleep-deprived hearts had higher expression levels of transforming growth factor beta (TGF-ß), phosphorylated Smad 2/3, and alpha-smooth muscle actin than lithium-treated REM sleep-deprived and control hearts. Moreover, lithium-treated REM sleep-deprived hearts had lower expression of angiotensin II type 1 receptor, phosphorylated nuclear factor kappa B p65, calcium release-activated calcium channel protein 1, transient receptor potential canonical (TRPC) 1, and TRPC3 than REM sleep-deprived hearts. The findings suggest that lithium attenuates REM sleep deprivation-induced cardiac fibrogenesis and dysfunction possibly through the downregulation of TGF-ß, angiotensin II, and Ca2+ signaling.

Peripheral inflammatory markers associated with brain volume reduction in patients with bipolar I disorder.

BACKGROUND: Neuroinflammation and brain structural abnormalities are found in bipolar disorder (BD). Elevated levels of cytokines and chemokines have been detected in the serum and cerebrospinal fluid of patients with BD. This study investigated the association between peripheral inflammatory markers and brain subregion volumes in BD patients. METHODS: Euthymic patients with bipolar I disorder (BD-I) aged 20-45 years underwent whole-brain magnetic resonance imaging. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (also known as YKL-40), fractalkine (FKN), soluble tumour necrosis factor receptor-1 (sTNF-R1), interleukin-1ß, and transforming growth factor-ß1 were measured on the day of neuroimaging. Clinical data were obtained from medical records and interviewing patients and reliable others. RESULTS: We recruited 31 patients with a mean age of 29.5 years. In multivariate regression analysis, plasma level YKL-40, a chemokine, was the most common inflammatory marker among these measurements displaying significantly negative association with the volume of various brain subareas across the frontal, temporal, and parietal lobes. Higher YKL-40 and sTNF-R1 levels were both significantly associated with lower volumes of the left anterior cingulum, left frontal lobe, right superior temporal gyrus, and supramarginal gyrus. A greater number of total lifetime mood episodes were also associated with smaller volumes of the right caudate nucleus and bilateral frontal lobes. CONCLUSIONS: The volume of brain regions known to be relevant to BD-I may be diminished in relation to higher plasma level of YKL-40, sTNF-R1, and more lifetime mood episodes. Macrophage and macrophage-like cells may be involved in brain volume reduction among BD-I patients.

Age Effect on Incidence, Physical, and Psychiatric Comorbidity for Sudden Cardiac Death in Schizophrenia: Effet de l'âge sur l'incidence, la comorbidité physique et psychiatrique de la mort cardiaque subite dans la schizophrénie.

OBJECTIVE: The pathogenesis of sudden cardiac death may differ between younger and older adults in schizophrenia, but evidence remains scant. This study investigated the age effect on the incidence and risk of the physical and psychiatric comorbidity for sudden cardiac death. METHODS: Using 2000 to 2016 data from the Taiwan National Health Insurance Research Database and Department of Health Death Certification System, we identified a national cohort of 170,322 patients with schizophrenia, 1,836 of whom had a sudden cardiac death. Standardized mortality ratios (SMRs) were estimated. Hazard ratios and population attributable fractions of distinctive comorbidities for sudden cardiac death were assessed. RESULTS: The SMRs of sudden cardiac death were all >1.00 across each age group for both sexes, with the highest SMR in male patients aged <35 years (30.88, 95% CI: 26.18-36.18). The fractions of sudden cardiac death attributable to hypertension and congestive heart failure noticeably increased with age. By contrast, the fraction attributable to drug-induced mental disorder decreased with age. Additionally, chronic hepatic disease and sleep disorder increased the risk of sudden cardiac death in patients aged <35 years. Dementia and organic mental disorder elevated the risk in patients aged between 35-54 years. Ischemic heart disease raised the risk in patients aged ≥55 years. CONCLUSIONS: The risk is increased across the lifespan in schizophrenia, particularly for younger male patients. Furthermore, physical and psychiatric comorbidities have age-dependent risks. The findings suggest that prevention strategies targeted toward sudden cardiac death in patients with schizophrenia must consider the age effect.

Incidence and method of suicide mortality in patients with schizophrenia: a Nationwide Cohort Study.

PURPOSE: Suicide is a leading cause of death in patients with schizophrenia. This nationwide cohort study investigated the incidence of each suicide method in patients with schizophrenia compared with the general population. METHODS: In total, records of 174,039 patients with schizophrenia were obtained from the National Health Insurance Research Database in Taiwan from 2001 to 2016. This schizophrenia cohort was linked with the national mortality database, and 26,926 patients died during this follow-up period. Of the deceased, 3033 had died by suicide. Univariate Cox regression was used to estimate the demographic variables associated with suicide. We estimated the difference in the proportion of each suicide method used in patients with schizophrenia compared with the general population. The incidence and standardized mortality ratio (SMR) of each suicide method were calculated and stratified based on sex. RESULTS: Patients aged 25-34 years exhibited the highest suicide risk. Compared with the general population, patients with schizophrenia were more likely to commit suicide by jumping and drowning and less likely to use charcoal-burning and hanging. Women showed a higher incidence of suicide by drowning and jumping than did men. Comorbidity with substance use disorders (SUDs) was associated with a high suicide SMR (26.9, 95% confidence interval [CI] = 23.4-28.9), particularly for suicide by jumping (61.2, 95% CI = 48.3-76.3). CONCLUSIONS: Patients with schizophrenia had higher suicide rates for all methods than did the general population. Suicide method differed based on sex. Patients with SUDs exhibit a high SMR for each suicide method and warrant intensive clinical attention.

Lithium Reduces Migration and Collagen Synthesis Activity in Human Cardiac Fibroblasts by Inhibiting Store-Operated Ca2+ Entry.

Cardiac fibrosis plays a vital role in the pathogenesis of heart failure. Fibroblast activity is enhanced by increases in store-operated Ca2+ entry (SOCE) and calcium release-activated calcium channel protein 1 (Orai1) levels. Lithium regulates SOCE; however, whether therapeutic concentrations of lithium can be used to inhibit cardiac fibrogenesis is unknown. Migration and proliferation assays, Western blotting, real-time reverse-transcription polymerase chain reaction analysis, and calcium fluorescence imaging were performed in human cardiac fibroblasts treated with or without LiCl at 1.0 mM (i.e., therapeutic peak level) or 0.1 mM (i.e., therapeutic trough level) for 24 h. Results showed that LiCl (0.1 mM, but not 1.0 mM) inhibited the migration and collagen synthesis ability of cardiac fibroblasts. Additionally, thapsigargin-induced SOCE was reduced in fibroblasts treated with LiCl (0.1 mM). The expression level of Orai1 was lower in LiCl (0.1 mM)-treated fibroblasts relative to the fibroblasts without LiCl treatment. Fibroblasts treated with a combination of LiCl (0.1 mM) and 2-APB (10 µM, an Orai1 inhibitor) demonstrated similar migration and collagen synthesis abilities as those in LiCl (0.1 mM)-treated fibroblasts. Altogether, lithium at therapeutic trough levels reduced the migration and collagen synthesis abilities of human cardiac fibroblasts by inhibiting SOCE and Orai1 expression.

Nationwide Analysis of Changes in Medical Utilization Before and After a New Panic Disorder Diagnosis.

OBJECTIVE: Panic disorder (PD) is associated with somatization and high medical utilization in primary care settings. Treatment of PD could reduce the frequency of panic attacks and visits to emergency departments, but the associated change in medical utilization is unknown. This study investigated the change in medical utilization before and after a PD diagnosis. METHOD: This study identified 8722 patients with PD enrolled in the National Health Insurance Research Database in Taiwan between January 1, 2000, and December 31, 2012. We used a case-crossover study design to compare medical utilizations with a 1-year time window before and after new PD diagnoses, including medical examinations, specialty visits, and medication used. A conditional logistic regression model was used to estimate changes in comorbidity before and after new PD diagnoses. RESULTS: The utilization of examinations-including electrocardiography, radiography, and sonography-decreased within 1 year after PD diagnosis compared with 1 year before PD diagnosis. Outpatient and emergency department visits to nonpsychiatric departments decreased (risk ratio [RR] = 0.989 [95% confidence interval {CI} = 0.985-0.993] and RR = 0.924 [95% CI = 0.894-0.956], respectively), whereas outpatient visits to psychiatric departments increased (RR = 1.193, 95% CI = 1.171-1.215). PD diagnosis is associated with increased use of antidepressants (RR = 12.65) and benzodiazepines (RR = 11.63), an increased ratio of comorbid depressive disorder (RR = 3.06) and bipolar disorder (RR = 1.77), and a decreased ratio of nonpanic anxiety disorder (RR = 0.69). CONCLUSIONS: New PD diagnoses are associated with decreased laboratory examination and nonpsychiatric service utilization, along with increased psychiatric service utilization. We suggest that PD should be detected earlier for mitigating potentially unnecessary use of nonpsychiatric examinations and services.

Clinical Risk Factors for Therapeutic Lithium-Associated Electrocardiographic Changes in Patients With Bipolar Disorder.

PURPOSE/BACKGROUND: Lithium, a common medication used in bipolar disorder treatment, can exert an inhibitory effect on sodium and potassium channels and potentially cause cardiac electrical conduction disturbance and corrected QT (QTc) prolongation. This study aimed to examine whether lithium at therapeutic levels can change electrocardiographic parameters in different groups of patients with bipolar disorder and to identify the potential clinical risk factors. METHODS/PROCEDURES: Standard 12-lead electrocardiogram data before and after lithium treatment in bipolar disorder patients after at least 2-week dropout of psychotropic medications were analyzed. FINDINGS/RESULTS: A total of 39 patients with bipolar disorder receiving lithium treatment were enrolled. Nineteen patients (48.7%) exhibited increased from P wave beginning to QRS complex beginning intervals after lithium treatment (mean serum level, 0.653 ± 0.247 mmol/L). Twenty-four patients (61.5%) exhibited increased a combination of Q, R, and S waves complex durations and increased QTc intervals. Twenty-three patients (59.0%) exhibited increased corrected JT (JTc) intervals. The patient group with increased QTc or JTc intervals exhibited a higher mean systolic blood pressure than did the patient group without increased QTc (134.7 ± 19.2 mm Hg vs 115.7 ± 11.8 mm Hg, P = 0.020) or JTc intervals (134.4 ± 19.6 mm Hg vs 117.6 ± 13.3 mm Hg, P = 0.054), respectively. Biochemical and hemodynamic parameters were comparable between patients with and without increased a combination of Q, R, and S waves complex durations or from P wave beginning to QRS complex beginning intervals. IMPLICATIONS/CONCLUSIONS: Elevated systolic blood pressure may be the risk factor for the ventricular conduction delay in bipolar disorder patients receiving lithium at therapeutic levels.

Call to action regarding the vascular-bipolar link: A report from the Vascular Task Force of the International Society for Bipolar Disorders.

OBJECTIVES: The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular-bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment. METHODS: An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps. RESULTS: The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular-bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets. CONCLUSIONS: Further research focused on the vascular-bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

Body mass index, residual psychotic symptoms, and inflammation associated with brain volume reduction in older patients with schizophrenia.

Obesity, aging, and pathophysiology of schizophrenia (SCZ) may collectively contribute to the gray matter loss in brain regions of SCZ. We attempted to examine the association between volumes of specific brain regions, body mass index (BMI), inflammatory markers, and clinical features in older SCZ patients. METHOD: Clinically stable outpatients with schizophrenia (DSM-IV) aged ≥50 years were recruited to undergo whole-brain magnetic resonance imaging. We measured patients' plasma levels of soluble tumor necrosis factor receptor-1, soluble interleukin (IL)-2 receptor (sIL-2R), IL-1ß, and IL-1 receptor antagonist (IL-1Ra). Clinical data were obtained from medical records and interviewing patients along with their reliable others. RESULTS: There were 32 patients with mean age 58.8 years in this study. Multivariate regression analysis found only higher BMI significantly associated with lower volume of total gray matter, bilateral orbitofrontal and prefrontal cortexes, and the right hippocampal and frontal cortexes. Increased intensity of residual symptoms (higher Positive and Negative Syndrome Scale scores) was related to lower volumes of frontal lobe, prefrontal cortex, insula, hippocampus, left hemisphere amygdala, and total white matter. The lower volume of left anterior cingulum was associated with older age and higher sIL-2R plasma level; and higher IL-1Ra level was associated with greater right anterior cingulate volume. Older age at illness onset was significantly associated with the smaller right insula volume. CONCLUSIONS: Higher BMI, more residual symptoms, and inflammatory activity in IL-2 and IL-1 systems may play a role in gray matter loss in various brain regions of schizophrenia across the life span.

The association between carotid atherosclerosis and treatment with lithium and antipsychotics in patients with bipolar disorder.

OBJECTIVES: Patients with bipolar disorder are at high risk of cardiovascular diseases. Among cardiovascular diseases, coronary heart disease and stroke are the leading causes of premature death and both share the pathogenesis of arterial atherosclerosis. Increased carotid intima-media thickness is sensitive for detecting early atherosclerosis and a practical index for predicting cardiovascular diseases. However, few studies investigated carotid intima-media thickness in adults with bipolar disorder. We attempted to determine the factors associated with carotid intima-media thickness in adults with bipolar disorder. METHODS: The euthymic out-patients with bipolar I disorder aged over 20 years were recruited to measure the carotid intima-media thickness value through B-mode carotid ultrasound. Those with any psychiatric disorder, acute or life-threatening medical condition were excluded. All clinical information was obtained by reviewing medical records and directly interviewing patients with reliable others. RESULTS: Of the 106 participants with a mean age of 44.5 years, 40.6% (N = 43) had concurrent cardiovascular/endocrine/metabolic diseases. A multivariate regression indicated that higher assumed daily lithium dosage was significantly associated with a decreased carotid intima-media thickness in the whole sample. In the young subgroup (⩽45 years old, N = 63), higher current daily lithium dosage and lower body mass index were associated with lower carotid intima-media thickness. In those without concurrent cardiovascular/endocrine/metabolic diseases, higher ratio of first-generation antipsychotics exposure in relation to illness chronicity was associated with higher carotid intima-media thickness, after controlling for body mass index or age. CONCLUSION: Lithium treatment may be associated with less progression in carotid intima-media thickness and the reduced risk for atherosclerosis in adults with bipolar disorder, including those with high cardiovascular disease risk. In addition to age and body mass index, antipsychotics may increase carotid intima-media thickness even in the low cardiovascular disease-risk patients.

Age effect of antipsychotic medications on the risk of sudden cardiac death in patients with schizophrenia: A nationwide case-crossover study.

AIM: Research regarding the effects of age in patients with schizophrenia taking antipsychotics on the risk of sudden cardiac death is lacking. We determined the effect of patient age on the association between exposure to antipsychotics and the risk of sudden cardiac death in a nationwide schizophrenia cohort. METHODS: From the Taiwan National Health Insurance Research Database and Department of Health Death Certification System, data of 1836 patients with schizophrenia who had experienced sudden cardiac death between 2000 and 2016 were included. A case-crossover design by using a 14-day window was applied, and subgroup analyses were performed by stratifying patients into three age subgroups (<45, 45-65, and >65 years) to assess the effect of age on the risk of sudden cardiac death in patients taking antipsychotics. RESULTS: No association between exposure to antipsychotic agents and sudden cardiac death risk was found in patients aged >65 years who were characterized by a high burden of medical illnesses. However, zotepine significantly increased the risk of sudden cardiac death in patients aged <45 years (adjusted relative risk [RR] = 2.68, P = 0.046). Flupentixol (adjusted RR = 5.30, P = 0.004) and risperidone (adjusted RR = 1.68, P = 0.01) significantly elevated the risk of sudden cardiac death in patients aged 45-65 years. CONCLUSION: This study suggests that individual antipsychotics pose different risks of sudden cardiac death in patients with schizophrenia across their lifespan. Clinicians should consider patient age when evaluating the risks and benefits of antipsychotic treatment.

Differences in outcomes between older community-dwelling patients with bipolar disorder and schizophrenia with illness onset at young age.

AIM: Older community-dwelling patients with severe mental illness (SMI), particularly those with illness onset at young age, constitute a group of survivors with unique long-term care needs. Using an Asian sample in Taiwan, we attempted to find out the differences in outcomes related to physical health, cognition, and social functioning between older community-dwelling adults with bipolar disorder and schizophrenia with early age onset. METHODS: Community-dwelling patients aged >50 years with bipolar I disorder or schizophrenia whose illness developed before the age of 40 years were recruited. Clinical data were obtained by reviewing all available medical records and by interviewing the patients and their reliable family members. Medical morbidities, Mini-Mental State Examination (MMSE), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), and Global Assessment of Functioning (GAF) scores were compared between the two groups. RESULTS: In total, 113 bipolar patients and 104 schizophrenic ones (mean ages = 59.8 and 59.2 years, respectively) became the final subjects. The rates of cognitive impairment (MMSE score <24) were comparable in bipolar disorder (26.5%) and schizophrenia (24.0%) and the mean MMSE scores did not significantly differ from each other. The concurrence (54.9%) of cardiovascular disease (CVD) in the bipolar group was also similar to 51.0% in the schizophrenic one. In a multiple logistic regression analysis, the bipolar group exhibited significantly higher CIRS-G total scores (95% confidence interval (CI) for odds ratio (OR) = 1.01-1.27), body mass index (95% CI for OR = 1.02-1.21), and GAF scores (95% CI for OR = 1.04-1.14). CONCLUSION: Given better social functioning and the same cognitive function in older community-dwelling patients with bipolar disorder, they may remain at higher risk for obesity and medical morbidity than schizophrenic patients. Treatments targeting cognitive impairment and CVDs across their life span are both necessary to promote the health of community-dwellers with SMI.

Mood stabilisers and risk of stroke in bipolar disorder.

BACKGROUND: Research on the risk of stroke following the use of mood stabilisers specific to patients with bipolar disorder is limited.AimsIn this study, we investigated the risk of stroke following the exposure to mood stabilisers in patients with bipolar disorder. METHOD: Data for this nationwide population-based study were derived from the Taiwan National Health Insurance Research Database. Among a retrospective cohort of patients with bipolar disorder (n = 19 433), 609 new-onset cases of stroke were identified from 1999 to 2012. A case-crossover study design utilising 14-day windows was applied to assess the acute exposure effect of individual mood stabilisers on the risk of ischaemic, haemorrhagic and other types of stroke in patients with bipolar disorder. RESULTS: Mood stabilisers as a group were significantly associated with the increased risk of stroke in patients with bipolar disorder (adjusted risk ratio, 1.26; P = 0.041). Among individual mood stabilisers, acute exposure to carbamazepine had the highest risk of stroke (adjusted risk ratio, 1.68; P = 0.018), particularly the ischaemic type (adjusted risk ratio, 1.81; P = 0.037). In addition, acute exposure to valproic acid elevated the risk of haemorrhagic stroke (adjusted risk ratio, 1.76; P = 0.022). In contrast, acute exposure to lithium and lamotrigine did not significantly increase the risk of any type of stroke. CONCLUSIONS: Use of carbamazepine and valproic acid, but not lithium and lamotrigine, is associated with increased risk of stroke in patients with bipolar disorder.Declaration of interestNone.

Homocysteine, rather than age of onset, is a better predictor for cognitive function in older adults with bipolar disorder.

OBJECTIVES: The association between older-age bipolar disorder and cognitive impairments may be mediated by vascular burden. The aim of the study was to examine the difference of cognitive function between older people with late-onset bipolar disorder (LOBD) and early-onset bipolar disorder (EOBD) by considering rigorous vascular risk burden evaluation, comprehensive cognitive tests, and relevant biochemistry data. METHODS: We recruited 95 outpatients aged over 55 with a DSM-IV-TR diagnosis of bipolar I disorder. Fifty had LOBD, defined by age of onset after 40. Cognitive function was evaluated through a battery of tests assessing verbal memory, attention/speed, visuospatial function, verbal fluency, and cognitive flexibility. Vascular risk assessments included individual disorders, 10-year Framingham cardiovascular risk scores, and serum levels of homocysteine, vitamin B12, folate, and triiodothyronine. RESULTS: No differences were observed between LOBD and EOBD on any cognitive test after adjusting for potential confounders. In addition to age and educational years, multiple linear regression analyses indicated significantly negative associations between serum homocysteine levels and cognitive performances in attention, psychomotor speed, verbal memory, and executive function. CONCLUSIONS: Among older people with bipolar disorder, LOBD is not associated with more cognitive dysfunction in this study. However, higher serum homocysteine levels were significantly associated with worse cognitive performance in this particular group. Clinicians therefore have to pay attention to the cognitive function in older bipolar patients with higher levels of homocysteine.

Excessive mortality and causes of death among patients with personality disorder with comorbid psychiatric disorders.

PURPOSE: Excessive mortality has been seen in patients with personality disorder (PD), but it has not been well-studied when patients also have other psychiatric comorbidities. This study investigated the mortality rates and causes of death in an Asian cohort with PD. METHOD: We enrolled patients ≥ 18 years of age with PD as defined by DSM-IV criteria (N = 1172), who had been admitted to a psychiatric service center in northern Taiwan between 1985 and 2008. By linking with the national mortality database (1985-2008), cases of mortality (n = 156, 13.3%) were obtained. We calculated the standardized mortality ratios (SMRs) to estimate the mortality gap between patients with PD and the general population. Stratified analyses of mortality rates by Axis I psychiatric comorbidity and sex were performed. RESULTS: Borderline PD (n = 391, 33.4%) was the dominant disorder among the subjects. The SMRs for all-cause mortality of PD alone, PD comorbid with non-substance use disorder(non-SUD), and PD comorbid with SUD were 4.46 (95% CI 1.94-6.98), 7.42 (5.99-8.85), and 15.96 (11.07-20.85), respectively. Among the causes of death, the SMR for suicide was the highest (46.92, 95% CI 34.29-59.56). The SMR for suicide in PD patients with comorbid SUD was unusually high (74.23, 95% CI 33.88-114.58). Women had a significant increase in suicide with an SMR of 59.00 (95% CI 37.89-80.11). Men had significant increase in SMRs for cardiovascular disease and gastrointestinal disease. CONCLUSIONS: We found significant synergistic effects of PD and SUD on mortality risk. A personality assessment should be mandatory in all clinical settings to prevent premature death and detect SUD early.