Mitochondrial DNA Copy Number Is Associated With Treatment Response and Cognitive Function in Euthymic Bipolar Patients Receiving Valproate.

BACKGROUND: Bipolar disorder (BD) is associated with cognitive impairment and mitochondrial dysfunction. However, the associations among mitochondrial DNA copy number (MCN), treatment response, and cognitive function remain elusive in BD patients. METHODS: Sixty euthymic BD patients receiving valproate (VPA) and 66 healthy controls from the community were recruited. The indices of metabolic syndrome (MetS) were measured. Quantitative polymerase chain reaction analysis of blood leukocytes was used to measure the MCN. Cognitive function was measured by calculating perseverative errors and completed categories on the Wisconsin Card Sorting Test (WCST). The VPA treatment response was measured using the Alda scale. RESULTS: BD patients had significantly higher MCN, triglyceride, and C-reactive protein (CRP) levels, waist circumference, and worse performance on the WCST than the controls. Regression models showed that BD itself and the VPA concentration exerted significant effects on increased MCN levels. Moreover, the receiver operating characteristic curve analysis showed that an MCN of 2.05 distinguished VPA responders from nonresponders, with an area under the curve of 0.705 and a sensitivity and specificity of 0.529 and 0.816, respectively. An MCN level ≥2.05 was associated with 5.39 higher odds of being a VPA responder (P = .006). BD patients who were stratified into the high-MCN group had a higher VPA response rate, better WCST performance, lower CRP level, and less MetS. CONCLUSIONS: The study suggests a link between the peripheral MCN and cognitive function in BD patients. As an inflammatory status, MetS might modulate this association.

Identification of psychiatric patients with high mortality and low medical utilization: a population-based propensity score-matched analysis.

BACKGROUND: The decreased life expectancy and care costs of mental disorders could be enormous. However, research that compares mortality and utilization concurrently across the major category of mental disorders is absent. This study investigated all-cause mortality and medical utilization among patients with and without mental disorders, with an emphasis on identifying the psychiatric category of high mortality and low medical utilization. METHODS: A total of 570,250 individuals identified from the 2002-2013 Taiwan National Health Insurance Reearch Database consistuted 285,125 psychiatric patients and 285,125 non-psychiatric peers through 1:1 dual propensity score matching (PSM). The expenditure survival ratio (ESR) was proposed to indicate potential utilization shortage. The category of mental disorders and 13 covariates were analyzed using the Cox proportional hazard model and general linear model (GLM) through SAS 9.4. RESULTS: PSM analyses indicated that mortality and total medical expenditures per capita were both significantly higher in psychiatric patients than those in non-psychiatric patients (all P <.0.0001). Patients with substance use disorders were reported having the youngest ages at diagnosis and at death, with the highest 25.64 of potential years of life loss (YPLL) and relevant 2904.89 of ESR. Adjusted Cox model and GLM results indicated that, compared with anxiety disorders, affective disorders and substance use disorders were significantly associated with higher mortality (HR = 1.246 and 1.064, respectively; all P < 0.05); schizophrenia was significantly associated with higher total medical expenditures per capita (P < 0.0001). Thirteen additional factors were significantly associated with mortality or utilization (all P < 0.05). CONCLUSION: Substance use disorders are the category of highest YPLL but notably in insufficient utilization. Health care utilization in patients with substance use disorders should be augmented timely after the diagnosis, especially toward home and community care. The factors related to mortality and utilization identified by this study merit clinical attention.

Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient.

Delirium is common in daily practice. Drug-induced delirium constitutes approximately one-third of all cases of delirium. In cases characterized by the limited efficacy of a single antidepressant, a combination of two antidepressants is required, which may induce a complex drug-drug interaction. We reviewed a case of duloxetine- and bupropion-related delirium in an elderly male patient in our clinical practice. The patient was diagnosed with major depressive disorder and was treated with duloxetine. However, he developed delirium 10 days after bupropion was added to his treatment regimen. Three days after the cessation of bupropion, his delirious condition gradually improved. Duloxetine and bupropion are both cytochrome P450 2D6 inhibitors that may result in a higher level of hydroxybupropion. An increased level of hydroxybupropion may cause the elevation of dopamine and a risk of subsequent delirium. We should be aware of the risk of delirium induced by drug-drug interactions.

Mitochondrial DNA variation and increased oxidative damage in euthymic patients with bipolar disorder.

AIM: The aim of this study was to compare alterations of mitochondrial DNA (mtDNA) copy number, single nucleotide polymorphisms, and oxidative damage of mtDNA in clinically stable patients with bipolar I disorder (BD). METHODS: Patients meeting DSM-IV diagnostic criteria for BD were recruited from the psychiatric outpatient clinic at Changhua Christian Hospital, Taiwan. They were clinically stable and their medications had not changed for at least the preceding 2 months. Exclusion criteria were substance-induced psychotic disorder, eating disorder, anxiety disorder or illicit substance abuse. Comparison subjects did not have any history of major psychiatric disorders and they were non-smokers. By analyzing peripheral blood leukocytes, copy number, single nucleotide polymorphisms and oxidative damage of mtDNA were compared between the two groups. RESULTS: The median age of the subjects was 38 years and 41.5 years in the comparison and BD groups, respectively. The leukocyte mtDNA copy number of the BD group was significantly lower than that of the comparison group (P < 0.001). BD patients had significantly higher mitochondrial oxidative damage than the comparison group (6.1 vs 3.9, P < 0.001). After generalized linear model adjusting with age, sex, smoking, family history, and psychotropic use, mtDNA copy number was still significantly lower in the BD group (P < 0.001). MtDNA oxidative damage was positively correlated with age (P = 0.034), although mtDNA oxidative damage was similar between these two groups. CONCLUSION: Possible involvement of oxidative stress and mitochondria in the pathophysiology of BD needs more large-scale studies. It is important that psychiatrists retain a high level of suspicion for mitochondrial dysfunction in patients with bipolar disorder.

Gender difference on the mediation effects of filial piety on the association between chronic obstructive pulmonary disease and depressive symptoms in older adults: A community-based study.

Filial piety is viewed as strong family support for older Chinese people, and strongly associated with depressive symptoms. It is unknown if there exists gender difference in the mediation effects of filial piety on the relationship between chronic obstructive pulmonary disease (manifested as lung function) and depression. We investigated whether filial piety mediates the association between lung function and depression in community-dwelling older men and women using the Healthy Aging Longitudinal Study in Taiwan (HALST). Community dwelling adults aged 65 and above were analyzed. Pulmonary function, depressive symptoms, and filial piety expectation (FPE) and receipt of filial piety (RFP) were collected. The interaction and mediation of filial piety between lung function and depression was analyzed. We found that in older men, forced expiratory volume in the first second (FEV1) was inversely correlated with depression (ß = -0.1281, p = 0.004) with no mediation effect of FPE. In older women, FEV1 was negatively associated with FPE, but FPE did not increase the risk of depression (ß = 0.0605, p = 0.12). In both older men and women, FEV1 was negatively associated with RFP, while RFP reduced the risk of depression (p< 0.001). In older women, the correlation between FEV1 was complete mediation of RFP. Results indicate that feelings of insufficient filial piety may increase the likelihood of depression, especially in elderly women with worse lung function. Although modest, the main mediation effect of filial piety was improvement of lung function in older subjects, which might decrease depression.

Spousal Concordance and Cross-Disorder Concordance of Mental Disorders: A Nationwide Cohort Study.

OBJECTIVE: Although both partners of a married couple can have mental disorders, the concordant and cross-concordant categories of disorders in couples remain unclear. Using national psychiatric population-based data only from patients with mental disorders, we examined married couples with mental disorders to examine spousal concordance and cross-disorder concordance across the full spectrum of mental disorders. METHODS: Data from the 1997 to 2012 Taiwan Psychiatric Inpatient Medical Claims data set were used and a total of 662 married couples were obtained. Concordance of mental disorders was determined if both spouses were diagnosed with mental disorder of an identical category in the International Classification of Diseases, Ninth Revision, Clinical Modification; otherwise, cross-concordance was reported. RESULTS: According to Cohen's kappa coefficient, the most concordant mental disorder in couples was substance use disorder, followed by bipolar disorder. Depressive and anxiety disorders were the most common cross-concordant mental disorders, followed by bipolar disorder. The prevalence of the spousal concordance of mental disorders differed by monthly income and the couple's age disparity. CONCLUSION: Evidence of spousal concordance and cross-concordance for mental disorders may highlight the necessity of understanding the social context of marriage in the etiology of mental illness. Identifying the risk factors from a common environment attributable to mental disorders may enhance public health strategies to prevent and improve chronic mental illness of married couples.

Prediction of Institutionalization for Patients With Dementia in Taiwan According to Condition at Entry to Dementia Collaborative Care.

This study aimed to examine the institutionalization rate in patients with dementia in Taiwan, identify the predictors of institutionalization, and conduct a mediation analysis of caregiver burden between neuropsychiatric symptoms and institutionalization. We analyzed data from a retrospective cohort registered in dementia collaborative care (N = 518). The analyses applied univariate and multivariate Cox proportional hazard regression with Firth's penalized likelihood to assess the relationship between each predictor at entry and institutionalization for survival analysis. Thirty (5.8%) patients were censored due to institutionalization after a median follow-up of one-and-a-half years. Neuropsychiatric symptoms, loss of walking ability, and living alone predicted institutionalization. Caregiver burden may partially mediate the effects of neuropsychiatric symptoms and institutionalization. High caregiver burden due to presence of neuropsychiatric symptoms may partially contribute to institutionalization among people living with dementia in Taiwan. However, proper management of neuropsychiatric symptoms and caregiver empowerment may ameliorate institutionalization risk.

Suicide Ideation among Outpatients with Alcohol Use Disorder.

INTRODUCTION: Individuals with substance use disorders, particularly those with alcohol use disorder (AUD), have a high risk of suicide. Therefore, identifying risk factors for suicide in these individuals is crucial. METHODS: This retrospective study reviewed the medical records of individuals with AUD who participated in an alcohol treatment program in central Taiwan during 2019-2020. We collected data using the Cut down, Annoyed, Guilty, and Eye-opener questionnaire, Alcohol Use Disorders Identification Test (AUDIT), Brief Michigan Alcoholism Screening Test (MAST), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and a suicidal ideation question. Furthermore, we collected information on several related variables, namely, sex, age, marital status, years in school, employment status, family history of alcohol problems, age at first exposure to alcohol, duration of alcohol use, history of alcohol cessation, history of domestic violence, and history of drunk driving. In total, 136 individuals were recruited to participate in this study. RESULTS: The suicidal ideation group had significantly younger participants, a higher proportion of women, a higher proportion of participants with a history of domestic violence, a greater severity of alcohol addiction (based on both AUDIT and MAST scores), higher depression scores, higher anxiety scores, less social support, a lower quality of life (World Health Organization Quality of Life (WHOQOL)), and poorer sleep quality (Pittsburgh Sleep Quality Index, PSQI) compared with the nonsuicidal ideation group. The suicidal ideation score was correlated with the AUDIT score after age, and BDI, BAI, WHOQOL, and PSQI scores were controlled for (P = 0.034). CONCLUSION: Individuals with higher AUDIT scores visiting a clinic for alcohol treatment might have a higher risk of suicidal ideation. Therefore, clinicians should pay close attention to the suicidal ideation problem in this population. Furthermore, appropriate medication or management programs for suicide prevention should be considered.

Reduction of dorsolateral prefrontal cortex gray matter in late-life depression.

Postmortem studies have documented abnormalities in the dorsolateral prefrontal cortex (dlPFC) in depressed subjects. In this study we used magnetic resonance imaging to test for dlPFC volume differences between older depressed and non-depressed individuals. Eighty-eight subjects meeting DSM IV criteria for major depressive disorder and thirty-five control subjects completed clinical evaluations and cranial 3T magnetic resonance imaging. After tissue types were identified using an automated segmentation process, the dlPFC was measured in both hemispheres using manual delineation based on anatomical landmarks. Depressed subjects had significantly lower gray matter in the left and right dorsolateral prefrontal cortex (standardized to cerebral parenchyma) after controlling for age and sex. Our study confirmed the reduction of dorsolateral prefrontal cortex in elderly depressed subjects, especially in the gray matter. These regional abnormalities may be associated with psychopathological changes in late-life depression.

Poorer Wisconsin card-sorting test performance in healthy adults with higher positive and negative schizotypal traits.

Non-clinical schizotypy was found to be related to poorer Wisconsin Card-Sorting Test (WCST) performance, but the results were inconsistent. Two subgroups, the higher negative-higher positive and the lower negative-lower positive (15 vs 16), were selected from the top and the bottom quartiles of negative and positive scale scores of the Schizotypal Personality Questionnaire (SPQ) completed by 177 healthy volunteers, respectively. The higher negative-higher positive SPQ score subgroup had significantly poorer performance regarding the completed categories of WCST than the lower negative-lower positive SPQ score subgroup. Subjects with higher non-clinical schizotypy trait showed relatively mild cognitive dysfunction.

Acute Hepatitis Due to Agomelatine Use in Elderly Women with Depression: Case Series.

Although agomelatine may be associated with an increased risk of hepatotoxicity, the incidence rate of acute hepatitis seemed divergent between clinical trials and daily practice. Whether aging or gender is a risk factor in developing hepatotoxicity due to agomelatine is not clear. We present 3 older female cases with acute hepatitis occurring due to highly probable idiosyncratic drug-induced liver injury caused by agomelatine. From these cases, regular surveillance on liver function in the older women taking antidepressants would be of benefits.

Association Between Caregivers' Burden and Neuropsychiatric Symptoms in Female Patients with Alzheimer's Disease with Varying Dementia Severity.

PURPOSE: This study examined the attributes causing higher burdens for caregivers caring for female patients with Alzheimer's disease by analyzing a combination of various variables, including demographic data, dementia severity, and neuropsychiatric symptoms. PATIENTS AND METHODS: This study included 99 female patients with Alzheimer's disease who were cared for by the dementia collaborative care team at Changhua Christian Hospital, Taiwan. Neuropsychiatric symptoms used in this study included affections (9 types), behavior symptoms (9 symptoms), and psychological symptoms (3 symptoms). The Apriori algorithm was employed to identify association rules that reveal the relationships among demographic data, dementia severity, neuropsychiatric symptoms, and caregivers' burden. RESULTS: A total of 185 rules were determined, including 51 rules with little or no burden, 108 rules with mild to moderate burden, and 26 rules with moderate to severe burden. The major findings are as follows. Neuropsychiatric symptoms were associated with varying degrees of caregivers' burden among female patients aged 75 to 84 years with mild dementia. Crying spells and aggression were specifically associated with a moderate to severe burden. Delusion was associated with a mild to moderate and moderate to severe burden. Dysthymia and depression were associated with little or no burden to moderate to severe burden. CONCLUSION: Clinicians can provide early interventions to reduce the burden of caregivers caring for female patients with Alzheimer's disease and can refer caregivers for timely assistance to reduce their burden.

Multiple Factors Associated With Child Abuse Perpetration: A Nationwide Population-Based Retrospective Study.

Differences in child abuse perpetration between individuals with and without mental disorders remain obscure. This study compared the risk difference and further investigated the association between the category of mental disorders and child abuse perpetration. A total of 681,970 adults from the 2002 to 2013 Taiwan National Health Insurance Research Database were analyzed, including 340,985 patients with psychiatric disorders (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 290.x-319.x) and 340,985 sex- and age-matched individuals without psychiatric disorders. Child abuse perpetration (ICD-9-CM N-codes 995.5x and E-code E967) was the outcome variable. Matched analyses indicated that the risk of child abuse among patients with psychiatric disorders (0.25%) was significantly higher than that among those without psychiatric disorders (0.16%; odds ratio [OR] = 1.464, p < .0001). Among the six categories of mental disorders, the prevalence rates of committing child abuse were significantly higher for personality disorders, substance use, and affective disorders (0.56%, 0.45%, and 0.40%, respectively; p < .0001). Compared with anxiety disorders, substance use disorders were significantly associated with higher odds of child abuse perpetration (OR = 2.032, p < .05), especially physical abuse (OR = 2.018, p < .0001). Psychiatric morbidity was associated with higher odds of child abuse, with substance use determined as the major risk category. Screening high-risk families by using the associated factors is crucial.

Using the Apriori Algorithm to Explore Caregivers' Depression by the Combination of the Patients with Dementia and Their Caregivers.

PURPOSE: The purpose of this study was to identify the caring scenarios that result in severe depression in caregivers caring for dementia patients. PATIENTS AND METHODS: A cross-sectional study with 1111 dementia patients and their caregivers in Taiwan from October 2015 to January 2020 was conducted. Gender, age, type of dementia, clinical dementia rating, walking ability, mood symptoms, behavioral symptoms, and psychological symptoms were the variables from the dementia patients. Age, relation to the patient, employment, type of primary care, frequency of care, mood symptoms, and the score from the Center for Epidemiologic Studies Depression Scale were the variables from the caregivers. A comprehensive viewpoint of both dementia patients and their caregivers was evaluated by the Apriori algorithm to find the attributes resulting in different caregiving depressions. RESULTS: Forty-seven rules were found with 18 rules of mild depressive symptomatology, 17 rules of moderate depressive symptomatology, and 12 rules of severe depressive symptomatology. A total of 7 general rules were summarized to be the severe depressive symptomatology. The results showed that an unemployed or retired caregiver with the mood symptoms such as helplessness, anger, emotional liability, or anxiety who took care of AD patients or AD patients with a moderate severity would have severe depression. Increased care frequencies (≥6 days per week) and multiple mood problems from caregivers result in severe depression. The composition of adult children, patients' aggression, and caregivers' helplessness as well as the combinations of male patients aged 75-84 years with the caregiver's mood of helplessness or nervousness and hopelessness were highly associated with severe depression. CONCLUSION: For those caring for AD patients, severe depression was associated with the combination of different parameters to constitute each of these seven scenarios. Unlike previous studies which often evaluated one or two variables related to caregiver's depression, this study provided a more comprehensive viewpoint that enabled the collaborative team to efficiently identify and manage different scenarios by summarizing the rules of caregivers with severe depression from a systematic viewpoint.

Simultaneous determination of aripiprazole and its active metabolite, dehydroaripiprazole, in plasma by capillary electrophoresis combining on-column field-amplified sample injection and application in schizophrenia.

A sensitive high-performance CZE combining on-column field-amplified sample injection (FASI) has been developed for simultaneous determination of aripiprazole and its active metabolite, dehydroaripiprazole, in human plasma. A sample pretreatment by means of liquid-liquid extraction (LLE) (diethyl ether) with subsequent quantitation by FASI-CZE was used. The separation of aripiprazole and dehydroaripiprazole was performed using a BGE containing 150 mM phosphate buffer (pH 3.5) with 40% methanol and 0.02% PVA as a dynamic coating to reduce interaction of analytes with the capillary wall. Before sample loading, a methanol plug (0.3 psi, 6 s) was injected to permit FASI for stacking. The samples were injected electrokinetically (10 kV, 30 s) to introduce sample cations and the applied voltage was 20 kV with on-column detection at 214 nm. Several parameters affecting the separation and sensitivity of the drug and its active metabolite were studied, including reconstitution solvent, organic modifier, pH and concentration of phosphate buffer. The linear ranges of the method for test drug and its active metabolite, in plasma using amlodipine as an internal standard, were over the range 5.0-100.0 ng/mL. One female volunteer (25 years old) was orally administered a single dose of 10 mg aripiprazole (Abilify, Otsuka) and blood samples were drawn over a 60 h period for pharmacokinetic study. The method was also applied to monitor the concentration of aripiprazole and dehydroaripiprazole in plasma collected after oral administration of 20 or 30 mg aripiprazole (Abilify, Otsuka) daily at steady state in one schizophrenic patient.

Mental Disorders and Interferon Nontreatment in Hepatitis C Virus Infection-a Population Based Cohort Study.

OBJECTIVE: This study investigates the association between mental disorders and interferon nontreatment in patients with chronic hepatitis C virus (HCV) infection in a large national sample. METHODS: Using the National Health Insurance Research Database of Taiwan, we conducted a nationwide population-based study. Each case was matched to five controls by age, sex, urbanization, and income. Conditional logistic regression was used to assess odds of HCV nontreatment in different mental disorders. RESULTS: From 1999 to 2013, we identified 92,970 subjects with HCV infection and 15,495 HCV cases (16.7%) had received IFN therapy. Other than chronic obstructive pulmonary disease, the medical diseases and mental disorders were significantly different between IFN and non-IFN treated HCV patients. After adjusting for medical diseases, depressive disorder and anxiety disorder was positively associated with receiving IFN therapy. Patients with schizophrenia, bipolar disorders and alcohol use disorders were significantly less likely to receive interferon. Antidepressant exposure (cumulative daily exposure or cumulative daily dose) was associated with lower odds of IFN treatment. CONCLUSION: Our nationwide cohort study demonstrated that INF nontreatment rate was lower in certain mental disorders. Antidepressant exposure might lower the chance of receiving IFN treatment. Our results may help to identify and to overcome the obstacles for HCV treatment and further apply to DAAs regimen.

The association between cigarette smoking and obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) is a serious sleep disorder characterized by repetitive episodes of paused or shallow breathing during sleep. Patients with OSA often have excessive daytime sleepiness. The role of cigarette smoking in OSA remains controversial. The aim of this study was to examine the relationship between cigarette smoking and OSA. METHODS: In this retrospective chart review, we reviewed 18-month sleep laboratory charts in central Taiwan. We collected data regarding sleep, current cigarette smoking status, sex, age, body mass index (BMI), neck circumference, Epworth Sleepiness Scale score, and polysomnographic sleep parameters. In total, 733 subjects were recruited; among these, 151 were smokers and 582 were non-smokers. RESULTS: Smokers had significantly higher apnea-hypopnea index (p<0.001) for non-rapid eye movement sleep stage, higher apnea-hypopnea index (p<0.001) for total sleep time, and higher snore frequency (p<0.001) in t-test analysis. They also demonstrated higher Epworth Sleepiness Scale scores, shorter sleep times, lower percentage of slow-wave (deep) sleep, and longer snore times. However, no significant association was found between cigarette smoking and OSA after adjusting for sex, age, and BMI (OR=1.02, 95% CI: 0.66-1.57). CONCLUSIONS: We did not find any significant association between cigarette smoking and OSA after adjusting for age, sex, and BMI. Further well-designed prospective controlled cohort studies might clarify the relationship between cigarette smoking and OSA.

Antidepressant use and hepatocellular carcinoma in patients with hepatitis C who had received interferon therapy: A population-based cohort study.

BACKGROUND: Using data from the National Health Insurance (NHI) of Taiwan, we conducted a nationwide population-based cohort study to investigate the association between antidepressant (ATD) use and the risk of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) who had received interferon (IFN) therapy. METHODS: This study included a total of 274,952 HCV-infected patients without hepatitis B virus infection who were enrolled in the NHI program between January 1, 1997 and December 31, 2013. Among these patients, only 10,713 (age ≥18 years) had received IFN therapy between 2004 and 2008. Among the patients who had received IFN therapy, 2014 had received ATDs, and 8684 had not. A Cox proportional hazards regression model was applied after adjusting for age, sex, income, urbanization, medical comorbidity, and medication use. RESULTS: Compared with non-ATD-treated patients, ATD-treated patients were more likely to receive a diagnosis of alcohol-related disease, diabetes mellitus (DM), hypertension, and hyperlipidemia. ATD-treated patients had a significantly lower incidence of HCC than non-ATD-treated patients (P = 0.0019). Female, older (age ≥50 years), and non-DM patients who had received cumulative high doses of ATDs had a significantly lower risk of HCC than non-ATD-treated patients. After adjustment, only high-dose selective serotonin reuptake inhibitor (SSRI) use was inversely associated with HCC risk (adjusted hazard ratio 0.37, 95% confidence interval 0.19-0.71, P = 0.0027). CONCLUSIONS: Our study showed that ATD use, especially a relatively high cumulative dose of SSRIs, in HCV-infected patients who had received IFN was associated with reduced HCC risk. Future clinical studies are warranted to explore the underlying mechanisms and to apply them to newer direct-acting antiviral agent treatments.