Risk evaluation of diabetic ketoacidosis associated with antipsychotics among patients with schizophrenia in the Japanese adverse event report database.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a serious life-threatening condition and can be associated with antipsychotic medication. Asian patients with diabetes exhibit less insulin resistance than Caucasians; however, all previous studies concerning antipsychotic-related DKA have been conducted in Western populations. We analyzed the rank order of the association of antipsychotic agents for schizophrenia with DKA using the Japanese Adverse Drug Event Report database, a spontaneous reporting system database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and March 2021. The study population comprised 7435 patients with schizophrenia, and the total number of antipsychotic-related DKA reports was 55. RESULTS: Among the 55 cases of DKA in patients with schizophrenia, 6% (3/55) patients died after DKA. The signals of DKA were reported after treatment with olanzapine, with a significant adjusted reporting odds ratio (95% CI) of 3.26 (1.87-5.66). In 1399 olanzapine treatment cases, multivariable logistic regression analysis using a forward selection method showed that being male (adjusted RORs 2.72 (1.07-6.90)) was associated with the onset of DKA. CONCLUSION: Our study revealed that treatment with olanzapine was associated with the development of DKA among patients with schizophrenia. The results also clarified that male patients were at higher risk for DKA among patients treated with olanzapine. The application of these data will aid in risk monitoring and management that may reduce the occurrence of antipsychotic-related DKA in treatment for schizophrenia.

Effects of age on suicide attempts by medication in patients transferred to the emergency rooms of two advanced medical centers: A retrospective chart review of the DJ project.

AIMS: The means of suicide vary, but in cases of impaired consciousness, it is often difficult to determine the initial treatment because it is not known whether a patient has overdosed or used pesticides or poisons. Therefore, we investigated the clinical characteristics of suicide by medication in patients with suicide attempts who were brought to the emergency department, especially the influence of age. METHODS: Patients with suicide attempts were transported to the two hospitals. There were 96 males (38.4%) and 154 females (61.6%). The mean age was 43.5 ± 20 years, and both males and females were most often in their 20s. Data on sex, age, motive for suicide, means of suicide attempt, psychiatric diagnosis, length of hospital stay, and place of discharge were retrospectively analyzed. RESULTS: The average age of the patients by means of suicide attempt was 40.5 years for "prescription drugs," 30.2 years for "over-the-counter drugs," and 63.5 years for "pesticide/poison." For each means of suicide attempt, there was a significant difference in age among patients with suicide attempts using "prescription drugs," "over-the-counter drugs" and "pesticides/poisons." There was a statistical bias in the means and reasons for each suicide attempt. CONCLUSION: The results showed that the age of patients who used over-the-counter medicines and pesticides and poisons varied significantly. It was thought that pesticide use should be considered first, especially when patients aged 50 years and over are brought to the hospital with impaired consciousness due to suicide attempts.

Survey of Health Literacy Among Japanese Outpatients with Mental Illness.

Purpose: Low health literacy has been associated with adverse outcomes in health maintenance and the course of chronic physical illness. In particular, anxiety disorders can also affect one's physical health, causing issues including cardiovascular, respiratory, gastrointestinal and immune system disorders. However, there are no reports on physical health literacy among Japanese patients with mental illness. Patients and Methods: A patient background questionnaire, the Japanese version of the Ten-Item Personality Inventory, and the Japanese version of the Health Literacy Scale (HLS-EU-Q47; European Health Literacy Survey Questionnaire) were distributed face to face to 1000 psychiatric outpatients. A total of 785 valid responses including 211 patients with schizophrenia, 261 patients with mood disorders, and 234 patients with anxiety disorders were obtained by mail. Results: Health literacy was "limited" in 52% of patients with schizophrenia, 51% of those with mood disorders, and 38% of those with anxiety disorders. Among patients with mood disorders, there were no differences between those with major depressive disorder and those with bipolar disorder. Anxiety disorders were associated with higher health literacy than schizophrenia and mood disorders (odds ratio (OR) 1.85, 95% confidence interval (95% CI) 1.07, 3.34), and in terms of personality, neuroticism (OR 0.85, 95% CI 0.75, 0.97) and openness (OR 0.85, 95% CI 0.74, 0.98) were associated with limited health literacy, while agreeableness (OR 1.36, 95% CI 1.18, 1.57) and extraversion OR 1.34, 95% CI 1.17, 1.52) were associated with higher health literacy. Conclusion: The results of this study indicate limited health literacy in patients with mental illness, in particular, limited health literacy in outpatients with schizophrenia and mood disorders. In addition, gender and some personality traits were associated with physical health literacy. Based on these results, physical health education should be individualized.

Item response theory analysis of the University Personality Inventory in medical students.

AIM: Young adulthood has been recognized as an important period for the transition from adolescence to adulthood. The University Personality Inventory (UPI), a mental health questionnaire for young adulthood, is widely used to screen university students in East Asia. However, dichotomous systems do not allow respondent choose responses other than two options on each symptom. This study employed item response theory (IRT) to examine the properties and performance of UPI items for mental health problems. METHODS: Japanese medical students (n = 1185) participated in this study, and the UPI was completed at the time of university admission. The two-parameter IRT model was used to assess the measurement characteristics of the UPI items. RESULTS: Among all participants, 35.4% (420/1185) had total UPI score of 21 or more, and 10.6% (126/1185) indicated that they had the idea of wanting to die (item 25). For further IRT analysis, unidimensionality was confirmed by exploratory factor analysis, in which the primary factor accounted for 39.6% of the variance. The scale has sufficient discrimination power. In the test characteristic curves, the rising slopes of the lines were between θ 0 and 2. CONCLUSION: The UPI is useful to assess mild or moderate mental health problems, while precision may decline among individuals experiencing both little and extremely high levels of stress. Our findings provide a basis for identifying people who have mental health concerns.

[Drug Interactions in Neurology and Psychiatry].

Among drug-drug interactions, pharmacokinetic drug interactions are those in which multiple drugs interact to produce fluctuations in their blood concentrations, and mainly involve drug-metabolizing enzymes (cytochrome P450, UDP-glucuronyltransferase) and drug transporters (P-glycoprotein, etc.). The risk of drug interactions along with an increase in the number of drugs being used simultaneously; therefore, it is important to know the mechanisms of drug interactions, and the drugs to be wary of, as well as to make efforts to reduce the number of drugs used as much as possible.

A case of panic attack developing after THC-O acetate inhalation using an e-cigarette device.

AIM: Tetrahydrocannabinol acetate (THC-O) is a cannabinoid-based product, and few medical studies have evaluated the effects of THC-O on humans. Recently, e-cigarettes have become popular among teenagers and young adults worldwide. However, there have been reports of people misusing this device as a delivery system for drugs of abuse. CASE PRESENTATION: We herein report a case of panic attack after THC-O inhalation using an e-cigarette device in an 18-year-old male with no history of psychiatric disorders. Although he started smoking both regular cigarettes and e-cigarettes in junior high school, he had never vaped delta-9 THC or THC-O until the present episode. A total of 20 min after his first inhalation of THC-O, he experienced a sudden attack that lasted 2 h. After this episode, he did not inhale THC-O. Throughout the subsequent 6 months of follow-up, he maintained improvement with no panic attacks. CONCLUSION: In this case, we intend to emphasize that THC-O is not safe, even if the substance is regarded as loophole drug. The use of e-cigarette devices might accelerate substance abuse.

Prescribing Trends for the Same Patients with Schizophrenia Over 20 Years.

Background: Recent pharmacoepidemiology data show an increase in the proportion of patients receiving second-generation antipsychotic (SGA) monotherapy, but no studies have analyzed the same patients over a long period of time. Therefore, in this study, we retrospectively evaluated schizophrenia patients with available data for 20 years to determine whether the drug treatments in the same patients have changed in the past 20 years. Methods: The study began in April 2021 and was conducted in 15 psychiatric hospitals in Japan. Schizophrenia patients treated in the same hospital for 20 years were retrospectively examined for all prescriptions in 2016, 2011, 2006, and 2001 (ie, every 5 years). Results: The mean age of the 716 patients surveyed in 2021 was 61.7 years, with 49.0% being female. The rate of antipsychotic monotherapy use showed a slight increasing trend over the past 20 years; the rate of SGA use showed a marked increasing trend from 28.9% to 70.3% over the past 20 years, while the rate of SGA monotherapy use showed a gradual increasing trend over the past 20 years. The rates of concomitant use of anticholinergics, antidepressants, anxiolytics/sleep medications, and mood stabilizers showed decreasing, flat, flat, and flat trends over the past 20 years, respectively. Conclusion: The results of this study showed a slow but steady substitution of SGAs for first-generation antipsychotics (FGAs) over time, even in the same patients.

Predictors of psychiatric hospitalization among outpatients with bipolar disorder in the real-world clinical setting.

Background: Bipolar disorder is a psychiatric disorder that causes recurrent manic and depressive episodes, leading to decreased levels of social functioning and suicide. Patients who require hospitalization due to exacerbation of bipolar disorder have been reported to subsequently have poor psychosocial functioning, and so there is a need to prevent hospitalization. On the other hand, there is a lack of evidence regarding predictors of hospitalization in real-world clinical practice. Methods: The multicenter treatment survey on bipolar disorder (MUSUBI) in Japanese psychiatric clinics was an observational study conducted to provide evidence regarding bipolar disorder in real-world clinical practice. Psychiatrists were asked, as part of a retrospective medical record survey, to fill out a questionnaire about patients with bipolar disorder who visited 176 member clinics of the Japanese Association of Neuro-Psychiatric Clinics. Our study extracted baseline patient characteristics from records dated between September and October 2016, including comorbidities, mental status, duration of treatment, Global Assessment of Functioning (GAF) score, and pharmacological treatment details. The incidence and predictors of hospitalization among patients with bipolar disorder over a 1-year period extending from that baseline to September-October 2017 were examined. Results: In total, 2,389 participants were included in our study, 3.06% of whom experienced psychiatric hospitalization over the course of 1 year from baseline. Binomial logistic regression analysis revealed that the presence of psychiatric hospitalization was correlated with bipolar I disorder, lower baseline GAF scores, unemployment, substance abuse and manic state. Conclusions: Our study revealed that 3.06% of outpatients with bipolar disorder were subjected to psychiatric hospitalization during a 1-year period that extended to September-October 2017. Our study suggested that bipolar I disorder, lower baseline GAF scores, unemployment, substance abuse and baseline mood state could be predictors of psychiatric hospitalization. These results may be useful for clinicians seeking to prevent psychiatric hospitalization for bipolar disorder.

The relationship of stress coping styles on substance use, depressive symptoms, and personality traits of nurses in higher education institution.

AIM: This study examined the collective characteristics of nurses and their stress coping style. METHODS: We conducted a cluster analysis of the stress coping strategies of 841 nurses belonging to Dokkyo Medical University Hospital, as measured by the Brief COPE (Coping Orientation to Problems Experienced). We also conducted multivariate analyses of each cluster's sociodemographic characteristics, personality traits, depressive symptoms, work attitudes, sense of fairness, and turnover intention. RESULTS: The results of cluster analysis using the standardized z scores of the Brief COPE demonstrated that the study participants were classified into three clusters. The "emotional-response type" tended to favor the use of emotional support, venting, and self-blame. The "reality-escape type" tended to prefer alcohol and substance use, behavioral resignation, use of instrumental support, and lack of acceptance. The "problem-solving type" tended to prefer planning, positive reframing, and acceptance and to dislike "alcohol and substance use" and behavioral disengagement. A multinomial logistic regression analysis revealed that compared to the problem-solving type, the emotional-response type had a lower job title, a higher "neuroticism" score on the TIPI-J, and a higher K6 score. However, compared to the problem-solving type, the reality-escape type was younger, consumed more alcohol and substances, and had a higher K6 score. CONCLUSIONS: Stress coping styles were found to be associated with substance use, depressive symptoms, and personality traits among nurses in higher education institutions. Thus, the results suggest that nurses who choose maladaptive stress coping styles require mental support and early identification of depressive symptoms and alcohol problems.

A case of musical hallucinations induced by tramadol.

AIM: Although tramadol has been suggested to have a higher risk of producing hallucinations than other opioids, reports of musical hallucinations are extremely rare. CASE PRESENTATION: A 72-year-old woman came to our department complaining of auditory hallucinations. She had been diagnosed with lumbar spinal canal stenosis associated with herniated and slipped disks. Due to persistent back pain, tramadol was started, and the dose was increased to 300 mg/day. The next day, she began to hear nursery rhymes, songs of the Ministry of Education, and folk songs. The musical auditory hallucinations disappeared with the use of antipsychotics and the discontinuation of tramadol. No relapse of musical auditory hallucinations was observed after the discontinuation of antipsychotics. CONCLUSION: Based on the clinical course, we concluded that the auditory hallucinations were musical hallucinations induced by tramadol.

Development and validation of the Japanese version of EPDS-P for indirect screening of paternal perinatal depression based on maternal reporting: Protocol for a prospective longitudinal observational study.

AIMS: The main purpose of this study is to develop an indirect screening system for paternal perinatal depression based on the female partner's assessment in the Japanese population. The Japanese version of the Edinburgh Postnatal Depression Scale-Partner (EPDS-P) will be used as the indirect screening tool, and its accuracy will be studied in this longitudinal prospective observational study. METHODS: Public health nurses and midwives at the participating community health center are currently inviting couples to participate, and are distributing self-rating scales to the participants. The primary evaluation scales being used in this study are the Japanese versions of the Center for Epidemiologic Studies Depression Scale (CES-D) and the Japanese version of the EPDS-P which evaluates paternal perinatal depression by women. We will evaluate EPDS-P performance against CES-D, including accuracy, sensitivity, specificity, and correlations. RESULTS AND CONCLUSIONS: Perinatal depression is a mental illness that occurs between pregnancy and postpartum within the 12 months, and it is known to increase the risk of adversely impacting on child development. Men may also experience a psychosocial crisis during their partners' perinatal period. Although it was recently reported that the EPDS-P can indirectly detect paternal perinatal depression, there is, as yet, insufficient evidence of this because the previous studies had relatively small sample sizes and were limited to cross-sectional studies in the postpartum period. The development of a screening system for paternal perinatal depression using the EPDS-P will lead to increased awareness of the disease and provide an opportunity to establish a family-based support system in Japan.

Effect of antipsychotic use by patients with schizophrenia on deceleration capacity and its relation to the corrected QT interval.

OBJECTIVE: Schizophrenia patients treated with antipsychotics are at higher risk of sudden cardiac death. Decreased deceleration capacity (DC) of the heart rate is an accurate predictor of cardiac mortality. We evaluated the risk of sudden cardiac death due to antipsychotic use by assessing DC and examining the association between DC and the corrected QT interval (QTc) in schizophrenia patients. METHODS: We measured the DC and QTc of 138 schizophrenia patients. We then compared the DC of 86 age- and sex-matched healthy controls with that of 86 schizophrenia patients. We investigated the correlation of DC of approximately 138 schizophrenia patients with prescribed doses of antipsychotics using linear regression analysis. We compared the DC of schizophrenia patients with and without prolonged QT intervals. RESULTS: We found DC significantly differed between schizophrenia patients on antipsychotic medication and healthy controls. Additionally, DC was negatively correlated with antipsychotic use, especially chlorpromazine, zotepine, olanzapine and clozapine, in a dose-dependent manner. There was no significant association between DC and the QTc. CONCLUSION: Assessing DC could facilitate monitoring and identification of increased risk of cardiac mortality in patients with schizophrenia that take antipsychotics. Assessing both DC and the QTc may enhance the accuracy of predicting sudden cardiac death.

Predictors of psychological distress and sleep deprivation in caregivers of stroke survivors.

BACKGROUND: Caregivers for stroke survivors (CSS) suffer from long hours of care, limited support, and financial difficulties, which often affect their mental health. OBJECTIVES: This study sought to determine the factors affecting psychological distress and sleep duration among CSS. METHODS: We analyzed cross-sectional data from the 2013 Comprehensive Survey of the Living Conditions for Stroke Survivors and CSS. Linked data from 841 pairs of stroke survivors and CSS were extracted. Kessler's Psychological Distress scale (K6) was used to evaluate psychological distress. CSS who slept less than 5 hours per day were classified as having short sleep duration. Factors predictive of psychological distress and short sleep duration were evaluated using multivariable logistic regression analysis with the forward selection method. RESULTS: The mean (SD) age of the CSS was 65.4 (12.5) years. A total of 5.6% of these caregivers presented with serious psychological distress, and 12.0% were sleep deprived. Serious psychological distress was associated with not having someone to consult with, having subjective symptoms within a few days, and having short sleep duration, while having their own houses reduced the risk of serious psychological distress. Furthermore, short sleep duration was associated with stroke survivors in long-term care levels 4 or 5, not having someone to consult with, participation in sponge baths as part of nursing care activities, and having serious psychological distress. CONCLUSIONS: This nationwide survey identified several risk factors for psychological stress and sleep deprivation among CSS and suggests the need for multidimensional approaches to reduce their distress.

Effect of age and sex on prescriptions for outpatients with bipolar disorder in the MUSUBI study: a cross­sectional study.

BACKGROUND: Childbearing-aged female patients and elderly patients with bipolar disorder need special attention for pharmacological treatments, but current guidelines provide little information on their pharmacological treatment. In particular, the risk/benefit balance of pharmacological treatment for childbearing-aged females with bipolar disorder is a growing concern. Therefore, we aimed to address the effect of age and sex on psychotropic drug prescription for outpatients with bipolar disorder. METHODS: The MUlticenter treatment SUrvey for BIpolar disorder in Japanese psychiatric clinics (MUSUBI) study was conducted, and data on age, sex, and details of pharmacological treatment were collected. RESULTS: A total of 3106 outpatients were included in this study. Among young females (age ≤ 39), 25% were prescribed valproate. There was no significant difference in the frequency and daily dose of valproate prescription for young females among all groups. Valproate prescriptions were significantly less frequent among young males and more frequent among middle-aged males. Lithium prescriptions were significantly less frequent among young females and more frequent among older males (age ≥ 65) and older females. Lamotrigine prescriptions were significantly more frequent among young males and young females and less frequent among older males and older females. Carbamazepine prescriptions were significantly less frequent among young males and more frequent among older males. CONCLUSIONS: Biased information about the risk and safety of valproate and lithium for young females was suggested, and further study to correct this bias is needed. Older patients were prescribed lithium more commonly than lamotrigine. Further studies are needed to determine the actual pharmacotherapy for elderly individuals.

HomotopicLI: Rationale, characteristics, and implications of a new threshold-free lateralization index of functional magnetic resonance imaging.

The reliable preoperative estimation of brain hemispheric asymmetry may be achieved through multiple lateralization indices using functional magnetic resonance imaging. Adding to our previously developed AveLI, we devised a novel threshold-free lateralization index, HomotopicLI, which computes a basic formula, (Left - Right) / (Left + Right), using voxel values of pairs located symmetrically in relation to the midsagittal line as the terms Left and Right, and averages them within the regions-of-interest. The study aimed to evaluate HomotopicLI before clinical applications. Data were collected from 56 healthy participants who performed four language tasks. We compared seven index types, including HomotopicLI, AveLI, and BaseLI; BaseLI was calculated using the sums of voxel values as the terms. Contrary to our expectations, HomotopicLI performed similarly to AveLI but better than BaseLI in detecting right dominance. A detailed analysis of unilaterally activated voxels of the homotopic pairs revealed that unilateral activation occurred more frequently on the right than on the left when HomotopicLI indicated right dominance. The voxel values during right unilateral activation were smaller than those in the left, causing right dominances in the homotopic pairs by HomotopicLI. These unique features provide an advantage in detecting residual, compensative functions spreading weakly in the non-dominant hemisphere.

Blood Levels of Ammonia and Carnitine in Patients Treated with Valproic Acid: A Meta-analysis.

Objective: Long-term valproic acid (VPA) administration is associated with adverse metabolic effects, including hyperammonemia and hypocarnitinemia. However, the pathogeneses of these adverse events remain unclear, and not enough reviews have been performed. The aim of this study was to conduct a meta-analysis of studies examining blood levels of ammonia and carnitine in patients treated with VPA. Methods: We conducted database searches (PubMed, Web of Science) to identify studies examining blood levels of ammonia and carnitine in patients treated with VPA. A meta-analysis was performed to conduct pre- and post-VPA treatment comparisons, cross-sectional comparisons between groups with and without VPA use, and estimations of the standardized correlations between blood levels of ammonia, carnitine, and VPA. Results: According to the cross-sectional comparisons, the blood ammonia level in the VPA group was significantly higher than that in the non-VPA group. Compared to that in the non-VPA group, the blood carnitine level in the VPA group was significantly lower. In the meta-analysis of correlation coefficients, the blood VPA level was moderately correlated with blood ammonia and blood free carnitine levels in the random effects model. Furthermore, the blood ammonia level was moderately correlated with the blood free carnitine level. Conclusion: Although the correlation between ammonia and free carnitine levels in blood was significant, the moderate strength of the correlation does not allow clinicians to infer free carnitine levels from the results of ammonia levels. Clinicians should measure both blood ammonia and free carnitine levels, especially in patients receiving high dosages of VPA.

A case of mood disorder with severe side effects of antidepressants in association with resistance to thyroid hormone beta with a THRB mutation.

BACKGROUND: Although resistance to thyroid hormone beta (RTHß) is associated with attention-deficit/hyperactivity disorder, there are few reports of other concomitant mood disorders in individuals with RTHß. CASE PRESENTATION: A 67-year-old woman who had been previously diagnosed with RTHß (Refetoff syndrome) came to our department as a depressed patient. She was hospitalized twice for depression and treated with antidepressants both times. Paroxetine (37.5 mg/day) treatment during the first hospitalization did not cause any side effects, but treatment with mirtazapine (15 mg/day) and venlafaxine (150 mg/day) during the second hospitalization caused clonus and disturbance of consciousness, and these adverse effects resulted in a prolonged period of hospitalization. Finally, the patient's symptoms were controlled with quetiapine (75 mg/day). CONCLUSION: Poor tolerability to antidepressants was observed, which may be related to thyroid hormone intolerance. Low doses of quetiapine may contribute to improvements in depression.

Asymptomatic syndrome of inappropriate secretion of antidiuretic hormone (SIADH) following duloxetine treatment for pain with depression: Two case reports.

BACKGROUND: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a common side effect in patients treated with SSRIs and venlafaxine, while there is little information on SIADH in the treatment of duloxetine for pain. CASE PRESENTATION: The patients were an 83-year-old Japanese male and a 71-year-old Japanese female. Several years earlier, they complained of pain. Accidentally, blood tests revealed hyponatremia of 110 mmol/L and 108 mmol/L 35 days and 40 days after initiating duloxetine 20 mg/day, respectively. The hyponatremia of both patients recovered after switching from duloxetine to mianserin. CONCLUSION: We conclude that asymptomatic SIADH was induced by use of duloxetine. Psychiatrists should be aware of this syndrome.