Pharmacoepidemiology and Clinical Correlates of Lithium Treatment for Bipolar Disorder in Asia.

BACKGROUND: As clinical practices with lithium salts for patients diagnosed with bipolar disorder (BD) are poorly documented in Asia, we studied the prevalence and clinical correlates of lithium use there to support international comparisons. METHODS: We conducted a cross-sectional study of use and dosing of lithium salts for BD patients across 13 Asian sites and evaluated bivariate relationships of lithium treatment with clinical correlates followed by multivariate logistic regression modeling. RESULTS: In a total of 2139 BD participants (52.3% women) of mean age 42.4 years, lithium salts were prescribed in 27.3% of cases overall, varying among regions from 3.20% to 59.5%. Associated with lithium treatment were male sex, presence of euthymia or mild depression, and a history of seasonal mood change. Other mood stabilizers usually were given with lithium, often at relatively high doses. Lithium use was associated with newly emerging and dose-dependent risk of tremors as well as risk of hypothyroidism. We found no significant differences in rates of clinical remission or of suicidal behavior if treatment included lithium or not. CONCLUSIONS: Study findings clarify current prevalence, dosing, and clinical correlates of lithium treatment for BD in Asia. This information should support clinical decision-making regarding treatment of BD patients and international comparisons of therapeutic practices.

Clozapine Use for Bipolar Disorder: An Asian Psychotropic Prescription Patterns Consortium Study.

BACKGROUND: Pharmacoepidemiological studies of clozapine use to treat bipolar disorder (BD), especially in Asia, are rare, although they can provide insights into associated clinical characteristics and support international comparisons of indications and drug dosing. METHODS: We examined the prevalence and clinical correlates of clozapine treatment for BD in 13 Asian countries and regions (China, Hong Kong SAR, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, and Thailand) within an Asian Prescription Patterns Research Consortium. We compared BD patients treated with clozapine or not in initial bivariate comparisons followed by multivariable logistic regression modeling. RESULTS: Clozapine was given to 2.13% of BD patients overall, at a mean daily dose of 275 (confidence interval, 267-282) chlorpromazine-equivalent mg/day. Patients receiving clozapine were older, more likely males, hospitalized, currently manic, and given greater numbers of mood-stabilizing and antipsychotic drugs in addition to clozapine. Logistic regression revealed that older age, male sex, current mania, and greater number of other antipsychotics remained significantly associated with clozapine treatment. Clozapine use was not associated with depressed mood, remission of illness, suicidal risk, or electroconvulsive treatment within the previous 12 months. CONCLUSIONS: The identified associations of clozapine use with particular clinical features call for vigilance in personalized clinical monitoring so as to optimize clinical outcomes of BD patients and to limit risks of adverse effects of polytherapy.

Psychological dominant stressor modification to an animal model of depression with chronic unpredictable mild stress.

Background and Aim: Chronic unpredictable mild stress (CUMS) is a protocol widely used to create an animal model of depression with food deprivation, water deprivation, and physical-dominant stressors as routine procedures. However, human depression mainly involves psychological stressors and does not always involve a lack of food and water; thus, CUMS procedures should be modified accordingly. Therefore, this study aimed to create an animal model of depression, mainly focusing on a psychologically dominant stressor without food and water deprivation. Materials and Methods: The CUMS and control groups, respectively, received CUMS modification (psychologically dominant stressors without food and water deprivation) for 21 days. A 24-h sucrose preference test (SPT) was used to assess the successful creation of an animal model of depression. Daily food intake measurements, weekly weight monitoring, and weight gain calculations were performed. Either an independent sample t-test or the Mann-Whitney test was used. Results: Of the 42 rats included, 39 completed the study. Chronic unpredictable mild stress procedures for 21 days significantly reduced the SPT (p < 0.05), mean body weight (p < 0.05), and weekly weight gain (p < 0.05) in the CUMS group compared to the control group. However, the weekly average food intake did not statistically differ between the two groups. Conclusion: Psychological dominant CUMS modification to an animal model of depression resulted in lower SPT, body weight, and weekly weight gain in the CUMS group than in the control group.

The factor structure of extrapyramidal symptoms evaluated using the Drug-Induced Extrapyramidal Symptoms Scale in patients with schizophrenia: Results from the 2016 REAP AP-4 study.

INTRODUCTION: Drug-induced extrapyramidal syndrome (EPS) remains a major problem in clinical psychiatry. This study aimed to examine the factor structure of drug-induced extrapyramidal symptoms observed in patients with schizophrenia and assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). METHODS: The participants were 1478 patients with a diagnosis of schizophrenia whose EPS was assessed using the DIEPSS in India, Indonesia, Japan, Malaysia, and Taiwan in the 2016 REAP AP-4 study. The records of the participants were randomly divided into two subgroups: the first for exploratory factor analysis of the eight DIEPSS items, and the second for confirmatory factor analysis. RESULTS: The factor analysis identified three factors: F1 (gait and bradykinesia), F2 (muscle rigidity and tremor), and F3 (sialorrhea, akathisia, dystonia, and dyskinesia). CONCLUSION: The results suggest that the eight individual items of the DIEPSS could be composed of three different mechanisms: acute parkinsonism observed during action (F1), acute parkinsonism observed at rest (F2), and central dopaminergic mechanisms with pathophysiology other than acute parkinsonism (F3).

A Southeast Asia Consensus on the Definition and Management of Treatment-Resistant Depression.

Introduction: Despite the abundance of literature on treatment-resistant depression (TRD), there is no universally accepted definition of TRD and available treatment pathways for the management of TRD vary across the Southeast Asia (SEA) region, highlighting the need for a uniform definition and treatment principles to optimize the management TRD in SEA. Methods: Following a thematic literature review and pre-meeting survey, a SEA expert panel comprising 13 psychiatrists with clinical experience in managing patients with TRD convened and utilized the RAND/UCLA Appropriateness Method to develop consensus-based recommendations on the appropriate definition of TRD and principles for its management. Results: The expert panel agreed that "pharmacotherapy-resistant depression" (PRD) is a more suitable term for TRD and defined it as "failure of two drug treatments of adequate doses, for 4-8 weeks duration with adequate adherence, during a major depressive episode". A stepwise treatment approach should be employed for the management of PRD - treatment strategies can include maximizing dose, switching to a different class, and augmenting or combining treatments. Non-pharmacological treatments, such as electroconvulsive therapy and repetitive transcranial magnetic stimulation, are also appropriate options for patients with PRD. Conclusion: These consensus recommendations on the operational definition of PRD and treatment principles for its management can be adapted to local contexts in the SEA countries but should not replace clinical judgement. Individual circumstances and benefit-risk balance should be carefully considered while determining the most appropriate treatment option for patients with PRD.

Dosing of Mood Stabilizers for Bipolar Disorder Patients in the Research on Asian Psychotropic Prescription Patterns Consortium Study.

BACKGROUND: Because use and dosing of mood stabilizers (MSs) to treat bipolar disorder (BD) patients in Asia are not well documented, we examined prevalence and clinical correlates of treatment of Asian BD patients with relatively high doses of MSs. METHODS: We conducted a pharmacoepidemiological survey across 13 Asian countries and territory in the Research on Asian Psychotropic Prescription Patterns Consortium. Mood stabilizer doses were converted to lithium carbonate equivalents (Li-eq milligrams per day). We compared relatively high (>900 Li-eq mg/day) versus lower MS doses by bivariate comparisons, followed by multivariable linear regression to identify factors associated with higher MS doses. RESULTS: Among 1647 participants, MS dose averaged 584 (confidence interval, 565-603 Li-eq mg/d). Preliminarily, the 13.1% of the subjects given greater than 900 mg/d versus those given lower doses were younger, male, currently hospitalized, not currently depressed, and reported lifetime suicidal ideation; they also received relatively high doses of antipsychotics, received electroconvulsive treatment within the previous 12 months, and had greater ratings of tremors and sedation. By linear regression modeling, the mean proportion given high doses of MS was associated significantly and independently with higher doses of antipsychotics, younger age, male sex, hospitalized, more years of illness, country, higher body mass index, recent electroconvulsive treatment, and being in illness remission. CONCLUSIONS: Relatively high doses of MSs for BD are prevalent, but vary markedly among Asian countries, and are particularly likely among young males, ill for many years, and given high doses of antipsychotics or ECT. These characteristics allow better identification of patient profiles that can guide treatment of BD patients.

The biopsychosocial-spiritual factors influencing relapse of patients with schizophrenia.

OBJECTIVE: High relapse rate of patients with schizophrenia has a large impact on patients and their families that can be reviewed from biopsychosocial and spiritual factors. Determining all the potential risk factors of relapse in schizophrenia can help increase awareness of physicians, patients, and families. Physicians are the ones who examine patients and have responsibility to manage and educate them and expect to prevent relaps. This study analyze various biopsychosocial and spiritual factors affecting relapse occurrence in patients with schizophrenia. METHODS: Cross sectional observational analytic study on 226 subjects with schizophrenia in three places in East Java, Indonesia, namely Soetomo Academic Hospital Surabaya (33.2%), Menur Hospital Surabaya (32.7%), and Radjiman Wediodiningrat Mental Hospital Lawang (34.1%) that met the inclusion and exclusion criteria. Data collection including 33 biopsychosocial and spiritual factors and were analyzed using bivariate and multivariate logistic regression. RESULTS: Relapse rate within 1 year was 59.73%. There were 12 factors significantly affected the relapse of schizophrenia, namely history of physical disease of mothers during pregnancy (p < .001; B = 27.31; 95% CI 3.96-188.52), presence of trigger (p < .000; B = 6.25; 95% CI 2.61-14.96), negative beliefs (p < .000; B = 4.94; 95% CI 2.10-11.61), hereditary factors (p < .001; B = 4.84; 95% CI 1.93-12.10), insight (p < .003; B = 4.27; 95% CI 1.62-11.27), 1-year GAF Scale (p < .015; B = 3.79; 95% CI 1.30-11.09), response to treatment (p < .006; B = 3.68; 95% CI 1.45-9.36), family knowledge (p < .011; B = 3.23; 95% CI 1.31-7.93), history of head trauma (p < .029; B = 3.13; 95% CI 1.13-8.69), medication side effects (p < .028; B = 2.92; 95% CI 1.12-7.61), substance use history (p < .031; B = 2.86; 95% CI 1.10-7.45), and occupation (p < .040; B = 2.40; 95% CI 1.04-5.52). CONCLUSIONS: The 12 factors of biopsychosocial-spiritual are determinant to predict the risk of relapse in patients with schizophrenia. These factors should be emphasized in psychoeducation for patients and their families to enable intervention and relapse prevention.

Effects of Playing Angklung and Practicing Silence on Emotion, Cognition and Oxytocin Levels in Children: A Preliminary Study.

BACKGROUND: Playing angklung, an Indonesian traditional musical instrument and practicing silence have been shown to exert beneficial effects on emotion and cognition; the mechanism of such an effect possibly involve oxytocin. To date, only a few clinical and biomolecular studies have investigated the effects of playing angklung and practicing silence. This study aimed to examine the effects of playing angklung and practicing silence on human emotion and cognition and on oxytocin levels. METHODS: This experimental study involved 61 Fourth Grade students from Surabaya, East Java, Indonesia. The participants were divided into two groups: the angklung intervention group and silence intervention group. The two interventions were performed for 15 min before the morning classes for 2 months. The control group attended their classes as usual. Clinical parameters, namely, emotion and cognition, as well as the saliva oxytocin levels were measured. RESULTS: No significant differences were observed among the three groups in terms of concentration and cognitive flexibility. However, changes in oxytocin levels significantly differed among the three groups (P < 0.001) and the oxytocin levels were highest in the silence intervention group. CONCLUSION: Practicing silence significantly increased the oxytocin levels, but it did not elicit changes in cognitive function and emotion of the students.

Anxiety and Resilience of Healthcare Workers During COVID-19 Pandemic in Indonesia.

INTRODUCTION: The COVID-19 pandemic has an impact on the physical health and mental health of the community, including healthcare workers. Several studies have shown symptoms of depression, anxiety, and sleep disorders in healthcare workers during this pandemic. However, not many studies have examined the resilience of healthcare workers during this pandemic. Resilience is a person's ability to rise and adapt when times are difficult and is considered to have a protective effect on mental problems. PURPOSE: This study aims to determine the correlation between resilience and anxiety in healthcare workers during COVID-19 pandemic. MATERIALS AND METHODS: This research was a cross-sectional study with observational analytic methods. The respondents were healthcare workers at Dr. Soetomo Hospital as the COVID-19 referral hospital in Surabaya, East Java, Indonesia. Data were collected from 10 to 16 June 2020 by distributing online questionnaires through the Google form application. There were three questionnaires used: demographic data, the State-Trait Anxiety Inventory (STAI) questionnaire, and the Connor-Davidson Resilience Scale (CR-RISC) questionnaire. RESULTS: The 227 respondents had filled out the questionnaire online with 33% had high state anxiety and 26.9% had high trait anxiety. The mean score of the respondents' resilience was 69 ± 15.823. The Spearman correlation test showed a significant relationship between anxiety and resilience (p <0.05), both S-Anxiety and T-Anxiety. CONCLUSION: A significant correlation was found between the level of resilience and anxiety experienced by healthcare workers during the COVID-19 pandemic. The lower the resilience, the higher the anxiety experienced.

Impaired Cognitive Flexibility and Working Memory Precedes Depression: A Rat Model to Study Depression.

INTRODUCTION: Depressive disorders are the 4th leading cause of health problems and the 2nd leading cause of burden among all diseases. Almost all depressive disorder patients have cognitive impairments to a certain extend. Studies about cognitive impairments in depression had been conducted, but whether cognitive dysfunctions are the cause or the effect is still not clear. OBJECTIVES: To analyze the process of working memory and cognitive flexibility impairments in a rat model of depression. METHODS: In this experimental study, chronic unpredictable mild stress (CUMS) was used as a model of depression in 30 rats (Rattus novergicus). Cognitive function was assessed with the Morris water maze and attentional set shifting test. RESULTS: This study found a significant difference on day 21 in working memory (p = 0.002) and cognitive flexibility (p = 0.036), which continued to day 41 in working memory (p = 0.001) and cognitive flexibility (p = 0.020). In the CUMS model of depression, parameters peak on day 41 and reveal parameter changes in weight gain (p = 0.018), food intake (p < 0.001), changes in food intake (p = 0.001), and the sucrose preference (p = 0.005), elevated plus maze (p = 0.001), and light dark box tests (p = 0.020). CONCLUSION: In a rat model of depression, cognitive impairment preceded depression, but it might be caused by anxiety-like behavior that occurred in early stimulation of chronic unpredictable mild stress.

Depression screening in Surabaya Indonesia: Urgent need for better mental health care for high-risk communities and suicide prevention for men.

OBJECTIVES: Despite its high prevalence and considerable burden, depression is not handled with the required urgency in Indonesia. Existing data from the government does not specifically note its prevalence and symptoms manifestation. This study screened depression in Surabaya, where the prevalence of mood disorder was reported to be higher than the national prevalence, in order to identify where action is most needed. METHODS: Cross-sectional study with non-random sampling. Participants consisted of samples from general population categorised as non-high-risk group, and prisoners, sex workers and drug users categorised as high-risk group. Depression screening was done using MINI-ICD10 self-rated depression questionnaire. Correlation between screening results and demographic data was analysed using chi-square test. RESULTS: Positive depression screening was significantly associated with grouping and educational background. High-risk group and participants with lower education background had significantly higher number of positive screening. Significantly higher proportion of participants in the high-risk group experience eight of the ten depression symptoms regardless of screening results. Higher proportion of depression positive male participants experienced suicidal/self-harm symptom. LIMITATIONS: This study used non-random sampling method, therefore the results may not fully represent the general population. The screening instrument used did not account for depression and symptoms severity. CONCLUSION: High-risk group with low educational background is in most urgent need of mental health help, and suicide prevention strategy is most needed for men.

Concurrent antipsychotic use in older adults treated with antidepressants in Asia.

AIM: Depressive disorders are common in old age. Antipsychotics (APs) are often used as an adjunctive treatment with antidepressants (ADs) in this population but its patterns of use in Asia are not known. This study explored the rate of combination of APs and ADs in older adult psychiatric patients in Asia. METHODS: This is a secondary analysis of the database of a multicentre study which recorded participants' basic demographical and clinical data in standardised format in 10 Asian countries and territories. The data were analysed using univariate and multivariate logistic regression analyses. RESULTS: A total of 955 older adult psychiatric in- and outpatients were included in this study. The proportion of concurrent AP and AD use was 32.0%, ranging from 23.3% in Korea to 44.0% in Taiwan. Multivariate logistic regression analysis found that younger age, inpatient status and diagnosis of schizophrenia, anxiety and other mental disorders were significantly related to a higher proportion of concurrent use of APs and ADs. CONCLUSION: Around a third of older adult psychiatric patients had concurrent AP and AD use in the Asian countries/regions surveyed. Considering the uncertain effectiveness and questionable safety of the AP and AD combination in this patient population, such should be cautiously used.

Concurrent benzodiazepine use in older adults treated with antidepressants in Asia.

ABSTRACTBackground:Little is known about the combined use of benzodiazepines and antidepressants in older psychiatric patients. This study examined the prescription pattern of concurrent benzodiazepines in older adults treated with antidepressants in Asia, and explored its demographic and clinical correlates. METHODS: The data of 955 older adults with any type of psychiatric disorders were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Demographic and clinical characteristics were recorded using a standardized protocol and data collection procedure. Both univariate and multiple logistic regression analyses were performed. RESULTS: The proportion of benzodiazepine and antidepressant combination in this cohort was 44.3%. Multiple logistic regression analysis revealed that higher doses of antidepressants, younger age (<65 years), inpatients, public hospital, major comorbid medical conditions, antidepressant types, and country/territory were significantly associated with more frequent co-prescription of benzodiazepines and antidepressants. CONCLUSIONS: Nearly, half of the older adults treated with antidepressants in Asia are prescribed concurrent benzodiazepines. Given the potentially adverse effects of benzodiazepines, the rationale of benzodiazepines and antidepressants co-prescription needs to be revisited.

Physical comorbidities in older adults receiving antidepressants in Asia.

BACKGROUND: The present study explored the patterns of physical comorbidities and their associated demographic and clinical factors in older psychiatric patients prescribed with antidepressants in Asia. METHODS: Demographic and clinical information of 955 older adults were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Standardized data collection procedure was used to record demographic and clinical data. RESULTS: Proportion of physical comorbidities in this cohort was 44%. Multiple logistic regression analyses showed that older age (OR = 1.7, P < 0.001), higher number of depressive symptoms (OR = 1.09, P = 0.016), being treated in psychiatric hospital (OR = 0.5, P = 0.002), living in high income countries/territories (OR = 2.4, P = 0.002), use of benzodiazepines (OR = 1.4, P = 0.013) and diagnosis of 'other psychiatric disorders' (except mood, anxiety disorders and schizophrenia) (OR = 2.7, P < 0.001) were significantly associated with physical comorbidities. CONCLUSIONS: Physical comorbidities in older patients prescribed with antidepressants were common in Asia. Integrating physical care into the treatment of older psychiatric patients should be urgently considered.

A comparison of clinical characteristics of older adults treated with antidepressants in general and psychiatric hospitals in Asia.

AIM: This study compared the demographics, clinical characteristics, and antidepressant prescription patterns between Asian patients aged 50 years and older attending psychiatric hospitals and those attending general hospitals. METHODS: In total, 955 patients (604 in general hospitals, 351 in psychiatric hospitals) aged 50 years or older treated with antidepressants in 10 Asian countries and territories were examined. Patients' demographics, clinical features, and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. RESULTS: Binary logistic regression revealed that high income and diagnosis of schizophrenia were independently associated with psychiatric hospital treatment, whereas outpatient care, diagnosis of anxiety disorders, and multiple major medical conditions were independently associated with general hospital treatment. In addition, tetracyclic and noradrenergic and specific serotonergic antidepressants were more likely to be prescribed in general hospitals. CONCLUSION: Older adults treated with antidepressants showed different demographic and clinical features between general hospitals and psychiatric hospitals in Asia.

Clinical Use of Mood Stabilizers With Antidepressants in Asia: Report From the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) Projects in 2004 and 2013.

OBJECTIVE: As most reports concerning treatment with combinations of mood stabilizer (MS) with antidepressant (AD) drugs are based in the West, we surveyed characteristics of such cotreatment in 42 sites caring for the mentally ill in 10 Asian countries. METHODS: This cross-sectional, pharmacoepidemiologic study used 2004 and 2013 data from the REAP-AD (Research Study on Asian Psychotropic Prescription Patterns for Antidepressants) to evaluate the rates and doses of MSs given with ADs and associated factors in 4164 psychiatric patients, using standard bivariate methods followed by multivariable logistic regression modeling. RESULTS: Use of MS + AD increased by 104% (5.5% to 11.2%) between 2004 and 2013 and was much more associated with diagnosis of bipolar disorder than major depression or anxiety disorder, as well as with hospitalization > outpatient care, psychiatric > general-medical programs, and young age (all P < 0.001), but not with country, sex, or AD dose. CONCLUSIONS: The findings provide a broad picture of contemporary use of MSs with ADs in Asia, support predictions that such treatment increased in recent years, and was associated with diagnosis of bipolar disorder, treatment in inpatient and psychiatric settings, and younger age.

Suicidal thoughts/acts and clinical correlates in patients with depressive disorders in Asians: results from the REAP-AD study.

OBJECTIVE: Using data from the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study, we aimed to present the rates and clinical correlates of suicidal thoughts/acts in patients recruited from a total of 40 centres in 10 Asian countries/areas: China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand. METHODS: Data from 1122 patients with depressive disorders in the REAP-AD study were used. The ICD-10 was employed to diagnose depressive episodes and recurrent depressive disorder. The presence or absence of suicidal thoughts/acts and profile of other depressive symptoms was established using the National Institute for Health and Clinical Excellence guidelines for depression. Country/area differences in rates of suicidal thoughts/acts were evaluated with the χ2 test. In addition, depressive symptom profiles, other clinical characteristics, and patterns of psychotropic drug prescription in depressed patients with and without suicidal thoughts/acts were compared using analysis of covariance for continuous variables and logistic regression analysis for discrete variables to adjust the effects of covariates. RESULTS: The rates of suicidal thoughts/acts in 10 countries/areas varied from 12.8% in Japan to 36.3% in China. Patients with suicidal thoughts/acts presented more persistent sadness (adjusted odds ratio [aOR]=2.64, p<0.001), loss of interest (aOR=2.33, p<0.001), fatigue (aOR=1.58, p<0.001), insomnia (aOR=1.74, p<0.001), poor concentration (aOR=1.88, p<0.001), low self-confidence (aOR=1.78, p<0.001), poor appetite (aOR=2.27, p<0.001), guilt/self-blame (aOR=3.03, p<0.001), and use of mood stabilisers (aOR=1.79, p<0.001) than those without suicidal thoughts/acts. CONCLUSION: Suicidal thoughts/acts can indicate greater severity of depression, and are associated with a poorer response to antidepressants and increased burden of illness. Hence, suicidal thoughts/acts can provide a clinical index reflecting the clinical status of depressive disorders in Asians.