Efficacy and safety of endoxifen in bipolar disorder: A systematic review.

BACKGROUND: Endoxifen, a protein kinase C inhibitor and selective estrogen receptor modulator, primarily used in breast cancer treatment, has recently emerged as a potential therapeutic option for managing manic episodes associated with bipolar disorder (BD). This review aims to assess the existing evidence base for endoxifen in BD treatment and evaluate the strengths and limitations of current research findings. METHODS: A systematic search was conducted on Medline, Embase, and Web of Science databases. We included studies published in English that used endoxifen in BD, alongside any relevant studies identified through manual searching and conference papers with full-text availability. Information pertaining to dose, duration, clinical effects, and safety profiles was extracted from the included studies. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in clinical trials. RESULTS: The final review included seven case reports (including two conference presentations), two clinical trials, and one prospective study. Most studies administered endoxifen 8 mg and reported an improvement in manic symptoms. Several case reports included patients with comorbid substance use, and most patients received mood stabilizers concurrently. Few reports lacked any structured outcome measures. The clinical trials used divalproex 1000 mg as an active comparator, which was deemed sub-therapeutic. Despite being multicentric, the first trial lacked data on center-wise recruitment, and certain methodological concerns were observed across the included trials. There were no serious adverse effects noted, except for a significant elevation in lipid profile within a 3-week period. Limited data were available regarding endoxifen efficacy and safety in mixed episodes, depressive episodes, and maintenance treatment. CONCLUSION: There is a paucity of research on the efficacy and safety of endoxifen in BD. While existing evidence suggests short-term efficacy in manic episodes, significant limitations were identified in most of the included studies. Further research is imperative to establish the efficacy and safety of endoxifen in BD before considering its recommendation as a viable treatment option.

Unmet need for mental health care among adolescents in Asia and Europe.

The unmet need for mental health care is a global concern. There is a lack of cross-cultural studies examining adolescent help-seeking behavior from both formal and informal sources, including both high-and lower-income countries. This study investigates mental health help-seeking behavior in eight Asian and European countries. Data from 13,184 adolescents aged 13-15 (51% girls) was analysed using mixed-effects logistic regression with school-wise random intercepts to compare countries and genders. Although a significant proportion of adolescents considered getting or sought informal help, formal help-seeking remained exceptionally low, especially in middle-income countries (< 1%), while it ranged from 2 to 7% in high-income countries. Among adolescents with high emotional and behavioral problems (scoring above the 90th percentile on the Strengths and Difficulties Questionnaire), 1-2% of those in middle-income countries and 6-25% of those in high-income countries sought formal help. Girls generally seek more help than boys. The study shows the most adolescents do not receive formal help for mental health problems. The unmet need gap is enormous, especially in lower-income countries. Informal sources of support, including relatives, peers, and teachers, play a crucial role, especially in lower-income countries.

Valproate-Associated Hyperammonemic Encephalopathy: Clinical Correlates and Management Strategies in a Tertiary Care Center.

BACKGROUND: Common adverse effects of valproate include sedation, tremor, gastrointestinal effects, and weight gain. Valproate-associated hyperammonemic encephalopathy (VHE) is an uncommon adverse effect of valproate therapy, which includes symptoms such as tremors, ataxia, seizures, confusion, sedation and coma. We report clinical features and management of 10 cases of VHE in a tertiary care center. METHODS: In a retrospective chart review of case records from January 2018 to June 2021, 10 patients with VHE were identified and included in this case series. The data collected include demographic information, psychiatric diagnosis, comorbidities, liver function tests, serum ammonia and serum valproate levels, dosages and duration of valproate, management of hyperammonemia including dosage variations, discontinuation, adjuvant drugs used, and whether rechallenge was done. RESULTS: The most common indication of starting valproate was bipolar disorder (n = 5). All the patients had more than one physical comorbidity and risk factors for developing hyperammonemia. Seven patients received valproate at a dose higher than 20 mg/kg. The duration of valproate use varied from 1 week to 19 years before developing VHE. Dose reduction or discontinuation and lactulose were the most common management strategies used. All 10 patients improved. Among the 7 patients in whom valproate was discontinued, for 2 patients valproate was reinitiated in inpatient care with careful monitoring and was found to be well tolerated. CONCLUSIONS: This case series highlights the need for a high index of suspicion for VHE as it is frequently associated with a delayed diagnosis and recovery in psychiatric settings. Screening for risk factors and serial monitoring may allow earlier diagnosis and management.

Peripheral edema associated with antidepressant use: Systematic review of case reports.

BACKGROUND: Oedema associated with psychotropics can impose a considerable burden, leading to increased morbidity and cost. Peripheral oedema is sometimes related to the use of antidepressants, which are among the most prescribed psychotropic medications. We reviewed the reported cases of antidepressant-associated oedema to understand the risk factors, aetiology and outcome. METHODS: We searched the Medline, Web of Science and Embase databases to identify reported cases of peripheral oedema associated with antidepressant use. We included studies published in English and those with full-text availability. A systematic review of the reports was done to identify the antidepressants associated with oedema, explore possible risk factors, investigate potential mechanisms, and assess the outcome. RESULTS: We identified a total of 45 cases (27 case reports and five case series) that reported oedema associated with antidepressant use. Almost all major classes of antidepressants were found to be associated with oedema. Among these drugs, trazodone, mirtazapine, and escitalopram were the most implicated. Older age and female gender were more commonly associated with oedema. Etiologically, antagonism of α1 adrenergic receptors and 5HT2A receptors, leading to vasodilation and oedema, emerged as the most prevalent mechanisms. In most cases, the oedema subsided following the discontinuation of the antidepressants. CONCLUSIONS: Peripheral oedema associated with antidepressant use can represent a significant adverse drug reaction involving various classes of antidepressants. To ensure timely identification and proper management of oedema, regular monitoring is crucial.

Electroconvulsive Therapy in Patients With Cardiac Implantable Electronic Devices: A Case Report and Systematic Review of Published Cases.

OBJECTIVE: The aims of the study were to report the case of a 54-year-old man with recurrent depressive disorder with multiple medical comorbidities having a dual-chamber pacemaker, treated successfully with 11 sessions of electroconvulsive therapy, and to conduct a systematic review of published cases documenting the use of electroconvulsive therapy (ECT) in patients with cardiac implantable electronic devices (CIEDs) for treating major psychiatric disorders. METHODS: We searched electronic databases (MEDLINE, PubMed, Google Scholar, Embase, Cochrane Library, PsycINFO, and Crossref) and included studies reporting on the use of electroconvulsive therapy in patients with CIEDs. RESULTS: Thirty-five publications across 53 years (1967-2021) reported on 76 patients (including current report) who received a pooled total of 979 modified ECT sessions. The most common adverse events were premature ventricular contraction and hypertension. There have been no reports of serious adverse effects that necessitated the cessation of ECT. CONCLUSIONS: Electroconvulsive therapy is a safe and efficacious treatment for major psychiatric disorders, and the presence of CIEDs should not delay or deter the use of ECT in these patients.

Factors associated with lifetime suicide attempts: findings from the bipolar disorder course and outcome study from India (BiD-CoIN study).

AIM: To evaluate the risk factors associated with lifetime suicide attempts in bipolar disorder (BD) patients. METHODOLOGY: 773 BD patients with a duration of illness of at least ten years, currently in clinical remission, were evaluated for suicidal attempts in their lifetime. Those with and without lifetime suicide attempt(s) were compared for various demographic and clinical risk factors. RESULTS: 242 (31.3%) patients had a history of at least one lifetime suicide attempt. Compared to those without lifetime suicide attempts, those with suicidal attempts were less educated, were more often females, spent more time in episodes, and had a significantly more number of total episodes (in the lifetime, first five years of illness, and per year of illness), had significantly more number of total depressive episodes (in the lifetime, first five years of illness, and per year of illness), spent more time in depressive episodes, had more severe depressive episodes, more often had depression as the first episode in the lifetime, spent more time in mania/hypomania/mixed episodes, had higher residual depressive and manic symptoms, more often had rapid cycling affective disorder pattern in the lifetime, use of cannabis in dependence pattern, had poorer insight into their illness and had a higher level of disability (especially in three out of the four domains of Indian disability evaluation assessment scale). CONCLUSIONS: About one-third of the patients with BD have at least one-lifetime suicidal attempt, and those with suicide attempts usually have a poorer course of illness.

Pathways to care in alcohol use disorders: A cross-sectional study from a tertiary hospital in South India.

The study examined the pathway patients with alcohol use disorders followed to access tertiary care psychiatry services. We assessed 110 patients and one family member for each patient who sought psychiatry care for alcohol-related problems for the first time using the WHO encounter form. Only 5.5% of patients followed a direct pathway. The rest reached the tertiary hospital after third, fourth, and fifth encounters with other service providers such as traditional and faith healers, medical practitioners, and general hospitals. Although the family decided to seek the first consultation, medical professionals played a pivotal role in referring patients to psychiatry care.

Valproate-associated hair abnormalities: Pathophysiology and management strategies.

OBJECTIVE: To review the literature on valproate-associated hair abnormalities and the available treatment options. METHODS: We searched PubMed and Google Scholar with keywords including "valproate", "valproic acid", "hair", "alopecia", and "effluvium," supplemented with hand search from cross-references. We included all types of studies including case reports in this review. RESULTS: The pathophysiology of hair loss includes telogen effluvium, biotin, mineral deficiency, and possibly hyperandrogenism. Diagnosis is based on history of hair loss or abnormalities following valproate treatment, and is confirmed by use of simple clinical tests such as pull test and modified wash test. Treatment involves reassurance and advice on hair care, and if possible drug discontinuation or dose reduction. Medications such as biotin and other vitamins with minerals supplementation is effective for most individuals with hair loss. Other treatment options are agomelatine, topical valproate or minoxidil, though these lack evidence. CONCLUSION: Hair abnormalities with valproate are common, benign adverse effects, and management includes general measures and specific treatment options.

Victimization by traditional bullying and cyberbullying and the combination of these among adolescents in 13 European and Asian countries.

There has been a lack of studies on bullying in non-western low-income and middle-income countries. This study reported the prevalence of traditional victimization, cybervictimization, and the combination of these, in 13 European and Asian countries, and explored how psychiatric symptoms were associated with victimization. The data for this cross-sectional, school-based study of 21,688 adolescents aged 13-15 were collected from 2011 to 2017. The main outcomes were traditional and cybervictimization obtained from student self-reports. The Strengths and Difficulties Questionnaire was used to assess psychiatric symptoms. Generalized estimating equation and logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). The mean prevalence of any victimization was 28.9%, of traditional victimization only, this was 17.7%, and for cybervictimization only this was 5.1%. Cybervictimization occurred both independently, and in combination with, traditional victimization. The mean prevalence of combined victimization was 6.1%. The mean proportion of those who were cyberbullied only among those who were either cyberbullied only or bullied both traditionally and in cyber was 45.1%. The rates of prevalence varied widely between countries. In the total sample, those who experienced combined victimization, reported the highest internalizing symptoms (girls, OR 1.25, 95% CI 1.22-1.29; boys, OR 1.29, 95% CI 1.25-1.33). The study findings suggest that anti-bullying interventions should include mental health components and target both traditional and cyberbullying. Due to the overlap between these, targeting bullying should primarily focus on how to reduce bullying behavior rather than just focusing on where bullying takes place.

Is unipolar mania a distinct entity: findings from the bipolar disorder course and outcome study from India (BiD-CoIN study).

AIM: This study aimed to evaluate the prevalence of unipolar mania (UM) in a group of patients of bipolar disorder (BD). Additionally, effort was made to evaluate the demographic, clinical and treatment related factors, which distinguish subjects of UM from BD. METHODOLOGY: Seven hundred and seventy-three patients with BD, of at least 10 years duration, recruited from 14 General Hospital Units of tertiary care centers from India were evaluated for UM. RESULTS: The prevalence of UM, varied from 5.4% to 20.3%, depending on the definition used. With the most stringent definition of ≥4 episodes of mania and at least 5 years of follow-up, the prevalence of UM was 5.4%. Compared to patients of BD, who have episodes other than mania too, those with UM had lower proportion of patients with lifetime history of suicide attempts, spent less time in the episodes in their lifetime and had lower severity of residual depressive and manic symptoms. Further, compared to those with episodes other than mania too, those with UM had higher number of manic episodes per year of illness, had higher proportion of patients who had more than five episodes in the lifetime and had higher proportion of those with at least one episode with psychotic symptoms in the lifetime. CONCLUSION: The present study suggests that a small proportion of patients with BD have UM course and this runs a different clinical course compared to that seen in patients with traditionally recognized as BD.

Gender Differences in Clinical Characteristics and Comorbidities in Bipolar Disorder: a Study from South India.

The clinical features and course of bipolar disorder differ between women and men; however, studies are limited in Indian population. The objective of this study was to identify gender differences in patients with bipolar disorder. This was a cross-sectional, hospital-based observational study conducted over a period of 25 months. The sample consisted of 110 males and 90 females with a diagnosis of bipolar disorder according to ICD-10 Diagnostic Criteria for Research. Socio-demographic and clinical details were collected using semi-structured proforma. All patients were evaluated on Mini International Neuropsychiatric Interview Plus, Presumptive Stressful Life Events Scale and Clinical Global Impression. Sample consisted of 55% men and 45% women. The total number of episodes was similar between genders, however, the number of manic episodes (p = 0.004) was significantly more in males and the number of depressive (p = 0.003) and mixed episodes (p = 0.018) were significantly more in females. Majority of males had first episode of mania, whereas, first episode in females were mostly depressive (p < 0.001). Comorbid physical disorders were seen in 61.1% females and 40% males. Bipolar disorder subtype, episode types and number varied across gender. Co-morbid hypothyroidism, migraine, and obesity are seen more often in women and substance use was higher in men.

Reduced Serum Levels of Cluster of Differentiation 200 in Alcohol-Dependent Patients.

AIM: Chronic alcohol consumption can activate and dysregulate the neuroimmune system which leads to neuroinflammation. Neuroimmune regulatory proteins (NIReg) (e.g. Cluster of Differentiation 200 (CD200)) are the regulators of innate immune response and are responsible for silencing the innate immunity and suppression of inflammation. In this study, we explored the changes of serum levels of CD200 in patients with alcohol dependence at baseline, after one-week alcohol withdrawal and after one-month of alcohol abstinence. METHODS: Seventeen patients with alcohol dependence admitted for de-addiction treatment and 12 healthy controls were enrolled in the study. Blood samples were collected at baseline, after one-week, and after one-month, and CD200 levels were measured using enzyme-linked immunosorbent assay kit and compared with the healthy controls. RESULTS: The serum level of the neuroimmune regulatory protein CD200 in alcohol dependent group (at baseline) was significantly lower compared to healthy controls (p=0.003), and increased after one-week, and one-month period. CONCLUSION: The present study indicates that decrease of CD200 serum levels in alcohol dependent patients and its rise during alcohol withdrawal and abstinence may provide a preliminary evidence of the role of neuroimmune regulatory proteins in neuroadaptation during alcohol withdrawal.

Quality of life after coronary artery bypass graft & percutaneous transluminal coronary angioplasty: A follow up study from India.

Coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are treatments of choice for coronary artery disease. Quality of life (QoL) is an important factor in determining optimum treatment. This study was aimed to compare changes in QoL, six months post procedure, between CABG and PTCA, and to understand the confounding effect of various contributing factors. Thirty stable angina patients each in CABG and PTCA groups, were followed up for six months. QoL was assessed with WHO-QoL-BREF. Depression was rated on the Hamilton Depression Rating Scale. Changes in QoL and depression within and between CABG and PTCA groups were compared. Multinomial logistic regression was used to measure the predictive strength of treatment type (CABG and PTCA) on QoL, controlling for significant confounders. Although scores of QoL and depression significantly changed over time in both the groups, time×group interaction did not reach to a significance. Significant confounding effects of diabetes (P<0.01), hypertension (P<0.05) and diet restriction (P<0.05) were found. Controlling for confounding effects of these factors, group distribution to PTCA, compared to CABG, significantly predicted greater improvements in QoL (P<0.01).

Efficacy and Safety of Asenapine Versus Olanzapine in Combination With Divalproex for Acute Mania: A Randomized Controlled Trial.

BACKGROUND: Atypical antipsychotics are used for the treatment of acute mania, either as monotherapy or in combination with lithium or divalproex, which have a better tolerability profile as compared with typical antipsychotics. Asenapine, a newer atypical antipsychotic, has been found to be effective for the treatment of mania, with efficacy similar to olanzapine. The objective of the study was to compare the efficacy and safety of asenapine and olanzapine when used in combination with divalproex in patients with acute mania. METHODS: One hundred twenty patients aged 18 to 55 years, diagnosed with manic episode, were randomized to receive either flexible dose of sublingual asenapine (10-20 mg/d) or tablet olanzapine (10-20 mg/d), in combination with valproate 20 mg/kg per day for a period of 6 weeks. Efficacy was measured as change in Young Mania Rating Scale and Clinical Global Impression-Bipolar using intention-to-treat analysis with last observation carried forward, and safety was measured using Udvalg for Kliniske Undersøgelser scale and Modified Simpson-Angus Extrapyramidal Side Effects Scale. RESULTS: There was a significant reduction in Young Mania Rating Scale and Clinical Global Impression-Bipolar scores over time in both groups, with a significantly higher reduction in the olanzapine group as shown by the group × time interaction effect. Higher weight gain, increased sleep and appetite, and tremors were seen in the olanzapine-treated patients as compared with asenapine-treated patients; however, tongue hypesthesia was seen in the asenapine group only. CONCLUSIONS: This study found that asenapine was an effective and well-tolerated atypical antipsychotic alternative to olanzapine in combination with divalproex for the short-term management of acute mania.

Prevalence and Factors Associated With Clozapine-Related Constipation: An Observational Study.

BACKGROUND: Despite being a very effective treatment for resistant schizophrenia and bipolar disorder, use of clozapine is limited by adverse effects. Constipation is a common but potentially life-threatening adverse effect of clozapine that is understudied. The objective was to study the prevalence and factors associated with constipation in those receiving clozapine compared with control subjects. METHODS: Fifty patients in age group of 18 to 55 years receiving clozapine were compared with 50 patients in the same age group receiving medications other than clozapine. Presence of constipation was ascertained using the World Gastroenterology Organization Practice Guidelines definition. The severity of constipation was assessed using Constipation Assessment Scale and Bristol Stool Form Scale, and anticholinergic burden was assessed using Anticholinergic Burden Scale. RESULTS: Among clozapine-treated patients, 28 (56%) had constipation as compared with 11 (22%) in the control subjects (P < 0.001); the odds of developing constipation was 4.5 (95% confidence interval, 1.9-10.8). Kaplan-Meier survival analysis showed median time to onset of constipation in clozapine-treated patients was 60 days (SE, 13.1 days; 95% confidence interval, 34.3-85.7 days) and median dose of clozapine was 300 mg/d (interquartile range, 312 mg/d). Clozapine group had high Constipation Assessment Scale scores (P = 0.005, Cohen d = 1.17) and higher prevalence of types 1 and 2 Bristol stool types (Fisher exact P = 0.005, Cramer V = 0.59). CONCLUSIONS: Constipation was prevalent in more than half of patients receiving clozapine, which was severe and took longer time for recovery. Limitations include using a hospital-based sample and that dietary habits and lifestyle factors were not studied.