FGF2 gene's antisense protein, NUDT6, plays a depressogenic role by promoting inflammation and suppressing neurogenesis without altering FGF2 signalling.

Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behaviour and shows antidepressant effects through the Akt and extracellular signal regulated kinase (ERK) 1/2 pathways. Nudix hydrolase 6 (NUDT6) protein is encoded from FGF2 gene's antisense strand and its role in the regulation of affective behaviour is unknown. Here, we overexpressed NUDT6 in the hippocampus and investigated its behavioural effects and the underlying molecular mechanisms affecting the behaviour. We showed that increasing hippocampal NUDT6 results in depression-like behaviour in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acted by inducing inflammatory signalling, specifically by increasing S100 calcium binding protein A9 (S100A9) levels, activating nuclear factor-kappa B-p65 (NF-κB-p65), and elevating microglia numbers along with a reduction in neurogenesis. Our results suggest that NUDT6 could play a role in major depression by inducing a proinflammatory state. This is the first report of an antisense protein acting through a different mechanism of action than regulation of its sense protein. The opposite effects of NUDT6 and FGF2 on depression-like behaviour may serve as a mechanism to fine-tune affective behaviour. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behaviour, as well as in neuropsychiatric disorders. KEY POINTS: Hippocampal overexpression of nudix hydrolase 6 (NUDT6), the antisense protein of fibroblast growth factor-2 (FGF2), increases depression-like behaviour in rats. Hippocampal NUDT6 overexpression triggers a neuroinflammatory cascade by increasing S100 calcium binding proteinA9 (S100A9) expression and nuclear NF-κB-p65 translocation in neurons, in addition to microglial recruitment and activation. Hippocampal NUDT6 overexpression suppresses neurogenesis. NUDT6 exerts its actions without altering the levels or downstream signalling pathways of FGF2.

Potential diagnostic and prognostic biomarkers of pediatric Burkitt lymphoma identified through miRNA expression profiling.

BACKGROUND: Pediatric Burkitt lymphoma (pBL) is the most common non-Hodgkin lymphoma in children. These patients require prompt diagnosis and initiation of therapy due to rapid tumor growth. The roles of tumor tissue and circulating microRNAs (miRNAs) in the diagnosis or prognostication have not been fully elucidated in pBLs. METHODS: Differentially expressed (DE) miRNAs were identified with microRNA sequencing (miRNA-Seq) in tumor tissues and plasma of diagnostic pBLs. The diagnostic potential of total miRNA concentrations and overexpressed miRNAs were evaluated through receiver operating characteristic (ROC) analyses. Log-rank test was employed to evaluate survival differences associated with DE miRNAs. Selected miRNA expressions were cross-validated with quantitative reverse transcription PCR (qRT-PCR). RESULTS: Total circulating cell-free miRNAs were higher in pBL cases compared to controls. Cancer-associated pathways were enriched among miRNAs differentially expressed in pBL tumor tissues. Several upregulated miRNAs in pBL tumors demonstrated high diagnostic potential. Similarly, ROC analysis of overexpressed plasma miRNAs revealed circulating cell-free or exosomal miRNAs that can distinguish pBLs from control cases. Indeed, integrative analysis of overexpressed circulating exosomal miRNAs showed an enhanced diagnostic potential for certain triple combinations. Kaplan-Meier analyses of DE miRNAs in tumor tissues identified miRNAs predicting overall survival. CONCLUSIONS: Differentially expressed miRNAs in tumor tissue and plasma of pBL have the potential to improve diagnosis and prognosis. IMPACT: Differentially expressed miRNAs in treatment-naive pediatric Burkitt lymphoma cases have diagnostic or prognostic biomarker potential. This is the first study that applied miRNA-Seq on treatment-naive pediatric Burkitt lymphoma cases for identification of differentially expressed miRNAs both in tumor tissue and plasma samples with diagnostic potential. Through systematic analysis of differentially expressed miRNAs, tumor tissue miRNAs associated with the overall survival of pBLs have been discovered. The clinically significant, differentially expressed miRNAs identified in pediatric Burkitt lymphoma cases can potentially improve the current tissue-based or non-invasive clinical practice in terms of diagnosis or prognostication.

Gaps in clinical research in frontotemporal dementia: A call for diversity and disparities-focused research.

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.

Perspectives of Family Caregivers of People With Alzheimer's Disease on Caregiving Experience and Needs: A Qualitative Study.

The current study aimed to investigate the perspectives of family caregivers of people with Alzheimer's disease on caregiving experience and needs. A qualitative descriptive method was used with a sample of 23 family caregivers. Data were collected through in-depth, face-to-face interviews using a pilot-tested semi-structured interview guide. Data analysis was performed via content analysis. Three major themes emerged: (1) Stuck in Caregiving, (2) A Life in Metamorphosis, and (3) Needs. Findings revealed that caregivers struggled to manage the care process, adapt to life changes, and fulfill their needs. This study provides rich data to help create interventions to assist family caregivers. [Journal of Psychosocial Nursing and Mental Health Services, xx(xx), xx-xx.].

Clinical findings and mutational spectrum of neurofibromatosis type 1 patients in a single center of south part of Turkey.

AIM: The aim of this study is to determine the mutation spectrums and clinical characteristics of NF1 patients followed up in our center and to investigate whether there is a genotype-phenotype relationship. MATERIAL AND METHODS: Sixty-three children and 34 relatives diagnosed with NF1 were included in the study. Age, gender, family history, clinical features, tumors detected in the patient at the time of diagnosis or during follow-up, orbital and cerebral magnetic resonance imaging (MRI) findings were recorded. Also results of the NF1 gene analysis results were recorded. RESULTS: Fifty-three different mutations were found as a result of the NF1 gene analysis studied from patients and their family members. Among these 53 mutations, stop codon mutation was the most frequently detected mutations. Sixteen out of 50 (32%) mutations were found to be novel mutations. Twenty-eight tumors developed in our patients. Twenty of them were optic gliomas and others were medullary thyroid carcinoma, glioblastome multiforme, pons glioma, acute lymphoblastic leukemia, pilocytic astrositoma, hypothalamic glioma, cerebral hamartoma and cardiac fibroma. No genotype-phenotype relationship was detected in patients Conclusion: Comprehensive mutation analysis of NF1 will increase our knowledge due to its different phenotypic characteristics even in the same mutation.

A Systematic Review of Neuropsychological Tests for the Assessment of Dementia in Non-Western, Low-Educated or Illiterate Populations.

OBJECTIVE: Neuropsychological tests are important instruments to determine a cognitive profile, giving insight into the etiology of dementia; however, these tests cannot readily be used in culturally diverse, low-educated populations, due to their dependence upon (Western) culture, education, and literacy. In this review we aim to give an overview of studies investigating domain-specific cognitive tests used to assess dementia in non-Western, low-educated populations. The second aim was to examine the quality of these studies and of the adaptations for culturally, linguistically, and educationally diverse populations. METHOD: A systematic review was performed using six databases, without restrictions on the year or language of publication. RESULTS: Forty-four studies were included, stemming mainly from Brazil, Hong Kong, Korea, and considering Hispanics/Latinos residing in the USA. Most studies focused on Alzheimer's disease (n = 17) or unspecified dementia (n = 16). Memory (n = 18) was studied most often, using 14 different tests. The traditional Western tests in the domains of attention (n = 8) and construction (n = 15), were unsuitable for low-educated patients. There was little variety in instruments measuring executive functioning (two tests, n = 13), and language (n = 12, of which 10 were naming tests). Many studies did not report a thorough adaptation procedure (n = 39) or blinding procedures (n = 29). CONCLUSIONS: Various formats of memory tests seem suitable for low-educated, non-Western populations. Promising tasks in other cognitive domains are the Stick Design Test, Five Digit Test, and verbal fluency test. Further research is needed regarding cross-cultural instruments measuring executive functioning and language in low-educated people.

Effective High-dose Interferon-α Therapy in a 13-Year-Old Girl With Erdheim-Chester Disease.

Erdheim-Chester disease (ECD) is a proliferative disorder of non-Langerhans histiocytes with a higher incidence in the fifth to seventh decades and rarer occurrence in the pediatric population. Although ECD typically involves bone, it can also affect the central nervous system, cardiovascular system, retro-orbital space, retroperitoneal space, and kidneys, lungs, and skin. A 13-year-old Syrian girl who presented with multisystemic involvement was diagnosed with ECD. The B-Raf proto-oncogene V600E mutation was not detected in ECD lesions. Response to the high-dose interferon-α therapy was excellent in this pediatric patient. In this article, pediatric ECD case reports are also reviewed.

Adaptation of the Modified Mini-Mental State Examination (3MS) and Determination of Its Normative Values in Turkey.

BACKGROUND/AIMS: This study aimed to adapt the Modified Mini-Mental State Examination (3MS) and determine its normative values in Turkey. METHODS: After translation and cultural adaptation processes, a population-based study was conducted between February and June 2016 in Ankara with individuals over the age of 55 years. Subjects with a previous diagnosis of dementia along with neuropsychiatric disorders that might affect cognition were excluded. Data analyses were performed to assess the association of sociodemographic variables with 3MS scores. RESULTS: Two versions of the Turkish 3MS (for educated and minimally educated individuals) were developed. A total of 2,235 participants were included in the field study. After exclusion, the data on the final sample of 1,909 individuals were analyzed, where age, gender, and education accounted for variance in 3MS scores. Younger age and higher educational attainment were associated with better 3MS performance. CONCLUSIONS: A widely applicable dementia screening test was adapted to Turkish and its normative values were determined. The test will make it possible to evaluate the cognitive performance of both educated and minimally educated elderly individuals based on their age, gender, and educational level.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.

Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

Etomidate is associated with longer seizure duration, lower stimulus intensity, and lower number of failed trials in electroconvulsive therapy compared with thiopental.

OBJECTIVE: Induction agents used for electroconvulsive therapy (ECT) may alter seizure parameters. In this study, we aimed to investigate the effects of etomidate and thiopental on seizure-related variables. METHODS: Registries of patients who received ECT between 2010 and 2013 in a tertiary psychiatry clinic were evaluated retrospectively. The information of patients who were on the same induction agent and muscle relaxant during the whole treatment course was assessed. Primary outcome measures were total number of ECT sessions, mean peripheral and central seizure duration, cumulative stimulus intensity, and the number of adequate seizures per total number of stimuli. Secondary measures were maximum systolic-diastolic and mean blood pressure, peak heart rate, and the frequency of antihypertensive drug use during the sessions. RESULTS: Although the total number of ECT sessions is similar between the etomidate (n = 43) and thiopenthal (n = 31) groups, the mean seizure duration per stimuli was significantly longer whereas the cumulative stimulus intensity was lower in the etomidate group. The number of adequate seizures obtained in relation with the number of stimuli was also significantly higher, indicating increased probability of eliciting an adequate seizure with etomidate. During threshold determination, the number of stimuli needed to provide an adequate seizure was marginally less with etomidate. No group difference was observed in hemodynamic changes and the frequency of antihypertensive use. CONCLUSIONS: Etomidate use, compared with thiopental as an induction agent, is associated with longer seizure duration with less cumulative intensity. The use of etomidate reduces the number of failed trials and may prevent the application of unnecessary electrical stimuli with a possibly safe hemodynamic profile.

Association between ADH1C and ALDH2 polymorphisms and alcoholism in a Turkish sample.

BACKGROUND: Polymorphisms in the genes encoding alcohol metabolizing enzymes are associated with alcohol dependence. AIM: To evaluate the association between the alcohol dehydrogenase 1C (ADH1C) Ile350Val and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphisms and alcohol dependence in a Turkish sample. METHODS: 235 individuals (115 alcohol-dependent patients and 120 controls) were genotyped for ADH1C and ALDH2 with PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Association between the polymorphisms and family history, daily and maximum amount of alcohol consumed was investigated. The associations between alcohol dependence, severity of consumption and family history and the polymorphisms were analyzed by chi-square or Fisher's exact test where necessary. Relationship between genotypes and dependence related features was evaluated using analysis of variance (ANOVA). RESULTS: The -350Val allele for ADH1C (ADH1C*2) was increased in alcohol-dependent patients (P = 0.05). In individuals with a positive family history, the genotype distribution differed significantly (P = 0.031) and more patients carried the Val allele compared with controls (P = 0.025). Genotyping of 162 participants did not reveal the -504Lys allele in ALDH2. CONCLUSIONS: These findings suggest that ADH1C*2 is associated with alcohol dependence in the Turkish population displaying a dominant inheritance model. ADH1C*2 allele may contribute to the variance in heritability of alcohol dependence. The ALDH2 -504Lys/Lys or Glu/Lys genotypes were not present in alcohol-dependent patients, similar to that seen in European populations and in contrast to the findings in the Asian populations.

Recurrent Psychotic Depression Associated with Chronic Subdural Haematoma: A Case Report.

Chronic subdural hematomas (CSDH) with isolated psychiatric presentation are rare. In this paper, we report a case of 77-year-old-female patient who had psychotic depression after repetitive head trauma without any neurological symptoms. The brain magnetic resonance imaging revealed an 20 mm subdural hematoma in the right frontoparietal region and a 7 mm subdural hematoma in the left frontal region. The psychiatric symptoms improved within the first week after evacuation but relapsed with the occurrence of right sided pneumocephalus. In the follow up, with the disappearance of the pneumocephalus, the psychiatric symptoms improved. It should be kept in mind that isolated psychiatric symptoms can be seen due to subdural hematoma and evacuation of the hematoma has an important role in improving the psychiatric symptoms.

Clinical predictors of Alzheimer's disease-like brain atrophy in individuals with memory complaints.

OBJECTIVES: The definition and assessment methods for subjective cognitive decline (SCD) vary among studies. We aimed to investigate which features or assessment methods of SCD best predict Alzheimer's disease (AD)-related structural atrophy patterns. METHODS: We assessed 104 individuals aged 55+ with memory complaints but normal cognitive screening. Our research questions were as follows: To improve the prediction of AD related morphological changes, (1) Would the use of a standardized cognitive screening scale be beneficial? (2) Is conducting a thorough neuropsychological evaluation necessary instead of relying solely on cognitive screening tests? (3) Should we apply SCD-plus research criteria, and if so, which criterion would be the most effective? (4) Is it necessary to consider medical and psychiatric comorbidities, vitamin deficiencies, vascular burden on MRI, and family history? We utilized Freesurfer to analyze cortical thickness and regional brain volume meta-scores linked to AD or predicting its development. We employed multiple linear regression models for each variable, with morphology as the dependent variable. RESULTS: AD-like morphology was associated with subjective complaints in males, individuals with advanced age, and higher education. Later age of onset for complaints, complaints specifically related to memory, excessive deep white matter vascular lesions, and using medications that have negative implications for cognitive health (according to the Beers criteria) were predictive of AD-related morphology. The subjective cognitive memory questionnaire scores were found to be a better predictor of reduced volumes than a single-question assessment. It is important to note that not all SCD-plus criteria were evaluated in this study, particularly the APOE genotype, amyloid, and tau status, due to resource limitations. CONCLUSIONS: The detection of AD-related structural changes is impacted by demographics and assessment methods. Standardizing SCD assessment methods can enhance predictive accuracy.

Clean Words Come Out of Clean Minds

No abstract available.

Management of Psychiatric Symptoms in Dementia.

Behavioral and Psychological Symptoms of Dementia (BPSD) are frequent, may start early in the disease and increase in frequency and severity over time. BPSD may be associated with medical, social, emotional, and environmental factors and potential triggers should be eliminated. Each BPSD has a unique anatomic and neurochemical profile that may help in making a diagnosis and choosing a therapy. Structured management plans help create an effective framework. Treatment options are understudied and the evidence is inconclusive for many of the pharmacological interventions. Effective nonpharmacological options should be utilized where available. Treatments should be monitored for their efficacy and safety.

Empathy as a crucial skill in disrupting disparities in global brain health.

Brain health refers to the state of a person's brain function across various domains, including cognitive, behavioral and motor functions. Healthy brains are associated with better individual health, increased creativity, and enhanced productivity. A person's brain health is intricately connected to personal, social and environmental factors. Racial, ethnic, and social disparities affect brain health and on the global scale these disparities within and between regions present a hurdle to brain health. To overcome global disparities, greater collaboration between practitioners and healthcare providers and the people they serve is essential. This requires cultural humility driven by empathy. Empathy is a core prosocial value, a cognitive-emotional skill that helps us understand ourselves and others. This position paper aims to provide an overview of the vital roles of empathy, cooperation, and interdisciplinary partnerships. By consciously integrating this understanding in practice, leaders can better position themselves to address the diverse challenges faced by communities, promote inclusivity in policies and practices, and further more equitable solutions to the problem of global brain health.

Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder.

BACKGROUND: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. METHODS: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. RESULTS: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. CONCLUSION: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

PsiNorm: A fast, efficient and free open-source software for interpreting, reporting and archiving neuropsychological test results. / PsiNorm: Nöropsikolojik Test Verilerinin Degerlendirilmesi, Rapor Hazirlanmasi ve Arsivlenmesi için Hizli ve Etkin Bir Açik Yazilim.

OBJECTIVE: In many clinics, calculation and interpretation of neuropsychological test results, along with reporting, data organization and archiving of the data are done manually. In this era where most of the similar processes are automated, manual application may result in excessive time consumption, unnecessary use of qualified work-force, and is also open to error. A software that automates these processes for neuropsychological tests used for dementia assessment may overcome these issues. METHOD: We aimed to develop a free, open source software not requiring specialized training, which would optimise the calculation, preparation of personal reports and archiving processes of neuropsychological tests, hence would easily be incorporated in to the daily work of psychologists. We've used Python 3.6 as the programming language, and JSON was used as the data interchange format to allow for personal alterations in the content. The tests were selected among those which are in common use for neuropsychological evaluation of adults in Turkey, with available norm values. (Funding: TUBITAK 214S048). RESULTS: PsiNorm was developed, comprising widely used standardized tests for cognitive evaluation of adults in Turkey. The software is lightweight, compatible with most common operating systems, and easy-to-use. We've shown that Psinorm significantly reduced the time required for calculation of percentiles and norms as well as for producing a draft report. The reports are prepared in .txt format and the databases are prepared in MS Excel ve CSV formats. PsiNorm is available freely at psinorm.org. CONCLUSION: PsiNorm is a free, open-source software which is available for researchers and clinicians who perform neuropsychological tests. PsiNorm provides significant time and labor-force benefits, is easy-touse and can be customized by the user.

The superiority of ketofol and etomidate against propofol or thiopental anesthesia for ECT.

OBJECTIVES: Most anesthetic drugs used for electroconvulsive therapy (ECT) have dose-dependent anticonvulsive effects, counter-acting seizure induction, lowering seizure quality. However, a consummate drug for ECT anesthesia has not yet been established. Therefore, in this study, we aimed to investigate the effects of etomidate, thiopental, propofol and co-administration of ketamine-propofol (ketofol) on seizure quality and hemodynamic safety. METHODS: Registries of 121 patients (1077 sessions) were retrospectively evaluated. The effects of anesthetics on ECT-related parameters (stimulation charge, central seizure duration, number of failed stimulation trials, mean arterial pressure, and peak heart rate) were analyzed via linear mixed-effects models. RESULTS: Overall, the seizure duration decreased, and the stimulation charge increased in time with continuing sessions within a course of ECT. The decrease in seizure duration and the increase in required stimulation charge was significantly lower with etomidate and ketofol. Additionally, ketofol was significantly related to a lower number of failed stimulation trials compared to propofol. Ketofol and propofol use was associated with a significantly lower postictal mean arterial pressure. CONCLUSION: Ketofol and etomidate were equivalently superior in the rate of decrease in seizure duration and the required elevation in stimulus charge, which would interpret into valuable clinical guidance, especially for "seizure resistant" patients, and their use may potentially lower ECT related cognitive side effects.

Association between polarity of first episode and solar insolation in bipolar I disorder.

OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth. METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer. RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001). CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.