Synergistic interferon alpha-based drug combinations inhibit SARS-CoV-2 and other viral infections in vitro

There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggers intrinsic and extrinsic cellular antiviral responses, as well as reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Although IFNa alone was insufficient to completely abolish SARS-CoV-2 replication, combinations of IFNa with remdesivir or other antiviral agents (EIDD-2801, camostat, cycloheximide, or convalescent serum) showed strong synergy and effectively inhibited SARS-CoV-2 infection in human lung epithelial Calu-3 cells. Furthermore, we showed that the IFNa-remdesivir combination suppressed virus replication in human lung organoids, and that its single prophylactic dose attenuated SARS-CoV-2 infection in lungs of Syrian hamsters. Transcriptome and metabolomic analyses showed that the combination of IFNa-remdesivir suppressed virus-mediated changes in infected cells, although it affected the homeostasis of uninfected cells. We also demonstrated synergistic antiviral activity of IFNa2a-based combinations against other virus infections in vitro. Altogether, our results indicate that IFNa2a-based combination therapies can achieve higher efficacy while requiring lower dosage compared to monotherapies, making them attractive targets for further pre-clinical and clinical development.

Identification of novel antiviral drug combinations in vitro and tracking their development

Combination therapies have become a standard for the treatment for HIV and HCV infections. They are advantageous over monotherapies due to better efficacy and reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify several new synergistic combinations against emerging and re-emerging viral infections in vitro. We observed synergistic activity of nelfinavir with investigational drug EIDD-2801 and convalescent serum against SARS-CoV-2 infection in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of vemurafenib combination with emetine, homoharringtonine, gemcitabine, or obatoclax against echovirus 1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar and niclosamide were synergistic against HCV infection in hepatocyte derived Huh-7.5 cells, whereas combinations of monensin with lamivudine and tenofovir were synergistic against HIV-1 infection in human cervical TZM-bl cells. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status. Overall, the development of combinational therapies could have a global impact improving the preparedness and protection of the general population from emerging and re-emerging viral threats.

Population-Level Mortality Rates from Novel Coronavirus (COVID-19) in South Korea

BackgroundSouth Korea was among the first countries to report a case of the novel coronavirus (COVID-19) outside of China. As of 22 March, 2020, South Korea reported 8897 confirmed cases of and 104 deaths from COVID-19. MethodsWe collected the number of laboratory-confirmed cases and deaths in South Korea from the World Health Organization (as of 21 March, 2020) and case distribution and fatality rates by age from the Korean Center for Disease Control and Prevention (as of 22 March, 2020). We estimated population-level mortality rates by fitting a negative binomial regression model with the number of deaths as the outcome and population by age as an offset. We then calculated the age-standardized death rate (ASDR) based on the current COVID-19 figures and for alternative scenarios of increased prevalence. FindingsThe COVID-19 population-level mortality rate (per 100,000 person-years) increased with age: from 0.1 deaths among 30-39 year olds to 9.5 deaths among [≥]80 year olds. The ASDR (per 100,000 person-years) was 0.8 deaths. The ASDR would increase to 52.0 deaths at a 1% prevalence (becoming the third leading cause of death) and 155.9 deaths at 3% prevalence (becoming the leading cause of death). InterpretationCurrently, the population-level mortality burden of COVID-19 in South Korea, as measured by the ASDR, was relatively low compared to other causes of death partly due to the low prevalence of COVID-19. If the prevalence increases from another outbreak, the mortality burden could increase substantially and surpass other leading causes. FundingGrant P2C-HD041022, California Center for Population Research, University of California, Los Angeles (US NIH).

Association of Insulin Resistance with Lower Bone Volume and Strength Index of the Proximal Femur in Nondiabetic Postmenopausal Women

BACKGROUND: Type 2 diabetes mellitus is associated with an increased risk of osteoporotic fracture despite relatively preserved bone mineral density (BMD). Although this paradox might be attributed to the influence of insulin resistance (IR) on bone structure and material properties, the association of IR with femur bone geometry and strength indices remains unclear. METHODS: Using data from the Cardiovascular and Metabolic Disease Etiology Research Center cohort study, we conducted a cross-sectional analysis among nondiabetic postmenopausal women. IR was estimated using the homeostasis model assessment of IR (HOMA-IR). Compartment-specific volumetric BMD (vBMD) and bone volume of proximal femur were measured using quantitative computed tomography. The compressive strength index (CSI), section modulus (Z), and buckling ratio of the femoral neck were calculated as bone strength indices. RESULTS: Among 1,008 subjects (mean age, 57.3 years; body mass index [BMI], 23.6 kg/m²), BMI, waist circumference, and vBMD of the femoral neck and total hip increased in a linear trend from the lowest ( < 1.37) to highest (≥2.27) HOMA-IR quartile (P < 0.05 for all). The HOMA-IR showed an independent negative association with total bone volume (standardized β=−0.12), cortical volume (β=−0.05), CSI (β=−0.013), and Z (β=−0.017; P < 0.05 for all) of the femoral neck after adjustment for age, weight, height, physical activity, and vitamin D and high-sensitivity C-reactive protein levels. However, the association between HOMA-IR and vBMD was attenuated in the adjusted model (femoral neck, β=0.94; P=0.548). CONCLUSIONS: Elevated HOMA-IR was associated with lower cortical bone volume and bone strength indices in nondiabetic postmenopausal women, independent of age and body size.

Factors that Affect the Adherence to ADHD Medications during a Treatment Continuation Period in Children and Adolescents: A Nationwide Retrospective Cohort Study Using Korean Health Insurance Data from 2007 to 2011

OBJECTIVE: Several factors, such as male gender, older age, type of insurance, comorbid conditions, and medication type, have been associated with attention-deficit/hyperactivity disorder (ADHD) medication adherence rates, but the results have been inconsistent. We analyzed data to answer several questions: 1) How old were patients who first refilled their treatment medications used primarily for ADHD, regardless of the medication type? 2) What socio-demographic factors are associated with medication adherence? 3) What medical conditions, such as medication type and comorbid diagnosis, influence adherence? METHODS: We analyzed National Health Insurance data, which comprised continuously enrolled Korean National Medical Insurance children (6–18 years) with at least 2 ADHD prescription claims (January 2008–December 2011). The persistence of use regarding the days of continuous therapy without a 30-day gap were measured continuously and dichotomously. Adherence, using a medication possession ratio (MPR), was measured dichotomously (80% cut-off). RESULTS: The cumulative incidence of index cases that initiated medication refills for ADHD treatment during the 4 year period was 0.85%. The patients who exhibited a MPR greater than 80 comprised approximately 66%. The medication type, high school age groups, physician speciality, treatment at a private clinic, and comorbid conditions were associated with medication adherence during continuous treatment using a multivariate analysis. CONCLUSION: A better understanding of ADHD treatment patterns may lead to initiatives targeted at the improvement of treatment adherence and persistence. Other factors, including the severity, family history, costs, type of comorbidities, and switching patterns, will be analyzed in future studies.

Are Serum Vitamin D Levels Associated With Dry Eye Disease? Results From the Study Group for Environmental Eye Disease / 예방의학회지

OBJECTIVES: Dry eye disease (DED) is an increasingly important public health problem in Korea. Previous studies conducted in Korea have reported inconsistent results regarding the protective effects of vitamin D on DED, and these discrepancies may be related to the relatively simple questionnaire that has been used. Thus, we evaluated the association of serum vitamin D levels with DED using the ocular surface disease index (OSDI). METHODS: The present study evaluated data from participants in the Study Group for Environmental Eye Disease (2014-2015). This group included data from 752 participants, and data from 740 participants (253 men and 487 women) were analyzed in the present study. DED severity was evaluated using the OSDI. RESULTS: Higher serum vitamin D levels were associated with a non-significantly reduced risk of DED in the crude analysis (odds ratio [OR], 0.991; 95% confidence interval [CI], 0.971 to 1.011) and in the adjusted analysis (OR, 0.988; 95% CI, 0.966 to 1.010). In the crude analysis of no/mild DED vs. moderate/severe DED, men exhibited a decreased risk with increasing serum vitamin D levels (OR, 0.999; 95% CI, 0.950 to 1.051), while women exhibited an increased risk (OR, 1.003; 95% CI, 0.979 to 1.027). In these analyses, we found no significant associations. CONCLUSIONS: The findings of the present study support previous reports that serum vitamin D levels are not associated with DED.

Differences in Utilization Patterns among Medications in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: a 36-Month Retrospective Study Using the Korean Health Insurance Review and Assessment Claims Database

We evaluated the differences in utilization patterns including persistence and adherence among medications in children and adolescents with attention deficit hyperactivity disorder (ADHD). The current study was performed using data from the Korean Health Insurance Review and Assessment claims database from January 1, 2009 to December 31, 2013. Our study sample consisted of 10,343 children and adolescents with ADHD who were not given their newly prescribed medication in 360 days before the initial claim in 2010. Data were followed up from the initiation of treatment with ADHD medications in 2010 to December 31, 2013. Discontinuation rates for 4 ADHD medications in our sample ranged from 97.7% for immediate-release methylphenidate to 99.4% for atomoxetine using refill gap more than 30 days and from 56.7% for immediate-release methylphenidate to 62.3% for extended-release methylphenidate using refill gap more than 60 days. In the number of discontinued, we found significant differences among medications using refill gap more than 30 days. Among 4 ADHD medications, extended-release methylphenidate and atomoxetine had more days than immediate-release methylphenidate and osmotic-controlled oral delivery system methylphenidate. In logistic regression analyses, extended-release methylphenidate, osmotic-controlled oral delivery system methylphenidate, and atomoxetine showed less discontinuation compared to immediate-release methylphenidate group when a refill gap more than 30 days was used. In logistic regression analysis of adherence, we could not find any differences among 4 medication types. We suggest that the utilization patterns should be assessed regularly in order to improve future outcomes in children and adolescents with ADHD.

Differences in Utilization Patterns among Medications in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: a 36-Month Retrospective Study Using the Korean Health Insurance Review and Assessment Claims Database

We evaluated the differences in utilization patterns including persistence and adherence among medications in children and adolescents with attention deficit hyperactivity disorder (ADHD). The current study was performed using data from the Korean Health Insurance Review and Assessment claims database from January 1, 2009 to December 31, 2013. Our study sample consisted of 10,343 children and adolescents with ADHD who were not given their newly prescribed medication in 360 days before the initial claim in 2010. Data were followed up from the initiation of treatment with ADHD medications in 2010 to December 31, 2013. Discontinuation rates for 4 ADHD medications in our sample ranged from 97.7% for immediate-release methylphenidate to 99.4% for atomoxetine using refill gap more than 30 days and from 56.7% for immediate-release methylphenidate to 62.3% for extended-release methylphenidate using refill gap more than 60 days. In the number of discontinued, we found significant differences among medications using refill gap more than 30 days. Among 4 ADHD medications, extended-release methylphenidate and atomoxetine had more days than immediate-release methylphenidate and osmotic-controlled oral delivery system methylphenidate. In logistic regression analyses, extended-release methylphenidate, osmotic-controlled oral delivery system methylphenidate, and atomoxetine showed less discontinuation compared to immediate-release methylphenidate group when a refill gap more than 30 days was used. In logistic regression analysis of adherence, we could not find any differences among 4 medication types. We suggest that the utilization patterns should be assessed regularly in order to improve future outcomes in children and adolescents with ADHD.

Changes of Heart Rate Variability during Methylphenidate Treatment in Attention-Deficit Hyperactivity Disorder Children: A 12-Week Prospective Study

PURPOSE: The aim of this study was to clarify the relationship between the autonomic nervous system and attention deficit hyperactivity disorder (ADHD) rating scales and to evaluate the usefulness of heart rate variability (HRV) as a psychophysiological biomarker for ADHD. MATERIALS AND METHODS: Subjects were recruited from outpatients in the Department of Child and Adolescent Psychiatry at the Korea University Medical Center from August 2007 to December 2010. Subjects received methylphenidate. Time- and frequency-domain analyses of HRV, the Korean ADHD rating scale (K-ARS), and computerized ADHD diagnostic system were evaluated before treatment. After a 12-week period of medication administration, we repeated the HRV measurements and K-ARS rating. RESULTS: Eighty-six subjects were initially enrolled and 37 participants completed the 12-week treatment and HRV measurements subsequent to the treatment. Significant correlations were found between the K-ARS inattention score and some HRV parameters. All of the HRV parameters, except the standard deviations of the normal-to-normal interval, very low frequency, and low frequency to high frequency, showed a significant positive correlation between baseline and endpoint measures in completers. High frequency (HF) and the square root of the mean squared differences of successive normal-to-normal intervals (RMSSD), which are related to parasympathetic vagal tone, showed significant decreases from baseline to endpoint. CONCLUSION: The HRV test was shown to be reproducible. The decrease in HF and RMSSD suggests that parasympathetic dominance in ADHD can be altered by methylphenidate treatment. It also shows the possibility that HRV parameters can be used as psychophysiological markers in the treatment of ADHD.

Development of Korean Adult ADHD Rating Scale

OBJECTIVES: Symptoms of attention-deficit hyperactivity disorder (ADHD) during childhood may persist into adulthood. This study included the development and validation process of the Korean Adult ADHD Rating Scale (K-AARS), which was developed for screening and monitoring treatment of adults with ADHD. METHODS: Preliminary questionnaires of the K-AARS were based on the reviews of previous adult ADHD scales and clinical experiences of the board certified child and adolescent psychiatrists in Korea. For this study, 136 adults (18-50 years old) with inattention, hyperactivity and/or impulsivity symptoms were enrolled as ADHD subjects, and compared with 406 control subjects (18-50 years old) without ADHD symptoms. Construct validity was examined using explorative factor analysis and Cronbach's alpha to obtain internal reliability coefficients. Concurrent validity was evaluated by comparison with the Conners' Adult ADHD Rating Scale (CAARS). RESULTS: An explorative factor analysis showed that the K-AARS had 8 factors (inattention, hyperactivity, impulsivity, antisocial personality disorder/conduct disorder/oppositional defiant disorder, impairment, driving, emotional dysregulation, disorganization). K-AARS was highly reliable in terms of internal consistency (Cronbach's alpha 0.77-0.95) and correlation between factors (0.57-0.86). Concurrent validity with the CAARS and discriminant validity were statistically significant. CONCLUSION: The K-AARS is a valid and reliable measure for assessment of Korean adults with ADHD.

The Early Childhood Care and Education Policy in the United Kingdom and Similar Policies in Korea: A Comparison of the Sure Start Children's Centres and Dream Start

In an effort to expand working opportunities for women and encourage childbirth, the government of Korea introduced the free infant care policy in 2013. This policy, however, was controversial with regard to issues, such as budget shortages and dissatisfaction based on socioeconomic status. In addition, the lack of evidence-based data regarding adequate age criteria for the entry of children into childcare facilities was noted as a challenge. As child development professionals who are concerned with mental health issues, we investigated the influence and challenges of the free infant care policy with regard to infant mental health. In this review, we examined the policies enacted by developed countries, such as the United Kingdom (UK), and compared them with those in Korea. The childcare systems in Korea and the UK differ historically and socially, but show some similarities, such as maternal responsibility for parenting and household issues. Like Korea, the need for UK childcare facilities increased in the 1990's in response to market recovery and associated increase in female employment. Among the new policies in the UK, the Sure Start program has begun to provide integrated services for infants, particularly to those 0-4 years of age, who are vulnerable to social exclusion. Similar to the Dream Start program in Korea, it has been successful in providing family-related services, resulting in improvements in problematic behaviors of children, enhanced parenting skills, and decreased rates of severely injured children.

Current Situation and Policies of Early Childhood Care and Education in North Korea

In order to resolve the decline in population due to low birthrates, the South Korean government is expanding its free child care policies with an increased budget. In anticipating the effects and problems of our system, it will be worthy of attention to refer to the child care systems of other countries. In this paper, we reviewed the past and present policies and the current situation of the child care system in North Korea. North Korea started its free child care system earlier than that of South Korea, for the purpose of utilizing the women's labor force and rearing children to be revolutionary men of Juche type (Kimilsungism), in order to construct a communistic society. 'Child Care Education Law', which is the legal foundation of the child care system, regulates institutions for nursery schools and kindergarten and informs people that the country is responsible for support of child care. Despite their interest and progress in both quantity and quality in the child care system until the 1980s, the free child care system was partially disrupted, and discrepancies between ideology and actual situation were revealed due to economic difficulties from the 1990s. Because people's survival and physical health have been threatened, it is barely possible to find any study investigating the effect of institutional child care from early childhood and the instillation of unique ideology by group education from the preschool period on mental health.

Alcohol Problems and Related Service Needs in Urban Korean Community / 정신신체의학

OBJECTIVES: The purpose of this study is to investigate the characteristics of drinking patterns and the prevalence of hazardous drinking and alcohol use disorder with the assessment of alcohol policy needs in community population of urban city in Korea. METHODS: Data was collected from 1,000 residents in a single urban city in Korea, from June 1 to July 31, 2011 by a questionnaire. As research tools, socio-demographic characteristics composed of variables based on study purpose, alcohol problems and alcohol use disorder state scales composed with Alcohol Use Disorder Identification Test(AUDIT) and Cut down, Annoyed, Guilty, Eye-opener(CAGE), and the assessment of alcohol policy needs in community population questions were used. RESULTS: The lifetime experience of alcohol drinking was 97.4%. For the frequency of drinking, 21.9% of population responded 2 to 4 times per weekly. 24.4% of male had one time or more high risk drinking, defined as having four or more drinks in a sitting, per week. 51.6% experienced the first time drinking of alcohol in adolescence. The lifetime prevalence of hazardous drinking and alcohol use disorder were 14.9% and 3.3%, respectively using AUDIT. Alcohol use disorder were 9.6% with the CAGE scale. Problem drinking were 8.4% in this study. They requested the program such as prevention education(57.2%), construction of liaison system to treatment facilities( 50.1%), alcohol counseling and intervention(41.7%), and rehabilitation program(39.8%). CONCLUSIONS: These results demonstrate that alcohol problem and alcohol use disorder were much prevalent, and these problem started in the earlier age. It is necessary to develop an effective alcohol prevention program or policy with considering the needs in community population.

Variables Influencing Drug Adherence in Patients with Alzheimer's Disease

OBJECTIVES: Many patients with Alzheimer's disease have difficulty in taking their medicine by themselves and their poor drug adherence possibly results in aggravating various symptoms. The aim of this study was to assess the variables influencing drug adherence of Alzheimer's disease patients. METHODS: In a four-week period, 33 outpatients over 65 years old diagnosed with Alzheimer's disease were monitored. Drug adherences were assessed by the Medication Event Monitoring System (MEMS), the pill count, the clinician rating scale, and self-report. Agreements among adherence measures and the relationships between MEMS adherence and other clinical factors were assessed. RESULTS: The adherence rates for the MEMS, the pill count, the clinician rating scale and, self-report were 51.5%, 82.8%, 82.8%, and 87.9%. The Kappa coefficients were 0.382 (pill count vs. MEMS, clinician rating scale vs. MEMS) and 0.256 (self-report vs. MEMS). Males showed better adherence than females but the other clinical variables did not show significant differences between adherence group and non-adherence group. CONCLUSION: These findings suggest that clinicians should be concerned when assessing drug adherence in patients with Alzheimer's disease only by subjective reporting and pill counting since these methods may make patient's adherence underestimate. Clinicians should also take in mind that caregivers play an important role in improving adherence.

Influence of Early Childhood Care and Education on Children's Mental Health (I) - Status and Prospects of Child Care and Education Policies of Korea -

Most preschool children in Korea attend kindergarten (KG) or a child care center (CCC). CCCs, which focus on caring for the child, belong to the ministry of health and welfare. On the other hand, KGs are responsible for education, and belong to the ministry of education, science and technology. In order to resolve the decline in population due to low birthrates, the government is expanding the free child care and education policies. CCCs and KGs are combined together to form the 'NURI curriculum' and supporting funds have been increased in both governmental departments. In addition, economic support is provided for homeschooling households. Because this is a nationwide policy and applies to every single household, thorough preparation regarding the effect and side effects must be made. This policy is currently being implemented, and as child and adolescent psychiatrists, great consideration should be given to the influence on the population. Therefore, the Korean Academy of Child and Adolescent Psychiatry intends to investigate the effects and problems of the nationwide policy by analyzing the current condition of Korea's free child care and education and foreign policies. In the current paper, we reviewed the developmental process of Korea's free child care and education policy, as well as suggested future directions.

Adherence with Electronic Monitoring and Symptoms in Children with Attention Deficit Hyperactivity Disorder

OBJECTIVE: The primary aim of this study was to compare electronic monitoring with other measures of adherence to Osmotic-controlled Release Oral delivery System methylphenidate in children with attention-deficit hyperactivity disorder (ADHD). The secondary aim was to analyze the relationships between adherence and clinical factors, including ADHD symptoms. METHODS: Thirty-nine children diagnosed with ADHD were monitored for adherence to medication over the course of eight weeks. Medication adherence was assessed using the Medication Event Monitoring System (MEMS), which is a bottle cap with a microprocessor that records all instances and times that the bottle is opened; patient self-report; clinician rating; and pill count. Information, including demographic and clinical characteristics, symptom rating scale, and psychological test results, were also collected. The relationships between adherence and clinical factors, including ADHD rating scores of baseline and of the changes, were assessed. RESULTS: The rate of non-adherence measured by the MEMS was found to be 46.2%, which was considerably higher than those of the patient self-report (17.9%), clinician rating (31.7%), and pill count (12.8%) of non-adherence. The rate of adherence measured by the MEMS was not significantly associated with baseline symptom severity or symptom changes over the eight weeks, although non-adherent group showed more severe baseline symptoms and inferior improvement. CONCLUSION: Adherence as measured by the MEMS showed a discrepancy with other measures of adherence in patients with ADHD. The symptom severity and level of improvement were not related to adherence with MEMS. Further studies are needed to evaluate the variables that may impact medication adherence in children with ADHD.

Treatment for Attention-Deficit/Hyperactivity Disorder in Adults

This review examined the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. It briefly addresses the issues about the cause of hospital visit, diagnosis, and impact of disease, specific to adults. The article focused on the evidence regarding the efficacy and tolerability of short- and long-acting stimulant medications, as well as the non-stimulant medications such as atomoxetine and bupropion in the treatment of the adult ADHD. Generally speaking, variability in diagnostic criteria, dosing parameters and response rates between the various studies were considerable. The aggregated literature shows that both the stimulants and non-stimulants had clinically significant beneficial effect on treating ADHD in adults. Special attention is given to the pharmacological treatment for patients with adult ADHD and various comorbidities. In summary, medications are effective and combined medication and psychosocial treatment is the most beneficial treatment option for most adult patients with ADHD.

Treatment for Attention-Deficit/Hyperactivity Disorder in Adults

This review examined the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. It briefly addresses the issues about the cause of hospital visit, diagnosis, and impact of disease, specific to adults. The article focused on the evidence regarding the efficacy and tolerability of short- and long-acting stimulant medications, as well as the non-stimulant medications such as atomoxetine and bupropion in the treatment of the adult ADHD. Generally speaking, variability in diagnostic criteria, dosing parameters and response rates between the various studies were considerable. The aggregated literature shows that both the stimulants and non-stimulants had clinically significant beneficial effect on treating ADHD in adults. Special attention is given to the pharmacological treatment for patients with adult ADHD and various comorbidities. In summary, medications are effective and combined medication and psychosocial treatment is the most beneficial treatment option for most adult patients with ADHD.

Characteristics of PMS and PMDD in Female College Students / 정신신체의학

OBJECTIVES: We investigated the prevalence and functional impairment of premenstrual dysphoric disorder (PMDD) and premenstrual syndrome(PMS) in young women. METHODS: A total of 1063 female college students were recruited from two urban areas(Seoul and Suwon) of Korea. Questionnaires for sociodemographic data and risk factors of PMDD, attitude about menstruation, and the Premenstrual Symptoms Screening Tool(PSST) were applied. RESULTS: The prevalence of severe moderate to severe PMS and PMDD were 16.9% and 11.7%, respectively. There were differences in the alcohol and coffee consumption, severity of menstrual cramp, and family history of PMS among the moderate to severe PMS, PMDD, and no/mild PMS groups. Although some participants did not fulfill diagnostic criteria for PMDD, they showed significant functional impairment. Participants with negative attitude about menstruation reported premenstrual symptoms more frequently than those with positive or ambivalent attitude about menstruation. CONCLUSION: These results suggest that PMS and PMDD were prevalent and associated with functional impairment in young females. Some participants reported significant functional impairments although they did not meet the full DSM-IV diagnostic criteria for PMDD. Negative attitude about menstruation was associated with more premenstrual symptoms experiences.

Effects of Long-Term Combination Treatment with Valproate and Atypical Antipsychotics on Bone Mineral Density and Bone Metabolism in Premenopausal Patients with Bipolar Disorder: A Preliminary Study

OBJECTIVE: We investigated bone mineral density (BMD) and bone metabolism in female bipolar patients who were undergoing long-term treatment with valproate combined with a low-dose atypical antipsychotic. METHODS: Nineteen premenopausal women with bipolar disorder who were treated with valproate combined with atypical antipsycho-tics for at least 2 years were evaluated. The BMD was measured at lumbar spine and femur sites using dual-energy X-ray absorptiometry (DE-XA). The biochemical markers of bone turnover and circulating levels of gonadal hormones were assessed. Subjects with abnormal DEXA scans were compared to those with normal scans. RESULTS: Nine (47%) of nineteen subjects showed osteopenia or osteoporosis. The T-score for subjects with abnormal DEXA scans was -1.988. Decreased BMD was more prominent in the proximal femur than in the lumbar spine. Subjects with abnormal DEXA scans had high phosphorus and low testosterone levels relative to subjects with normal scans (p=0.008 and p=0.028, respectively). There was a significant negative correlation between phosphorus, osteocalcin, and femur neck BMD (p<0.05). However, multivariate analysis did not show a significant association between femur and lumbar BMD and biochemical markers of bone turnover. CONCLUSION: Long-term treatment with valproate combined with low-dose atypical antipsychotics may adversely affect BMD in premenopausal women with bipolar disorder. A prospective, controlled-study with a larger population is warranted, and assessment of BMD and bone metabolism should be taken into consideration in long-term therapy with valproate and atypical antipsychotics.