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  1. Razali S, Tukhvatullina D, Hashim NA, Raduan NJN, Anne SJ, Ismail Z, et al.
    East Asian Arch Psychiatry, 2022 Dec;32(4):82-88.
    PMID: 36578182 DOI: 10.12809/eaap2204
    OBJECTIVES: To determine the prevalence of depression and the sociodemographic factors associated with depression in Malaysia during the COVID-19 pandemic METHODS. This study is part of the COVID-19 Mental Health International Study to collect data on the impact of the pandemic on mental health through an online survey. People who were aged ≥18 years, able to read Malay or English, had access to the internet, and consented to participate were asked to complete a pro forma questionnaire to collect their sociodemographic data. The presence of distress and depression was assessed using the English or Malay version of the Center for Epidemiologic Studies Depression Scale.

    RESULTS: Of 963 participants, 451 (46.8%) had depression and 512 (53.2%) had no depression who were either normal (n = 169, 17.5%) or had distress (n = 343, 35.6%). Participants had higher odds of having depression when living with two people (adjusted odds ratio [AOR] = 3.896, p = 0.001), three people (AOR = 2.622, p < 0.001) or four people (AOR = 3.135, p < 0.001). Participants with three children had higher odds of having depression (AOR = 2.084, p = 0.008), whereas having only one child was a protective factor for depression (AOR = 0.481, p = 0.01). Participants had higher odds of having depression when self-employed (AOR = 3.825, p = 0.003), retired (AOR = 4.526, p = 0.001), being housekeeper (AOR = 7.478, p = 0.004), not working by choice (AOR = 5.511, p < 0.001), or unemployed (AOR = 3.883, p = 0.009). Participants had higher odds of depression when living in a small town (AOR = 3.193, p < 0.001) or rural area (AOR = 3.467, p < 0.001). Participants with no chronic medical illness had lower odds of having depression (AOR = 0.589, p = 0.008).

    CONCLUSION: In Malaysia during the COVID-19 pandemic, people who are living with two, three, or four people, having three children, living in a small town or rural areas, and having unstable income have higher odds of having depression. Urgent intervention for those at risk of depression is recommended.

  2. Fountoulakis KN, Alias NA, Bjedov S, Fountoulakis NK, Gonda X, Hilbig J, et al.
    Front Psychiatry, 2023;14:1320156.
    PMID: 38293595 DOI: 10.3389/fpsyt.2023.1320156
    INTRODUCTION: The aim of the study was to search rates of depression and mental health in university students, during the COVID-19 pandemic.

    MATERIALS AND METHODS: This is an observational cross-sectional study. A protocol gathering sociodemographic variables as well as depression, anxiety and suicidality and conspiracism was assembled, and data were collected anonymously and online from April 2020 through March 2021. The sample included 12,488 subjects from 11 countries, of whom 9,026 were females (72.2%; aged 21.11 ± 2.53), 3,329 males (26.65%; aged 21.61 ± 2.81) and 133 "non-binary gender" (1.06%; aged 21.02 ± 2.98). The analysis included chi-square tests, correlation analysis, ANCOVA, multiple forward stepwise linear regression analysis and Relative Risk ratios.

    RESULTS: Dysphoria was present in 15.66% and probable depression in 25.81% of the total study sample. More than half reported increase in anxiety and depression and 6.34% in suicidality, while lifestyle changes were significant. The model developed explained 18.4% of the development of depression. Believing in conspiracy theories manifested a complex effect. Close to 25% was believing that the vaccines include a chip and almost 40% suggested that facemask wearing could be a method of socio-political control. Conspiracism was related to current depression but not to history of mental disorders.

    DISCUSSION: The current study reports that students are at high risk for depression during the COVID-19 pandemic and identified specific risk factors. It also suggested a role of believing in conspiracy theories. Further research is important, as it is targeted intervention in students' groups that are vulnerable both concerning mental health and conspiracism.

  3. Bauer M, Glenn T, Alda M, Andreassen OA, Angelopoulos E, Ardau R, et al.
    Eur. Psychiatry, 2015 Jan;30(1):99-105.
    PMID: 25498240 DOI: 10.1016/j.eurpsy.2014.10.005
    PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.

    METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.

    RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.

    CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

  4. Bauer M, Glenn T, Alda M, Andreassen OA, Angelopoulos E, Ardau R, et al.
    J Affect Disord, 2014;167:104-11.
    PMID: 24953482 DOI: 10.1016/j.jad.2014.05.032
    The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode.
  5. Bauer M, Glenn T, Alda M, Andreassen OA, Angelopoulos E, Ardau R, et al.
    J Psychiatr Res, 2015 May;64:1-8.
    PMID: 25862378 DOI: 10.1016/j.jpsychires.2015.03.013
    Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association.
  6. Bauer M, Glenn T, Alda M, Aleksandrovich MA, Andreassen OA, Angelopoulos E, et al.
    Acta Psychiatr Scand, 2017 Dec;136(6):571-582.
    PMID: 28722128 DOI: 10.1111/acps.12772
    OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.

    METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density.

    RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001).

    CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

  7. Bauer M, Glenn T, Alda M, Andreassen OA, Angelopoulos E, Ardau R, et al.
    J Psychiatr Res, 2019 06;113:1-9.
    PMID: 30878786 DOI: 10.1016/j.jpsychires.2019.03.001
    In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p 
  8. de Leon J, Schoretsanitis G, Smith RL, Molden E, Solismaa A, Seppälä N, et al.
    Pharmacopsychiatry, 2021 Dec 15.
    PMID: 34911124 DOI: 10.1055/a-1625-6388
    This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.
  9. Bauer M, Glenn T, Achtyes ED, Alda M, Agaoglu E, Altınbaş K, et al.
    Int J Bipolar Disord, 2021 Sep 01;9(1):26.
    PMID: 34467430 DOI: 10.1186/s40345-021-00231-7
    BACKGROUND: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries.

    METHODS: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries).

    RESULTS: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p 

  10. Bauer M, Glenn T, Achtyes ED, Alda M, Agaoglu E, Altınbaş K, et al.
    Int J Bipolar Disord, 2023 Jun 22;11(1):22.
    PMID: 37347392 DOI: 10.1186/s40345-023-00303-w
    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.

  11. Fountoulakis KN, Karakatsoulis GN, Abraham S, Adorjan K, Ahmed HU, Alarcón RD, et al.
    CNS Spectr, 2024 Apr;29(2):126-149.
    PMID: 38269574 DOI: 10.1017/S1092852924000026
    BACKGROUND: The prevalence of medical illnesses is high among patients with psychiatric disorders. The current study aimed to investigate multi-comorbidity in patients with psychiatric disorders in comparison to the general population. Secondary aims were to investigate factors associated with metabolic syndrome and treatment appropriateness of mental disorders.

    METHODS: The sample included 54,826 subjects (64.73% females; 34.15% males; 1.11% nonbinary gender) from 40 countries (COMET-G study). The analysis was based on the registration of previous history that could serve as a fair approximation for the lifetime prevalence of various medical conditions.

    RESULTS: About 24.5% reported a history of somatic and 26.14% of mental disorders. Mental disorders were by far the most prevalent group of medical conditions. Comorbidity of any somatic with any mental disorder was reported by 8.21%. One-third to almost two-thirds of somatic patients were also suffering from a mental disorder depending on the severity and multicomorbidity. Bipolar and psychotic patients and to a lesser extent depressives, manifested an earlier (15-20 years) manifestation of somatic multicomorbidity, severe disability, and probably earlier death. The overwhelming majority of patients with mental disorders were not receiving treatment or were being treated in a way that was not recommended. Antipsychotics and antidepressants were not related to the development of metabolic syndrome.

    CONCLUSIONS: The finding that one-third to almost two-thirds of somatic patients also suffered from a mental disorder strongly suggests that psychiatry is the field with the most trans-specialty and interdisciplinary value and application points to the importance of teaching psychiatry and mental health in medical schools and also to the need for more technocratically oriented training of psychiatric residents.

  12. Bauer M, Glenn T, Achtyes ED, Alda M, Agaoglu E, Altınbaş K, et al.
    J Psychosom Res, 2022 Sep;160:110982.
    PMID: 35932492 DOI: 10.1016/j.jpsychores.2022.110982
    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.

  13. Fountoulakis KN, Vrublevska J, Abraham S, Adorjan K, Ahmed HU, Alarcón RD, et al.
    J Affect Disord, 2024 May 01;352:536-551.
    PMID: 38382816 DOI: 10.1016/j.jad.2024.02.050
    BACKGROUND: The COVID-19 pandemic has brought significant mental health challenges, particularly for vulnerable populations, including non-binary gender individuals. The COMET international study aimed to investigate specific risk factors for clinical depression or distress during the pandemic, also in these special populations.

    METHODS: Chi-square tests were used for initial screening to select only those variables which would show an initial significance. Risk Ratios (RR) were calculated, and a Multiple Backward Stepwise Linear Regression Analysis (MBSLRA) was followed with those variables given significant results at screening and with the presence of distress or depression or the lack of both of them.

    RESULTS: The most important risk factors for depression were female (RR = 1.59-5.49) and non-binary gender (RR = 1.56-7.41), unemployment (RR = 1.41-6.57), not working during lockdowns (RR = 1.43-5.79), bad general health (RR = 2.74-9.98), chronic somatic disorder (RR = 1.22-5.57), history of mental disorders (depression RR = 2.31-9.47; suicide attempt RR = 2.33-9.75; psychosis RR = 2.14-10.08; Bipolar disorder RR = 2.75-12.86), smoking status (RR = 1.15-5.31) and substance use (RR = 1.77-8.01). The risk factors for distress or depression that survived MBSLRA were younger age, being widowed, living alone, bad general health, being a carer, chronic somatic disorder, not working during lockdowns, being single, self-reported history of depression, bipolar disorder, self-harm, suicide attempts and of other mental disorders, smoking, alcohol, and substance use.

    CONCLUSIONS: Targeted preventive interventions are crucial to safeguard the mental health of vulnerable groups, emphasizing the importance of diverse samples in future research.

    LIMITATIONS: Online data collection may have resulted in the underrepresentation of certain population groups.

  14. Fountoulakis KN, Karakatsoulis G, Abraham S, Adorjan K, Ahmed HU, Alarcón RD, et al.
    Eur Neuropsychopharmacol, 2022 Jan;54:21-40.
    PMID: 34758422 DOI: 10.1016/j.euroneuro.2021.10.004
    INTRODUCTION: There are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study.

    MATERIAL AND METHODS: During the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively.

    STATISTICAL ANALYSIS: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables.

    RESULTS: Probable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed.

    CONCLUSIONS: The final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them.

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