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  1. 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.
  2. N Fountoulakis K, N Karakatsoulis G, Abraham S, Adorjan K, Ahmed HU, Alarcón RD, et al.
    Soc Psychiatry Psychiatr Epidemiol, 2023 Sep;58(9):1387-1410.
    PMID: 36867224 DOI: 10.1007/s00127-023-02438-8
    INTRODUCTION: The current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak.

    MATERIALS AND METHODS: The data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical 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: Clinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. 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 (24.64% vs. 9.62%; p 

  3. 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.

  4. 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.

  5. 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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