A multi-center, randomized, parallel-group study to compare the efficacy of enhanced cognitive behavior therapy (CBT-E) with treatment as usual (TAU) for anorexia nervosa: study protocol.

BACKGROUND: The superiority of Enhanced Cognitive Behavior Therapy (CBT-E) with regard to weight gain and improvement of psychopathology of eating disorders for patients with anorexia nervosa (AN) over other psychotherapies and treatment as usual (TAU) has not been demonstrated in randomized controlled trials (RCTs). However, a previous RCT showed that patients with AN whose baseline body mass index (BMI) was less than 17.5 kg/m2 gained more weight when treated with CBT-E than with other psychotherapies. The aim of the study is to compare the efficacy of CBT-E and TAU for patients with AN. It was hypothesized that CBT-E would be superior to TAU, at least in terms of weight gain, as most patients with AN are likely to have a BMI lower than 17.5 kg/m2. METHODS/DESIGN: A randomized parallel-group multicenter trial will be conducted in three teaching hospitals in Japan between January 2023 and March 2026. Patients with DSM-5 AN, aged 16 years and older, with a BMI equal to or above 14.0 and below 18.5 will be eligible to participate. 56 patients will be randomly and evenly assigned to two intervention groups (CBT-E and TAU). Those assigned to CBT-E will be offered 25-40 sessions in accordance with their initial BMI. Patients assigned to TAU will have at least one session every 2 weeks, with the number of sessions and treatment period not fixed in advance. The primary outcome is BMI at 40 weeks after treatment initiation. The secondary outcomes are the results from the Japanese version of the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment questionnaire to measure eating disorder psychopathology and psychological impairment. The follow-up assessment will be performed 6 months after the 40-week assessment. DISCUSSION: This multi-center randomized controlled study will probably evaluate the efficacy of CBT-E compared with TAU for patients with more severe AN than in previous studies since Japanese patients are likely to have a lower BMI than those in Western countries. While it may be difficult to generalize the results of a study conducted in Japan, it would be valuable to clarify the efficacy of CBT-E as a treatment package. TRIAL REGISTRATION: UMIN, UMIN000048847. Registered 12 Sep 2022.

Thrombocytopenia and PT-INR in patients with anorexia nervosa and severe liver dysfunction.

BACKGROUND: We previously reported a case that led us to hypothesize that decreased production of thrombopoietin (TPO) leads to thrombocytopenia in patients with anorexia nervosa (AN) with severe liver dysfunction and that prolonged prothrombin time-international normalized ratio (PT-INR) predicts thrombocytopenia in such cases. To validate this hypothesis, we report another case in which TPO levels were measured. In addition, we examined the association between prolonged PT-INR and thrombocytopenia in such patients. MAIN BODY: Similar to the previously reported patient, a patient with AN with severe liver dysfunction showed that TPO levels increased after improvements in liver enzyme levels and PT-INR, followed by recovery of platelet count. In addition, a retrospective study was also conducted to review patients with AN whose liver enzyme levels were > 3 × the upper limit of normal (aspartate aminotransferase > 120 U/L or alanine aminotransferase > 135 U/L). The study included 58 patients and showed a correlation coefficient of -0.486 (95% confidence interval [CI], -0.661 to -0.260; P < 0.001) between maximum PT-INR and minimum platelet count. These patients showed higher PT-INR (ß, 0.07; 95% CI, 0.02 to 0.13; P = 0.005) and lower platelet count (ß, -5.49; 95% CI, -7.47 to -3.52; P < 0.001) than the 58 matched control patients without severe liver dysfunction, even after adjusting for body mass index. CONCLUSIONS: In patients with AN with severe liver dysfunction, prolongation of PT-INR could predict thrombocytopenia, which may be mediated by decreased TPO production due to decreased hepatic synthetic function.

Increased prevalence of eating disorders in Japan since the start of the COVID-19 pandemic.

PURPOSE: The study aimed to investigate the effect of the COVID-19 pandemic on the prevalence of eating disorders in Japan. METHODS: We retrospectively reviewed the medical records of new patients with eating disorders who visited an outpatient eating disorders clinic of a single university hospital in Tokyo, Japan, from April 2020 to March 2021 (FY2020) and April 2019 to March 2020 (FY2019). We determined whether the onset or course in each patient in FY2020 was associated with the COVID-19 pandemic and classified COVID-19-associated medical histories into the following categories: (1) fatness phobia, (2) acceleration of dieting, (3) family relationships, (4) social factors, and (5) mood change. We performed the Kolmogorov-Smirnov test to compare the cumulative distribution of disease onset by month in FY2020 and FY2019. RESULTS: We reviewed the records of 112 and 77 patients with eating disorders in FY2020 and FY2019, respectively. The onset or course of 35 patients (31.3%) in FY2020 was associated with the COVID-19 pandemic. We classified 14 patients to fatness phobia category, 11 to acceleration of dieting, 4 to family relationships, 2 to social factors, and 4 to mood change. No COVID-19-associated cases were associated with fear of contracting the disease. The cumulative distribution of disease onset differed significantly in FY2020 and FY2019 (D = 0.248; P = 0.007). CONCLUSION: This chart review suggests that the COVID-19 pandemic may increase the prevalence of eating disorders. LEVEL OF EVIDENCE: III, cohort study.

Comparative study on nobiletin metabolism with liver microsomes from rats, Guinea pigs and hamsters and rat cytochrome p450.

In vitro metabolism of nobiletin, a polymethoxy-flavonoid abundantly present in citrus peels, was studied using liver microsomes of rats, hamsters and guinea pigs and ten cDNA-expressed rat cytochrome P450 (P450). The effects of P450 inducers on nobiletin metabolism were also investigated. Aerobical incubation with NADPH and animal liver microsomes transformed nobiletin to five metabolites, M-1, M-2, M-3, M-4 and M-5. From LC-MS and (1)H-NMR data and a time-course study, these were assumed to be 4'-hydroxy (OH)-, 7-OH-, 6-OH-, 3',4'-diOH- and 6,7-diOH-metabolites, respectively. Pretreatment of animals with phenobarbital increased M-2 and M-3 to about 2-fold that in untreated animals. Pretreatment with 3-methylcholanthrene (MC) resulted in remarkable increases of both M-1 and M-4 (3 to 9-fold that of untreated). Males had 2-3 times higher M-2 and M-3 formation activities in rats, and for M-2 in hamsters than did females. Immunoinhibition study using antiserum against P450 revealed the involvement of hamster CYP1A2 in the formation of M-1 and M-4 in hamster liver. Of ten rat P450s, CYP2C11, CYP3A1, CYP3A2 and CYP2D1 had high activities for the formation of M-1, M-2 and M-3. Another P450s (CYP1A1, CYP2C12 and CYP1A2) also showed activity for the formation of M-1. Only CYP1A1 produced 3',4'-diOH-metabolites (M-4). However, CYP2A1, CYP2B1 and CYP2E1 had no activity for nobiletin. These results suggested that constitutive P450s such as CYP2C11, CYP2D1, CYP3A1, CYP3A2 and CYP2C12 are responsible for the demethylation at the 6-, 7-, 3'- and 4'-positions; whereas, MC-inducible P450s, CYP1A1 and CYP1A2, preferentially catalyzed demethylation at the 3'-and 4'-positions.

[Metabolism of 2,2',4,5,5'-pentachlorobiphenyl (CB101) by liver microsomes of rats, hamsters and guinea pigs].

Our previous studies have shown that six metabolites, namely 3-hydroxy (OH)-, 3'OH-, 4'-OH-, 3',4'-dihydroxy (diOH)-, 3'-methylsulfone (CH3SO2)- and 4'-CH3SO2-2,2',4,5,5'-pentachlorobiphenyl (CB101), were found in the serum and liver of rats, hamsters and guinea pigs 4 days after administration of CB101. In this study, the in vitro metabolism of CB101 was studied using liver microsomes of rats, hamsters and guinea pigs, and the effect of cytochrome P450 inducers, phenobarbital (PB) and 3-methylcholanthrene (MC) on CB101 metabolism was also compared. 3-OH-, 3'-OH-, 4'-OH- and 3',4'-diOH-CB101 were formed by liver microsomes of rats, hamsters and guinea pigs except that 3-OH-CB101 was not formed by hamster liver microsomes. In untreated animals, both 3'-OH- and 4'-OH-CB101 were major metabolites. By treatment of PB, 3'-OH-CB101 was increased remarkably to 140-fold of untreated in rats and to 79-fold of untreated in hamsters, and was also increased slightly to 4-fold of untreated in guinea pigs. Moreover, PB-treatment showed a significant increase of 3', 4'-diOH-CB101 in rats and hamsters. In contrast, MC-treatment increased 4'-OH-CB101 to 2.0-, 9.6- and 3.4-fold of untreated animals in rats, hamsters and guinea pigs, respectively. In all animal species, the formation of 3',4'-diOH-CB101 from 3'-OH- and 4'-OH-CB101 proceeded at much higher rate than that from CB101 and was accelerated by PB-treatment. Only in hamster, MC-treatment decreased 3',4'-diOH-CB101 from 3'-OH- and 4'-OH-CB101 to less than 50% of untreated. Addition of 5 mM reduced glutathione suppressed the formation of 4'-OH-CB101 to 43% of control by liver microsomes of MC-treated hamsters, suggesting that 4'-OH-CB101 can be formed mainly via 3',4'-epoxide from CB101. These results indicate that the metabolism of CB101 to 3',4'-diOH-CB101 is principally catalyzed by CYP2B enzymes, which prefer 4'-OH- and 3'-OH-CB101 to CB101.