Update to the study protocol Face Your Fears: Virtual reality-based cognitive behavioral therapy (VR-CBT) versus standard CBT for paranoid ideations in patients with schizophrenia spectrum disorders: a randomized clinical trial.

We unfortunately need to make an update to our published study protocol that describes a significant change in the design of the study. The Committee on Health Research Ethics of the Capital Region Denmark recently rejected the approval of changing the primary outcome in the trial, on the invariable grounds that the trial has already commenced. It is therefore necessary to retain the Green Paranoid Thought Scale (GPTS) part B, ideas of persecution, as our primary outcome, and GPTS part A, ideas of social reference, as a secondary outcome, which is described opposite in our published study protocol. The exchange of outcomes has not affected participation in our trial or the informed consent. Intervention in both groups and assessments are unchanged. The two outcomes together constitute GPTS and the unifying concept we attempt to treat, namely paranoid ideations. As this is a blinded, methodologically rigorous trial, we did not have-and still do not have-access to preliminary data, and therefore, we have no knowledge of the distribution of our two intervention groups nor the potential effect of the intervention. The power calculation remains unchanged irrespective of the selection of the primary outcome. We have been fully transparent with the changes in primary and secondary outcomes on ClinicalTrials.gov throughout the trial. Due to the considerations mentioned above, we assumed that there would not be any ethical implications of the change of primary outcome. We sincerely apologize for the irregularity caused because of this assumption.Trial registrationClinicalTrials.gov NCT04902066 . Initial release April 19th, 2021.

Face Your Fears: Virtual reality-based cognitive behavioral therapy (VR-CBT) versus standard CBT for paranoid ideations in patients with schizophrenia spectrum disorders: a randomized clinical trial.

BACKGROUND: Schizophrenia spectrum disorders cause suffering for patients, relatives, and the surrounding society. Paranoid ideations, encompassing ideas of social reference and manifest persecutory delusions, are among the most frequent symptoms in this population and a cause of significant distress. Recent meta-analyses of cognitive behavioral therapy (CBT) for psychosis show small to moderate effect sizes in reducing paranoid ideations. Virtual reality-based CBT (VR-CBT) could improve therapy efficacy as exposure and behavioral experiments in VR can be optimized, individualized, and carried out in a safe environment. Few VR-CBT studies exist for paranoid ideations and there is a need for large-scale, methodologically rigorous trials. METHODS: This study is a randomized, assessor-blinded parallel-groups multi-center superiority clinical trial, fulfilling the CONSORT criteria for non-pharmacological treatment. A total of 256 patients diagnosed with schizophrenia spectrum disorder, including schizotypal disorder (ICD-10 F20-29), will be allocated to either 10 sessions of symptom-specific CBT-VR plus treatment as usual-versus 10 sessions of standard symptom-specific CBT for paranoid ideations (CBT) plus treatment as usual. All participants will be assessed at baseline, treatment end (3 months post baseline), and then 9 months post baseline. A stratified block-randomization with concealed randomization sequence will be conducted. Independent assessors blinded to the treatment will evaluate the outcome. Analysis of outcome will be carried out with the intention to treat principles. The primary outcome is ideas of social reference measured with Green Paranoid Thought Scale Part A (GPTS-A) at the cessation of treatment at 3 months post baseline. Secondary outcomes are ideas of persecution (GPTS-B), Social Interaction Anxiety Scale (SIAS), Personal and Social Performance scale (PSP), Safety Behavior Questionnaire (SBQ), and CANTAB Emotion Recognition Task. DISCUSSION: The trial will elucidate whether VR-CBT can enhance therapy efficacy for paranoid ideations. Additionally, Trial findings will provide evidence on the effectiveness and cost-effectiveness of VR-CBT for paranoid ideations that can guide the possible dissemination and implementation into clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04902066 . Initial release April 9th, 2021.

Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer.

The response of tumor cells to platinum-based chemotherapy involves DNA repair mechanisms. Excision repair cross-complementation group 1 (ercc1) is one of the leading genes involved in DNA repair, and several studies have linked ercc1 to platinum resistance in cell lines and in human cancers. A common single nucleotide polymorphism (SNP) of ercc1 at codon 118 has been proposed to impair ercc1 translation and reduce ERCC1 protein expression and consequently influence the response to platinum-based chemotherapy. The primary aim of the present study was to evaluate ERCC1 expression and ercc1 codon 118 polymorphism in epithelial ovarian cancer (EOC) and their possible predictive value in patients treated with platinum-based chemotherapy. Formalin-fixed, paraffin-embedded tissue sections from 159 patients with advanced EOC were used for immunohistochemistry. Ercc1 codon 118 SNP genotyping was performed by real-time polymerase chain reaction. ERCC1 protein overexpression was found in 37.7% of the tumors. The CA-125 response rate was 94.5% (52/55) in patients with ERCC1-negative tumors compared to 80% (36/45) in patients with ERCC1-positive tumors (P = 0.026, chi(2)). The T/T genotype (44%) signalized a better response to chemotherapy than C/C (15%) + C/T (41%) variants (P = 0.045, trend test). Patients with ERCC1-negative tumors appear to have significantly better response to platinum-based chemotherapy compared to patients with ERCC1-positive tumors, but the differences in response rates did not translate into differences in survival. In addition, the TT genotype seems to be favorable toward better response to platinum-based chemotherapy.

A fluvoxamine-caffeine interaction study.

The selective serotonin reuptake inhibitor fluvoxamine is a very potent inhibitor of the liver enzyme CYP1A2, which is the major P450 catalysing the biotransformation of caffeine. Thus, a pharmacokinetic study was undertaken with the purpose of documenting a drug-drug interaction between fluvoxamine and caffeine. The study was carried out as a randomized, in vivo, cross-over study including eight healthy volunteers. In Period A of the study, each subject took 200 mg caffeine orally, and in Period B, the subjects took fluvoxamine 50 mg per day for 4 days and 100 mg per day for 8 days. On day 8 in Period B, the subjects again ingested 200 mg caffeine. After caffeine intake, blood and urine were sampled at regular intervals. Caffeine and its three primary demethylated metabolites, paraxanthine, theobromine and theophylline in plasma and the same four compounds plus 11 more metabolites in urine were assayed by HPLC. During fluvoxamine, the median of the total clearance of caffeine decreased from 107 ml min-1 to 21 ml min-1 and the half-life increased from 5 to 31 h. The N3-demethylation clearance of caffeine to paraxanthine decreased from 46 to 9 ml min-1; the N1- and N7-demethylation clearances decreased from 21 to 9 ml min-1 and from 14 to 6 ml min-1, respectively. The results confirm that CYP1A2 is the main enzyme catalysing the biotransformation of caffeine, in particular the N3-demethylation and partly the N1- and N7-demethylation. The results indicate that intake of caffeine during fluvoxamine treatment may lead to caffeine intoxication. Finally, our study provides additional evidence that fluvoxamine can be used to probe CYP1A2 in drug metabolism.

The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine.

The selective serotonin reuptake inhibitor fluoxetine is administered as a racemic mixture, and R- and S-fluoxetine are metabolized in the liver by N-demethylation to R- and S-norfluoxetine, respectively. R- and S-fluoxetine and S-norfluoxetine are equally potent selective serotonin reuptake inhibitors, but R-norfluoxetine is 20-fold less potent in this regard. Racemic fluoxetine and norfluoxetine are potent inhibitors of cytochrome P450 (CYP) 2D6 in vivo and in vitro and recent studies in vivo have shown that racemic fluoxetine is metabolized by CYP2D6. The primary aim of the present study was to investigate the stereoselective metabolism of fluoxetine and norfluoxetine by CYP2D6 in vivo. A single oral dose of fluoxetine (60 mg) was administered to six poor and six extensive metabolizers of sparteine. Blood samples were collected during 6 weeks for poor metabolizers and 3 weeks for extensive metabolizers. Once a week a sparteine test was performed. The R- and S-enantiomers of fluoxetine and norfluoxetine were determined by a stereoselective gas chromatography-mass spectroscopy method. In the poor metabolizers, the oral clearance of R- and S-fluoxetine was 3.0 l/h and 17 l/h, respectively, the corresponding values in the extensive metabolizers were 36 l/h and 40 l/h, respectively. For both enantiomers, the phenotype difference was statistically significant. In poor metabolizers, the elimination half-lives were 6.9 days and 17.4 days for R- and S-norfluoxetine, respectively, and in the extensive metabolizers it was 5.5 days for both enantiomers, a significant phenotypical difference only for S-norfluoxetine. For fluoxetine the elimination half-lives were 9.5 and 6.1 days in poor metabolizers for the R- and S-enantiomer, respectively. The corresponding values in the extensive metabolizers were 2.6 and 1.1 days, respectively. Also for this parameter, the differences were statistically significant. This study shows that CYP2D6 catalyses the metabolism of R- and S-fluoxetine and most likely the further metabolism of S-norfluoxetine but not of R-norfluoxetine.

Fluvoxamine inhibits the CYP2C19-catalyzed bioactivation of chloroguanide.

OBJECTIVE: To investigate the interaction between fluvoxamine and chloroguanide (INN, proguanil) to confirm that fluvoxamine inhibits CYP2C19. METHODS: The study was carried out with a randomized, in vivo, crossover design. Six volunteers were extensive metabolizers of the S-mephenytoin oxidation polymorphism, and six volunteers were poor metabolizers. In period A of the study, each subject took 200 mg chloroguanide orally. In period B, each subject took 100 mg/day fluvoxamine for 8 days and on day 6 ingested 200 mg chloroguanide. In both periods, blood and urine were sampled at regular intervals. Chloroguanide and its two metabolites cycloguanil and 4-chlorphenylbiguanide in plasma and in urine were assayed by means of HPLC. RESULTS: During fluvoxamine use, the median of the total clearance of chloroguanide decreased in a statistically significant way from 1282 ml/min to 782 ml/min among the extensive metabolizers, whereas there was no change among the poor metabolizers. The partial clearance of chloroguanide by means of cydoguanil and 4-chlorphenylbiguanide formation among the extensive metabolizers decreased from 222 ml/min and 97 ml/min before to 33 ml/min and 11 ml/min during fluvoxamine intake, respectively. Among poor metabolizers the corresponding values were 35 ml/min and 7.6 ml/min before and 38 ml/min and 6.9 ml/min during fluvoxamine intake. For each metabolite clearance the change was statistically significant among the extensive metabolizers but not among the poor metabolizers. Both cycloguanil and 4-chlorphenylbiguanide formation clearances were statistically significantly higher among the extensive metabolizers than the poor metabolizers in period A but not in period B (phenocopy). CONCLUSION: Fluvoxamine is an effective inhibitor of CYP2C19.

Statins and risk of polyneuropathy: a case-control study.

BACKGROUND: Several case reports and a single epidemiologic study indicate that use of statins occasionally may have a deleterious effect on the peripheral nervous system. The authors therefore performed a population-based study to estimate the relative risk of idiopathic polyneuropathy in users of statins. METHOD: The authors used a population-based patient registry to identify first-time-ever cases of idiopathic polyneuropathy registered in the 5-year period 1994 to 1998. For each case, validated according to predefined criteria, 25 control subjects were randomly selected among subjects from the background population matched for age, sex, and calendar time. The authors used a prescription register to assess exposure to drugs and estimated the odds ratio of use of statins (ever and current use) in cases of idiopathic polyneuropathy compared with control subjects. RESULTS: The authors verified a diagnosis of idiopathic polyneuropathy in 166 cases. The cases were classified as definite (35), probable (54), or possible (77). The odds ratio linking idiopathic polyneuropathy with statin use was 3.7 (95% CI 1.8 to 7.6) for all cases and 14.2 (5.3 to 38.0) for definite cases. The corresponding odds ratios in current users were 4.6 (2.1 to 10.0) for all cases and 16.1 (5.7 to 45.4) for definite cases. For patients treated with statins for 2 or more years the odds ratio of definite idiopathic polyneuropathy was 26.4 (7.8 to 45.4). CONCLUSIONS: Long-term exposure to statins may substantially increase the risk of polyneuropathy.

[Women's attitude towards gynecologic examinations]. / Kvinders holdning til den gynaekologiske undersøgelse.

Twelve women aged between 27 and 76 years were interviewed one week before hospitalization for a planned gynaecological operation with the aim of illustrating their experience of the pelvic examination. The study demonstrated that women's experience of pelvic examination was unpleasant when the communication between the women and the doctors was poor. The pelvic examination could be a positive experience, if the doctor gave information about the procedure and about the findings. Information about the genitals' anatomy could also diminish the discomfort of the situation. The oldest women had the least experience of pelvic examination.

The prognostic importance of cyclooxygenase 2 and HER2 expression in epithelial ovarian cancer.

Both cyclooxygenase 2 (COX2) and human epidermal growth factor receptor 2 (HER2, also called c-erbB-2) overexpression have been related to a worse prognosis in epithelial ovarian cancer (EOC), but the data are conflicting and the percentage of tumors with overexpression varies widely in different studies. The aim of this study was to investigate the potential prognostic value of COX2 and HER2 expression in EOC. A further purpose was to investigate a possible coexpression of the two markers, and finally, to elucidate the agreement between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for evaluation of the HER2 status in EOC. Immunostaining was performed for COX2/HER2 together with FISH analysis for HER2 gene amplification in 160 patients with EOC, FIGO stages IIB-IV. Follow-up was more than 10 years. COX2 overexpression was found in 20.0% of the tumors. With HER2 staining, 64.4% were scored as 0, 24.4% as 1+, 6.9% as 2+, and 4.4% as 3+. Median survival time for COX2-negative tumors was 21.6 versus 36 months for COX2-positive tumors. The longer survival for COX2 positive was significant by both univariate analysis (P= 0.015) and multivariate analysis (P= 0.025). Positive immunostaining for HER2 was associated with poor overall survival (P= 0.03). Agreement between IHC and FISH was seen in all cases (P < 0.0000001). With long-term observation, patients with negative COX2 expression had significantly shorter survival compared to patients with COX2-positive tumors. Positive HER2 expression also notified a grave prognosis, but the low rate of overexpression reduces its potential clinical application.

Griseofulvin and fluvoxamine interactions with the metabolism of theophylline.

Theophylline is predominantly metabolized by cytochrome P4501A2 (CYP1A2). A possible interaction between griseofulvin and theophylline was reported to our laboratory, which led us to form the hypothesis that griseofulvin induces the metabolism of theophylline. One purpose of this study was to investigate this hypothesis. The study was carried out as a randomized crossover study of 12 healthy volunteers. In period A of the study, each volunteer received a single dose of 300 mg theophylline ethylenediamine orally. In period B, the subjects took fluvoxamine, 50 mg for 1 day and 100 mg for 6 days, and on day 4, the subjects ingested 300 mg theophylline ethylenediamine. Fluvoxamine is a potent inhibitor of CYP1A2, and period B was included as a positive control. In period C, the subjects took 500 mg griseofulvin for 9 days; on day 8 the subjects again ingested 300 mg theophylline ethylenediamine. Theophylline and its metabolites (1-methyluric acid [IMU], 3-methylxanthine [3MX], and 1,3-dimethyluric acid [13DMU]) in plasma and urine were assayed by high-performance liquid chromatography. During fluvoxamine intake, the median of the total clearance of theophylline decreased from 80 ml/min to 24 ml/min, and the half-life increased from 6.6 to 22 h. The partial formation clearances of the metabolites decreased from 17 to 1.7 ml/min, from 8.9 to 0.9 ml/min, and from 21 to 6.8 ml/min for 1MU, 3MX, and 13DMU, respectively. The results confirm that assessment of theophylline metabolism indeed serves as a biomarker for CYP1A2. During griseofulvin ingestion, the median of the total and partial clearances of theophylline were 84 ml/min, 22 ml/min (1MU), 9.4 ml/min (3MX), and 25 ml/min (13DMU). The half-life decreased significantly from 6.6 to 5.7 h. The increase in partial formation clearances of 1MU and 13DMU, but not of 3MX, were statistically significant. The increase in the total clearance reached only borderline significance. In four subjects a marked induction was seen for all pharmacokinetic parameters, suggesting that the susceptibility to induction is more pronounced in some subjects. This susceptibility could theoretically be explained by a polymorphism in the inducibility of the gene coding for the CYP1A2 enzyme.

Statins and peripheral neuropathy.

Within the past 3 years seven cases of reversible peripheral neuropathy apparently caused by statins have been reported. Here we report seven additional cases associated with long-term statin therapy, in which other causes of neuropathy were thoroughly excluded. The neuropathy was in all cases axonal and with affection of both thick and thin nerve fibers. The symptoms of neuropathy persisted during an observation period lasting from 10 weeks to 1 year in four cases after statin treatment had been withdrawn. We suggest that long-term statin treatment may be associated with chronic peripheral neuropathy.

Effect of grapefruit juice on Sandimmun Neoral absorption among stable renal allograft recipients.

BACKGROUND: The oral formulation of cyclosporin A (CsA)-Sandimmun-has a highly variable absorption. The development of a CsA microemulsion-Sandimmun Neoral-resulted in increased bioavailability, and decreased variability of absorption. The first oral formulation (Sandimmun) interacted with numerous other drugs and grapefruit juice. Several of these interactions might be explained by decreased pre-systemic metabolism by a cytochrome-enzyme (e.g. CYP3A4) located in the enteral mucosa, and/or via the P-glycoprotein-mediated decreased transport of CsA back from enterocytes into the gut lumen. The purpose of this pharmacokinetic study was to investigate the interaction between Sandimmun Neoral and grapefruit juice. METHOD: Eight stable renal transplant recipients were studied during two 8-h sessions in a randomized cross-over design with 4 weeks interval. Following an overnight fast the patients ingested their habitual morning dose of Neoral either with water or with grapefruit juice. During the 8-h study period 10 blood samples were taken for determination of CsA concentration. These results formed the basis for calculation of area under curve (AUC), and half-life (t(1/2)). Maximum concentration (C(max)) and time until C(max) (t(max)) were obtained from the concentration-time profile. RESULTS: The median AUC increased by 38% (12-194%) (P<0.05) following co-administration of Neoral with grapefruit juice. There were no significant changes in C(max), t(max), and t((1/2)). CONCLUSION: Co-administration of Sandimmun Neoral with grapefruit juice resulted in an increased bioavailability of CsA, indicating unchanged pre-systemic enterocyte first-pass metabolism as compared to Sandimmun. There was no impact of an oral grapefruit juice load on systemic clearance of CsA. It seems prudent to advise renal allograft recipients treated with Sandimmun Neoral not to ingest their medication with grapefruit juice.

Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine.

OBJECTIVE: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. METHODS: The study was carried out as an in vivo single-dose study including 24 young, healthy men. All volunteers had been identified as sparteine- and mephenytoin-extensive metabolisers. The volunteers received in randomised order, at weekly intervals, increasing single oral doses of one of the four SSRIs, followed 3 h later by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given in doses of 25, 50, 100 and 200 mg. RESULTS: With increasing doses, there was a statistically significant increase in the sparteine metabolic ratio (MR) (P < 0.01, Page's test for trend) for all four SSRIs. The increase was modest after intake of citalopram and fluvoxamine, while the increase was more pronounced after fluoxetine intake, although no volunteers changed phenotype from extensive metabolisers to poor metabolisers. Three of the six volunteers changed phenotype from extensive metabolisers to poor metabolisers after intake of 40 or 80 mg paroxetine. There was a statistically significant increase in the mephenytoin S/R ratio (P < 0.01, Page's test for trend) with increasing doses of fluoxetine and fluvoxamine, but not after citalopram and paroxetine. However, no volunteers changed phenotype from extensive to poor metabolisers of S-mephenytoin. After intake of fluvoxamine, the urinary excretion of the metabolites related to N3 demethylation of caffeine were below the limit of quantification, whereas there were no significant changes in the urinary caffeine metabolic ratios after intake of the other three SSRIs. CONCLUSION: This investigation confirms that paroxetine and fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady-state after multiple doses into account.