The use of ketamine to cope with depression and post-traumatic stress disorder:A qualitative analysis of the discourses posted on a popular online forum

Background Because of the shortcomings of traditional pharmacotherapy for major depressive disorder and post-traumatic stress disorder (PTSD), there has been growing interest in the rapid mood-enhancing effect of ketamine. Objectives To analyze what has been posted about ketamine use for dealing with self-reported depression and/or PTSD on one of the biggest international message boards on the internet. Methods Qualitative study with online observation of threaded discussions on Bluelight. In-depth online searches were conducted in 2018. Twenty-nine threads, with a total of 708 units of analysis, were selected and subjected to content analysis, where, via a coding process, the units of analysis were organized into nodes. Results Despite having several negative effects (e.g. dizziness, nausea and inability to talk), the examined discourses suggested that the use of ketamine to elevate mood was both efficient and worthwhile. Intranasal use was the most common route of administration mentioned. We traced how the mood enhancement caused by ketamine is perceived: the loss of pleasure disappears, as well as the depressed mood; the markedly diminished interest in activities vanishes and motivation comes back. From all the posts analyzed, only two reported negative outcomes (i.e. no mood-enhancing effect). The most mentioned adverse event was damage to the urinary bladder and the kidneys in cases of misuse. Conclusion Although online research of user-generated content has its limitations in terms of reliability and validity, the present study adds relevant information on the use of ketamine for managing depression and PTSD, whether this use is done legally or not

Inflammation-mediated Phenoconversion: A Potential Threat to COVID-19 Pharmacotherapy

One of the important hallmarks of coronavirus disease 2019 (COVID-19) is the existence of severe inflammatory responses. Many reports indicated that inflammatory mediators might suppress the biological functions of some drug metabolizing enzymes and transporters, and therefore result in a transient mismatch between their genotype and phenotype expressions, a phenomenon which is called phenoconversion. The incidence might be clinically relevant to the COVID-19 patients with comorbidities. The patients are treated with multiple drugs that are prone to be altered pharmacokinetically by inflammation-mediated phenoconversion, leading to the modification of their effectiveness and safety. In this review, we discuss the regulation of inflammatory responses during COVID-19 infection and the evidence as well as potential mechanisms of inflammation-mediated phenoconversion. We also provide possible clinical implications of such phenoconversion events as a potential threat in the management of COVID-19 patients

Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies

Economic evaluations of pharmacogenetic and pharmacogenomic screening tests : a systematic review : second update of the literature

Objective : Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. Methods : A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. Results : We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing. Conclusions : Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests' efficacy remains of utmost importance

No significant association of type 2 diabetes-related genetic risk scores with glycated haemoglobin levels after initiating metformin or sulphonylurea derivatives

AIM: To explore the added value of diabetes-related genetic risk scores (GRSs) to readily available clinical variables in the prediction of glycated haemoglobin (HbA1c) levels after initiation of glucose-regulating drugs. MATERIALS AND METHODS: We conducted a cohort study in people with type 2 diabetes (T2DM) from the Groningen Initiative to Analyse Type 2 Diabetes Treatment (GIANTT) database who initiated metformin (MET) or sulphonylurea derivatives (SUs) and for whom blood samples were genotyped. The primary outcome was HbA1c level at 6 months, adjusted for baseline HbA1c. GRSs were based on single nucleotide polymorphisms linked to insulin sensitivity, β-cell activity, and T2DM risk in general. Associations were analysed using multiple linear regression to assess whether adding the GRSs increased the explained variance in a prediction model that included age, gender, diabetes duration and cardio-metabolic biomarkers. RESULTS: We included 282 patients initiating MET and 89 patients initiating SUs. In the MET prediction model, diabetes duration of >3 months when starting MET was associated with 2.7-mmol/mol higher HbA1c level. For SUs, no significant clinical predictors were identified. Addition of the GRS linked to insulin sensitivity (for MET), β-cell activity (for SUs) and T2DM risk (for both) to the models did not improve the explained variance significantly (22% without vs. 22% with GRS) for the MET and (14% without vs. 14% with GRS) for the SUs model, respectively. CONCLUSION: This study did not indicate a significant effect of GRS related to T2DM in general or to the drugs' mechanism of action for prediction of inter-individual HbA1c variability in the short term after initiation of MET or SU therapy

National differences in requirements for ethical and competent authority approval for a multinational vaccine trial under the EU directive 2001/20/EC

Obtaining approval for a multinational vaccine trial from an ethics committee and the national competent authority of different Member States of the European Union (EU) is challenging under clinical trial Directive 2001/20/EC because of the differences in the implementation of the directive in national laws of Member States. In this review the national differences in requirements for ethical and competent authority approval are illustrated. The national ethical and competent authority review procedures in Finland, Hungary, The Netherlands, Norway and Slovenia are described under the EU trial directive after discussing the provisions of the trial directive related to both review procedures. The review illustrates the differences between the countries in the documents that have to be submitted for the review procedures, the submission procedures and the language requirements of the documents, the organization of the ethics committees and the role of the competent authority in the approval procedure

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone

Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score1 (P valu

The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug–drug interaction (DDI):Co-medication of metoprolol and paroxetine or fluoxetine in the elderly

Purpose: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. Method: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (60years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. Results: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences=3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences=1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences=2320) than paroxetine/fluoxetine users (incidences=1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD=0.47) regardless whether they were prescribed paroxetine/fluoxetine. Conclusion: Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation

Clinical response to antipsychotic drug treatment:Association study of polymorphisms in six candidate genes

AbstractPharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response

Nationwide analysis of treatment outcomes in children and adolescents routinely treated for tuberculosis in The Netherlands

Background: As a vulnerable population, children and adolescents with tuberculosis (TB) are faced with many challenges, even those who live in low TB incidence countries. We aimed to evaluate factors associated with TB treatment outcomes allowing more focused interventions to support this population once diagnosed. Methods: A retrospective cohort study using a nationwide surveillance database was performed in children and adolescents (aged 0-18 years) treated for TB in the Netherlands from 1993 to 2018. Logistic regression analyses were used to estimate adjusted odds ratios (aOR) for associated factors of mortality and loss to follow-up (LTFU). Results: Among 3253 eligible patients with known outcomes, 94.4% (95.9% children and 92.8% adolescents) were cured or completed treatment, 0.7% died during treatment and 4.9% were LTFU. There were no reported treatment failures. Risk factors of death included children aged 2-4 years (aOR 10.42), central nervous system TB (aOR 5.14), miliary TB (aOR 10.25), HIV co-infection (aOR 8.60), re-treated TB cases (aOR 10.12) and drug-induced liver injury (aOR 6.50). Active case-finding was a protective factor of death (aOR 0.13). Risk factors of LTFU were adolescents aged 15-18 years (aOR 1.91), illegal immigrants (aOR 4.28), urban domicile (aOR 1.59), unknown history of TB contact (aOR 1.99), drug-resistant TB (aOR 2.31), single adverse drug reaction (aOR 2.12), multiple adverse drug reactions (aOR 7.84) and treatment interruption >14 days (aOR 6.93). Treatment in recent years (aOR 0.94) and supervision by public health nurses (aOR 0.14) were protective factors of LTFU. Conclusion: Highly successful treatment outcomes were demonstrated in children and adolescents routinely treated for TB. Special attention should be given to specific risk groups to improve treatment outcomes