A survey was conducted to determine attitudes, knowledge, and educational needs of mental health professionals regarding pharmacogenomics. We recruited 128 clinicians working in mental health in England, and we assessed their experiences using an adapted version of the “U‐PGx Clinician’s Questionnaire”. Responding clinicians had positive attitudes towards pharmacogenomics testing, although they lacked confidence in ordering and interpreting tests, for which most had never received any formal training. Only 6% of clinicians answered all 4 knowledge testing questions correctly, and barriers to clinical implementation included lack of familiarity and knowledge for several pharmacogenomics concepts, such as drug metabolism and genetics, as well as needing support from their working institution. Looking ahead, we found that accredited workshops and patient cases were preferred learning formats, and we suggest tailored education programmes to enable mental health professionals to apply pharmacogenomics in clinical practice.

Background/Objectives: Antipsychotic treatment response varies considerably between individuals, with one potential reason being genetic variation affecting the cytochrome P450 enzymes that metabolise them. Methods: With a diverse sample of 453 participants, we studied the influence of CYP1A2, CYP2D6, and CYP3A4 variation on three antipsychotic treatment outcomes: participant-reported adverse antipsychotic drug reactions, health-related quality of life, and the dose of antipsychotic medication prescribed. These measures were taken from the baseline assessment, before a pharmacogenetic intervention was delivered. Results: Over half of our sample (62.9%) were carriers of an allele associated with altered metabolism of antipsychotic medications on CYP2D6 or CYP3A4, the two genes with pharmacogenetic guidelines for antipsychotic medications. Ultrarapid CYP2D6 metabolisers reported significantly lower levels of adverse antipsychotic drug reactions than normal CYP2D6 metabolisers (mean difference: −11.1; 95% confidence interval [CI]: −18.9, −3.3; p = 0.00575). There was also suggestive evidence of lower quality of life scores in those carrying one (mean difference: −0.0863; 95% CI: −0.1806, 0.0081; p = 0.0731) or two copies (mean difference: −0.0803; 95% CI: −0.1734, 0.0129; p = 0.0914) of the CYP1A2*30-inducible allele. Conclusions: Our findings suggest that even when looking at a small number of cytochrome P450 genes, carrying an allele associated with altered antipsychotic medication metabolism is relatively common. We also found evidence that the CYP genotype can influence antipsychotic treatment outcomes, specifically adverse drug reactions and quality of life scores.

Clozapine is licenced for treatment‐resistant schizophrenia and psychosis in Parkinson's disease. In the United Kingdom, there is a mandatory requirement for absolute neutrophil count (ANC) and white blood cell count (WBC) monitoring to safeguard against agranulocytosis. Some people have naturally low ANCs without increased infection risk, caused by a homozygous T > C variant in ACKR1 , commonly called the Duffy‐null genotype. This condition is known as ADAN ( ACKR1 / DARC ‐associated neutropenia) and synonyms include DANC (Duffy‐null associated neutrophil count) and BEN (benign ethnic neutropenia). It is usual UK practice to lower WBC/ANC thresholds for people confirmed to have ADAN. However, ADAN often remains undetected, resulting in unnecessary discontinuation and exclusion from clozapine. This CERSI‐PGx guideline provides a framework to offer ACKR1 genotype testing within the existing clinical pathway. We recommend three eligibility criteria, including pre‐emptive testing for all people starting clozapine, testing for people registered in the Central Non‐Rechallenge Database and reactive testing following a below‐threshold blood result (defined as ‘amber’ or ‘red’). We recommend that people with the Duffy‐null genotype should be monitored using revised WBC/ANC thresholds for ADAN. Regardless of ACKR1 genotype, haematology input is required for people returning a WBC < 2.0 × 10 ⁹ /L and/or ANC < 1.0 × 10 ⁹ /L who present with a key clinical feature, such as sustained temperature ≥38°C. Finally, we summarize health economic evidence, estimating in the first year of testing, 129 people with the Duffy‐null genotype could be identified, resulting in savings ranging from £42 732 to £727 990. We propose ACKR1 testing as a cost‐effective approach for facilitating access to clozapine, the optimal therapy for treatment‐resistant schizophrenia.

BACKGROUND AND AIMS: Survival rates for esophageal squamous cell carcinoma (ESCC) are extremely low due to the late diagnosis of most cases. An understanding of the early molecular processes that lead to ESCC may facilitate opportunities for early diagnosis; however, these remain poorly defined. Tylosis with esophageal cancer (TOC) is a rare syndrome associated with a high lifetime risk of ESCC and germline mutations in RHBDF2, encoding iRhom2. Using TOC as a model of ESCC predisposition, this study aimed to identify early-stage transcriptional changes in ESCC development. METHODS: Esophageal biopsies were obtained from control and TOC individuals, the latter undergoing surveillance endoscopy, and adjacent diagnostic biopsies were graded as having no dysplasia or malignancy. Bulk RNA-Seq was performed, and fi ndings were compared with sporadic ESCC vs normal RNASeq datasets. RESULTS: Multiple transcriptional changes were identified in TOC samples, relative to controls, and many were detected in ESCC. Accordingly, pathway analyses predicted an enrichment of cancer-associated processes linked to cellular proliferation and metastasis, and several transcription factors were predicted to be associated with TOC and ESCC, including negative enrichment of GRHL2. Subsequently, a fi ltering strategy revealed 22 genes that were significantly dysregulated in both TOC and ESCC. Moreover, Keratin 17, which was upregulated in TOC and ESCC, was also found to be overexpressed at the protein level in ' normal ' TOC esophagus tissue. CONCLUSION: Transcriptional changes occur in TOC esophagus prior to the onset of dysplasia, many of which are associated with ESCC. These fi ndings support the utility of TOC to help reveal the early molecular processes that lead to sporadic ESCC.