Serotonin syndrome-A focused review.

BACKGROUND: Serotonin syndrome is a potentially life-threatening syndrome with manifestations spanning from mild adverse effects to life-threatening toxicity. The syndrome is caused by overstimulation of serotonin receptors by serotonergic drugs. Since the use of serotonergic drugs is increasing, primarily due to the widespread use of selective serotonin reuptake inhibitors, cases of serotonin syndrome have likely seen a parallel increase. The true incidence of serotonin syndrome remains unknown due to its diffuse clinical presentation. OBJECTIVES: This review aims to provide a clinically focused overview of serotonin syndrome, covering its pathophysiology, epidemiology, clinical manifestations, diagnostic criteria, differential diagnosis and treatment, as well as classifying serotonergic drugs and their mechanism of action. The pharmacological context is emphasized, as it is crucial for the detection and management of serotonin syndrome. METHODS: Focused review based on a literature search using the PubMed database. FINDINGS AND CONCLUSION: Serotonin syndrome can occur through therapeutic use or overdose of a single serotonergic drug or as a drug interaction between two or more serotonergic drugs. Central clinical features consist of neuromuscular excitation, autonomic dysfunction and altered mental status, occurring in a patient undergoing new or altered serotonergic therapy. Early clinical recognition and treatment are crucial to prevent significant morbidity.

Use of hydrochlorothiazide in Denmark following publication of skin cancer risk findings.

PURPOSE: The antihypertensive agent hydrochlorothiazide has recently been linked to increased risk of skin cancer. We sought to describe the impact of the dissemination of these findings on the use of hydrochlorothiazide and health care utilization among antihypertensive users in Denmark. METHODS: In this nationwide observational study, we performed descriptive analyses of a cohort comprising all Danish antihypertensive treatment users January 2016 through September 2020 (n = 1 316 476) with special focus on hydrochlorothiazide users (n = 309 743). Data were retrieved from the Danish nationwide health registries, including the Danish National Prescription Registry. RESULTS: The use of hydrochlorothiazide dropped by 44% from January 2016 to September 2020, with the proportion of all antihypertensive fills constituted by hydrochlorothiazide dropping from 12.7% to 7.2%. This decline was more pronounced among younger patients and patients with a history of skin cancer. Simultaneously, the monthly rate of new hydrochlorothiazide users in Denmark dropped from ≈2350 throughout 2017 to 652 during 2020. The publication of an increased risk of nonmelanoma skin cancer led to an estimated excess of up to 11 510 physical and 22 870 e-mail/phone consultations to general practitioners. No evidence for increased risk of adverse outcomes was found. CONCLUSIONS: The publication of increased risk of skin cancer with hydrochlorothiazide use has led to a marked decline in the use of hydrochlorothiazide in Denmark. A temporary increase in rate of GP contacts was also observed. This highlights the potential impact from disseminating research findings to patients and clinicians.

Hydrochlorothiazide and risk of melanoma subtypes.

BACKGROUND: Hydrochlorothiazide (HCTZ), a common diuretic known to be photosensitizing and previously associated with non-melanoma skin cancer, was recently reported to be associated with two melanoma subtypes, nodular and lentigo, among residents of Denmark. Our goal was to examine whether Danish findings could be replicated in a US cohort, using a similar study design and analysis. METHODS: Among non-Hispanic White enrollees of Kaiser Permanente Northern California, we conducted an analysis of 9176 melanoma cases and 264 781 controls, matched on age, sex and time in health plan. We examined use of HCTZ prior to cancer diagnosis (cases) or comparable date for controls, categorized as never use, ever use and high use (≥50 000 mg). Electronic health records provided data on prescriptions, cancer diagnoses, and covariates. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for education, income and number of dermatology, internal medicine and urgent care visits. RESULTS: We observed a small increase in risk of melanoma, all types combined, associated with high use (≥50 000 mg) of HCTZ (OR = 1.11, 95% CI 1.00-1.23) and no evidence of a dose-response. Risk was more elevated for lentigo subtype (OR = 1.57, 95% CI 1.01-2.42). The somewhat elevated risk for nodular subtype was not statistically significant (OR = 1.22, 95% CI 0.78-1.90). There was very little association of high use with the superficial spreading subtype (OR = 1.05, 95% CI 0.80-1.37). CONCLUSIONS: Our findings support a recent report of an association between high use of HCTZ and increased risk of the lentigo subtype of melanoma.

Use of antiepileptic drugs and risk of skin cancer: A nationwide case-control study.

BACKGROUND: Several antiepileptic drugs are photosensitizing; however, it is not known whether this confers an increased risk of skin cancer. OBJECTIVE: To examine the association between common antiepileptic drugs and basal cell carcinoma, squamous cell carcinoma (SCC), and malignant melanoma. METHODS: We conducted a nested case-control study identifying skin cancer patients in Denmark from 2004 through 2015 matched 1:10 with disease-free controls. We estimated odds ratios (ORs) for skin cancer associated with high cumulative use of antiepileptic drugs (≥500 defined daily doses) compared with nonuse. RESULTS: Most antiepileptic drugs were not associated with skin cancer. SCC was associated with use of carbamazepine (OR, 1.88; 95% confidence interval, 1.42-2.49) and lamotrigine (OR, 1.57; 95% confidence interval, 1.12-2.22) with evidence of a dose-response relationship for carbamazepine. The estimated absolute risks were low; for example, 6335 person-years of high cumulative exposure to carbamazepine were required for 1 additional SCC to occur. LIMITATIONS: Data on important risk factors for skin cancer, such as sun exposure, were not available. CONCLUSIONS: Most antiepileptic drugs were not associated with skin cancer; however, carbamazepine and lamotrigine were associated with SCC. These findings need to be replicated and characterized further in other settings and have no direct clinical implications.

Use of hydrochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study.

BACKGROUND: The antihypertensive agent hydrochlorothiazide has been associated with increased risks of non-melanoma skin cancer (NMSC) and possibly some melanoma subtypes. Previous studies were, however, conducted in predominantly Caucasian populations. We therefore examined the association between hydrochlorothiazide and skin cancer risk in an Asian population. METHODS: By using Taiwan's National Health Insurance Research Database (NHIRD), we conducted three separate case-control studies of lip cancer, non-lip non-melanoma skin cancer and melanoma. Cases (n = 29,082) with a first-ever skin cancer diagnoses (2008-2015) were matched 1:10 to population controls. We estimated odds ratios (ORs) associating hydrochlorothiazide use with skin cancer risk by using conditional logistic regression. RESULTS: Hydrochlorothiazide use showed no overall association with any of the three outcomes: ORs for high cumulative use of HCTZ (≥50,000 mg) were 0.86 (95% CI 0.09-7.81) for lip cancer, 1.16 (95% CI 0.98-1.37) for non-lip NMSC and 1.07 (95% CI 0.65-1.76) for melanoma. There was some evidence of a dose-response pattern for non-lip NMSC, with an OR of 1.66 (95% CI 0.82-3.33) for 100,000-149,999 mg of HCTZ. The null findings were robust across subgroup and sensitivity analyses. CONCLUSION: Use of HCTZ appears safe in terms of skin cancer risk in an Asian population.

Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study.

BACKGROUND: Hydrochlorothiazide use has been associated with markedly increased risk for squamous cell carcinoma. No previous studies have investigated the association between hydrochlorothiazide use and the risk for Merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST). OBJECTIVE: To examine the association between hydrochlorothiazide use and the risk for MCC and MAST. METHODS: Using Danish nationwide health registries, we identified all patients with incident MCC or MAST during 2004-2015 and matched the cases individually to cancer-free population controls by risk set sampling. Using conditional logistic regression, we estimated the odds ratios (ORs) and confidence intervals (CIs) associated with cumulative use of hydrochlorothiazide. RESULTS: The adjusted ORs for MCC and MAST associated with high use (≥50,000 mg) of hydrochlorothiazide was 2.3 (95% CI 1.1-4.8) and 3.6 (95% CI 1.9-7.0), respectively, which increased to 3.3 (95% CI 1.3-8.3) and 5.6 (95% CI 2.4-13.3), respectively, with highest use (≥100,000 mg). We found no increased risk for these tumors in analyses of drugs with similar indications as hydrochlorothiazide, except there was a tendency toward an increased risk for MCC associated with the use of furosemide (OR 1.9, 95% CI 0.9-4.0). LIMITATIONS: No data on sun exposure was available. CONCLUSION: Hydrochlorothiazide use is associated with an increased risk for MCC and MAST.

Melanoma of the Skin in the Danish Cancer Registry and the Danish Melanoma Database: A Validation Study.

BACKGROUND: The nationwide Danish Cancer Registry and the Danish Melanoma Database both record data on melanoma for purposes of monitoring, quality assurance, and research. However, the data quality of the Cancer Registry and the Melanoma Database has not been formally evaluated. METHODS: We estimated the positive predictive value (PPV) of melanoma diagnosis for random samples of 200 patients from the Cancer Registry (n = 200) and the Melanoma Database (n = 200) during 2004-2014, using the Danish Pathology Registry as "gold standard" reference. We further validated tumor characteristics in the Cancer Registry and the Melanoma Database. Additionally, we estimated the PPV of in situ melanoma diagnoses in the Melanoma Database, and the sensitivity of melanoma diagnoses in 2004-2014. RESULTS: The PPVs of melanoma in the Cancer Registry and the Melanoma Database were 97% (95% CI = 94, 99) and 100%. The sensitivity was 90% in the Cancer Registry and 77% in the Melanoma Database. The PPV of in situ melanomas in the Melanoma Database was 97% and the sensitivity was 56%. In the Melanoma Database, we observed PPVs of ulceration of 75% and Breslow thickness of 96%. The PPV of histologic subtypes varied between 87% and 100% in the Cancer Registry and 93% and 100% in the Melanoma Database. The PPVs for anatomical localization were 83%-95% in the Cancer Registry and 93%-100% in the Melanoma Database. CONCLUSIONS: The data quality in both the Cancer Registry and the Melanoma Database is high, supporting their use in epidemiologic studies.

Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark.

BACKGROUND: Hydrochlorothiazide, one of the most frequently used diuretic and antihypertensive drugs in the United States and Western Europe, is photosensitizing and has previously been linked to lip cancer. OBJECTIVE: To examine the association between hydrochlorothiazide use and the risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). METHODS: From the Danish Cancer Registry, we identified patients (cases) with nonmelanoma skin cancer (NMSC) during 2004-2012. Controls were matched 1:20 by age and sex. Cumulative hydrochlorothiazide use (in 1995-2012) was assessed from the Danish Prescription Registry. Using conditional logistic regression, we calculated odds ratios (ORs) for BCC and SCC associated with hydrochlorothiazide use. RESULTS: High use of hydrochlorothiazide (≥50,000 mg) was associated with ORs of 1.29 (95% confidence interval [CI], 1.23-1.35) for BCC and 3.98 (95% CI, 3.68-4.31) for SCC. We found clear dose-response relationships between hydrochlorothiazide use and both BCC and SCC; the highest cumulative dose category (≥200,000 mg of HCTZ) had ORs of 1.54 (95% CI, 1.38-1.71) and 7.38 (95% CI, 6.32-8.60) for BCC and SCC, respectively. Use of other diuretics and antihypertensives was not associated with NMSC. LIMITATIONS: No data on sun exposure were available. CONCLUSIONS: Hydrochlorothiazide use is associated with a substantially increased risk of NMSC, especially SCC.