Risk of major depressive disorder in Japanese cancer patients: A matched cohort study using employer-based health insurance claims data.

OBJECTIVE: Patients with cancer are at high risk of depression. However, the risk of major depressive disorder (MDD) after cancer diagnosis has not been studied in a population setting in Japan. This cohort study used a Japanese medical claims database to examine time to MDD in cancer patients and the risk of MDD (hazard ratio; HR) compared with matched cancer-free controls. METHODS: Primary endpoint was time to MDD (starting 6 months before cancer diagnosis) in adult (18-74 years) cancer patients; secondary endpoint was time to MDD (6 months before to 12 months after cancer diagnosis) in a matched cohort of cancer patients and cancer-free controls. Multivariate analyses were performed to determine HRs for all cancers and for each cancer site. RESULTS: Of 35 008 cancer patients (mean age, 53.3 years), 2201 (6.3%) were diagnosed with MDD within 66 months. Matched cancer patients (n = 30 372) had an elevated risk of MDD compared with cancer-free controls (n = 303 720; HR [95% confidence interval] 2.96 [2.77-3.16]). MDD risk was highest in patients with multiple cancers, pancreatic cancer, and brain cancer. Compared with middle-aged patients, risk was higher in patients <40 years old and lower in patients ≥65 years old; risk tended to be higher in women than in men. CONCLUSIONS: Compared with cancer-free individuals, Japanese patients with cancer, mostly <65 years old, had an almost threefold higher risk of developing MDD within 12 months of cancer diagnosis. Physicians should watch for MDD in cancer patients and treat when necessary.

A new class of non-thiazolidinedione, non-carboxylic-acid-based highly selective peroxisome proliferator-activated receptor (PPAR) γ agonists: design and synthesis of benzylpyrazole acylsulfonamides.

Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) γ agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARγ ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid-based agonist 1 and acylsulfonamide 3d.

Structure-activity relationships and key structural feature of pyridyloxybenzene-acylsulfonamides as new, potent, and selective peroxisome proliferator-activated receptor (PPAR) γ Agonists.

In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.

Treatment of Major Depressive Disorder in Japanese Patients with Cancer: A Matched Cohort Study Using Employer-Based Health Insurance Claims Data.

BACKGROUND AND OBJECTIVE: Patients with cancer are at high risk of major depressive disorder (MDD), but little is known about their MDD treatment. We investigated the use of antidepressants and other drugs for MDD after cancer diagnosis, and patient characteristics associated with their use. METHODS: Adults with a new cancer diagnosis were matched to cancer-free patients using a Japanese employee health insurance database (JMDC); this exploratory analysis included only cohort patients diagnosed with MDD between 6 months before and 12 months after the cancer diagnosis index month. Initial prescription frequencies of antidepressants and other MDD medications were compared between cancer and cancer-free groups and analyzed according to age, sex, and hospital characteristics. RESULTS: Compared with the cancer-free group (n = 4097), significantly fewer patients in the cancer group (n = 1199) were prescribed antidepressants {622 (51.9%) [95% CI 49.0-54.7] vs 2385 (58.2%) [95% CI 56.7-59.7]}, particularly selective serotonin reuptake inhibitors. In contrast, prescription of other medications, especially antipsychotics and anxiolytics (tandospirone, hydroxyzine), was more frequent in the cancer group than in the cancer-free group. In the cancer group, women were prescribed antidepressants (mostly selective serotonin reuptake inhibitors) and other medications (mostly benzodiazepines) more than men. Antidepressant prescription decreased with age; patients aged < 40 years had the highest selective serotonin reuptake inhibitor and the lowest conventional antidepressant prescription rate compared with patients aged 40-64 years and ≥ 65 years. Lower selective serotonin reuptake inhibitor and benzodiazepine prescription rates were seen in large (≥ 100 beds) hospitals and in hospitals where patients received their cancer diagnosis. CONCLUSIONS: These results suggest Japanese patients with cancer may be undertreated for MDD compared with cancer-free patients. However, when prescribed, medications may be chosen according to patient needs, including avoiding adverse effects and drug-drug interactions.

Differences between patient and physician opinions on adherence to medication for hypertension and diabetes mellitus.

BACKGROUND: Non-adherence to prescribed medication presents a barrier to effective treatment. In order to find improved ways of tackling non-adherence, it is important to understand the perspective of both patients and physicians. METHOD: A web-based survey study was performed to obtain the views and opinions of patients receiving medical treatment for hypertension or diabetes mellitus in Japan, and physicians treating such patients, on adherence to medication. RESULTS: Forty-four percent of both physicians and patients placed great importance on medication adherence, but 11% of patients considered it of low importance. Overall, 85% of patients reported taking their medication correctly. Patients missed a mean of 4.8 or 5.4 daily doses per 30 day prescription based on patient and physician estimates, respectively. Both patients (64%) and physicians (23%) considered the main reason patients forgot to take their medication was that they "inadvertently forgot". Only 1% of physicians said they do not specifically check for residual drugs, but 46% of patients said they do not report missed doses to their doctor. Measures taken by physicians to reduce residual drugs included use of single packs (64%) and reductions in administration frequency (55%); 63% adjusted prescriptions to take account of any remaining drugs. Only 4% of physicians were satisfied with the effectiveness of measures to reduce non-adherence, whereas 59% of patients felt they managed to successfully perform measures to avoid forgetting to take drugs. LIMITATION: The study questionnaires were newly developed and did not incorporate validated instruments to assess adherence. CONCLUSION: Similar proportions of physicians and patients consider medication adherence to be important, but their opinions about measures used to improve adherence differ to some extent. Importantly, almost half of patients do not tell their doctor about missed doses.

Synthesis and biological activity of novel 5-(omega-aryloxyalkyl)oxazole derivatives as brain-derived neurotrophic factor inducers.

A novel series of 5-(omega-aryloxyalkyl)oxazole derivatives was prepared and their effects on brain-derived neurotrophic factor (BDNF) production were evaluated in human neuroblastoma (SK-N-SH) cells. Syntheses were performed by construction of an oxazole ring as a key reaction. Most of the 5-(omega-aryloxyalkyl)oxazole derivatives markedly increased BDNF production in SK-N-SH cells. 4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-[3-(2-methoxyphenoxy)propyl]-1, 3-oxazole, one of the most promising compounds, showed potent activity (EC(50)=7.9 microM) and the improvement of the motor nerve conduction velocity and the tail-flick response accompanied by a recovery of the brain-derived neurotrophic factor level in the sciatic nerve of streptozotocin (STZ)-diabetic rats.