Self-administered generational surveys combine with genetic analysis to reveal foundations of depression in Japanese adults.

BACKGROUND: Major depressive disorder is a prevalent psychiatric illness characterized by mood disturbances and influenced by various environmental and genetic factors, yet its etiology remains largely unknown. METHODS: We profiled a self-reported depressive population in Japan with a focus on sociodemographic background, lifestyle, comorbidities, and genetic background, using data from two cohorts, a population-based cohort and a three-generation cohort, recruited by the Tohoku Medical Megabank Organization until December 2021. RESULTS: Our findings revealed that depression in the Japanese population is strongly associated with certain sociocultural features prevalent in Japan, such as social isolation, neuroticism, and introversion, as well as with well-known risk factors that include age and gender. Environmental factors related to the Great East Japan Earthquake, considered as cohort characteristics, were also strongly associated with the onset of depression. Moreover, using GWAS analysis of whole-genome sequencing data, we identified novel candidate genetic risk variants located on chromosomes 21 and 22 that are associated with depression in Japanese individuals; further validation of these risk variants is warranted. LIMITATIONS: Our study has limitations, including uncertain clinical relevance resulting from the use of self-reported questionnaires for depression assessment. Additionally, the cohort exhibited a population bias, with greater representation of women than men. CONCLUSIONS: Our results provide holistic insights into depression risk factors in Japanese adults, although their associations with depression are correlations. This supports the idea that targeted interventions and individualized approaches are important for addressing depression in the Japanese population.

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study.

BACKGROUND: Esketamine nasal spray (Spravato) in conjunction with oral antidepressants (ADs) is approved in the European Union, United States, and other markets for treatment-resistant depression (TRD). Efficacy, safety, and tolerability of esketamine nasal spray in Japanese patients with TRD needs to be assessed. METHODS: This Phase 2b, randomized, double-blind (DB), placebo-controlled study was conducted in adult Japanese patients with TRD meeting the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) criteria of major depressive disorder with nonresponse to ≥ 1 but < 5 different ADs in the current episode at screening. Patients were treated with a new oral AD for 6 weeks (prospective lead-in phase); nonresponders were randomized (2:1:1:1) to placebo or esketamine (28-, 56-, or 84-mg) nasal spray along with the continued use of AD for 4 weeks (DB induction phase). Responders (≥50% reduction from baseline in the Montgomery-Asberg Depression Rating Scale [MADRS] total score) from the DB induction phase continued into the 24-week posttreatment phase and patients who relapsed could participate in a 4-week open-label (OL) second induction (flexibly-dosed esketamine). The primary efficacy endpoint, change from baseline in the MADRS total score at Day 28 in the DB induction phase, was based on mixed-effects model using repeated measures pairwise comparisons using a Dunnett adjustment. RESULTS: Of the 202 patients randomized in the DB induction phase (esketamine [n = 122] or placebo [n = 80]), the MADRS total scores decreased from baseline to Day 28 of the DB induction phase (- 15.2, - 14.5, - 15.1, and - 15.3 for esketamine 28 mg, 56 mg, 84 mg, and placebo groups, respectively), indicating an improvement in depressive symptoms; however, the difference between the esketamine and placebo groups was not statistically significant. The most common treatment-emergent adverse events during the DB induction phase in the combined esketamine group (incidences ranging from 12.3 to 41.0%) were blood pressure increased, dissociation, dizziness, somnolence, nausea, hypoaesthesia, vertigo, and headache; the incidence of each of these events was > 2-fold higher than the corresponding incidence in the placebo group. CONCLUSIONS: Efficacy of esketamine plus oral AD in Japanese TRD patients was not established; further investigation is warranted. All esketamine doses were safe and tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02918318 . Registered: 28 September 2016.

Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study.

BACKGROUND: ß-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS: In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [Aß1-40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. RESULTS: In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aß1-40 levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% Aß1-40 reductions, respectively. The trend of the reduction was similar across the Aß1-37, Aß1-38, and Aß1-42 fragments in both atabecestat dose groups, consistent with Aß1-40. CSF amyloid precursor protein fragment (sAPPß) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. CONCLUSIONS: JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aß1-40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. TRIAL REGISTRATION: ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.

Two placebo-controlled, randomized withdrawal studies to evaluate the fentanyl 1 day patch in opioid-naïve patients with chronic pain.

OBJECTIVE: To evaluate the efficacy and safety of fentanyl 1 day patch in opioid-naïve patients with non-cancer chronic pain insufficiently relieved by non-opioid analgesics. RESEARCH DESIGN AND METHODS: Two phase III placebo-controlled, double-blind, group-comparison, randomized withdrawal studies were conducted in patients with osteoarthritis and/or low back pain (N01 study) and post-herpetic neuralgia, complex regional pain syndrome, or chronic postoperative pain (N02) in Japan. Both studies consisted of period I (10-29 days of titration, fentanyl 12.5-50.0 µg/h) and period II (12 weeks double-blind). CLINICAL TRIAL REGISTRATION: N01, NCT01008618; N02, NCT01008553 MAIN OUTCOME MEASURES: The primary endpoint was the number of days until study discontinuation due to insufficient pain relief in period II, and secondary endpoints included pain scored on visual analog scale (VAS), subject's overall assessment, the number of rescue dose, brief pain inventory short form score, score on short-form 36-item health survey version 2.0, physician's overall assessment, and assessment of adverse events. RESULTS: Of the 218 (N01) and 258 (N02) subjects who entered period I, 150 and 163 subjects entered period II, respectively. In the N01 study, the between-group difference was significant in the VAS score (95% CI: 7.3 [1.1, 13.5] mm, P = 0.0215) but not in the primary endpoint (P = 0.0846, log-rank test). In the N02 study, both primary efficacy (P = 0.0003) and VAS (8.7 [2.4, 15.0] mm, P = 0.0071) results showed that fentanyl was more effective than placebo. The major adverse events were nervous system and gastrointestinal disorders typically associated with opioid analgesic use. The incidence of adverse events in the fentanyl group was 68.5% to 85.7%. CONCLUSIONS: Although the primary efficacy results showed significant effects of fentanyl in the N02 but not the N01 study, overall results showed that fentanyl 1 day patch is effective and well tolerated.

Ready conversion of patients with well-controlled, moderate to severe, chronic malignant tumor-related pain on other opioids to tapentadol extended release.

BACKGROUND AND OBJECTIVES: The effectiveness and tolerability of tapentadol extended release (ER), a centrally acting analgesic with µ-opioid receptor agonist and norepinephrine (noradrenaline) reuptake inhibitor activities, have been demonstrated in patients with chronic pain, including those switching directly from prior opioid therapy. The objective of the current study was to evaluate the effectiveness and safety of conversion to oral tapentadol ER (50-250 mg twice daily) from previous around-the-clock strong opioid therapy in patients with moderate to severe, chronic malignant tumor-related cancer pain that was well-controlled. METHODS: This randomized, open-label, phase III study, which was conducted in Japan, included a 1- to 2-week screening period (on previous opioid) and an 8-week, open-label treatment period. Eligible patients, who were taking a strong opioid analgesic and had a mean pain intensity score <4 during the 3 days prior to randomization (adequate pain control on previous strong opioid), were randomized (1:1) to receive twice-daily treatment with tapentadol ER (100-500 mg/day) or morphine sustained release (SR; 20-140 mg/day; reference for assay sensitivity). Initial doses were estimated based on the conversion ratio of tapentadol ER:oxycodone:morphine:fentanyl = 10:2:3:0.03. The primary effectiveness endpoint was the proportion of patients who maintained pain control [change from baseline in mean pain intensity (11-point numerical rating scale) less than +1.5 for 3 consecutive days and no more than two doses of rescue medication per day for 3 consecutive days) during the first week of open-label treatment. RESULTS: In the tapentadol ER group (n = 50), 84.0 % of patients (42/50; 95 % CI, 70.89-92.83) maintained pain control during Week 1. On the Patient Global Impression of Change, 2.1 % (1/48), 2.1 % (1/48), 22.9 % (11/48), and 50.0 % (24/48) of patients in the tapentadol ER group reported that their overall condition was "very much improved," "much improved," "minimally improved," and "not changed," respectively, at Week 1 compared with 0 %, 10.7 % (3/28), 28.6 % (8/28), and 53.6 % (15/28) reporting these ratings at Week 8. The sensitivity of effectiveness analyses was validated based on results using morphine SR; 98.0 % (49/50; 95 % CI, 89.35-99.95) of patients in the morphine SR group maintained pain control after 1 week of treatment. The overall safety profile was similar to that demonstrated in previous studies; tapentadol ER was associated with a lower incidence of gastrointestinal treatment-emergent adverse events than morphine SR [38.0 % (19/50) vs. 54.0 % (27/50)], including constipation [12.0 % (6/50) vs. 20.0 % (10/50)] and vomiting [6.0 % (3/50) vs. 26.0 % (13/50)]. CONCLUSIONS: Overall, results indicate that conversion from previous strong opioids to tapentadol ER (50-250 mg twice daily) was successful and resulted in safe and effective pain control with improved gastrointestinal tolerability versus morphine SR in patients with moderate to severe cancer-related pain that was well-controlled on their previous opioid.

A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of osmotic-controlled release oral delivery system methylphenidate HCl in adults with attention-deficit/hyperactivity disorder in Japan.

OBJECTIVES: To evaluate the safety and efficacy of osmotic-controlled release oral delivery system (OROS) methylphenidate (MPH) HCl in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this study, 284 adults with ADHD were randomized to OROS MPH or placebo. During the 4-week titration period, patients were titrated from a starting dose of 18 mg once daily to an individually-optimized dose of up to 72 mg once daily in weekly 18-mg increments. Patients continued on their individualized dose during the 4-week efficacy assessment period. The primary efficacy endpoint was change in DSM-IV Total ADHD Symptoms subscale score of Conners' Adult ADHD Rating Scale-Observer: Screening Version (CAARS-O:SV) from baseline to endpoint. RESULTS: The mean change in DSM-IV Total ADHD Symptoms subscale score of CAARS-O:SV was significantly larger with OROS MPH compared with placebo (P < 0.0001, ANCOVA). Similar results were observed for the majority of secondary endpoints, including CAARS-O:SV total score and other subscale scores. Although treatment-emergent adverse events were reported more frequently in the OROS MPH group (81.8%) versus the placebo group (53.9%), OROS-MPH showed a well-tolerated safety profile overall. CONCLUSIONS: OROS MPH in a dose range of 18-72 mg once daily was effective and well-tolerated in adult patients with ADHD.

Efficacy and safety of oral tapentadol extended release in Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain.

OBJECTIVE: This phase 3 study evaluated the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for the management of moderate to severe, chronic malignant tumor-related cancer pain. RESEARCH DESIGN AND METHODS: This randomized, double-blind, active-controlled study included Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Patients were randomized (1:1) to receive oral tapentadol ER (25-200 mg bid) or oral oxycodone HCl CR (5-40 mg bid) for 4 weeks of double-blind treatment. ClinicalTrials.gov identifier: NCT01165281. MAIN OUTCOME MEASURES: This study was designed to evaluate the non-inferiority of the efficacy provided by tapentadol ER versus oxycodone CR, based on the mean change in average pain intensity (11 point numerical rating scale) from baseline to the last 3 days of study drug administration. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. RESULTS: Of the 374 patients who were screened, 343 were randomized and 236 completed treatment. The least-squares mean difference in the change in pain intensity from baseline to the last 3 days of study treatment between tapentadol ER and oxycodone CR was -0.06 (95% confidence interval [CI], -0.506 to 0.383). The upper limit of the 95% CI was <1 (the predefined threshold value for non-inferiority), indicating that tapentadol ER provided analgesic efficacy that was non-inferior to that of oxycodone CR. The percentage of patients reporting at least one TEAE was similar in the tapentadol ER (87.5% [147/168]) and oxycodone CR (90.1% [155/172]) treatment groups, but the incidence of gastrointestinal TEAEs was lower in the tapentadol ER group (55.4% [93/168]) than in the oxycodone CR group (67.4% [116/172]). CONCLUSIONS: Tapentadol ER (25-200 mg bid) provides analgesic efficacy that is non-inferior to that provided by oxycodone HCl CR (5-40 mg bid) for the management of moderate to severe, chronic malignant tumor-related pain, and is well tolerated overall, with a better gastrointestinal tolerability profile than oxycodone CR.

Blockade of body weight gain and plasma corticosterone levels in Zucker fatty rats using an orally active neuropeptide Y Y1 antagonist.

1. An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. 2. Oral administration of the Y1 antagonist (30 and 100 mg x kg(-1), once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. 3. Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. 4. These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity.