Aripiprazole augmentation to antidepressant therapy in Japanese patients with major depressive disorder: A randomized, double-blind, placebo-controlled study (ADMIRE study)

AbstractObjectiveThis randomized, placebo-controlled study evaluated the efficacy and safety of a fixed dose (3mg/day) and flexible dose (3–15mg/day) schedule of aripiprazole as augmentation therapy in Japanese patients with inadequate response to antidepressant therapy (ADT).MethodDuring an 8-week prospective treatment phase, patients experiencing a major depressive episode received clinicians' choice of ADT. Subjects with inadequate response to ADT were randomized to receive adjunctive treatment with placebo (n=195), fixed dose aripiprazole (n=197) or flexible dose aripiprazole (n=194) for 6 weeks. The primary efficacy endpoint was mean change in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score from the end of prospective treatment (baseline) to the end of randomized treatment.ResultsMore than 90% of patients in all treatment groups completed the 6-week double-blind treatment phase. Mean MADRS total score was improved to a significantly greater extent with fixed dose aripiprazole and flexible dose aripiprazole (−10.5 and −9.6, respectively) than with placebo (−7.4). Aripiprazole was well tolerated. The incidence of akathisia observed in the flexible dose group may relate to a higher prevalence of the CYP2D6*10 allele in Asian populations.LimitationsSix weeks of adjunctive treatment is insufficient to draw conclusions about the long-term benefits of aripiprazole. Exclusion of patients with established medical comorbidities does not reflect real-world practice.ConclusionsAripiprazole augmentation at a fixed or flexible dose was superior to ADT alone and was reasonably well tolerated in Japanese patients with inadequate response to ADT.Clinical trials registrationClinicalTrials.gov identifier NCT00876343

Similarity between the C18O (J=1-0) core mass function and the IMF in the S 140 region

We present the results of C18O(J=1-0) mapping observations of a 20'x18' area in the Lynds 1204 molecular cloud associated with the Sharpless 2-140 (S140) H II region. The C18O cube (alpha-delta-vLSR) data shows that there are three clumps with sizes of \sim 1 pc in the region. Two of them have peculiar red shifted velocity components at their edges, which can be interpreted as the results of the interaction between the cloud and the Cepheus Bubble. From the C18O cube data, the clumpfind identified 123 C18O cores, which have mean radius, velocity width in FWHM, and LTE mass of 0.36\pm0.07 pc, 0.37\pm0.09 km s-1, and 41\pm29 Msun, respectively. All the cores in S140 are most likely to be gravitationally bound by considering the uncertainty in the C18O abundance. We derived a C18O core mass function (CMF), which shows a power-law-like behavior above a turnover at 30 Msun. The best-fit power-law index of -2.1\pm0.2 is quite consistent with those of the IMF and the C18O CMF in the OMC-1 region by Ikeda & Kitamura (2009). Kramer et al. (1998) estimated the power-law index of -1.65 in S140 from the C18O(J=2-1) data, which is inconsistent with this study. However, the C18O(J=2-1) data are spatially limited to the central part of the cloud and are likely to be biased toward high-mass cores, leading to the flatter CMF. Consequently, this study and our previous one strongly support that the power-law form of the IMF has been already determined at the density of \sim 10^{3-4} cm^{-3}, traced by the C18O(J=1-0) line.Comment: 36 pages, 9 figures, accepted for the Astrophysical Journa

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential

Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model.

Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease

Symptomatic small schwannoma is a risk factor for surgical complications and correlates with difficulty of enucleation

Postoperative neurological deficits of schwannomas are the complications that we want to avoid most. Predicting postoperative neurological deficits is crucial; however, the correlation between preoperative symptoms and neurological findings with postoperative neurological complications has not yet been completely clarified. Here we analyzed the risk factors for postoperative neurological complications. The study included 131 tumors from 107 patients histologically confirmed as schwannomas, which developed in the extremities and trunk without spinal cord involvement. The correlation between clinical findings and postoperative complications were statistically analyzed. One-hundred three tumors (78.6 %) had the preoperative neurological symptoms; these symptoms were detected in 93.3 % of small tumors (<4 cm3). We defined it as follows about the anatomical location of schwannomas. One is “central type” that normal nerve bundles widely splayed over the tumor’s capsule (tumor located in the central region of the nerve). Another is “peripheral type” that easy to enucleate without neurolysis (tumor located in the peripheral region of the nerve). Static analysis showed a significant difference in the Tinel sign, numbness, and postoperative neurological deficits (p = 0.04, 0.006, p < 0.001, respectively). Twenty-one cases (16.0 %) showed new postoperative neurological symptoms, including numbness in 12 cases, dysesthesia in three cases, pain in three cases, and slight motor palsy in two cases. In statistical analysis, small tumors (<4 cm3) significantly correlated with Tinel sign (p < 0.001), and was marginally significant with postoperative neurological deficits (p = 0.05). Moreover, small tumors (<4 cm3) accompanying numbness preoperatively significantly correlated with postoperative neurological deficits (p = 0.04). Small (<4 cm3) tumors significantly correlated with the preoperative neurological symptoms. Those tumors accompanying numbness also significantly correlated with the difficulty of the enucleation and postoperative neurological deficits. These findings will help to predict the neurological complication. © 2015, Abe et al