Real-world effectiveness of vortioxetine in outpatients with major depressive disorder: functioning and dose effects.

BACKGROUND: Functional recovery is an important treatment goal in major depressive disorder (MDD). This study assessed the real-world effectiveness of vortioxetine in patients with MDD, with particular focus on functioning; dose-response was also assessed. METHODS: This was a non-interventional, prospective, multicenter study conducted in Greece. Adult outpatients with MDD (n = 336) initiating vortioxetine (5-20 mg/day flexible dosing) as treatment for a current major depressive episode were followed for 3 months. Analyses were stratified according to vortioxetine dosage at 3 months: 5-10 mg/day versus 15-20 mg/day. Functioning was assessed using the Sheehan Disability Scale (SDS). RESULTS: Mean ± standard error SDS total score decreased (improved) from 18.7 ± 0.3 at baseline to 12.9 ± 0.3 after 1 month of vortioxetine treatment and 7.8 ± 0.4 after 3 months (p < 0.001 vs. baseline for all comparisons). Functional recovery (SDS score ≤ 6) was achieved in 14.6% of patients after 1 month of treatment and 48.4% of patients after 3 months. Improvement from baseline in SDS total and domain scores at 3 months was more pronounced in patients receiving vortioxetine 15-20 mg/day than in those receiving vortioxetine 5-10 mg/day. The mean ± standard error change in SDS total score from baseline was 9.2 ± 0.8 in the 5-10 mg/day group and 12.1 ± 0.4 in the 15-20 mg/day group (p < 0.001). Limitations of this study include its non-interventional study design and lack of a control group or active comparator. CONCLUSIONS: Statistically significant and clinically relevant improvements in functioning were seen in patients with MDD treated with vortioxetine in a real-world setting. Higher doses of vortioxetine were associated with significantly greater improvements in functioning.

Effects of AraC treatment on motor coordination and cerebellar cytoarchitecture in the adult rat. A possible protective role of NAC.

Intact cerebellum cytoarchitecture and cellular communication are indispensable for successful motor coordination and certain forms of memory. Cytosine arabinoside (AraC), often used as an anti-neoplastic agent in humans, can have cerebellum-targeting adverse effects. In order to characterize the nature of AraC-induced cerebellar lesions in an adult rodent model, we have administered AraC (400 mg/kg b.w., i.p.) in adult male Wistar rats for 5 days. The animals' walking pattern, motor coordination, locomotion, spatial navigation and cognition were evaluated, along with neurofilament- and calbindin-like distribution in the cerebellum. AraC-treated rats demonstrated a disturbed walking pattern and a reduced ability of motor learning and coordination, indicative of a mild cerebellar deficit. Although the general locomotion and spatial cognition of AraC-treated rats was not significantly altered, their navigation into the water, in terms of swimming velocity, was irregular, compared to vehicle-treated animals. Neurofilament-like immunostaining was reduced in the molecular cerebellar layer, while calbindin D 28 kDa levels were increased in Purkinje neurons, following AraC treatment. Administration of the antioxidant N-acetylcysteine (NAC) (200 mg/kg b.w., p.o.), for 14 days (prior to and during AraC treatment) largely prevented the AraC-induced behavioral deficits. Our in vivo model of neurotoxicity provides data on the AraC-induced behavioral and cellular alterations concerning the adult rat cerebellum. Furthermore, it provides evidence of a possible neuroprophylactic role of the antioxidant N-acetylcysteine in this model of chemotherapy-induced toxicity.

Estrogens influence behavioral responses in a kainic acid model of neurotoxicity.

The behavioral and neuroprotective effects of 17beta-estradiol (E2), on ovariectomized rats treated with a subconvulsive dose (7 mg/kg bw, ip) of kainic acid (KA), were examined. Estradiol was administered either acutely (150 mug/rat, ip) along with KA, 14 days post-ovariectomy, or chronically (sc capsules providing proestrus estrogen levels in serum) starting at ovariectomy. Exploratory behavior, as deduced by sniffing in the open field test, was reduced in KA-treated rats. Both hormonal schemes partially restored sniffing behavior in KA-lesioned subjects. Moreover, acute and chronic E2 administration in KA-treated rats resulted in increased vertical and horizontal activity of these animals in the open field test. Memory for object recognition was reduced following KA and was not restored by hormonal treatments. Acute, but not chronic, E2 coadministration with KA significantly impaired spatial performance in the water maze task, while KA alone had no effect. Both acute and chronic estradiol administration rescued hilar and CA1 neurons from KA-induced cell death. Chronic, but not acute, E2 increased neurofilament immunoreactivity in the mossy fibers of the dentate gyrus neurons, similarly to KA. Our results show that although estradiol administration in KA-treated rats has beneficial effects on cell survival, it has diverse effects on exploratory behavior, object, and spatial memory. Estradiol effects on KA-lesioned animals depended on the duration and timing of exposure to the hormone, implying different mechanisms of hormone actions.

Reduction of GnRH and infertility in the R6/2 mouse model of Huntington's disease.

Reductions in testosterone and luteinizing hormone levels and reduced sexual functions have been reported in Huntington's disease (HD) patients. Atrophy of the reproductive organs and loss of fertility have also been observed in the R6/2 mouse, which is currently the most studied transgenic model of HD. In an effort to define the cause of infertility we studied the expression of gonadotropin-releasing hormone (GnRH) in the medial septum, diagonal band of Broca and hypothalamus of R6/2 male mice during sexual maturation. We found a progressive reduction in the numbers of GnRH-immunoreactive neurons in the analysed brain areas of R6/2 mice starting at 5 weeks of age and becoming statistically significant with only 10% of the neurons remaining by 9 weeks of age. Atrophy of testes and seminal vesicles combined with a significant reduction in serum and testicular testosterone levels were detected in 12-week-old R6/2mice. These results suggest that infertility in the R6/2 males is due either to death of GnRH neurons or to a reduction in GnRH expression leading to a downstream impairment of the gonadotropic hormones. Gonadotropic hormone replacement did not mitigate weight loss or restore motor function in R6/2 males.