A meta-analysis of the efficacy of vortioxetine in patients with major depressive disorder (MDD) and high levels of anxiety symptoms

Background: Comorbid anxiety is common in major depressive disorder (MDD) and more difficult to treat than depression without anxiety. This analysis assessed the efficacy, safety, and tolerability of vortioxetine in MDD patients with high levels of anxiety (baseline Hamilton Anxiety Rating Scale [HAM-A] total score ?20).Methods: Efficacy was assessed using an aggregated, study-level meta-analysis of 10 randomized, placebo-controlled, 6/8-week trials of vortioxetine 5-20 mg/day in adults (18-75 years), with a study in elderly patients (?65 years) analyzed separately. Outcome measures included mean differences from placebo in change from baseline to endpoint (?) in the Montgomery-Åsberg Depression Rating Scale (MADRS), HAM-A total, and HAM-A subscales. Safety and tolerability were assessed by treatment-emergent adverse events (TEAEs).Results: A total of 1497 (48.6%) vortioxetine-treated and 860 (49.1%) placebo-treated patients had baseline HAM-A?20. There were significant differences from placebo in MADRS (vortioxetine 5 mg/day, n=415, ??2.68, P=0.005; 10 mg/day, n=373, ??3.59, P<0.001; 20 mg/day, n=207, ??4.30, P=0.005) and HAM-A total (5 mg/day, n=419, ??1.64, P=0.022; 10 mg/day, n=373, ??2.04, P=0.003; 20 mg/day, n=207, ??2.19, P=0.027). There were significantly greater improvements versus placebo on the HAM-A psychic subscale for all doses. The most common TEAEs (?5.0%) were nausea, headache, dizziness, dry mouth, diarrhea, nasopharyngitis, constipation, and vomiting. Incidence of serious TEAEs was 1.3% (placebo) and ?1.3% (vortioxetine, across doses).Limitations: Study heterogeneity limits this analysis. Patients with baseline HAM-A?20 were not directly compared to baseline HAM-A<20 or total MDD population.Conclusions: Vortioxetine was efficacious in reducing depressive and anxiety symptoms in patients with MDD and high levels of anxiety

A survey of shipping finance research: setting the future research agenda

Financing shipping related investment projects has always been a focal area of debate and research within the international maritime industry since access to funding can determine the competitiveness of a capital-intensive business as well as its success or failure under adverse market conditions. This paper provides, for the first time, a comprehensive and structured survey of all published research in the area of shipping finance and investment. The review spans approximately four decades (1979-2018) of empirical evidence, including 162 studies published in 48 scholarly journals, complemented with select books and book chapters. The study provides a bibliometric analysis and comprehensive synthesis of existing research offering an invaluable source of information for both the academic community and business practice, shaping the future research agenda in shipping finance and investment

Collision sellar lesions: experience with eight cases and review of the literature

The concomitant presence of a pituitary adenoma with a second sellar lesion in patients operated upon for pituitary adenoma is an uncommon entity. Although rare, quite a great variety of lesions have been indentified coexisting with pituitary adenomas. In fact, most combinations have been described before, but an overview with information on the frequency of combined pathologies in a large series has not been published. We present a series of eight collision sellar lesions indentified among 548 transsphenoidally resected pituitary adenomas in two Neurosurgical Departments. The histological studies confirmed a case of sarcoidosis within a non-functioning pituitary adenoma, a case of intrasellar schwannoma coexisting with growth hormone (GH) secreting adenoma, two Rathke’s cleft cysts combined with pituitary adenomas, three gangliocytomas associated with GH-secreting adenomas, and a case of a double pituitary adenoma. The pertinent literature is discussed with emphasis on pathogenetic theories of dual sellar lesions. Although there is no direct evidence to confirm the pathogenetic relationship of collision sellar lesions, the number of cases presented in literature makes the theory of an incidental occurrence rather doubtful. Suggested hypotheses about a common embryonic origin or a potential interaction between pituitary adenomas and the immune system are presented

ORIGINAL INVESTIGATION CB 1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat

Abstract Rationale: Addictive drugs have a number of commonalities in animal behavioral models. They lower intracranial self-stimulation (ICSS) thresholds, support selfadministration, and produce conditioned place preference (CPP). However, cannabinoids appear atypical as drugs of abuse, since there are controversial data in the literature concerning their reinforcing properties. Objectives: The aim of the present study was to examine the effects of cannabinoids on brain reward using the rate-frequency curve shift paradigm of ICSS. Methods: Male Sprague-Dawley rats were implanted with electrodes into the medial forebrain bundle (MFB). Rate-frequency functions were deterined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain stimulation reward thresholds stabilized rats received intraperitoneal (IP) injections of the potent CB 1 receptor agonists WIN 55,212-2 (graded doses 0.1, 0.3, 1 and 3 mg/kg), CP 55,940 (graded doses 10, 30, 56 and 100 μg/kg), or HU-210 (graded doses 10, 30, 100 μg/kg). Results: With the exception of the highest dose of all cannabinoid agonists tested, which significantly increased the threshold frequency required for MFB ICSS, all other doses of the tested drugs did not affect ICSS thresholds. The CB 1 receptor antagonist SR141716A reversed the actions of WIN 55,212-2 and CP 55,940, but not HU-210. However, the selective CB 1 cannabinoid receptor antagonist AM 251 counteracted the effect of HU-210. Both CB 1 receptor antagonists, at the doses used in the present study, did not affect reward thresholds by themselves. Conclusions: The present results indicate that cannabinoid agonists do not exhibit reinforcing properties in the ICSS paradigm, but rather have an inhibitory influence on reward mechanisms. The results suggest that the anhedonic effects of cannabinoids are probably mediated by cannabinoid CB 1 receptors

Adolescent Female Cannabinoid Exposure Diminishes the Reward-Facilitating Effects of Δ9-Tetrahydrocannabinol and d-Amphetamine in the Adult Male Offspring

Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to Δ9-tetrahydrocannabinol (Δ9-THC) induces transgenerational effects on the reward-facilitating effects of Δ9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received Δ9-THC (0.1 or 1 mg/kg, i.p.) or vehicle during postnatal days 28–50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the Δ9-THC’s (0, 0.1, 0.5, and 1 mg/kg, i.p.) and d-amphetamine’s (0, 0.1, 0.5, and 1 mg/kg, i.p.) reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS) procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of Δ9-THC was abolished in the F1 offspring of females that were exposed to Δ9-THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of Δ9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to Δ9-THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female Δ9-THC exposure during adolescence can diminish the reward-facilitating effects of Δ9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that Δ9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs

Lack of rewarding effects of 9-tetrahydrocannabinol in the intracranial self-stimulation and conditioned place preference paradigms

Data on the ability of [DELTA]9-tetrahydrocannabinol (THC) to modify reward processes in experimental animals are inconsistent. This study examined the effects of [DELTA]9-THC on brain reward function using the rate-frequency curve shift paradigm of intracranial self-stimulation (ICSS) and the conditioned place preference (CPP) paradigm. In ICSS tests, rats were implanted with electrodes into the medial forebrain bundle. After brain stimulation reward thresholds stabilized, rats received intraperitoneal injections of [DELTA]9-THC (0, 0.5, 1 and 2 mg/kg) or the CB1 receptor antagonist SR141716A (0, 0.02 mg/kg) and [DELTA]9-THC (0, 2 mg/kg). The two highest doses of [DELTA]9-THC significantly increased the threshold ICSS frequency. SR141716A reversed the action of [DELTA]9-THC (2 mg/kg), without affecting reward thresholds by itself. In the CPP test, mice received intraperitoneal injections of [DELTA]9-THC (0, 1 or 3 mg/kg). [DELTA]9-THC showed neither statistically significant preference nor aversion in either of the doses tested. These findings indicate that [DELTA]9-THC, in contrast to other drugs of abuse, does not facilitate ICSS or support CPP under the present experimental conditions, but rather has a dose-dependent inhibitory influence on ICSS