Short-active gestational photoperiod reduces effortful choice behavior in mice, partial normalization by d-amphetamine.

RATIONALE: Seasonal birth patterns consistently implicate winter gestation as a risk factor for several psychiatric conditions. We recently demonstrated that short-active (SA; 19:5 light:dark)-i.e., "winter-like"-photoperiod exposure across gestation and early life (E0-P28) induces psychiatrically relevant behavioral abnormalities in adult mice, including reduced immobility in the forced swim test (FST) and effortful amotivation. It is unknown, however, whether these effects were driven primarily by prenatal or postnatal mechanisms, and whether perinatal SA photoperiod would similarly reduce effort expenditure in a task relevant to everyday decision-making. OBJECTIVES AND METHODS: We first tested male and female mice exposed to either gestational (E0-P0) or postnatal (E0-P28) SA photoperiod in the FST to determine whether the previously observed alteration was driven primarily by prenatal versus postnatal photoperiod. We then assessed whether SA gestational photoperiod reduces effortful choice behavior in the cross-species effort-based decision-making task (EBDMT) and whether any such deficit could be remediated by d-amphetamine (0.1 and 0.3 mg/kg, i.p.). RESULTS: Mice exposed to prenatal, but not postnatal, SA photoperiod exhibited reduced FST immobility relative to controls and also demonstrated condition-dependently reduced preference for high-effort/high-reward versus low-effort/low-reward contingencies in the EBDMT. This effortful choice deficit was normalized by 0.1 mg/kg amphetamine. CONCLUSIONS: These data: (1) suggest a greater contribution of gestational versus postnatal light conditions to the behavioral effects of perinatal SA photoperiod; and (2) implicate altered dopamine signaling in the behavioral phenotype of the SA-born mouse and possibly in the etiology of winter gestation-associated cases of psychiatric disease.

Chloro-cobalt complexes with pyridyl-ethyl-derived di-aza-cyclo-alkanes.

Syntheses are described for the blue/purple complexes of cobalt(II) chloride with the tetra-dentate ligands 1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine (Ppz), 1,4-bis-[2-(pyridin-2-yl)eth-yl]homopiperazine (Phpz), trans-2,5-dimethyl-1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine (Pdmpz) and tridentate 4-methyl-1-[2-(pyridin-2-yl)eth-yl]homopiperazine (Pmhpz). The CoCl2 complexes with Ppz, namely, {µ-1,4-bis-[2-(pyridin-2-yl)eth-yl]piperazine}bis-[di-chlorido-cobalt(II)], [Co2Cl4(C18H24N4)] or Co2(Ppz)Cl4, and Pdmpz (structure not reported as X-ray quality crystals were not obtained), are shown to be dinuclear, with the ligands bridging the two tetra-hedrally coordinated CoCl2 units. Co2(Ppz)Cl4 and {di-chlorido-{4-methyl-1-[2-(pyridin-2-yl)eth-yl]-1,4-di-aza-cyclo-hepta-ne}cobalt(II) [CoCl2(C13H21N3)] or Co(Pmhpz)Cl2, crystallize in the monoclinic space group P21/n, while crystals of the penta-coordinate mono-chloro chelate 1,4-bis-[2-(pyr-id-in-2-yl)eth-yl]piperazine}chlorido-cobalt(II) perchlorate, [CoCl(C18H24N4)]ClO4 or [Co(Ppz)Cl]ClO4, are also monoclinic (P21). The complex {1,4-bis-[2-(pyridin-2-yl)eth-yl]-1,4-di-aza-cyclo-hepta-ne}di-chlorido-cobalt(II) [CoCl2(C19H26N4)] or Co(Phpz)Cl2 (P ) is mononuclear, with a penta-coordinated CoII ion, and entails a Phpz ligand acting in a tridentate fashion, with one of the pyridyl moieties dangling and non-coordinated; its displacement by Cl- is attributed to the solvophobicity of Cl- toward MeOH. The penta-coordinate Co atoms in Co(Phpz)Cl2, [Co(Ppz)Cl]+ and Co(Pmhpz)Cl2 have substantial trigonal-bipyramidal character in their stereochemistry. Visible- and near-infrared-region electronic spectra are used to differentiate the two types of coordination spheres. TDDFT calculations suggest that the visible/NIR region transitions contain contributions from MLCT and LMCT character, as well as their expected d-d nature. For Co(Pmhpz)Cl2 and Co(Phpz)Cl2, variable-temperature magnetic susceptibility data were obtained, and the observed decreases in moment with decreasing temperature were modelled with a zero-field-splitting approach, the D values being +28 and +39 cm-1, respectively, with the S = 1/2 state at lower energy.

The burden of disease in early schizophrenia - a systematic literature review.

BACKGROUND: Schizophrenia is a heterogeneous disorder with a burden that can vary greatly depending on the severity and the duration. Previous research has suggested that patients in the earlier stages of schizophrenia (typically first-episode schizophrenia) benefit from effective early treatment, however, a comprehensive review of the burden specifically in this population has not been undertaken. A systematic literature review was therefore conducted to characterize the clinical, economic, and humanistic burden, as reported in naturalistic studies of schizophrenia populations specifically at an early stage of disease in comparison with healthy controls, patients with chronic schizophrenia, and patients with other psychiatric disorders. METHODS AND MATERIALS: Searches were conducted in MEDLINE, MEDLINE In-Process, Embase, PsycINFO, and EconLit databases for records published between January 2005 and April 2019, and of relevant conference abstracts published between January 2014 and May 2019. Data were extracted from relevant publications and subjected to qualitative evaluation. RESULTS: Fifty-two publications were identified for inclusion and revealed a considerable burden for early schizophrenia with regards to mortality, psychiatric comorbidities such as substance abuse and depression, poor social functioning, and unemployment. Comparisons with chronic schizophrenia suggested a greater burden with longer disease duration, while comparisons with other psychiatric disorders were inconclusive. This review uncovered various gaps in the available literature, including limited or no data on incarcerations, caregiver burden, and costs associated with early schizophrenia. CONCLUSIONS: Overall, the burden of schizophrenia is apparent even in the early stages of the disease, although further research is required to quantify the burden with chronic schizophrenia and other psychiatric disorders.

Systematic literature review and network meta-analysis of sodium-glucose co-transporter inhibitors vs metformin as add-on to insulin in type 1 diabetes.

AIMS: To identify and synthesize phase 3 and phase 4 randomized controlled trials (RCTs) of sodium-glucose co-transporter (SGLT) inhibitors and metformin as adjuncts to insulin in type 1 diabetes (T1DM) using network meta-analysis (NMA). MATERIALS AND METHODS: A systematic literature review (SLR) identified relevant RCTs of ≥12 Weeks duration. MEDLINE, Embase, the Cochrane Library and grey literature were searched through October 2018. NMAs indirectly compared SGLT inhibitors and metformin for change from baseline in HbA1c, weight, total daily insulin dose and systolic blood pressure at Week 24 to 26 and Week 52. Safety outcomes were also explored. RESULTS: Nine trials (N = 6780) were included in the SLR. NMAs indicated that all therapies performed better than placebo for the efficacy outcomes at both time points. Compared with metformin at Week 24 to 26, the SGLT inhibitors dapagliflozin (5 mg), sotagliflozin (200 mg) and empagliflozin (10 mg) had larger reductions in HbA1c (mean difference [MD] = -0.24, 95% credible interval [CrI], -0.41 to -0.07, MD = -0.23, 95% CrI, -0.39 to -0.08 and MD = -0.35, 95% CrI, -0.51 to -0.19, respectively) and in weight, which were sustained in sensitivity analyses. There were few differences observed in the results of safety outcomes, such as risk of diabetic ketoacidosis (DKA), which should be interpreted cautiously because of wide CrIs. CONCLUSIONS: Adjunctive use of SGLT inhibitors in T1DM can improve glycaemic control compared with metformin while enabling weight loss, with consistent efficacy across the class. However, these results are based on indirect evidence so confirmation in a head-to-head study would be valuable.