An animal model of depression combining genetic vulnerability and early-life stress (ELS) was prepared by submitting the Flinders Sensitive Line (FSL) rats to a standard paradigm of maternal separation. We analysed hippocampal synaptic transmission and plasticity in vivo and ionotropic receptors for glutamate in FSL rats, in their controls Flinders Resistant Line (FRL) rats, and in both lines subjected to ELS. A strong inhibition of long-term potentiation (LTP) and lower synaptic expression of NR1 subunit of the NMDA receptor were found in FSL rats. Remarkably, ELS induced a remodelling of synaptic plasticity only in FSL rats, reducing inhibition of LTP; this was accompanied by marked increase of synaptic NR1 subunit and GluR2/3 subunits of AMPA receptors. Chronic treatment with escitalopram inhibited LTP in FRL rats, but this effect was attenuated by prior ELS. The present results suggest that early gene-environment interactions cause lifelong synaptic changes affecting functional and molecular aspects of plasticity, partly reversed by antidepressant treatments.

Delivery of peptides by the oral route greatly appeals due to commercial, patient convenience and scientific arguments. While there are over 60 injectable peptides marketed worldwide, and many more in development, most delivery strategies do not yet adequately overcome the barriers to oral delivery. Peptides are sensitive to chemical and enzymatic degradation in the intestine, and are poorly permeable across the intestinal epithelium due to sub-optimal physicochemical properties. A successful oral peptide delivery technology should protect potent peptides from presystemic degradation and improve epithelial permeation to achieve a target oral bioavailability with acceptable intra-subject variability. This review provides a comprehensive up-to-date overview of the current status of oral peptide delivery with an emphasis on patented formulations that are yielding promising clinical data.

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post-traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long-term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor-dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage-dependent Ca(2+) channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress-induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long-lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus-dependent cognition by excessive acute inescapable stress.

Aims To examine the risk of mortality associated with interruptions to the continuity of methadone maintenance treatment (MMT), including transfers between services, in opioid‐dependent individuals attending specialist addiction services. Design Retrospective cohort study using addiction services and primary care dispensing records, the National Methadone Register and National Drug‐Related Death Index (NDRDI). Setting Geographically defined population in Dublin, Ireland. Participants A total of 2899 people prescribed and dispensed methadone in specialist addiction services between January 2010 and December 2015. There were five exposure groups: weeks 1–4 following transfer between treatment providers; weeks 1–4 out of treatment; weeks 5–52 out of treatment; weeks 1–4 of treatment initiation; and weeks 5+ of continuous treatment (reference category). Measurements Primary outcome: drug‐related poisoning (DRP) deaths. Secondary outcome: all‐cause mortality (ACM). Mortality rates calculated by dividing number of deaths (DRP; ACM) in exposure groups by person‐years exposure. Unadjusted and adjusted Poisson regression (covariates age, sex, incarceration, methadone dose and comorbidities) estimated differences in mortality rates. Findings There were 154 ACM deaths, 55 (35.7%) identified as DRP deaths. No deaths were observed in the first month following transfer between treatment providers. The risk of DRP mortality was highest in weeks 1–4 out of treatment [adjusted relative risk (aRR = 4.04, 95% confidence interval (CI) = 1.43–11.43, P = 0.009] and weeks 1–4 of treatment initiation (ARR = 3.4, 95% CI = 1.2–9.64, P = 0.02). Similarly, risk of ACM was highest in weeks 1–4 out of treatment (ARR = 11.78, 95% CI = 7.73–17.94, P < 0.001), weeks 1–4 of treatment initiation (aRR = 5.11, 95% CI = 2.95–8.83, P < 0.001) and weeks 5–52 off treatment (aRR = 2.04, 95% CI = 1.2–3.47, P = 0.009). Conclusions Interruptions to the continuity of methadone maintenance treatment by treatment provider do not appear to be periods of risk for drug‐related poisoning or all‐cause mortality deaths. Risk of drug related poisoning and all‐cause mortality deaths appears to be greatest during the first 4 weeks of treatment initiation/re‐initiation and after treatment cessation.

The aim of the present study was to investigate the influence of process shear stressors on the stability of a model monoclonal antibody, trastuzumab. Trastuzumab, at concentrations of 0.4–4.0 mg/mL, was subjected to sonication, freeze-thaw, lyophilisation, spray drying and was encapsulated into micro- and nanoparticles. The stressed samples were analysed for structural integrity by gel electrophoresis, SDS-PAGE, and size exclusion chromatography (SEC), while the conformational integrity was analysed by circular dichroism (CD). Biological activity of the stressed trastuzumab was investigated by measuring the inhibition of cell proliferation of HER-2 expressing cell lines. Results show that trastuzumab was resistant to the process shear stresses applied and to microencapsulation processes. At the lowest concentration of 0.4 mg/mL, a low percent (<9%) of soluble/reversible aggregates may have been formed. No loss of structural integrity, conformation was observed and no significant change in the biological activity of trastuzumab was observed (ANOVA; p > 0.05). The results of this study conclude that trastuzumab may be resistant to various processing stresses. These findings have important implications with respect to pharmaceutical processing of monoclonal antibodies.