Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial - CORRIGENDUM.

This notice describes a correction to the above mentioned paper.

Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial.

BackgroundKetamine has recently become an agent of interest as an acute treatment for severe depression and as the anaesthetic for electroconvulsive therapy (ECT). Subanaesthetic doses result in an acute reduction in depression severity while evidence is equivocal for this antidepressant effect with anaesthetic or adjuvant doses. Recent systematic reviews call for high-quality evidence from further randomised controlled trials (RCTs).AimsTo establish if ketamine as the anaesthetic for ECT results in fewer ECT treatments, improvements in depression severity ratings and less memory impairment than the standard anaesthetic.MethodDouble-blind, parallel-design, RCT of intravenous ketamine (up to 2 mg/kg) with an active comparator, intravenous propofol (up to 2.5 mg/kg), as the anaesthetic for ECT in patients receiving ECT for major depression on an informal basis. (Trial registration: European Clinical Trials Database (EudraCT): 2011-000396-14 and clinicalTrials.gov: NCT01306760)ResultsNo significant differences were found on any outcome measure during, at the end of or 1 month following the ECT course.ConclusionsKetamine as an anaesthetic does not enhance the efficacy of ECT.

Pregnancy and Litter Size, But Not Lamb Sex, Affect Feed Intake and Wool Production by Merino-Type Ewes.

Two experiments (Australia and Mexico) tested whether feed intake (FI) and wool production (WP) are affected by pregnancy (PRG), litter size (LZ), or lamb sex (LS) in Merino-type ewes. In Experiment-1, ewes were either not pregnant (NPR; n = 6), or carrying 1 (PR1; n = 7) or 3 (PR3; n = 11) fetuses, were studied in individual pens. NPR ewes had lower (p < 0.02) FI throughout PRG and lactation (LAC), except around lambing (p < 0.001). Following lambing, FI increased in PRG ewes (p < 0.001) to double the values in NPR ewes. PRG reduced WP (p < 0.001); in PR3, WP was lower than for both PR1 and NPR (p < 0.001). WP decreased during LAC and was lower in ewes rearing lambs than in NPR ewes (p < 0.001). Experiment-2 used 48 pregnant ewes (28 bearing singles and 20 bearing twins). Dam and lamb live weights (LW) and body condition (BC) were recorded from birth to weaning at 60 d, and dam fleece weight (DFW) was measured at weaning (12 months growth). WP was higher in ewes bearing and rearing single lambs than in ewes bearing twins (p < 0.001). DFW was positively (p < 0.01) related to LZ, dam LW, and BC, but not to changes in dam LW during LAC, or to lamb weight at birth or weaning, or LW gain, or LS. In conclusion, FI was affected during PRG and by LZ during LAC, whereas WP was influenced by LZ, but not LS, only during pregnancy.

The effect of stress on the expression of the amyloid precursor protein in rat brain.

The abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology.

The effects of chronic nicotine on spatial learning and bromodeoxyuridine incorporation into the dentate gyrus of the rat.

RATIONALE: Nicotine is reported to improve learning and memory in experimental animals. Improved learning and memory has also been related to increased neurogenesis in the dentate gyrus (DG) of the hippocampal formation. Surprisingly, recent studies suggest that self-administered nicotine depresses cell proliferation in the DG. OBJECTIVE: To test the hypothesis that the effects of nicotine on cell proliferation in the DG and learning and memory depend upon the nicotine dose administered. METHODS: Rats were chronically infused from subcutaneous osmotic mini pumps with nicotine (0.25 or 4 mg kg(-1) day(-1)) or the saline vehicle for 10 days. Half the rats in each treatment group were trained to locate a hidden platform in a water maze task on days 4-7; a probe trial was performed on day 8. The remaining rats remained in their home cages. The effects of nicotine and of training in the water maze task on cell genesis in the DG were determined by measuring 5-bromo-2'-deoxyuridine (BrDU) uptake using fluorescence immunohistochemistry. RESULTS: Training in the water maze task increased cell proliferation in the DG. Infusions of nicotine at 4 mg kg(-1) day(-1), but not 0.25 mg kg(-1) day(-1), decreased cell proliferation in both untrained animals and animals trained in the maze and impaired spatial learning. CONCLUSIONS: The data suggest that learning in the water maze task is impaired by higher doses of nicotine tested, and that this response may be related to reduced cell genesis in the DG.

Ketamine pre-treatment dissociates the effects of electroconvulsive stimulation on mossy fibre sprouting and cellular proliferation in the dentate gyrus.

Electroconvulsive stimulation (ECS), the experimental analogue of electroconvulsive therapy (ECT), has been shown to produce both functional and structural effects in the hippocampal formation in infrahuman species. These changes may relate to the antidepressant and cognitive effects of ECT observed in patients treated for severe depressive disorders. Recent studies have described both enhanced neurogenesis in the dentate gyrus of the hippocampus and sprouting of mossy fibre projections from granule cells. The behavioural significance of these effects remains uncertain. In this study, we examined whether ketamine, a clinically available non-competitive NMDA receptor channel blocker, could block both of these "trophic" effects. Rats were given a course of eight spaced ECS or sham treatments under either halothane or ketamine anaesthesia. The thymidine analogue bromodeoxyuridine was administered to assess the degree of hippocampal cell proliferation and mossy fibre sprouting was quantified using the Timm staining method. Pre-treatment with ketamine dissociated these effects such that mossy fibre sprouting was attenuated significantly, while cell proliferation was unaffected. This dissociation may prove useful in determining the behavioural significance of these hippocampal changes, if any, for either the antidepressant or cognitive consequences of ECT.

High fat feeding is associated with stimulation of the hypothalamic-pituitary-adrenal axis and reduced anxiety in the rat.

Previous studies have shown that diet-induced obesity is associated with insulin resistance and impaired feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to test the hypothesis that hyper-secretion of glucocorticoid, evoked by feeding rats a high fat (HF) diet for 12 weeks, also influences behavioural and neural responses to the elevated plus-maze (EPM) test of anxiety. HF-fed animals exhibited anxiolytic-like behaviour in the EPM but were also hyperactive in this test. Covariant analysis established that the anxiolytic-like behaviour was not secondary to the increase in activity. The HF diet significantly increased basal levels of plasma corticosterone. The groups exposed to the EPM also displayed increased plasma corticosterone levels compared to the relevant control group, although the increment was smaller in the HF-fed animals. Glucocorticoid receptor (GR) immunoreactivity in the cytoplasmic fraction of parietal cortex and hypothalamus and the particulate fraction of the parietal cortex were increased by HF feeding. The behavioural changes evoked by HF feeding did not correlate significantly with changes in GR immunoreactivity in each treatment group or 5-HT turnover in the brain areas studied. It is concluded that anxiolytic properties evoked in the EPM by high fat feeding are unlikely to be related to the changes in HPA function seen in animals fed this diet.

Enhanced evoked responses after early adversity and repeated platform exposure: the neurobiology of vulnerability?

BACKGROUND: There is a long-standing clinical awareness of the significance of adverse early experiences and subsequent stress in the evolution of psychiatric disorder. METHODS: We investigated the impact of a single episode of preweaning maternal separation on in vivo electrophysiologic responses in the hippocampus of the mature rat after repeated exposure to an open elevated platform. RESULTS: Only rats that had experienced both maternal separation followed by stressful platform exposure when mature had significantly increased granule cell response to perforant path stimulation, compared with control rats. Rats exposed to either maternal separation or the elevated platform in adulthood alone did not differ significantly from control rats. CONCLUSIONS: Adverse early experience seems to induce functional changes in the hippocampus that remain latent until activated by stress in adulthood. Such electrophysiologic changes might represent a neural substrate for vulnerability to stress-associated psychopathology.

Brain plasticity and antidepressant treatments: new cells, new connections.

It is now a decade since we first wrote about the impact of antidepressant agents on plastic processes in the hippocampus (Stewart and Reid, 1993). Since then, the roles of various forms of brain plasticity have moved centre stage in efforts to understand the pathophysiology of depressive disorder. Here, we review the background to current views relating cytoarchitectural and synaptic changes to the aetiology and treatment of affective disease.

Nicotine modifies in vivo and in vitro rat hippocampal amyloid precursor protein processing in young but not old rats.

Previous studies have shown that administration of nicotine modifies the expression and secretion of amyloid precursor protein (APP) in various cell lines. The present study investigated the extent to which chronic subcutaneous nicotine administration influences APP levels and processing in cerebral cortex, striatum and hippocampus of young and old rat brains. The results showed that constant nicotine infusion (0.25 or 4.00mg/kg/day) increased the levels of particulate APP (APPp) but not secreted APP (APPs) in the hippocampus of young rats in vivo. This response to nicotine was not observed in the striatum or cerebral cortex of young rats or in any of the brain regions examined in old animals. Subsequent in vitro analysis demonstrated that nicotine enhanced the release of APPs from hippocampal slice preparations and that this increase was attenuated by mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist. The in vitro effect of nicotine on APPs was age-related, being only detected from hippocampal slices derived from the young but not the older animals. These results suggest that nicotine modulates APP expression and secretion in the hippocampus and that the responses observed to the drug are age-dependent being only detected in younger rats.

High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task.

Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer's disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer's disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer's pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non-matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes.

Chronic lithium administration down regulates transthyretin mRNA expression in rat choroid plexus.

Transthyretin (TTR) accounts for a quarter of the protein content of ventricular cerebrospinal fluid (CSF) yet its exact role in the brain remains unknown. Patients with a diagnosis of depression have reduced CSF levels of TTR and the locus encoding the TTR gene has been implicated in a Danish pedigree of bipolar patients. Lithium, the major treatment for bipolar disorder in the UK, was subcutaneously infused into rats for 28 days in the form of lithium chloride using osmotic minipumps. In situ hybridizations using oligonucleotide probes targeted against the TTR transcript were performed on coronal brain sections. Lithium significantly reduced the level of transthyretin mRNA in the rat choroid plexus within the lateral and third ventricle. The down-regulation was confirmed using semi-quantitative reverse transcription PCR on dissected brain tissue. Recent studies in mice suggest that the TTR gene is implicated in depression-like behavior therefore this effect of lithium may be relevant to its use as a mood stabilizer or an adjuvant to antidepressant drugs.