Low intensity cognitive behavioural therapy for psychosis: a pilot study.

BACKGROUND AND OBJECTIVES: The dissemination and delivery of psychological therapies for people with psychosis has been limited by workforce and organisational factors. 'Low Intensity' (LI) delivery, whereby staff are trained to deliver brief, focused, manualised interventions, may be one way of improving access. In this study, we piloted a new LI intervention specifically for people with psychosis, aimed at helping people to reach a personal recovery goal, whilst targeting anxious avoidance or depression-related inactivity. Frontline mental health workers were trained to deliver the intervention. We report here on the impact of the intervention on therapeutic outcomes. METHODS: Twelve people with psychosis and either anxious avoidance or low mood, who wanted to work towards a personal goal, completed the intervention and a battery of assessments of mood, functioning and psychotic symptoms. RESULTS: Eleven out of the twelve participants achieved their personal goals. The results of a series of Friedman K related sample tests revealed significant improvements in depression, clinical distress, activity levels, negative symptoms and delusions across the three time points, and no change in hallucinations, or anxious avoidance. Staff and participant satisfaction was high. LIMITATIONS: The study is a small uncontrolled pilot study. Outcomes should therefore be interpreted with caution, pending replication. CONCLUSIONS: The new LI intervention shows preliminary evidence of effectiveness and is a feasible model of therapy delivery for people with psychosis. The results suggest that frontline mental health workers can be trained relatively easily to deliver the intervention. A larger, randomised controlled trial is warranted to determine the effectiveness of the intervention and training programme.

Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from -21% to 66%. Thirty-seven monkeys from the high and low ends of the ACTH suppression distribution (18 'high' and 19 'low' animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the 'risk' genotypes from these three loci was detected, with an increasing number of 'risk' genotypes associated with a blunted ACTH response (P = 0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.

Domestic violence and severe psychiatric disorders: prevalence and interventions.

BACKGROUND: The lifetime prevalence of domestic violence in women is 20-25%. There is increasing recognition of the increased vulnerability of psychiatric populations to domestic violence. We therefore aimed to review studies on the prevalence of, and the evidence for the effectiveness of interventions in, psychiatric patients experiencing domestic violence. METHOD: Literature search using Medline, PsycINFO and EMBASE applying the following inclusion criteria: English-language papers, data provided on the prevalence of or interventions for domestic violence, adults in contact with mental health services. RESULTS: Reported lifetime prevalence of severe domestic violence among psychiatric in-patients ranged from 30% to 60%. Lower rates are reported for men when prevalence is reported by gender. No controlled studies were identified. Low rates of detection of domestic violence occur in routine clinical practice and there is some evidence that, when routine enquiry is introduced into services, detection rates improve, but identification of domestic violence is rarely used in treatment planning. There is a lack of evidence on the effectiveness of routine enquiry in terms of morbidity and mortality, and there have been no studies investigating specific domestic violence interventions for psychiatric patients. CONCLUSIONS: There is a high prevalence of domestic violence in psychiatric populations but the extent of the increased risk in psychiatric patients compared with other populations is not clear because of the limitations of the methodology used in the studies identified. There is also very limited evidence on how to address domestic violence with respect to the identification and provision of evidence-based interventions in mental health services.

Growth factors differentially regulate neuronal Cav channels via ERK-dependent signalling.

Voltage-gated calcium channels (Ca(v)) are tonically up-regulated via Ras/extracellular signal-regulated kinase (ERK) signalling in sensory neurones. However, the mechanisms underlying the specificity of cellular response to this pathway remain unclear. Neurotrophic factors are attractive candidates to be involved in this process as they are key regulators of ERK signalling and have important roles in neuronal survival, development and plasticity. Here, we report that in rat dorsal root ganglion neurones, endogenous nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) and epidermal growth factor (EGF) are all involved in tonic ERK-dependent up-regulation of Ca(v) channels. Chronic (overnight) deprivation of growth factors inhibits total Ca(v) current according to developmental changes in expression of the cell surface receptors for NGF, GDNF and EGF. Whilst EGF specifically regulates transcriptional expression of Ca(v)s, NGF and GDNF also acutely modulate Ca(v) channels within a rapid ( approximately 10min) time-frame. These acute effects likely involve changes in the biophysical properties of Ca(v)s, including altered channel gating rather than changes in surface expression. Furthermore, NGF, GDNF and EGF differentially regulate specific populations of Ca(v)s. Thus, ERK-dependent regulation of Ca(v) activity provides an elegant and extremely flexible system with which to tailor calcium influx to discrete functional demands.

Voltage-dependence of contraction in streptozotocin-induced diabetic myocytes.

Cardiac contractile dysfunction is frequently reported in human patients and experimental animals with type-1 diabetes mellitus. The aim of this study was to investigate the voltage-dependence of contraction in ventricular myocytes from the streptozotocin (STZ)-induced diabetic rat. STZ-induced diabetes was characterised by hyperglycaemia and hypoinsulinaemia. Other characteristics included reduced body and heart weight and raised blood osmolarity. Isolated ventricular myocytes were patched in whole cell, voltage-clamp mode after correcting for membrane capacitance and series resistance. From a holding membrane potential of -40 mV, test pulses were applied at potentials between -30 and +50 mV in 10 mV increments. L-type Ca2+ current (I Ca,L) density and contraction were measured simultaneously using a video-edge detection system. Membrane capacitance was not significantly altered between control and STZ-induced diabetic myocytes. The I Ca,L density was significantly (p < 0.05) reduced throughout voltage ranges (-10 mV to +10 mV) in myocytes from STZ-treated rats compared to age-matched controls. Moreover, the amplitude of contraction was significantly reduced (p < 0.05) in myocytes from STZ-treated rats at all test potentials between -20 mV and +30 mV. However, in electrically field-stimulated (1 Hz) myocytes, the amplitude of contraction was not altered by STZ-treatment. It is suggested that in field-stimulated myocytes taken from STZ-induced diabetic hearts, prolonged action potential duration may promote increased Ca2+ influx via the sodium-calcium exchanger (NCX), which may compensate for a reduction in Ca2+ trigger through L-type-Ca2+-channels and lead to normalised contraction.

Excitatory actions of propofol and ketamine in the snail Lymnaea stagnalis.

This study compares the actions of the intravenous anaesthetics propofol and ketamine on animal behaviour and neuronal activity in the snail Lymnaea stagnalis, particularly in relation to excitatory effects observed clinically. When injected into the whole animal, neither agent induced total anaesthesia. Rather, behavioural activity was enhanced by propofol (10(-5) M) and ketamine (10(-7) M), indicating excitatory effects. When superfused over the isolated central nervous system (CNS), differential effects were produced in two identified neurons, right pedal dorsal 1 (RPeD1) and visceral dorsal 4 (VD4). Resting membrane properties were largely unaffected. However, spike after hyperpolarisation was significantly reduced in RPeD1, but not VD4, with some evidence of increased excitability. In addition, an intrinsic bursting property (post-stimulus burst) in VD4 was altered by propofol (10(-7) M). The results suggest significant excitatory components in the actions of some intravenous anaesthetics, as well as a potential role in modifying excitation and bursting mechanisms in the CNS.

DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine.

Oxidative DNA damage is important in aging and the degenerative diseases of aging such as cancer. Estimates commonly rely on measurements of 8-oxo-2'-deoxyguanosine (oxo8dG), an adduct that occurs in DNA and is also excreted in urine after DNA repair. Here we examine difficulties inherent in the analysis of oxo8dG, identify sources of artifacts, and provide solutions to some of the common methodological problems. A frequent criticism has been that phenol in DNA extraction solutions artificially increases the measured level of oxo8dG. We found that phenol extraction of DNA contributes a real but minor increase in the level of oxo8dG when compared, under equivalent conditions, with a successful nonphenol method. A more significant reduction in the baseline level was achieved with a modification of the recently introduced chaotropic NaI method, reducing our estimate of the level of steady-state oxidative adducts by an order of magnitude to 24,000 adducts per cell in young rats and 66,000 adducts per cell in old rats. Of several alternative methods tested, the use of this chaotropic technique of DNA isolation by using NaI produced the lowest and least variable oxo8dG values. In further studies we show that human urinary 8-oxo-guanine (oxo8Gua) excretion is not affected by the administration of allopurinol, suggesting that, unlike some methylated adducts, oxo8Gua is not derived enzymatically from xanthine oxidase. Lastly, we discuss remaining uncertainties inherent both in steady-state oxo8dG measurements and in estimates of endogenous oxidation ("hit rates") based on urinary excretion of oxo8dG and oxo8Gua.

Carotenoids and protection of phospholipids in solution or in liposomes against oxidation by peroxyl radicals: relationship between carotenoid structure and protective ability.

The ability of carotenoids to protect egg-yolk phosphatidylcholine (EYPC) lipids against oxidation by peroxyl radicals generated from azo-initiators was studied. In homogeneous organic solution, all the carotenoids tested ameliorated lipid peroxidation by AMVN, but none was as effective as alpha-tocopherol. Beta-ring carotenoids showed a correlation between protective effect and rate of carotenoid destruction. Beta,beta-Carotene and zeaxanthin, which react with peroxyl radicals at similar rates, gave a similar degree of protection in organic solution. The reactivity and protective ability of the 4,4'-diketocarotenoids, astaxanthin and canthaxanthin was less. Carotenoids incorporated into ordered membrane systems (EYPC liposomes) displayed different protective efficacies. Zeaxanthin and beta-cryptoxanthin were more effective than beta,beta-carotene against oxidation initiated in the aqueous and lipid phases. Astaxanthin and canthaxanthin afforded less protection to the liposomal lipids. Lycopene was destroyed most rapidly but was least effective as an antioxidant. Located in the hydrophobic inner core of the bilayer, the hydrocarbons lycopene and beta,beta-carotene would not be in a position to readily intercept free-radicals entering the membrane from the aqueous phase. Carotenoids with polar end groups span the bilayer with their end groups located near the hydrophobic-hydrophillic interface where free-radical attack from AAPH first occurs. Hydrogen abstraction from C-4 may be one of the mechanisms of carotenoid antioxidant activity in this system. The chemical reactivity of a carotenoid is not the only factor that determines its ability to protect membranes against oxidation. The position and orientation of the carotenoid in the bilayer is also of importance.

Oxidation of carotenoids by free radicals: relationship between structure and reactivity.

The relationship between structure and reactivity is reported for a collection of carotenoids in solution reacted with oxidants generated by a modified Fenton process or with peroxyl radicals generated via the azo-initiators AMVN and AIBN. The initial rates of oxidation were in the order: lycopene > beta,beta-carotene, zeaxanthin > echinenone, isozeaxanthin > astaxanthin, canthaxanthin. The oxidative degradation caused rapid bleaching, due to disruption and breakdown of the polyene chromophore. A number of reaction mechanisms are likely to be involved. Isozeaxanthin, canthaxanthin and astaxanthin, in which the C-4 and C-4' positions are occupied by functional groups, react more slowly than beta,beta-carotene and zeaxanthin, in which this position is free. Products such as the 4-methoxy (or 4-ethoxy) and 4,4'-dimethoxy (or 4,4'-diethoxy) derivatives were isolated from reactions of beta,beta-carotene with peroxyl radicals in the presence of methanol or ethanol. Electron density calculations suggest that the different reactivities cannot be attributed solely to differences in electron distribution along the polyene chain of the different chromophores, which would alter the susceptibility to free-radical addition to the conjugated double-bond system. Other reactions must therefore be considered, including hydrogen abstraction from positions allylic to the polyene chain (C-4 of beta,beta-carotene and its derivatives, and of lycopene). Lycopene, lutein and zeaxanthin all reacted rapidly with oxidising agents, so these dietary carotenoids must also be considered as potential antioxidants.

gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications.

Peroxynitrite, a powerful mutagenic oxidant and nitrating species, is formed by the near diffusion-limited reaction of .NO and O2.- during activation of phagocytes. Chronic inflammation induced by phagocytes is a major contributor to cancer and other degenerative diseases. We examined how gamma-tocopherol (gammaT), the principal form of vitamin E in the United States diet, and alpha-tocopherol (alphaT), the major form in supplements, protect against peroxynitrite-induced lipid oxidation. Lipid hydroperoxide formation in liposomes (but not isolated low-density lipoprotein) exposed to peroxynitrite or the .NO and O2.- generator SIN-1 (3-morpholinosydnonimine) was inhibited more effectively by gammaT than alphaT. More importantly, nitration of gammaT at the nucleophilic 5-position, which proceeded in both liposomes and human low density lipoprotein at yields of approximately 50% and approximately 75%, respectively, was not affected by the presence of alphaT. These results suggest that despite alphaT's action as an antioxidant gammaT is required to effectively remove the peroxynitrite-derived nitrating species. We postulate that gammaT acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens, forming stable carbon-centered adducts through the nucleophilic 5-position, which is blocked in alphaT. Because large doses of dietary alphaT displace gammaT in plasma and other tissues, the current wisdom of vitamin E supplementation with primarily alphaT should be reconsidered.

Dietary supplementation with carotenoids: effects on alpha-tocopherol levels and susceptibility of tissues to oxidative stress.

The ability of dietary supplementation with carotenoids to protect chick tissues against oxidative stress in vitro was examined. Male Leghorn chicks were fed on diets supplemented (100 mg supplement/kg diet) with either beta-carotene, zeaxanthin (beta,beta-carotene-3,3'-diol), canthaxanthin (beta,beta-carotene-4,4'-dione) or alpha-tocopherol, or on a control diet, from 1 d old until 37 d of age. Tissues (liver, heart, skeletal muscle and plasma) were removed and assayed for total carotenoids and alpha-tocopherol content and portions subjected to oxidative stress by incubation of homogenates with cumene hydroperoxide and FeSo4. Animals receiving zeaxanthin and canthaxanthin had significantly greater carotenoid concentrations in liver, heart, muscle and plasma compared with untreated controls (P < 0.05); animals fed on diets supplemented with beta-carotene, or alpha-tocopherol did not have significantly different tissue carotenoid contents compared with untreated controls. alpha-Tocopherol supplementation elevated alpha-tocopherol levels in all tissues examined (P < 0.05). Supplementation with carotenoids did not affect tissue alpha-tocopherol levels, but beta-carotene lowered plasma alpha-tocopherol levels by 50% (P < 0.05). Incubation of plasma or tissue homogenates with oxidant stressors induced lipid peroxidation (production of thiobarbituric-acid reactive substances) in all tissues. Animals given alpha-tocopherol, beta-carotene or zeaxanthin had a reduced susceptibility to oxidant stress in liver compared with unsupplemented controls (P < 0.05), and alpha-tocopherol-supplemented animals had reduced susceptibility in skeletal muscle compared with tocopherol-supplemented animals had reduced susceptibility in skeletal muscle compared with unsupplemented controls (P < 0.05). Canthaxanthin supplementation did not influence the susceptibility to oxidant stress in any tissue examined. These results suggest that zeaxanthin, a carotenoid present in animal and human diets, may have significant activity as an antioxidant against oxidative stress in tissues.