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Oxidative stress has been suggested to increase after electroconvulsive therapy (ECT), a treatment which continues to be the most effective for severe depression. Oxidative stress could potentially be mechanistically involved in both the therapeutic effects and side effects of ECT.
We measured sensitive markers of systemic and central nervous system (CNS) oxidative stress on DNA and RNA (urinary 8-oxodG/8-oxoGuo, cerebrospinal fluid 8-oxoGuo, and brain oxoguanine glycosylase mRNA expression) in male rats subjected to electroconvulsive stimulations (ECS), an animal model of ECT. Due to the previous observations that link hypothalamic–pituitary–adrenal (HPA)-axis activity and age to DNA/RNA damage from oxidation, groups of young and middle-aged male animals were included, and markers of HPA-axis activity were measured.
ECS induced weight loss, increased corticosterone (only in middle-aged animals), and decreased cerebral glucocorticoid receptor mRNA expression, while largely leaving the markers of systemic and CNS DNA/RNA damage from oxidation unaltered.
These results suggest that ECS is not associated with any lasting effects on oxidative stress on nucleic acids neither in young nor middle-aged rats.
To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms.
Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle.
Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase.
Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.
Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood–brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.
Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.
None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity.
Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.
To explore whether and how group cognitive-behavioural therapy (GCBT) plus medication differs from medication alone for the treatment of generalised anxiety disorder (GAD).
Hundred and seventy patients were randomly assigned to the GCBT plus duloxetine (n=89) or duloxetine group (n=81). The primary outcomes were Hamilton Anxiety Scale (HAMA) response and remission rates. The explorative secondary measures included score reductions from baseline in the HAMA total, psychic, and somatic anxiety subscales (HAMA-PA, HAMA-SA), the Hamilton Depression Scale, the Severity Subscale of Clinical Global Impression Scale, Global Assessment of Functioning, and the 12-item Short-Form Health Survey. Assessments were conducted at baseline, 4-week, 8-week, and 3-month follow-up.
At 4 weeks, HAMA response (GCBT group 57.0% vs. control group 24.4%, p=0.000, Cohen’s d=0.90) and remission rates (GCBT group 21.5% vs. control group 6.2%, p=0.004; d=0.51), and most secondary outcomes (all p<0.05, d=0.36−0.77) showed that the combined therapy was superior. At 8 weeks, all the primary and secondary significant differences found at 4 weeks were maintained with smaller effect sizes (p<0.05, d=0.32−0.48). At 3-month follow-up, the combined therapy was only significantly superior in the HAMA total (p<0.045, d=0.43) and HAMA-PA score reductions (p<0.001, d=0.77). Logistic regression showed superiority of the combined therapy for HAMA response rates [odds ratio (OR)=2.12, 95% confidence interval (CI) 1.02−4.42, p=0.04] and remission rates (OR=2.80, 95% CI 1.27−6.16, p=0.01).
Compared with duloxetine alone, GCBT plus duloxetine showed significant treatment response for GAD over a shorter period of time, particularly for psychic anxiety symptoms, which may suggest that GCBT was effective in changing cognitive style.
Obesity represents a tremendous global health problem. Studies over the past decade have suggested that food addiction (FA), that is, physical cravings for certain foods – high in fat/sugar – and addiction-like overeating of these types of food, is a likely contributor to the obesity epidemic. While FA has been studied extensively, there are some significant gaps in the literature that need to be addressed: (I) Most estimates of the prevalence of FA are based on nonprobability sampling, which significantly limits the representativeness of the prevalence estimates. (II) Although addiction disorders are prevalent among individuals with mental disorders, large studies of FA among patients with clinically diagnosed mental disorders are lacking. (III) Most addiction disorders are heritable, but the familial transmission of FA remains virtually unknown. (IV) Due to a relative lack of longitudinal studies, little is known about the risk factors for and outcomes of FA. To close these gaps in the literature, we designed the Food Addiction Denmark (FADK) Project.
The FADK study is a nationwide survey with retrospective and prospective register-based elements. Four randomly sampled cohorts were invited to participate in the survey: 5000 adults and 3750 adolescents from the general population and 5000 adults and 3529 adolescents with a mental disorder. The FADK questionnaire includes the Yale Food Addiction Scale 2.0 and rating scales measuring psychopathology. Data from Danish health and socio-economic registers will be linked to all invitees.
We expect that the FADK Project will contribute significantly to our understanding of FA.
Both bipolar disorder (BD) and schizophrenia (SZ) are associated with language and thought symptoms that probably reflect a semantic memory-related impairment. We conducted a preliminary study to explore the nature of semantic processing in these disorders, using event-related potentials (ERPs).
Twelve patients with BD, 10 patients with SZ and a matched group of 21 healthy controls (HC) underwent EEG recording while they heard sentences containing homophones or control words and performed a semantic ambiguity resolution task on congruent or incongruent targets.
Mean N400 amplitude differed between groups for homophones. Patients with SZ made more resolution errors than HC and exhibited a greater N400 congruity effect in ambiguous conditions than BD. In BD, the opposite N400 congruity effect was observed in ambiguous conditions.
Results indicated differences in semantic processing between BD and SZ. Further studies with larger populations are needed in order to develop neurophysiological markers of these disorders.
In ambiguous conditions, patients with SZ exhibited a greater N400 difference between congruent and incongruent conditions than patients with BD.
In ambiguous conditions, patients with SZ exhibited greater N400 amplitude in incongruent conditions than in congruent ones, whereas patients with BD exhibited the opposite N400 congruity effect.
Ambiguity resolution results suggest that patients with SZ have difficulty considering the context, while patients with BD overactivate the dominant meaning of homophones and have difficulty inhibiting it.
Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia.
GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms.
We found a negative correlation between GSH levels and age at onset (r = −0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076).
Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.
The ongoing translational and reproducibility crisis dominates preclinical research today as results from animal studies often disappoint when transferred to human clinical studies. This problem is especially relevant in the field of brain diseases and translational neuropsychiatry.
Here, we discuss if the 3R concept could be part of the translational crisis.
The focus has been on the second R, which is to reduce the variation between the experimental animals, so that the number of animals per study can be reduced. However, the risk of obtaining false results has also increased. We, therefore, recommend that researchers use a broader perspective as also suggest by Russell and Burch who founded the 3Rs when considering the 3R concept, which involves the translational aspects described in detail in their 3R book from 1959.
This may together with systematic reviews and well-designed and well-performed animal studies and accurate reporting of the results indeed contribute to solving the translational crisis in preclinical research.