Genetic and environmental factors interact in the development of major depressive disorder (MDD). While neurobiological correlates have only partially been elucidated, altered levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) in animal models and in the cerebrospinal fluid of depressed patients were reported, suggesting that CGRP may be involved in the pathophysiology and/or be a trait marker of MDD. However, changes in CGRP brain levels resulting from interactions between genetic and environmental risk factors and the response to antidepressant treatment have not been explored.

We therefore superimposed maternal separation (MS) onto a genetic rat model (Flinders-sensitive and -resistant lines, FSL/FRL) of depression, treated these rats with antidepressants (escitalopram and nortriptyline) and measured CGRP-LI in selected brain regions.

CGRP was elevated in the frontal cortex, hippocampus and amygdala (but not in the hypothalamus) of FSL rats. However, MS did not significantly alter levels of this peptide. Likewise, there were no significant interactions between the genetic and environmental factors. Most importantly, neither escitalopram nor nortriptyline significantly altered brain CGRP levels.

Our data demonstrate that increased brain levels of CGRP are present in a well-established rat model of depression. Given that antidepressants have virtually no effect on the brain level of this peptide, our study indicates that further research is needed to evaluate the functional role of CGRP in the FSL model for depression.

Oxidative stress and dysregulated antioxidant defence may be involved in the pathophysiology of schizophrenia. In the present study, we investigated changes in antioxidants and oxidative stress from an acute to a later stable phase. We hypothesised that the levels of oxidative markers are increased in schizophrenia compared with healthy controls; change from the acute to the stable phase; and are associated with the levels of membrane polyunsaturated fatty acids (PUFAs) and symptom severity.

Fifty-five patients with schizophrenia spectrum disorders, assessed during an acute phase and 5 years later during a stable phase, and 51 healthy controls were included. We measured antioxidants (α-tocopherol, uric acid, albumin and bilirubin), markers of oxidative stress (F2-isoprostane and reactive oxygen metabolites) and membrane fatty acids. Antioxidants and oxidative stress markers were compared in schizophrenia versus healthy controls, adjusting for differences in sex, age and smoking, and changes over time. Associations between symptoms and PUFA were also investigated.

In the acute phase, α-tocopherol was significantly higher (p < 0.001), while albumin was lower (p < 0.001) compared with the stable phase. Changes in α-tocopherol were associated with PUFA levels in the acute phase. In the stable phase, schizophrenia patients had higher uric acid (p = 0.009) and lower bilirubin (p = 0.046) than healthy controls. CRP was higher in patients in the stable phase (p < 0.001), and there was no significant change from the acute phase.

The present findings of change in antioxidant levels in the acute versus stable phase of schizophrenia the present findings suggest that redox regulation is dynamic and changes during different phases of the disorder.

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.

Inverse relationships between the C-reactive protein (CRP) levels and cognitive performance in acute psychosis have been demonstrated. We aimed to investigate how the serum level and initial change of CRP in acutely admitted patients with psychosis was correlated with cognitive performance during a 6-months follow-up period.

The study is part of a pragmatic, randomised trial comparing four different second-generation antipsychotic drugs, and consists of 208 acute phase patients recruited at admittance for psychosis. This study reports data for all groups collectively, and does not compare treatment groups. Measurements of CRP and cognitive performance were conducted at baseline (T1) and after 4 weeks on average after inclusion (T2). Cognition was also assessed after 3 months (T3) and 6 months (T4) of follow-up.

Global cognition improved during the follow-up period of 6 months, especially in the T1–T2 interval. The different cognitive subdomains showed different time-dependent profiles of improvement, with memory and attention improving significantly also in the later phases. Reduction of the CRP level during the initial follow-up interval (T1–T2) was associated with increased overall cognitive performance in the T2–T4 interval, but not in the T1–T2 interval. For the cognitive subdomains, we found an inverse association between change in CRP level and verbal abilities (T2–T4 interval), and attention (T2–T3 interval).

These findings indicate that initial changes in the serum level of CRP in the acute phase of psychosis may predict cognitive function in later phases of the disease.

NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors.

Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment.

We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL.

Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.

Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with Adrenocorticotropic hormone (ACTH) appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate receptor in ACTH-treated animals.

Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 µg/0.1 ml/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out.

We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment.

The present data confirm development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment-resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.

To investigate oxidative stress parameters [total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), paraoxonase (PON), arylesterase (ARE) and thiol-disulphide homeostasis] in patients who were diagnosed as having somatic symptom disorder in accordance with Diagnostic and Statistical Manual of Mental Disorders-5.

The study included 41 medication-free patients with somatic symptom disorder and 47 age, sex, and sociodemographic-matched healthy individuals. The patients were administered the Patient Health Questionnaire-15, Somatic Symptom Amplification Scale, Beck Depression Inventory, and Beck Anxiety Inventory. TOS, TAS, OSI, PON, ARE thiol, disulphide levels, and routine biochemical parameters were compared between the two groups.

TOS, OSI, disulphide levels, disulphide/native thiol, and disulphide/total thiol ratios were found significantly higher in the patient group compared with the control group (p < 0.001). There was no significant difference in PON, ARE, and TAS parameters between the two groups (p > 0.05).

This study showed that the level of oxidants increased and oxidative balance was impaired in somatic symptom disorder. Oxidative stress may play a role in the aetiopathogenesis of this disorder. This is the first study to report an association between oxidative stress and somatic symptom disorder.

To investigate the association between suicide death and serum cholesterol levels as measured at times close to suicide death.

We conducted a nested case-control study of 41 cases of suicide deaths and 205 matched controls with serum total cholesterol (TC) levels till 3 years before suicide death in a large cohort of Japanese workers.

Individuals in the lowest versus highest tertile/predefined category of TC in a Japanese working population had a three- to four-fold greater risk of suicide death. Each 10 mg/dl decrement of average TC was associated with an 18% increased chance of suicide death (95% confidence interval, 2–35%). Similar results were found for TC levels at each year.

These results suggest that a low serum TC level in recent past is associated with an increased risk of suicide death.

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.

Whereas long-term administration of selective serotonin reuptake inhibitors (SSRIs) is effective for the treatment of anxiety disorders, acute administration of these drugs may exert a paradoxical anxiogenic effect. The aim of the present study was to explore the possible effect of an SSRI in situations of unconditioned or limited conditioned fear.

Male Sprague Dawley rats were administered a single dose of an SSRI, escitalopram, before acquisition or expression of context conditioned fear, where noise bursts were used as the unconditioned stimulus. Freezing was assessed as a measure of unconditioned fear (=the acute response to noise bursts) or conditioned fear (=the response to the context), respectively.

Noise bursts elicited an acute increase in freezing but no robust conditioned response 7 days after exposure. Administration of escitalopram before testing exacerbated the freezing response during presentation of the unconditioned stimulus and also unmasked a conditioned response; in contrast, administration of escitalopram prior to acquisition did not influence the conditioned response.

The data suggest that freezing in rats exposed to a stimulus inducing relatively mild fear may be enhanced by acute pretreatment with an SSRI regardless of whether the freezing displayed by the animals is an acute unconditioned response to the stimulus in question or a conditioned response to the same stimulus.

Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression.

Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration.

Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected.

Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.

Depression is a common, serious, but under-recognised problem in multiple sclerosis (MS). The primary objective of this study was to assess whether a rapid visual analogue screening tool for depression could operate as a quick and reliable screening method for depression, in patients with MS.

Patients attending a regional MS outpatient clinic completed the Emotional Thermometer 7 tool (ET7), the Hospital Anxiety and Depression Scale – Depression Subscale (HADS-D) and the Major Depression Inventory (MDI) to establish a Diagnostic and Statistical Manual, 4th edition (DSM-IV) diagnosis of Major Depression. Full ET7, briefer subset ET4 version and depression and distress thermometers alone were compared with HADS-D and MDI. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and receiver operating characteristic (ROC) curve were calculated to compare the performance of all the screening tools.

In total, 190 patients were included. ET4 performed well as a ‘rule-out’ screening step (sensitivity 0.91, specificity 0.72, NPV 0.98, PPV 0.32). ET4 performance was comparable to HADS-D (sensitivity 0.96, specificity 0.77, NPV 0.99, PPV 0.37) without need for clinician scoring. The briefer ET4 performed as well as the full ET7.

ET are quick, sensitive and useful screening tools for depression in this MS population, to be complemented by further questioning or more detailed psychiatric assessment where indicated. Given that ET4 and ET7 perform equally well, we recommend the use of ET4 as it is briefer. It has the potential to be widely implemented across busy neurology clinics to assist in depression screening in this under diagnosed group.

Electroconvulsive therapy (ECT) is a safe and validated technique used to treat various psychiatric conditions. It triggers an artificially-induced seizure. This seizure is defined using several parameters such as the amount of energy, duration, frequency, pulse width and intensity. Efficacy and adverse events depend on the amount of energy delivered. Due to technical control, the amount of energy delivered by our unit’s ECT device was limited to 614 mC, 60% of the maximum possible output of the device. We wondered if lowering the dose would lead to better seizure quality among maintenance ECT patients.

We assessed seizure quality based on the EEG, using a validated tool created by MacPherson. Two evaluators independently rated the seizures. Pre- and post-control scores were compared using Student’s t-test for paired samples.

We analysed data from 15 patients. Mean age was 65 years old. Twelve had depressive disorder, two had schizophrenia and one had schizo-affective disorder. Mean duration of seizure before control was 41.1 s [95% confidence interval (95CI)=26.1, 51.1]. The mean MacPherson’s score was 20.3 (95CI=16.2, 24.4). After control, the mean MacPherson’s score was 28.2 (23.1, 33.3), showing a significant difference with the pre-control dataset (p=0.032; t=−2.4; df=14). Specifically, peak mid-ictal amplitude increased from 6.9 (95CI=5.1, 8.7) to 10.0 (95CI=7.2, 12.8). Other sub-scores remained unchanged.

Lowering the energy delivered led to an overall increase of seizure quality among our sample. This highlights the necessity and utility of retitration during ECT maintenance, possibly leading to better management of our patients.

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.

Road traffic injuries are the leading cause of death among young people. Recognition of the contribution of impulsive behaviour may help novice drivers to behave more safely. Previously a brief intervention focusing on impulsive traffic behaviour conducted by psychologists in driving schools had been effective. The aim of this study was an independent re-evaluation of the effect of the intervention, as conducted by driving school teachers, and assessment of the potential associations with candidate genotypes.

Driving school students (mean age 22.5, SD=7.9) were divided into intervention (n=704) and control (n=737) groups. Driving school teachers were trained to administer the intervention which consisted of a lecture and group work (1.5 h in total) on impulsivity. Traffic offences and crashes were monitored during 3 years, using police and traffic insurance fund databases. Functional polymorphisms of the dopamine transporter (DAT) and serotonin transporter genes (DAT1 VNTR and 5-HTTLPR) were assessed.

The intervention significantly lowered general traffic risk and prevalence of traffic accidents. DAT1 VNTR 9R carriers, particularly males, had higher general traffic risk in the whole sample. Female 5-HTTLPR s’ allele carriers of the intervention group had the lowest general traffic risk. Intervention was most effective in female DAT1 VNTR 10R/10R homozygotes.

Brief impulsivity-centred intervention appears as a promising strategy for preventing risk-taking behaviour in novice drivers and can be fully integrated to driving school curriculum.

The immune system has been suggested to be associated with neuropsychiatric disorders; for example, elevated levels of cytokines and the inflammation-related transcription factor nuclear factor kappa-B (NF-κB) have been reported in individuals with autism spectrum disorder (ASD). The aim of this study was to investigate possible associations between autistic-like traits (ALTs) and single nucleotide polymorphisms (SNPs) in NFKB1 (encoding a subunit of the NF-κB protein complex) and NF-κB inhibitor-like protein 1 (NFKBIL1).

The study was conducted in a cohort from the general population: The Child and Adolescent Twin Study in Sweden (CATSS, n = 12 319, 9–12 years old). The subjects were assessed by the Autism-Tics, ADHD, and Other Comorbidities Inventory. Five SNPs within the two genes were genotyped (NFKBIL1: rs2857605, rs2239707, rs2230365 and rs2071592; NFKB1: rs4648022).

We found significant associations for two SNPs in NFKBIL1: rs2239707 showed a significant distribution of genotype frequencies in the case-control analysis both for all individuals combined and in boys only, and rs2230365 was significantly associated with the ALTs-module language impairment in boys only. Furthermore, we found nominal association in the case-control study for rs2230365, replicating earlier association between this SNP and ASD in an independent genome-wide association study.

The shown associations between polymorphisms in NFKBIL1 and ALTs are supporting an influence of the immune system on neuropsychiatric symptoms.

To examine the association of psychological distress with serum C-reactive protein (CRP) in a South African cohort.

Data were analysed on individuals aged ≥15 years from the South African National Health and Nutrition Examination Survey (SANHANES) of 2012. Psychological distress was evaluated using the Kessler Psychological Distress Scale. Linear regression models assessed the association of psychological distress with serum CRP, adjusting for possible confounding factors.

The analytic sample comprised n = 3944 individuals (mean age = 40 and sex = 36% males). Psychological distress was significantly associated with increased serum CRP levels (B = 0.31 and p = 0.001). This association was no longer significant after adjusting for demographic variables, lifestyle factors, cardiac disease, diabetes, hypertension, trauma and anti-inflammatory medication use (B = 0.15 and p = 0.062).

Psychological distress was associated with elevated levels of CRP among South African adults. However, the association was confounded by a range of factors, with demographic variables (age, sex and population group) having the largest confounding effect. These findings indicate that CRP is not a useful biomarker of psychological distress, and that additional work is needed on the underlying psychobiology of psychological distress.

The present study explores the relationship between neuroactive hormones and religious commitment. We hypothesised that religious commitment is mediated by neuropeptide Y and oxytocin. These neurohormones have a well-established role in general well-being, anxiety regulation, stress-resilience, social affiliation and spirituality.

Sixty healthy women (median age 21) participated in the study and completed the Religious Commitment Inventory and other psychometric surveys. Blood was sampled from each participant and serum levels of neuropeptide Y were measured using radioimmunoassay. Oxytocin, stress and sex hormones were measured using enzyme-linked immunosorbent assay. Correlations were tested using non-parametric statistical methods.

We found a positive correlation between serum neuropeptide Y levels and religious commitment, but not between oxytocin and religious commitment.

The present study provides preliminary evidence that neuropeptide Y is a biological correlate of religious commitment.