Preclinical studies suggest that cannabidiol (CBD), a non-intoxicating phytocannabinoid, may reduce addiction-related behaviours for various drug classes in rodents, including ethanol, opiates, and psychostimulants. CBD modulates contextual memories and responses to reward stimuli. Nonetheless, research on the impact of CBD on cocaine addiction-like behaviors is limited and requires further clarification. This study tested the hypothesis that CBD administration inhibits the acquisition and retrieval of cocaine-induced conditioned place preference (CPP) in adult male and female C57BL6/J mice. We also ought to characterise a 5-day CPP protocol in these animals.

Male and female C57BL/6J mice were administered CBD (3, 10, and 30 mg/kg) 30 minutes before cocaine (15 mg/kg) acquisition of expression of CPP.

Cocaine induces a CPP in both female and male mice in the 5-day CPP protocol. CBD failed to prevent the acquisition or retrieval of place preference induced by cocaine. CBD did not decrease the time spent on the side paired with cocaine at any of the doses tested in male and female mice, in either acquisition or expression of contextual memory.

This study found no support for the hypothesis that CBD decreases reward memory involved in the formation of cocaine addiction. Further research is necessary to investigate the involvement of CBD in other behavioural responses to cocaine and other psychostimulant drugs. This study, however, characterised a 5-day CPP protocol for both female and male C57BL/6J mice.

We aimed to answer the questions of whether early-life (perinatal and/or juvenile) exercise can induce antidepressant-like effects in a validated rodent model of depression, and whether such early-life intervention could prevent or reverse the adverse effects of early-life stress in their offspring.

Male and female Flinders sensitive line rats born to a dam that exercised during gestation, or not, were either maternally separated between PND02 and 16 and weaned on PND17 or not. Half of these animals then underwent a fourteen-day low-intensity exercise regimen from PND22. Baseline depressive-like behaviour was assessed on PND21 and then reassessed on PND36, whereafter hippocampal monoamine levels, redox state markers and metabolic markers relevant to mitochondrial function were measured.

Pre-pubertal exercise was identified as the largest contributing factor to the observed effects, where it decreased immobility time in the FST by 6%, increased time spent in the open arms of the EPM by 9%. Hippocampal serotonin and norepinephrine levels were also increased by 35% and 26%, respectively, whilst nicotinic acid was significantly decreased.

These findings suggest that pre-pubertal low-intensity exercise induces beneficial biological alterations that could translate into antidepressant behaviour in genetically susceptible individuals.

This cross-sectional study aimed to observe the occurrence of metabolic syndrome in untreated individuals with bipolar disorders.

A total of 125 untreated individuals with bipolar disorders were collected as the study group, and 201 cases from the health examination centre of our hospital were selected as the control group. The participants enrolled were assessed for general demographic data, case characteristics, and metabolic indexes including body mass index (BMI), blood pressure, triglyceride, high-density lipoprotein-cholesterol, cholesterol, low-density lipoprotein-cholesterol, and fasting plasma glucose.

The incidence of metabolic syndrome in the bipolar disorders group was higher compared to the control group (9.6% VS. 8.5%). After calibrating sex and age data, a significant difference between the two groups was observed (P < 0.05). Diastolic and systolic blood pressure were higher in the bipolar disorders group compared to the control group (P < 0.01). Men with bipolar disorders had a higher risk of developing metabolic syndrome than women (14.5% vs. 5.8%). Bipolar disorders, sex, age, and BMI were identified as independent risk factors for metabolic syndrome. No significant difference was found in terms of metabolic index and incidence of metabolic syndrome between individuals with depressive episodes (n = 37) and manic episodes (n = 75).

Patients with bipolar disorders were found to have a higher risk of developing metabolic syndrome than healthy individuals. Bipolar disorders, male sex, age, and BMI may contribute to an increased risk of developing metabolic syndrome.

Major depressive disorder (MDD) is one of the leading causes of disability. We aimed to report the MDD-attributable prevalence, incidence and years lived with disability (YLDs) in the Middle East and North Africa (MENA) region from 1990 to 2019 by age, sex and socio-demographic index (SDI).

Publicly available data on the burden of MDD were retrieved from the Global Burden of Disease (GBD) study 2019 for the 21 countries in MENA. The counts and age-standardised rates (per 100,000) were presented, along with their corresponding 95% uncertainty intervals.

In 2019, MDD had an age-standardised point prevalence of 3322.1 and an incidence rate of 4921.7 per 100,000 population in MENA. Furthermore, there were 4.1 million YLDs in 2019. However, there were no substantial changes in the MDD burden over the period 1990–2019. In 2019, Palestine had the highest burden of MDD. The highest prevalence, incidence and YLDs attributable to MDD were found in the 35–39 age group. In 2019, the YLD rate in MENA was higher than the global rate for almost all age groups. Furthermore, there was a broadly negative association between the YLD rate and SDI.

The study highlights the need to prevent the disorder using a multidisciplinary approach and for the provision of cost-effective treatments for those affected, in order to increase their quality of life.

Cloninger’s temperament dimensions have been studied widely in relation to genetics. In this study, we examined Cloninger’s temperament dimensions grouped with cluster analyses and their association with single nucleotide polymorphisms (SNPs). This study included 212 genotyped Finnish patients from the Ostrobothnia Depression Study.

The temperament clusters were analysed at baseline and at six weeks from the beginning of the depression intervention study. We selected depression-related catecholamine and serotonin genes based on a literature search, and 59 SNPs from ten different genes were analysed. The associations of single SNPs with temperament clusters were studied. Using the selected genes, genetic risk score (GRS) analyses were conducted considering appropriate confounding factors.

No single SNP had a significant association with the temperament clusters. Associations between GRSs and temperament clusters were observed in multivariate models that were significant after permutation analyses. Two SNPs from the DRD3 gene, two SNPs from the SLC6A2 gene, one SNP from the SLC6A4 gene, and one SNP from the HTR2A gene associated with the HHA/LRD/LP (high harm avoidance, low reward dependence, low persistence) cluster at baseline. Two SNPs from the HTR2A gene were associated with the HHA/LRD/LP cluster at six weeks. Two SNPs from the HTR2A gene and two SNPs from the COMT gene were associated with the HP (high persistence) cluster at six weeks.

GRSs seem to associate with an individual’s temperament profile, which can be observed in the clusters used. Further research needs to be conducted on these types of clusters and their clinical applicability.

Depression is a common mental disorder that endangers physical and mental health. In our study, we aimed to explore whether B vitamins are associated with depression and cognitive dysfunction.

We enrolled a total of 220 patients with depression and selected 100 controls at the same time. We determined depression and cognitive impairment by assessments. We recorded the basic parameters of the participants and collected blood samples. In addition, we measured serum levels of B vitamins and brain-derived neurotrophic factor (BDNF).

We found significant differences in the duration of depression, education, and Hamilton Depression Rating Scale scores between the D-NCI and D-CI groups. We also identified the independent risk factors for patients with depression and cognitive dysfunction. Compared with the healthy controls, serum folate, vitamin B6, and vitamin B12 positively correlated with cognitive dysfunction. The patients with depression and cognitive dysfunction had the lowest levels of B vitamins compared with the other two groups. Our results also showed that the levels of serum folate, vitamin B6, and vitamin B12 in the patients with depression had a positive correlation with each other.

Our results indicate that vitamin B is associated with depression and cognitive dysfunction and is positively associated with cognitive dysfunction.

Natural language processing (NLP) methods hold promise for improving clinical prediction by utilising information otherwise hidden in the clinical notes of electronic health records. However, clinical practice – as well as the systems and databases in which clinical notes are recorded and stored – change over time. As a consequence, the content of clinical notes may also change over time, which could degrade the performance of prediction models. Despite its importance, the stability of clinical notes over time has rarely been tested.

The lexical stability of clinical notes from the Psychiatric Services of the Central Denmark Region in the period from January 1, 2011, to November 22, 2021 (a total of 14,811,551 clinical notes describing 129,570 patients) was assessed by quantifying sentence length, readability, syntactic complexity and clinical content. Changepoint detection models were used to estimate potential changes in these metrics.

We find lexical stability of the clinical notes over time, with minor deviations during the COVID-19 pandemic. Out of 2988 data points, 17 possible changepoints (corresponding to 0.6%) were detected. The majority of these were related to the discontinuation of a specific note type.

We find lexical and syntactic stability of clinical notes from psychiatric services over time, which bodes well for the use of NLP for predictive modelling in clinical psychiatry.

Rumination is a passive form of negative self-focused cognition that predicts depressive episodes for individuals with bipolar disorder (BD). Individuals with BD also have impaired inhibitory executive control; rumination in BD may therefore reflect executive dysfunction. We investigated the relationship between a neural measure of executive functioning (functional connectivity between the frontoparietal control network [FPCN] and the default mode network [DMN] during an effortful task), behavioural measures of executive functioning (the Behavior Rating Inventory of Executive Function) and rumination (the Ruminative Responses Scale).

Fifteen individuals with BD and fifteen healthy controls underwent MRI scans during mental distraction. Using CONN toolbox, between-network FPCN-DMN connectivity values were calculated. We conducted Pearson’s r bivariate correlations between connectivity values, BRIEF and RRS scores.

RRS scores were positively correlated with BRIEF Behavioral Regulation Index (BRI) scores. In individuals with BD, there was a positive correlation between FPCN-DMN functional connectivity during distraction and BRIEF BRI scores. FPCN-DMN functional connectivity was also positively correlated with RRS ruminative brooding scores. Healthy controls did not show significant correlations between these behavioural and neural measures of executive functioning and rumination.

For individuals with BD, the greater the tendency to ruminate and the higher the executive dysfunction, the stronger the connectivity between an executive control network and a network involved in rumination during an unrelated cognitive task. This could reflect continual attempts to inhibit ruminative thinking and shift back to the distraction task. Therefore, engagement in rumination may reflect failed inhibitory executive control.

Although disconnectivity among brain regions has been one of the main hypotheses for schizophrenia, the superficial white matter (SWM) has received less attention in schizophrenia research than the deep white matter (DWM) owing to the challenge of consistent reconstruction across subjects.

We obtained the diffusion magnetic resonance imaging (dMRI) data of 223 healthy controls and 143 patients with schizophrenia. After harmonising the raw dMRIs from three different studies, we performed whole-brain two-tensor tractography and fibre clustering on the tractography data. We compared the fractional anisotropy (FA) of white matter tracts between healthy controls and patients with schizophrenia. Spearman’s rho was adopted for the associations with clinical symptoms measured by the Positive and Negative Syndrome Scale (PANSS). The Bonferroni correction was used to adjust multiple testing.

Among the 33 DWM and 8 SWM tracts, patients with schizophrenia had a lower FA in 14 DWM and 4 SWM tracts than healthy controls, with small effect sizes. In the patient group, the FA deviations of the corticospinal and superficial–occipital tracts were negatively correlated with the PANSS negative score; however, this correlation was not evident after adjusting for multiple testing.

We observed the structural impairments of both the DWM and SWM tracts in patients with schizophrenia. The SWM could be a potential target of interest in future research on neural biomarkers for schizophrenia.

The corpus callosum (CC) is a brain structure with a high heritability and potential role in psychiatric disorders. However, the genetic architecture of the CC and the genetic link with psychiatric disorders remain largely unclear. We investigated the genetic architectures of the volume of the CC and its subregions and the genetic overlap with psychiatric disorders.

We applied multivariate genome-wide association study (GWAS) to genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank, aiming to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) obtained by FreeSurfer 7.1. Multivariate GWAS was run combining all subregions, co-varying for relevant variables. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression (LDSC) was used to determine Single nucleotide polymorphism (SNP)-based heritability of total CC volume and volumes of its subregions as well as their genetic correlations with relevant psychiatric traits.

We identified 70 independent loci with distributed effects across the five subregions of the CC (p < 5 × 10−8). Additionally, we identified 33 significant loci in the anterior subregion, 23 in the mid-anterior, 29 in the central, 7 in the mid-posterior and 56 in the posterior subregion. Gene-set analysis revealed 156 significant genes contributing to volume of the CC subregions (p < 2.6 × 10−6). LDSC estimated the heritability of CC to (h2SNP = 0.38, SE = 0.03) and subregions ranging from 0.22 (SE = 0.02) to 0.37 (SE = 0.03). We found significant genetic correlations of total CC volume with bipolar disorder (BD, rg = −0.09, SE = 0.03; p = 5.9 × 10−3) and drinks consumed per week (rg = −0.09, SE = 0.02; p = 4.8 × 10−4), and volume of the mid-anterior subregion with BD (rg = −0.12, SE = 0.02; p = 2.5 × 10−4), major depressive disorder (MDD) (rg = −0.12, SE = 0.04; p = 3.6 × 10−3), drinks consumed per week (rg = −0.13, SE = 0.04; p = 1.8 × 10−3) and cannabis use (rg = −0.09, SE = 0.03; p = 8.4 × 10−3).

Our results demonstrate that the CC has a polygenic architecture implicating multiple genes and show that CC subregion volumes are heritable. We found that distinct genetic factors are involved in the development of anterior and posterior subregions, consistent with their divergent functional specialisation. Significant genetic correlation between volumes of the CC and BD, drinks per week, MDD and cannabis consumption subregion volumes with psychiatric traits is noteworthy and deserving of further investigation.

A range of neuropathological changes occur in the brains of individuals with adult Niemann-Pick type C disease (NPC), a recessive disorder of cholesterol trafficking that results in accumulation of cholesterol and gangliosides in lysosomes, particularly in neurons. One of the most significant regions of grey matter loss occurs in the thalami, which abut the midline. What is not known is whether these are neurodevelopmental in origin well prior to symptomatic onset. We aimed to examine other markers of midline developmental anomalies in adults with NPC.

We examined the size of adhesio interthalamica (AI) and cavum septum pellucidum (CSP) (if present) in nine individuals diagnosed with NPC and nine healthy comparison subjects, matched for age and gender, using a 3T magnetic resonance volumetric sequence and measured the length of the AI and CSP in mm.

We found that 5/9 NPC patients and 0/9 controls had a missing AI. AI length was significantly shorter in the patient group. No subject in other group had a large CSP, and CSP length did not differ. Duration of illness showed a trend to a negative correlation with AI length in patients.

Our findings suggest that adult NPC patients show some markers of early neurodevelopmental disturbance, matching findings seen in psychotic disorders. The differences in AI, but not CSP, suggest neurodevelopmental change may occur early in gestation rather than post-partum. The relationship with duration of illness suggests that there may be atrophy over time in these structures, consistent with prior analyses of grey matter regions in NPC.

Cannabidiol (CBD) is a phytocannabinoid with great potential in clinical applications. The mechanism(s) of action of CBD require further investigation. Previous studies suggested that adenosine A2A receptors (A2ARs) could play a role in CBD-induced effects. Here, we evaluated the ability of CBD to modify the function of A2AR.

We used HEK-293T cells transfected with the cDNA encoding the human A2AR and Gαs protein, both modified to perform bioluminescence-based assays. We first assessed the effect of CBD on A2AR ligand binding using an A2AR NanoLuciferase sensor. Next, we evaluated whether CBD modified A2AR coupling to mini-Gαs proteins using the NanoBiT™ assay. Finally, we further assessed CBD effects on A2AR intrinsic activity by recording agonist-induced cAMP accumulation.

CBD did not bind orthosterically to A2AR but reduced the coupling of A2AR to Gαs protein and the subsequent generation of cAMP.

CBD negatively modulates A2AR functioning.

Suicide prevention for major depressive disorder (MDD) is a worldwide challenge, especially for suicide attempt (SA). Viewing suicide as a state rather than a lifetime event provided new perspectives on suicide research.

This study aimed to verify and complement SAs biomarkers of MDD with a recent SA sample.

This study included 189 participants (60 healthy controls; 47 MDD patients with non-suicide (MDD-NSs), 40 MDD patients with suicide ideation (MDD-SIs) and 42 MDD patients with SA (MDD-SAs)). MDD patients with an acute SA time was determined to be within 1 week since the last SA. SUICIDALITY Part in MINI was applied to evaluate suicidality. Absolute powers in 14 frequency bands were extracted from subject’s resting-state electroencephalography data and compared within four groups. The relationship among suicidality, the number of SA and powers in significant frequency bands were investigated.

MDD-SIs had increased powers in delta, theta, alpha and beta band on the right frontocentral channels compared to MDD-NSs, while MDD-SAs had decreased powers in delta, beta and gamma bands on widely the right frontocentral and parietooccipital channels compared to MDD-SIs. Beta 1 power was the lowest in MDD-SAs and was modulated by the number of SA. The correlation between suicidality and beta 1 power was negative in MDD-SAs and positive in MDD-SIs.

Reduced beta 1 (12–15 Hz) power could be essential in promoting suicidal behaviour in MDD. Research on recent SA samples contributes to a better understanding of suicide mechanisms and preventing suicidal behaviour in MDD.

In Alzheimer’s disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators.

Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy–Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

We previously reported that dual injections of lipopolysaccharide (LPS) in mice constitute a valuable tool for investigating the contribution of inflammation to psychotic disorders. The present study investigated how immune activation affects the kynurenine pathway and rat behaviour of relevance for psychotic disorders.

Male Sprague Dawley rats were treated with either dual injections of LPS (0.5 mg/kg + 0.5 mg/kg, i.p.) or dual injections of saline. Twenty-four hours after the second injection, behavioural tests were carried out, including locomotor activity test, fear conditioning test, spontaneous alternation Y-maze test, and novel object recognition test. In a separate batch of animals, in vivo striatal microdialysis was performed, and tryptophan, kynurenine, quinolinic acid, and kynurenic acid (KYNA) in the dialysate were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

Dual-LPS treatment decreased spontaneous locomotion, exaggerated d-amphetamine-induced locomotor activity, and impaired recognition memory in male Sprague-Dawley rats. In vivo microdialysis showed that dual-LPS treatment elicited metabolic disturbances in the kynurenine pathway with increased extracellular levels of kynurenine and KYNA in the striatum.

The present study further supports the feasibility of using the dual-LPS model to investigate inflammation-related psychotic disorders and cognitive impairments.

Early-life adversity (ELA) is one of the strongest predictors of childhood depression that may be exacerbated by a genetic predisposition to develop depression. We therefore investigated the bio-behavioural effects of an early-life stressor in an accepted rodent model of depression.

The Flinders sensitive line (FSL) and resistant line (FRL) rats were subjected to an early-life stressor, whereafter their bio-behavioural response during pubertal onset was evaluated. Male and female pups were maternally separated for 3 h per day from postnatal day 02 (PND02) to 17, when they were also weaned. Control animals were left undisturbed, until weaning on PND21. Depressive-like behaviour was analysed on PND21 and reassessed on PND36. Hippocampal monoamine levels, markers of oxidative stress and metabolic markers implicating mitochondrial function were also measured.

On PND21, the non-maternal separation and early weaning (non-MSEW) FSL rats spent 10% more time mobile than their FRL controls in the tail suspension test (TST) yet displayed increased depressive-like behaviour in the forced swim test (FST) on PND36. This depressive-like behaviour coincided with increased hippocampal norepinephrine levels, serotonin turnover and a dysfunctional redox state. Maternal separation and early weaning (MSEW) appeared to initially reduce early-life (PND21) depressive-like behaviour in the TST but then induced depressive-like behaviour on PND36 and increased norepinephrine levels more profoundly in the FRL rats.

These findings highlight the need to further investigate the stress response pathway in these animals and that the absence or presence of genetic susceptibility may influence the presentation of ELA effects.