Cardiac autonomic dysregulation has been reported in major depressive disorder (MDD), but scarce studies investigated that in fully remitted MDD.

To examine cardiac autonomic function in remitted MDD, 470 unmedicated individuals with a diagnosis of MDD earlier in life and 462 healthy volunteers, aged 18–65 years, were recruited for a case–control analysis. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters. Frequency-domain indices of HRV were obtained. The obtained results were evaluated in association with personality traits assessed by the Tridimensional Personality Questionnaire.

In patients with remitted MDD, no differences in RR intervals and all frequency-domain indices of HRV could be detected as compared with controls. Stratified analyses by the presence of a history of suicide ideation (the SI+ vs. the SI-subgroup) revealed decreased cardiac vagal control in the SI+ subgroup. The correlation analysis revealed an inverse relation between HRV levels and the harm avoidance score (which has been suggested to be associated with serotonergic activity), mainly attributable to the robust association in the SI+ subgroup.

Our study shows that cardiac autonomic dysregulation is not shown in remitted MDD patients as a whole but is limited to the subgroup of remitted MDD patients with a history of suicidal ideation. In view of the higher risk for cardiac complications in these vulnerable individuals, one might consider the treatment to restore their autonomic function.

Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies.

Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2–4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1–4 mg), 52-week, placebo-controlled maintenance study.

The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of −20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs.

Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.

The clinical and etiologic implications of comorbid psychiatric and substance-use disorders are relevant across countries and cultures. The DSM-IV now places greater emphasis on the clinical and research utility of the substance-induced disorders classification, and clarifies several important diagnostic issues specific to primary and substance-induced disorders. However, no research consensus exists over the core problem of identifying and differentiating the drug and alcohol intoxication and withdrawal symptoms that can mimic psychiatric symptoms in heavy drinkers and drug users.

To investigate how various diagnostic instruments have measured comorbid psychiatric and substance-use disorders and how each instrument operationalizes the DSM-IV classification.

We review the evolution of the concept of comorbidity beginning with its formalization as the ‘primary–secondary’ distinction in the Feighner Criteria. We address the ‘organic–non-organic’ distinction found in the RDC, DSM-III, and DSM-III-R; and finally, review the ‘primary’ and ‘substance-induced’ categories of DSM-IV, DSM-IV-TR and ICD-10. We describe how these distinctions have been operationalized in widely used diagnostic instruments.

Further understanding of these classifications and the relationship of co-occurring psychiatric and substance disorders can be accomplished with the range of available measures, particularly the Psychiatric Research Interview for Substance and Mental Disorders (PRISM), which reliably utilizes and refines DSM-IV classification distinctions.

Objective: The association between metabolic syndrome (MS) and the risk of cognitive impairment or dementia remains unclear. In this article, we systematically review studies on the risk of cognitive disorders in patients with MS to determine the strength of the association between MS and cognitive decline.

Methods: Electronic databases through December 2009 were searched to identify prospective population-based studies that examined the association between MS and risk of cognitive disorders. Two reviewers used a standardised form to collect data and assess eligibility. The quality of study was assessed by the Newcastle–Ottawa Scale.

Results: We found nine eligible studies that involve 19 876 participants. All studies but two indicate that MS is associated with cognitive decline (from one-fold to more than two-fold increase in risk). It seems that MS may be associated with cognitive impairment (positive results in three of five) and vascular dementia (positive results in two of three), whereas three studies involving patients with Alzheimer's disease (AD) did not find the association between MS and AD. When examining the association of the individual risk factors of the MS and cognition in seven eligible studies, glucose (three studies) and hypertension (three studies) showed positive results associated with cognitive decline.

Conclusion: The MS may be associated with cognitive impairment and vascular dementia but not for AD, which need to be further investigated with high-quality studies.

Brain-derived neurotrophic factor (BDNF) plays a critical role in brain plasticity processes and serum levels have been demonstrated to be altered in patients with different mental disorder including suicidal behaviour. The objective of this study was to examine the association between serum BDNF levels as a possible peripheral indicator of suicide behaviour in subjects suffering from depression, personality disorders (PDs) and adjustment disorders (ADs) with or without suicide attempt.

The research included 172 randomly selected individuals suffering from recurrent depressive disorder (RDD; F 33.2), emotionally unstable PD (F 60.3) and AD (F 43.2), with or without attempted suicide according to the criteria of the ICD-10 (International Statistical Classification of Diseases and Related Health Problems 10th Revision) and 60 phenotypically health control subjects. In the group of patients, 73% subjects took some form of psychopharmacotherapy. Serum BDNF levels were measured by enzyme linked immunosorbent assay.

Subjects with PD and AD with suicide attempts had significantly lower serum BDNF levels than those without suicide attempts. In groups of subjects with PD and AD, those taking psychopharmacotherapy had higher serum BDNF levels. In the group of subjects with RDD, there were no differences with respect to suicide attempts or psychopharmacotherapy. Logistical regression analysis was indicated that psychopharmcotherapy and serum BDNF levels statistically correlated with suicide attempts.

The lower levels of BDNF in subjects suffering from PD and AD with suicide attempts, suggest that the serum BDNF level is a potential marker of suicidal behaviour, independent of mental disorders.

The present study examined whether low birth weight, prematurity or low birth weight adjusted for gestational age are risk factors for the subsequent development of affective disorder, especially depression.

A population-based case–control design was applied to the Danish Medical Birth Register and the Danish Psychiatric Central Register to identify all individuals born between 1 January 1974 and 31 December 1990 and diagnosed prior to 29 August 2003 with affective disorder alone (ICD-10 F3; 4297 females, 1861 males), schizophrenia alone (ICD-10 F2; 1364 females, 2292 males) or both disorders (ICD-10 F3 + F2; 450 females, 405 males). The association between low birth weight and the risk of developing affective disorder and/or schizophrenia was analysed by conditional logistic regression analysis.

Low birth weight was found to be associated with a significantly elevated risk of developing schizophrenia alone (p = 0.021) and both affective disorder and schizophrenia (p = 0.024), and a non-significantly elevated risk of developing affective disorder alone (p = 0.063). The effect remained significant in the affective disorder and schizophrenia groups (p = 0.039) when correcting for gestational age (premature birth), but was lost in the group with both disorders. Premature birth per se was found to be associated with a significantly elevated risk of developing both affective disorder and schizophrenia (p = 0.00018), an effect that remained significant after adjustment for low birth weight.

Prematurity and low birth weight were found to be risk factors for subsequent development of affective disorder (especially depression) and schizophrenia.

This study aimed to assess the feasibility of a low-literacy adaptation of the Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog) for use in rural sub-Saharan Africa (SSA) for interventional studies in dementia. No such adaptations currently exist.

Tanzanian and Nigerian health professionals adapted the ADAS-Cog by consensus. Validation took place in a cross-sectional sample of 34 rural-dwelling older adults with mild/moderate dementia alongside 32 non-demented controls in Tanzania. Participants were oversampled for lower educational level. Inter-rater reliability was conducted by two trained raters in 22 older adults (13 with dementia) from the same population. Assessors were blind to diagnostic group.

Median ADAS-Cog scores were 28.75 (interquartile range (IQR), 22.96–35.54) in mild/moderate dementia and 12.75 (IQR 9.08–16.16) in controls. The area under the receiver operating characteristic curve (AUC) was 0.973 (95% confidence interval (CI) 0.936–1.00) for dementia. Internal consistency was high (Cronbach’s α 0.884) and inter-rater reliability was excellent (intra-class correlation coefficient 0.905, 95% CI 0.804–0.964).

The low-literacy adaptation of the ADAS-Cog had good psychometric properties in this setting. Further evaluation in similar settings is required.

To assess the psychiatric side effects of ketamine when administered in subanesthetic doses to hospitalized patients. It is hypothesized that such effects occur frequently.

In this retrospective study, the medical records of 50 patients hospitalized on medical and surgical units at our facility who had continuous intravenous infusions of ketamine for pain or mild sedation were reviewed. Patient progress in the days following the start of ketamine infusion was reviewed and response to ketamine was noted.

Twenty-two percent of the patients were noted to have some type of psychiatric reaction to ketamine, including agitation, confusion, and hallucinations. These reactions were relatively short lived, namely, occurring during or shortly after the infusions. No association was found between patient response to ketamine and gender, age, or infusion rate.

Awareness of the psychiatric side effects of ketamine is an important consideration for clinicians administering this medication either for pain control or for depressive illness.

Adverse effects of antidepressant drug treatmenton sexual function are well documented but the effects of antidepressants on sperm production have not been researched extensively.

A narrative of an interventional case report of sperm parameters in a 30-year-old Caucasian man with a diagnosis of mixed depressive and anxiety disorder, who underwent citalopram treatment, followed by agomelatine treatment. Clinical observations prompted a review of the pre-clinical and clinical literature on the effects of antidepressant administration or treatment on sperm production and parameters. Findings from the review are discussed to suggest potential underlying mechanisms.

Abnormal sperm parameters were associated with treatment with the SSRI citalopram. There was an improvement in sperm concentration, motility, progressive motility and sperm morphology following its withdrawal. There was no similar association during subsequent treatment with agomelatine. The clinical observations reflect findings from animal studies, which indicate that antidepressants can have untoward effects on spermatogenesis.

SSRI treatment can be associated with impaired semen quality. Potential underlying mechanisms include changes in sperm DNA integrity, activation of IDO and shifting tryptophan metabolism. Further studies of the effects of antidepressants on spermatogenesis might benefit from including investigation of changes in IDO activity during antidepressant administration.

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder. It is conceivable that Gamma aminobutyric acid (GABA) neurotransmission is implicated in the pathophysiology of ADHD. This study investigated the effect of GABA transporter 1 (GAT-1) on the anxiety-like behaviours and cognitive function in knockout mice.

In all, 20 adult male mice were divided into two groups: wild-type (WT) group and GAT-1−/− group. The open field test, elevated O-maze (EZM) and Morris water maze were used to evaluate behavioural traits relevant to ADHD.

Compared with WT mice, the GAT-1−/− mice travelled longer and displayed an enhanced kinematic velocity with the significant reduction of rest time in the open field test (p<0.05). The EZM showed that GAT-1−/− mice displayed a significant increase in total entries into the open sectors and the closed sectors compared with the WT mice. The WT mice showed shorter latencies after the training session (p<0.01), whereas the GAT-1−/− mice made no difference during probe test, the GAT-1−/− mice spent less time in the target quadrant (p<0.01).

Our results demonstrated that GAT-1−/− mice have phenotypes of hyperactivity, impaired sustained attention and learning deficiency, and the performance of GAT-1−/− mice is similar to ADHD symptoms. So, the study of the GAT-1−/− mice may provide new insights into the mechanisms and the discovery of novel therapeutics for the treatment of ADHD.

The cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are proposed to mediate opposite behavioural responses. Their common denominator is the endocannabinoid ligand anandamide (AEA), which is believed to mediate antidepressant-like effect via CB1-R stimulation and depressive-like effect via TRPV1 activation. This is supposed to explain the bell-shaped dose-response curve for anandamide in preclinical models.

We investigated this assumption by administering the dual inhibitor of AEA hydrolysis and TRPV1 activation N-arachidonoyl-serotonin (AA-5HT) into the medial prefrontal cortex of rats. AA-5HT was given in three different doses (0.125, 0.250, 0.500 nmol/0.4 µl/side) and rat behaviour was assessed in the forced swim test.

Our results show significant antidepressant-like effect of AA-5HT (0.250 nmol) but no effects of low or high doses. The effect of 0.250 nmol AA-5HT was partially attenuated when coadministering the inverse CB1-agonist rimonabant (1.6 µg).

A 0.250 nmol of AA-5HT administration into the medial prefrontal cortex induced a significant antidepressant-like effect that was partially attenuated by locally blocking CB1-receptor.

Impulsivity has been shown to load on two separate factors, rash impulsivity and sensitivity to reward (SR) in several factor analytic studies. The aims of the current study were to explore the nature of impulsivity in women with borderline personality disorder (BPD) and matched controls, and the underlying neuronal correlates for rash impulsivity and SR.

Fifteen females diagnosed with BPD and 15 matched controls were recruited. All completed the impulsiveness-venturesomeness scale (I7), the sensitivity to punishment (SP) - sensitivity to reward (SR) questionnaire, and performed a Go-NoGo block-design functional magnetic resonance imaging (fMRI) paradigm at 3T. Correlation analyses were done with I7, SP and SR scores with the level of activation in different brain areas in the whole group. An independent group t-test was used to explore any differences between the BPD group and the matched controls.

I7 scores correlated negatively with activity in the left orbitofrontal cortex, amygdala and precuneus, and bilaterally in the cingulate cortices during response inhibition for the entire sample. SP yielded negative correlations in the right superior frontal gyrus and parahippocampal gyrus. No activity related to response inhibition correlated to SR. The Go-NoGo task gave similar brain activity in BPD and matched controls, but behaviourally the BPD group had significantly more commission errors in the NoGo blocks. The BPD group had increased I7 and SP scores indicating rash impulsiveness combined with heightened SP.

These results imply that successful impulse inhibition involves interaction between the impulsive and the emotional systems. Furthermore, impulsivity in BPD is described as rash impulsivity, coexisting with increased SP.

Little accurate information is available about the symptomatology of real-life panic attacks and about how well they are reproduced by an experimental model such as the 35% CO2 challenge.

Real-life panic symptoms were assessed in a group of 67 panic disorder patients, using daily life monitoring. Panic symptoms elicited by a 35% CO2 challenge were assessed in 61 panic disorder patients, and their frequency was compared with the real-life symptoms.

The most frequent real-life symptoms were palpitations, dizziness and trembling. The 35% CO2 challenge reproduced well the majority of real-life symptoms.

The findings suggest that the 35% CO2 challenge is a marker for spontaneous panic attacks, which are considered the core of panic disorder.

Co-morbid depression with post-traumatic stress disorder (PTSD) is often treatment resistant. In developing a preclinical model of treatment-resistant depression (TRD), we combined animal models of depression and PTSD to produce an animal with more severe as well as treatment-resistant depressive-like behaviours.

Male Flinders sensitive line (FSL) rats, a genetic animal model of depression, were exposed to a stress re-stress model of PTSD [time-dependent sensitisation (TDS)] and compared with stress-naive controls. Seven days after TDS stress, depressive-like and coping behaviours as well as hippocampal and cortical noradrenaline (NA) and 5-hydroxyindoleacetic acid (5HIAA) levels were analysed. Response to sub-chronic imipramine treatment (IMI; 10 mg/kg s.c.×7 days) was subsequently studied.

FSL rats demonstrated bio-behavioural characteristics of depression. Exposure to TDS stress in FSL rats correlated negatively with weight gain, while demonstrating reduced swimming behaviour and increased immobility versus unstressed FSL rats. IMI significantly reversed depressive-like (immobility) behaviour and enhanced active coping behaviour (swimming and climbing) in FSL rats. The latter was significantly attenuated in FSL rats exposed to TDS versus unstressed FSL rats. IMI reversed reduced 5HIAA levels in unstressed FSL rats, whereas exposure to TDS negated this effect. Lowered NA levels in FSL rats were sustained after TDS with IMI significantly reversing this in the hippocampus.

Combining a gene-X-environment model of depression with a PTSD paradigm produces exaggerated depressive-like symptoms that display an attenuated response to antidepressant treatment. This work confirms combining FSL rats with TDS exposure as a putative animal model of TRD.

Chronic stress responses can lead to physical and behavioural health problems, often experienced and observed in the care of people with intellectual disabilities or people with dementia. Electrodermal activity (EDA) is a bio-signal for stress, which can be measured by wearables and thereby support stress management. However, the how, when and to what extent patients and healthcare providers can benefit is unclear. This study aims to create an overview of available wearables enabling the detection of perceived stress by using EDA.

Following the PRISMA-SCR protocol for scoping reviews, four databases were included in the search of peer-reviewed studies published between 2012 and 2022, reporting detection of EDA in relation to self-reported stress or stress-related behaviours. Type of wearable, bodily location, research population, context, stressor type and the reported relationship between EDA and perceived stress were extracted.

Of the 74 included studies, the majority included healthy subjects in laboratory situations. Field studies and studies using machine learning (ML) to predict stress have increased in the last years. EDA is most often measured on the wrist, with offline data processing. Studies predicting perceived stress or stress-related behaviour using EDA features, reported accuracies between 42% and 100% with an average of 82.6%. Of these studies, the majority used ML.

Wearable EDA sensors are promising in detecting perceived stress. Field studies with relevant populations in a health or care context are lacking. Future studies should focus on the application of EDA-measuring wearables in real-life situations to support stress management.

To evaluate brexpiprazole adjunctive to antidepressant therapies (ADTs) as maintenance treatment in patients with major depressive disorder with inadequate response to ADT, utilising a novel study design.

The study comprised an 8-week prospective treatment period with open-label ADT with double-blind placebo treatment and a 24-week randomised treatment period. Investigators and patients were blinded to treatment periods, randomisation criteria, and timing of randomisation. Patients with early response to open-label ADT were withdrawn at Week 6. Patients fulfilling criteria for inadequate response were randomised to ADT+brexpiprazole 1–3 mg/day, or ADT+placebo. The primary endpoint was full remission: Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤10 and ≥50% decrease from randomisation (i.e. baseline) in MADRS total score for at least 8 consecutive weeks.

The primary efficacy analysis failed to show a statistically significant difference between the proportions of patients on ADT+brexpiprazole (21.4%) and ADT+placebo (24.9%) achieving full remission; odds ratio: 0.83; p=0.2641. The secondary endpoint of change from baseline to Week 6 in MADRS total score showed no difference between ADT+brexpiprazole and ADT+placebo (−0.4; p=0.3259). The most frequent treatment-emergent adverse event (TEAE) in patients receiving ADT+brexpiprazole was weight increased (9.5% vs. 5.0% in ADT+placebo). The incidence of TEAEs leading to withdrawal in the randomised treatment period was 6.3% in the ADT+brexpiprazole group and 3.4% in the ADT+placebo group.

Adjunctive brexpiprazole did not differentiate from ADT+placebo on the primary endpoint of full remission. A number of design elements in this previously untried study design may have contributed to the study result. Brexpiprazole was well tolerated.

The hot water tail-flick test is widely used to measure the degree of nociception experienced by laboratory animals. This study was carried out to optimise interval times for the hot water immersion tail-flick tests in rats.

Ten different intervals from 10 s to 1 h were tested in 60 Sprague–Dawley male rats. At least eight rats were tested for each interval in three consecutive hot water tail-flick tests. Dixon's up-and-down method was also used to find the optimal intervals. The same rats were then divided into two groups. In Group N, naloxone was injected to reverse the prolonged latency times, whereas saline was used in the control Group S.

Intervals of 10 s, 20 s, 30 min and 1 h did not significantly impact latencies, yielding similar results in three consecutive tests (p > 0.05). However, interval times of between 30 s and 20 min, inclusively, caused significantly prolonged latencies in the second and third tests (p < 0.001). Dixon's up-and-down method showed that 95% of the rats had prolonged latencies in hot water tail-flick tests at intervals longer than 32 s. Naloxone reversed prolonged latencies in Group N, whereas the latencies in Group S were further prolonged in 5 min interval tests.

The optimal intervals for hot water tail-flick tests are either shorter than 20 s or longer than 20 min. The prolonged latencies after repetitive tests were attributable to an endocrine opioid.