The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures.

T1-weighted MRI scans were subsegmented and multi-stage quality controlled using FreeSurfer. Left/right hemispheric amygdala nuclei volumes were cross-sectionally compared between females with AN (n = 168, 12–29 years) and age-matched healthy females (n = 168) applying general linear models. Associations with plasma leptin, body mass index (BMI), illness duration, and psychiatric symptoms were analyzed via robust linear regression.

Globally, most amygdala nuclei volumes in both hemispheres were reduced in AN v. healthy control participants. Importantly, four specific nuclei (accessory basal, cortical, medial nuclei, corticoamygdaloid transition in the rostral-medial amygdala) showed greater volumetric reduction even relative to reductions of whole amygdala and total subcortical gray matter volumes, whereas basal, lateral, and paralaminar nuclei were less reduced. All rostral-medially clustered nuclei were positively associated with leptin in AN independent of BMI. Amygdala nuclei volumes were not associated with illness duration or psychiatric symptom severity in AN.

In AN, amygdala nuclei are altered to different degrees. Severe volume loss in rostral-medially clustered nuclei, collectively involved in olfactory/food-related reward processing, may represent a structural correlate of AN-related symptoms. Hypoleptinemia might be linked to rostral-medial amygdala alterations.

Technology-based interventions (TBIs) are a useful approach when attempting to provide therapy to more patients with psychosis.

Randomized controlled trials of outcomes of TBIs v. face-to-face interventions in psychosis were identified in a systematic search conducted in PubMed/Ovid MEDLINE. Data were extracted independently by two researchers, and standardized mean changes were pooled using a three-level model and network meta-analysis.

Fifty-eight studies were included. TBIs complementing treatment as usual (TAU) were generally superior to face-to-face interventions (g = 0.16, p ≤ 0.0001) and to specific outcomes, namely, neurocognition (g = 0.13, p ≤ 0.0001), functioning (g = 0.25, p = 0.006), and social cognition (g = 0.32, p ≤ 0.05). Based on the network meta-analysis, the effect of two TBIs differed significantly from zero; these were the TBIs cognitive training for the neurocognitive outcome [g = 0.16; 95% confidence interval (CI) 0.09–0.23] and cognitive behavioral therapy for quality of life (g = 1.27; 95% CI 0.46–2.08). The variables educational level, type of medication, frequency of the intervention, and contact during the intervention moderated the effectiveness of TBIs over face-to-face interventions in neurocognition and symptomatology.

TBIs are effective for the management of neurocognition, symptomatology, functioning, social cognition, and quality of life outcomes in patients with psychosis. The results of the network meta-analysis showed the efficacy of some TBIs for neurocognition, symptomatology, and quality of life. Therefore, TBIs should be considered a complement to TAU in patients with psychosis.

Neuroprogressive models of the trajectory of cognitive dysfunction in patients with bipolar disorder (BD) have been proposed. However, few studies have explored the relationships among clinical characteristics of BD, cognitive dysfunction, and aging.

We conducted a cross-sectional analysis in euthymic participants with the MATRICS Cognitive Consensus Battery, the Trail Making Test B, the Stroop Test, and the Wechsler Test of Adult Reading. Age- and gender-equated control participants without a mental disorder [‘Healthy Controls’ – HC)] were assessed similarly. We compared cognitive performance both globally and in seven domains in four groups: younger BD (age ⩽49 years; n = 70), older BD (age ⩾50 years; n = 48), younger HC (n = 153), and older HC (n = 44). We also compared the BD and HC groups using age as a continuous measure. We controlled for relevant covariates and applied a Bonferroni correction.

Our results support both an early impairment (‘early hit’) model and an accelerated aging model: impairment in attention/vigilance, processing speed, and executive function/working memory were congruent with the accelerated aging hypothesis whereas impairment in verbal memory was congruent with an early impairment model. BD and HC participants exhibited similar age-related decline in reasoning/problem solving and visuospatial memory. There were no age- or diagnosis-related differences in social cognition.

Our findings support that different cognitive domains are affected differently by BD and aging. Longitudinal studies are needed to explore trajectories of cognitive performance in BD across the lifespan.

Little is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior.

This study examined whether a suicidality polygenic risk score (PRS) derived from a large genome-wide association study (N = 122,935) was associated with suicide attempts in a population-based sample of European-American US military veterans (N = 1664; 92.5% male), and whether cumulative lifetime trauma exposure moderated this association.

Eighty-five veterans (weighted 6.3%) reported a history of suicide attempt. After adjusting for sociodemographic and psychiatric characteristics, suicidality PRS was associated with lifetime suicide attempt (odds ratio 2.65; 95% CI 1.37–5.11). A significant suicidality PRS-by-trauma exposure interaction emerged, such that veterans with higher levels of suicidality PRS and greater trauma burden had the highest probability of lifetime suicide attempt (16.6%), whereas the probability of attempts was substantially lower among those with high suicidality PRS and low trauma exposure (1.4%). The PRS-by-trauma interaction effect was enriched for genes implicated in cellular and developmental processes, and nervous system development, with variants annotated to the DAB2 and SPNS2 genes, which are implicated in inflammatory processes. Drug repurposing analyses revealed upregulation of suicide gene-sets in the context of medrysone, a drug targeting chronic inflammation, and clofibrate, a triacylglyceride level lowering agent.

Results suggest that genetic liability to suicidality is associated with increased risk of suicide attempt among veterans, particularly in the presence of high levels of cumulative trauma exposure. Additional research is warranted to investigate whether incorporation of genomic information may improve suicide prediction models.

Cognitive symptoms are common during and following episodes of depression. Little is known about the persistence of self-reported and performance-based cognition with depression and functional outcomes.

This is a secondary analysis of a prospective naturalistic observational clinical cohort study of individuals with recurrent major depressive disorder (MDD; N = 623). Participants completed app-based self-reported and performance-based cognitive function assessments alongside validated measures of depression, functional disability, and self-esteem every 3 months. Participants were followed-up for a maximum of 2-years. Multilevel hierarchically nested modelling was employed to explore between- and within-participant variation over time to identify whether persistent cognitive difficulties are related to levels of depression and functional impairment during follow-up.

508 individuals (81.5%) provided data (mean age: 46.6, s.d.: 15.6; 76.2% female). Increasing persistence of self-reported cognitive difficulty was associated with higher levels of depression and functional impairment throughout the follow-up. In comparison to low persistence of objective cognitive difficulty (<25% of timepoints), those with high persistence (>75% of timepoints) reported significantly higher levels of depression (B = 5.17, s.e. = 2.21, p = 0.019) and functional impairment (B = 4.82, s.e. = 1.79, p = 0.002) over time. Examination of the individual cognitive modules shows that persistently impaired executive function is associated with worse functioning, and poor processing speed is particularly important for worsened depressive symptoms.

We replicated previous findings of greater persistence of cognitive difficulty with increasing severity of depression and further demonstrate that these cognitive difficulties are associated with pervasive functional disability. Difficulties with cognition may be an indicator and target for further treatment input.

Deficiency in contextual and enhanced responding in cued fear learning may contribute to the development of posttraumatic stress disorder (PTSD). We examined the responses to aversive Pavlovian conditioning with an unpredictable spatial context as conditioned stimulus compared to a predictable context. We hypothesized that the PTSD group would demonstrate less hippocampal and ventromedial prefrontal cortex (vmPFC) activation during acquisition and extinction of unpredictable contexts and an over-reactive amygdala response in the predictable contexts compared to controls.

A novel combined differential cue-context conditioning paradigm was applied using virtual reality with spatial contexts that required configural and cue processing. We assessed 20 patients with PTSD, 21 healthy trauma-exposed (TC) and 22 non-trauma-exposed (HC) participants using functional magnetic resonance imaging, skin conductance responses, and self-report measures.

During fear acquisition, patients with PTSD compared to TC showed lower activity in the hippocampi in the unpredictable and higher activity in the amygdalae in the predictable context. During fear extinction, TC compared to patients and HC showed higher brain activity in the vmPFC in the predictable context. There were no significant differences in self-report or skin conductance responses.

Our results suggest that patients with PTSD differ in brain activation from controls in regions such as the hippocampus, the amygdala, and the vmPFC in the processing of unpredictable and predictable contexts. Deficient encoding of more complex configurations might lead to a preponderance of cue-based predictions in PTSD. Exposure-based treatments need to focus on improving predictability of contextual processing and reducing enhanced cue reactivity.

Suicide risk is complex and nuanced, and how place impacts suicide risk when considered alongside detailed individual risk factors remains uncertain. We aimed to examine suicide risk in Denmark with both individual and neighbourhood level risk factors.

We used Danish register-based data to identify individuals born in Denmark from 1972, with full parental information and psychiatric diagnosis history. We fitted a two-level survival model to estimate individual and neighbourhood determinants on suicide risk.

We identified 1723 cases of suicide in Denmark during the follow-up period from 1982 to 2015. Suicide risk was explained mainly by individual determinants. Parental comorbidities, particularly maternal schizophrenia [incidence rate ratio (IRR): 2.29, 95% CI 1.56–3.16] and paternal death (2.29, 95% CI 1.31–3.72) partly explained suicide risk when adjusted for all other determinants. The general contextual effect of suicide risk across neighbourhoods showed a median incidence rate ratio (MRR) of 1.13 (1.01–1.28), which was further reduced with full adjustment. Suicide risk increased in neighbourhoods with a higher proportion of manual workers (IRR: 1.08; 1.03–1.14), and decreased with a higher population density (IRR: 0.89; 0.83–0.96).

Suicide risk varies mainly between individuals, with parental comorbidities having the largest effect on suicide risk. Suicide risk was less impacted by neighbourhood, though, albeit to a lesser extent than individual determinants, some characteristics were associated with suicide risk. Suicide prevention policies might consider targeting interventions towards individuals more vulnerable due to particular parental comorbidities, whilst taking into account that some neighbourhood characteristics might exacerbate this risk further.

Aggression is a transdiagnostic indicator of risk and represents one of the most common reasons children are referred for mental health treatment. Theory and research highlight the impact of maternal invalidation on child aggression and suggest that its influence may vary based on differences in child physiological reactivity. Moreover, the interaction between these risk factors may be particularly pronounced among children of mothers with emotion regulation (ER) difficulties. The current study examined the independent and interactive effects of maternal invalidation and child physiological reactivity to frustration on teacher-reported aggression in an at-risk sample of preschool children.

Participants included 77 mothers (Mage = 33.17 years, s.d. = 4.83; 35% racial/ethnic minority) and their children (Mage = 42.48 months; s.d. = 3.78; 56% female; 47% racial/ethnic minority). Groups of mothers with and without clinician-rated ER difficulties reported on maternal invalidation, and child respiratory sinus arrhythmia (RSA) was assessed continuously during a frustration task as an indicator of physiological reactivity. Teachers or daycare providers reported on child aggression.

Results demonstrated positive associations between maternal ER difficulties and both maternal invalidation and child RSA reactivity to frustration. As expected, the interaction between maternal invalidation and child RSA reactivity was significant, such that higher maternal invalidation and greater child RSA reactivity to frustration predicted more aggression in a daycare or preschool setting. Importantly, this effect was demonstrated while controlling for demographic covariates and baseline RSA.

Findings are in line with diathesis–stress and biosocial models of risk and point to multiple targets for prevention and early intervention.

Evidence on the long-term comparative effectiveness of posttraumatic stress disorder (PTSD) psychotherapies in adults remains unknown. Therefore, we performed an extensive network meta-analysis of randomised controlled trials (RCTs) to determine the comparative effectiveness of psychotherapies for people diagnosed with PTSD.

A comprehensive search was conducted in Cochrane library, Embase, Medline-OVID, PubMed, Scopus, and Psych-Info until March 2021. Studies on the effectiveness of cognitive processing therapy (CPT), cognitive therapy (CT), eye movement desensitisation reprocessing (EMDR), narrative exposure therapy (NET), prolonged exposure (PE), cognitive behavioural therapy (CBT), present-centred therapy (PCT), brief eclectic psychotherapies (BEP), psychodynamic therapy (PDT) or combination therapies compared to no treatment (NT) or treatment as usual (TAU) in adults with PTSD were included. Frequentist and Bayesian approaches were used for analysis in R-software.

We included 98 RCTs with 5567 participants from 18 897 studies. CPT, EMDR, CT, NET, PE, CBT, and PCT were significant to reduce PTSD symptoms (SMD range: −1.53 to −0.75; Certainty: very low to high) at immediate post-treatment and ranked accordingly. Longitudinal analysis found EMDR (1.02) and CPT (0.85) as the significant therapies with large effect size in short-term and long-term follow-up, respectively. NET and CPT showed higher proportion of loss of PTSD diagnosis (RR range: 5.51–3.45) while there were no significant psychotherapies for retention rate compared to NT.

Our findings provide evidence for improving current guidelines and informing clinical decision-making for PTSD management. However, the best PTSD treatment plan should be tailored to patients' needs, characteristics, and clinician expertise.

PROSPERO CRD42020162143

Studies investigating the long-term effect of attention bias modification (ABM) in clinical samples are lacking. This study investigates the 6-months follow-up effect of ABM on depressive symptoms in participant with major depressive disorder with and without comorbid disorders.

We conducted a double-blind randomized sham-controlled trial in 101 participants between 19 November 2019, and 17 August 2021. Follow-up ended 3 April 2022. Participants were allocated to ABM or sham condition twice daily for 14 consecutive days. Primary outcomes were the total score on the Beck Depression Inventory-II (BDI-II) at 6 months, mean Brief State Rumination Inventory (BSRI) score post-treatment and reduction in BSRI post-treatment. Secondary outcome was change in attentional bias (AB). The trial was preregistered in ClinicalTrials.gov (#NCT 04137367).

A total of 118 patients aged 18–65 years were assessed for eligibility, and 101 were randomized and subjected to intention-to-treat analyses. At 6 months, ABM had no effect on depression and anxiety compared to a sham condition. While rumination decreased during the intervention, there was no effect of condition on rumination and AB. Predictor analysis did not reveal differences between participants with ongoing major depressive episode or comorbid anxiety.

Compared to sham training, there was no effect of ABM on depressive symptoms at 6-months follow-up. Since the intervention failed at modifying AB, it is unclear whether changes in AB are related to long-term outcomes.

Enhanced post-awakening cortisol may serve as a biological marker for individuals with major depressive disorder. However, studies comparing post-awakening cortisol between patients with major depressive disorder (MDD) and healthy controls have produced conflicting findings. The aim of this study was to investigate whether this inconsistency could be due to the effects of childhood trauma.

A total of N = 112 patients with MDD and healthy controls were divided into four groups according to the presence of childhood trauma. Saliva samples were collected at awakening and 15, 30, 45, and 60 min later. The total cortisol output and the cortisol awakening response (CAR) were calculated.

The total post-awakening cortisol output was significantly higher in patients with MDD as compared to healthy controls, but only in those individuals reporting childhood trauma. The four groups did not differ regarding the CAR.

Elevated post-awakening cortisol in MDD may be confined to those with a history of early life stress. Tailoring and/or augmenting of currently available treatments may be required to meet the specific needs of this population.

Research suggests that there have been inequalities in the impact of the coronavirus disease 2019 (COVID-19) pandemic and related non-pharmaceutical interventions on population mental health. We explored generational, sex, and socioeconomic inequalities during the first year of the pandemic using nationally representative cohorts from the UK.

We analysed data from 26772 participants from five longitudinal cohorts representing generations born between 1946 and 2000, collected in May 2020, September–October 2020, and February–March 2021 across all five cohorts. We used a multilevel growth curve modelling approach to investigate generational, sex, and socioeconomic differences in levels of anxiety and depressive symptomatology, loneliness, and life satisfaction (LS) over time.

Younger generations had worse levels of mental and social wellbeing throughout the first year of the pandemic. Whereas these generational inequalities narrowed between the first and last observation periods for LS [−0.33 (95% CI −0.51 to −0.15)], they became larger for anxiety [0.22 (0.10, 0.33)]. Generational inequalities in depression and loneliness did not change between the first and last observation periods, but initial depression levels of the youngest cohort were worse than expected if the generational inequalities had not accelerated. Women and those experiencing financial difficulties had worse initial mental and social wellbeing levels than men and those financially living comfortably, respectively, and these gaps did not substantially differ between the first and last observation periods.

By March 2021, mental and social wellbeing inequalities persisted in the UK adult population. Pre-existing generational inequalities may have been exacerbated with the pandemic onset. Policies aimed at protecting vulnerable groups are needed.