The interaction between positive, negative and depressive symptoms experienced by people with schizophrenia is complex. We used longitudinal data to test the hypothesis that depressive symptoms mediate the links between positive and negative symptoms.

We analyzed data from the European Schizophrenia Cohort, randomly sampled from outpatient services in France, Germany and the UK (N = 1208). Initial measures were repeated after 6 and 12 months. Depressive symptoms were identified using the Calgary Depression Scale for Schizophrenia (CDSS), while positive and negative symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Latent variable structural equation modelling was used to investigate the mediating role of depression assessed at 6 months in relation to the longitudinal association between positive symptoms at baseline and negative symptoms at 12 months.

We found longitudinal associations between positive symptoms at baseline and negative symptoms at 12 months, as well as between both of these and CDSS levels at 6 months. However depression did not mediate the longitudinal association between PANSS scores; all the effect was direct.

Our findings are incompatible with a mediating function for depression on the pathway from positive to negative symptoms, at least on this timescale. The role of depression in schizophrenic disorders remains a challenge for categorical and hierarchical diagnostic systems alike. Future research should analyze specific domains of both depressive and negative symptoms (e.g. motivational and hedonic impairments). The clinical management of negative symptoms using antidepressant treatments may need to be reconsidered.

Depression and insomnia commonly co-occur. Yet, little is known about the mechanisms through which insomnia influences depression. Recent research and theory highlight reward system dysfunction as a potential mediator of the relationship between insomnia and depression. This study is the first to examine the impact of insomnia on reward learning, a key component of reward system functioning, in clinical depression.

The sample consisted of 72 veterans with unipolar depression who endorsed sleep disturbance symptoms. Participants completed the Structured Clinical Interview for DSM-IV, self-report measures of insomnia, depression, and reward processing, and a previously validated signal detection task (Pizzagalli et al., 2005, Biological Psychiatry, 57(4), 319–327). Trial-by-trial response bias (RB) estimates calculated for each of the 200 task trials were examined using linear mixed-model analyses to investigate change in reward learning.

Findings demonstrated diminished rate and magnitude of reward learning in the Insomnia group relative to the Hypersomnia/Mixed Symptom group across the task. Within the Insomnia group, participants with more severe insomnia evidenced the lowest rates of reward learning, with increased RB across the task with decreasing insomnia severity.

Among individuals with depression, insomnia is associated with decreased ability to learn associations between neutral stimuli and rewarding outcomes and/or modify behavior in response to differential receipt of reward. This attenuated reward learning may contribute to clinically meaningful decreases in motivation and increased withdrawal in this comorbid group. Results extend existing theory by highlighting impairments in reward learning specifically as a potential mediator of the association between insomnia and depression.

Preclinical findings suggest that transcranial infrared laser stimulation (TILS) improves fear extinction learning and cognitive function by enhancing prefrontal cortex (PFC) oxygen metabolism. These findings prompted our investigation of treating pathological fear using this non-invasive stimulation approach either alone to the dorsolateral PFC (dlPFC), or to the ventromedial PFC (vmPFC) in combination with exposure therapy.

Volunteers with pathological fear of either enclosed spaces, contamination, public speaking, or anxiety-related bodily sensations were recruited for this randomized, single-blind, sham-controlled trial with four arms: (a) Exposure + TILS_vmPFC (n = 29), (b) Exposure + sham TILS_vmPFC (n = 29), (c) TILS_dlPFC alone (n = 26), or (d) Sham TILS _dlPFC alone (n = 28). Post-treatment assessments occurred immediately following treatment. Follow-up assessments occurred 2 weeks after treatment.

A total of 112 participants were randomized [age range: 18–63 years; 96 females (85.71%)]. Significant interactions of Group × Time and Group × Context indicated differential treatment effects on retention (i.e. between time-points, averaged across contexts) and on generalization (i.e. between contexts, averaged across time-points), respectively. Among the monotherapies, TILS_dlPFC outperformed SHAM_dlPFC in the initial context, b = −13.44, 95% CI (−25.73 to −1.15), p = 0.03. Among the combined treatments, differences between EX + TILS_vmPFC and EX + SHAM_vmPFC were non-significant across all contrasts.

TILS to the dlPFC, one of the PFC regions implicated in emotion regulation, resulted in a context-specific benefit as a monotherapy for reducing fear. Contrary to prediction, TILS to the vmPFC, a region implicated in fear extinction memory consolidation, did not enhance exposure therapy outcome.

Few studies have examined online experience by young people who die by suicide.

A 3-year UK-wide consecutive case series of all young people aged 10–19 who died by suicide, based on national mortality data. We extracted information on the antecedents of suicide of 544 of these 595 deaths (91%) from official investigations, mainly inquests.

Suicide-related online experience was reported in 24% (n = 128/544) of suicide deaths in young people between 2014 and 2016, equivalent to 43 deaths per year, and was more common in girls than boys (OR 1.87, 95% CI 1.23–2.85, p = 0.003) and those identifying as LGBT (OR 2.35, 95% CI 1.10–5.05, p = 0.028). Searching for information about method was most common (n = 68, 13%), followed by posting suicidal ideas online (n = 57, 10%). Self-harm, bereavement (especially by suicide), social isolation, and mental and physical ill-health were more likely in those known to have suicide-related online experience compared to those who did not. 29 (5%) were bullied online, more often girls (OR 2.84, 1.34–6.04, p = 0.007). Online bullying often accompanied face-to-face bullying (n = 16/29, 67%).

Suicide-related online experience is a common, but likely underestimated, antecedent to suicide in young people. Although its causal role is unclear, it may influence suicidality in this population. Mental health professionals should be aware that suicide-related online experience – not limited to social media – is a potential risk for young patients, and may be linked to experiences offline. For public health, wider action is required on internet regulation and support for children and their families.

Gut microbiome and dietary patterns have been suggested to be associated with depression/anxiety. However, limited effort has been made to explore the effects of possible interactions between diet and microbiome on the risks of depression and anxiety.

Using the latest genome-wide association studies findings in gut microbiome and dietary habits, polygenic risk scores (PRSs) analysis of gut microbiome and dietary habits was conducted in the UK Biobank cohort. Logistic/linear regression models were applied for evaluating the associations for gut microbiome-PRS, dietary habits-PRS, and their interactions with depression/anxiety status and Patient Health Questionnaire (PHQ-9)/Generalized Anxiety Disorder-7 (GAD-7) score by R software.

We observed 51 common diet–gut microbiome interactions shared by both PHQ score and depression status, such as overall beef intake × genus Sporobacter [hurdle binary (HB)] (PPHQ = 7.88 × 10−4, Pdepression status = 5.86 × 10−4); carbohydrate × genus Lactococcus (HB) (PPHQ = 0.0295, Pdepression status = 0.0150). We detected 41 common diet–gut microbiome interactions shared by GAD score and anxiety status, such as sugar × genus Parasutterella (rank normal transformed) (PGAD = 5.15 × 10−3, Panxiety status = 0.0347); tablespoons of raw vegetables per day × family Coriobacteriaceae (HB) (PGAD = 6.02 × 10−4, Panxiety status = 0.0345). Some common significant interactions shared by depression and anxiety were identified, such as overall beef intake × genus Sporobacter (HB).

Our study results expanded our understanding of how to comprehensively consider the relationships for dietary habits–gut microbiome interactions with depression and anxiety.

There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin-assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT.

A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates.

The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective.

Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base.

Individuals present in lower Manhattan during the 9/11 World Trade Center (WTC) disaster suffered from significant physical and psychological trauma. Studies of longitudinal psychological distress among those exposed to trauma have been limited to relatively short durations of follow-up among smaller samples.

The current study longitudinally assessed heterogeneity in trajectories of psychological distress among WTC Health Registry enrollees – a prospective cohort health study of responders, students, employees, passersby, and residents in the affected area (N = 30 839) – throughout a 15-year period following the WTC disaster. Rescue/recovery status and exposure to traumatic events of 9/11, as well as sociodemographic factors and health status, were assessed as risk factors for trajectories of psychological distress.

Five psychological distress trajectory groups were found: none-stable, low-stable, moderate-increasing, moderate-decreasing, and high-stable. Of the study sample, 78.2% were classified as belonging to the none-stable or low-stable groups. Female sex, being younger at the time of 9/11, lower education and income were associated with a higher probability of being in a greater distress trajectory group relative to the none-stable group. Greater exposure to traumatic events of 9/11 was associated with a higher probability of a greater distress trajectory, and community members (passerby, residents, and employees) were more likely to be in greater distress trajectory groups – especially in the moderate-increasing [odds ratios (OR) 2.31 (1.97–2.72)] and high-stable groups [OR 2.37 (1.81–3.09)] – compared to the none-stable group.

The current study illustrated the heterogeneity in psychological distress trajectories following the 9/11 WTC disaster, and identified potential avenues for intervention in future disasters.

Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority.

We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case−control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups.

Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91–1.59) for any discrimination and 1.79 (95% CI 1.19–1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12–2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65–3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%).

Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.

Despite its pivotal role in prophylaxis for bipolar-I-disorders (BD-I), variability in lithium (Li) response is poorly understood and only a third of patients show a good outcome. Converging research strands indicate that rest–activity rhythms can help characterize BD-I and might differentiate good responders (GR) and non-responders (NR).

Seventy outpatients with BD-I receiving Li prophylaxis were categorized as GR or NR according to the ratings on the retrospective assessment of response to lithium scale (Alda scale). Participants undertook 21 consecutive days of actigraphy monitoring of sleep quantity (SQ), sleep variability (SV) and circadian rhythmicity (CR).

Twenty-five individuals were categorized as GR (36%). After correcting statistical analysis to minimize false discoveries, four variables (intra-daily variability; median activity level; amplitude; and relative amplitude of activity) significantly differentiated GR from NR. The odds of being classified as a GR case were greatest for individuals showing more regular/stable CR (1.41; 95% confidence interval (CI) 1.08, 2.05; p < 0.04). Also, there was a trend for lower SV to be associated with GR (odds ratio: 0.56; 95% CI 0.31, 1.01; p < 0.06).

To our knowledge, this is the largest actigraphy study of rest–activity rhythms and Li response. Circadian markers associated with fragmentation, variability, amount and/or amplitude of day and night-time activity best-identified GR. However, associations were modest and future research must determine whether these objectively measured parameters, singly or together, represent robust treatment response biomarkers. Actigraphy may offer an adjunct to multi-platform approaches aimed at developing personalized treatments or stratification of individuals with BD-I into treatment-relevant subgroups.

Major depressive disorder (MDD) is a highly prevalent psychiatric condition, yet many patients do not receive adequate treatment. Novel and highly scalable interventions such as internet-based cognitive-behavioral-therapy (iCBT) may help to address this treatment gap. Anhedonia, a hallmark symptom of MDD that refers to diminished interest and ability to experience pleasure, has been associated with reduced reactivity in a neural reward circuit that includes medial prefrontal and striatal brain regions. Whether iCBT can reduce anhedonia severity in MDD patients, and whether these therapeutic effects are accompanied by enhanced reward circuit reactivity has yet to be examined.

Fifty-two MDD patients were randomly assigned to either 10-week iCBT (n = 26) or monitored attention control (MAC, n = 26) programs. All patients completed pre- and post-treatment assessments of anhedonia (Snaith–Hamilton Pleasure Scale; SHAPS) and reward circuit reactivity [monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI)]. Healthy control participants (n = 42) also underwent two fMRI scans while completing the MID task 10 weeks apart.

Both iCBT and MAC groups exhibited a reduction in anhedonia severity post-treatment. Nevertheless, only the iCBT group exhibited enhanced nucleus accumbens (Nacc) and subgenual anterior cingulate cortex (sgACC) activation and functional connectivity from pre- to post-treatment in response to reward feedback. Enhanced Nacc and sgACC activations were associated with reduced anhedonia severity following iCBT treatment, with enhanced Nacc activation also mediating the reduction in anhedonia severity post-treatment.

These findings suggest that increased reward circuit reactivity may contribute to a reduction in anhedonia severity following iCBT treatment for depression.

Psychological trauma exposure and posttraumatic stress disorder (PTSD) have been associated with advanced epigenetic age. However, whether epigenetic aging measured at the time of trauma predicts the subsequent development of PTSD outcomes is unknown. Moreover, the neural substrates underlying posttraumatic outcomes associated with epigenetic aging are unclear.

We examined a multi-ancestry cohort of women and men (n = 289) who presented to the emergency department (ED) after trauma. Blood DNA was collected at ED presentation, and EPIC DNA methylation arrays were used to assess four widely used metrics of epigenetic aging (HorvathAge, HannumAge, PhenoAge, and GrimAge). PTSD symptoms were evaluated longitudinally at the time of ED presentation and over the ensuing 6 months. Structural and functional neuroimaging was performed 2 weeks after trauma.

After covariate adjustment and correction for multiple comparisons, advanced ED GrimAge predicted increased risk for 6-month probable PTSD diagnosis. Secondary analyses suggested that the prediction of PTSD by GrimAge was driven by worse trajectories for intrusive memories and nightmares. Advanced ED GrimAge was also associated with reduced volume of the whole amygdala and specific amygdala subregions, including the cortico-amygdaloid transition and the cortical and accessory basal nuclei.

Our findings shed new light on the relation between biological aging and trauma-related phenotypes, suggesting that GrimAge measured at the time of trauma predicts PTSD trajectories and is associated with relevant brain alterations. Furthering these findings has the potential to enhance early prevention and treatment of posttraumatic psychiatric sequelae.

Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia.

A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest.

The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms.

We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.