Early neurodevelopmental deviations, such as abnormal cortical folding patterns, are candidate biomarkers of major depressive disorder (MDD). We aimed to investigate the association of MDD with the local gyrification index (LGI) in each cortical region at the whole-brain level, and the association of the LGI with clinical characteristics of MDD.

We obtained T1-weighted images from 234 patients with MDD and 215 healthy controls (HCs). The LGI values from 66 cortical regions in the bilateral hemispheres were automatically calculated according to the Desikan–Killiany atlas. We compared the LGI values between the MDD and HC groups using analysis of covariance, including age, sex, and years of education as covariates. The association between the clinical characteristics and LGI values was investigated in the MDD group.

Compared with HCs, patients with MDD showed significantly decreased LGI values in the cortical regions, including the bilateral ventrolateral and dorsolateral prefrontal cortices, medial and lateral orbitofrontal cortices, insula, right rostral anterior cingulate cortex, and several temporal and parietal regions, with the largest effect size in the left pars triangularis (Cohen's f2 = 0.361; p = 1.78 × 10−13). Regarding the association of clinical characteristics with LGIs within the MDD group, recurrence and longer illness duration were associated with increased gyrification in several occipital and temporal regions, which showed no significant difference in LGIs between the MDD and HC groups.

These findings suggest that the LGI may be a relatively stable neuroimaging marker associated with MDD predisposition.

Examining neurobiological mechanisms that may transmit the effects of childhood maltreatment on mental health in youth is crucial for understanding vulnerability to psychopathology. This study investigated associations between childhood maltreatment, adolescent structural brain development, and mental health trajectories into young-adulthood.

Structural magnetic resonance imaging data was acquired from 144 youth at three time points (age 12, 16, and 18 years). Childhood maltreatment was reported to occur prior to the first scan. Linear mixed models were utilized to examine the association between total childhood maltreatment, neglect, abuse and (i) amygdala and hippocampal volume development, and (ii) maturational coupling between amygdala/hippocampus volume and the thickness of prefrontal regions. We also examined whether brain development mediated the association between maltreatment and depressive and anxiety symptoms trajectories from age 12 to 28.

Total maltreatment, and neglect, were associated with positive maturational coupling between the amygdala and caudal anterior cingulate cortex (cACC), whereby at higher and lower levels of amygdala growth, maltreatment was associated with lower and higher PFC thinning, respectively. Neglect was also associated with maturational coupling of the hippocampus with prefrontal regions. While positive amygdala-cACC maturational coupling was associated with greater increases in anxiety symptoms, it did not significantly mediate the association between maltreatment and anxiety symptom trajectories.

We found maltreatment to be associated with altered patterns of coupling between subcortical and prefrontal regions during adolescence, suggesting that maltreatment is associated with the development of socio-emotional neural circuitry. The implications of these findings for mental health require further investigation.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders.

PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC).

PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features.

The results support the possibility that PACAP plays a role in mood disorder pathophysiology.

Dissociative symptoms can emerge after trauma and interfere with attentional control and interoception; disruptions to these processes are barriers to mind-body interventions such as breath-focused mindfulness (BFM). To overcome these barriers, we tested the use of an exteroceptive augmentation to BFM, using vibrations equivalent to the amplitude of the auditory waveform of the actual breath, delivered via a wearable subwoofer in real time (VBFM). We tested whether this device enhanced interoceptive processes, attentional control and autonomic regulation in trauma-exposed women with dissociative symptoms.

65 women, majority (82%) Black American, aged 18–65 completed self-report measures of interoception and 6 BFM sessions, during which electrocardiographic recordings were taken to derive high-frequency heart rate variability (HRV) estimates. A subset (n = 31) of participants completed functional MRI at pre- and post-intervention, during which they were administered an affective attentional control task.

Compared to those who received BFM only, women who received VBFM demonstrated greater increases in interoception, particularly their ability to trust body signals, increased sustained attention, as well as increased connectivity between nodes of emotion processing and interoceptive networks. Intervention condition moderated the relationship between interoception change and dissociation change, as well as the relationship between dissociation and HRV change.

Vibration feedback during breath focus yielded greater improvements in interoception, sustained attention and increased connectivity of emotion processing and interoceptive networks. Augmenting BFM with vibration appears to have considerable effects on interoception, attention and autonomic regulation; it could be used as a monotherapy or to address trauma treatment barriers.

Serum levels of C-reactive protein (CRP) and interleukin-6 (IL-6) have been associated with anxiety and depression in cross-sectional and Mendelian randomisation studies, but results regarding the effect size and direction have been mixed. A recent Mendelian Randomisation (MR) study suggested that CRP may decrease and IL-6 may increase anxiety and depression symptoms.

Among 68 769 participants of the population-based Trøndelag Health Study (HUNT), we performed cross-sectional observational and one-sample MR analyses of serum CRP and two-sample MR analysis of serum IL-6. The main outcomes were symptoms of anxiety and depression assessed using the Hospital Anxiety and Depression Scale (HADS) and life satisfaction assessed using a seven-level ordinal questionnaire where higher scores indicate lower life satisfaction.

In cross-sectional observational analyses, a doubling in serum CRP level was associated with 0.27% (95% CI −0.20 to 0.75) difference in HADS depression score (HADS-D), −0.77% (95% CI −1.24 to −0.29) difference in HADS anxiety score (HADS-A) and −0.10% (95% CI −0.41 to 0.21) difference in life satisfaction score. In one-sample MR analyses, a doubling in serum CRP was associated with 2.43% (95% CI −0.11 to 5.03) higher HADS-D, 1.94% (95% CI −0.58 to 4.52) higher HADS-A, and 2.00% (95% CI 0.45 to 3.59) higher life satisfaction score. For IL-6, causal point estimates were in the opposite direction, but imprecise and far from conventional criteria for statistical significance.

Our results do not support a major causal role of serum CRP on anxiety and depression symptoms and life satisfaction, but provides weak evidence that serum CRP may modestly increase anxiety and depression symptoms and reduce life satisfaction. Our findings do not support the recent suggestion that serum CRP may lower anxiety and depression symptoms.

Midlife adults are experiencing a crisis of deaths of despair (i.e. deaths from suicide, drug overdose, and alcohol-related liver disease). We tested the hypothesis that a syndrome of despair-related maladies at midlife is preceded by psychopathology during adolescence.

Participants are members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972–73 and followed to age 45 years, with 94% retention. Adolescent mental disorders were assessed in three diagnostic assessments at ages 11, 13, and 15 years. Indicators of despair-related maladies across four domains – suicidality, substance misuse, sleep problems, and pain – were assessed at age 45 using multi-modal measures including self-report, informant-report, and national register data.

We identified and validated a syndrome of despair-related maladies at midlife involving suicidality, substance misuse, sleep problems, and pain. Adults who exhibited a more severe syndrome of despair-related maladies at midlife tended to have had early-onset emotional and behavioral disorders [β = 0.23, 95% CI (0.16–0.30), p < 0.001], even after adjusting for sex, childhood SES, and childhood IQ. A more pronounced midlife despair syndrome was observed among adults who, as adolescents, were diagnosed with a greater number of mental disorders [β = 0.26, 95% CI (0.19–0.33), p < 0.001]. Tests of diagnostic specificity revealed that associations generalized across different adolescent mental disorders.

Midlife adults who exhibited a more severe syndrome of despair-related maladies tended to have had psychopathology as adolescents. Prevention and treatment of adolescent psychopathology may mitigate despair-related maladies at midlife and ultimately reduce deaths of despair.

It is unknown how much variation in adult mental health problems is associated with differences between societal/cultural groups, over and above differences between individuals.

To test these relative contributions, a consortium of indigenous researchers collected Adult Self-Report (ASR) ratings from 16 906 18- to 59-year-olds in 28 societies that represented seven culture clusters identified in the Global Leadership and Organizational Behavioral Effectiveness study (e.g. Confucian, Anglo). The ASR is scored on 17 problem scales, plus a personal strengths scale. Hierarchical linear modeling estimated variance accounted for by individual differences (including measurement error), society, and culture cluster. Multi-level analyses of covariance tested age and gender effects.

Across the 17 problem scales, the variance accounted for by individual differences ranged from 80.3% for DSM-oriented anxiety problems to 95.2% for DSM-oriented avoidant personality (mean = 90.7%); by society: 3.2% for DSM-oriented somatic problems to 8.0% for DSM-oriented anxiety problems (mean = 6.3%); and by culture cluster: 0.0% for DSM-oriented avoidant personality to 11.6% for DSM-oriented anxiety problems (mean = 3.0%). For strengths, individual differences accounted for 80.8% of variance, societal differences 10.5%, and cultural differences 8.7%. Age and gender had very small effects.

Overall, adults' self-ratings of mental health problems and strengths were associated much more with individual differences than societal/cultural differences, although this varied across scales. These findings support cross-cultural use of standardized measures to assess mental health problems, but urge caution in assessment of personal strengths.

Prior research has identified altered brain structure and function in individuals at risk for self-directed violence thoughts and behaviors. However, these studies have largely utilized healthy controls and findings have been inconsistent. Thus, this study examined differences in resting-state functional network connectivity among individuals with lifetime suicide attempt(s) v. lifetime self-directed violence thoughts alone.

Using data from the UK Biobank, this study utilized a series of linear regressions to compare individuals with lifetime suicide attempt(s) (n = 566) v. lifetime self-directed violence thoughts alone (n = 3447) on within- and between- network resting-state functional connectivity subnetworks.

There were no significant between-group differences for between-network, within-network, or whole-brain functional connectivity after adjusting for age, sex, ethnicity, and body mass index and performing statistical corrections for multiple comparisons. Resting-state network measures may not differentiate between individuals with lifetime suicide attempt(s) and lifetime self-directed violence thoughts alone.

Null findings diverge from results reported in smaller neuroimaging studies of suicide risk, but are consistent with null findings in other large-scale studies and meta-analyses. Strengths of the study include its large sample size and stringent control group. Future research on a wider array of imaging, genetic, and psychosocial risk factors can clarify relative contributions of individual and combined variables to suicide risk and inform scientific understanding of ideation-to-action framework.

Frequently associated with early psychosis, depressive and manic dimensions may play an important role in its course and outcome. While manic and depressive symptoms can alternate and co-occur, most of the studies in early intervention investigated these symptoms independently. The aim of this study was therefore to explore the co-occurrence of manic and depressive dimensions, their evolution and impact on outcomes.

We prospectively studied first-episode psychosis patients (N = 313) within an early intervention program over 3 years. Based on latent transition analysis, we identified sub-groups of patients with different mood profiles considering both manic and depressive dimensions, and studied their outcomes.

Our results revealed six different mood profiles at program entry and after 1.5 years follow-up (absence of mood disturbance, co-occurrence, mild depressive, severe depressive, manic and hypomanic), and four after 3 years (absence of mood disturbance, co-occurrence, mild depressive and hypomanic). Patients with absence of mood disturbance at discharge had better outcomes. All patients with co-occurring symptoms at program entry remained symptomatic at discharge. Patients with mild depressive symptoms were less likely to return to premorbid functional level at discharge than the other subgroups. Patients displaying a depressive component had poorer quality of physical and psychological health at discharge.

Our results confirm the major role played by mood dimensions in early psychosis, and show that profiles with co-occurring manic and depressive dimensions are at risk of poorer outcome. An accurate assessment and treatment of these dimensions in people with early psychosis is crucial.

Negative symptoms (avolition, anhedonia, asociality) are a prevalent symptom in those across the psychosis-spectrum and also occur at subclinical levels in the general population. Recent work has begun to examine how environmental contexts (e.g. locations) influence negative symptoms. However, limited work has evaluated how environments may contribute to negative symptoms among youth at clinical high risk for psychosis (CHR). The current study uses Ecological Momentary Assessment to assess how four environmental contexts (locations, activities, social interactions, social interaction method) impact state fluctuations in negative symptoms in CHR and healthy control (CN) participants.

CHR youth (n = 116) and CN (n = 61) completed 8 daily surveys for 6 days assessing negative symptoms and contexts.

Mixed-effects modeling demonstrated that negative symptoms largely varied across contexts in both groups. CHR participants had higher negative symptoms than CN participants in most contexts, but groups had similar symptom reductions during recreational activities and phone call interactions. Among CHR participants, negative symptoms were elevated in several contexts, including studying/working, commuting, eating, running errands, and being at home.

Results demonstrate that negative symptoms dynamically change across some contexts in CHR participants. Negative symptoms were more intact in some contexts, while other contexts, notably some used to promote functional recovery, may exacerbate negative symptoms in CHR. Findings suggest that environmental factors should be considered when understanding state fluctuations in negative symptoms among those at CHR participants.

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.

Observational studies suggest a correlation between post-traumatic stress disorder (PTSD) and gastrointestinal tract (GIT) disorders. However, the genetic overlap, causal relationships, and underlining mechanisms between PTSD and GIT disorders were absent.

We obtained genome-wide association study statistics for PTSD (23 212 cases, 151 447 controls), peptic ulcer disease (PUD; 16 666 cases, 439 661 controls), gastroesophageal reflux disease (GORD; 54 854 cases, 401 473 controls), PUD and/or GORD and/or medications (PGM; 90 175 cases, 366 152 controls), irritable bowel syndrome (IBS; 28 518 cases, 426 803 controls), and inflammatory bowel disease (IBD; 7045 cases, 449 282 controls). We quantified genetic correlations, identified pleiotropic loci, and performed multi-marker analysis of genomic annotation, fast gene-based association analysis, transcriptome-wide association study analysis, and bidirectional Mendelian randomization analysis.

PTSD globally correlates with PUD (rg = 0.526, p = 9.355 × 10−7), GORD (rg = 0.398, p = 5.223 × 10−9), PGM (rg = 0.524, p = 1.251 × 10−15), and IBS (rg = 0.419, p = 8.825 × 10−6). Cross-trait meta-analyses identify seven genome-wide significant loci between PTSD and PGM (rs13107325, rs1632855, rs1800628, rs2188100, rs3129953, rs6973700, and rs73154693); three between PTSD and GORD (rs13107325, rs1632855, and rs3132450); one between PTSD and IBS/IBD (rs4937872 and rs114969413, respectively). Proximal pleiotropic genes are mainly enriched in immune response regulatory pathways, and in brain, digestive, and immune systems. Gene-level analyses identify five candidates: ABT1, BTN3A2, HIST1H3J, ZKSCAN4, and ZKSCAN8. We found significant causal effects of GORD, PGM, IBS, and IBD on PTSD. We observed no reverse causality of PTSD with GIT disorders, except for GORD.

PTSD and GIT disorders share common genetic architectures. Our work offers insights into the biological mechanisms, and provides genetic basis for translational research studies.

Nonsuicidal self-injury (NSSI) is prevalent in adolescent clinical samples. There is evidence that NSSI can be treated effectively but data on individual treatment outcomes is limited. The goal of this study was to examine response, remission, exacerbation, and relapse rates over one and two years, respectively, among a clinical sample of adolescents with NSSI. Furthermore, we aimed to identify clinically relevant predictors of NSSI trajectories.

The sample consists of n = 203 adolescents (12–17 y., 94% female) from a specialized outpatient clinic for risk-taking and self-harming behavior with NSSI on at least five days in the six months before first assessment. Assessments were completed at baseline and one (FU1) and two (FU2) years later using structured clinical interviews and self-report questionnaires.

At FU1, 75% reported a reduction in NSSI frequency by at least 50% (treatment response); among those, one third (25% of the entire sample) achieved a remission (0 NSSI); an exacerbation (⩾50% more NSSI) was observed in 11% of patients. Of those in remission, 41% relapsed one year later. Predictors of non-response or non-remission were inpatient treatment and depressive symptoms. Adolescents with lower NSSI frequency at baseline had a higher risk of exacerbation. Due to limited sample size at FU2 no prediction model for relapse was established.

While most adolescents presenting with NSSI achieved significant improvement, more attention should be paid to the rather low rates of full remission. Prediction and early detection of individuals who deteriorate during or relapse after treatment is critical.

Psychotic disorders develop gradually along a continuum of severity. Understanding factors associated with psychosis development, such as sleep, could aid in identification of individuals at elevated risk. This study aimed to assess (1) the dynamic relationship between psychotic experiences (PEs) and sleep quality and quantity, and (2) whether this relationship differed between different clinical stages along the psychosis continuum.

We used daily diary data (90 days) of individuals (N = 96) at early stages (i.e. before a first diagnosis of psychosis) along the psychosis continuum. Multilevel models were constructed with sleep quality and sleep quantity as predictors of PEs and vice versa. Post-hoc, we constructed a multilevel model with both sleep quality and quantity as predictors of PEs. In addition, we tested whether associations differed between clinical stages.

Within persons, poorer sleep predicted next day PEs (B = −0.02, p = 0.01), but not vice versa. Between persons, shorter sleep over the 90-day period predicted more PEs (B = −0.04, p = 0.002). Experiencing more PEs over 90-days predicted poorer (B = −0.02, p = 0.02) and shorter (B = −1.06, p = 0.008) sleep. We did not find any significant moderation effects for clinical stage.

We found a bidirectional relationship between sleep and PEs with daily fluctuations in sleep predicting next day PEs and general patterns of more PEs predicting poorer and shorter sleep. Our results highlight the importance of assessing sleep as a risk marker in the early clinical stages for psychosis.

Undergoing puberty ahead of peers (‘earlier pubertal timing’) is an important risk factor for mental health problems during early adolescence. The current study examined pathways between pubertal timing and mental health via connectivity of neural systems implicated in emotional reactivity and regulation (specifically corticolimbic connections) in 9- to 14-year-olds.

Research questions were examined in the Adolescent Brain Cognitive Development (ABCD) Study, a large population representative sample in the United States. Linear mixed models examined associations between pubertal timing and resting-state corticolimbic connectivity. Significant connections were examined as potential mediators of the relationship between pubertal timing and mental health (withdrawn depressed and rule-breaking) problems. Exploratory analyses interrogated whether the family environment moderated neural risk patterns in those undergoing puberty earlier than their peers.

Earlier pubertal timing was related to decreased connectivity between limbic structures (bilateral amygdala and right hippocampus) and the cingulo-opercular network, left amygdala and somatomotor (mouth) network, as well as between the left hippocampus and ventral attention network and visual network. Corticolimbic connections also mediated the relationship between earlier pubertal timing and increased withdrawn depressed problems (but not rule-breaking problems). Finally, parental acceptance buffered against connectivity patterns that were implicated in withdrawn depressed problems in those undergoing puberty earlier than their peers.

Findings highlight the role of decreased corticolimbic connectivity in mediating pathways between earlier pubertal timing and withdrawn depressed problems, and we present preliminary evidence that the family environment may buffer against these neural risk patterns during early adolescence.

Prevalence of psychotic-like experiences (PLEs) – reports of hallucinations and delusional thinking not meeting criteria for psychotic disorder – varies substantially across ethnoracial groups. What explains this range of PLE prevalence? Despite extensive research, the clinical significance of PLEs remains unclear. Are PLE prevalence and clinical severity differentially associated across ethnoracial groups?

We examined the lifetime prevalence and clinical significance of PLEs across ethnoracial groups in the Collaborative Psychiatric Epidemiology Surveys (N = 11 139) using the Composite International Diagnostic Interview (CIDI) psychosis symptom screener. Outcomes included mental healthcare use (inpatient, outpatient), mental health morbidity (self-perceived poor/fair mental health, suicidal ideation or attempts), and impairment (role interference). Individuals with outcome onsets prior to PLE onset were excluded. We also examined associations of PLEs with CIDI diagnoses. Cox proportional-hazards regression and logistic regression modeling identified associations of interest.

Contrary to previous reports, only Asian Americans differed significantly from other U.S. ethnoracial groups, reporting lower lifetime prevalence (6.7% v. 8.0–11.9%) and mean number (0.09 v. 0.11–0.18) of PLEs. In multivariate analyses, PLE clinical significance showed limited ethnoracial variation among Asian Americans, non-Caribbean Latinos, and Afro-Caribbeans. In other groups, mental health outcomes showed significant ethnoracial clustering by outcome (e.g. hospitalization and role interference with Caribbean-Latino origin), possibly due to underlying differences in psychiatric disorder chronicity or treatment barriers.

While there is limited ethnoracial variation in U.S. PLE prevalence, PLE clinical significance varies across U.S. ethnoracial groups. Clinicians should consider this variation when assessing PLEs to avoid exaggerating their clinical significance, contributing to mental healthcare disparities.

Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs' mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects.

Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008–2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication.

38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2–2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users' unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users' unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1–2.2 percentage points, representing 32.4–64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine's higher mortality risk held in sensitivity analyses.

Haloperidol's, olanzapine's, and risperidone's lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine's higher mortality risk proved robust. Findings expand the evidence on antipsychotics' risks, suggesting a need for caution in the use of quetiapine among individuals with SMI.