Depression runs in families, with both genetic and environmental mechanisms contributing to intergenerational continuity, though these mechanisms have often been studied separately. This study examined the interplay between genetic and environmental influences in the intergenerational continuity of depressive symptoms from parents to offspring.

Using data from the Dutch TRAILS cohort (n = 2201), a prospective, genetically informed, multiple-generation study, we examined the association between parents’ self-reported depressive symptoms (reported at mean age of 41 years) and offspring depressive symptoms, self-reported nearly two decades later, in adulthood (mean age: 29 years). We assessed the role of genetic (polygenic scores for depressive symptoms in parents and offspring) and environmental mechanisms (parental warmth during adolescence) in explaining intergenerational continuity of depressive symptoms in separate and combined models.

Parents’ depressive symptoms, offspring genetic predisposition, and parental warmth were associated with an increased risk of depressive symptoms in offspring. In the combined model, parents’ genetic predisposition was linked to their own depressive symptoms, which were linked to lower parental warmth, which, in turn, was linked to higher depressive symptoms in offspring, after accounting for offspring genetic predisposition, sex, age, and socioeconomic status.

Both genetic and environmental mechanisms contribute to the intergenerational continuity of depressive symptoms independently and in interplay. Despite a significant effect, the influence of parental warmth was modest, suggesting limited covariation between this particular parenting measure and depressive symptoms, at least when assessed with large temporal distance.

After remission of a first-episode psychosis (FEP), antipsychotic discontinuation is associated with an increased risk of relapse compared to maintenance treatment. We studied short and longer-term effects of discontinuation of D2 receptor (D2R) antagonist and partial agonist antipsychotics on striatal dopamine D2/3R availability in FEP patients.

Remitted FEP patients underwent two [11C]raclopride PET scans to measure striatal D2/3R availability: 1 week after antipsychotic discontinuation (n = 16 antagonist users, n = 6 partial agonist users) and after being medication free for 6–8 weeks (n = 8 antagonist users, n = 5 partial agonist users). Fifteen matched healthy controls were scanned once. Psychotic relapse was monitored up to 12 months after discontinuation.

One week after discontinuation, D2R antagonist discontinuers showed higher striatal binding potential (BPND) than partial D2R agonist discontinuers (p < 0.001, CI = 0.749 to 1.681) and controls (p = 0.045, CI = 0.008 to 0.708), while partial agonist discontinuers had significantly lower BPND than controls (p = 0.001, CI = -1.326 to -0.386). 6-8 weeks after discontinuation, former antagonist users showed similar BPND to controls (p > 0.25), whereas former partial agonist users had higher BPND than controls (p = 0.027, CI = 0.069 to 1.085). Participants who discontinued antagonists relapsed more often (81%) than those who discontinued partial agonists (17%)(χ2 = 5.32, p = 0.021).

Discontinuation of partial D2R agonists may affect D2/3R availability differently than discontinuation of antagonists, which might explain the greater relapse risk after tapering antagonists than partial agonist antipsychotics.

Psychological therapy (PT) along with antipsychotic medication is the recommended first line of treatment for first-episode psychosis (FEP). We investigated whether ethnicity, clinical, pathways to care (PtC) characteristics, and access to early intervention service (EIS) influenced the offer, uptake, and type of PT in an FEP sample.

We used data from the Clinical Record Interactive Search-First Episode Psychosis study. Inferential statistics determined associations between ethnicity, clinical, PtC, and PT offer/uptake. Multivariable logistic regression estimated the odds of being offered a PT and type of PT by ethnicity, clinical and PtC characteristics adjusting for confounders.

Of the 558 patients included, 195 (34.6%) were offered a PT, and 193 accepted. Cognitive behavioral therapy (CBT) (n = 165 of 195; 84.1%) was commonly offered than group therapy (n = 30 of 195; 13.3%). Patients who presented via an EIS (adj. OR = 2.24; 95%CI 1.39–3.59) were more likely to be offered a PT compared with those in non-EIS. Among the patients eligible for an EIS, Black African (adj. OR = 0.49; 95%CI = 0.25–0.94), Black Caribbean (adj. OR = 0.45; 95%CI = 0.21–0.97) patients were less likely to be offered CBT compared with their White British counterparts. Patients with a moderate onset of psychosis (adj. OR = 0.34; 95%CI = 0.15–0.73) had a reduced likelihood of receiving CBT compared with an acute onset.

Accessing EIS during FEP increased the likelihood of being offered a PT. However, treatment inequalities remain by ethnicity and clinical characteristics.

Research has pointed to important psychopathological differences between persistent and episodic depressive disorders. Here, we tested the hypothesis that people with persistent rather than episodic depression have difficulty revising established expectations in response to novel positive information. In terms of underlying mechanisms, we predicted that these differences between the two subtypes would be related to the engagement in cognitive immunization (i.e. devaluing expectation-disconfirming positive information).

Prior to their psychotherapeutic treatment, 54 outpatients with persistent depressive disorder and 102 outpatients with episodic major depressive disorder completed an experimental task. In this task, participants watched other patients’ reports of positive effects of psychotherapy. Our primary outcome was change in treatment expectations from before to after watching the positive reports.

Overall, people with persistent depression had lower treatment expectations than people with episodic depression. In addition, they changed their treatment expectations less in response to other patients’ positive reports. This effect was greater for psychotherapy outcome expectations than for role expectations. The lack of expectation change in persistent depression relative to episodic depression was particularly pronounced in a cognitive immunization-promoting experimental condition.

The results indicate that people with persistent depression have difficulty adjusting their treatment expectations in response to positive information on psychotherapy. This may be a risk factor for poor treatment outcome. The results regarding cognitive immunization suggest that for people with persistent depression, slight doubts about the value of information on the positive effects of psychotherapy may be sufficient to prevent them from integrating this information.

Studies highlight the thalamus as a key region distinguishing early- from late-onset obsessive-compulsive disorder (OCD). While structural thalamic correlates with OCD onset age are well-studied, resting-state functional connectivity (rsFC) remains largely unexplored. This study examines thalamic subregional rsFC to elucidate pathophysiological differences in OCD based on different onset times.

The study comprised 85 early-onset OCD (EO-OCD) patients, 94 late-onset OCD (LO-OCD) patients, and 94 age- and sex-matched healthy controls (HCs). rsFC analysis was conducted to assess thalamic connectivity across seven subdivisions among the groups.

Both EO-OCD and LO-OCD patients exhibited increased rsFC between the primary motor thalamus and the posterior central gyrus and between the thalamic premotor and the supplementary motor areas. EO-OCD patients showed significantly stronger rsFC between the prefrontal thalamus (Ptha) and the middle frontal gyrus (MFG) compared to both LO-OCD patients and HCs. In contrast, LO-OCD patients demonstrated reduced rsFC between the Ptha and the inferior parietal lobule (IPL) compared to EO-OCD patients and HCs. Additionally, the rsFC between the Ptha and both the MFG and IPL was negatively correlated with age of onset, with earlier onset linked to stronger connectivity.

These findings reveal both shared and distinct thalamic connectivity patterns in EO-OCD and LO-OCD patients. Sensory-motor networks exhibiting thalamic hyperconnectivity are critical for the manifestation of OCD, regardless of age of onset. The frontal–parietal network and thalamic hyperconnectivity may present a compensatory mechanism in EO-OCD patients, while hypoconnectivity with the frontoparietal network may reflect a neural mechanism underlying LO-OCD.

Neuroimaging studies provide compelling evidence that major depressive disorder (MDD) is associated with widespread gray matter morphological abnormalities. However, significant interindividual variability complicates the interpretation of group-level findings, highlighting the need for investigating potential MDD subtypes.

In this study, we aimed to identify subtypes of MDD based on individualized deviations from normative gray matter volumes (GMVs), as estimated using a normative model derived from healthy controls (HCs). We leveraged a large, multi-site dataset of high-resolution structural MRI scans, comprising 1,276 MDD patients and 1,104 matched HCs. To explore the transcriptional and molecular mechanisms underlying the observed structural abnormalities, we examined the relationships between GMV deviations, transcriptomic similarities (as measured by the correlated gene expression [CGE] connectome), and the distribution of neurotransmitter receptors/transporters.

Our results revealed two reproducible MDD subtypes, each exhibiting distinct patterns of GMV abnormalities across study sites. Subtype 1 displayed increased GMVs in cerebral regions and decreased GMVs in cerebellar regions, whereas subtype 2 showed the opposite pattern, with decreased GMVs in cerebral regions and increased GMVs in cerebellar areas. The identified GMV abnormalities were differentially associated with neurotransmitter receptor/transporter distributions. Furthermore, these abnormalities were linked to transcriptionally connected gene networks, suggesting genetic underpinnings for both subtypes. Notably, the two subtypes exhibited distinct CGE-informed disease epicenters.

This study identifies two robust MDD subtypes, providing new insights into the neurobiological and genetic bases of MDD and offering a potential advancement in the nosology of the disorder.

Insomnia disorder, characterized by chronic sleep disruption, often co-occurs with maladaptive emotional memory processing. However, much remains unknown regarding the evolution of emotional memories and their neural representations over time among individuals with insomnia disorder.

We examined the electroencephalographic (EEG) activities during emotional memory encoding, post-encoding sleep, and multiple retrieval phases – including immediate post-encoding, post-sleep, and a 7-day delayed retrieval – among 34 participants with insomnia disorder and 35 healthy control participants.

Healthy controls exhibited adaptive dissipation of emotional memory: memory declined over time, accompanied by reduced subjective feelings toward negative memories. In contrast, participants with insomnia exhibited impaired dissipation: they retained both the emotional content and affective tone of the memories, with diminished time-dependent declines in memory and affect. Beyond behavioral performance, only participants with insomnia maintained stable neural representations of emotion over time, a pattern absent in healthy controls. Additionally, during the post-encoding sleep, slow-wave sleep (SWS), and rapid eye movement (REM) sleep durations predicted the adaptive dissipation of emotional memory over time, but only among healthy participants.

These findings highlight abnormalities in emotional memory processing among individuals with insomnia disorder and underscore the important function of SWS and REM sleep in facilitating adaptive emotional memory processing.

MicroRNAs (miRNAs) alterations in patients with bipolar disorder (BD) are pivotal to the disease’s pathogenesis. Since obtaining brain tissue is challenging, most research has shifted to analyzing miRNAs in peripheral blood. One innovative solution is sequencing miRNAs in plasma extracellular vesicles (EVs), particularly those neural-derived EVs emanating from the brain.

We isolated plasma neural-derived EVs from 85 patients with BD and 39 healthy controls (HC) using biotinylated antibodies targeting a neural tissue marker, followed by miRNA sequencing and expression analysis. Furthermore, we conducted bioinformatic analyses and functional experiments to delve deeper into the underlying pathological mechanisms of BD.

Out of the 2,656 neural-derived miRNAs in EVs identified, 14 were differentially expressed between BD patients and HC. Moreover, the target genes of miR-143-3p displayed distinct expression patterns in the prefrontal cortex of BD patients versus HC, as sourced from the PsychENCODE database. The functional experiments demonstrated that the abnormal expression of miR-143-3p promoted the proliferation and activation of microglia and upregulated the expression of proinflammatory factors, including IL-1β, IL-6, and NLRP3. Through weighted gene co-expression network analysis, a module linking to the clinical symptoms of BD patients was discerned. Enrichment analyses unveiled these miRNAs’ role in modulating the axon guidance, the Ras signaling pathway, and ErbB signaling pathway.

Our findings provide the first evidence of dysregulated plasma miRNAs within neural-derived EVs in BD patients and suggest that neural-derived EVs might be involved in the pathophysiology of BD through related biological pathways, such as neurogenesis and neuroinflammation.

Identifying key areas of brain dysfunction in mental illness is critical for developing precision diagnosis and treatment. This study aimed to develop region-specific brain aging trajectory prediction models using multimodal magnetic resonance imaging (MRI) to identify similarities and differences in abnormal aging between bipolar disorder (BD) and major depressive disorder (MDD) and pinpoint key brain regions of structural and functional change specific to each disorder.

Neuroimaging data from 340 healthy controls, 110 BD participants, and 68 MDD participants were included from the Taiwan Aging and Mental Illness cohort. We constructed 228 models using T1-weighted MRI, resting-state functional MRI, and diffusion tensor imaging data. Gaussian process regression was used to train models for estimating brain aging trajectories using structural and functional maps across various brain regions.

Our models demonstrated robust performance, revealing accelerated aging in 66 gray matter regions in BD and 67 in MDD, with 13 regions common to both disorders. The BD group showed accelerated aging in 17 regions on functional maps, whereas no such regions were found in MDD. Fractional anisotropy analysis identified 43 aging white matter tracts in BD and 39 in MDD, with 16 tracts common to both disorders. Importantly, there were also unique brain regions with accelerated aging specific to each disorder.

These findings highlight the potential of brain aging trajectories as biomarkers for BD and MDD, offering insights into distinct and overlapping neuroanatomical changes. Incorporating region-specific changes in brain structure and function over time could enhance the understanding and treatment of mental illness.

Diagnostic tools, such as the Mini International Neuropsychiatric Interview (MINI) 7.0.2 and the Structured Clinical Interview for the DSM-5 (SCID), aim to increase the validity and reliability of diagnostic assessment. However, these tools were created in high-income countries (HICs) with limited investigation of the psychometrics of these tools when used in low- and middle-income countries (LMICs). Thus, there is a need to examine the psychometric properties of these measures in LMICs. The present investigation aimed to examine the use of the MINI in Ethiopia, Kenya, and Uganda.

A multicountry comparison of the validity and reliability of the MINI was conducted in a study of 954 participants (n = 667 cases; n = 287 controls) with and without a psychotic spectrum disorder, defined as any psychotic or bipolar spectrum disorder for the NeuroGAP – Psychosis study. Test–retest reliability of the MINI was examined in a subset of 303 participants (n = 164 cases; n = 139 controls) from the overall sample.

Results revealed the MINI and SCID provided excellent diagnostic accuracy with area under the curve (AUC) values of .91 (SE = .01) for the MINI and .95 (SE = .01) for the SCID. Positive predictive values (PPV) were the highest for the SCID (93.8%) and slightly lower for the MINI (88.7%). Reliability analyses revealed substantial agreement for psychotic and bipolar diagnostic groups.

Similar patterns of results were observed at the country level with a few notable differences. Limitations and future directions are discussed.

Schizophrenia patients with auditory hallucinations have distinct morphological abnormalities, but whether this population have a progressive gray matter atrophy pattern and specific transmission chain of causal effects remains unclear. This study was designed to construct a causal structural covariance network in schizophrenia patients with persistent auditory hallucinations.

T1-weighted MRI images were acquired from 90 schizophrenia patients with persistent auditory hallucinations (pAH group) and 83 healthy controls (HC group). Stage-specific independent t tests of gray matter volume (GMV) comparisons between the two groups were used to depict the GMV atrophic pattern and locate the atrophic origin. In the pAH group, the causal structural covariance network (CaSCN) was constructed to map causal effects between the atrophic origin and other regions as the auditory hallucination severity increased.

With the ascending of hallucinatory severity, GMV reductions began from the thalamus, bilateral medial frontal gyri, left Rolandic operculum, and left calcarine, and expanded to other frontal and temporal regions, hippocampal complex, insula, anterior cingulate gyri, fusiform, and cerebellum. Using the peak region (thalamus) as the causal origin in the network, transitional nodes including the right opercular part of the inferior frontal gyrus, bilateral postcentral gyri, left thalamus, and right middle frontal gyrus received the casual information and projected to target nodes from the frontal, temporal, parietal, and occipital cortices, limbic system, and cerebellum.

Our study revealed causal effects from the thalamus and a specific transmission pattern of causal information within the network, indicating a thalamic–cortical–cerebellar circuitry dysfunction related to auditory hallucinations.

The optimal duration for maintaining antidepressant treatment in individuals with obsessive-compulsive disorder (OCD) who achieve symptom stabilization remains unclear.

This systematic review and pairwise meta-analysis of double-blind randomized placebo-controlled trials (DBRPCTs) compared antidepressant maintenance and antidepressant discontinuation groups in terms of relapse rate at each DBRPCT study endpoint (primary outcome), OCD symptom improvement, all-cause discontinuation, and adverse event-related discontinuation. Furthermore, relapse rates at 4, 8, 12, 16, 20, and 24 weeks were compared between the groups. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. The absolute risk reduction (ARR) and number needed to treat to benefit (NNTB) for relapse rates were also estimated.

Nine trials (n = 1084; mean age: 32.8 years; proportion of males: 53.3%) were included. The antidepressant maintenance group had lower relapse rates at each DBRPCT study endpoint (RR [95% CI] = 0.53 [0.42–0.68]; ARR = 21.0%; NNTB = 5) and lower all-cause and adverse event-related discontinuation rates than the antidepressant discontinuation group. The maintenance group also exhibited lower relapse rates at 4 weeks (RR [95% CI] = 0.47 [0.31–0.70]; ARR: not significant; NNTB: not significant), 8 weeks (0.42 [0.31–0.57]; 12.0%; 8), 12 weeks (0.43 [0.32–0.56]; 18.0%; 6), 16 weeks (0.41 [0.32–0.52]; 25.0%; 4), 20 weeks (0.43 [0.34–0.53]; 26.0%; 4), and 24 weeks (0.42 [0.33–0.52]; 27.0%; 4) than the discontinuation group. Moreover, the maintenance group outperformed the discontinuation group regarding OCD symptom improvement.

Individuals with OCD may benefit from continued antidepressant treatment, provided that it is well tolerated.

Posttraumatic stress disorder (PTSD) exhibits marked heterogeneity, with relational (R; interpersonal) and nonrelational (NR; environmental) trauma subtypes demonstrating distinct psychopathological trajectories. Despite clinical recognition of these differences, their neurobiological underpinnings of emotion processing remain poorly understood. Guided by the Nested Hierarchical Model of Self (NHMS) – which posits trauma-type-specific disruptions in hierarchical self-processing systems – this study investigated neural mechanisms differentiating among PTSD subtypes during implicit emotion regulation.

A sample of 122 participants, including patients with PTSD (R: n = 51; NR: n = 29) and trauma-exposed controls matched by trauma type (R: n = 22; NR: n = 20), underwent functional magnetic resonance imaging while performing the Shifted Attention Emotion Appraisal Task. Behavioral assessments and trauma typology coding were complemented by regions of interest (ROI)-based and whole-brain analyses.

Results revealed that PTSD-R showed hypoactivation in right superior frontal gyrus (during implicit emotion regulation; BA9; p = 0.049, ηp2 = 0.033), whereas PTSD-NR exhibited hyperactivation in fusiform (during emotion modulation by attention shifting; p = 0.036, ηp2 = 0.037). Symptom severity inversely correlated with social support (r = −0.353 to −0.417, p < 0.01), with relational PTSD reporting the lowest support (p < 0.001). Across conditions, dorsolateral prefrontal clusters (BA8/9) demonstrated anticorrelations with default-mode regions (r = −0.272 to −0.549, p < 0.01) aligning with NHMS’ predictive coding framework.

These findings validate trauma-type-specific neural hierarchies, suggesting relational trauma disrupts top-down self-identity schemas, while NR trauma amplifies bottom-up threat detection. The study advances precision psychiatry by linking implicit regulation biomarkers to targeted interventions – cognitive restructuring for PTSD-R and interoceptive recalibration for PTSD-NR.

Adolescence is a period marked by high vulnerability to onset of depression. Neuroimaging studies have revealed considerableatrophy of brain structure in patients with major depressive disorder (MDD). However, the causal structural networks underpinning gray matter atrophies in depressed adolescents remain unclear. This study aimed to examine the initial gray matter alterations in MDD adolescents and investigate their causal relationships of abnormalities within brain structural networks.

First-episode adolescent patients with MDD (n = 80, age = 15.57 ± 1.78) and age- and sex-matched healthy controls (n = 82, age = 16.11 ± 2.76) were included. We analyzed T1-weighted structural images using voxel-based morphometry to identify gray matter alterations in patients and the disease stage-specific abnormalities. Granger causality analysis was then conducted to construct causal structural covariance networks. We also identified potential pathways between the causal source and target.

Compared to controls, MDD patients with shorter illness duration showed gray matter atrophy in localized brain regions such as ventral medial prefrontal cortex (vmPFC), anterior cingulate cortex, and insula. With a prolonged course of MDD, gray matter atrophy extended to widespread brain areas. Causal network results demonstrated that early abnormalities had positive effects on the default mode, frontoparietal networks, and reward circuits. Moreover, vmPFC demonstrated the highest out-degree value, possibly representing the initial source of brain abnormality in adolescent depression.

These findings revealed the progression of gray matter atrophy in adolescent depression and demonstrated the directional influences between initial localized alterations and subsequent deterioration in widespread brain networks.

In patients with remitted psychosis, the dosage of antipsychotics can be lowered without increased risk of relapse. Whether dose tapering can lead to improved cognition is unclear. We compared changes in cognitive performance between patients undergoing dose tapering and those receiving a fixed maintenance dose.

A 2-year prospective trial of patients with stable schizophrenia-related psychotic disorders was conducted: one group received guided dose reduction (GDR) and one group received maintenance treatment. Cognitive function was assessed using the Wechsler Adult Intelligence Scale-Third Edition, Mandarin Chinese version, at baseline, 1, and 2 years. The relations between the ratio of reduced dose and the extent of cognitive improvement were examined by Spearman’s correlation coefficient. We also examined cognitive performance between aripiprazole (ARI) users and non-ARI users.

GDR patients exhibited significantly greater improvements in total intellectual quotient (IQ), particularly working memory, and information and arithmetic subtest scores, with no significant difference in relapse rates between groups. Statistically significant dose–response correlations were found between the degree of dose reduction and improvements in total IQ (n = 72, r = 0.242, p = 0.041), Working Memory Index (n = 72, r = 0.284, p = 0.016), and Arithmetic subtest (n = 72, r = 0.295, p = 0.012). There were no differences in cognitive changes between ARI users and non-users.

Lowering antipsychotic dosage may ameliorate patient performance in several cognitive domains. This finding is worthy of consideration while evaluating the risk-to-benefit ratio of tapering antipsychotics in patients with remitted psychosis.

Methadone maintenance treatment (MMT) and protracted abstinence (PA) effectively reduce the craving for heroin among individuals with heroin use disorder (HUD). However, the difference in their effects on brain function, especially the coupling among the large-scale brain networks (default mode [DMN], salience [SN], and executive control [ECN] networks), remains unclear. This study analyzed the effects of the MMT and PA on these networks and the predictive value of the bilateral resource allocation index (RAI) for craving for heroin.

Twenty-five individuals undergoing the MMT, 22 undergoing the PA, and 51 healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). Independent component analysis identified the ECN, DMN, and SN. The SN-ECN and SN-DMN connectivity and the bilateral RAI were evaluated. The relationships between network coupling and clinical and psychological characteristics were analyzed. The multiple linear regression model identified significant variables for predicting craving scores.

The MMT group showed significantly stronger SN-left ECN (lECN) coupling and left RAI than the PA group. In the MMT group, SN-lECN connectivity and bilateral RAI were positively correlated with the total methadone dose. In both treatment groups, SN-right ECN (rECN) connectivity and right RAI were negatively correlated with craving. The models revealed that the bilateral RAI and the MMT and PA were associated with the craving.

The MMT enhances SN-lECN coupling and the left RAI more than the PA, possibly due to higher control modulation. The RAI could help predict heroin craving in individuals with HUD undergoing either treatment program.

Although heightened anxiety associated with social interaction or evaluation is the core diagnostic criterion for social anxiety disorder (SAD), there is growing evidence that SAD is characterized by more pervasive reactivity beyond social situations. We employed Ecological Momentary Assessment (EMA) to describe the affective dynamics and emotional reactivity to daily events in a community-based sample of adults with SAD compared with other anxiety disorders, and controls without anxiety or mood disorders.

A sample of 236 adults with a lifetime diagnosis of SAD (n = 53), other anxiety disorders (n = 120), and no mood or anxiety disorder (n = 63) based on comprehensive diagnostic interviews answered brief electronic interviews that assessed daily life events and mood and anxiety symptoms four times a day for two weeks. Linear mixed models were used to quantify reactivity to daily life events.

Persons with SAD had higher average levels of sad and anxious mood than those with other anxiety disorders or controls. Irrespective of comorbid mood disorders, people with SAD also demonstrated significantly greater decreases in both sad and anxious mood following positive events, and a greater increase in anxious mood following negative, particularly non-social events.

Our findings regarding pervasive reactivity beyond the social context in people with SAD confirm the need for broader conceptualization of this disorder as well as expansion of interventions beyond the social context. This work also demonstrates the utility of EMA as a powerful tool to track individual variability and reactivity in daily life that can inform etiology, treatment and prevention.