BACKGROUND:Although subtle differences in cortico-striato-thalamo-cortical circuit structure and function are critical to the current understanding of the neurocircuitry in obsessive-compulsive disorder (OCD), emerging evidence suggests that the cerebellum may also be involved. However, much of this evidence comes from studies with small samples and notable methodological heterogeneity. METHODS:We conducted a mega-analysis of individual-participant data on cerebellar subregional volumes, comparing individuals with OCD and healthy controls (HCs) from the ENIGMA-OCD Working Group. Three-dimensional T1-weighted volumetric structural brain magnetic resonance imaging (MRI) scans from 1954 individuals with OCD and 2091 HCs across 22 sites (40 datasets) were processed using the ACAPULCO (Automatic Cerebellum Anatomical parcellation using U-Net Locally Constrained Optimization) pipeline to extract cerebellar parcellations. We harmonized the volume measures across sites using the ComBat algorithm. Multiple linear regression models were fitted to estimate group differences separately within the pediatric (<12 years), adolescent (12-17 years), and adult (from 18 years) samples, adjusting for age, gender, and intracranial volume. RESULTS:In adults with OCD (vs. HCs), we found significantly smaller volumes of the corpus medullare (d = -0.093, false discovery rate (FDR)-corrected p = .036), left VIIb (d = -0.085, pFDR = .039) and right VIIb (d = -0.091, pFDR = .036). None of the comparisons between children or adolescents with OCD versus HCs remained statistically significant after FDR correction. In all 3 age groups, cerebellar (subregional) volumes were significantly moderated by medication status. CONCLUSIONS:We report novel findings implicating specific cerebellar subregions across developmental stages of OCD and the key impact of medication status. Additional research on the functional significance of these findings may offer new translational leads.

Impaired cognitive flexibility is observed in psychiatric disorders like obsessive-compulsive disorder and major depressive disorder. Here, we investigated how cortico-striatal communication is engaged during a cognitive flexibility task and its correlation with task- switching effort. We recorded local field potentials (LFPs) from the left ventral striatum (VS) together with scalp electroencephalography (EEG) in four treatment-refractory psychiatric patients undergoing deep brain stimulation surgery, providing a rare opportunity to investigate cortico-striatal communication during cognitive flexibility. Coherence between LFPs and scalp EEG was computed to identify frequency-specific coupling, and subsequent connectivity analyses focused on this frequency band to assess its association with task switching performance. EEG activity was subsequently source-localized using the Destrieux brain atlas. Patients exhibited the expected reaction time switch cost, with longer reaction times on switch trials than on repetition trials, whereas accuracy did not differ. Strong coherence in theta oscillatory activity and its positive correlation with switch costs. Source localization further identified dorsal anterior cingulate cortex (dACC) as the cortical region contributing to this VS-cortical coupling. These results suggest that stronger frontostriatal communication during task switching is associated with flexible adaptation to changing task demands, and may reflect network mechanisms contributing to cognitive inflexibility in severe psychiatric patients.

OBJECTIVE:To investigate whether age or gender moderates short-term antipsychotic efficacy, acceptability, or safety in adolescents with early-onset schizophrenia (EOS). METHOD:We analyzed data from 4 placebo-controlled, randomized registration trials of antipsychotics in EOS (2003-2015). An individual patient data meta-analysis evaluated how age and gender affected efficacy (Positive and Negative Syndrome Scale [PANSS] total change, response), acceptability (all-cause discontinuations), and safety (adverse event incidence). Covariates included age at onset, body mass index, baseline negative symptoms, and study year. The study was registered in the PROSPERO database (ID: CRD42024572863). RESULTS:We included 949 adolescents (61% male, 39% female; mean age = 15.4 years). Neither age (β = 0.251, 95% CI= -1.561-2.064) nor gender (β = 3.057, 95% CI = -0.206-8.175) significantly altered overall antipsychotic efficacy on mean PANSS improvement or response rate. All-cause discontinuation was likewise not affected. Younger adolescents on active medication showed a higher incidence of adverse events than those on placebo, whereas older adolescents exhibited similarly low rates across arms (correlation coefficient = -0.272, p < .001). Gender did not significantly influence adverse-event incidence (aggregate β = 0,037, p = .832). The overall correlation coefficient -0.131 (p = .342) between age and 5 major side effect classes (weight gain, extrapyramidal side effects, QTc prolongation, prolactin increase, sedation) suggested no meaningful age impact, with odds ratios ranging from 0.858 (p = .691) for weight gain to 1.244 (p = .225) for sedation. CONCLUSION:Younger adolescents demonstrated greater vulnerability to antipsychotic-related adverse events despite exhibiting efficacy and acceptability comparable to those in older adolescents. These findings suggest that age-based dosing and monitoring may be warranted when treating adolescents with EOS. STUDY REGISTRATION INFORMATION:Influence of age and gender on short-term efficacy and safety of antipsychotic drugs in the treatment of adolescents with schizophrenia: an Individual Patients Data Meta-Analysis; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024572863 DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

Studies of brain morphology in mental illness often focus on a few neuroimaging phenotypes. Here we present a comprehensive morphological characterization in obsessive-compulsive disorder (OCD) in a large sample (2255 OCD, 2264 controls) using nine cortical and four subcortical phenotypes, including several not previously examined in OCD, among them a subcortical structural similarity network phenotype developed here. Spatially distinct regional alterations emerged across structural phenotypes: cortical curvature alterations in default mode and frontoparietal networks, increased structural similarity network node degree in sensorimotor regions, widespread volume reductions associated with medication use, and localized subcortical shape alterations. In brain-behavior predictive models, curvature phenotypes showed the strongest associations with clinical features. Cortical alterations, especially in structural similarity networks, were associated with specific gene expression patterns, implicating dysregulation of excitatory neurons. RNA-sequencing data from tissue collected during functional neurosurgery revealed that genes downregulated in the dorsolateral prefrontal cortex in OCD contributed to the gene expression patterns linked to cortical alterations. Previously reported differentially expressed genes from postmortem brain studies of OCD also contributed. These findings support the importance of a comprehensive approach to characterizing brain morphology and suggest that cortical curvature and structural similarity alterations reflect key pathophysiological processes in OCD.

Pregnancy is known to induce profound structural adaptations in the female brain, especially in regions involved in social cognition. This pre-conception cohort fMRI study examined changes in neural signal variability and functional connectivity during mentalizing tasks among 110 women (Mage = 30.5 years, SD = 3.5, range = 25-41), including 40 first-time mothers, 30 s-time mothers, and 40 nulliparous control women. Participants completed a mentalizing task before and after pregnancy, and, for a subset, 1 year postpartum. First-time mothers exhibited increased neural variability in response to child-related stimuli in the early postpartum period relative to their pre-conception baseline, whereas control women and second-time mothers showed decreases consistent with typical age-related changes. In controls, decreased neural variability correlated with declines in mentalizing task performance, suggesting that neural variability supports flexible and effective cognitive processing. Effects were stimulus- and parity-specific, with first-time mothers showing selective increases to child-related cues and second-time mothers showing distinct changes in adult-related processing. These findings suggest that pregnancy, particularly in first-time mothers, selectively preserves or enhances neural flexibility for processing infant social cues and that neural variability is a key marker of these adaptations.

Alterations in cortical morphology have consistently been reported in obsessive-compulsive disorder (OCD). However, the microstructural properties of the cortex in OCD, including intracortical myelination, remain far less explored. The contrast between signal intensity in gray and subjacent white matter from T1-weighted magnetic resonance imaging (MRI), i.e. the gray/white matter contrast (GWC), is linked to intracortical myelination and may offer novel insights into the cortical microstructure of OCD. Here, we compared multivariate patterns of GWC defined from an independent component analysis between 454 adults with OCD and 394 healthy controls from eight international sites. To contextualize GWC results with the macrostructure of gray matter in OCD, we also investigated the association between GWC and each individual’s similarity with the pattern of gray matter morphology derived from ENIGMA-OCD using the Regional Vulnerability Index (RVI). Finally, we investigated the association of GWC with demographic and clinical characteristics of participants with OCD. Individuals with OCD showed significantly higher GWC in occipital and frontal regions relative to healthy controls. Moreover, OCD individuals had elevated OCD RVI, and individuals with a higher OCD RVI showed widespread higher GWC across the cortex. Finally, sexual/religious symptoms in OCD individuals were associated with higher GWC in frontal regions. In conclusion, we present new evidence of cortical microstructural alterations in OCD, with microstructural alterations relating to both the gray matter macrostructure and the clinical presentation of the disorder.

We have shown that pregnancy alters brain structure and brain activity, yet its effects on neural dynamics are unknown. This is the first study to investigate the effects of becoming a mother on neural variability, a measure of moment-to-moment fluctuations in brain activity. Longitudinal resting-state functional magnetic resonance imaging data were analyzed of 110 women participating in a prospective pre-conception study, including first-time mothers, second-time mothers and nulliparous control women. Significant differences were observed when comparing pre-to-post pregnancy variability changes in first-time mothers and second-time mothers to those in control women. Control women exhibited widespread reductions in neural variability across all neural networks over time, a pattern that may reflect normative aging and test-retest effects. In contrast, both first-time and second-time mothers showed relative stability in neural variability, diverging from the trajectory observed in controls. Notably, higher neural variability was associated with younger age across all groups, and age was positively associated with changes in attention and frontoparietal networks in first-time mothers. These findings show that pregnancy renders changes in the temporal dynamics of brain activity. Furthermore, becoming a mother alters the trajectory of reductions in neural variability typical for repeated scanning sessions and aging, suggesting compensatory neural adaptations.

BACKGROUND:In the treatment of obsessive-compulsive disorder (OCD) with antidepressant medication, the earliest reliable indication of treatment failure remains uncertain. We investigated if non-improvement following 4 weeks of treatment predicts nonresponse at the end of the trial. METHODS:We conducted a random-effects bivariate diagnostic accuracy study using individual patient data from industry-sponsored short-term trials of adults with OCD receiving selective serotonin reuptake inhibitors or clomipramine, submitted for marketing approval. The primary outcome was accuracy of non-improvement (<25% reduction on the Yale-Brown Obsessive Compulsive Scale [YBOCS] after 4 weeks) in predicting nonresponse (<35% YBOCS reduction at trial endpoint [10-13 weeks]). Secondary outcomes were accuracy of non-improvement after 6 weeks, nonresponse after 8 weeks, and inclusion of Clinical Global Impression Scale - Improvement in definitions of improvement and response. We performed meta-regressions for sex, age, severity, trial duration, dosing regimen, and compound. RESULTS:In 11 studies totaling 1,753 patients, non-improvement at week 4 predicted subsequent nonresponse (positive predictive value, PPV) in 86% of cases (95% confidence interval [CI] = 83-88%). Sensitivity was 78%, specificity was 70%, and the negative predictive value was 60%. Secondary outcomes showed similar PPV after 6 weeks and a PPV of 93% for nonresponse after 8 weeks. Predictive accuracy was significantly higher in men relative to women (β = -0.64, 95% CI = -1.12 to -0.16, p = 0.0089). CONCLUSIONS:Patients with OCD who do not improve after 4 weeks of antidepressants will likely not respond to short-term treatment. Thus, a change in strategy should be considered after 4 weeks without treatment benefits.

Deep brain stimulation (DBS) is a neurosurgical intervention for severe, treatment-refractory obsessive-compulsive disorder (OCD). Here, we conducted the first meta-analysis using individual participant outcome data, comparing DBS to sham-stimulation in randomized controlled trials (RCTs), and systematically evaluated adverse events and methodological trial quality. We conducted a comprehensive systematic search in multiple databases and included randomized-controlled trials comparing DBS with sham in adult patients with OCD. We obtained YBOCS data for individual participants and performed a two-stage random-effects meta-analysis. Nine RCTs with small sample sizes were included, resulting in a total sample of 91 patients. Meta-analysis of showed a decrease of 5.1 YBOCS points in favor of DBS compared to sham (95% confidence interval (CI) 2.3 – 7.9, 0.56 Hedges’ g). OR was 5.7, 95% CI 2.2 - 15), with a NNT of 3.3. Efficacy of studies that optimized DBS parameters was much higher than that of non-optimized studies (beta 5.1, 95% CI 0.59 – 9.5, p-value 0.026). Adverse events occurred during surgery, active and sham trial phases, and follow-up, with hypomania and cognitive problems being the most frequently reported stimulation-related adverse events. Concluding, we found a significant effect of DBS compared to sham in treating OCD, especially after DBS parameter optimization. However, the quality of evidence was low, and heterogeneity was high. More rigorous sham-controlled evidence could further improve credibility of DBS for OCD. PROSPERO-registration number: CRD42024546836

Partial remission after major depressive disorder (MDD) is common and a robust predictor of relapse. However, it remains unclear to which extent preventive psychological interventions reduce depressive symptomatology and relapse risk after partial remission. We aimed to identify variables predicting relapse and to determine whether, and for whom, psychological interventions are effective in preventing relapse, reducing (residual) depressive symptoms, and increasing quality of life among individuals in partial remission. This preregistered (CRD42023463468) systematic review and individual participant data meta-analysis (IPD-MA) pooled data from 16 randomized controlled trials (n = 705 partial remitters) comparing psychological interventions to control conditions, using 1- and 2-stage IPD-MA. Among partial remitters, baseline clinician-rated depressive symptoms (p = .005) and prior episodes (p = .012) predicted relapse. Psychological interventions were associated with reduced relapse risk over 12 months (hazard ratio [HR] = 0.60, 95% confidence interval [CI] 0.43-0.84), and significantly lowered posttreatment depressive symptoms (Hedges' g = 0.29, 95% CI 0.04-0.54), with sustained effects at 60 weeks (Hedges' g = 0.33, 95% CI 0.06-0.59), compared to nonpsychological interventions. However, interventions did not significantly improve quality of life at 60 weeks (Hedges' g = 0.26, 95% CI -0.06 to 0.58). No moderators of relapse prevention efficacy were found. Men, older individuals, and those with higher baseline symptom severity experienced greater reductions in symptomatology at 60 weeks. Psychological interventions for individuals with partially remitted depression reduce relapse risk and residual symptomatology, with efficacy generalizing across patient characteristics and treatment types. This suggests that psychological interventions are a recommended treatment option for this patient population.

BACKGROUND:Insecure attachment style has been associated with obsessive-compulsive disorder (OCD). Psychological stress is known to aggravate OCD symptoms and activate the attachment system. Here, we investigated reactivity of attachment-related neurocircuitry under psychological distress in OCD patients. METHODS:Twenty-two patients with OCD and twenty-three healthy controls underwent fMRI scanning after psychological stress induction and a control condition in a cross-over design. Neural responses were measured during presentation of negative emotional faces. Attachment insecurity was measured using the self-report experiences in close relationships scale (ECR) and the adult attachment interview (AAI). RESULTS:OCD participants showed higher scores on ECR attachment anxiety compared to controls. Stress was successfully induced as shown by subjective stress measurements and physiological parameters. OCD participants showed a blunted cortisol response to the stressor. However, no group differences were found in neural stress responses. Across participants, psychological distress decreased hippocampal responses. This effect was dependent on attachment style, with participants scoring high on attachment anxiety showing increased rather than decreased hippocampal activity when distressed. Participants scoring high on attachment insecurity as measured with the AAI showed increased activity in multiple attachment-related brain regions. CONCLUSIONS:Attachment style, but not OCD status, modulated neural responses to emotionally salient information under psychological distress. These findings provide further support for the assumption that attachment insecurity may be an important transdiagnostic vulnerability factor.

Little is known about the effect of ethnicity on drug treatment in patients with an acute manic episode. The aim of this study is to determine whether ethnicity moderates the response to drug treatment in patients with an acute manic episode, and whether this moderation is independent of potential confounders. We analysed ten short-term placebo-controlled registration trials of atypical antipsychotics and anticonvulsive mood stabilizers in patients with an acute manic episode (n = 2199). A one-step random effects individual patient data meta-analysis (IPD) was applied to establish the moderating effect of ethnicity on symptom improvement on the Young Mania Rating Scale (Y)MRS and on response defined as 50

BACKGROUND:Selective serotonin reuptake inhibitors (SSRIs) are the preferred pharmacological treatment for obsessive-compulsive disorder (OCD). However, insufficient response is common and it remains unclear whether specific patient-level factors influence the likelihood of treatment response. AIMS:To determine the efficacy and acceptability of SSRIs in adult OCD, and to identify patient-level modifiers of efficacy. METHODS:We conducted an individual patient data meta-analysis (IPDMA) of industry-sponsored short-term, randomised, placebo-controlled SSRI trials submitted for approval to the Dutch regulatory agency to obtain marketing approval for treating OCD in adults. We performed a two-stage meta-analysis, using crude data of available trials. The primary outcome was the difference in Yale-Brown Obsessive-Compulsive Scale (YBOCS) change between active treatment and placebo. Secondary outcomes were differences in response (defined as the odds ratio of ≥35% YBOCS point reduction) and acceptability (defined as the odds ratio for all-cause discontinuation). We examined the modifying effect of baseline characteristics: age, gender, illness severity, depressive symptoms, weight, illness duration and history of antidepressant use. RESULTS:After excluding three trials because of missing data, we analysed results from 11 trials (79% of all submitted trials, n = 2372). The trial duration ranged from 10 to 13 weeks. Mean difference of SSRIs relative to placebo was 2.65 YBOCS points (95% CI 1.85-3.46, p < 0.0001), equalling a small effect size (0.33 Hedges' g). The odds ratio for response was 2.21 in favour of active treatment (95% CI 1.72-2.83, p < 0.0001), with a number needed to treat of seven. Patient characteristics did not modify symptom change or response. Acceptability was comparable for SSRIs and placebo. CONCLUSIONS:Our IPDMA showed that SSRIs are well accepted and superior to placebo for treating OCD. The effects are modest and independent of baseline patient characteristics.

Deep brain stimulation (DBS) is being investigated as treatment for patients with refractory major depressive disorder (MDD). However, little is known about how DBS exerts its antidepressive effects. Here, we investigated whether ventral anterior limb of the internal capsule (vALIC) stimulation modulates a limbic network centered around the amygdala in patients with treatment resistant MDD. Nine patients underwent resting state functional magnetic resonance imaging (fMRI) before DBS surgery and after one year of treatment. In addition, they were scanned twice within two weeks during the subsequent double blind crossover phase with active and sham treatment. Eleven matched controls underwent fMRI scans at same time intervals to account for test-retest effects. The imaging data was investigated with functional connectivity analysis and dynamic causal modelling (DCM). Results showed that one year of DBS treatment was associated with increased functional connectivity of the left amygdala with precentral cortex and left insula along with decreased bilateral connectivity between nucleus accumbens and ventromedial prefrontal cortex. No changes in functional connectivity were observed during the crossover phase. Effective connectivity analyses using DCM revealed widespread amygdala-centric changes between pre-surgery and one year follow-up, while the crossover phase was associated with insula-centric changes between active and sham stimulation. These results suggest that vALIC DBS results in complex rebalancing of the limbic network involved in emotion, reward and interoceptive processing.

Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

Deep brain stimulation (DBS) reduces depressive symptom scores in many patients with treatment-resistant depression (TRD). However, it is unclear whether the observed improvement is similar across various symptom dimensions (e.g., anhedonia, anxiety, insomnia) or if some require additional clinical attention. Using a retrospective chart review, we assessed the trajectory of HAM-D-17 and MADRS scores during vALIC or slMFB DBS treatment within different symptom dimensions (HAM-D-17: 1) affective/anhedonia, 2) somatic/anxiety, 3) insomnia; MADRS: 1) affective/anhedonia, 2) anxiety/vegetative, 3) hopelessness) after at least a 25 ​% symptom reduction (partial response) at any time during their treatment course (n ​= ​34 for HAM-D-17, n ​= ​25 for MADRS). Results showed that each of the assessed symptom dimensions was significantly reduced compared to baseline at each of the assessed time periods (last follow-up: 2-15 years) after (partial) DBS response onset, which occurred at a median of approximately 2.5 months. Additionally, there was a significant interaction effect between symptom dimension and time period (HAM-D-17: F (12,1655.46) ​= ​5.46, p ​< ​0.001; MADRS: F (12,938.73) ​= ​2.40, p ​< ​0.01). Model coefficients indicated that insomnia symptoms (HAM-D-17) and anxiety/vegetative symptoms (MADRS) improved at a slower rate than the other symptom dimensions. Additionally, higher baseline scores in the HAM-D-17 somatic/anxiety dimension were significantly associated with a larger percentage reduction in overall symptoms after DBS (n ​= ​39, F (1,32) ​= ​12.371, p ​< ​0.01). Our findings demonstrate that DBS for TRD effectively treats depressive symptoms in all dimensions, although insomnia symptoms may improve at a slower rate, and that patients with more anxiety symptoms, who typically tend to have worse pharmacological treatment outcomes, may particularly benefit from DBS.