Patients with posttraumatic stress disorder (PTSD) exhibit smaller regional brain volumes in commonly reported regions including the amygdala and hippocampus, regions associated with fear and memory processing. In the current study, we have conducted a voxel-based morphometry (VBM) meta-analysis using whole-brain statistical maps with neuroimaging data from the ENIGMA-PGC PTSD working group.

T1-weighted structural neuroimaging scans from 36 cohorts (PTSD n = 1309; controls n = 2198) were processed using a standardized VBM pipeline (ENIGMA-VBM tool). We meta-analyzed the resulting statistical maps for voxel-wise differences in gray matter (GM) and white matter (WM) volumes between PTSD patients and controls, performed subgroup analyses considering the trauma exposure of the controls, and examined associations between regional brain volumes and clinical variables including PTSD (CAPS-4/5, PCL-5) and depression severity (BDI-II, PHQ-9).

PTSD patients exhibited smaller GM volumes across the frontal and temporal lobes, and cerebellum, with the most significant effect in the left cerebellum (Hedges’ g = 0.22, pcorrected = .001), and smaller cerebellar WM volume (peak Hedges’ g = 0.14, pcorrected = .008). We observed similar regional differences when comparing patients to trauma-exposed controls, suggesting these structural abnormalities may be specific to PTSD. Regression analyses revealed PTSD severity was negatively associated with GM volumes within the cerebellum (pcorrected = .003), while depression severity was negatively associated with GM volumes within the cerebellum and superior frontal gyrus in patients (pcorrected = .001).

PTSD patients exhibited widespread, regional differences in brain volumes where greater regional deficits appeared to reflect more severe symptoms. Our findings add to the growing literature implicating the cerebellum in PTSD psychopathology.

In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety.

A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites.

We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites.

The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

To determine the association between blood markers of white matter injury (e.g., serum neurofilament light and phosphorylated neurofilament heavy) and a novel neuroimaging technique measuring microstructural white matter changes (e.g., diffusion kurtosis imaging) in regions (e.g., anterior thalamic radiation and uncinate fasciculus) known to be impacted in traumatic brain injury (TBI) and associated with symptoms common in those with chronic TBI (e.g., sleep disruption, cognitive and emotional disinhibition) in a heterogeneous sample of Veterans and non-Veterans with a history of remote TBI (i.e., >6 months).

Participants with complete imaging and blood data (N=24) were sampled from a larger multisite study of chronic mild-moderate TBI. Participants ranged in age from young to middle-aged (mean age = 34.17, SD age = 10.96, range = 19-58) and primarily male (66.7%). The number of distinct TBIs ranged from 1-5 and the time since most recent TBI ranged from 0-30 years. Scores on a cognitive screener (MoCA) ranged from 22-30 (mean = 26.75). We performed bivariate correlations with mean kurtosis (MK) in the anterior thalamic radiation (ATR; left, right) uncinate fasciculus (UF; left, right), and serum neurofilament light (NFL), and phosphorylated neurofilament heavy (pNFH). Both were log transformed for non-normality. Significance threshold was set at p<0.05.

pNFH was significantly and negatively correlated to MK in the right (r=-0.446) and left (r=-0.599) UF and right (r=-0.531) and left (r=-0.469) ATR. NFL showed moderate associations with MK in the right (r=-0.345) and left (r=-0.361) UF and little to small association in the right (r=-0.063) and left (r=-0.215) ATR. In post-hoc analyses, MK in both the left (r=0.434) and right (r=0.514) UF was positively associated with performance on a frontally-mediated list-learning task (California Verbal Learning Test, 2nd Edition; Trials 1-5 total).

Results suggest that serum pNFH may be a more sensitive blood marker of microstructural complexity in white matter regions frequently impacted by TBI in a chronic mild-moderate TBI sample. Further, it suggests that even years after a mild-moderate TBI, levels of pNFH may be informative regarding white matter integrity in regions related to executive functioning and emotional disinhibition, both of which are common presenting problems when these patients are seen in a clinical setting.

To determine the association between in-vivo spectroscopy metabolite data, the local connectome, and markers of initial injury severity (I.e., history of loss of consciousness; LoC) in traumatic brain injury (TBI), in a heterogenous sample of Veterans and non-Veterans with a history of remote mild-to-moderate TBI (I.e., >6 months).

Participants with complete PRESS magnetic resonance spectroscopy (MRS) and diffusion weighted imaging (DWI) data (N = 41) were sampled from a larger multisite study of chronic mild-to-moderate TBI (Nmiid = 38; Nmoderate = 3; 54% with LoC; 46% with multiple TBI). The sample was predominantly male (76%) with ages ranging from 23-59 (M = 36.9, SD = 10.1), with 98% holding at least a high school degree (M = 14.5 years of education, SD = 2.4). Fully tissue-and-relaxation-corrected metabolite concentration estimates in the dorsal anterior cingulate (30x30x30mm voxel) were modeled using Osprey 2.4.0. Total creatine (tCr), total choline (tCho), total N-acetylaspartate (tNAA), glutamate/glutamine (Glx), and myo-inositol (mI) were analyzed. Logistic regression was used to measure the association between metabolites and history of TBI with LoC. Correlational connectometry using the normalized spin distribution function was performed for metabolites associated with LoC, to characterize the local connectome associated with metabolites of interest, controlling for age and sex, and correcting for multiple comparisons (FDR < .050 with 4000 permutations). A profile approach was used to interpret diffusion metrics, contrasting quantitative anisotropy (QA) with fractional anisotropy (FA). Local connectome tracks were then clustered to identify the larger white matter tract.

Glx (p = .008) and tCr (p = .032) were significantly associated with history of TBI with LoC. Increased Glx was associated with increased QA in 11,001 tracks, accounting for 1.4% of the total white matter tracks in the brain. 90% of tracks were identified in bilateral cingulum (33%), bilateral thalamic (13%), bilateral corticospinal (13%), corpus callosum (12%), left arcuate fasciculus (9%), left frontoparietal aslant tracts (6%), and bilateral inferior fronto-occipital fasciculus (4%) tracts. In contrast, FA was not associated with Glx. The same pattern emerged for tCr, with 10,542 tracks identified predominantly in bilateral cingulum (29%), corpus callosum (21%), bilateral corticospinal (15%), bilateral corticostriatal (7%), bilateral medial lemniscus (7%), left cortico-pontine (3%), left thalamic (2%), and bilateral superior longitudinal fasciculus (2%) tracts. Post-hoc exploratory analyses of mean QA across regions of cingulum found that increased QA was associated with self-report measures of headache intensity, fatigue, and perceived change in executive functioning.

Results provided evidence that multimodal imaging can identify subtle markers of initial TBI severity years after injury. Neurometabolite concentrations were associated with diffuse changes in the local connectome; the pattern of discrepancy between FA and QA was suggestive of reduced potential for neuroplasticity. Exploratory analyses further indicated that variability in white matter density in the cingulum, an important connection for limbic regions, was associated with a range of problems commonly reported in clinical settings, which may be informative for diagnosis and treatment planning.

Insecure attachment styles are associated with retrospectively reported suicide attempts (SAs). It is not known if attachment styles are prospectively associated with medically documented SAs.

A representative sample of US Army soldiers entering service (n = 21 772) was surveyed and followed via administrative records for their first 48 months of service. Attachment style (secure, preoccupied, fearful, dismissing) was assessed at baseline. Administrative medical records identified SAs. Discrete-time survival analysis examined associations of attachment style with future SA during service, adjusting for time in service, socio-demographics, service-related variables, and mental health diagnosis (MH-Dx). We examined whether associations of attachment style with SA differed based on sex and MH-Dx.

In total, 253 respondents attempted suicide. Endorsed attachment styles included secure (46.8%), preoccupied (9.1%), fearful (15.7%), and dismissing (19.2%). Examined separately, insecure attachment styles were associated with increased odds of SA: preoccupied [OR 2.5 (95% CI 1.7–3.4)], fearful [OR 1.6 (95% CI 1.1–2.3)], dismissing [OR 1.8 (95% CI 1.3–2.6)]. Examining attachment styles simultaneously along with other covariates, preoccupied [OR 1.9 (95% CI 1.4–2.7)] and dismissing [OR 1.7 (95% CI 1.2–2.4)] remained significant. The dismissing attachment and MH-Dx interaction was significant. In stratified analyses, dismissing attachment was associated with SA only among soldiers without MH-Dx. Other interactions were non-significant. Soldiers endorsing any insecure attachment style had elevated SA risk across the first 48 months in service, particularly during the first 12 months.

Insecure attachment styles, particularly preoccupied and dismissing, are associated with increased future SA risk among soldiers. Elevated risk is most substantial during first year of service but persists through the first 48 months. Dismissing attachment may indicate risk specifically among soldiers not identified by the mental healthcare system.

Despite replicated cross-sectional evidence of aberrant levels of peripheral inflammatory markers in individuals with major depressive disorder (MDD), there is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies.

To assess associations between plasma levels of pro-inflammatory markers and treatment response to escitalopram and adjunctive aripiprazole in adults with MDD.

In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10– 20 mg daily for 8 weeks. Responders continued on escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers – C-reactive protein, Interleukin (IL)-1β, IL-6, IL-17, Interferon gamma (IFN)-Γ, Tumour Necrosis Factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2) - measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyses to assess associations between inflammatory markers and treatment response.

Pre-treatment levels of IFN-Γ and CCL-2 were significantly higher in escitalopram non-responders compared to responders. Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.

Pre-treatment levels of IFN-Γ and CCL-2 were predictive of response to escitalopram. Increasing levels of these pro-inflammatory markers may predict non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.

None Declared

Bipolar disorder (BD) is a source of marked disability, morbidity, and premature death. There is a paucity of research on personalized psychosocial interventions for BD, especially in lowresource settings. A previously published pilot randomized controlled trial (RCT) of a Culturally adapted PsychoEducation (CaPE) intervention for BD in Pakistan reported higher patient satisfaction, enhanced medication adherence, knowledge and attitudes towards BD, and improvement in mood symptom scores and health-related quality of life measures compared to treatment-as-usual (TAU).

This protocol describes a larger multicentre RCT to confirm the clinical and cost-effectiveness of CaPE in Pakistan.

A multicentre individual, parallel arm, RCT of CaPE in 300Pakistani adults with BD. Participants over the age of 18, with adiagnosis of bipolar I and II and who are currently euthymic, will berecruited from seven sites including Karachi, Lahore, Multan, Rawalpindi,Peshawar, Hyderabad and Quetta. Time to recurrence will be the primaryoutcome assessed using Longitudinal Interval Follow-up Evaluation(LIFE). Secondary measures will include mood symptomatology, qualityof life and functioning, adherence to psychotropic medications, andknowledge and attitudes towards BD.

Full ethics approval has been received from National Bioethics Committee (NBC) of Pakistan and Centre for Addiction and Mental Health (CAMH), Toronto, Canada. The study has completed sixty-five screening across the seven centres, of which forty-eight participants have been randomised.

A successful trial will lead to rapid implementation of CaPE in clinical practice, not only in Pakistan, but also in other low-resource settings including those in high-income countries, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority patients with BD.

None Declared

Major Depressive Disorder (MDD) is one of the most common mental illnesses worldwide and is strongly associated with suicidality. Commonly used treatments for MDD with suicidality include crisis intervention, oral antidepressants (although risk of suicidal behavior is high among non-responders and during the first 10-14 days of the treatment) benzodiazepines and lithium. Although several interventions addressing suicidality exist, only few studies have characterized in detail patients with MDD and suicidality, including treatment, clinical course and outcomes. Patient Characteristics, Validity of Clinical Diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D)-study is an investigator-initiated trial funded by Janssen-Cilag GmbH.

For population 1 out of 3 OASIS-D populations, to assess the sub-population of patients with suicidality and its correlates in hospitalized individuals with MDD.

The ongoing OASIS-D study consecutively examines hospitalized patients at 8 German psychiatric university hospitals treated as part of routine clinical care. A sub-group of patients with persistent suicidality after >48 hours post-hospitalization are assessed in detail and a sub-group of those are followed for 6 months to assess course and treatment of suicidality associated with MDD. The present analysis focuses on a preplanned interim analysis of the overall hospitalized population with MDD.

Of 2,049 inpatients (age=42.5±15.9 years, females=53.2%), 68.0% had severe MDD without psychosis and 21.2% had moderately severe MDD, with 16.7% having treatment-resistant MDD. Most inpatients referred themselves (49.4%), followed by referrals by outpatient care providers (14.6%), inpatient care providers (9.0%), family/friends (8.5%), and ambulance (6.8%). Of these admissions, 43.1% represented a psychiatric emergency, with suicidality being the reason in 35.9%. Altogether, 72.4% had at least current passive suicidal ideation (SI, lifetime=87.2%), including passive SI (25.1%), active SI without plan (15.5%), active SI with plan (14.2%), and active SI with plan+intent (14.1%), while 11.5% had attempted suicide ≤2 weeks before admission (lifetime=28.7%). Drug-induced mental and behavioral disorders (19.6%) were the most frequent comorbid disorders, followed by personality disorders (8.2%). Upon admission, 64.5% were receiving psychiatric medications, including antidepressants (46.7%), second-generation antipsychotics (23.0%), anxiolytics (11.4%) antiepileptics (6.0%), and lithium (2.8%). Altogether, 9.8% reported nonadherence to medications within 6 months of admission.

In adults admitted for MDD, suicidality was common, representing a psychiatric emergency in 35.9% of patients. Usual-care treatments and outcomes of suicidality in hospitalized adults with MDD require further study.

None Declared

Olanzapine (OLA) is a common first-prescribed antipsychotic and has shown favorable efficacy in acutely exacerbated patients with schizophrenia. The mixed receptor activity of OLA and its greater affinity for serotonin 5-HT2A rather than dopamine D2 receptors are similar to those of clozapine. Pharmacokinetically, OLA is metabolized mainly by hepatic cytochrome enzyme P450 1A2 (CYP1A2). Because risks of antipsychotic polypharmacy include increased drug-drug interactions, pharmacokinetic considerations are important for selection of antipsychotics to be combined. Due to its pharmacological characteristics, amisulpride (AMI), another atypical antipsychotic with proven efficacy, is a promising adjuvant agent of special interest. AMI is unlikely to interact with other drugs due to the low plasma protein binding and metabolism and does not affect the activity of the CYP system. Furthermore, AMI is highly selective for dopamine D2/D3 receptors; has minimal or no affinity for D1, D4, or D5 receptors. Despite the potential benefits of the combination of OLA and AMI, only a few open-label studies have been conducted, and no randomized clinical trial has been performed to date to examine the efficacy and tolerability of the combination. Hence, the goals of this study were to test the hypothesis that AMI augmentation would improve psychotic symptoms and be well tolerated in schizophrenic patients who showed poor response to OLA monotherapy.

The purpose of this study was to compare the efficacy and tolerability of continued olanzapine (OLA) versus amisulpride (AMI) augmentation in schizophrenic patients with poor response to OLA monotherapy.

The present 4-week, randomized, rater-blinded study included 25 patients with schizophrenia who were partially or completely unresponsive to treatment with OLA monotherapy. Eligible subjects were randomly assigned at a 1:1 ratio to continuation of OLA monotherapy (OLA group) or OLA with AMI augmentation (AMI group). Efficacy was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS) at baseline and at 1, 2, and 4 weeks.

The changes in PANSS total score and PANSS-positive subscale score were significantly different (p < 0.05) between the OLA and AMI groups. The differences between the two groups in PANSS-negative subscale, PANSS-general subscale, Brief Psychiatric Rating Scale, and Clinical Global Impression-Severity (CGI-S) scale scores were not statistically significant.

AMI augmentation could be an effective strategy for patients with schizophrenia who show inadequate early response to OLA monotherapy.

W.-M. Bahk Grant / Research support from: Handok Pharmaceuticals, Seoul, Korea, Y. S. Woo: None Declared, S.-Y. Park: None Declared, B.-H. Yoon: None Declared, S.-M. Wang: None Declared, M.-D. Kim: None Declared