Gregor Gryglewski

Immune dysregulation is implicated in major depressive disorder (MDD), but its links to clinical features and in vivo brain phenotypes remain uncertain. We examined ten plasma biomarkers in 36 unmedicated MDD patients and 48 control participants using high-sensitivity immune profiling at baseline, alongside PET/MR imaging of brain serotonin transporter (SERT) binding and regional structural measures. Patients underwent three months of antidepressant treatment and were followed up with MR imaging. Glial fibrillary acidic protein (GFAP) was higher in MDD patients (β = 0.66, 95% CI 0.22 - 1.11), and interleukin-33 (IL-33) correlated with subcortical volumes across all participants (β = 0.22, 95% CI 0.07 - 0.38). No marker correlated with SERT binding or cortical thickness after correction, and neither SERT binding nor brain structural measures differed by diagnosis. In the longitudinal analysis, interleukin-13 (IL-13) was associated with greater antidepressant response during first-line treatment with escitalopram (β = 1.09, 95% CI 0.56 - 1.61). IL-15 and IL-13 showed nominal associations with hippocampal volume increase after treatment. These findings support astroglial involvement in MDD and link peripheral immune variation to subcortical brain structure. IL-13 is a candidate prognostic marker of response to selective serotonin reuptake inhibitors. Its tentative association with longitudinal changes in hippocampal volume suggests that immune processes in MDD may be related to both the capacity for clinical improvement and brain structural plasticity during treatment.

Background: Real-world data for intranasal esketamine in treatment-resistant depression (TRD) are needed to characterize effectiveness, suicidality, and tolerability in routine care. We evaluated induction phase outcomes in outpatients with TRD treated at the University Hospital Vienna. Methods: This retrospective single-center registry study included adults with TRD initiating supervised intranasal esketamine. The primary endpoint was the change in clinician-rated depressive symptom severity (MADRS) from the pre-treatment (PV) to the end of induction (EOI) visit. MADRS scores across baseline (BL), PV, and EOI were analyzed using a mixed model for repeated measures. Secondary outcomes included MADRS three-factor change, self-rated depression score trajectories (PHQ-9), response/remission rates, suicidal ideation, and tolerability. Results: Of 229 screened patients, 176 initiated esketamine and 156 completed induction. MADRS at BL was 31.5 (SD 6.4), PHQ-9 was 18.5 (SD 4.7). In the primary model, adjusted mean MADRS was 30.3 at PV and 17.7 at EOI, yielding a change of −12.5 points (95%CI −14.1 to −11.0; p < 0.001; Hedges’ g = 1.8). All MADRS factors improved, with the largest reduction in the affective–anhedonic domain. PHQ-9 decreased steadily across treatments. Remission was 27.2% and response 57.4% at EOI. Suicidal ideation decreased significantly; no suicide or serious self-harm occurred during induction. Adverse events (AEs) were recorded in 34.7%, with AE-related discontinuation in 3.4%. Conclusions: Esketamine induction was associated with marked improvement in depressive symptoms and suicidality, with acceptable tolerability under supervised administration. Longer-term registry follow-up and controlled comparative studies are needed to further define the benefit–risk profile beyond induction phase.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed antidepressants, though their mechanisms of action beyond serotonin transporter (SERT) blockade remain unclear [1]. As previous work on BOLD signal changes remain equivocal, pharmacological multimodal neuroimaging of energy demands and blood flow (CBF) holds promise due to increased specificity of these signals. This may advance the understanding of the involved pharmacodynamic mechanisms and guide treatment strategies of highly prevalent neuropsychiatric disorders. We combine new techniques of functional positron emission tomography (fPET) with high temporal resolution (3 seconds) using [ ¹⁸ F]FDG and simultaneously acquired pseudo-continuous arterial spin labelling (pcASL). Thus, we aimed for a highly quantitative assessment of changes in brain activation following an intravenous SSRI challenge using a randomized, placebo-controlled, double-blind study design. We demonstrate acute drug induced changes in glucose metabolism (K _i ) in serotonergic projections, i.e. the striatum and the occipital cortex in 16 healthy volunteers (7 females). In an exploratory analysis, acute effects were observed in the dorsal raphe nucleus. We did not observe corresponding changes in CBF, which suggests that observed SSRI effects are specific to brain energy demands. Our results complement the existing literature on the acute pharmacological effects of SSRIs by providing insights in specific aspects of neuronal activation. Moreover, our findings expand upon the results of existing BOLD fMRI studies and, thus, support the application of this pharmacological neuroimaging protocol in psychopharmacological research.

Positron emission tomography (PET) provides high-sensitivity molecular information in neuroimaging. However, its quantitative accuracy critically depends on attenuation correction (AC). Unlike PET/CT, hybrid PET/MRI systems cannot directly measure photon attenuation, necessitating alternative AC strategies. While several MRI-based AC tools exist, they often raise concerns regarding data privacy, long-term accessibility and reproducibility. We present an open-access framework for PET AC using pseudo-CT (pCT) methods. A database of 60 paired MRI-CT scans was curated and normalized to stereotactic MNI space. Three established pCT approaches (Boston, MaxProb, UCL) were adapted to enable their use with the normalized database. Method performance was assessed by comparison with a CT-based AC reference in an independent validation sample of 28 subjects, using the Jaccard index and [11C]DASB PET-derived serotonin transporter quantification as evaluation metrics. Boston and MaxProb demonstrated consistent performance across database subsets, while the UCL achieved the closest agreement with CT-derived AC and yielded the lowest quantification error (mean relative error <0.5%). This work demonstrates the feasibility of different pCT approaches using a database in MNI space thereby introducing an openly available reference database to support fast, reproducible and continued integration of MRI-based AC into PET reconstruction pipelines.

Considering the complexity of serotonergic influence on emotions, we conducted a comprehensive investigation of the interplay between emotion processing and the serotonergic system using simultaneous functional and molecular neuroimaging during pharmacological challenge while disentangling the effects of serotonin transporter (SERT) binding, genotype, and diagnosis of major depressive disorder (MDD). Herein, 153 subjects (44 with MDD) performed a facial emotion processing task during functional magnetic resonance imaging (fMRI) before and after an acute intravenous application of 8 mg citalopram or placebo. Patients with MDD were assessed again after at least three months of antidepressant treatment. Citalopram administration resulted in a reduced fMRI activation in regions involved in fear processing, including the anterior cingulate cortex (ACC), when viewing fearful faces contrasted against happy or neutral faces. ACC activation correlated negatively with striatal/thalamic SERT availability across drug conditions as measured by [11 C]DASB positron emission tomography. Across groups, citalopram-induced changes in ACC activation correlated with emotional attribution, indicating stronger reductions for subjects with higher self- versus other- attribution. Moreover, striatal SERT availability mediated the influence of the number of 5-HTTLPR/rs25531 L_A alleles on ACC activation under placebo. Patients with MDD exhibited increased activations in the intraparietal and superior frontal sulcus in response to fearful versus happy faces at baseline, and along the parieto-occipital/calcarine fissure after treatment. We interpret our findings on multiple levels of the serotonergic-emotional interaction within the context of enhanced passive coping and acute anxiolytic effects of citalopram following potential changes in serotonin or SERT availability.

Ketamine represents a significant advancement in antidepressant therapy, but the commonly used intravenous and intranasal application routes currently limit its availability beyond specialized centers. By contrast, oral ketamine treatment might constitute an alternative that is widely available, easy to administer, and has potential advantages with regard to tolerability. Forty-five patients diagnosed with a moderate to severe depressive episode received either 1mg/kg peroral ketamine or 0.03mg/kg midazolam solution as an active comparator, administered six times over two weeks in a double-blind trial. While statistical significance for the primary endpoint of MADRS score reduction after one week was not achieved, response rates favored ketamine with a number needed to treat (NNT) of 4.6 (95%-CI: [2.4, 62.6] at this timepoint. Treatment was well-tolerated, with no serious adverse events reported, potentially due to the lower exposure to ketamine compared to its metabolite norketamine measured in plasma. In a total of 592 patients, meta-analysis of randomized controlled trials on oral ketamine treatment demonstrated its antidepressant efficacy with a NNT = 4.89 (95%-CI: [3.41, 8.66]) for response and a NNT = 9.10 (95%-CI: [5.43, 28.03]) for remission. Despite that the current trial did not meet its primary endpoint, the cumulative evidence up-to-date suggests that oral ketamine treatment leads to relevant improvements in the outcomes of patients with depression. In light of the ease of administration and high tolerability with oral application, this evidence may contribute to removing some of the obstacles that currently restrict the availability of antidepressant treatment with ketamine to specialized centers.

With their ability to cross the blood-brain barrier, transport and regulate the release of various signaling molecules, extracellular vesicles (EVs) constitute a novel avenue to study intercellular communication in various pathologies, including psychiatric disorders. We studied 34 major depressive disorder (MDD) patients and 57 healthy controls and characterized EVs isolated from plasma using digital holographic tomography (DHT) and nanoparticle tracking analysis (NTA). EVs detected in DHT were markedly smaller and less variable in size in MDD patients. Furthermore, a lower variance of refractive indices related to the dry mass density of EVs was observed in patients. Meanwhile, NTA revealed a trend for elevated concentration of EVs in MDD. In DHT, EV dimensions correlated with plasma mRNA expression of exosomal markers CD63 and CD9 , with corresponding alterations in MDD. Levels of EV concentration and CD9 were both negatively correlated with antidepressant treatment response. Utilizing electron microscopy and immunoblots we confirmed the presence of serotonin transporters (SERT) as EV cargo. SERT levels in EVs correlated with cerebral SERT binding potential in the amygdala measured using positron emission tomography. Next to the implication of altered EV communication in mood disorders, the pronounced differences in plasma EV characteristics and exosomal markers in MDD might inform the development of assays with diagnostic or prognostic value for clinical practice.