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Unsupervised neurobiology-driven stratification of clinical heterogeneity in depression
- F. Colombo, F. Calesella, B. Bravi, L. Fortaner-Uyà, C. Monopoli, E. Maggioni, E. Tassi, R. Zanardi, F. Attanasio, I. Bollettini, S. Poletti, F. Benedetti, B. Vai
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S614
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Introduction
One of the main obstacles in providing effective treatments for major depressive disorder (MDD) is clinical heterogeneity, whose neurobiological correlates are not clearly defined. A biologically meaningful stratification of depressed patients is needed to promote tailored diagnostic procedures.
ObjectivesUsing structural data, we performed an unsupervised clustering to define clinically meaningful clusters of depressed patients.
MethodsT1-weighted and diffusion tensor images were obtained from 102 MDD patients. In 64 patients, clinical symptoms, number of stressful life events, severity and exposure to adverse childhood experiences were evaluated using the Beck Depression Inventory (BDI), Schedule of Recent Experiences (SRE), Risky Family Questionnaire (RFQ), and Childhood Trauma Questionnaire (CTQ). Clustering analyses were performed with extracted tract-based fractional anisotropy (TBSS, FSL), cortical thickness, surface area, and regional measures of grey matter volumes (CAT12). Gaussian mixture model was implemented for clustering, considering Support Vector Machine (SVM) as classifier. A 10x2 repeated cross-validation with grid search was performed for hyperparameters tuning and clusters’ stability. The optimal number of clusters was determined by normalized stability, Akaike and Bayesian information criterion. Analyses were adjusted for total intracranial volume, age, and sex. The clinical relevance of the identified clusters was assessed through MANOVA, considering domains of clinical scales as dependent variables and clusters’ labels as fixed factors. Discriminant analysis was subsequently performed to assess the discriminative power of these variables.
ResultsCross-validated clustering approach identified 2 highly stable clusters (normalized stability=0.316, AIC=-80292.48, BIC=351329.16). MANOVA showed a significant between-clusters difference in clinical scales scores (p=0.038). Discriminant analysis distinguished the two clusters with an accuracy of 78.1%, with BDI behavioural and CTQ minimisation/denial domains showing the highest discriminant values (0.325 and 0.313).
ConclusionsOur results defined two biologically informed clusters of MDD patients associated with childhood trauma and specific clinical profiles, which may assist in targeting effective interventions and treatments.
Disclosure of InterestNone Declared
Structural neuroimaging differentiates between depressed bipolar disorder and major depressive disorder patients: a machine learning study
- F. Calesella, F. Colombo, B. Bravi, L. Fortaner-Uyà, C. Monopoli, E. Tassi, E. Maggioni, I. Bollettini, S. Poletti, F. Benedetti, B. Vai
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S614-S615
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Introduction
Depression is the predominant mood alteration in bipolar disorder (BD), leading to overlapping symptomatology with major depressive disorder (MDD). Consequently, in clinical assessment, almost 60% of BD patients are misdiagnosed as affected by MDD. This calls for the creation of a framework for the differentiation of BD and MDD patients based on reliable biomarkers. Since machine learning (ML) enables to make predictions at the single-subject level, it appears to be particularly suitable for this task.
ObjectivesWe implemented a ML pipeline for the differentiation between depressed BD and MDD patients based on structural neuroimaging features.
MethodsDiffusion tensor imaging (DTI) and T1-weighted magnetic resonance imaging (MRI) data were acquired for 282 depressed BD (n=180) and MDD (n=102) patients. Axial (AD), radial (RD), mean (MD) diffusivity, and fractional anisotropy (FA) maps were extracted from DTI images, and voxel-based morphometry (VBM) measures were obtained from T1-weighted images. Each feature was entered separately into a 5-fold nested cross-validated ML pipeline differentiating between BD and MDD patients, comprising: confound regression for nuisance variables removal (i.e., age and sex), feature standardization, principal component analysis, and an elastic-net penalized regression. The models underwent 5000 random permutations as a test for significance, and the McNemar’s test was used to assess whether there was any significant difference between the models (significance threshold was set to p<0.05).
ResultsThe performance of the models and the results of the permutation tests are summarized in Table 1. McNemar’s test showed that the AD-, RD-, MD-, and FA-based models did not differ between each other and were significantly different from the VBM.
Table 1. Models’ performance and p-value at 5000 permutation test. Feature Overall accuracy MDD specifictiy BD sensitivity p-value VBM 0.61 0.38 0.74 0.058 AD 0.78 0.65 0.86 <0.001 FA 0.79 0.61 0.89 <0.001 MD 0.79 0.63 0.88 <0.001 RD 0.79 0.63 0.88 <0.001 ConclusionsIn conclusion, our models differentiated between BD and MDD patients at the single-subject level with good accuracy using structural MRI data. Notably, the models based on white matter integrity measures relying on true information, rather than chance.
Disclosure of InterestNone Declared
Resting State Functional Connectivity is Associated With Treatment Response in Major Depression: A Real World Study
- Y. Harrington, M. Paolini, V. Bettonagli, F. Colombo, S. Poletti, R. Zanardi, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S606-S607
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Introduction
Major depressive disorder (MDD) is largely considered the most prevalent psychiatric disorder worldwide. Despite its domineering presence, effective treatment for many individuals remains elusive. Investigation into relevant biological markers, specifically neuroimaging correlates, of MDD and treatment response have gained traction in recent years; however, findings are still inconsistent.
ObjectivesIn this study, we aimed to investigate the resting state functional connectivity patterns associated with treatment response in MDD inpatients in a real world setting.
MethodsForty-three inpatients suffering from a major depressive episode were recruited from the psychiatric ward at IRCCS San Raffaele Hospital in Milan, Italy. Symptom severity was assessed via the 21-item Hamilton Depression Rating Scale (HDRS). The percentage of decrease in HDRS scores from admission to discharge was then calculated with the formula [(HDRS admission – HDRS discharge) * 100] / HDRS admission. All patients underwent a 3T MRI scan within one week of admission to acquire resting-state fMRI images, which included 200 sequential T2*-weighted volumes. Images were preprocessed using the CONN toolbox, running within Statistical Parametric Mapping (SPM 12). Preprocessing was performed according to a standard pipeline. A voxel-wise metric, intrinsic connectivity contrast (ICC), was implemented to explore the global resting state functional connectivity (rs-FC) patterns associated with treatment response. ICC-derived maps were then entered in the second-level analyses to examine the effect of the percentage of HDRS decrease, including age, sex, admission HDRS score, duration of hospitalization, and antidepressant dose equivalents as nuisance covariates.
ResultsWe found that the percentage of HDRS decrease after treatment predicted rs-FC. ICC analysis identified 2 clusters where changes in HDRS scores were significantly associated with rs-FC, with increased connectivity in the supramarginal gyrus (pFDR = 0.002) and decreased connectivity in the amygdala and parahippocampal gyrus (pFDR = 0.047).
ConclusionsOur results suggest that altered connectivity of the supramarginal gyrus, amygdala and parahippocampal gyrus is related to antidepressant treatment response. Given that these brain areas are implicated in emotional processing and mood, it is conceivable that a better integrity of brain connectivity may facilitate treatment response in major depression.
Disclosure of InterestNone Declared
Inflammatory signature of post-COVID-19 depression
- M. Palladini, M. G. Mazza, V. Aggio, S. Spadini, F. Calesella, S. Poletti, P. Rovere-Querini, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S123-S124
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Introduction
Persisting and disabling depressive symptomatology represent a prominent feature of the post-acute COVID-19 syndrome. Sars-CoV-2-induced immune system dysregulation mainly result in a cytokine storm. Once in the brain, inflammatory mediators negatively affect neurotransmission, microglia activation, and oxidative stress, possibly disrupting critical brain neurocircuits which underpin depressive symptoms. So far, only inflammatory markers based on leukocyte counts have been linked to depressive outcome in COVID survivors. However, an accurate immune profile of post-COVID depression has yet to be elucidated.
ObjectivesIdentify inflammatory mediators that predict post-COVID depression among a panel of cytokines, chemokines, and growth factors, with a machine learning routine.
Methods88 COVID age- and sex-matched survivors’ (age 52.01 ± 9.32) were screened for depressive symptomatology one month after the virus clearance through the Beck Depression Inventory (BDI-13), with 12.5% of the individuals scoring in the clinical range (BDI-13 ≥ 9). Immune assay was performed through Luminex system on blood sampling obtained in the same context. We entered 42 analytes into an elastic net penalized regression model predicting presence of clinical depression, applied within a 5-fold nested cross-validation machine learning routine running in MATLAB. Significance of predictors was evaluated according to variable inclusion probability (VIP), as returned by 5000 bootstraps. Socio-demographics, previous psychiatric history, hospitalization, time after discharge were used as covariates.
ResultsThe model reached a balance accuracy of 73% and AUC of 77%, correctly identifying 73% of people suffering from clinically relevant depressive symptoms (Figure1). Depressive symptomatology was predicted by high levels of CCL17, ICAM-1, MIF, whereas CXCL13, CXCL12, CXCL10, CXCL5, CXCL2, CCL23, CCL15, CCL8, GM-CSF showed a protective effect (Figure2).
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ConclusionsThis is the first study highlighting a putative inflammatory signature of post-COVID depression. Consistently to the immune profile of Major Depressive disorder, upregulation of innate immunity mediators seems to foster depressive symptoms in the aftermath of COVID. Interestingly, recruiters of B and T cells promoting a physiological adaptive response to viral infection also mitigate its psychiatric sequelae. Understanding the biological basis of post-COVID depression could pave the way for personalized treatments capable of reducing its add-on burden.
Disclosure of InterestNone Declared
Identifying a predictive model of cognitive impairment in bipolar disorder patients: a machine learning study
- C. Monopoli, L. Fortaner-Uyà, F. Calesella, F. Colombo, B. Bravi, E. Maggioni, E. Tassi, I. Bollettini, S. Poletti, F. Benedetti, B. Vai
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S612
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Introduction
Bipolar patients (BP) frequently have cognitive deficits, that impact on prognosis and quality of life. Finding biomarkers for this condition is essential to improve patients’ healthcare. Given the association between cognitive dysfunctions and structural brain abnormalities, we used a machine learning approach to identify patients with cognitive deficits.
ObjectivesThe aim of this study was to assess if structural neuroimaging data could identify patients with cognitive impairments in several domains using a machine learning framework.
MethodsDiffusion tensor imaging and T1-weighted images of 150 BP were acquired and both grey matter voxel-based morphometry (VBM) and tract-based white matter fractional anisotropy (FA) measures were extracted. Support vector machine (SVM) models were trained through a 10-fold nested cross-validation with subsampling. VBM and FA maps were entered separately and in combination as input features to discriminate BP with and without deficits in six cognitive domains, assessed through the Brief Assessment of Cognition in Schizophrenia.
ResultsThe best classification performance for each cognitive domain is illustrated in Table 1. FA was the most relevant neuroimaging modality for the prediction of verbal memory, verbal fluency, and executive functions deficits, whereas VBM was more predictive for working memory and motor speed domains.
Table 1. Performance of best classification models. Input feature Balance Accuracy (%) Specificity (%) Sensitivity (%) Verbal Memory FA 60.17 51.31 43 Verbal Fluency FA 57.67 62 53.33 Executive functions FA 60 63.33 56.67 Working Memory VBM 56.50 56 57 Motor speed VBM 53.50 47.67 59.33 Attention and processing speed VBM + FA 58.33 49.17 67.5 ConclusionsOverall, the tested SVM models showed a good predictive performance. Although only partially, our results suggest that different structural neuroimaging data can predict cognitive deficits in BP with accuracy higher than chance level. Unexpectedly, only for the attention and processing speed domain the best model was obtained combining the structural features. Future research may promote data fusion methods to develop better predictive models.
Disclosure of InterestNone Declared
Brain correlates of perceived cognitive impairment after covid-19 infection: a multimodal MRI study.
- V. Bettonagli, M. Paolini, M. Palladini, M. G. Mazza, P. Rovere Guerini, S. Poletti, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S120
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Introduction
Many different long-term neuropsychiatric sequelae of the novel Coronavirus have been described after the pandemic outbreak. One of the most common symptoms in the months following infection is related to “brain fog”. This condition includes several signs of cognitive impairment like mental slowness, deficits in attention, executive functions, processing, memory, learning, and/or psychomotor coordination, which can be perceived on a subjective level and further confirmed by objective data. Since this kind of mental status has been documented in previous viral infections, and the SARS-COV-2 has been characterized by a worldwide diffusion, investigation into this condition in post-covid individuals is warranted. Currently, several hypotheses on its pathophysiology have been put forward, mostly hypothesizing a direct effect of the virus on the central nervous system or indirect consequences of the inflammatory response.
ObjectivesThe aim of our research is to analyze brain correlates of subjective cognitive complaints in Covid-19 survivors using multimodal brain imaging.
MethodsWe performed a voxel-based morphometry (VBM) and a resting state functional connectivity analysis on 60 post-COVID-19 individuals recruited from the San Raffaele Hospital in Milan, that underwent a 3 tesla MRI scan. We assessed the perceived cognitive impairment both after the infection and at the time of the MRI scan through the PROMIS Cognitive Abilities scale. The difference of the two scores (delta PROMIS) was calculated as a measure of cognitive improvement over time.
ResultsWe found the perceived amelioration of cognitive abilities (delta PROMIS) to be positively associated to grey matter volumes in the bilateral caudate, putamen and pallidum (pFWE: ˂0.001). Moreover, in the resting state fMRI analysis, subjective cognitive status at MRI was found to be associated with functional connectivity between the right putamen and pallidum, and two clusters belonging to the attentional (pFWE: ˂0.001) and salience (pFWE: 0.02) networks.
ConclusionsThis is one of the first studies investigating brain correlates of subjective cognitive impairment after COVID-19 infection; our main finding is the convergence of structural and functional results on brain areas located within the basal ganglia, implying their possible role in the pathophysiology of the condition. Moreover, this research could be interpreted as the first step toward understanding a very complex condition, with potential implications for the development of treatment and neurorehabilitative strategies.
Disclosure of InterestNone Declared
Choroid plexus volume as a proxy of neuroinflammation in depression
- B. Bravi, E. Melloni, L. Servidio, E. Agnoletto, M. Paolini, S. Poletti, C. Lorenzi, C. Colombo, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S244-S245
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Introduction
Choroid plexus (CP) is a physiological barrier, producing cerebrospinal fluid (CSF), neurotrophic, and inflammatory factors. It’s also involved in the neuro-immune axis, facilitating the interplay between central and peripheral inflammation, allowing trafficking of immune cells. Coherently, CP enlargement has been found in psychiatric diseases characterized by inflammatory signature. Although CP volume correlates with central microglia activation in major depressive disorder (MDD), it’s never been directly associated with peripheral markers in mood disorders.
ObjectivesExamine CP volume in mood disorders and healthy controls (HC) in relation to clinical features and peripheral inflammatory markers.
MethodsCP volume was extracted with FreeSurfer in 72 HC and 152 age- and sex-matched depressed patients: 79 BD and 73 MDD. Plasma analytes in patients were collected through immunoassay technology (Bioplex). We tested for the effect of age by group on CP volume. Then we focused on the interaction between illness duration and diagnosis in predicting CP volume. After testing the effect of specific analytes by diagnosis, we calculated moderated moderation models (SPSS, PROCESS) setting each analyte as independent variable, CP volume as predicted variable and illness duration and diagnosis as moderators. We get the effects’ significance with the likelihood ratio statistic, always controlling for age, sex, and intracranial volume.
ResultsPatients were comparable in illness duration and severity. CP volume is differentially distributed through groups (right: p=0.04; left: p<0.01), with higher volumes in the clinical groups. Age by group significantly predict right CP volume (p=0.01). Also, duration of illness differently predicts right CP volume in MDD and BD (p=0.03) (Figure1). Then, given the significant interaction effect of IL13 (p=0.02) and IL1ra (p=0.01) in predicting right CP, we run the moderated moderation model. Longer illness duration has an effect in strengthening the opposite predicting value of IL1ra (ΔR2=0.03, p<0.01) on right CP volume in MDD and BD (Figure2).
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ConclusionsOur findings propose CP as a proxy of inflammation in depression, being significantly predicted by peripheral immune markers in MDD and BD. In particular, the signature of inflammation in depression, could represent the neurotoxic load of the disease over the illness, with a worse effect in BD, with possible disruption of brain barriers permeability and an opposite effect of tightening and central segregation in MDD. Further analyses are needed to better elucidate this neurobiological mechanisms across mood disorders.
Disclosure of InterestNone Declared
Predicting Suicide Attempts among Major Depressive Disorder Patients with Structural Neuroimaging: A Machine Learning Approach
- L. Fortaner-Uyà, C. Monopoli, F. Calesella, F. Colombo, B. Bravi, E. Maggioni, E. Tassi, S. Poletti, I. Bollettini, F. Benedetti, B. Vai
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S1111-S1112
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Introduction
Every year at least one million people die by suicide, with major depressive disorder (MDD) being one of the major causes of suicide deaths. Current suicide risk assessments rely on subjective information, are time consuming, low predictive, and poorly reliable. Thus, finding objective biomarkers of suicidality is crucial to move clinical practice towards a precision psychiatry framework, enhancing suicide risk detection and prevention for MDD.
ObjectivesThe present study aimed at applying machine learning (ML) algorithms on both grey matter and white-matter voxel-wise data to discriminate MDD suicide attempters (SA) from non-attempters (nSA).
Methods91 currently depressed MDD patients (24 SA, 67 nSA) underwent a structural MRI session. T1-weighted images and diffusion tensor imaging scans were respectively pre-processed using Computational Atlas Toolbox 12 (CAT12) and spatial tract-based statistics (TBSS) on FSL, to obtain both voxel-based morphometry (VBM) and fractional anisotropy (FA) measures. Three classification models were built, entering whole-brain VBM and FA maps alone into a Support Vector Machine (SVM) and combining both modalities into a Multiple Kernel Learning (MKL) algorithm. All models were trained through a 5-fold nested cross-validation with subsampling to calculate reliable estimates of balanced accuracy, specificity, sensitivity, and area under the receiver operator curve (AUC).
ResultsModels’ performances are summarized in Table 1.
Table 1. Models’ performances.
Input features Algorithm Specificity Sensitivity Balanced accuracy AUC VBM SVM 55.00% 50.00% 52.50% 0.55 FA SVM 72.00% 54.00% 63.00% 0.62 VBM and FA MKL 68.00% 54.00% 61.00% 0.58 Abbreviations: AUC, area under the receiver operator curve; FA, fractional anisotropy; VBM, voxel-based morphometry.
ConclusionsOverall, although overcoming the random classification accuracy (i.e., 50%), performances of all models classifying SA and nSA MDD patients were moderate, possibly due to the imbalanced numerosity of classes, with SVM on FA reaching the highest accuracy. Thus, future studies may enlarge the sample and add different features (e.g., functional neuroimaging data) to develop an objective and reliable predictive model to assess and hence prevent suicide risk among MDD patients.
Disclosure of InterestNone Declared
The different effect of adverse childhood experiences on Theory of Mind brain networks in schizophrenia and healthy controls
- A. Pelucchi, F. Calesella, M. Bechi, R. Cavallaro, S. Poletti, B. Vai, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S373-S374
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Introduction
Deficit in Theory of Mind (ToM) is a core feature of schizophrenia (SZ), while adverse childhood experiences (ACEs) can contribute to worsen ToM abilities through their effect on brain functioning, structure and connectivity.
ObjectivesHere, we investigated the effects of ACEs on brain functional connectivity (FC) during an affective and cognitive ToM task (AToM, CToM) in healthy control (HC) and SZ, and whether FC can predict the performance at the ToM task and patients’ symptoms severity.
MethodsThe sample included 26 HC and 33 SZ. In an fMRI session, participants performed a ToM task targeting affective and cognitive domains. Whole-brain FC patterns of local correlation (LC) and multivariate pattern analysis (MVPA) were extracted. The significant MVPA clusters were used as seeds in further seed-based connectivity analyses. Second-level analyses were modelled to investigate the interaction between ACEs, the diagnosis, and the task, corrected for age, sex, and equivalent doses of chlorpromazine (p<0.05 FWE). FC values significantly affected by ACEs (Risky Family Questionnaire) were entered in a cross-validated LASSO regression predicting symptoms severity (Positive and Negative Syndrome Scale, PANSS) and task performance measures (accuracy and response time).
ResultsIn AToM, LC showed significant different effects of ACE between HC and SZ in frontal pole, caudate and cerebellum. MVPA showed significant widespread interaction in cortico-limbic regions, including prefrontal cortex, precuneus, insula, parahippocampus, cingulate cortex, temporal pole, thalamus, and cerebellum in AToM and CToM. SBC analyses found significant target regions in the frontal pole, cerebellum, pre and postcentral gyrus, precuneus, lateral occipital cortex, angular gyrus, and paracingulate gyrus. LASSO regression predicted PANSS score (R2=0.49) and AToM response latency time (R2=0.37).
ConclusionsOur findings highlighted a widespread different effect of ACEs on brain FC in ToM networks in HC and SZ. Notably, the FC in these regions is predictive of behavioral ToM performance and clinical outcomes.
Disclosure of InterestNone Declared
Effect of Neutrophil to Lymphocyte ratio on antidepressant treatment response: moderating effect of sex and mediating effect of Hippocampal volumes.
- M. Paolini, Y. Harrington, J. Ernst, R. Zanardi, S. Poletti, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S246
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Introduction
In recent years much focus has been put on the role of immune/inflammatory alterations in affecting Major Depression (MDD) development and antidepressant efficacy. Neutrophil-to-lymphocyte ratio (NLR) is an inexpensive inflammatory marker shown to be elevated in depressed patients, with large population studies reporting this effect only in women. However, its relation to treatment response is much less clear. Reduced hippocampal volumes (HV) are among the few consistent brain structural predictors of poor treatment response, and they have been shown to be influenced by inflammatory status.
ObjectivesTo investigate the effect of NLR on treatment response in MDD patients, testing a possible moderating role of sex. To investigate the effect of NLR on HV and test a possible mediating role of the latter in the relation between NLR and treatment response.
MethodsOur study was performed on a sample of 120 MDD inpatients suffering from a non psychotic depressive episode (F=78; M=42). Depression severity was assessed via the Hamilton Depression Rating Scale (HDRS), both at admission and discharge; as a measure of treatment response, delta HDRS was calculated subtracting the two scores. NLR was calculated for each subject. Patients underwent 3T MRI acquisition and bilateral HV were estimated.
ResultsWe found a significant moderating effect of sex on the relationship between NLR and Delta HDRS (p < 0.001): a negative relation was found in women (p < 0.001) and a positive one in men (p = 0.042). NLR was found to negatively affect left HV in the whole sample (p = 0.027) and in women (p = 0.038). A positive effect on Delta HDRS was found for both left (p = 0.038) and right (p = 0.027) HV. Finally, we found a significant indirect effect of NLR values on Delta HDRS through left HV in women (95% BCa CI [- 0.948, -0.017]); the direct effect of NLR on Delta HDRS also remained significant (p = 0.002).
ConclusionsSex was found to moderate the relation between NLR and treatment response. The detrimental effect in women is in line with previous reports linking inflammation to hampered antidepressant effect; the positive one in men is more surprising: however, the only studies to date on the effect of NLR on antidepressant efficacy report a positive effect in patients with psychotic depression. In women we found NLR to affect treatment response partially through its effect on left HV, providing a possible, albeit incomplete, mechanistic explanation of the effect of inflammatory status on antidepressant efficacy.
Disclosure of InterestNone Declared
The exploration of interoception construct in COVID-19 survivors
- G. D’Orsi, M. Palladini, A. Scalabrini, M. G. Mazza, S. Poletti, P. Rovere-Querini, F. Benedetti
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S791-S792
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Introduction
The new coronavirus disease (COVID-19) has important physical and mental health implications at short and long term. Some inflammatory parameters are implicated in the maintenance of psychiatric symptoms, especially those of anxiety and depression. Additionally, growing literature attributes a role to interoception in several mental health conditions.
ObjectivesWe investigated the involvement of the interoception in COVID-19 survivors and its possible associations with psychopathological and inflammatory variables.
MethodsOur study included 57 people surviving COVID-19 at one month follow-up after recovery. Individual interoceptive accuracy (IA) measure was obtained through heart-beat perception task. A measure of accuracy in external time perception (TA) was also obtained asking people to mentally produce a duration of 10s. Each participant completed State-Trait Anxiety Inventory - STAI-Y; Zung Self-Rating Depression Scale - ZSDS; Beck Depression Inventory - BDI-II; Impact of Events Scale - IES-R and Multidimensional Assessment of Interoceptive Awareness - MAIA. Peripheral inflammation markers were obtained in a subsample of 40 people by a blood sampling conducted at the time of admission and discharge from hospital. Correlation, regression and GLM analyses were performed with SPSS. Mediation analysis were performed with Hayes’ Process tool.
ResultsTA is not associated with IA, symptomatological measures and bodily awareness. Trusting is the only aspect of body awareness associated with IA (p=.021). Noticing (p=.010), Not-distracting (p=.009), Not-worrying (p=.012) and Trusting (p=.001) predict anxiety psychopathology. Poor IA predict anxiety symptomatology (p=.004) and part of this effect is mediated by Trusting [Fig.1]. In the end, platelets count at the time of hospitalization negatively correlates with anxiety symptoms (p=.003).
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ConclusionsCOVID-19 hospitalization could be considered a psychophysical traumatic experience which involved mental and physical health and the connection and integration between them. It’s necessary to deepen the different facets of body awareness and IA in post-covid stages and to study how interoceptive dimensions change over time. Further research is needed to investigate the specific role of platelets in prominent anxiety psychopathology detected in COVID-19 survivors, wondering about their possible involvement in the dysfunctional interoception process too.
Disclosure of InterestNone Declared
Predicting unipolar and bipolar depression using inflammatory markers, neuroimaging and neuropsychological data: a machine learning study
- L. Raffaelli, F. Colombo, F. Calesella, L. Fortaner-Uya, I. Bollettini, C. Lorenzi, E. Maggioni, E. Tassi, S. Poletti, R. Zanardi, F. Attanasio, F. Benedetti, B. Vai
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- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S621
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Introduction
About 60% of bipolar disorder (BD) cases are initially misdiagnosed as major depressive disorder (MDD), preventing BD patients from receiving appropriate treatment. An urgency exists to identify reliable biomarkers for improving differential diagnosis (DD). Machine learning methods may help translate current knowledge on biomarkers of mood disorders into clinical practice by providing individual-level classification. No study so far has combined biological data with clinical data to provide a multifactorial predictive model for DD.
ObjectivesDefine a predictive algorithm for BD and MDD by integrating structural neuroimaging and inflammatory data with neuropsychological measures (NM). Two different algorithms were compared: multiple kernel learning (MKL) and elastic net regularized logistic regression (EN).
MethodsIn a sample of 141 subjects (70 MDD; 71 BD), two different models were implemented for each algorithm: 1) structural neuroimaging measures only (i.e. voxel-based morphometry (VBM), white matter fractional anisotropy (FA), and mean diffusivity (MD)); 2) VBM, FA, and MD combined with NM. In a subsample of 71 subjects (36 BD; 38 MDD), two similar models were implemented: 1) VBM, FA, and, MD combined with only NM; 2) VBM, FA, and MD combined with NM and peripheral inflammatory markers. Finally, the best model was selected for comparison with healthy controls (HC).
ResultsOverall, the EN model based on all the modalities achieved the highest accuracy (AUC = 90.2%), outperforming MKL (AUC=85%). EN correctly classified BD and MDD with a diagnostic accuracy of 78.3%, sensitivity of 75%, and specificity of 81.6%. The most significant predictors of BD (variable inclusion probability (VIP) > 80%) were the parahippocampal cingulate, interleukin 9, chemokine CCL5, posterior thalamic radiation, and internal capsule, whereas MDD was best predicted by chemokine CCL23, the anterior cerebellum, and the sagittal stratum. In contrast, NM did not help to differentiate between MDD and BD. However, they help to distinguish patients from HC. Psychomotor coordination and speed of information processing discriminated between MDD and HC (VIP>90%), whereas fluency, working memory, and executive functions differentiated between BD and HC (VIP>80%).
ConclusionsIn summary, BD was predicted by a strong proinflammatory profile, whereas MDD was identified by structural neuroimaging data. A multimodal approach offers additional instruments to improve personalized diagnosis in clinical practice and enhance the ability to make DD.
Disclosure of InterestNone Declared
White matter integrity and pro-inflammatory cytokines as predictors of antidepressant response in MDD
- S. Breit, E. Mazza, S. Poletti, F. Benedetti
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- European Psychiatry / Volume 65 / Issue S1 / June 2022
- Published online by Cambridge University Press:
- 01 September 2022, p. S553
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Introduction
Major depressive disorder (MDD) often involves immune dysregulation with high peripheral levels of pro-inflammatory cytokines that might have an impact on the clinical course and treatment response. Moreover, MDD patients show brain volume changes and white matter (WM) alterations that are already existing in the early stage of illness.
ObjectivesThe aim of the present review is to elucidate the association between inflammation and WM integrity and its impact on the pathophysiology and progression of MDD as well as the role of possible novel biomarkers of treatment response to improve MDD prevention and treatment strategies.
MethodsWe conducted an electronic literature search of PubMed on studies that examined the role of inflammation in depression and that focused on WM integrity and pro-inflammatory cytokines as predictors of antidepressant response.
ResultsThere is evidence for central effects of peripheral inflammation which could activate microglia which, in turn, might trigger a cascade of inflammatory processes leading to neurotransmitter imbalances. Numerous studies indicated that both altered levels of peripheral inflammatory markers, particularly TNF-α, IL-6, and CRP as well as WM integrity might predict antidepressant treatment outcome.
ConclusionsDespite mounting evidence on the impact of the immune system on WM microstructure, no study has yet addressed the interaction between the two factors in influencing antidepressant response. There is a lack of reproducible biomarkers predicting treatment response on an individual basis. The availability of such biomarkers would enable more efficient and personalized treatments with a faster treatment response and better prevention of treatment resistance.
DisclosureNo significant relationships.
Social cognition in adolescents at risk for psychosis: A 2-year follow-up study
- L. Pelizza, S. Azzali, S. Garlasdi, I. Scazza, F. Paterlini, M. Poletti, S. Pupo, A. Raballo
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- Journal:
- European Psychiatry / Volume 64 / Issue S1 / April 2021
- Published online by Cambridge University Press:
- 13 August 2021, p. S226
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Introduction
Deficits in social cognition have been reported in people at ultra-high risk (UHR) of psychosis exclusively using socio-cognitive tasks and in adolescent and young adult mixed population.
ObjectivesAim of this study was (1) to assess subjective experience of social cognition in adolescent help-seekers identified through UHR criteria, (2) to explore its significant correlations with psychopathology and functioning in UHR individuals; and (3) to monitor longitudinally its stability after a 24-month follow-up period.
MethodsParticipants [51 UHR, 91 first-episode psychosis (FEP), and 48 non-UHR/FEP patients], aged 13–18 years, completed the comprehensive assessment of at-risk mental states and the GEOPTE scale of social cognition for psychosis.
ResultsIn comparison with non-UHR/FEP patients, both UHR and FEP adolescents showed significantly higher GEOPTE total scores. After 12 months of follow-up, UHR individuals had a significant decrease in severity on GEOPTE “Social Cognition” subscore. In the UHR group at baseline, GEOPTE scores had significant positive correlations with general psychopathology, positive and negative dimensions. Across the 2-year follow-up period, social cognition subscores specifically showed more stable associations with general psychopathology and negative symptoms.
ConclusionsSocial cognition deficits are prominent in UHR adolescents and similar in severity to those of FEP patients at baseline. However, these impairments decreased over time, presumably together with delivery of targeted, specialized models for early intervention in psychosis.
Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia
- B. Vai, G. Sferrazza Papa, S. Poletti, D. Radaelli, E. Donnici, I. Bollettini, A. Falini, R. Cavallaro, E. Smeraldi, F. Benedetti
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- Journal:
- European Psychiatry / Volume 30 / Issue 5 / July 2015
- Published online by Cambridge University Press:
- 15 April 2020, pp. 590-597
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Background
Impaired emotional processing is a core feature of schizophrenia (SZ). Consistent findings suggested that abnormal emotional processing in SZ could be paralleled by a disrupted functional and structural integrity within the fronto-limbic circuitry. The effective connectivity of emotional circuitry in SZ has never been explored in terms of causal relationship between brain regions. We used functional magnetic resonance imaging and Dynamic Causal Modeling (DCM) to characterize effective connectivity during implicit processing of affective stimuli in SZ.
MethodsWe performed DCM to model connectivity between amygdala (Amy), dorsolateral prefrontal cortex (DLPFC), ventral prefrontal cortex (VPFC), fusiform gyrus (FG) and visual cortex (VC) in 25 patients with SZ and 29 HC. Bayesian Model Selection and average were performed to determine the optimal structural model and its parameters.
ResultsAnalyses revealed that patients with SZ are characterized by a significant reduced top-down endogenous connectivity from DLPFC to Amy, an increased connectivity from Amy to VPFC and a decreased driving input to Amy of affective stimuli compared to HC. Furthermore, DLPFC to Amy connection in patients significantly influenced the severity of psychopathology as rated on Positive and Negative Syndrome Scale.
ConclusionsResults suggest a functional disconnection in brain network that contributes to the symptomatic outcome of the disorder. Our findings support the study of effective connectivity within cortico-limbic structures as a marker of severity and treatment efficacy in SZ.
Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia
- S. Poletti, D. Radaelli, M. Bosia, M. Buonocore, A. Pirovano, C. Lorenzi, R. Cavallaro, E. Smeraldi, F. Benedetti
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- Journal:
- European Psychiatry / Volume 29 / Issue 4 / May 2014
- Published online by Cambridge University Press:
- 15 April 2020, pp. 219-225
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Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses being glutamatergic. An altered glutamatergic transmission could play a critical role in working memory deficts observed in schizophrenia and could underline progressive changes such as grey matter loss throughout the brain. The aim of the study was to investigate if gray matter volume and working memory could be modulated by a genetic polymorphism related to glutamatergic function. Fifty schizophrenia patients underwent magnetic resonance and working memory testing outside of the scanner and were genotyped for rs4354668 EAAT2 polymorphism. Carriers of the G allele had lower gray matter volumes than T/T homozygote and worse working memory performance. Poor working memory performance was associated with gray matter reduction. Differences between the three genotypes are more relevant among patients showing poor performance at the 2-back task. Since glutamate abnormalities are known to be involved in excitotoxic processes, the decrease in cortical thickness observed in schizophrenia patients could be linked to an excess of extracellular glutamate. The differential effect of EAAT2 observed between good and poor performers suggests that the effect of EEAT2 on gray matter might reveal in the presence of a pathological process affecting gray matter.
Fronto-limbic disconnection in bipolar disorder
- D. Radaelli, G. Sferrazza Papa, B. Vai, S. Poletti, E. Smeraldi, C. Colombo, F. Benedetti
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- Journal:
- European Psychiatry / Volume 30 / Issue 1 / January 2015
- Published online by Cambridge University Press:
- 15 April 2020, pp. 82-88
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Background:
Bipolar disorder (BD) is a severe, disabling and life-threatening illness. Disturbances in emotion and affective processing are core features of the disorder with affective instability being paralleled by mood-congruent biases in information processing that influence evaluative processes and social judgment. Several lines of evidence, coming from neuropsychological and imaging studies, suggest that disrupted neural connectivity could play a role in the mechanistic explanation of these cognitive and emotional symptoms. The aim of the present study is to investigate the effective connectivity in a sample of bipolar patients.
Methods:Dynamic causal modeling (DCM) technique was used to study 52 inpatients affected by bipolar disorders consecutively admitted to San Raffaele hospital in Milano and forty healthy subjects. A face-matching task was used as activation paradigm.
Results:Patients with BD showed a significantly reduced endogenous connectivity in the DLPFC to Amy connection. There was no significant group effect upon the endogenous connection from Amy to ACC, from ACC to Amy and from DLPFC to ACC.
Conclusions:Both DLPFC and ACC are part of a network implicated in emotion regulation and share strong reciprocal connections with the amygdale. The pattern of abnormal or reduced connectivity between DLPFC and amygdala may reflect abnormal modulation of mood and emotion typical of bipolar patients.
Quality of Life and Anxious-depressive Symptoms in Cancer Patients Undergoing Mindfulness-based Interventions: Feasibility and Preliminary Outcomes on Prospective Single-centre Case-control Study (MIND4ME St.)
- G. Pontoni, M. Maur, R. Ferrari, A. Guida, S. Poletti, F. Caggia, A. Fontana, F. Gavioli, V. Tarantino, S. Cascinu, S. Ferrari
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- Journal:
- European Psychiatry / Volume 41 / Issue S1 / April 2017
- Published online by Cambridge University Press:
- 23 March 2020, p. S252
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Background
Mindfulness based interventions (MBIs) have shown efficacy in improving psychological symptoms including depression and anxiety in cancer patients (pts). The study aimed to explore feasibility and reproducibility of MBIs in an Italian Cancer Centre measuring biochemical and psychological parameters.
MethodsIn this pilot prospective case-control study, we recruited newly diagnosed pts receiving adjuvant chemotherapy (CT). A MBIs program was designed consisting of 2.5 hours weekly for 8 weeks and, including meditation, yoga and body scan. Material for 45 minutes (mn) home daily practice was provided. Primary endpoint was to evaluate feasibility. Secondary endpoints were assessment of quality of life (QoL), psychological and biochemical outcomes of stress, tested at baseline (W0), W4, W8, W24, W48. PSS (Perceived Stress Reduction), POMS (profile of mood states scores), EuroQoL (EQ-5D-3L) were administered.
ResultsTen pts underwent MBIs program arm. We present preliminary results, while data of control arm are being collected. All pts were female, two pts (20%) dropped out. Median age was 56 years. All received adjuvant CT, 5/8 received radiotherapy and hormone therapy. Mean of sessions attending was 6.8 (76%). Median daily practice was 30 mn. EQ-5D item for depression and anxiety showed decreasing trend in mean score from moderate to light (P = 0.15) and significant improvement of auto-perceived QoL was observed comparing W0 and W8 (P = 0.02)
ConclusionsIn a sensitive setting such as start CT, we found high pts compliance to MBIs. Improvement in self-perceived QoL after starting program was found and comparing anxious-depressive symptoms outcomes with control arm is still needed.
Disclosure of interestThe authors have not supplied their declaration of competing interest.
Catechol-O-methyltransferase Val(108/158)Met polymorphism affects fronto-limbic connectivity during emotional processing in bipolar disorder
- B. Vai, M. Riberto, S. Poletti, I. Bollettini, C. Lorenzi, C. Colombo, F. Benedetti
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- European Psychiatry / Volume 41 / Issue 1 / March 2017
- Published online by Cambridge University Press:
- 03 February 2017, pp. 53-59
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Catechol-O-methyltransferase (COMT) inactivates catecholamines, Val/Val genotype was associated to an increased amygdala (Amy) response to negative stimuli and can influence the symptoms severity and the outcome of bipolar disorder, probably mediated by the COMT polymorphism (rs4680) interaction between cortical and subcortical dopaminergic neurotransmission. The aim of this study is to explore how rs4680 and implicit emotional processing of negative emotional stimuli could interact in affecting the Amy connectivity in bipolar depression. Forty-five BD patients (34 Met carriers vs. 11 Val/Val) underwent fMRI scanning during implicit processing of fearful and angry faces. We explore the effect of rs4680 on the strength of functional connectivity from the amygdalae to whole brain. Val/Val and Met carriers significantly differed for the connectivity between Amy and dorsolateral prefrontal cortex (DLPFC) and supramarginal gyrus. Val/Val patients showed a significant positive connectivity for all of these areas, where Met carriers presented a significant negative one for the connection between DLPFC and Amy. Our findings reveal a COMT genotype-dependent difference in corticolimbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of clinical and prognostic outcome of BD. Specifically, a worse antidepressant recovery and clinical outcome previously detected in Val/Val patients could be associated to a specific increased sensitivity to negative emotional stimuli.
Brain-Derived Neurotrophic Factor (Bdnf) and Gray Matter Volume in Bipolar Disorder
- S. Poletti, V. Aggio, T.A. Hoogenboezem, O. Ambrée, H. de Wit, A.J.M. Wijkhuijs, C. Locatelli, C. Colombo, V. Arolt, H.A. Drexhage, F. Benedetti
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- Journal:
- European Psychiatry / Volume 40 / February 2017
- Published online by Cambridge University Press:
- 10 November 2016, pp. 33-37
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Introduction
Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC).
MethodsWe studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was P < 0.05, Family Wise Error (FWE) corrected for multiple comparisons. All the analyses were controlled for the effect of nuisance covariates known to influence GM volumes, such as age, gender and lithium treatment.
ResultsBD patients showed significantly higher serum BDNF levels compared with HC. Reduced GM volumes in BD patients compared to HC were observed in several brain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD.
DiscussionOur study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF.