Publications by authors named "Francesco Benedetti"

205 Publications

Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life.

Eur Arch Psychiatry Clin Neurosci 2021 Oct 26. Epub 2021 Oct 26.

Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, San Raffaele Turro, Via Stamira d'Ancona 20, Milan, Italy.

Neurologic and psychiatric symptoms have been reported in the months following the infection with COVID-19. A low-grade inflammation has been associated both with depression and cognitive symptoms, suggesting a link between these disorders. The aim of the study is to investigate cognitive functioning 6 months following hospital discharge for COVID-19, the impact of depression, and the consequences on quality of life. Ninety-two COVID-19 survivors evaluated at 1-month follow-up, 122 evaluated at 3 months and 98 evaluated at 6 months performed neuropsychological and psychiatric evaluations and were compared with a healthy comparison group (HC) of 165 subjects and 165 patients with major depression (MDD). Cognitive performances were adjusted for age, sex, and education. Seventy-nine percent of COVID-19 survivors at 1 month and 75% at 3- and 6-month follow-up showed cognitive impairment in at least one cognitive function. No significant difference in cognitive performances was observed between 1-, 3-, and 6-months follow-up. COVID-19 patients performed worse than HC but better than MDD in psychomotor coordination and speed of information processing. No difference between COVID-19 survivors and MDD was observed for verbal fluency, and executive functions, which were lower than in HC. Finally, COVID-19 survivors performed the same as HC in working memory and verbal memory. The factor that most affected cognitive performance was depressive psychopathology which, in turn, interact with cognitive functions in determining quality of life. Our results confirm that COVID-19 sequelae include signs of cognitive impairment which persist up to 6 months after hospital discharge and affect quality of life.
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http://dx.doi.org/10.1007/s00406-021-01346-9DOI Listing
October 2021

CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study.

Mol Med 2021 10 18;27(1):129. Epub 2021 Oct 18.

Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milano, Italy.

Background: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment.

Methods: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers.

Results: Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233-0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547-0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital.

Conclusions: CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19.
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http://dx.doi.org/10.1186/s10020-021-00390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521494PMC
October 2021

Rapid response to selective serotonin reuptake inhibitors in post-COVID depression.

Eur Neuropsychopharmacol 2021 Oct 8;54:1-6. Epub 2021 Oct 8.

Vita-Salute San Raffaele University, Milano, Italy; Psychiatry & Clinical Psychobiology, Division of Neuroscience, Scientific Institute IRCCS Ospedale San Raffaele, Milano.

The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. After COVID-19, depression was reported in 40% of patients at one-, three-, and six-months follow-up. Emerging literature suggests anti-inflammatory and antiviral properties of antidepressants in the treatment of SARS-CoV-2. We aim to investigate the efficacy of Selective Serotonin Reuptake Inhibitor (SSRI) in treating post-COVID depression. We included 60 patients affected by a major depressive episode and treated with SSRI in the six months following recovery from COVID. The severity of depression was rated at baseline and after four weeks on the Hamilton Depression Rating Scale (HDRS). Response to treatment was considered when the patients achieved a 50% HDRS reduction. To investigate changes of depressive symptomatology over time, repeated measures ANOVAs according to clinical variables were performed. We found that 55 (92%) patients showed a clinical response to antidepressant. Patients showed a significant decrease over time of HDRS score (baseline HDRS = 23.37 ± 3.94, post-treatment HDRS = 6.71±4.41, F = 618.90, p < 0.001), irrespectively of sex, previous psychiatric history, previous history of mood disorder, and SSRI type. This is the first study to explore the SSRI efficacy in post-COVID depression, suggesting rapid antidepressant effects in most patients. SSRIs treatment could contribute to the rapid antidepressant response by directly targeting the neuroinflammation triggered by SARS-CoV-2. We suggest screening psychopathology of COVID-19 survivors to diagnose emergent depression and pharmacologically treat it to reduce the disease burden and related years of life lived with disability.
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http://dx.doi.org/10.1016/j.euroneuro.2021.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500775PMC
October 2021

Effective Antidepressant Chronotherapeutics (Sleep Deprivation and Light Therapy) Normalize the IL-1β:IL-1ra Ratio in Bipolar Depression.

Front Physiol 2021 1;12:740686. Epub 2021 Sep 1.

Vita-Salute San Raffaele University, Milan, Italy.

Background: Mood disorders associate with peripheral markers of low-grade inflammation, among which circulating levels of interleukin-1β (IL-1β) consistently predict diagnosis and poor outcomes. Antidepressant chronotherapeutics (total sleep deprivation and light therapy, TSD+LT) prompts response in drug-resistant bipolar depression, but its effect on peripheral inflammation were never assessed. Here we explored the effects of TSD+LT on IL-1β signaling.

Methods: We studied the ratio between IL-1β and its receptor antagonist (IL-1β:IL1ra) in 33 healthy participants, and in 26 inpatients with a major depressive episode in course of Bipolar Disorder, before and after treatment with three cycles of repeated TSD+LT, interspersed with sleep recovery nights, administered during 1 week. Treatment effects of mood and on IL-1β:IL1ra were analyzed in the context of the Generalized Linear Model (GLM).

Results: At baseline, patients had higher IL-1β, IL1ra, and IL-1β:IL1ra than controls. Treatment significantly decreased IL-1β:IL1ra, by decreasing IL-1β and increasing IL1ra, the effect being proportional to baseline levels and normalizing values. Patients with higher baseline levels showed the highest decrease in IL-1β:IL-1ra, which associated with the immediate antidepressant response at the first cycle; while patients with lower baseline values showed negligible changes in the IL-1β:IL-1ra, unrelated to treatment response.

Conclusion: We observed a parallel change of inflammatory biomarkers and severity of depression after chronotherapeutics, suggesting that a reduction in inflammation associated with depression could contribute to the mechanism of action of TSD+LT, and warranting interest for controlled studies addressing the role of inflammation in the recovery from bipolar depression.
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http://dx.doi.org/10.3389/fphys.2021.740686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440979PMC
September 2021

Effective Antidepressant Chronotherapeutics (Sleep Deprivation and Light Therapy) Normalize the IL-1β:IL-1ra Ratio in Bipolar Depression.

Front Physiol 2021 1;12:740686. Epub 2021 Sep 1.

Vita-Salute San Raffaele University, Milan, Italy.

Background: Mood disorders associate with peripheral markers of low-grade inflammation, among which circulating levels of interleukin-1β (IL-1β) consistently predict diagnosis and poor outcomes. Antidepressant chronotherapeutics (total sleep deprivation and light therapy, TSD+LT) prompts response in drug-resistant bipolar depression, but its effect on peripheral inflammation were never assessed. Here we explored the effects of TSD+LT on IL-1β signaling.

Methods: We studied the ratio between IL-1β and its receptor antagonist (IL-1β:IL1ra) in 33 healthy participants, and in 26 inpatients with a major depressive episode in course of Bipolar Disorder, before and after treatment with three cycles of repeated TSD+LT, interspersed with sleep recovery nights, administered during 1 week. Treatment effects of mood and on IL-1β:IL1ra were analyzed in the context of the Generalized Linear Model (GLM).

Results: At baseline, patients had higher IL-1β, IL1ra, and IL-1β:IL1ra than controls. Treatment significantly decreased IL-1β:IL1ra, by decreasing IL-1β and increasing IL1ra, the effect being proportional to baseline levels and normalizing values. Patients with higher baseline levels showed the highest decrease in IL-1β:IL-1ra, which associated with the immediate antidepressant response at the first cycle; while patients with lower baseline values showed negligible changes in the IL-1β:IL-1ra, unrelated to treatment response.

Conclusion: We observed a parallel change of inflammatory biomarkers and severity of depression after chronotherapeutics, suggesting that a reduction in inflammation associated with depression could contribute to the mechanism of action of TSD+LT, and warranting interest for controlled studies addressing the role of inflammation in the recovery from bipolar depression.
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http://dx.doi.org/10.3389/fphys.2021.740686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440979PMC
September 2021

Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis.

Lancet Psychiatry 2021 09 17;8(9):797-812. Epub 2021 Jul 17.

University Psychiatric Hospital Campus Duffel, Duffel, Belgium; Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp, Belgium. Electronic address:

Background: Mental disorders might be a risk factor for severe COVID-19. We aimed to assess the specific risks of COVID-19-related mortality, hospitalisation, and intensive care unit (ICU) admission associated with any pre-existing mental disorder, and specific diagnostic categories of mental disorders, and exposure to psychopharmacological drug classes.

Methods: In this systematic review and meta-analysis, we searched Web of Science, Cochrane, PubMed, and PsycINFO databases between Jan 1, 2020, and March 5, 2021, for original studies reporting data on COVID-19 outcomes in patients with psychiatric disorders compared with controls. We excluded studies with overlapping samples, studies that were not peer-reviewed, and studies written in languages other than English, Danish, Dutch, French, German, Italian, and Portuguese. We modelled random-effects meta-analyses to estimate crude odds ratios (OR) for mortality after SARS-CoV-2 infection as the primary outcome, and hospitalisation and ICU admission as secondary outcomes. We calculated adjusted ORs for available data. Heterogeneity was assessed using the I statistic, and publication bias was tested with Egger regression and visual inspection of funnel plots. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle Ottawa Scale to assess study quality. We also did subgroup analyses and meta-regressions to assess the effects of baseline COVID-19 treatment setting, patient age, country, pandemic phase, quality assessment score, sample sizes, and adjustment for confounders. This study is registered with PROSPERO, CRD42021233984.

Findings: 841 studies were identified by the systematic search, of which 33 studies were included in the systematic review and 23 studies in the meta-analysis, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. The sample included 130 807 females (8·9% of the whole sample) and 130 373 males (8·8%). Nine studies provided data on patient race and ethnicity, and 22 studies were rated as high quality. The presence of any mental disorder was associated with an increased risk of COVID-19 mortality (OR 2·00 [95% CI 1·58-2·54]; I=92·66%). This association was also observed for psychotic disorders (2·05 [1·37-3·06]; I=80·81%), mood disorders (1·99 [1·46-2·71]; I=68·32%), substance use disorders (1·76 [1·27-2·44]; I=47·90%), and intellectual disabilities and developmental disorders (1·73 [1·29-2·31]; I=90·15%) but not for anxiety disorders (1·07 [0·73-1·56]; I=11·05%). COVID-19 mortality was associated with exposure to antipsychotics (3·71 [1·74-7·91]; I=90·31%), anxiolytics (2·58 [1·22-5·44]; I=96·42%), and antidepressants (2·23 [1·06-4·71]; I=95·45%). For psychotic disorders, mood disorders, antipsychotics, and anxiolytics, the association remained significant after adjustment for age, sex, and other confounders. Mental disorders were associated with increased risk of hospitalisation (2·24 [1·70-2·94]; I=88·80%). No significant associations with mortality were identified for ICU admission. Subgroup analyses and meta-regressions showed significant associations of baseline COVID-19 treatment setting (p=0·013) and country (p<0·0001) with mortality. No significant associations with mortality were identified for other covariates. No evidence of publication bias was found. GRADE assessment indicated high certainty for crude mortality and hospitalisation, and moderate certainty for crude ICU admission.

Interpretation: Pre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiolytics were associated with COVID-19 mortality in both crude and adjusted models. Although further research is required to determine the underlying mechanisms, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in at-risk patient groups identified in this study.

Funding: None.

Translations: For the Italian, French and Portuguese translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2215-0366(21)00232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285121PMC
September 2021

Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Dec 23;111:110391. Epub 2021 Jun 23.

Department of Immunology, Erasmus Medical Center, Rotterdam 3015 GD, Netherlands.

Background: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD).

Methods: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters.

Results: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation.

Conclusions: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110391DOI Listing
December 2021

Circulating inflammatory markers impact cognitive functions in bipolar depression.

J Psychiatr Res 2021 08 2;140:110-116. Epub 2021 Jun 2.

Division of Neuroscience, Scientific Institute Ospedale San Raffaele, Milano, Italy; University Vita-Salute San Raffaele, Milano, Italy.

Background: Cognitive impairment is a core feature of bipolar disorder, with a prevalence of about 64.4% during episodes and 57.1% in euthymia. Recent evidences suggest that cognitive deficits in BD may follow immune dysfunction and elevated levels of inflammatory cytokines have been reported during periods of depression, mania and euthymia, suggesting the presence of a chronic, low-grade inflammatory state. The aim of the study is to investigate if immune/inflammatory markers and especially chemokines associate to cognitive performances.

Methods: Seventy-six consecutively admitted inpatients with a depressive episode in course of bipolar disorder performed a neuropsychological evaluation with the Brief Assessment of Cognition in Schizophrenia and plasma blood levels of cytokines, chemokines and growth factors were analyzed with Luminex technology.

Results: Higher levels of IL-1β, IL-6, CCL2, CCL4, CCL5, CXCL10, and bFGF are associated with the likelihood of having a poor cognitive performance.

Limitations: Limitation include the lack of a group of healthy controls and the lack of information regarding previous psychopharmacological treatments, alcohol and tobacco use.

Conclusions: Our results confirm the importance of chemokines in bipolar disorder and suggest that inflammatory markers suggestive of a low-grade inflammatory state could contribute to the neurocognitive deficits observed in depressed patients.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.071DOI Listing
August 2021

Physical and psychological sequelae at three months after acute illness in COVID-19 survivors.

Panminerva Med 2021 Jun 1. Epub 2021 Jun 1.

Vita-Salute San Raffaele University, Milan, Italy -

Background: Coronavirus disease 2019 (COVID-19) may leave behind an altered health status early after recovery. We evaluated the clinical status of COVID-19 survivors at three months after hospital discharge.

Methods: In this prospective observational cohort study, hospitalized patients aged ≥18 years, evaluated at one (M1) and three (M3) months post-discharge were enrolled. 251 patients (71.3% males, median [IQR] age 61.8 [53.5-70.7] years) were included. Median (IQR) time from discharge to M3 was 89 (79.5-101) days. Primary outcome was residual respiratory dysfunction (RRD), defined by tachypnea, moderate to very severe dyspnea, or peripheral oxygen saturation ≤95% on room air at M3.

Results: RRD was found in 30.4% of patients, with no significant difference compared with M1. Chronic obstructive pulmonary disease and length of stay were independent predictors of RRD at multivariable logistic regression (odds ratio, OR, [95% confidence interval, CI] 4.13 [1.17-16.88], p 0.033; OR [95% CI] 1.02 [1.00-1.04], p 0.047, respectively). Obesity and C-reactive protein levels upon admission were additional predictors at regression tree analysis. Impaired quality of life (QoL) was reported by 53.2% of patients. Anxiety and insomnia were each present in 25.5% of patients, and PTSD in 22.4%. No difference was found between M1 and M3 in QoL, anxiety or PTSD. Insomnia decreased at M3. Current major psychiatric disorder as well as anxiety, insomnia and PSTD at M1 independently predicted PTSD at M3.

Conclusions: Clinical damage may persist at three months after discharge in COVID-19 survivors. Post-recovery follow-up is an essential component of patient management.
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http://dx.doi.org/10.23736/S0031-0808.21.04399-8DOI Listing
June 2021

Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients.

J Neurol 2021 May 10. Epub 2021 May 10.

Institute of Experimental Neurology, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.

Background And Aims: Patients infected with SARS-CoV-2 range from asymptomatic, to mild, moderate or severe disease evolution including fatal outcome. Thus, early predictors of clinical outcome are highly needed. We investigated markers of neural tissue damage as a possible early sign of multisystem involvement to assess their clinical prognostic value on survival or transfer to intensive care unit (ICU).

Methods: We collected blood from 104 patients infected with SARS-CoV-2 the day of admission to the emergency room and measured blood neurofilament light chair (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau protein levels.

Results: We found that NfL, GFAP, and tau were significantly increased in patients with fatal outcome, while NfL and UCH-L1 in those needing ICU transfer. ROC and Kaplan-Meier curves indicated that total tau levels at admission accurately predict mortality.

Conclusions: Blood neural markers may provide additional prognostic value to conventional biomarkers used to predict COVID-19 outcome.
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http://dx.doi.org/10.1007/s00415-021-10595-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108733PMC
May 2021

Adiponectin predicts poor response to antidepressant drugs in major depressive disorder.

Hum Psychopharmacol 2021 May 4. Epub 2021 May 4.

Vita-Salute San Raffaele University, Milano, Italy.

Objective: Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting.

Methods: We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings.

Results: Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index.

Conclusions: The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets. KEYWORDS antidepressant, adiponectin, depression, SNRI, SSRI.
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http://dx.doi.org/10.1002/hup.2793DOI Listing
May 2021

ENIGMA-Sleep: Challenges, opportunities, and the road map.

J Sleep Res 2021 Apr 28:e13347. Epub 2021 Apr 28.

Department of Sleep and Cognition, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.
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http://dx.doi.org/10.1111/jsr.13347DOI Listing
April 2021

Association between body mass index and subcortical brain volumes in bipolar disorders-ENIGMA study in 2735 individuals.

Mol Psychiatry 2021 Apr 16. Epub 2021 Apr 16.

Unit for Psychosomatics / CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.
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http://dx.doi.org/10.1038/s41380-021-01098-xDOI Listing
April 2021

White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group.

Transl Psychiatry 2021 03 17;11(1):173. Epub 2021 Mar 17.

Department of Psychiatry, Oxford University, Oxford, UK.

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive-compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = -0.21, z = -3.21, p = 0.001) and posterior thalamic radiation (d = -0.26, z = -4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = -2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = -1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.
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http://dx.doi.org/10.1038/s41398-021-01276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969744PMC
March 2021

Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: Effect of inflammatory biomarkers at three-month follow-up.

Brain Behav Immun 2021 05 24;94:138-147. Epub 2021 Feb 24.

Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy.

COVID-19 outbreak is associated with mental health implications during viral infection and at short-term follow-up. Data on psychiatric and cognitive sequelae at medium-term follow-up are still lacking. During an ongoing prospective cohort study, the psychopathological and cognitive status of 226 COVID-19 pneumonia survivors (149 male, mean age 58) were prospectively evaluated one and three months after hospital discharge. Psychiatric clinical interview, self-report questionnaires, and neuropsychological profiling of verbal memory, working memory, psychomotor coordination, executive functions, attention and information processing, and verbal fluency were performed. Three months after discharge from the hospital, 35.8% still self-rated symptoms in the clinical range in at least one psychopathological dimension. We observed persistent depressive symptomatology, while PTSD, anxiety, and insomnia decreased during follow-up. Sex, previous psychiatric history, and the presence of depression at one month affected the depressive symptomatology at three months. Regardless of clinical physical severity, 78% of the sample showed poor performances in at least one cognitive domain, with executive functions and psychomotor coordination being impaired in 50% and 57% of the sample. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, predicted self-rated depressive symptomatology and cognitive impairment at three-months follow-up; and changes of SII predicted changes of depression during follow-up. Neurocognitive impairments associated with severity of depressive psychopathology, and processing speed, verbal memory and fluency, and psychomotor coordination were predicted by baseline SII. We hypothesize that COVID-19 could result in prolonged systemic inflammation that predisposes patients to persistent depression and associated neurocognitive dysfunction. The linkage between inflammation, depression, and neurocognition in patients with COVID-19 should be investigated in long-term longitudinal studies, to better personalize treatment options for COVID-19 survivors.
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http://dx.doi.org/10.1016/j.bbi.2021.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903920PMC
May 2021

Sexual Regional Dimorphism of Post-Adolescent and Middle Age Brain Maturation. A Multi-center 3T MRI Study.

Front Aging Neurosci 2021 5;13:622054. Epub 2021 Feb 5.

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Sex-related differences are tied into neurodevelopmental and lifespan processes, beginning early in the perinatal and developmental phases and continue into adulthood. The present study was designed to investigate sexual dimorphism of changes in gray matter (GM) volume in post-adolescence, with a focus on early and middle-adulthood using a structural magnetic resonance imaging (MRI) dataset of healthy controls from the European Network on Psychosis, Affective disorders and Cognitive Trajectory (ENPACT). Three hundred and seventy three subjects underwent a 3.0 T MRI session across four European Centers. Age by sex effects on GM volumes were investigated using voxel-based morphometry (VBM) and the Automated Anatomical Labeling atlas regions (ROI). Females and males showed overlapping and non-overlapping patterns of GM volume changes during aging. Overlapping age-related changes emerged in bilateral frontal and temporal cortices, insula and thalamus. Both VBM and ROI analyses revealed non-overlapping changes in multiple regions, including cerebellum and vermis, bilateral mid frontal, mid occipital cortices, left inferior temporal and precentral gyri. These findings highlight the importance of accounting for sex differences in cross-sectional analyses, not only in the study of normative changes, but particularly in the context of psychiatric and neurologic disorders, wherein sex effects may be confounded with disease-related changes.
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http://dx.doi.org/10.3389/fnagi.2021.622054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892767PMC
February 2021

Severe mental illness and European COVID-19 vaccination strategies.

Lancet Psychiatry 2021 05 17;8(5):356-359. Epub 2021 Feb 17.

IMRB Translational Neuropsychiatry Lab, Université Paris Est Creteil, Creteil, France; Department of Psychiatry and Addictology, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Creteil, France.

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http://dx.doi.org/10.1016/S2215-0366(21)00046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906735PMC
May 2021

Viewpoint | European COVID-19 exit strategy for people with severe mental disorders: Too little, but not yet too late.

Brain Behav Immun 2021 05 23;94:15-17. Epub 2021 Jan 23.

Translational Neuropsychiatry Lab, Université Paris Est Creteil (UPEC), INSERM U955, IMRB, F-94010 Creteil, France; Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), AP-HP, Hopital Henri Mondor, F-94010 Creteil, France; Fondation FondaMental, Creteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.01.008DOI Listing
May 2021

Brain-immune crosstalk in the treatment of major depressive disorder.

Eur Neuropsychopharmacol 2021 Apr 29;45:89-107. Epub 2020 Dec 29.

Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), Laboratoire Neuro-psychiatrie translationnelle, AP-HP, Université Paris Est Créteil, INSERM U955, IMRB, Hôpital Henri Mondor, Fondation FondaMental, F-94010 Créteil, France.

A growing number of studies are pointing out the need for a conceptual shift from a brain-centered to a body-inclusive approach in mental health research. In this perspective, the link between the immune and the nervous system, which are deeply interconnected and continuously interacting, is one of the most important novel theoretical framework to investigate the biological bases of major depressive disorder and, more in general, mental illness. Indeed, depressed patients show high levels of inflammatory markers, administration of pro-inflammatory drugs triggers a depressive symptomatology and antidepressant efficacy is reduced by excessive immune system activation. A number of molecular and cellular mechanisms have been hypothesized to act as a link between the immune and brain function, thus representing potential pharmacologically targetable processes for the development of novel and effective therapeutic strategies. These include the modulation of the kynurenine pathway, the crosstalk between metabolic and inflammatory processes, the imbalance in acquired immune responses, in particular T cell responses, and the interplay between neural plasticity and immune system activation. In the personalized medicine approach, the assessment and regulation of these processes have the potential to lead, respectively, to novel diagnostic approaches for the prediction of treatment outcome according to the patient's immunological profile, and to improved efficacy of antidepressant compounds through immune modulation.
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http://dx.doi.org/10.1016/j.euroneuro.2020.11.016DOI Listing
April 2021

Proinflammatory Cytokines Predict Brain Metabolite Concentrations in the Anterior Cingulate Cortex of Patients With Bipolar Disorder.

Front Psychiatry 2020 8;11:590095. Epub 2020 Dec 8.

Psychiatry & Clinical Psychobiology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Bipolar disorder (BD) is a severe psychiatric illness characterized by abnormalities in the immune/inflammatory function and in brain metabolism. Evidences suggest that inflammation may affect the levels of brain metabolites as measured by single-proton magnetic resonance spectroscopy (H-MRS). The aim of the study was to investigate whether a wide panel of inflammatory markers (i.e., cytokines, chemokines, and growth factors) can predict brain metabolite concentrations of glutamate, -inositol, -acetylaspartate, and glutathione in a sample of 63 bipolar patients and 49 healthy controls. Three cytokines influenced brain metabolite concentrations: IL-9 positively predicts glutamate, IL-1β positively predicts -inositol, and CCL5 positively predicts -acetylaspartate concentrations. Furthermore, patients showed higher concentrations of glutamate, -inositol, and glutathione and lower concentrations of -acetylaspartate in respect to healthy controls. Our results confirm that inflammation in BD alters brain metabolism, through mechanisms possibly including the production of reactive oxygen species and glia activation.
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http://dx.doi.org/10.3389/fpsyt.2020.590095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753118PMC
December 2020

Risk Perception and Media in Shaping Protective Behaviors: Insights From the Early Phase of COVID-19 Italian Outbreak.

Front Psychol 2020 5;11:563426. Epub 2020 Nov 5.

Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

In the absence of target treatments or vaccination, the SARS-CoV-2 pandemic can be impeded by effectively implementing containment measures and behaviors. This relies on individuals' adoption of protective behaviors, their perceived risk, and the use and trust of information sources. During a health emergency, receiving timely and accurate information enables individuals to take appropriate actions to protect themselves, shaping their risk perception. Italy was the first western country plagued by COVID-19 and one of the most affected in the early phase. During this period, we surveyed 2,223 Italians before the national lockdown. A quarter of the sample perceived COVID-19 less threatening than flu and would not vaccinate, if a vaccine was available. Besides, most people perceived containment measures, based on social distancing or wearing masks, not useful. This perceived utility was related to COVID-19 threat perception and efficacy beliefs. All these measures were associated with the use of media and their truthfulness: participants declared to mainly use the Internet, while health organizations' websites were the most trusted. Although social networks were frequently used, they were rated lower for trustfulness. Our data differ from those obtained in other community samples, suggesting the relevance to explore changes across different countries and during the different phases of the pandemic. Understanding these phenomena, and how people access the media, may contribute to improve the efficacy of containment measures, tailoring specific policies and health communications.
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http://dx.doi.org/10.3389/fpsyg.2020.563426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674945PMC
November 2020

Tuning Selectivities in Gas Separation Membranes Based on Polymer-Grafted Nanoparticles.

ACS Nano 2020 Nov 20. Epub 2020 Nov 20.

Department of Chemical Engineering, Columbia University, New York, New York 10027, United States.

Polymer membranes are critical to many sustainability applications that require the size-based separation of gas mixtures. Despite their ubiquity, there is a continuing need to selectively affect the transport of different mixture components while enhancing mechanical strength and hindering aging. Polymer-grafted nanoparticles (GNPs) have recently been explored in the context of gas separations. Membranes made from pure GNPs have higher gas permeability and lower selectivity relative to the neat polymer because they have increased mean free volume. Going beyond this ability to manipulate the mean free volume by grafting chains to a nanoparticle, the conceptual advance of the present work is our finding that GNPs are spatially heterogeneous transport media, with this free volume distribution being easily manipulated by the addition of free polymer. In particular, adding a small amount of appropriately chosen free polymer can increase the membrane gas selectivity by up to two orders of magnitude while only moderately reducing small gas permeability. Added short free chains, which are homogeneously distributed in the polymer layer of the GNP, reduce the permeability of all gases but yield no dramatic increases in selectivity. In contrast, free chains with length comparable to the grafts, which populate the interstitial pockets between GNPs, preferentially hinder the transport of the larger gas and thus result in large selectivity increases. This work thus establishes that we can favorably manipulate the selective gas transport properties of GNP membranes through the entropic effects associated with the addition of free chains.
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http://dx.doi.org/10.1021/acsnano.0c07049DOI Listing
November 2020

Higher baseline interleukin-1β and TNF-α hamper antidepressant response in major depressive disorder.

Eur Neuropsychopharmacol 2021 01 13;42:35-44. Epub 2020 Nov 13.

Psychiatry and Clinical Psychobiology, Division of Neuroscience, IRCCS Scientific Institute Ospedale San Raffaele, Milano, Italy; Vita-Salute San Raffaele University, Milano, Italy.

Raised pro-inflammatory immune/inflammatory setpoints, leading to an increased production of peripheral cytokines, have been associated with Major Depressive Disorder (MDD) and with failure to respond to first-line antidepressant drugs. However, the usefulness of these biomarkers in clinical psychopharmacology has been questioned because single findings did not translate into the clinical practice, where patients are prescribed treatments upon clinical need. We studied a panel of 27 inflammatory biomarkers in a sample of 108 inpatients with MDD, treated with antidepressant monotherapy for 4 weeks upon clinical need in a specialized hospital setting, and assessed the predictive effect of baseline peripheral measures of inflammation on antidepressing efficacy (response rates and time-lagged pattern of decrease of depression severity) using a machine-learning approach with elastic net penalized regression, and multivariate analyses in the context of the general linear model. When considering both categorical and continuous measures of response, baseline levels of IL-1β predicted non-response to antidepressants, with the predicted probability to respond being highly dispersed at low levels of IL-1β, and stratifying toward non-response when IL-1β is high. Significant negative effects were also detected for TNF-α, while IL-12 weakly predicted response. These findings support the usefulness of inflammatory biomarkers in the clinical psychopharmacology of depression, and add to ongoing research efforts aiming at defining reliable cutoff values to identify depressed patients in clinical settings with high inflammation, and low probability to respond.
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http://dx.doi.org/10.1016/j.euroneuro.2020.11.009DOI Listing
January 2021

Higher polygenic risk scores for schizophrenia may be suggestive of treatment non-response in major depressive disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2021 06 10;108:110170. Epub 2020 Nov 10.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Up to 60% of patients with major depressive disorder (MDD) do not respond to the first treatment with antidepressants. Response to antidepressants is a polygenic trait, although its underpinning genetics has not been fully clarified. This study aimed to investigate if polygenic risk scores (PRSs) for major psychiatric disorders and trait neuroticism (NEU) were associated with non-response or resistance to antidepressants in MDD. PRSs for bipolar disorder, MDD, NEU, and schizophrenia (SCZ) were computed in 1,148 patients with MDD. Summary statistics from the largest meta-analyses of genome-wide association studies were used as base data. Patients were classified as responders, non-responders to one treatment, non-responders to two or more treatments (treatment-resistant depression or TRD). Regression analyses were adjusted for population stratification and recruitment sites. PRSs did not predict either non-response vs response or TRD vs response after Bonferroni correction. However, SCZ-PRS was nominally associated with non-response (p = 0.003). Patients in the highest SCZ-PRS quintile were more likely to be non-responders than those in the lowest quintile (OR = 2.23, 95% CI = 1.21-4.10, p = 0.02). Patients in the lowest SCZ-PRS quintile showed higher response rates when they did not receive augmentation with second-generation antipsychotics (SGAs), while those in the highest SCZ-PRS quintile had a poor response independently from the treatment strategy (p = 0.009). A higher genetic liability to SCZ may reduce treatment response in MDD, and patients with low SCZ-PRSs may show higher response rates without SGA augmentation. Multivariate approaches and methodological refinements will be necessary before clinical implementations of PRSs.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110170DOI Listing
June 2021

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group.

Hum Brain Mapp 2020 Oct 19. Epub 2020 Oct 19.

Department of Psychiatry, University of Münster, Münster, Germany.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.
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http://dx.doi.org/10.1002/hbm.25249DOI Listing
October 2020

Residual clinical damage after COVID-19: A retrospective and prospective observational cohort study.

PLoS One 2020 14;15(10):e0239570. Epub 2020 Oct 14.

School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.

Data on residual clinical damage after Coronavirus disease-2019 (COVID-19) are lacking. The aims of this study were to investigate whether COVID-19 leaves behind residual dysfunction, and identify patients who might benefit from post-discharge monitoring. All patients aged ≥18 years admitted to the Emergency Department (ED) for COVID-19, and evaluated at post-discharge follow-up between 7 April and 7 May, 2020, were enrolled. Primary outcome was need of follow-up, defined as the presence at follow-up of at least one among: respiratory rate (RR) >20 breaths/min, uncontrolled blood pressure (BP) requiring therapeutic change, moderate to very severe dyspnoea, malnutrition, or new-onset cognitive impairment, according to validated scores. Post-traumatic stress disorder (PTSD) served as secondary outcome. 185 patients were included. Median [interquartile range] time from hospital discharge to follow-up was 23 [20-29] days. 109 (58.9%) patients needed follow-up. At follow-up evaluation, 58 (31.3%) patients were dyspnoeic, 41 (22.2%) tachypnoeic, 10 (5.4%) malnourished, 106 (57.3%) at risk for malnutrition. Forty (21.6%) patients had uncontrolled BP requiring therapeutic change, and 47 (25.4%) new-onset cognitive impairment. PTSD was observed in 41 (22.2%) patients. At regression tree analysis, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) and body mass index (BMI) at ED presentation, and age emerged as independent predictors of the need of follow-up. Patients with PaO2/FiO2 <324 and BMI ≥33 Kg/m2 had the highest odds to require follow-up. Among hospitalised patients, age ≥63 years, or age <63 plus non-invasive ventilation or diabetes identified those with the highest probability to need follow-up. PTSD was independently predicted by female gender and hospitalisation, the latter being protective (odds ratio, OR, 4.03, 95% confidence interval, CI, 1.76 to 9.47, p 0.0011; OR 0.37, 95% CI 0.14 to 0.92, p 0.033, respectively). COVID-19 leaves behind physical and psychological dysfunctions. Follow-up programmes should be implemented for selected patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239570PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556454PMC
October 2020

A peripheral inflammatory signature discriminates bipolar from unipolar depression: A machine learning approach.

Prog Neuropsychopharmacol Biol Psychiatry 2021 03 9;105:110136. Epub 2020 Oct 9.

Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, Psychiatry and Clinical Psychobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: Mood disorders (major depressive disorder, MDD, and bipolar disorder, BD) are considered leading causes of life-long disability worldwide, where high rates of no response to treatment or relapse and delays in receiving a proper diagnosis (~60% of depressed BD patients are initially misdiagnosed as MDD) contribute to a growing personal and socio-economic burden. The immune system may represent a new target to develop novel diagnostic and therapeutic procedures but reliable biomarkers still need to be found.

Methods: In our study we predicted the differential diagnosis of mood disorders by considering the plasma levels of 54 cytokines, chemokines and growth factors of 81 BD and 127 MDD depressed patients. Clinical diagnoses were predicted also against 32 healthy controls. Elastic net models, including 5000 non-parametric bootstrapping procedure and inner and outer 10-fold nested cross-validation were performed in order to identify the signatures for the disorders.

Results: Results showed that the immune-inflammatory signature classifies the two disorders with a high accuracy (AUC = 97%), specifically 92% and 86% respectively for MDD and BD. MDD diagnosis was predicted by high levels of markers related to both pro-inflammatory (i.e. IL-1β, IL-6, IL-7, IL-16) and regulatory responses (IL-2, IL-4, and IL-10), whereas BD by high levels of inflammatory markers (CCL3, CCL4, CCL5, CCL11, CCL25, CCL27, CXCL11, IL-9 and TNF-α).

Conclusions: Our findings provide novel tools for early diagnosis of BD, strengthening the impact of biomarkers research into clinical practice, and new insights for the development of innovative therapeutic strategies for depressive disorders.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110136DOI Listing
March 2021

Lightening depression.

Bipolar Disord 2020 12 27;22(8):872-873. Epub 2020 Oct 27.

Institut des Neurosciences Cellulaires et Intégratives, CNRS-UPR 3212, Strasbourg, France.

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http://dx.doi.org/10.1111/bdi.13018DOI Listing
December 2020
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