Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell... more Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 +T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 +immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.
Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by al... more Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by altered levels of immune/inflammatory markers and disrupted white matter (WM) microstructure. A pro-inflammatory state was suggested to activate indoleamine 2,3-dioxygenase which, in turn, increases the amount of tryptophan (Trp) converted into kynurenine (Kyn). We investigated whether plasma levels of Trp, Kyn and Kyn/Trp ratio are associated with peripheral levels of immune/inflammatory markers and whether they are related to WM integrity in 100 MDD and 66 BD patients. Patients also underwent MRI, and fractional anisotropy (FA) was estimated as a measure of WM microstructure. BD patients showed higher Kyn levels and Kyn/Trp ratio than MDD patients, and lower FA in several WM tracts, including the corpus callosum and the inferior fronto-occipital fasciculus (IFO). Lower Trp levels associated with a more severe depressive symptomatology irrespective of diagnosis and with lower FA in the corpus callosum (CC) and external capsule (EC). We found an association of immune/inflammatory markers with Kyn/Trp ratio selectively in BD patients: IL-1β and TNF-α showed a positive relationship and IL-2 and IL-9 a negative relationship; in addition, higher IL-4 correlated with lower Kyn levels; higher Kyn/Trp ratio and IL-1β correlated with lower FA in the CC and IFO. Notably, the detrimental effect of IL-1β on the IFO was moderated by the Kyn/Trp ratio. These data suggest that in BD, cytokines and the conversion of Trp into Kyn may affect WM microstructure and support the idea that distinct mechanisms underlie the pathophysiology of BD and MDD.
IntroductionBipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter ... more IntroductionBipolar 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...
Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state... more Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state functional connectivity (rsFC) in various neural networks and especially in default-mode network (DMN). However, inconsistent findings, i.e., increased and decreased DMN rsFC, have been reported, which raise the question for the source of DMN changes in MDD. Testing whether the DMN abnormalities in MDD can be traced to either a local, i.e., intra-network, or a global, i.e., inter-network, source, we conducted a novel sequence of rsFC analyses, i.e., global FC, intra-network FC, and inter-network FC. Moreover, all analyses were conducted without global signal regression (non-GSR) and with GSR in order to identify the impact of specifically the global component of functional connectivity on within-network functional connectivity within specifically the DMN. In MDD our findings demonstrate (i) increased representation of global signal correlation (GSCORR) in DMN regions, as confirmed independently by degree of centrality (DC) and by an independent DMN template, (ii) increased within-network DMN rsFC, (iii) highly increased inter-network rsFC of both lower- and higher order non-DMN networks with DMN, (iv) high accuracy in classifying MDD vs. healthy subjects by using GSCORR as predictor. Further supporting the global, i.e., non-DMN source of within-network rsFC of the DMN, all results were obtained only when including the global signal, i.e., non-GSR, but not when conducting GSR. Together, we show for the first time increased global signal representation within rsFC of DMN as stemming from inter-network sources as distinguished from local sources, i.e., within- or intra-DMN.
Human Psychopharmacology: Clinical and Experimental, 2021
OBJECTIVE Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specif... more 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.
Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state... more Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state functional connectivity (rsFC) in various neural networks and especially in default-mode network (DMN). However, inconsistent findings, i.e., increased and decreased DMN rsFC, have been reported, which raise the question for the source of DMN changes in MDD. Testing whether the DMN abnormalities in MDD can be traced to either a local, i.e., intra-network, or a global, i.e., inter-network, source, we conducted a novel sequence of rsFC analyses, i.e., global FC, intra-network FC, and inter-network FC. Moreover, all analyses were conducted without global signal regression (non-GSR) and with GSR in order to identify the impact of specifically the global component of functional connectivity on within-network functional connectivity within specifically the DMN. In MDD our findings demonstrate (i) increased representation of global signal correlation (GSCORR) in DMN regions, as confirmed independently by degree of centrality (DC) and by an independent DMN template, (ii) increased within-network DMN rsFC, (iii) highly increased inter-network rsFC of both lower- and higher order non-DMN networks with DMN, (iv) high accuracy in classifying MDD vs. healthy subjects by using GSCORR as predictor. Further supporting the global, i.e., non-DMN source of within-network rsFC of the DMN, all results were obtained only when including the global signal, i.e., non-GSR, but not when conducting GSR. Together, we show for the first time increased global signal representation within rsFC of DMN as stemming from inter-network sources as distinguished from local sources, i.e., within- or intra-DMN.
Bipolar disorder (BD) is a severe psychiatric illness characterized by abnormalities in the immun... more 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 (1H-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, myo-inositol, N-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 Myo-inositol, and CCL5 positively predicts N-acetylaspartate concentrations. Furthermore, patients showed higher concentrations of glutamate, Myo-inositol, and glutathione and lower concentrations of N-acetylaspartate in respect to healthy controls. Our results confirm that in...
BACKGROUND In bipolar disorder (BD) the risk of suicide in adult life can be influenced by the in... more BACKGROUND In bipolar disorder (BD) the risk of suicide in adult life can be influenced by the interaction of adverse childhood experiences with the serotonin transporter polymorphism (5-HTTLPR). The cortico-limbic connectivity is a candidate endophenotype for the disorder, also related to suicidality and affected by the 5-HT system. METHODS In 64 (*s carriers = 41; l/l = 23) depressed BD patients, we explored the effect of 5-HTTLPR on corticolimbic functional connectivity (FC) during emotional processing, and the role of FC in moderating/mediating the effect of early stressful events on suicidality among 5-HTTLPR groups, by implementing Generalized Structural Equation Model. RESULTS 5-HTTLPR affects FC between amygdala (Amy) and anterior cingulate cortex (ACC), temporal pole, putamen/thalamus, and precuneus. The short allele was associated to a more inefficient corticolimbic connectivity. In 5-HTTLPR*s carriers, but not in l/l, the Amy-ACC functional coupling mediated the relationship between stress load and current suicidality. LIMITATIONS Patients were not drug-naive, and the recruitment took place in a single center, thus raising the possibility of population stratifications. The sample size is relatively small, but our findings can provide the background for replication study in independent and larger datasets. CONCLUSIONS Our results confirm the link between the 5-HTT promoter polymorphism and susceptibility to stress in BD, and suggest that cortico-limbic functional connectivity mediates these effects. This pattern could identify a vulnerability factor for the exacerbation of mood episodes after stressful life events particularly relevant in *s carriers.
BACKGROUND Bipolar disorder (BD) is a severe mental illness characterised by reduced grey matter ... more BACKGROUND Bipolar disorder (BD) is a severe mental illness characterised by reduced grey matter (GM) volumes and cortical thickness, and disrupted white matter (WM) microstructure. Activation of indoleamine 2,3-dioxygenase following a pro-inflammatory state could increase the amount of tryptophan (Trp) converted to kynurenine (Kyn) possibly leading to the production of detrimental catabolites of the Kyn pathway with neurotoxic effects. We investigated if peripheral levels of Trp-and Kyn and the breakdown of Trp-into Kyn (Kyn/Trp-ratio) are related to WM and GM integrity in BD. METHODS Peripheral levels of Trp-and Kyn were analysed in 72 patients with BD and 33 controls. Patients also underwent MRI in a Philips 3T scanner. RESULTS Patients showed higher Kyn levels and Kyn/Trp-ratio compared to controls. MRI analyses performed in patients with BD showed a negative association between the Kyn/Trp-ratio and the integrity of corpus callosum microstructure, the volume of the amygdala and cortical thickness in fronto-parietal regions. LIMITATION The lack of information on the levels of downstream metabolites of Kyn prevent us to confirm the possible unbalance between quinolinic and kynurenic acids as well as their possible relationship with changes in GM and WM markers. The activation of the Kyn pathway as suggested by the increased Kyn/Trp-ratio may lead to an imbalance of the neurotoxic vs the neuroprotective arm of the biochemical pathway, resulting in significant changes in GM and WM regions of brain areas strongly implicated in the pathophysiology of BD, such as amygdala and corpus callosum.
Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune disea... more Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 ...
The aim of the study is to investigate if gene polymorphisms in sterol regulatory element binding... more The aim of the study is to investigate if gene polymorphisms in sterol regulatory element binding protein transcriptional factors SREBF-1 and SREBF-2, which regulate lipid and cholesterol metabolism, could affect white matter (WM) microstructure, the most recognized structural biomarker of bipolar disorder (BD). In a sample of 93 patients affected by BD, we investigated the effect of SREBF-1 rs11868035, and SREBF-2 rs1052717, on WM microstructure, using diffusion tensor imaging and tract-based spatial statistics. We observed increased radial diffusivity in the rs1052717 A/A genotype compared to A/G and G/G, and reduced fractional anisotropy (FA) in the rs1052717 A/A genotype compared to G carriers in cingulum, corpus callosum, superior and inferior longitudinal fasciculi, and anterior thalamic radiation. These results seem to suggest an involvement of SREBF-2 in the integrity of white matter tracts in BD and therefore a possible role of SREBP pathway in CNS myelination processes.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, Jun 1, 2016
Growth factors involved in neurogenesis and neuroplasticity could play a role in biological proce... more Growth factors involved in neurogenesis and neuroplasticity could play a role in biological processes that drive depression recovery. Combined total sleep deprivation and morning light therapy (TSD + LT) can acutely reverse depressive symptoms, thus allowing to investigate the neurobiological correlates of antidepressant response. We tested if changes on plasma levels of Brain Derived Neurotrophic Factor (BDNF), S100 calcium binding protein B (S100-B), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Vascular Endothelial Growth Factor (VEGF) are associated with response to TSD + LT in 26 inpatients affected by a major depressive episode in the course of bipolar disorder. Regional grey matter (GM) volumes were assessed at baseline, and BOLD fMRI neural responses to a moral valence decision task were recorded before and after treatment. 61.5 % of patients responded to treatme...
At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinas... more At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3-beta as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.
Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses b... more 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 in...
Objective A major limitation of current suicide research is the lack of power to identify robust ... more Objective A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behaviour. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Method Here, we examine this issue through two approaches: (i) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments; and (ii) by pooling data (N~6,000 participants) from cohorts from the ENIGMA-Major Depressive Disorder (ENIGMA-MDD) and ENIGMA-Suicidal Thoughts and Behaviour (ENIGMA-STB) working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behaviour. Results Our results suggested a pattern of moderate-to-high correlations between instruments, consistent with the wide range of correlations, r=0.22-0.97, reported in the literature. Two common complex instruments, the Columbia Suicide Seve...
Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell... more Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 +T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 +immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.
Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by al... more Bipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by altered levels of immune/inflammatory markers and disrupted white matter (WM) microstructure. A pro-inflammatory state was suggested to activate indoleamine 2,3-dioxygenase which, in turn, increases the amount of tryptophan (Trp) converted into kynurenine (Kyn). We investigated whether plasma levels of Trp, Kyn and Kyn/Trp ratio are associated with peripheral levels of immune/inflammatory markers and whether they are related to WM integrity in 100 MDD and 66 BD patients. Patients also underwent MRI, and fractional anisotropy (FA) was estimated as a measure of WM microstructure. BD patients showed higher Kyn levels and Kyn/Trp ratio than MDD patients, and lower FA in several WM tracts, including the corpus callosum and the inferior fronto-occipital fasciculus (IFO). Lower Trp levels associated with a more severe depressive symptomatology irrespective of diagnosis and with lower FA in the corpus callosum (CC) and external capsule (EC). We found an association of immune/inflammatory markers with Kyn/Trp ratio selectively in BD patients: IL-1β and TNF-α showed a positive relationship and IL-2 and IL-9 a negative relationship; in addition, higher IL-4 correlated with lower Kyn levels; higher Kyn/Trp ratio and IL-1β correlated with lower FA in the CC and IFO. Notably, the detrimental effect of IL-1β on the IFO was moderated by the Kyn/Trp ratio. These data suggest that in BD, cytokines and the conversion of Trp into Kyn may affect WM microstructure and support the idea that distinct mechanisms underlie the pathophysiology of BD and MDD.
IntroductionBipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter ... more IntroductionBipolar 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...
Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state... more Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state functional connectivity (rsFC) in various neural networks and especially in default-mode network (DMN). However, inconsistent findings, i.e., increased and decreased DMN rsFC, have been reported, which raise the question for the source of DMN changes in MDD. Testing whether the DMN abnormalities in MDD can be traced to either a local, i.e., intra-network, or a global, i.e., inter-network, source, we conducted a novel sequence of rsFC analyses, i.e., global FC, intra-network FC, and inter-network FC. Moreover, all analyses were conducted without global signal regression (non-GSR) and with GSR in order to identify the impact of specifically the global component of functional connectivity on within-network functional connectivity within specifically the DMN. In MDD our findings demonstrate (i) increased representation of global signal correlation (GSCORR) in DMN regions, as confirmed independently by degree of centrality (DC) and by an independent DMN template, (ii) increased within-network DMN rsFC, (iii) highly increased inter-network rsFC of both lower- and higher order non-DMN networks with DMN, (iv) high accuracy in classifying MDD vs. healthy subjects by using GSCORR as predictor. Further supporting the global, i.e., non-DMN source of within-network rsFC of the DMN, all results were obtained only when including the global signal, i.e., non-GSR, but not when conducting GSR. Together, we show for the first time increased global signal representation within rsFC of DMN as stemming from inter-network sources as distinguished from local sources, i.e., within- or intra-DMN.
Human Psychopharmacology: Clinical and Experimental, 2021
OBJECTIVE Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specif... more 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.
Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state... more Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state functional connectivity (rsFC) in various neural networks and especially in default-mode network (DMN). However, inconsistent findings, i.e., increased and decreased DMN rsFC, have been reported, which raise the question for the source of DMN changes in MDD. Testing whether the DMN abnormalities in MDD can be traced to either a local, i.e., intra-network, or a global, i.e., inter-network, source, we conducted a novel sequence of rsFC analyses, i.e., global FC, intra-network FC, and inter-network FC. Moreover, all analyses were conducted without global signal regression (non-GSR) and with GSR in order to identify the impact of specifically the global component of functional connectivity on within-network functional connectivity within specifically the DMN. In MDD our findings demonstrate (i) increased representation of global signal correlation (GSCORR) in DMN regions, as confirmed independently by degree of centrality (DC) and by an independent DMN template, (ii) increased within-network DMN rsFC, (iii) highly increased inter-network rsFC of both lower- and higher order non-DMN networks with DMN, (iv) high accuracy in classifying MDD vs. healthy subjects by using GSCORR as predictor. Further supporting the global, i.e., non-DMN source of within-network rsFC of the DMN, all results were obtained only when including the global signal, i.e., non-GSR, but not when conducting GSR. Together, we show for the first time increased global signal representation within rsFC of DMN as stemming from inter-network sources as distinguished from local sources, i.e., within- or intra-DMN.
Bipolar disorder (BD) is a severe psychiatric illness characterized by abnormalities in the immun... more 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 (1H-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, myo-inositol, N-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 Myo-inositol, and CCL5 positively predicts N-acetylaspartate concentrations. Furthermore, patients showed higher concentrations of glutamate, Myo-inositol, and glutathione and lower concentrations of N-acetylaspartate in respect to healthy controls. Our results confirm that in...
BACKGROUND In bipolar disorder (BD) the risk of suicide in adult life can be influenced by the in... more BACKGROUND In bipolar disorder (BD) the risk of suicide in adult life can be influenced by the interaction of adverse childhood experiences with the serotonin transporter polymorphism (5-HTTLPR). The cortico-limbic connectivity is a candidate endophenotype for the disorder, also related to suicidality and affected by the 5-HT system. METHODS In 64 (*s carriers = 41; l/l = 23) depressed BD patients, we explored the effect of 5-HTTLPR on corticolimbic functional connectivity (FC) during emotional processing, and the role of FC in moderating/mediating the effect of early stressful events on suicidality among 5-HTTLPR groups, by implementing Generalized Structural Equation Model. RESULTS 5-HTTLPR affects FC between amygdala (Amy) and anterior cingulate cortex (ACC), temporal pole, putamen/thalamus, and precuneus. The short allele was associated to a more inefficient corticolimbic connectivity. In 5-HTTLPR*s carriers, but not in l/l, the Amy-ACC functional coupling mediated the relationship between stress load and current suicidality. LIMITATIONS Patients were not drug-naive, and the recruitment took place in a single center, thus raising the possibility of population stratifications. The sample size is relatively small, but our findings can provide the background for replication study in independent and larger datasets. CONCLUSIONS Our results confirm the link between the 5-HTT promoter polymorphism and susceptibility to stress in BD, and suggest that cortico-limbic functional connectivity mediates these effects. This pattern could identify a vulnerability factor for the exacerbation of mood episodes after stressful life events particularly relevant in *s carriers.
BACKGROUND Bipolar disorder (BD) is a severe mental illness characterised by reduced grey matter ... more BACKGROUND Bipolar disorder (BD) is a severe mental illness characterised by reduced grey matter (GM) volumes and cortical thickness, and disrupted white matter (WM) microstructure. Activation of indoleamine 2,3-dioxygenase following a pro-inflammatory state could increase the amount of tryptophan (Trp) converted to kynurenine (Kyn) possibly leading to the production of detrimental catabolites of the Kyn pathway with neurotoxic effects. We investigated if peripheral levels of Trp-and Kyn and the breakdown of Trp-into Kyn (Kyn/Trp-ratio) are related to WM and GM integrity in BD. METHODS Peripheral levels of Trp-and Kyn were analysed in 72 patients with BD and 33 controls. Patients also underwent MRI in a Philips 3T scanner. RESULTS Patients showed higher Kyn levels and Kyn/Trp-ratio compared to controls. MRI analyses performed in patients with BD showed a negative association between the Kyn/Trp-ratio and the integrity of corpus callosum microstructure, the volume of the amygdala and cortical thickness in fronto-parietal regions. LIMITATION The lack of information on the levels of downstream metabolites of Kyn prevent us to confirm the possible unbalance between quinolinic and kynurenic acids as well as their possible relationship with changes in GM and WM markers. The activation of the Kyn pathway as suggested by the increased Kyn/Trp-ratio may lead to an imbalance of the neurotoxic vs the neuroprotective arm of the biochemical pathway, resulting in significant changes in GM and WM regions of brain areas strongly implicated in the pathophysiology of BD, such as amygdala and corpus callosum.
Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune disea... more Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 ...
The aim of the study is to investigate if gene polymorphisms in sterol regulatory element binding... more The aim of the study is to investigate if gene polymorphisms in sterol regulatory element binding protein transcriptional factors SREBF-1 and SREBF-2, which regulate lipid and cholesterol metabolism, could affect white matter (WM) microstructure, the most recognized structural biomarker of bipolar disorder (BD). In a sample of 93 patients affected by BD, we investigated the effect of SREBF-1 rs11868035, and SREBF-2 rs1052717, on WM microstructure, using diffusion tensor imaging and tract-based spatial statistics. We observed increased radial diffusivity in the rs1052717 A/A genotype compared to A/G and G/G, and reduced fractional anisotropy (FA) in the rs1052717 A/A genotype compared to G carriers in cingulum, corpus callosum, superior and inferior longitudinal fasciculi, and anterior thalamic radiation. These results seem to suggest an involvement of SREBF-2 in the integrity of white matter tracts in BD and therefore a possible role of SREBP pathway in CNS myelination processes.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, Jun 1, 2016
Growth factors involved in neurogenesis and neuroplasticity could play a role in biological proce... more Growth factors involved in neurogenesis and neuroplasticity could play a role in biological processes that drive depression recovery. Combined total sleep deprivation and morning light therapy (TSD + LT) can acutely reverse depressive symptoms, thus allowing to investigate the neurobiological correlates of antidepressant response. We tested if changes on plasma levels of Brain Derived Neurotrophic Factor (BDNF), S100 calcium binding protein B (S100-B), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Vascular Endothelial Growth Factor (VEGF) are associated with response to TSD + LT in 26 inpatients affected by a major depressive episode in the course of bipolar disorder. Regional grey matter (GM) volumes were assessed at baseline, and BOLD fMRI neural responses to a moral valence decision task were recorded before and after treatment. 61.5 % of patients responded to treatme...
At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinas... more At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3-beta as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.
Glutamate is the major excitatory neurotransmitter in the brain, with up to 40% of all synapses b... more 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 in...
Objective A major limitation of current suicide research is the lack of power to identify robust ... more Objective A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behaviour. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Method Here, we examine this issue through two approaches: (i) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments; and (ii) by pooling data (N~6,000 participants) from cohorts from the ENIGMA-Major Depressive Disorder (ENIGMA-MDD) and ENIGMA-Suicidal Thoughts and Behaviour (ENIGMA-STB) working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behaviour. Results Our results suggested a pattern of moderate-to-high correlations between instruments, consistent with the wide range of correlations, r=0.22-0.97, reported in the literature. Two common complex instruments, the Columbia Suicide Seve...
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Papers by Sara Poletti
we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 +T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 +immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.
we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 +T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 +immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.