The role of clinical and Personological features in predicting high lethality suicide attempts: A study among mood disorder patients.

Suicidal attempts (SA) represent heterogeneous behaviours ranging in their seriousness from fatal and near-fatal (high-lethality) cases to those that do not require medical attention (low lethality). These considerations stress the need to identify high-risk individuals for high lethality SA in order to target suicide preventive interventions. The present study aims at evaluating the role of sociodemographic and clinical variables and examining personality pathological features in predicting high lethality SA. The sample was composed by 94 patients who were consecutively admitted to the Mood Disorders Unit of the San Raffaele Turro Hospital in Milan. The results of binary logistic regression analyses showed that previous SA and current suicide ideation play a role in predicting serious SA. Considering the DSM-5 personality dysfunctional domains assessed by the Personality Inventory for DSM-5, our logistic regression analyses suggested that high lethality SA was associated with Detachment PID-5 domain. Finally, binary hierarchical regression analysis showed that Detachment domain remained a significant predictor of serious SA over and above the effect of previous SA and suicide ideation. As a whole, our results highlight the importance of a multidimensional approach to develop adequate assessment, effective treatments and prevention of high lethality SA risk.

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

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-1ß predicted non-response to antidepressants, with the predicted probability to respond being highly dispersed at low levels of IL-1ß, and stratifying toward non-response when IL-1ß 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.

White Matter Microstructure in Bipolar Disorder Is Influenced by the Interaction between a Glutamate Transporter EAAT1 Gene Variant and Early Stress.

Glutamate is the principal excitatory neurotransmitter in the central nervous system. In mature brains, it is critically involved in neuroplasticity and, at high levels, neurotoxicity. The concentrations of glutamate in the extracellular space are maintained at low physiological levels by molecular glutamate transporters (excitatory amino acid transporters-EAATs). Adverse childhood experiences (ACEs) are highly reported in bipolar disorder (BD) and interact with the glutamatergic system in the brain. The aim of the study is to investigate the effect of a glutamate transporter polymorphism EAAT2-181A > C (rs4354668) and exposure to ACE on white matter microstructure in patients with BD. We assessed 175 bipolar subjects using diffusion tensor imaging, Risky Families Questionnaire, and EEAT2 rs4354668 variants. We observed an interaction between ACE and rs4354668: carriers of the G allele showed lower axial diffusivity compared to T/T homozygotes when exposed to high stress and higher axial diffusivity than T/T when exposed to low stress. Since the mutant G allele has been associated with a reduced transcriptional activity and expression of the transporter protein, and early stress is associated with a reduced expression of the EAAT2, we could hypothesize that after exposure to high levels of ACE G/G homozygotes are more vulnerable to stress reporting the highest damage as a consequence of an excess of free glutamate.

A Glutamate Transporter EAAT1 Gene Variant Influences Amygdala Functional Connectivity in Bipolar Disorder.

Bipolar disorder (BD) is a severe illness characterized by recurrent depressive and manic episodes and by emotional dysregulation. Altered cortico-limbic connectivity could account for typical symptoms of the disorder such as mood instability, emotional dysregulation, and cognitive deficits. Functional connectivity positively associated with glutamatergic neurotransmission. The inactivation of glutamate is handled by a series of glutamate transporters, among them, the excitatory amino acid transporter 1 (EAAT1) which is modulated by a SNP rs2731880 (C/T) where the C allele leads to increased EAAT1 expression and glutamate uptake. We hypothesized that rs2731880 would affect cortico-limbic functional connectivity during an implicit affective processing task. Sixty-eight BD patients underwent fMRI scanning during implicit processing of fearful and angry faces. We explored the effect of rs2731880 on the strength of functional connectivity from the amygdalae to the whole brain. A significant activation in response to emotional processing was observed in two main clusters encompassing the right and left amygdala. Amygdalae to whole-brain functional connectivity analyses revealed a significant interaction between rs2731880 and the task (emotional stimuli vs geometric shapes) for the functional connections between the right amygdala and right subgenual anterior cingulate cortex. Post-hoc analyses revealed that T/T patients showed a significant negative connectivity between the amygdala and anterior cingulate cortex compared to C carriers. T/T subjects also performed significantly better in the face-matching task than rs2731880*C carriers. Our findings reveal an EAAT1 genotype-associated difference in cortico-limbic connectivity during affective regulation, possibly identifying a neurobiological underpinning of emotional dysfunction in BD.

Impact of early and recent stress on white matter microstructure in major depressive disorder.

BACKGROUND: Major Depressive Disorder (MDD) is a worldwide-spread pathology, characterized by lifetime-recurrent episodes. Adverse childhood experiences (ACE) increase the lifetime risk of developing depression and affect the structure of the brain. Recent stressful events (RSE) can trigger the onset of depressive episodes, and affect grey matter volume. The aim of our study is to analyse the effect of both early and recent stress events on white matter microstructure in MDD patients and healthy volunteers. METHODS: Sixty-five MDD inpatients and fifty-nine healthy controls underwent MRI acquisition of diffusion tensor images with a 3.0T scanner. Severity of ACE and RSE was rated, respectively, on the Risky Families Questionnaire and on the Social Readjustment Rating Scale. RESULTS: A significant effect of diagnosis was observed, with MDD subjects showing reduced fractional anisotropy (FA) and axial diffusivity (AD) compared to healthy controls in all the major association, projection and commissural tracts. In patients with MDD, but not in healthy controls, both ACE and RSE correlated with measures of WM microstructure: ACE correlated negatively with AD and MD, whereas RSE correlated negatively with FA. LIMITATIONS: The two diagnostic groups differed for age and education, previous and current medications, and treatment periods. CONCLUSIONS: Exposure to both early and recent stress exerts a widespread effect on WM microstructure of MDD patients, with a different impact possibly depending from the developmental period in which the stress has occurred.

A Homer 1 gene variant influences brain structure and function, lithium effects on white matter, and antidepressant response in bipolar disorder: A multimodal genetic imaging study.

BACKGROUND: The Homer family of postsynaptic scaffolding proteins plays a crucial role in glutamate-mediated synaptic plasticity, a phenotype associated with Bipolar Disorder (BD). Homer is a target for antidepressants and mood stabilizers. The AA risk genotype of the Homer rs7713917 A>G SNP has been associated with mood disorders and suicide, and in healthy humans with brain function. Despite the evidence linking Homer 1 gene and function to mood disorder, as well as its involvement in animal models of depression, no study has yet investigated the role of Homer in bipolar depression and treatment response. METHODS: We studied 199 inpatients, affected by a major depressive episode in course of BD. 147 patients were studied with structural MRI of grey and white matter, and 50 with BOLD functional MRI of emotional processing. 158 patients were treated with combined total sleep deprivation and light therapy. RESULTS: At neuroimaging, patients with the AA genotype showed lower grey matter volumes in medial prefrontal cortex, higher BOLD fMRI neural responses to emotional stimuli in anterior cingulate cortex, and lower fractional anisotropy in bilateral frontal WM tracts. Lithium treatment increased axial diffusivity more in AA patients than in G*carriers. At clinical evaluation, the same AA homozygotes showed a worse antidepressant response to combined SD and LT. CONCLUSIONS: rs7713917 influenced brain grey and white matter structure and function in BD, long term effects of lithium on white matter structure, and antidepressant response to chronotherapeutics, thus suggesting that glutamatergic neuroplasticity and Homer 1 function might play a role in BD psychopathology and response to treatment.

Multidimensional cognitive impairment in unipolar and bipolar depression and the moderator effect of adverse childhood experiences.

AIM: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. These deficits are observable both in major depressive disorder (MDD) and in bipolar disorder (BD) and are present in each phase of the illness, including euthymia. Adverse childhood experiences (ACE) have been associated with an increased risk of developing psychiatric disorders and cognitive deficits. The aim of this study was to assess neuropsychological performances in a sample of MDD and BD patients during a depressive episode compared to healthy controls (HC) and, to investigate if ACE affect the cognitive profiles in the three groups. METHODS: Seventy-six BD patients, 57 MDD patients, and 57 HC underwent neuropsychological assessment for cognitive performances through the Brief Assessment of Cognition in Schizophrenia and Wisconsin Card Sorting Test. RESULTS: Both BD and MDD patients obtained significantly lower domain scores across the entire battery compared to HC. Splitting the sample according to exposure to ACE (high and low), the differences observed in the whole sample persisted only in the subsample of those patients exposed to high ACE. CONCLUSION: This study confirms that cognitive impairment is present both in MDD and BD, albeit in different degrees of severity, and highlights the importance of early stress as a moderator factor when investigating cognitive functions in mood disorders.