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Purpose Anorexia nervosa (AN) is a serious and complex mental disorder affecting mainly young adult women. AN patients are characterized by low body weight in combination with self-induced starvation, intense fear of gaining weight, and distortion of body image. AN is a multifactorial disease, linked by recent evidence to a dysregulation of the immune system. Methods In this pilot study, 22 blood serums from AN patients were tested for the presence of autoantibodies against primate hypothalamic periventricular neurons by immunofluorescence and by a home-made ELISA assay. Cellular fluorescence suggests the presence of autoantibodies which are able to recognize these neurons (both to body cell and fiber levels). By means of ELISA, these autoantibodies are quantitatively evaluated. In addition, orexigenic and anorexigenic molecules were measured by ELISA. As control, 18 blood serums from healthy age matched woman were analysed. Results All AN patients showed a reactivity against hypothalamic neurons both by immunofluorescence and ELISA. In addition, ghrelin, pro-opiomelanocortin (POMC), and agouti-related peptide (AGRP) were significantly higher than in control serums (p p Conclusions Immunoreaction and ELISA assays on AN blood serum suggest the presence of autoantibodies AN related. However, it is not easy to determine the action of these antibodies in vivo: they could interact with specific ligands expressed by hypothalamic cells preventing their physiological role, however, it is also possible that they could induce an aspecific stimulation in the target cells leading to an increased secretion of anorexigenic molecules. Further studies are needed to fully understand the involvement of the immune system in AN pathogenesis. Level of evidence V, descriptive study.

Background and aim of the work: Suicide is a worldwide phenomenon, with a relevant number of victims. Moreover, repercussions of suicidality-across its entire spectrum-involve not only the individual but also survivors and communities, in a profound and lasting way. As such, suicidality represents a crucial public mental health concern, in which risk/protection factors’ study represent a key issue. However, research primarily focused on suicidality risk factors. This study, moving from Frankl’s first observations on “Meaning in Life” (MiL) as protective against suicidality, aimed to identify the main themes that suicidal patients identified as MiL carriers, or potential carriers, in their existences. Methods: Qualitative study on 144 patients admitted to the Geneva University Hospital’s emergency department for suicidal ideation (SI) and suicide attempt (SA). Results: Interpersonal/affective relationships constituted the main theme (71.53%), with emphasis on family (39.80%), children/grandchildren (36.89%). Profession/education, intellectual/non-intellectual pleasures, and transcendental dimension also emerged. Conclusions: These aspects could be considered among a public health agenda’s points for suicide prevention programs taking into account also protective factors promotion/support, including community’s mental health resources. Reconnecting to introduction’s historical part, our findings are consistent with Frankl’s observations. Even if exposed to “absurd” and reluctant to deliberate on this, he seems approach Camus conceptualization who, confronted to the necessity of predictable and conform to recognizable personal patterns transcending chaos for a sense-giving perspective, invited to imagine that a meaning, even a “non-absolute meaning”, may lie in apparent smallest things and that Sisyphus can have “the possibility to revolt by trying to be happy”.

Environmental variables can regulate behavior in healthy subjects. Recently, some authors investigated the role of meteorological variables in bipolar patients with an impact on both the onset and course of bipolar disorder (BD). The aim of this study was to investigate the impact of meteorological variables and other indexes in bipolar hospitalized patients. We examined all patients admitted to the Psychiatric Inpatient Unit of San Luigi Gonzaga Hospital, Orbassano (Turin, Italy) from September 2013 to August 2015, collecting several socio-demographic and clinical characteristics. Seven hundred and thirty patients were included. Compared to the day of admission of control individuals, patients with BD were admitted on a day that presented higher minimum, medium, and maximum temperature, higher maximum humidity, higher solar radiation, and higher hours of sunshine. After logistic regression analysis, admissions to the emergency psychiatric ward due to a primary diagnosis of BD were associated with maximum temperature and solar radiation. The current study provides a novel perspective on the question surrounding seasonal mood patterns in patients with BD. A greater awareness of all possible precipitating factors is needed to inform self-management and psycho-educational programs as well as to improve resilience regarding affective recurrences in the clinical practice.

Depressive and manic phases in bipolar disorder show opposite constellations of affective, cognitive, and psychomotor symptoms. At a neural level, these may be related to topographical disbalance between large-scale networks, such as the default mode network (DMN) and sensorimotor network (SMN). We investigated topographical patterns of variability in the resting-state signal-measured by fractional SD (fSD) of the BOLD signal-of the DMN and SMN (and other networks) in two frequency bands (Slow5 and Slow4) with their ratio and clinical correlations in depressed (n = 20), manic (n = 20), euthymic (n = 20) patients, and healthy controls (n = 40). After controlling for global signal changes, the topographical balance between the DMN and SMN, specifically in the lowest frequency band, as calculated by the Slow5 fSD DMN/SMN ratio, was significantly increased in depression, whereas the same ratio was significantly decreased in mania. Additionally, Slow5 variability was increased in the DMN and decreased in the SMN in depressed patients, whereas the opposite topographical pattern was observed in mania. Finally, the Slow5 fSD DMN/SMN ratio correlated positively with clinical scores of depressive symptoms and negatively with those of mania. Results were replicated in a smaller independent bipolar disorder sample. We demonstrated topographical abnormalities in frequency-specific resting-state variability in the balance between DMN and SMN with opposing patterns in depression and mania. The Slow5 DMN/SMN ratio was tilted toward the DMN in depression but was shifted toward the SMN in mania. The Slow5 fSD DMN/SMN pattern could constitute a state-biomarker in diagnosis and therapy.

Affective temperaments have been described since the early 20th century and may play a central role in psychiatric illnesses, such as bipolar disorder (BD). However, the neuronal basis of temperament is still unclear. We investigated the relationship of temperament with neuronal variability in the resting state signal—measured by fractional standard deviation (fSD) of Blood‐Oxygen‐Level Dependent signal—of the different large‐scale networks, that is, sensorimotor network (SMN), along with default‐mode, salience and central executive networks, in standard frequency band (SFB) and its sub‐frequencies slow4 and slow5, in a large sample of healthy subject (HC, n = 109), as well as in the various temperamental subgroups (i.e., cyclothymic, hyperthymic, depressive, and irritable). A replication study on an independent dataset of 121 HC was then performed. SMN fSD positively correlated with cyclothymic z‐score and was significantly increased in the cyclothymic temperament compared to the depressive temperament subgroups, in both SFB and slow4. We replicated our findings in the independent dataset. A relationship between cyclothymic temperament and neuronal variability, an index of intrinsic neuronal activity, in the SMN was found. Cyclothymic and depressive temperaments were associated with opposite changes in the SMN variability, resembling changes previously described in manic and depressive phases of BD. These findings shed a novel light on the neural basis of affective temperament and also carry important implications for the understanding of a potential dimensional continuum between affective temperaments and BD, on both psychological and neuronal levels.

Summary Backgrounds Nerve growth factor (NGF) is involved in the modulation of the neuro–endocrine–immune (NEI) system, whereas alterations in neuroplasticity and NEI homeostasis seem to play a role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate NGF levels variations in MDD patients during antidepressant treatment with duloxetine, a relatively newer SNRI. Methods 30 MDD patients and 32 healthy controls were assessed using Hamilton depression scale (HAM-D) and monitored for NGF serum levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. Results According to early clinical response to duloxetine (defined at week 6 by reduction >50% of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who overall reached clinical response at week 12. Laboratory analysis showed overall significant lower baseline NGF levels among depressed patients compared to healthy controls, not significantly in ER and significantly in ENR. During duloxetine treatment NGF levels further decreased in association with clinical response, reaching significantly lower values in ER at W6 compared to controls, and in ENR at W12 compared to baseline. Conclusions A decrease in NGF levels during duloxetine treatment in association to clinical response could be indicative of a relative restoring of NEI stress-adaptation system, since stressors, inducing neuronal instability due to neurotrophins activity changes, permits circuitry remodeling as background in the selection of alternative adaptive behaviors. However, the lower baseline NGF levels found in MDD patients that further decrease during the treatment could represent a lower neurotrophin set point, possibly reflecting a functional impairment in stress-adaptive neuroplasticity in depressive disorders.

Objective The objective of the study was to investigate the relationship between structural connectivity (SC) and functional connectivity (FC) in the cingulum in bipolar disorder (BD) and its various phases. Method We combined resting-state functional magnetic resonance imaging and probabilistic tractographic diffusion tensor imaging to investigate FC and SC of the cingulum and its portions, the SC–FC relationship, and their correlations with clinical and neurocognitive measures on sustained attention in manic (n = 21), depressed (n = 20), and euthymic (n = 20) bipolar patients and healthy controls (HC) (n = 42). Results First, we found decreased FC between the anterior and posterior parts of the cingulum in manic patients when compared to depressed patients and HC. Second, we observed decreased SC of the cingulum bundle, particularly in its anterior part, in manic patients when compared to HC. Finally, alterations in the cingulum FC (but not SC) correlated with clinical severity scores while changes in the cingulum SC (but not FC) were related with neurocognitive deficits in sustained attention in BD. Conclusion We demonstrate for the first time a reduction in FC and concomitantly in SC of the cingulum in mania, which correlated with psychopathological and neurocognitive parameters, respectively, in BD. This supports the central role of cingulum connectivity specifically in mania.

Background In recent years, diffusion tensor imaging (DTI) studies have detected subtle microstructural abnormalities of white matter (WM) in type I bipolar disorder (BD). However, WM alterations in the different phases of BD remain to be explored. The aims of this study is to investigate the WM alterations in the various phases of illness and their correlations with clinical and neurocognitive features. Methods We investigated the DTI-derived fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) in patients with type I BD (n=61) subdivided in manic (n=21), depressive (n=20) and euthymic phases (n=20) vs. healthy controls (n=42), using a tract-based spatial statistics (TBSS) approach. Then, we investigated whether the subgroups of patients in the various phases of illness present different patterns of WM abnormalities. Finally we studied the correlations between WM alterations and clinical-cognitive parameters. Results We found a widespread alteration in WM microstructure (decrease in FA and increase in MD and RD) in BD when compared to controls. The various subgroups of BD showed different spatial patterns of WM alterations. A gradient of increasing WM abnormalities from the euthymic (low degree and localized WM alterations mainly in the midline structures) to the manic (more diffuse WM alterations affecting both midline and lateral structures) and, finally, to the depressive phase (high degree and widespread WM alterations), was found. Furthermore, the WM diffuse alterations correlated with cognitive deficits in BD, such as decreased fluency prompted by letter and decreased hits and increased omission errors at the continuous performance test. Limitations Patients under treatment. Conclusions The WM alterations in type I BD showed different spatial patterns in the various phases of illness, mainly affecting the active phases, and correlated with some cognitive deficits. This suggests a complex trait- and state-dependent pathogenesis of WM abnormalities in BD.

Introduction: The cortical midline structures seem to be involved in the modulation of different resting state networks, such as the default mode network (DMN) and salience network (SN). Alterations in these systems, in particular in the perigenual anterior cingulate cortex (PACC), seem to play a central role in bipolar disorder (BD). However, the exact role of the PACC, and its functional connections to other midline regions (within and outside DMN) still remains unclear in BD. Methods: We investigated functional connectivity (FC), standard deviation (SD, as a measure of neuronal variability) and their correlation in bipolar patients (n = 40) versus healthy controls (n = 40), in the PACC and in its connections in different frequency bands (standard: 0.01–0.10 Hz; Slow‐5: 0.01–0.027 Hz; Slow‐4: 0.027–0.073 Hz). Finally, we studied the correlations between FC alterations and clinical‐neuropsychological parameters and we explored whether subgroups of patients in different phases of the illness present different patterns of FC abnormalities. Results: We found in BD decreased FC (especially in Slow‐5) from the PACC to other regions located predominantly in the posterior DMN (such as the posterior cingulate cortex (PCC) and inferior temporal gyrus) and in the SN (such as the supragenual anterior cingulate cortex and ventrolateral prefrontal cortex). Second, we found in BD a decoupling between PACC‐based FC and variability in the various target regions (without alteration in variability itself). Finally, in our subgroups explorative analysis, we found a decrease in FC between the PACC and supragenual ACC (in depressive phase) and between the PACC and PCC (in manic phase). Conclusions: These findings suggest that in BD the communication, that is, information transfer, between the different cortical midline regions within the cingulate gyrus does not seem to work properly. This may result in dysbalance between different resting state networks like the DMN and SN. A deficit in the anterior DMN‐SN connectivity could lead to an abnormal shifting toward the DMN, while a deficit in the anterior DMN‐posterior DMN connectivity could lead to an abnormal shifting toward the SN, resulting in excessive focusing on internal contents and reduced transition from idea to action or in excessive focusing on external contents and increased transition from idea to action, respectively, which could represent central dimensions of depression and mania. If confirmed, they could represent diagnostic markers in BD. Hum Brain Mapp 36:666–682, 2015. © 2014 Wiley Periodicals, Inc.

It has been frequently reported that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate BDNF levels variations in MDD patients during antidepressant treatment with duloxetine. 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for BDNF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. According to early clinical response to duloxetine (defined at week 6 by reduction >50 % of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non-responders (ENR), who reached clinical response at week 12. Laboratory analysis showed significant lower baseline BDNF levels among patients compared to controls. During duloxetine treatment, in ENR BDNF levels increased, reaching values not significantly different compared to controls, while in ER BDNF levels remained nearly unchanged. Lower baseline BDNF levels observed in patients possibly confirm an impairment of the NEI stress-adaptation system and neuroplasticity in depression, while BDNF increase and normalization observed only in ENR might suggest differential neurobiological backgrounds in ER vs. ENR within the depressive syndrome.

Background The vascular endothelial growth factor (VEGF) signaling, which modulates angiogenesis and neurogenesis within the neurovascular unit, might play an important role in the neuro-endocrine-immune (NEI) stress-adaptation system. Recent evidence suggests that VEGF is involved in the pathophysiology of a number of diseases including major depressive disorder (MDD) and is affected by some treatments, including antidepressants. The objective of the study was to investigate the VEGF level variations in MDD patients during antidepressant treatment with duloxetine, a relatively new SNRI. Methods A total of 30 MDD patients and 32 healthy controls were assessed using the Hamilton Depression Scale (HAM-D) and monitored for VEGF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. Results According to early clinical response to duloxetine (defined at week 6 by reduction>50% of baseline HAM-D score), the MDD patients were divided into early responders (ER) and early non-responders (ENR). During duloxetine treatment, we found an opposite trend in the VEGF levels between ER and ENR: in ER the VEGF levels significantly increased in association with clinical response at W6, while in ENR the VEGF levels significantly decreased in association with an overall clinical response at W12. Limitations Small sample size. Conclusions The opposite trends in VEGF levels, increasing in ER and decreasing in ENR, might reflect differential Norepinephrine/Serotonin effects of duloxetine on differential neurobiological backgrounds of depressive syndromes. Overall, the modulation of VEGF signaling within the neurovascular unit during antidepressant treatment could hypothetically favor the remodeling of neural circuitry, contributing to adaptive adjustment of the NEI stress-adaptation system.

Background Correlational studies investigating neurohormonal-cytokine modulation by antidepressants suggest, among others, variations in cytokines balances as state markers of different biological subtypes of major depressive disorder (MDD) and response predictors to specific treatments. Objective of the study was to investigate cytokines modulation by duloxetine, a relatively newer SNRI with “clean” dual serotonin/norepinephrine mechanism. Methods 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for levels of IL-1β, IL-2, IL-4, IL-10, IL-12, IFN-γ and TNF-α, at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. Results Early responders (ER: defined at week 6 by reduction >50% of baseline HAM-D score) and early non-responders (ENR) showed opposite trends in cytokine levels during duloxetine treatment: ENR were characterized by baseline Th2 shift compared to controls (lower IL-1β, IFN-γ and TNF-α) with increase in Th1 cytokines levels during treatment (increase of IL-1β, IL-12, IFN-γ, IL-1β/IL-10 and TNF-α/IL-10, decrease of IL-10), achieving clinical response at week 12; ER were characterized by baseline Th2-to-Th1 relative switch compared to ENR (higher IL-1β, IL-1β/IL-10 and TNF-α/IL-10) with reduction in Th1 cytokines levels during treatment (decrease of TNF-α and TNF-α/IL-10), achieving clinical response at week 6. Limitations Small sample size. Conclusions In accordance to early clinical response, duloxetine treatment could divide depressed patients into at least 2 subgroups characterized by clinical and laboratory differentiated behavior, suggesting different neurobiological background within depressive syndrome differentially sensitive to different drug components: pro-serotonergic effect and increase in Th1 cytokines in ENR vs. pro-noradrenergic effect and decrease in Th1 cytokines in ER.

Introduction Despite intense research efforts, still too little is known about the biological determinants of depression, thus soliciting diverse study approaches. Among others, the electroretinography (ERG) has been proposed even as a putative proxy (retinal) measurement of central dopaminergic activity for Major Depressive Disorder (MDD) both in drug-naive patients and subjects receiving antidepressant treatments. Nonetheless, current evidences are merely preliminary, essentially considering just older classes of antidepressants, thus requiring confirmation studies even with newer agents as duloxetine. Method Twenty MDD subjects and 20 matched controls received duloxetine 60 mg/day for 12 weeks, being monitored both by standard ERG recording and by administration of the Hamilton scales for Depression and Anxiety and the Young Mania Rating Scale at baseline and week 12 (end of the study). Results ERG mean rod b-wave amplitude significantly reduced from baseline to week 12 in those depressed subjects achieving final response ( p = .024), decreasing from the highest rank values to the ones, substantially unmodified, seen among non-responders and controls. Limitations Small sample size and lack of multiple assessments. Conclusions At least some MDD patients responding to duloxetine might exhibit a peculiar ERG pattern, hypothetically indicating a specific biological background. If confirmed by larger-sampled studies, these results might shed further light in the understanding of the biological determinants of different subtypes of depression, ideally showing alternative patters of response upon different treatment interventions.