A working model of neural activity and phenomenal experience in psychosis.

According to classical phenomenology, phenomenal experience is composed of perceptions (related to environmental stimuli) and imagery/ideas (unrelated to environmental stimuli). Intensity/vividness is supposed to represent the key phenomenal difference between perceptions and ideas, higher in perceptions than ideas, and thus the core subjective criterion to distinguish reality from imagination. At a neural level, phenomenal experience is related to brain activity in the sensory areas, driven by receptor stimulation (underlying perception) or associative areas (underlying imagery/ideas). An alteration of the phenomenal experience that leads to a loss of contact with reality characterizes psychosis, which mainly consists of hallucinations (false perceptions) and delusions (fixed ideas). According to the current data on their neural correlates across subclinical conditions and different neuropsychiatric disorders (such as schizophrenia), hallucinations are mainly associated with: transient (modality-specific) activations of sensory cortices (primarily superior temporal gyrus, occipito-temporal cortex, postcentral gyrus, and insula) during the hallucinatory experience; increased intrinsic activity/connectivity of associative/default-mode network (DMN) areas (primarily temporoparietal junction, posterior cingulate cortex, and medial prefrontal cortex); and deficits in the sensory systems. Analogously, delusions are mainly associated with increased intrinsic activity/connectivity of associative/DMN areas (primarily medial prefrontal cortex). Integrating these data into our three-dimensional model of neural activity and phenomenal-behavioral patterns, we propose the following model of psychosis. A functional/structural deficit in the sensory systems complemented by a functional reconfiguration of intrinsic brain activity favoring hyperactivity of associative/DMN areas may drive neuronal activations in the sensory (auditory/visual/somatosensory) areas and insular (interoceptive) areas with spatiotemporal configurations maximally independent from environmental stimuli and predominantly related to associative processing. This manifests in perception deficit and imagery/ideas composed of exteroceptive-like and interoceptive/affective-like elements that show a phenomenal intensity indistinguishable from perceptions, impairing the reality monitoring, along with minimal changeability by environmental stimuli, ultimately resulting in dissociation of the phenomenal experience from the environment, i.e., psychosis.

A three-dimensional model of neural activity and phenomenal-behavioral patterns.

How phenomenal experience and behavior are related to neural activity in physiology and psychopathology represents a fundamental question in neuroscience and psychiatry. The phenomenal-behavior patterns may be deconstructed into basic dimensions, i.e., psychomotricity, affectivity, and thought, which might have distinct neural correlates. This work provides a data overview on the relationship of these phenomenal-behavioral dimensions with brain activity across physiological and pathological conditions (including major depressive disorder, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, anxiety disorders, addictive disorders, Parkinson's disease, Tourette syndrome, Alzheimer's disease, and frontotemporal dementia). Accordingly, we propose a three-dimensional model of neural activity and phenomenal-behavioral patterns. In this model, neural activity is organized into distinct units in accordance with connectivity patterns and related input/output processing, manifesting in the different phenomenal-behavioral dimensions. (1) An external neural unit, which involves the sensorimotor circuit/brain's sensorimotor network and is connected with the external environment, processes external inputs/outputs, manifesting in the psychomotor dimension (processing of exteroception/somatomotor activity). External unit hyperactivity manifests in psychomotor excitation (hyperactivity/hyperkinesia/catatonia), while external unit hypoactivity manifests in psychomotor inhibition (retardation/hypokinesia/catatonia). (2) An internal neural unit, which involves the interoceptive-autonomic circuit/brain's salience network and is connected with the internal/body environment, processes internal inputs/outputs, manifesting in the affective dimension (processing of interoception/autonomic activity). Internal unit hyperactivity manifests in affective excitation (anxiety/dysphoria-euphoria/panic), while internal unit hypoactivity manifests in affective inhibition (anhedonia/apathy/depersonalization). (3) An associative neural unit, which involves the brain's associative areas/default-mode network and is connected with the external/internal units (but not with the environment), processes associative inputs/outputs, manifesting in the thought dimension (processing of ideas). Associative unit hyperactivity manifests in thought excitation (mind-wandering/repetitive thinking/psychosis), while associative unit hypoactivity manifests in thought inhibition (inattention/cognitive deficit/consciousness loss). Finally, these neural units interplay and dynamically combine into various neural states, resulting in the complex phenomenal experience and behavior across physiology and neuropsychiatric disorders.

Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model.

Bipolar disorder (BD) shows complex alterations in psychomotor, affective, and thought dimensions, as described by Kraepelin in his fundamental model of manic-depressive illness. In turn, the expression of behavioral/phenomenological dimensions is traceable to intrinsic brain activity. We reported a data overview on intrinsic brain functioning and its changes in BD. Accordingly, we proposed a three-dimensional model of the relationship between brain functioning and behavioral/phenomenological patterns, along with its application to BD. In this model, intrinsic brain activity is organized in distinct units in accordance to connectivity patterns and related setting of input/output processing, underlying the different behavioral/phenomenological dimensions. An external unit (mainly involving the sensorimotor network) is connected with the external environment and sets the exteroceptive input/somatomotor output processing, underlying the psychomotor dimension. An internal unit (mainly involving the salience network) is connected to the internal/body environment and sets the interoceptive input/visceromotor output processing, underlying the affective dimension. Finally, an associative unit (mainly involving the default-mode network) is not connected with the environment and sets the processing of associative inputs/outputs, underlying the thought dimension. In each unit, neurotransmitter signaling couples the subcortical-cortical loop, which modulates the network activity levels, in turn setting input/output processing and related expression levels of the behavioral/phenomenological dimension. Different combinations in neurotransmitter signaling favor network balancing into distinct functional brain states, which manifest in different combinations of excitation or inhibition in psychomotricity, affectivity, and thought, resulting in the manic, depressive, and mixed states of BD. Our working model might provide a coherent framework for tracing the complex BD psychopathology to core functional brain alterations.

A unified model of the pathophysiology of bipolar disorder.

This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the pathophysiology of BD. Data on immune-inflammatory changes, structural brain abnormalities (in gray and white matter), and functional brain alterations (from neurotransmitter signaling to intrinsic brain activity) in BD were reviewed. Based on the reported data, (1) we hypothesized that the core pathological alteration in BD is a damage of the limbic network that results in alterations of neurotransmitter signaling. Although heterogeneous conditions can lead to such damage, we supposed that the main pathophysiological mechanism is traceable to an immune/inflammatory-mediated alteration of white matter involving the limbic network connections, which destabilizes the neurotransmitter signaling, such as dopamine and serotonin signaling. Then, (2) we suggested that changes in such neurotransmitter signaling (potentially triggered by heterogeneous stressors onto a structurally-damaged limbic network) lead to phasic (and often recurrent) reconfigurations of intrinsic brain activity, from abnormal subcortical-cortical coupling to changes in network activity. We suggested that the resulting dysbalance between networks, such as sensorimotor networks, salience network, and default-mode network, clinically manifest in combined alterations of psychomotricity, affectivity, and thought during the manic and depressive phases of BD. Finally, (3) we supposed that an additional contribution of gray matter alterations and related cognitive deterioration characterize a clinical-biological subgroup of BD. This model may provide a general framework for integrating the current data on BD and suggests novel specific hypotheses, prompting for a better understanding of the pathophysiology of BD.

All roads lead to the motor cortex: psychomotor mechanisms and their biochemical modulation in psychiatric disorders.

Psychomotor abnormalities have been abundantly observed in psychiatric disorders like major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCH). Although early psychopathological descriptions highlighted the truly psychomotor nature of these abnormalities, more recent investigations conceive them rather in purely motor terms. This has led to an emphasis of dopamine-based abnormalities in subcortical-cortical circuits including substantia nigra, basal ganglia, thalamus, and motor cortex. Following recent findings in MDD, BD, and SCH, we suggest a concept of psychomotor symptoms in the literal sense of the term by highlighting three specifically psychomotor (rather than motor) mechanisms including their biochemical modulation. These include: (i) modulation of dopamine- and substantia nigra-based subcortical-cortical motor circuit by primarily non-motor subcortical raphe nucleus and serotonin via basal ganglia and thalamus (as well as by other neurotransmitters like glutamate and GABA); (ii) modulation of motor cortex and motor network by non-motor cortical networks like default-mode network and sensory networks; (iii) global activity in cortex may also shape regional distribution of neural activity in motor cortex. We demonstrate that these three psychomotor mechanisms and their underlying biochemical modulation are operative in both healthy subjects as well as in MDD, BD, and SCH subjects; the only difference consists in the fact that these mechanisms are abnormally balanced and thus manifest in extreme values in psychiatric disorders. We conclude that psychomotor mechanisms operate in a dimensional and cross-nosological way as their degrees of expression are related to levels of psychomotor activity (across different disorders) rather than to the diagnostic categories themselves. Psychomotor mechanisms and their biochemical modulation can be considered paradigmatic examples of a dimensional approach as suggested in RDoC and the recently introduced spatiotemporal psychopathology.

Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.

Alterations in brain intrinsic activity-as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN), and default-mode network (DMN)-and in neurotransmitters signaling-such as dopamine (DA) and serotonin (5-HT)-have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link, as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, whereas the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, whereas a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitter-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, whereas 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia.

Depression is associated with disconnection of neurotransmitter-related nuclei in multiple sclerosis.

BACKGROUND: Depression is frequently associated with multiple sclerosis (MS). However, the biological background underlying such association is poorly understood. OBJECTIVE: Investigating the functional connections of neurotransmitter-related brainstem nuclei, along with their relationship with white matter (WM) microstructure, in MS patients with depressive symptomatology (MS-D) and without depressive symptomatology (MS-nD). METHODS: Combined resting-state functional magnetic resonance imaging (fMRI) and diffusion-weighted MRI (dMRI) study on 50 MS patients, including 19 MS-D and 31 MS-nD patients, along with 37 healthy controls (HC). Main analyses performed are (1) comparison between groups of raphe nuclei (RN)-related functional connectivity (FC); (2) correlation between RN-related FC and whole brain dMRI-derived fractional anisotropy (FA) map; and (3) comparison between groups of FA in the RN-related WM area. RESULTS: (1) RN-related FC was reduced in MS-D when compared to MS-nD and HC; (2) RN-related FC positively correlated with FA in a WM cluster mainly encompassing thalamic/basal ganglia regions, including the fornix; and (3) FA in such WM area was reduced in MS-D. CONCLUSION: Depressive symptomatology in MS is specifically associated to a functional disconnection of neurotransmitter-related nuclei, which in turn may be traced to a distinct spatial pattern of WM alterations mainly involving the limbic network.

Opposing patterns of neuronal variability in the sensorimotor network mediate cyclothymic and depressive temperaments.

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.

Contrasting variability patterns in the default mode and sensorimotor networks balance in bipolar depression and mania.

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.

White matter microstructure alterations correlate with terminally differentiated CD8+ effector T cell depletion in the peripheral blood in mania: Combined DTI and immunological investigation in the different phases of bipolar disorder.

BACKGROUND: White matter (WM) microstructural abnormalities and, independently, signs of immunological activation were consistently demonstrated in bipolar disorder (BD). However, the relationship between WM and immunological alterations as well as their occurrence in the various phases of BD remain unclear. METHOD: In 60 type I BD patients - 20 in manic, 20 in depressive, 20 in euthymic phases - and 20 controls we investigated: (i) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) using a tract-based spatial statistics (TBSS) approach; (ii) circulating T cell subpopulations frequencies, as well as plasma levels of different cytokines; (iii) potential relationships between WM and immunological data. RESULTS: We found: (i) a significant widespread combined FA-RD alteration mainly in mania, with involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR); (ii) significant increase in CD4+ T cells as well as significant decrease in CD8+ T cells and their subpopulations effector memory (CD8+ CD28-CD45RA-), terminal effector memory (CD8+ CD28-CD45RA+) and CD8+ IFNγ+ in mania; (iii) a significant relationship between WM and immunological alterations in the whole cohort, and a significant correlation of FA-RD abnormalities in the BCC and SCR with reduced frequencies of CD8+ terminal effector memory and CD8+ IFNγ+ T cells in mania only. CONCLUSIONS: Our data show a combined occurrence of WM and immunological alterations in mania. WM abnormalities highly correlated with reduction in circulating CD8+ T cell subpopulations that are terminally differentiated effector cells prone to tissue migration, suggesting that these T cells could play a role in WM alteration in BD.

Functional connectivity and neuronal variability of resting state activity in bipolar disorder--reduction and decoupling in anterior cortical midline structures.

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.

BDNF plasma levels variations in major depressed patients receiving duloxetine.

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.

Evidence of alterations of Beta-endorphin levels and Mu-opioid receptor gene expression in bipolar disorder.

Despite the well-recognized effects of endogenous opioids on mood and behavior, research on its role in bipolar disorder (BD) is still limited to small or anecdotal reports. Considering that Beta-endorphins (ß-END) and Mu-opioid receptors (MOR), in particular, have a crucial activity in affective modulation, we hypothesized their alteration in BD. A cross-sectional study was conducted. We compared: (1) BD type I (BD-I) patients (n = 50) vs healthy controls (n = 27), (2) two BD-I subject subgroups: manic (MAN; n = 25) vs depressed (DEP; n = 25) subjects. Plasma levels of ß-END and MOR gene expression in peripheral blood mononuclear cells were analyzed using ELISA Immunoassay qRT-PCR. We found that subjects with BD exhibited a significant upregulation of MOR gene expression and a decrease of ß-END (p<0.0001 for both). MAN display higher MOR levels than DEP (p<0.001) and HC (p<0.0001). Plasma levels of ß-END were lower in DEP compared to MAN (p<0.05) and HC (p<0.0001). The main limitations are the cross-sectional design and the lack of a group of euthymic subjects. Although preliminary, our results suggest a dysregulation of the endogenous opioid systems in BD. In particular, both MAN and DEP showed a reduction of ß-END levels, whereas MAN was associated with MOR gene overexpression.

Systematic total arch replacement with thoraflex hybrid graft in acute type A aortic dissection: A single centre experience.

Introduction: In the last two decades, a more aggressive approach has been encouraged to treat patients with acute type A aortic dissection (ATAAD), extending the repair to the aortic arch and proximal descending thoracic aorta with the frozen elephant trunk (FET) implantation. Here, we report our single-centre experience with the FET technique for the systematic treatment of emergency type A aortic dissection. Materials and methods: Between December 2017 and January 2022, 69 consecutive patients were admitted with ATAAD; of those, 66 patients (62.9 ± 10.2 years of age, 81.8% men) underwent emergency hybrid aortic arch and FET repair with the multibranched Thoraflex hybrid graft and were enrolled in the study. Primary endpoints were 30 days- and in-hospital mortality. Secondary endpoints were postoperative morbidity and follow-up survival. To better clarify the impact of age on surgical outcomes, we have divided the study population into two groups: group A for patients <70 years of age (47 patients), and group B for patients ≥70 years (19 patients). Time-to-event analysis has been conducted using the Log-rank test and is displayed with Kaplan-Meier curves. A multiple Cox proportional Hazard model was developed to identify predictors of long-term survival with a stepwise backward/forward selection process. Results: 30-days- and in-hospital mortality were 10.6 and 13.6%, respectively. Stroke occurred in three (4.5%) patients. Two (3.0%) patients experienced spinal cord ischemia. We did not find any statistically significant difference between the two groups in terms of main post-operative outcomes. The multivariable Cox proportional hazard model showed left ventricular ejection fraction (HR: 0.83, 95% CI: 0.79-0.92, p < 0.01), peripheral vascular disease (HR: 15.8, 95% CI: 3.9-62.9, p < 0.01), coronary malperfusion (HR: 0.10, 95% CI: 0.01-0.77, p =0.03), lower limbs malperfusion (HR: 5.1, 95% CI: 1.10-23.4, p = 0.04), and cardiopulmonary bypass time (HR: 1.02, 95% CI: 1-1.04, p = 0.01) as independent predictors of long term mortality. Conclusions: Frozen elephant trunk repair to treat emergency type A aortic dissection appears to be associated with good early and mid-term clinical outcomes even in the elderly.

An open pilot study of zonisamide augmentation in major depressive patients not responding to a low dose trial with duloxetine: preliminary results on tolerability and clinical effects.

BACKGROUND: Despite multiple antidepressant options, major depressive disorder (MDD) still faces high non-response rates, eventually requiring anticonvulsant augmentation strategies too. The aim of this study was to explore such a potential role for zonisamide. METHODS: A total of 40 MDD outpatients diagnosed using the Diagnostic and Statistical Manual for Mental Disorders, fourth edition criteria entered a 24 week open trial receiving duloxetine 60 mg/day for the first 12 weeks and subsequently (weeks 12 to 24) augmentation with zonisamide 75 mg/day if they did not respond to the initial monotherapy. Efficacy and tolerability were assessed using the Hamilton Scales for Anxiety and Depression (a 12 week score ≥50% vs baseline defined 'non-response'), the Arizona Sexual Experience Scale, the Patient Rated Inventory of Side Effects and the Young Mania Rating Scale. RESULTS: At week 12, 15 patients out of 39 (38.5%) were responders, and 1 had dropped out; remarkably, 14 patients out of 24 (58.3%) had achieved response by week 24. Poor concentration and general malaise were associated with non-response both at week 12 and 24 (P = 0.001), while loss of libido and reduced energy were prominent among final timepoint non-responders. Patients receiving zonisamide also experienced weight reduction (2.09 ± 12.14 kg; P = 0.001) independently of the outcome. CONCLUSIONS: Although only a preliminary study due to strong methodological limitations, and thus requiring confirmation by further controlled investigations, the current results indicate zonisamide may be a potential augmentation option for some depressed patients receiving low doses of duloxetine.

Adding 5-hydroxytryptamine receptor type 3 antagonists may reduce drug-induced nausea in poor insight obsessive-compulsive patients taking off-label doses of selective serotonin reuptake inhibitors: a 52-week follow-up case report.

Poor-insight obsessive-compulsive disorder (PI-OCD) is a severe form of OCD where the 'typically obsessive' features of intrusive, 'egodystonic' feelings and thoughts are absent. PI-OCD is difficult to treat, often requiring very high doses of serotonergic drugs as well as antipsychotic augmentation. When this occurs, unpleasant side effects as nausea are common, eventually further reducing compliance to medication and increasing the need for pharmacological alternatives. We present the case of a PI-OCD patient who developed severe nausea after response to off-label doses of the selective serotonin reuptake inhibitor (SSRI), fluoxetine. Drug choices are discussed, providing pharmacodynamic rationales and hypotheses along with reports of rating scale scores, administered within a follow-up period of 52 weeks. A slight reduction of fluoxetine dose, augmentation with mirtazapine and a switch from amisulpride to olanzapine led to resolution of nausea while preserving the anti-OCD therapeutic effect. Mirtazapine and olanzapine have already been suggested for OCD treatment, although a lack of evidence exists about their role in the course of PI-OCD. Both mirtazapine and olanzapine also act as 5-hydroxytryptamine receptor type 3 (5-HT3) blockers, making them preferred choices especially in cases of drug-induced nausea.

Opposing Changes in the Functional Architecture of Large-Scale Networks in Bipolar Mania and Depression.

OBJECTIVE: Manic and depressive phases of bipolar disorder (BD) show opposite symptoms in psychomotor, thought, and affective dimensions. Neuronally, these may depend on distinct patterns of alterations in the functional architecture of brain intrinsic activity. Therefore, the study aimed to characterize the spatial and temporal changes of resting-state activity in mania and depression, by investigating the regional homogeneity (ReHo) and degree of centrality (DC), in different frequency bands. METHODS: Using resting-state functional magnetic resonance imaging (fMRI), voxel-wise ReHo and DC were calculated-in the standard frequency band (SFB: 0.01-0.10 Hz), as well as in Slow5 (0.01-0.027 Hz) and Slow4 (0.027-0.073 Hz)-and compared between manic (n = 36), depressed (n = 43), euthymic (n = 29) patients, and healthy controls (n = 112). Finally, clinical correlations were investigated. RESULTS: Mania was mainly characterized by decreased ReHo and DC in Slow4 in the medial prefrontal cortex (as part of the default-mode network [DMN]), which in turn correlated with manic symptomatology. Conversely, depression was mainly characterized by decreased ReHo in SFB in the primary sensory-motor cortex (as part of the sensorimotor network [SMN]), which in turn correlated with depressive symptomatology. CONCLUSIONS: Our data show a functional reconfiguration of the spatiotemporal structure of intrinsic brain activity to occur in BD. Mania might be characterized by a predominance of sensorimotor over associative networks, possibly driven by a deficit of the DMN (reflecting in internal thought deficit). Conversely, depression might be characterized by a predominance of associative over sensorimotor networks, possibly driven by a deficit of the SMN (reflecting in psychomotor inhibition).

Opioidergic System and Functional Architecture of Intrinsic Brain Activity: Implications for Psychiatric Disorders.

The opioidergic system and intrinsic brain activity, as organized in large-scale networks such as the salience network (SN), sensorimotor network (SMN), and default-mode network (DMN), play core roles in healthy behavior and psychiatric disorders. This work aimed to investigate how opioidergic signaling affects intrinsic brain activity in healthy individuals by reviewing relevant neuroanatomical, molecular, functional, and pharmacological magnetic resonance imaging studies in order to clarify their physiological links and changes in psychiatric disorders. The SN shows dense opioidergic innervations of subcortical structures and high expression levels of opioid receptors in subcortical-cortical areas, with enhanced or reduced activity with low or very high doses of opioids, respectively. The SMN shows high levels of opioid receptors in subcortical areas and functional disconnection caused by opioids. The DMN shows low levels of opioid receptors in cortical areas and inhibited or enhanced activity with low or high doses of opioids, respectively. Finally, we proposed a working model. Opioidergic signaling enhances SN and suppresses SMN (and DMN) activity, resulting in affective excitation with psychomotor inhibition; stronger increases in opioidergic signaling attenuate the SN and SMN while disinhibiting the DMN, dissociating affective and psychomotor functions from the internal states; the opposite occurs with a deficit of opioidergic signaling.