Combined treatment of myo-inositol and d-chiro-inositol (80:1) as a therapeutic approach to restore inositol eumetabolism in patients with bipolar disorder taking lithium and valproic acid.

OBJECTIVE: Patients with bipolar disorder (BD) experience a poor quality of life (QoL) and a weak adherence to the therapy due to the various side effects occurring during the pharmacological therapy. To date clinicians have no tools to intervene on such effects, considering them as an unavoidable part of the therapy. This review paves the way for a step forward in the management of patients with BD bridging the therapeutic gap in clinical practice. MATERIALS AND METHODS: We reviewed the literature, searching through different databases (MEDLINE, Scopus, Google Scholar). We used different keywords, including bipolar disorder, lithium and valproic acid, inositol role in bipolar disorder, side effects, inositol depletion, supplementation of inositols under lithium treatment, inositol role in metabolism, hypothyroidism, renal and cardiac functionality. In particular, we narrowed the search down to English literature, excluding works before 1980s. Regarding clinical studies, we included case reports and both preclinical and clinical studies, especially only those exhibiting a control group. The outcome of the database search was to highlight the threat of side effects and the relationship with inositol lower levels, paving the way for a step forward in the management of patients with BD. RESULTS: Based on the collected evidence, the combined administration of myo-inositol (myo-ins) and d-chiro-inositol (d-chiro-ins) is strongly recommended in order to restore levels and metabolism of inositols. Previous studies pointed out the beneficial effects of inositols in recovering pathological conditions, like polycystic ovary syndrome (PCOS), hypothyroidism, weight gain, cardiac functionality, being all these conditions related to the depletion of inositols. Furthermore, a controlled dosage of inositols, up to 6 grams/daily, may reduce the side effects caused by lithium therapy, without hindering its central therapeutic role on patients' mood. CONCLUSIONS: Considering the iatrogenic depletion of inositols, the tailored ratio 80:1 in favour of myo-ins, may become a safe and effective strategy to counteract side effects, by providing a large amount of myo-ins and an adequate one of d-chiro-ins. The clinical dosage of inositols used as dietary supplementation is 4 grams/daily, and it may allow the recovery of the side effects and improve patients' QoL, without reducing the central therapeutic effect of the pharmacological therapy.

Auditory Oddball Responses Across the Schizophrenia-Bipolar Spectrum and Their Relationship to Cognitive and Clinical Features.

OBJECTIVE: Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features. METHODS: Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values >0.94 between B-SNIP1 and B-SNIP2). RESULTS: Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups. CONCLUSIONS: Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

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.

Effects of Omega 3 Fatty Acids on Main Dimensions of Psychopathology.

The usefulness of polyunsaturated fatty acids on inflammatory, cardiovascular, and the nervous system was studied in the last decades, but the mechanisms underlying their benefic properties are still partially unknown. These agents seem to express their action on the membrane phospholipid composition and permeability and modulation of second messenger cascades. In psychiatry, the efficacy and tolerability of omega-3 fatty acids were investigated in several psychiatric disorders, including major depression, bipolar disorder, personality disorders, high-risk conditions to develop psychosis, attention-deficit hyperactivity disorder, and autism spectrum disorders. Initial findings in this field are promising, and some relevant questions need to be addressed. In particular, the effects of these agents on the main symptom dimensions have to be investigated in a trans-diagnostic perspective. The present systematic review is aimed to examine the available data on the efficacy of omega-3 fatty acids on domains of psychotic symptoms, affective symptoms, impulsivity, and aggressiveness, and harmful behaviors, and suicide risk.

Associations of mismatch negativity with psychotic symptoms and functioning transdiagnostically across psychotic disorders.

Mismatch negativity (MMN) amplitude has been widely shown to be diminished in schizophrenia and, more recently, in other psychotic disorders. Although there is considerable evidence linking MMN reduction to cognitive and functional deficits in schizophrenia, there is little evidence of associations with specific psychotic symptoms. Further, it is unclear if MMN reductions relate to specific symptoms, cognitive, and functional deficits transdiagnostically across different psychotic disorders. The present study examines MMN amplitude in a large cohort of cases diagnosed with psychotic disorders including schizophrenia and schizoaffective disorder (N = 116); bipolar disorder and major depressive disorder (N = 75); and other psychotic disorders (N = 25), as well as individuals with no psychotic disorder diagnoses (N = 248). Furthermore, we examined the association of MMN with symptoms, cognitive functioning, and real-world functioning to determine whether these relationships differ by diagnosis. Results showed that MMN amplitude was reduced in cases overall compared to never-psychotic individuals, with no differences between psychotic disorders. Furthermore, there were transdiagnostic associations of reduced duration MMN (MMN-D) with worse auditory hallucinations (r = .14) and disorganization (r = .14), frequency MMN (MMN-F) with real-word functioning (r = .20) and episodic memory (r = -.22), and both components with executive functioning (MMN-D: r = -.17; MMN-F: r = -.15). Our findings relating MMN reductions with cognitive and real-world functioning replicate earlier research in schizophrenia and extend these relationships to other psychotic disorders. Furthermore, our correlations with MMN-D are consistent with computational modeling research and theoretical proposals that view MMN reduction, cognitive dysfunction, and psychotic symptoms as reflecting underlying predictive coding deficits. However, differences in relationships with MMN-F suggest that additional work is warranted on this topic. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Interleukin-6 and total antioxidant capacity levels following N-acetylcysteine and a combination nutraceutical intervention in a randomised controlled trial for bipolar disorder.

OBJECTIVE: The aims of this study were to evaluate changes in inflammatory and oxidative stress levels following treatment with N-acetylcysteine (NAC) or mitochondrial-enhancing agents (CT), and to assess the how these changes may predict and/or moderate clinical outcomes primarily the Montgomery-Åsberg Depression Rating Scale (MADRS). METHODS: This study involved secondary analysis of a placebo-controlled randomised trial (n = 163). Serum samples were collected at baseline and week 16 of the clinical trial to determine changes in Interleukin-6 (IL-6) and total antioxidant capacity (TAC) following adjunctive CT and/or NAC treatment, and to explore the predictability of the outcome or moderator effects of these markers. RESULTS: In the NAC-treated group, no difference was observed in serum IL-6 and TAC levels after 16 weeks of treatment with NAC or CT. However, results from a moderator analysis showed that in the CT group, lower IL-6 levels at baseline was a significant moderator of MADRS χ2 (df) = 4.90, p = 0.027) and Clinical Global Impression-Improvement (CGI-I, χ2 (df) = 6.28 p = 0.012). In addition, IL-6 was a non-specific but significant predictor of functioning (based on the Social and Occupational Functioning Assessment Scale (SOFAS)), indicating that individuals with higher IL-6 levels at baseline had a greater improvement on SOFAS regardless of their treatment (p = 0.023). CONCLUSION: Participants with lower IL-6 levels at baseline had a better response to the adjunctive treatment with the mitochondrial-enhancing agents in terms of improvements in MADRS and CGI-I outcomes.

Abnormal Functional Relationship of Sensorimotor Network With Neurotransmitter-Related Nuclei via Subcortical-Cortical Loops in Manic and Depressive Phases of Bipolar Disorder.

OBJECTIVE: Manic and depressive phases of bipolar disorder (BD) show opposite psychomotor symptoms. Neuronally, these may depend on altered relationships between sensorimotor network (SMN) and subcortical structures. The study aimed to investigate the functional relationships of SMN with substantia nigra (SN) and raphe nuclei (RN) via subcortical-cortical loops, and their alteration in bipolar mania and depression, as characterized by psychomotor excitation and inhibition. METHOD: In this resting-state functional magnetic resonance imaging (fMRI) study on healthy (n = 67) and BD patients (n = 100), (1) functional connectivity (FC) between thalamus and SMN was calculated and correlated with FC from SN or RN to basal ganglia (BG)/thalamus in healthy; (2) using an a-priori-driven approach, thalamus-SMN FC, SN-BG/thalamus FC, and RN-BG/thalamus FC were compared between healthy and BD, focusing on manic (n = 34) and inhibited depressed (n = 21) patients. RESULTS: (1) In healthy, the thalamus-SMN FC showed a quadratic correlation with SN-BG/thalamus FC and a linear negative correlation with RN-BG/thalamus FC. Accordingly, the SN-related FC appears to enable the thalamus-SMN coupling, while the RN-related FC affects it favoring anti-correlation. (2) In BD, mania showed an increase in thalamus-SMN FC toward positive values (ie, thalamus-SMN abnormal coupling) paralleled by reduction of RN-BG/thalamus FC. By contrast, inhibited depression showed a decrease in thalamus-SMN FC toward around-zero values (ie, thalamus-SMN disconnection) paralleled by reduction of SN-BG/thalamus FC (and RN-BG/thalamus FC). The results were replicated in independent HC and BD datasets. CONCLUSIONS: These findings suggest an abnormal relationship of SMN with neurotransmitters-related areas via subcortical-cortical loops in mania and inhibited depression, finally resulting in psychomotor alterations.

A positive emotion regulation intervention for bipolar I disorder: Treatment development and initial outcomes.

OBJECTIVE: Dysfunction in positive affect is a defining symptom of bipolar I disorder (BD), both during and between mood episodes. We hypothesize that helping people with BD learn skills to create balance in their affective experiences by engaging in strategies that increase low activation positive emotion (LAP; e.g., relaxation) could help to improve well-being during periods of symptom remission. We discuss the development and preliminary outcomes of a positive emotion regulation (PER) group treatment for people with BD, designed as a supplement to pharmacological treatment. METHOD: The Learning Affective Understanding for a Rich Emotional Life (LAUREL) intervention is a group-based intervention covering 10 empirically supported skills designed to increase LAP. Sixteen people with BD enrolled in the LAUREL intervention and twelve completed baseline and post-intervention assessments. RESULTS: Participants who completed the study (n = 12) attended the majority of groups (87.96%) and reported practicing skills, on average, 16 times a week. We were unable to detect significant differences in mania symptoms following engagement in this PER intervention. Finally, participants reported increases in several areas associated with well-being post-intervention, including mindfulness, reappraisal, and self-compassion. CONCLUSION: This study provides a theoretical framework and preliminary support for a PER intervention for BD.

Bipolar disorder and the endocannabinoid system.

OBJECTIVE: Bipolar disorder (BD) is a debilitating, lifelong neuropsychiatric illness characterised by unsteady mood states which vacillate from (hypo)mania to depression. Despite the availability of pharmaceutical agents which can be effective in ameliorating the acute affective symptoms and prevent episodic relapse, BD is inadequately treated in a subset of patients. The endocannabinoid system (ECS) is known to exert neuromodulatory effects on other neurotransmitter systems critical in governing emotions. Several studies ranging from clinical to molecular, as well as anecdotal evidence, have placed a spotlight on the potential role of the ECS in the pathophysiology of BD. In this perspective, we present advantages and disadvantages of cannabis use in the management of illness course of BD and provide mechanistic insights into how this system might contribute to the pathophysiology of BD. RESULTS: We highlight the putative role of selective cannabinoid receptor 2 (CB2) agonists in BD and briefly discuss findings which provide a rationale for targeting the ECS to assuage the symptoms of BD. Further, data encourage basic and clinical studies to determine how cannabis and cannabinoids (CBs) can affect mood and to investigate emerging CB-based options as probable treatment approaches. CONCLUSION: The probable role of the ECS has been almost neglected in BD; however, from data available which suggest a role of ECS in mood control, it is justified to support conducting comprehensive studies to determine whether ECS manipulation could positively affect BD. Based on the limited available data, we suggest that activation of CB2 may stabilise mood in this disorder.

An Activation Likelihood Estimate Meta-analysis of Thalamocortical Dysconnectivity in Psychosis.

BACKGROUND: Thalamocortical dysconnectivity is hypothesized to underlie the pathophysiology of psychotic disorders, including schizophrenia and bipolar disorder, and individuals at clinical high risk. Numerous studies have examined connectivity networks seeding from the thalamus during rest, revealing a pattern of thalamo-fronto-cerebellar hypoconnectivity and thalamosensory hyperconnectivity. However, given variability in these networks, as well as their relationships with clinical and cognitive symptoms, thalamocortical connectivity's status as a biomarker and treatment target for psychotic disorders remains unclear. METHODS: A literature search was performed to identify thalamic seed-based connectivity studies conducted in patients with psychotic disorders. Activation likelihood estimate analysis examined the reported coordinates for hypoconnectivity (healthy control participants > patients with psychosis) and hyperconnectivity (patients with psychosis > healthy control participants). The relationship between hypoconnectivity and hyperconnectivity, as well as their relationships with clinical and cognitive measures, was meta-analyzed. RESULTS: Each activation likelihood estimate included 20 experiments (from 17 publications). Thalamocortical hypoconnectivity was observed in middle frontal, cingulate, and thalamic regions, while hyperconnectivity was observed in motor, somatosensory, temporal, occipital, and insular cortical regions. Meta-analysis of the studies reporting correlations between hypo- and hyperconnectivity showed a strong negative relationship. Meta-analysis of studies reporting correlations between hyperconnectivity and symptoms showed small but significant positive relationships. CONCLUSIONS: Activation likelihood estimates of thalamocortical hypoconnectivity revealed a network of prefrontal and thalamic regions, while hyperconnections identified sensory areas. The strong negative relationship between these thalamocortical deflections suggests that they arrive from a common mechanism and may account for aspects of psychosis. These findings identify reliable thalamocortical networks that may guide future studies and serve as crucial treatment targets for psychotic disorders.

Daytime light exposure in daily life and depressive symptoms in bipolar disorder: A cross-sectional analysis in the APPLE cohort.

OBJECTIVES: Controlled artificial daylight exposure, such as light therapy, is effective in bipolar depression, but the association between uncontrolled daytime light and depressive symptoms in bipolar disorder (BD) is unclear. This study investigated the association between daytime light exposure under real-life situations and depressive symptom in patients with BD. METHODS: This cross-sectional study enrolled 181 outpatients with BD. The average daytime light intensity and the total duration of light intensity of ≥1000 lux were recorded over 7 consecutive days using an actigraph that measured ambient light. Depressive symptoms were assessed using Montgomery-Åsberg Depression Rating Scale, and scores of ≥8 points were treated as depressed state. RESULTS: Ninety-seven (53.6%) subjects were depressed state. At higher average daytime light intensity tertiles, the proportion of depressed state was significantly lower (P for trend, 0.003). In multivariable analysis adjusted for age, employment status, age at onset of BD, Young Mania Rating Scale score, bedtime, and physical activity, the highest tertile group in average daytime light intensity suggested a significantly lower odds ratio (OR) for depressed state than the lowest tertile group (OR, 0.33; 95% confidence interval [CI], 0.14-0.75; P = 0.009). Similarly, the longest tertile group in light intensity ≥1000 lux duration was significantly associated with lower OR for depressed state than lowest tertile group (OR, 0.42; 95% CI, 0.18-0.93; P = 0.033). CONCLUSIONS: The findings suggest that greater daytime light exposure in daily life is associated with decreased depressive symptoms in BD.

Use of "Lights" for Bipolar Depression.

PURPOSE: In this review, we will review the background and diagnosis of bipolar disorder (BD); describe the efficacy data and potential circadian and neural mechanisms underlying the effects of bright light for bipolar depression; and discuss the implementation of light therapy in clinical practice. RECENT FINDINGS: To date, morning bright light is the most widely tested form of light therapy for all mood disorders. Clinical trial reports suggest that midday or morning bright light treatment and novel chronotherapeutic interventions are effective for bipolar depression. Mechanisms of response may relate to effects on the circadian system and other changes in neural functioning. Using bright light to manage depressive symptoms in BD is reasonable but also requires concurrent antimanic treatment and careful clinical monitoring for response, safety, and mood polarity switch.

Improving Functioning, Quality of Life, and Well-being in Patients With Bipolar Disorder.

People with bipolar disorder frequently experience persistent residual symptoms, problems in psychosocial functioning, cognitive impairment, and poor quality of life. In the last decade, the treatment target in clinical and research settings has focused not only on clinical remission, but also on functional recovery and, more lately, in personal recovery, taking into account patients' well-being and quality of life. Hence, the trend in psychiatry and psychology is to treat bipolar disorder in an integrative and holistic manner. This literature review offers an overview regarding psychosocial functioning in bipolar disorder. First, a brief summary is provided regarding the definition of psychosocial functioning and the tools to measure it. Then, the most reported variables influencing the functional outcome in patients with bipolar disorder are listed. Thereafter, we include a section discussing therapies with proven efficacy at enhancing functional outcomes. Other possible therapies that could be useful to prevent functional decline and improve functioning are presented in another section. Finally, in the last part of this review, different interventions directed to improve patients' well-being, quality of life, and personal recovery are briefly described.

Neurophysiological effects of multiple mood episodes in bipolar disorder.

OBJECTIVES: Bipolar disorder is marked by progressive symptomatic changes, which have been linked with episode-related structural findings-particularly in the prefrontal cortex. However, few studies have examined neurofunctional and neurochemical effects of disease burden. In this study, we compared first- and multi-episode bipolar individuals. We hypothesized that the latter would demonstrate evidence of neurophysiological differences consistent with a model of progressive functional degradation of these networks. METHODS: First- and multi-episode manic bipolar subjects participated in functional magnetic resonance imaging (fMRI) including a continuous performance task with emotional distractors, and in single-voxel (1 H) magnetic resonance spectroscopy (MRS). A priori fMRI regions-of-interest (ROI) included structures comprising prefrontal-striatal-amygdala networks; (1 H)MRS voxels were placed within bilateral ventrolateral prefrontal (VLPFC) and anterior cingulate cortex (ACC). Both ROI and voxel-based brain activation in response to emotional stimuli, and neurochemical concentrations derived from (1 H)MRS were compared across bipolar groups. RESULTS: Multi-episode bipolar subjects showed relatively lower regional activation across prefrontal-striatal-amygdala networks, including bilateral VLPFC, orbitofrontal cortex, ACC, putamen, caudate, and amygdala. Exploratory whole-brain, voxel-based analysis suggested additional areas of lower activation extending into Brodmann area 22, posterior parietal regions, and right thalamus. Glutamate and N-acetylaspartate (NAA) concentrations were also relatively lower in the ACC of multi-episode subjects. CONCLUSIONS: Disease burden, exemplified by multiple affective episodes is associated with evidence of widespread decrements in affective network activity. Lower ACC NAA concentration is similarly consistent with a model of progressive functional deficits. These findings support the functional significance of previously observed progressive structural changes throughout these regions.

Treating Circadian Rhythm Disruption in Bipolar Disorder.

PURPOSE OF REVIEW: Disruptions in circadian rhythms are believed to underlie the illness course of bipolar disorder (BD). This review evaluates recent studies on the treatment of circadian dysfunction in BD. RECENT FINDINGS: Targeted social rhythm therapy may be useful for bipolar depression though some studies suggest that a non-targeted psychosocial or pharmacological intervention may be just as efficacious. Lithium holds potential for addressing circadian dysfunction in BD. Blue-blocking therapy may be useful for mania and midday bright light therapy may relieve depression. CONCLUSIONS: Psychosocial, pharmacological, and light-based approaches are promising avenues for treating circadian dysfunction in BD.

Evaluation of the effect of insulin sensitivity-enhancing lifestyle- and dietary-related adjuncts on antidepressant treatment response: protocol for a systematic review and meta-analysis.

BACKGROUND: Depression is the leading cause of disability worldwide and is known to be associated with insulin resistance (IR). Insulin resistance worsens the symptoms of depression and reduces the effectiveness of antidepressant medications in some depressed patients. Many studies have assessed the effect of adjunctive exercise, vitamin D supplementation, zinc supplementation, magnesium, probiotics, unsaturated fatty acids, and hygienic-dietary recommendations (sleep hygiene, healthy diet, physical activity, and sunlight exposure, combined or singly used), individually, on antidepressant treatment response. However, despite the reported insulin sensitivity-enhancing potential of these adjuncts, no systematic review has collectively analysed their antidepressant effect with regards to insulin sensitivity. METHODS/DESIGN: In this systematic review, we will analyse the effect of the above-stated adjuncts on antidepressant treatment response (primary outcome) in comparison with treatment as usual with or without adjunctive placebo after identifying the relevant trials from a systematic literature search. Randomised controlled trials involving clinically depressed patients with diagnosis of major depressive, dysthymic or bipolar disorder will be considered. Changes in insulin sensitivity parameters, following treatment, will also be analysed as the secondary outcome. Effect estimates of the included trials will be combined using random-effects meta-analysis, while addressing risk of bias issues. Any significant heterogeneity between studies will be explored using sensitivity and subgroup analyses. DISCUSSION: The findings of this review will contribute to the evidence base regarding the utility of non-pharmacological insulin-sensitising treatments in enhancing conventional antidepressant treatment response.

Altered functional connectivity among frontal eye fields, thalamus and cerebellum in bipolar disorder. / Zaburzenia polaczen funkcjonalnych miedzy czolowymi polami okoruchowymi, wzgórzem a mózdzkiem w chorobie afektywnej dwubiegunowej.

OBJECTIVES: The aim of our study is to evaluate functional connectivity of cerebellothalamo-cortical networks linking frontal eye fields (FEF) and cerebellar regions associated with oculomotor control: nodulus (X), uvula (IX), flocculus (H X) and ventral paraflocculus (H IX) in bipolar disorder (BD) with the use of resting state functional magnetic resonance imaging (rsfMRI). METHODS: 19 euthymic BD patients and 14 healthy controls underwent rsfMRI examination. Functional connectivity between bilateral FEF, thalamus and cerebellar regions associated with oculomotor control was evaluated. RESULTS: BD patients revealed decreased functional connectivity between following structures: right FEF and bilateral thalamus, flocculus (H X), uvula (IX); right thalamus and right FEF; between right flocculus (H X) and right FEF, left thalamus; between left thalamus and bilateral FEF and right flocculus (H X). CONCLUSIONS: BD patients presented decreased functional connectivity among FEF, thalamus and cerebellar structures associated with eye movements control. Oculomotor evaluation of BD patients assessed with rsfMRI may help to determine whether altered functional connectivity observed in our study is associated with eye movements deficits in BD.

Pathways to mental health care for patients with severe mental illness in Tunisia.

INTRODUCTION: Schizophrenia, bipolar disorder and schizoaffective disorders are severe mental illnesses (SMI) associated with high levels of co-morbid psychopathology and premature mortality. Reducing delays in accessing services and providing early intervention are key strategies in preventing morbidity and mortality associated with these diseases. The pathways to psychiatric care have been studied in many countries worldwide. To the best of our knowledge, no study on this subject has so far been conducted in Tunisia. The purpose of the present study was to understand the pathways of care adopted by patients, to determine the care delay and to explore the relationship between delayed consultation and socio-demographic and clinical variables. METHODS: This is a cross-sectional descriptive study conducted at the Department Psychiatry A of Razi Hospital including patients with SMI consulting the outpatient clinic between January and March 2018. Data was collected by one medical investigator who conducted face-to-face interviews with patients using a questionnaire based on the World Health Organization's "Pathway Questionnaire". Data analysis was done using the SPSS software version 17. A multivariate analysis was performed to study the relation between delayed consultation and socio-demographic and clinical variables. RESULTS: A total of 232 patients responded to the questionnaire. The average age was 41.3 years ± 10.1 and the gender ratio was 1.2. More than the third of the study population consulted a traditional healer in the first place and sixty percent of the patients had recourse to a medical doctor. The average consultation delay was 15 months (±23.0) with a median of 6 months. The delay was more than 6 months in around half of the cases. The symptoms that motivated the first consultation were hallucinations, sleep disorders and aggressive behavior. The main reason of delayed consultation was lack of knowledge about psychiatric symptoms followed by illness beliefs and insidious onset of the illness. The multivariate analysis showed a significant relationship between aggressive behavior and non-delayed consultation. CONCLUSION: The principal recommendations are to strengthen public education and awareness about SMI in the Tunisian population and to implement an early detection program of these disorders.

Lamotrigine as a mood stabilizer: insights from the pre-clinical evidence.

INTRODUCTION: Lamotrigine (LTG) is a well-established anticonvulsant that is also approved for the prevention of mood relapses in bipolar disorder. However, the mechanisms underlying LTG mood stabilizing effects remain unclear. Areas covered: Herein, the pre-clinical evidence concerning LTG's' mode of action in depression and mania is reviewed. Bottlenecks and future perspectives for this expanding and promising field are also discussed. Pre-clinical studies have indicated that neurotransmitter systems, especially serotoninergic, noradrenergic and glutamatergic, as well as non-neurotransmitter pathways such as inflammation and oxidative processes might play a role in LTG's antidepressant effects. The mechanisms underlying LTG's anti-manic properties remain to be fully explored, but the available pre-clinical evidence points out to the role of glutamatergic neurotransmission, possibly through AMPA-receptors. Expert opinion: A major limitation of current pre-clinical investigations is that there are no experimental models that recapitulate the complexity of bipolar disorder. Significant methodological differences concerning time and dose of LTG treatment, administration route, animal strains, and behavioral paradigms also hamper the reproducibility of the findings, leading to contradictory conclusions. Moreover, the role of other mechanisms (e.g. inositol phosphate and GSK3ß pathways) implicated in the mode of action of different mood-stabilizers must also be consolidated with LTG.

Neural response during emotion regulation in monozygotic twins at high familial risk of affective disorders.

PURPOSE: We investigated the neural correlates of emotion regulation and -reactivity in adult unaffected monozygotic twins with a co-twin history of unipolar or bipolar disorder (high-risk), remitted or partially remitted twins with a personal history of unipolar or bipolar disorder (affected) and twins with no personal or first-degree family history of unipolar or bipolar disorder (low-risk). METHODS: We assessed 37 high-risk, 56 affected and 28 low-risk participants. Participants viewed unpleasant and neutral pictures during functional magnetic resonance imaging and were instructed to down-regulate their emotional response through reappraisal or mental imagery, as well as to maintain the elicited emotion. RESULTS: After adjusting for subsyndromal depressive symptoms, bilateral supplementary motor areas, posterior dorsal anterior cingulate cortices and the left frontal eye field showed less activity during reappraisal of unpleasant pictures in high-risk than low-risk participants. Notably, affected participants did not differ from high-risk or low-risk participants in neural response during reappraisal. There were no group differences in ventrolateral prefrontal cortex seed based functional connectivity during reappraisal or neural response during mental imagery or emotional reactivity. CONCLUSION: Lesser response in dorsal midline areas might reflect familial risk related abnormalities during down regulation of emotional reactivity through reappraisal.