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Bipolar disorder is a chronic and severe psychiatric illness affecting many patients during their childbearing years. Bipolar disorder is often managed with aripiprazole, a generally well tolerated second-generation antipsychotic medication. Published data regarding its safety profile are reassuring and aripiprazole is prescribed during pregnancy, postpartum and during lactation. Pregnancy and the postpartum period represent times of increased vulnerability for patients with bipolar disorder, especially those who are untreated, highlighting the need for medical management. However, aripiprazole may interfere with human milk production. Currently, there is limited evidence to understand lactation failure in patients who take aripiprazole. This case reinforces the need for shared decision making regarding the potential impact on lactation when aripiprazole is being considered for the pregnant patient with bipolar disorder., Highlights • Bipolar disorder affects 2–4 % of the world’'s population and is the 4th leading cause of disability among young people. • Aripiprazole is a second generation antipsychotic used for treatment of BD during pregnancy and lactation. • Aripiprazole may cause lactation failure, interfering with maternal, infant bonding. • Shared decision making is essential when working with patients who have Bipolar disorder during childbearing years.

BackgroundDepressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. Overcoming these disorders is an extremely important public health problem today. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. Due to advances in technology, it has become possible to quantify important features that clinicians perceive as reflective of disorder severity. Such features include facial expressions, phonic/speech information, body motion, daily activity, and sleep. The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders.MethodsThis is a multi-center prospective study. DSM-5 criteria for major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders are inclusion criteria for the depressive and neurocognitive disorder samples. Healthy samples are confirmed to have no history of psychiatric disorders by Mini-International Neuropsychiatric Interview, and have no current cognitive decline based on the Mini Mental State Examination. Participants go through approximately 10-minute interviews with a psychiatrist/psychologist, where participants talk about non-specific topics such as everyday living, symptoms of disease, hobbies, etc. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. The interviews take place ≤10 times within up to five years of follow-up. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms.DiscussionThe PROMPT goal is to develop objective digital biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity.Trial RegistrationUMIN000021396, University Hospital Medical Information Network (UMIN)

Mental disorders (MDs) are highly prevalent and potentially debilitating complex disorders which causes remain elusive. Looking into deeper aspects of etiology or pathophysiology underlying these diseases would be highly beneficial, as the scarce knowledge in mechanistic and molecular pathways certainly represents an important limitation. Association between MDs and inflammation/neuroinflammation has been widely discussed and accepted by many, as high levels of pro-inflammatory cytokines were reported in patients with several MDs, such as schizophrenia (SCZ), bipolar disorder (BD) and major depression disorder (MDD), among others. Correlation of pro-inflammatory markers with symptoms intensity was also reported. However, the mechanisms underlying the inflammatory dysfunctions observed in MDs are not fully understood yet. In this context, microglial dysfunction has recently emerged as a possible pivotal player, as during the neuroinflammatory response, microglia can be over-activated, and excessive production of pro-inflammatory cytokines, which can modify the kynurenine and glutamate signaling, is reported. Moreover, microglial activation also results in increased astrocyte activity and consequent glutamate release, which are both toxic to the Central Nervous System (CNS). Also, as a result of increased microglial activation in MDs, products of the kynurenine pathway were shown to be changed, influencing then the dopaminergic, serotonergic, and glutamatergic signaling pathways. Therefore, in the present review, we aim to discuss how neuroinflammation impacts on glutamate and kynurenine signaling pathways, and how they can consequently influence the monoaminergic signaling. The consequent association with MDs main symptoms is also discussed. As such, this work aims to contribute to the field by providing insights into these alternative pathways and by shedding light on potential targets that could improve the strategies for pharmacological intervention and/or treatment protocols to combat the main pharmacologically unmatched symptoms of MDs, as the SCZ., Highlights • Alterations in the cytokine profile in mental disorders patients. • Unbalanced kynurenine pathway leads to excitotoxicity and NMDA hypoactivation. • Increased glutamate production leads to excitotoxicity. • Microglial and astrocytic activation influences in neurotransmission pathways.

The brain underpinnings of schizophrenia and bipolar disorders are multidimensional, reflecting complex pathological processes and causal pathways, requiring multivariate techniques to disentangle. Furthermore, little is known about the complementary clinical value of brain structural phenotypes when combined with data on cognitive performance and genetic risk. Using data-driven fusion of cortical thickness, surface area, and gray matter density maps (GMD), we found six biologically meaningful patterns showing strong group effects, including four statistically independent multimodal patterns reflecting co-occurring alterations in thickness and GMD in patients, over and above two other independent patterns of widespread thickness and area reduction. Case-control classification using cognitive scores alone revealed high accuracy, and adding imaging features or polygenic risk scores increased performance, suggesting their complementary predictive value with cognitive scores being the most sensitive features. Multivariate pattern analyses reveal distinct patterns of brain morphology in mental disorders, provide insights on the relative importance between brain structure, cognitive and polygenetic risk score in classification of patients, and demonstrate the importance of multivariate approaches in studying the pathophysiological substrate of these complex disorders., Highlights • Linked ICA showed six independent multivariate morphology patterns sensitive to SZ. • Machine learning used to compare brain structure, cognitive and genetic scores. • Cognition showed highest prediction of SZ, boosted by brain structure or genetics.

Highlights • Effects of lithium treatment duration on deep grey matter shape in BD are investigated. • Treatment duration impacts nucleus accumbens shape. • Extroflection effects, are related to longer duration in accumbens core. • Left accumbens core shape is correlated with increased depression severity., The effects of lithium treatment duration on deep grey matter structures in bipolar disorder are not well known. In this cross-sectional neuroimaging case-control study, we tested the hypothesis that shape characteristics of deep grey matter structures in bipolar disorder are associated with the duration of lithium treatment and with clinical phenomenology. In a setting of neuropsychiatry outpatient clinic, we included 74 patients with bipolar disorder (BD) and 74 matched healthy control subjects (HC). Both groups underwent a Magnetic Resonance Imaging acquisition and an exhaustive assessment of clinical and psychiatrics dimensions. Shape measures of seven deep grey matter structures (hippocampus, amygdala, caudate, nucleus accumbens, putamen, globus pallidus and thalamus) were obtained from T1 weighted images in both groups, using FSL FIRST segmentation tool. The segmented structures were then analysed vertex-by-vertex with FSL Randomise tool. First, we investigated the presence of significant associations between the duration of lithium treatment and shape measures in BD sample. Then, for structures that resulted significantly associated with the duration of lithium treatment, comparisons between BD and HC were performed either considering the BD group as a whole or dividing it in three groups based on the duration of treatment (lithium drug-naïve, short and long treated). Any deformation uncovered by group comparisons was subsequently associated with depressive and hypomanic/manic symptoms. The relationship between structures shape and the duration of lithium treatment in BD sample was significant for bilateral nucleus accumbens. Specifically, significant bilateral extroflection effects, related to longer duration of lithium treatment, were found bilaterally over the surface shape of core accumbens nuclei (r2R-Accu-Core = 0.12, p = 0.016, r2L-Accu-Core = 0.1, p = 0.031). Moreover, introflection effect related to longer duration of treatment resulted over the shell of right accumbens (r2R-Accu-Shell = 0.17, p = 0.002). Nucleus accumbens shape did not differ between BD and HC considering BD group as a whole. By contrast, categorizing BD in subgroups as a function of the duration of lithium treatment revealed significant inward deformation on the core of left accumbens nucleus and outward deformation on the shell of the right accumbens nucleus in lithium-naive patients, compared to both patients with long duration of lithium treatment (pL-Accu-Core = 0.016, pR-Accu-Shell = 0.005) and HC (pL-Accu-Core = 0.002; pR-Accu-Shell = 0.005). Moreover, compared to HC, inward deformation on the core of the left accumbens surface was found for patients with short duration of treatment (pLAccu-Core = 0.027). Finally, measures of surface deformation on the core of left accumbens observed in the group comparison showed significant positive correlations with depressive symptoms severity, as assessed by the Hamilton Depression Rating Scale (total score: r2L-AccuCore = 0.07, p = 0.02, somatic score: r2L-Accu-Core = 0.1, p = 0.005) and Beck Hopelessness Scale (r2LAccu-Core = 0.05, p = 0.03). Findings demonstrate that lithium untreated BD patients are characterised by localized shape abnormalities in the nucleus accumbens. Lithium treatment could act modulating these morphometric features as part of its mechanism of action in mood stabilizing.

Bipolar disorder (BD) is characterized by emotion dysregulation and involves changes in the gray matter (GM) and white matter (WM). Although previous diffusion tensor imaging (DTI) studies reported changes in the diffusion properties of the deep WM (DWM) in BD patients, the diffusion properties of the superficial WM (SWM) are rarely investigated. In this study, we tried to determine whether the diffusion parameters of the SWM were altered in BD patients compared to controls and whether the changes were associated with the disrupted emotion regulation of the BD patients. We collected DTI data from 37 BD patients and 42 gender- and age-matched healthy controls (HC). Using probabilistic tractography, we defined a population-based SWM mask based on all the subjects. After performing the tract-based spatial statistical (TBSS) analyses, we identified the SWM areas in which the BD patients differed from the controls. This study showed significantly reduced fractional anisotropy in the SWM (FASWM) in the BD patients compared to the HC in the bilateral dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), medial prefrontal cortex (mPFC), and the left parietal cortex. Moreover, compared to the controls, the BD patients showed significantly increased mean diffusivity (MDSWM) and radial diffusivity (RDSWM) in the SWM in the right frontal cortex. This study presents altered cortico-cortical connections proximal to the regions related to the emotion dysregulation of BD patients, which indicated that the SWM may serve as the brain's structural basis underlying the disrupted emotion regulation of BD patients. The disrupted FASWM in the parietal cortex may indicate that the emotion dysregulation in BD patients is related to the cognitive control network., Highlights • BD patients showed altered FASWM in the regions related to emotion dysregulation. • Disrupted SWM may be the brain's structural basis underlying emotion dysregulation in BD patients. • FASWM between the vlPFC and dlPFC was negatively correlated with disease exacerbations in BD patients. • Emotion dysregulation in BD patients may be related to a disrupted cognitive control network.

Recent investigations have used diffusion-weighted imaging to reveal disturbances in the neurocircuitry that underlie cognitive-emotional control in bipolar disorder (BD) and in unaffected siblings or children at high genetic risk (HR). It has been difficult to quantify the mechanism by which structural changes disrupt the superimposed brain dynamics, leading to the emotional lability that is characteristic of BD. Average controllability is a concept from network control theory that extends structural connectivity data to estimate the manner in which local neuronal fluctuations spread from a node or subnetwork to alter the state of the rest of the brain. We used this theory to ask whether structural connectivity deficits previously observed in HR individuals (n = 84, mean age 22.4), patients with BD (n = 38, mean age 23.9), and age- and gender-matched controls (n = 96, mean age 22.6) translate to differences in the ability of brain systems to be manipulated between states. Localized impairments in network controllability were seen in the left parahippocampal, left middle occipital, left superior frontal, right inferior frontal, and right precentral gyri in BD and HR groups. Subjects with BD had distributed deficits in a subnetwork containing the left superior and inferior frontal gyri, postcentral gyrus, and insula (p = 0.004). HR participants had controllability deficits in a right-lateralized subnetwork involving connections between the dorsomedial and ventrolateral prefrontal cortex, the superior temporal pole, putamen, and caudate nucleus (p = 0.008). Between-group controllability differences were attenuated after removal of topological factors by network randomization. Some previously reported differences in network connectivity were not associated with controllability-differences, likely reflecting the contribution of more complex brain network properties. These analyses highlight the potential functional consequences of altered brain networks in BD, and may guide future clinical interventions., Graphical abstract Unlabelled Image, Highlights • Control theory estimates how neuronal fluctuations spread from local networks. • We compare brain controllability in bipolar disorder and their high-risk relatives. • These groups have impaired controllability in networks supporting cognitive and emotional control. • Weaker connectivity as well as topological alterations contribute to these changes.

Disruption of functional connectivity may be a key feature of bipolar disorder (BD) which reflects disturbances of synchronization and oscillations within brain networks. We investigated whether the resting electroencephalogram (EEG) in patients with BD showed altered synchronization or network properties. Resting-state EEG was recorded in 57 BD type-I patients and 87 healthy control subjects. Functional connectivity between pairs of EEG channels was measured using synchronization likelihood (SL) for 5 frequency bands (δ, θ, α, β, and γ). Graph-theoretic analysis was applied to SL over the electrode array to assess network properties. BD patients showed a decrease of mean synchronization in the alpha band, and the decreases were greatest in fronto-central and centro-parietal connections. In addition, the clustering coefficient and global efficiency were decreased in BD patients, whereas the characteristic path length increased. We also found that the normalized characteristic path length and small-worldness were significantly correlated with depression scores in BD patients. These results suggest that BD patients show impaired neural synchronization at rest and a disruption of resting-state functional connectivity., Highlights • Global synchronization of BD patients was reduced in the alpha-band at resting. • De-synchronized connectivity was localized in fronto-centro-parietal connections. • Global topology of BD had decreased network clustering and increased path length. • BD showed the less efficient network processing. • Network characteristics of BD patients were associated with depression severity.

Major depressive disorder (MDD) and bipolar disorder (BD) are severe psychiatric diseases with overlapping symptomatology. Although previous studies reported abnormal brain structures in MDD or BD patients, the disorder-specific underlying neural mechanisms remain poorly understood. The purpose of this study was to investigate the whole-brain gray matter morphological patterns in unmedicated patients with MDD or BD and to identify the shared and disease-specific brain morphological alterations in these two disorders. We acquired high-resolution brain structural MRI data from a sample of 36 MDD patients, 32 BD patients, and 30 healthy controls. Using FreeSurfer, we estimated their brain cortical thickness (CT) and compared between-group difference in multiple locations across the continuous cortical surface. Compared to the healthy controls, both the MDD and BD patient groups showed significantly reduced CT in the left inferior temporal cortex (ITC). However, compared to the MDD patients, the BD patients showed a significantly thinner CT in the left rostral middle frontal region. In addition, compared to the healthy controls, the BD patients displayed thinner CT in the left ITC, left frontal pole (FPO), left superior frontal, right lateral occipital, right pars triangularis (PTRI) and right lateral orbitofrontal regions. Further analysis revealed a significantly positive correlation between the mean CT in the left FPO and the onset age, but a negative correlation between the mean CT in the right PTRI and the number of episodes, in the BD patients. Our findings revealed that the BD and MDD patients had variations in CT that were in common, but many more that were distinct, suggesting potential differences in their neural mechanisms., Highlights • We found thinner CT in the left ITC in both MDD and BD groups compared to controls. • We detected thinner CT in the left rMFC in the BD group compared to the MDD group. • The BD group had more pronounced abnormality in CT primarily in the PFC than the MDD group. • Clinical variables of BD group were associated with decreased CT in the left FPO and right PTRI. This study aims to detect abnormal cortical thickness in patients with major depressive disorder (MDD) or bipolar disorder (BD), and to identify the shared and disease-specific brain morphological alterations in these two disorders. The two patient groups showed several common but more distinct variation patterns in cortical thickness, and the BD patients had lower cortical thickness in widespread brain areas than the MDD and the controls. These findings may have potential clinical implications for distinguishing BD from MDD patients.