Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications.

Although deep brain stimulation (DBS) is an established treatment choice for Parkinson's disease (PD), essential tremor and movement disorders, its effectiveness for the management of treatment-resistant depression (TRD) remains unclear. Herein, we conducted an integrative review on major neuroanatomical targets of DBS pursued for the treatment of intractable TRD. The aim of this review article is to provide a critical discussion of possible underlying mechanisms for DBS-generated antidepressant effects identified in preclinical studies and clinical trials, and to determine which brain target(s) elicited the most promising outcomes considering acute and maintenance treatment of TRD. Major electronic databases were searched to identify preclinical and clinical studies that have investigated the effects of DBS on depression-related outcomes. Overall, 92 references met inclusion criteria, and have evaluated six unique DBS targets namely the subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), ventral capsule/ventral striatum or anterior limb of internal capsule (ALIC), medial forebrain bundle (MFB), lateral habenula (LHb) and inferior thalamic peduncle for the treatment of unrelenting TRD. Electrical stimulation of these pertinent brain regions displayed differential effects on mood transition in patients with TRD. In addition, 47 unique references provided preclinical evidence for putative neurobiological mechanisms underlying antidepressant effects of DBS applied to the ventromedial prefrontal cortex, NAc, MFB, LHb and subthalamic nucleus. Preclinical studies suggest that stimulation parameters and neuroanatomical locations could influence DBS-related antidepressant effects, and also pointed that modulatory effects on monoamine neurotransmitters in target regions or interconnected brain networks following DBS could have a role in the antidepressant effects of DBS. Among several neuromodulatory targets that have been investigated, DBS in the neuroanatomical framework of the SCG, ALIC and MFB yielded more consistent antidepressant response rates in samples with TRD. Nevertheless, more well-designed randomized double-blind, controlled trials are warranted to further assess the efficacy, safety and tolerability of these more promising DBS targets for the management of TRD as therapeutic effects have been inconsistent across some controlled studies.

Hippocampal subfield volumes in mood disorders.

Volume reduction and shape abnormality of the hippocampus have been associated with mood disorders. However, the hippocampus is not a uniform structure and consists of several subfields, such as the cornu ammonis (CA) subfields CA1-4, the dentate gyrus (DG) including a granule cell layer (GCL) and a molecular layer (ML) that continuously crosses adjacent subiculum (Sub) and CA fields. It is known that cellular and molecular mechanisms associated with mood disorders may be localized to specific hippocampal subfields. Thus, it is necessary to investigate the link between the in vivo hippocampal subfield volumes and specific mood disorders, such as bipolar disorder (BD) and major depressive disorder (MDD). In the present study, we used a state-of-the-art hippocampal segmentation approach, and we found that patients with BD had reduced volumes of hippocampal subfields, specifically in the left CA4, GCL, ML and both sides of the hippocampal tail, compared with healthy subjects and patients with MDD. The volume reduction was especially severe in patients with bipolar I disorder (BD-I). We also demonstrated that hippocampal subfield volume reduction was associated with the progression of the illness. For patients with BD-I, the volumes of the right CA1, ML and Sub decreased as the illness duration increased, and the volumes of both sides of the CA2/3, CA4 and hippocampal tail had negative correlations with the number of manic episodes. These results indicated that among the mood disorders the hippocampal subfields were more affected in BD-I compared with BD-II and MDD, and manic episodes had focused progressive effect on the CA2/3 and CA4 and hippocampal tail.

Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits.

BACKGROUND: Schizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia. METHOD: A total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Of the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB. CONCLUSIONS: IGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-(7) Li Magnetic Resonance Spectroscopy Study.

OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.

Identifying neuroanatomical signatures of anorexia nervosa: a multivariate machine learning approach.

BACKGROUND: There are currently no neuroanatomical biomarkers of anorexia nervosa (AN) available to make clinical inferences at an individual subject level. We present results of a multivariate machine learning (ML) approach utilizing structural neuroanatomical scan data to differentiate AN patients from matched healthy controls at an individual subject level. METHOD: Structural neuroimaging scans were acquired from 15 female patients with AN (age = 20, s.d. = 4 years) and 15 demographically matched female controls (age = 22, s.d. = 3 years). Neuroanatomical volumes were extracted using the FreeSurfer software and input into the Least Absolute Shrinkage and Selection Operator (LASSO) multivariate ML algorithm. LASSO was 'trained' to identify 'novel' individual subjects as either AN patients or healthy controls. Furthermore, the model estimated the probability that an individual subject belonged to the AN group based on an individual scan. RESULTS: The model correctly predicted 25 out of 30 subjects, translating into 83.3% accuracy (sensitivity 86.7%, specificity 80.0%) (p < 0.001; χ 2 test). Six neuroanatomical regions (cerebellum white matter, choroid plexus, putamen, accumbens, the diencephalon and the third ventricle) were found to be relevant in distinguishing individual AN patients from healthy controls. The predicted probabilities showed a linear relationship with drive for thinness clinical scores (r = 0.52, p < 0.005) and with body mass index (BMI) (r = -0.45, p = 0.01). CONCLUSIONS: The model achieved a good predictive accuracy and drive for thinness showed a strong neuroanatomical signature. These results indicate that neuroimaging scans coupled with ML techniques have the potential to provide information at an individual subject level that might be relevant to clinical outcomes.

Illness-course modulates suicidality-related prefrontal gray matter reduction in women with bipolar disorder.

OBJECTIVE: Explore interrelationships between suicide attempt history (Objective 1) or suicide attempt severity (Objective 2) with prefrontal cortex gray matter (PFCGM ) volume and illness-course in patients with bipolar disorder (BD). METHOD: Ninety-three women with BD-I or -II diagnosis (51 with and 42 without suicide attempt history) underwent structural MRI and filled out questionnaires. Measured were GM volumes of 11 PFC regions, BD illness-course, and attempt history and severity. Effects were examined with repeated measures GLM or logit analyses. RESULTS: Objective 1: Attempt history was associated with increased trait impulsivity and aggression, and higher prevalence of BD-I, past drug use disorder, and past psychiatric hospitalization. PFCGM volume was lower in patients with than without attempt history in those with past psychiatric hospitalization. PFCGM volume was higher in patients with than without attempt history in those without hospitalization. Higher trait aggression predicted attempt history. Objective 2: Increased frontal pole volume and younger age at first hospitalization predicted many suicide attempts. CONCLUSION: Attempt history in patients with BD related to PFCGM volume reduction or increase. Volume modulation by psychiatric hospitalization could reflect effects of illness-course or care. Attempt severity was not related to volume reduction. Research on suicidality-brain relationships should include illness-course and attempt severity measures.

New structural brain imaging endophenotype in bipolar disorder.

Neuroimaging studies suggest anterior-limbic structural brain abnormalities in patients with bipolar disorder (BD), but few studies have shown these abnormalities in unaffected but genetically liable family members. In this study, we report morphometric correlates of genetic risk for BD using voxel-based morphometry. In 35 BD type I (BD-I) patients, 20 unaffected first-degree relatives (UAR) of BD patients and 40 healthy control subjects underwent 3 T magnetic resonance scanner imaging. Preprocessing of images used DARTEL (diffeomorphic anatomical registration through exponentiated lie algebra) for voxel-based morphometry in SPM8 (Wellcome Department of Imaging Neuroscience, London, UK). The whole-brain analysis revealed that the gray matter (GM) volumes of the left anterior insula and right inferior frontal gyrus showed a significant main effect of diagnosis. Multiple comparison analysis showed that the BD-I patients and the UAR subjects had smaller left anterior insular GM volumes compared with the healthy subjects, the BD-I patients had smaller right inferior frontal gyrus compared with the healthy subjects. For white matter (WM) volumes, there was a significant main effect of diagnosis for medial frontal gyrus. The UAR subjects had smaller right medial frontal WM volumes compared with the healthy subjects. These findings suggest that morphometric brain abnormalities of the anterior-limbic neural substrate are associated with family history of BD, which may give insight into the pathophysiology of BD, and be a potential candidate as a morphological endophenotype of BD.

Chitosan: antimicrobial action upon staphylococci after impregnation onto cotton fabric.

BACKGROUND: High levels of viable Staphylococcus aureus, which are often found on inflamed skin surfaces, are usually associated with atopic dermatitis. Textiles, owing to their high specific surface area and intrinsic hydrophilicity, retain moisture while also providing excellent environmental conditions for microbial growth and proliferation. Recently, a number of chemicals have been added to textiles, so as to confer antimicrobial activity. AIMS: To evaluate the antimicrobial action of chitosan upon selected skin staphylococci. METHODS AND RESULTS: We isolated staphylococci from normal skin of 24 volunteers and studied their survival upon contact with chitosan-impregnated cotton fabric. Low and high molecular weight chitosans were used at two concentrations; all four did effectively reduce the growth of some staphylococci (namely Staph. aureus), by up to 5 log cycles, thus unfolding a potential towards control and even prevention of related skin disorders. CONCLUSION: Our data suggest an effective, but selective antibacterial action of chitosans towards skin bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: The possibility to use a natural biopolymer incorporated in a textile to alleviate and even treat some of the symptoms associated with this skin condition may raise an alternative to existing medical treatments. The selectivity observed prevents full elimination of bacteria from the skin surface, which is an advantage.

Morphological and morphometric study of the opossum's dorsal root ganglia neurons.

The ultrastructural characteristics and the morphometric evaluation of the different types of neurons present in the dorsal root ganglia (DRG) of the South American opossum (Didelphis albiventris) were studied. Four adult male animals were used and the neurons from cervical and lumbar DRG were removed and processed for histological and transmission electron microscopy observations. The morphometric data were obtained from serial sections stained by H/E and Masson's trichrome. The number of neurons in cervical and lumbar DRG was 22 300 and 31 000, respectively. About 68% of the cervical neurons and 62.5% of the lumbar neurons presented areas up to 1300 µm(2) and were considered as the small neurons of the DRG. The ultrastructural observations revealed two morphological types of neurons: clear large neurons and dark small neurons. The nuclei of both cell types are spherical and the chromatin is disperse and rarefected. The cytoplasm of the dark small neuron is more electron dense and shows a regular distribution of small mitochondria and many rough reticulum cisterns in the periphery. A small Golgi apparatus was close to the nucleus and many disperse neurofilaments occupy most parts of the cytoplasm. Smooth reticulum cisterns are rare and lipofucsin-like inclusions are present at some points. In the clear large neurons, the organelles are homogenously scattered through the cytoplasm. The neurofilaments are close packed forming bundles and small mitochondria and rough reticulum cisterns are disperse. Lipofucsin-like inclusions are more frequent in these cells.

Influence of micro-channel shape and magnetic material on the magneto-refrigeration process of integrated circuits.

We developed a two dimensional transient numerical model that solves the first step of heat transfer of an active magnetic regenerative refrigerator (AMR) using the heat conduction equation for an adiabatic system. For micro-refrigeration, an AMR device is constituted by a magnetic material, placed on a silicon wafer containing micro-channels where a heat exchanging fluid flows. The magnetic materials used in the simulations are the promising the Gd5Si2Ge2, La(Fe0.88Si0.22)13 and La0.66Sr0.33MnO3 compounds, because they exhibit a giant magnetocaloric effect near room temperature. We considered different initial conditions, namely different micro-channel shapes, sizes and separations, aiming to increase the performance of the micro-cooler device. The influence of the thickness of the magnetic material on refrigeration power is also studied.

A focus on valproate and cognitive deficits in Bipolar Disorders: A mini-review: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD.

BACKGROUND: Cognitive deficits represent a core feature of Bipolar Disorder (BD), which seem to characterize this disorder regardless of the mood phase. However, the role of pharmacological treatment in determining cognitive alterations is still not clear. Indeed, although drugs improve cognition by targeting mood symptoms, they could also carry their own cognitive side effects. This is true especially for mood stabilizers as they are the most commonly prescribed drugs in patients affected by BD and they are usually administered also during euthymic phases. METHODS: In this context, the present review aimed at summarizing the results of the studies evaluating the impact of valproate on cognitive functions in patients suffering from BD, as primary or secondary results. The inclusion criteria were met by ten studies. Specifically, we included one double-blind quasi-randomized study and nine cross-sectional or naturalistic studies, which a) used healthy subjects as control group (N = 1), b) compared valproate treated patients with healthy individuals and other treatments (N = 5), and c) compared valproate treated patients just with other treatments, with a specific focus on lithium (N = 3). RESULTS: Overall the results suggested a negative effect of valproate on cognitive functions in chronically-treated patients affected by BD. Notably, it has been found that the working memory was the most affected cognitive domain. LIMITATIONS: Few studies directly explored the effect of valproate on cognition in BD. CONCLUSIONS: These findings seem to suggest that valproate might have a negative effect on cognitive functions, especially on working memory domain. However, the results should be taken cautiously since the limited number of available studies published so far. In conclusion, these evidences seem to point out that the possible cognitive side effects of pharmacological treatments should be carefully taken into account, especially in chronic patients.

Association between serum BDNF levels and maternal perinatal depression: A review: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD.

INTRODUCTION: A large amount of studies demonstrated reduced serum Brain-Derived Neurotrophic Factor (BDNF) levels in stress-related and depressive disorders. However, it is still unclear if a similar deficit in BDNF concentrations might also characterize maternal perinatal depression. METHODS: We performed a bibliographic search on PUBMED of all the studies investigating the association between maternal BDNF levels and perinatal depression. The inclusion criteria were met by thirteen studies. RESULTS: Overall, the majority of the studies reported a significant reduction in serum BDNF levels among depressed mothers compared to healthy mothers either during pregnancy or in the postpartum period. Moreover, some studies also demonstrated that the BDNF reduction could be more evident in those depressed mothers with perinatal stressful life events and suicide risk. LIMITATIONS: BDNF were collected at different time points across the studies. Potential confounding factors, including the clinical characteristics of the samples employed by the original studies, might have influenced the results. CONCLUSIONS: So far, the evidences suggested the presence of decreased BDNF concentrations in perinatal depressive disorders. However, further studies are needed in order to confirm the role of BDNF in this disorder.

Intravenous valproate in the treatment of acute manic episode in bipolar disorder: A review.

BACKGROUND: Mania is a state of elated or irritable mood characterizing Bipolar Disorder type I (BD-I). Among the pharmacological treatments for the management of mania, mood stabilizers are regularly employed, with valproate being one of the most used because of its effectiveness. However, while the oral formulation is approved for acute mania, it is unclear whether the intravenous (IV) formulation could be a valid and safe alternative. METHODS: We performed a bibliographic research on PUBMED of all studies investigating the use of IV valproate as a treatment of acute mania in BD-I. A total of 13 studies met our inclusion criteria. RESULTS: Overall, the results suggest that IV valproate as a loading therapy is an efficacious, safe and well tolerated treatment for manic episodes, and it is comparable to the oral loading regimen. Interestingly, only a few patients experienced significant side effects due to the administration of the IV valproate. LIMITATIONS: Few open label clinical trials have explored the effect of IV valproate in manic patients. Moreover, the original studies employed different clinical assessments and included manic patients taking other drugs, which made it impossible to determine whether the resolution of symptoms was due to valproate therapy alone. Additionally, serum valproate levels were not assessed by all studies. CONCLUSIONS: IV valproate may represent a valid option for the management of acute mania, with comparable effects in terms of efficacy and safety to the oral valproate. However, larger and more homogeneous studies are warranted in order to collect more precise information on the beneficial effect of IV valproate.

Disease-discordant twin structural MRI studies on affective disorders.

Magnetic resonance imaging (MRI) studies have identified neural structures implicated in the pathophysiology of mood disorders, especially bipolar disorder (BD) and major depressive disorder (MDD). However, the role of genetic and environmental influences on such brain deficits is still unclear. In this context, the present review summarizes the current evidence from structural MRI and Diffusion Tensor Imaging (DTI) studies on twin samples concordant or discordant for BD or MDD, with the aim of clarifying the role of genetic and environmental risk factors on brain alterations. Although the results showed a complex interplay between gene and environment in affective disorders, the evidence seem to underline that both genetic and environmental risk factors have an impact on brain areas and vulnerability to MDD and BD. However, the precise mechanism of action and the interaction between these factors still needs to be unveiled. Therefore, future larger studies on concordant or discordant twins should be encouraged, because this population provides a unique opportunity to probe separately genetic and environmental markers of disease vulnerability.

Microstructural white matter alterations in borderline personality disorder: A minireview.

BACKGROUND: Borderline personality disorder (BPD) affects 1-5% of the population and is characterized by a complex symptomatology and selective functional impairments. Although brain imaging studies have contributed to better characterizing the pathophysiological mechanisms underlying BPD, the white matter (WM) deficits associated with this disorder are still unclear. Therefore, the present review aims at providing an overview of the findings emerged from the available diffusion tensor imaging (DTI) studies on BPD. METHODS: From a bibliographic research in PubMed until May 2019, we collected 12 studies that fulfilled our inclusion criteria, including a total sample of 291 BPD subjects and 293 healthy controls. RESULTS: Overall, the DTI studies reviewed showed impairments in selective WM tracts that are part of the prefronto-limbic system, including frontal WM (short and long tracts), anterior cingulate cortex, corpus callosum, corona radiata, hippocampal fornix and thalamic radiation, in BPD patients compared to healthy controls. LIMITATIONS: Few DTI studies with heterogeneous findings. CONCLUSIONS: Overall these results reported that BPD is characterized by selective structural connectivity alterations in prefronto-limbic structures, further supporting the neurobiological model of BPD that suggests the presence of an abnormal modulation of frontal regions over limbic structures. Finally, the results also highlighted that the disrupted WM integrity in selective brain regions may also explain key-aspects of BPD symptomatology, including emotional dysregulation, ambivalence, contradictory behaviors and cognitive dysfunctions.

The identification, assessment and management of difficult-to-treat depression: An international consensus statement.

BACKGROUND: Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials - often termed "treatment resistant depression". A broader, perhaps more empathic concept of "difficult-to-treat depression" (DTD) was considered. METHODS: A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic. RESULTS: The group proposed that DTD be defined as "depression that continues to cause significant burden despite usual treatment efforts". All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive. LIMITATIONS: The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials. CONCLUSIONS: DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients.

Gray matter differences between affective and non-affective first episode psychosis: A review of Magnetic Resonance Imaging studies: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

BACKGROUND: Non-affective and affective psychoses are very common mental disorders. However, their neurobiological underpinnings are still poorly understood. Therefore, the goal of the present review was to evaluate structural Magnetic Resonance Imaging (MRI) studies exploring brain deficits in both non-affective (NA-FEP) and affective first episode psychosis (A-FEP). METHODS: A bibliographic search on PUBMED of all MRI studies exploring gray matter (GM) differences between NA-FEP and A-FEP was conducted. RESULTS: Overall, the results from the available evidence showed that the two diagnostic groups share common GM alterations in fronto-temporal regions and anterior cingulate cortex. In contrast, unique GM deficits have also been observed, with reductions in amygdala for A-FEP and in hippocampus and insula for NA-FEP. LIMITATIONS: Few small MRI studies with heterogeneous methodology. CONCLUSIONS: Although the evidences are far to be conclusive, they suggest the presence of common and distinct pattern of GM alterations in NA-FEP and A-FEP. Future larger longitudinal studies are needed to further characterize specific neural biomarkers in homogenous NA-FEP and A-FEP samples.

MRI features of clinical outcome in bipolar disorder: A selected review: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

BACKGROUND: Bipolar disorder (BD) is a severe and disabling mental illness, which is characterized by selective gray matter (GM) and white matter (WM) brain alterations, as observed by several imaging studies. However, the clinical course of the disease is uncertain and can vary across BD patients, with some having a benign course and others a severe disability. In this perspective, magnetic resonance imaging (MRI) can help identifying biological markers of worse prognosis. METHODS: The present selected review aimed at summarizing structural MRI (sMRI) studies exploring the correlation between brain morphology and features of clinical outcome, which could include treatment response, cognitive impairment and global functioning. RESULTS: Overall, the results from the reviewed sMRI studies reported that WM hyperintensities and GM volume reductions, mainly in fronto-limbic areas, correlate with worse outcome in BD. However, the selected outcome measures vary across studies, thus these observations cannot be conclusive. LIMITATIONS: Heterogeneity across studies and inconsistency on the outcome measures adopted limit the conclusion of the present review. Absence of widely shared definitions of outcome should be object of further research on BD in order to indicate more stable features of illness course. CONCLUSIONS: In summary, WM hyperintensities and fronto-temporo-limbic GM alterations may be potential indices of worse outcome in BD patients, particularly in terms of illness severity and progression. The identification of stable markers of prognosis can help the clinicians in selecting subgroups of bipolar patients who need specific treatment to preserve cognitive / psychosocial functioning, in the light of personalized approaches. To further characterize outcome in BD, future sMRI studies should a) longitudinally investigate patients with either poor or good course of the disease, and b) correlate neuroimaging measures with clinical, cognitive and genetic markers.