Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Preliminary Evidence for Heterogeneity of Beliefs About Auditory Verbal Hallucinations Intent.

ABSTRACT: Perceptions of patient's auditory verbal hallucinations (AVHs), commonly termed voices, have important impacts on their everyday lives. Despite research emphasizing the consequences of malevolent voices, preliminary results suggest that beliefs about voices may not be mutually exclusive. As such, we aimed to characterize the heterogeneity of beliefs about AVHs and describe their clinical correlates. We recruited 78 patients referred to a Voices group therapy for refractory and distressing voices. Based on the Revised Beliefs About Voices Questionnaire, clustering analysis yielded four subgroups of patients with distinct pattern of beliefs about AVHs. These subgroups differed significantly in terms of affective disturbances, engagement, and resistance to their voices. Furthermore, no significant changes in beliefs about voices were observed after 6 weeks. Results of the current study suggest that the heterogeneity regarding the beliefs about AVHs should be targeted in treatment to reduce their associated negative outcomes.

Risk Factors, Clinical Features, and Polygenic Risk Scores in Schizophrenia and Schizoaffective Disorder Depressive-Type.

There is controversy about the status of schizoaffective disorder depressive-type (SA-D), particularly whether it should be considered a form of schizophrenia or a distinct disorder. We aimed to determine whether individuals with SA-D differ from individuals with schizophrenia in terms of demographic, premorbid, and lifetime clinical characteristics, and genetic liability to schizophrenia, depression, and bipolar disorder. Participants were from the CardiffCOGS sample and met ICD-10 criteria for schizophrenia (n = 713) or SA-D (n = 151). Two samples, Cardiff Affected-sib (n = 354) and Cardiff F-series (n = 524), were used for replication. For all samples, phenotypic data were ascertained through structured interview, review of medical records, and an ICD-10 diagnosis made by trained researchers. Univariable and multivariable logistic regression models were used to compare individuals with schizophrenia and SA-D for demographic and clinical characteristics, and polygenic risk scores (PRS). In the CardiffCOGS, SA-D, compared to schizophrenia, was associated with female sex, childhood abuse, history of alcohol dependence, higher functioning Global Assessment Scale (GAS) score in worst episode of psychosis, lower functioning GAS score in worst episode of depression, and reduced lifetime severity of disorganized symptoms. Individuals with SA-D had higher depression PRS compared to those with schizophrenia. PRS for schizophrenia and bipolar disorder did not significantly differ between SA-D and schizophrenia. Compared to individuals with schizophrenia, individuals with SA-D had higher rates of environmental and genetic risk factors for depression and a similar genetic liability to schizophrenia. These findings are consistent with SA-D being a sub-type of schizophrenia resulting from elevated liability to both schizophrenia and depression.

Baseline Cortical Thickness Reductions in Clinical High Risk for Psychosis: Brain Regions Associated with Conversion to Psychosis Versus Non-Conversion as Assessed at One-Year Follow-Up in the Shanghai-At-Risk-for-Psychosis (SHARP) Study.

OBJECTIVE: To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC). METHODS: Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained. RESULTS: CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters. CONCLUSIONS: These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions.

Neurocognition in Bipolar and Depressive Schizoaffective Disorder: A Comparison with Schizophrenia.

INTRODUCTION: Schizoaffective disorder (SA) is classified into bipolar (bSA) and depressive (dSA) subtypes. Although clinical differences between both have been reported, there is no clear information regarding their specific cognitive profile. OBJECTIVE: To compare neurocognition between SA subtypes and schizophrenia (SC). METHODS: A total of 61 patients were assessed and divided into 3 groups: 35 SC, 16 bSA, and 10 dSA. All participants signed an informed consent letter. The MATRICS Consensus Cognitive Battery, Central and South American version was used to assess neurocognition. The study was performed at the Instituto Nacional de Psiquiatría "Ramón de la Fuente". Participants were identified by specialized psychiatrists. Trained neuropsychologists carried out the clinical and cognitive assessment, which lasted 2 h approximately. RESULTS: The cognitive assessment showed a significant difference in Trail Making Test part A subtest (F[2,58] = 4.043; p = 0.023]. Post hoc analyses indicated that dSA obtained a significantly higher score than SC (MD = -11.523; p = 0.018). The f test showed a large effect size (f = 0.401). No statistical differences were observed regarding other cognitive variables. CONCLUSIONS: The cognitive profile of SA subtypes and SC is similar since no differences were found in most subtests. However, dSA may be less impaired than SC in measures of processing speed. Further research with larger samples must be conducted.

Heterogeneity of Outcomes and Network Connectivity in Early-Stage Psychosis: A Longitudinal Study.

Imaging studies in psychotic disorders typically examine cross-sectional relationships between magnetic resonance imaging (MRI) signals and diagnosis or symptoms. We sought to examine changes in network connectivity identified using resting-state functional MRI (fMRI) corresponding to divergent functional recovery trajectories and relapse in early-stage psychosis (ESP). Prior studies have linked schizophrenia to hyperconnectivity in the default mode network (DMN). Given the correlations between the DMN and behavioral impairments in psychosis, we hypothesized that dynamic changes in DMN connectivity reflect the heterogeneity of outcomes in ESP. Longitudinal data were collected from 66 ESP patients and 20 healthy controls. Longitudinal cluster analysis identified subgroups of patients with similar trajectories in terms of symptom severity and functional outcomes. DMN connectivity was measured in a subset of patients (n = 36) longitudinally over 2 scans separated by a mean of 12 months. We then compared connectivity between patients and controls, and among the different outcome trajectory subgroups. Among ESP participants, 4 subgroups were empirically identified corresponding to: "Poor," "Middle," "Catch-up," and "Good" trajectory outcomes in the complete dataset (n = 36), and an independent replication (n = 30). DMN connectivity changes differed significantly between functional subgroups (F3,32 = 6.06, P-FDR corrected = .01); DMN connectivity increased over time in the "Poor" outcome cluster (ß = +0.145) but decreased over time in the "Catch-up" cluster (ß = -0.212). DMN connectivity is dynamic and correlates with a change in functional status over time in ESP. This approach identifies a brain-based marker that reflects important neurobiological processes required to sustain functional recovery.

Sex Differences in Verbal Memory Predict Functioning Through Negative Symptoms in Early Psychosis.

Verbal memory (VM) is one of the most affected cognitive domains in first-episode psychosis (FEP) and is a robust predictor of functioning. Given that healthy females demonstrate superior VM relative to males and that female patients show less-severe illness courses than male patients, this study examined whether normative sex differences in VM extend to FEP and influence functioning. Four hundred and thirty-five patients (299 males, 136 females) with affective or nonaffective psychosis were recruited from a catchment-based specialized FEP intervention service and 138 nonclinical controls (96 males, 42 females) were recruited from the same community. One of the two neurocognitive batteries comprising six cognitive domains (VM, visual memory, working memory, attention, executive function, processing speed) were administered at baseline. In patients, positive and negative symptoms were evaluated at baseline and functioning was assessed at 1-year follow-up. Patients were more impaired than controls on all cognitive domains, but only VM showed sex differences (both patient and control males performed worse than females), and these results were consistent across batteries. In patients, better baseline VM in females was related to better functioning after 1 year, mediated through fewer baseline negative symptoms. Supplemental analyses revealed these results were not driven by affective psychosis nor by age and parental education. Thus, normative sex differences in VM are preserved in FEP and mediate functioning at 1-year follow-up via negative symptoms. This study highlights the importance of investigating sex effects for understanding VM deficits in early psychosis and suggests that sex may be a disease-modifying variable with important treatment implications.

Auditory brainstem response (ABR) profiling in schizoaffective disorder.

OBJECTIVE: The aim of the study was to assess whether the auditory brainstem response (ABR) profiling test for schizophrenia (SZ) would recognise schizoaffective disorder (SZA) patients as SZ or not. METHOD: Male and female SZA patients (n = 16) from the psychosis unit at Uppsala University Hospital were investigated. Coded sets of randomised ABR recordings intermingled with patients with SZ, adult attention-deficit hyperactivity disorder (ADHD) and healthy controls were analysed by an independent party blinded to clinical diagnoses. RESULTS: The ABR profiling test for SZ was positive in 5/16 patients (31%) and negative in 11/16 patients (69%) with SZA. A surprising finding was that 4/16 (25%) SZA patients were positive for the ABR profiling test for ADHD. CONCLUSION: With the ABR profiling test, a minority of patients with SZA tested positive for SZ. In contrast, a majority (85%) of patients with SZ in a previous study tested positive. These preliminary results leave us ignorant whether SZA should be regarded as a SZ-like disorder or a psychotic mood disorder and add to the questions regarding the validity of this diagnostic entity. However, the ABR profiling method is still in its infancy and its exploration in a range of psychiatric disorders is warranted.

Personality traits across the psychosis spectrum: A Hierarchical Taxonomy of Psychopathology conceptualization of clinical symptomatology.

Psychotic disorders have varied clinical presentations, diagnostic stability is poor and other mental disorders often co-occur with the conditions. To improve the clinical and pathophysiological utility of classification systems for psychosis, it is necessary to consider how symptoms may reflect dimensions of psychopathology that extend beyond the boundaries of traditional diagnostic classifications. We examined personality deviation as a means for explaining symptom variation across individuals with serious mental illness. Participants (N = 312) with psychosis, first-degree biological relatives and healthy controls underwent comprehensive clinical evaluations that included symptom ratings and Diagnostic Statistical Manual consensus diagnoses. They completed the Personality Inventory for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PID-5), which provides multidimensional assessment of personality disturbances and characterizes psychosis-relevant phenomena, and the Schizotypal Personality Questionnaire (SPQ), a widely accepted measure of schizotypal traits. PID-5 was comparable with SPQ in differentiating between participants with and without psychosis. Greater psychotic symptomatology and higher scores on the SPQ Cognitive-perceptual dimension were associated with higher scores on PID-5 Psychoticism. Facet-level traits showed diverse associations with existing clinical syndromes, suggesting they have utility for quantifying separable symptom dimensions that cut across existing disorders. Yet the patient groups were similar across four of the five PID-5 personality trait domains, indicating shared patterns of personality expression that challenge existing categorical delineations. © 2019 John Wiley & Sons, Ltd.

Functional Connectivity of the Striatum in Schizophrenia and Psychotic Bipolar Disorder.

BACKGROUND: The striatum is abnormal in schizophrenia and possibly represents a common neurobiological mechanism underlying psychotic disorders. Resting-state functional magnetic resonance imaging studies have not reached a consensus regarding striatal dysconnectivity in schizophrenia, although these studies generally find impaired frontoparietal and salience network connectivity. The goal of the current study was to clarify the pattern of corticostriatal connectivity, including whether corticostriatal dysconnectivity is transdiagnostic and extends into psychotic bipolar disorder. METHODS: We examined corticostriatal functional connectivity in 60 healthy subjects and 117 individuals with psychosis, including 77 with a schizophrenia spectrum illness and 40 with psychotic bipolar disorder. We conducted a cortical seed-based region-of-interest analysis with follow-up voxelwise analysis for any significant results. Further, a striatum seed-based analysis was conducted to examine group differences in connectivity between the striatum and the whole cortex. RESULTS: Cortical region-of-interest analysis indicated that overall connectivity of the salience network with the striatum was reduced in psychotic disorders, which follow-up voxelwise analysis localized to the left putamen. Striatum seed-based analyses showed reduced ventral rostral putamen connectivity with the salience network portion of the medial prefrontal cortex in both schizophrenia and psychotic bipolar disorder. CONCLUSIONS: The current study found evidence of transdiagnostic corticostriatal dysconnectivity in both schizophrenia and psychotic bipolar disorder, including reduced salience network connectivity, as well as reduced connectivity between the putamen and the medial prefrontal cortex. Overall, the current study points to the relative importance of salience network hypoconnectivity in psychotic disorders.

Impact of integrated district level mental health care on clinical and social outcomes of people with severe mental illness in rural Ethiopia: an intervention cohort study.

AIM: There is limited evidence of the safety and impact of task-shared care for people with severe mental illnesses (SMI; psychotic disorders and bipolar disorder) in low-income countries. The aim of this study was to evaluate the safety and impact of a district-level plan for task-shared mental health care on 6 and 12-month clinical and social outcomes of people with SMI in rural southern Ethiopia. METHODS: In the Programme for Improving Mental health carE, we conducted an intervention cohort study. Trained primary healthcare (PHC) workers assessed community referrals, diagnosed SMI and initiated treatment, with independent research diagnostic assessments by psychiatric nurses. Primary outcomes were symptom severity and disability. Secondary outcomes included discrimination and restraint. RESULTS: Almost all (94.5%) PHC worker diagnoses of SMI were verified by psychiatric nurses. All prescribing was within recommended dose limits. A total of 245 (81.7%) people with SMI were re-assessed at 12 months. Minimally adequate treatment was received by 29.8%. All clinical and social outcomes improved significantly. The impact on disability (standardised mean difference 0.50; 95% confidence interval (CI) 0.35-0.65) was greater than impact on symptom severity (standardised mean difference 0.28; 95% CI 0.13-0.44). Being restrained in the previous 12 months reduced from 25.3 to 10.6%, and discrimination scores reduced significantly. CONCLUSIONS: An integrated district level mental health care plan employing task-sharing safely addressed the large treatment gap for people with SMI in a rural, low-income country setting. Randomised controlled trials of differing models of task-shared care for people with SMI are warranted.

Basic self-disturbances independently predict recovery in psychotic disorders: A seven year follow-up study.

BACKGROUND: Recovery is the ultimate goal of psychosis treatment. Basic self-disturbances (BSDs) are non-psychotic phenomena associated with clinical outcome, present in prodromal, psychotic and residual phases of psychotic disorders. AIM: To investigate the relationship between BSDs and recovery seven years after first treatment in patients with psychotic disorders. METHOD: Prospective longitudinal study of 56 patients recruited during first adequate treatment for schizophrenia (n = 35) and other psychotic disorders (n = 21) (psychotic bipolar disorder, delusional disorder, psychotic disorder NOS). At baseline and follow-up BSDs were assessed using the Examination of Anomalous Self-Experience (EASE) manual, while standard clinical instruments were used to ascertained diagnosis, clinical symptom severity, and functioning. Recovery was defined as absence of psychotic symptoms and regaining of functioning that persisted the last two years before follow-up. RESULTS: At follow up, 34% achieved recovery (5 (14%) with schizophrenia and 14 (67%) with other psychoses at baseline). Recovery was predicted by an absence of a schizophrenia diagnosis, low baseline level of BSDs and further reductions in BSDs from baseline to follow-up. Change in BSDs was the strongest predictor, also after adjusting for premorbid adjustment and duration of untreated psychosis, and was not confounded by diagnosis. CONCLUSION: Low baseline levels of basic self-disturbances and further reductions over time independently predict recovery seven years later in first treated psychosis patients.

HPA axis in psychotic major depression and schizophrenia spectrum disorders: Cortisol, clinical symptomatology, and cognition.

The Hypothalamic Pituitary Adrenal (HPA) axis has been implicated in the pathophysiology of a variety of mood and cognitive disorders. Neuroendocrine studies have demonstrated HPA axis overactivity in major depression, a relationship of HPA axis activity to cognitive performance, and a potential role of HPA axis genetic variation in cognition. In schizophrenia differential HPA activity has been found, including higher rates of non-suppression to dexamethasone challenge and higher salivary cortisol levels, which have been a premonitory risk factor for conversion to psychosis in adolescents at risk for developing schizophrenia. The present study investigated the simultaneous roles HPA axis activity and clinical symptomatology play in poor cognitive performance. Patients with major depression with psychosis (PMD) or schizophrenia spectrum disorder (SCZ) and healthy controls (HC) were studied. All participants underwent a diagnostic interview and psychiatric ratings, a comprehensive neuropsychological battery, and overnight hourly blood sampling for cortisol. Cognitive performance did not differ between the clinical groups, though they both performed more poorly than the HC's across a variety of cognitive domains. Across all subjects, cognitive performance was negatively correlated with higher cortisol, and PMD patients had higher evening cortisol levels than did SCZ and HCs. Cortisol and clinical symptoms, as well as age, sex, and antipsychotic use predicted cognitive performance. Diathesis stress models and their links to symptomatology, cognition, and HPA function are discussed.

Auditory steady-state EEG response across the schizo-bipolar spectrum.

Deviant auditory steady-state responses (aSSRs) in the gamma range (30-90 Hz) may be translational biomarkers for schizophrenia (SZ). This study tests whether aSSR deviations are (i) specific to SZ across the psychosis dimension, (ii) specific to particular frequency bands, and (iii) present in bipolar I disorder without psychosis (BDNP). METHODS: Beta (20-), low- (40-), and high-gamma (80-Hz) aSSRs were measured with EEG and compared across 113 SZ, 105 schizoaffective disorder (SAD), 99 bipolar disorder with psychosis (BDP), 68 BDNP, and 137 healthy comparison subjects (HC). Standard aSSR measures (single-trial power [STP] and inter-trial phase coherence [ITC]), as well as evoked responses to stimulus onsets/offsets and pre-stimulus power, were quantified. Multivariate canonical discriminant analysis was used to summarize variables that efficiently and maximally differentiated groups. RESULTS: (i) Psychosis groups showed reduced responses on ITC 20 Hz, STP/ITC 40 Hz, STP/ITC 80 Hz, indicating dimensional reductions in aSSR across the psychosis spectrum not specific to aSSR frequency. For the 40- and 80-Hz ITCs there was greater reduction in SZ compared to SAD, possibly indexing cortical disruptions linked to psychosis without mood symptoms. (ii) All probands had elevated pre-stimulus power, possibly compromising neural entrainment to the steady-state stimuli. (iii) Onset/Offset and 80 Hz ITC responses were most important for group discrimination and showed dimensional reduction across the schizo-bipolar spectrum. CONCLUSIONS: Deviant aSSRs were found across the schizo-bipolar spectrum at multiple frequencies with psychosis status and severity linked to greatest reductions at low and high gamma.

Working Memory Impairment Across Psychotic disorders.

BACKGROUND: Working memory (WM) has been a central focus of cognitive neuroscience research because WM is a resource that is involved in many different cognitive operations. The goal of this study was to evaluate the clinical utility of WM paradigms developed in the basic cognitive neuroscience literature, including methods designed to estimate storage capacity without contamination by lapses of attention. METHODS: A total of 61 people with schizophrenia, 49 with schizoaffective disorder, 47 with bipolar disorder with psychosis, and 59 healthy volunteers were recruited. Participants received multiple WM tasks, including two versions each of a multiple Change Detection paradigm, a visual Change Localization paradigm, and a Running Span task. RESULTS: Healthy volunteers performed better than the combined patient group on the visual Change Localization and running span measures. The multiple Change Detection tasks provided mixed evidence about WM capacity reduction in the patient groups, but a mathematical model of performance suggested that the patient groups differed from controls in their rate of attention lapsing. The 3 patient groups performed similarly on the WM tasks. Capacity estimates from the Change Detection and Localization tasks showed significant correlations with functional capacity and functional outcome. CONCLUSIONS: The patient groups generally performed in a similarly impaired fashion across tasks, suggesting that WM impairment and attention lapsing are general features of psychotic disorders. Capacity estimates from the Change Localization and Detection tasks were related to functional capacity and outcome, suggesting that these methods may be useful in a clinical context.

ERP indices of performance monitoring and feedback processing in psychosis: A meta-analysis.

BACKGROUND: Although individuals with, or at risk for, psychotic disorders often show difficulties with performance monitoring and feedback processing, findings from studies using event-related potentials (ERPs) to index these processes are not consistent. This meta-analytic review focused on studies of two different indexes of performance monitoring, the early error-related negativity (ERN; n = 25) and the later error positivity (Pe; n = 17), and one index of feedback processing, the feedback negativity (FN; n = 6). METHODS: We evaluated whether individuals (1) with psychotic disorders, or (2) at heightened risk for these disorders differ from healthy controls in available studies of the ERN, Pe, and FN. RESULTS: There was a significant, large ERN reduction in those with psychosis (g = -0.96) compared to controls, and a significant, moderate ERN reduction in those at-risk (g = -0.48). In contrast, there were uniformly non-significant, small between-group differences for Pe and FN (gs ≤ |0.16|). CONCLUSIONS: The results reveal a differential pattern of impairment in psychosis. Early performance monitoring (ERN) impairments are substantial among those with psychotic disorders in general and may be a useful vulnerability indicator for these disorders. However, later performance monitoring (Pe) and basic feedback processing (FN) appear to be relatively spared in psychosis.

Cognitive reserve as an outcome predictor: first-episode affective versus non-affective psychosis.

OBJECTIVE: Cognitive reserve (CR) refers to the brain's capacity to cope with pathology in order to minimize the symptoms. CR is associated with different outcomes in severe mental illness. This study aimed to analyze the impact of CR according to the diagnosis of first-episode affective or non-affective psychosis (FEP). METHOD: A total of 247 FEP patients (211 non-affective and 36 affective) and 205 healthy controls were enrolled. To assess CR, common proxies have been integrated (premorbid IQ; education-occupation; leisure activities). The groups were divided into high and low CR. RESULTS: In non-affective patients, those with high CR were older, had higher socioeconomic status (SES), shorter duration of untreated psychosis, and a later age of onset. They also showed greater performance in most cognitive domains. In affective patients, those with a greater CR showed a higher SES, better functioning, and greater verbal memory performance. CONCLUSION: CR plays a differential role in the outcome of psychoses according to the diagnosis. Specifically, in order to address the needs of non-affective patients with low CR, cognitive rehabilitation treatments will need to be 'enriched' by adding pro-cognitive pharmacological agents or using more sophisticated approaches. However, a functional remediation therapy may be of choice for those with an affective psychosis and low CR.

Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review.

BACKGROUND: Bipolar disorder is chronic and debilitating. Studies investigating resting-state functional connectivity in individuals with bipolar disorder may help to inform neurobiological models of illness. METHODS: We conducted a systematic review with the following goals: to summarize the literature on resting-state functional connectivity in bipolar disorder during clinical remission (euthymia) compared with healthy controls; to critically appraise the literature and research gaps; and to propose directions for future research. We searched PubMed/MEDLINE, Embase, PsycINFO, CINAHL and grey literature up to April 2017. RESULTS: Twenty-three studies were included. The most consistent finding was the absence of differences in resting-state functional connectivity of the default mode network (DMN), frontoparietal network (FPN) and salience network (SN) between people with bipolar disorder and controls, using independent component analysis. However, 2 studies in people with bipolar disorder who were positive for psychosis history reported DMN hypoconnectivity. Studies using seed-based analysis largely reported aberrant resting-state functional connectivity with the amygdala, ventrolateral prefrontal cortex, cingulate cortex and medial prefrontal cortex in people with bipolar disorder compared with controls. Few studies used regional homogeneity or amplitude of low-frequency fluctuations. LIMITATIONS: We found heterogeneity in the analysis methods used. CONCLUSION: Stability of the DMN, FPN and SN may reflect a state of remission. Further, DMN hypoconnectivity may reflect a positive history of psychosis in patients with bipolar disorder compared with controls, highlighting a potentially different neural phenotype of psychosis in people with bipolar disorder. Resting-state functional connectivity changes between the amygdala, prefrontal cortex and cingulate cortex may reflect a neural correlate of subthreshold symptoms experienced in bipolar disorder euthymia, the trait-based pathophysiology of bipolar disorder and/or a compensatory mechanism to maintain a state of euthymia.

Gray matter bases of psychotic features in adult bipolar disorder: A systematic review and voxel-based meta-analysis of neuroimaging studies.

Psychotic bipolar disorder (P-BD) is a specific subset that presents greater risk of relapse and worse outcomes than nonpsychotic bipolar disorder (NP-BD). To explore the neuroanatomical bases of psychotic dimension in bipolar disorder (BD), a systematic review was carried out based on the gray matter volume (GMV) among P-BD and NP-BD patients and healthy controls (HC). Further, we conducted a meta-analysis of GMV differences between P-BD patients and HC using a whole-brain imaging approach. Our review revealed that P-BD patients exhibited smaller GMVs mainly in the prefronto-temporal and cingulate cortices, the precentral gyrus, and insula relative to HC both qualitatively and quantitatively. Qualitatively the comparison between P-BD and NP-BD patients suggested inconsistent GMV alterations mainly involving the prefrontal cortex, while NP-BD patients showed GMV deficits in local regions compared with HC. The higher proportions of female patients and patients taking psychotropic medication in P-BD and P-BD type I were associated with smaller GMV in the right precentral gyrus, and the right insula, respectively. In conclusions, psychosis in BD might be associated with specific cortical GMV deficits. Gender and psychotropic medication might have effects on the regional GMVs in P-BD patients. It is necessary to distinguish psychotic dimension in neuroimaging studies of BD.

The Genetic Relationship Between Psychological Distress, Somatic Distress, Affective Disorders, and Substance Use in Young Australian Adults: A Multivariate Twin Study.

Psychological distress (PSYCH), somatic distress (SOMA), affective disorders (AD), and substance use (SU) frequently co-occur. The genetic relationship between PSYCH and SOMA, however, remains understudied. We examined the genetic and environmental influences on these two disorders and their comorbid AD and SU using structural equation modeling. Self-reported PSYCH and SOMA were measured in 1,548 twins using the two subscales of a 12-item questionnaire, the Somatic and Psychological Health Report. Its reliability and psychometric properties were examined. Six ADs, involvement of licit and illicit substance, and two SU disorders were obtained from 1,663-2,132 twins using the World Mental Health Composite International Diagnostic Interview and/or from an online adaption of the same. SU phenotypes (heritability: 49-79%) were found to be more heritable than the affective disorder phenotypes (heritability: 32-42%), SOMA (heritability: 25%), and PSYCH (heritability: 23%). We fit separate non-parametric item response theory models for PSYCH, SOMA, AD, and SU. The IRT scores were used as the refined phenotypes for fitting multivariate genetic models. The best-fitting model showed the similar amount of genetic overlap between PSYCH-AD (genetic correlation rG = 0.49) and SOMA-AD (rG =0.53), as well as between PSYCH-SU (rG = 0.23) and SOMA-SU (rG = 0.25). Unique environmental factors explained 53% to 76% of the variance in each of these four phenotypes, whereas additive genetic factors explained 17% to 46% of the variance. The covariance between the four phenotypes was largely explained by unique environmental factors. Common genetic factor had a significant influence on all the four phenotypes, but they explained a moderate portion of the covariance.