Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

BACKGROUND AND HYPOTHESIS: Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. STUDY DESIGN: We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. STUDY RESULTS: Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. CONCLUSIONS: Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Systemic Cell Adhesion Molecules in Severe Mental Illness: Potential Role of Intercellular CAM-1 in Linking Peripheral and Neuroinflammation.

BACKGROUND: Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. METHODS: We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell-derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). RESULTS: Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell-derived neurons from patients with SCZ. CONCLUSIONS: Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

The significance of anti-neuronal antibodies for acute psychiatric disorders: a retrospective case-controlled study.

BACKGROUND: The clinical significance of anti-neuronal antibodies in patients with psychiatric disorders, but without encephalitis, remains unknown. In patients admitted to acute psychiatric inpatient care we aimed to identify clinical features distinguishing anti-neuronal antibody positive patients from matched controls. RESULTS: Patients who were serum-positive to N-methyl D-aspartate receptor (NMDAR) (n = 21), contactin-associated protein 2 (CASPR2) (n = 14) and/or glutamic acid decarboxylase 65 (GAD65) (n = 9) antibodies (cases) were age and sex matched (1:2) with serum-negative patients from the same cohort (controls). The prevalence and severity of psychiatric symptoms frequently encountered in NMDAR, CASPR2 and GAD65 antibody associated disorders were compared in cases and controls. NMDAR, CASPR2 and GAD65 antibody positive patients did not differ in their clinical presentation from matched serum negative controls. CONCLUSION: In this cohort, patients with and without NMDAR, CASPR2 and GAD65 antibodies admitted to acute psychiatric inpatient care had similar psychiatric phenotypes. This does not exclude their clinical relevance in subgroups of patients, and studies further investigating the clinical significance of anti-neuronal antibodies in patients with psychiatric symptomatology are needed.

Motor activity patterns in acute schizophrenia and other psychotic disorders can be differentiated from bipolar mania and unipolar depression.

The purpose of this study was to compare 24-h motor activity patterns between and within three groups of acutely admitted inpatients with schizophrenia and psychotic disorders (n = 28), bipolar mania (n = 18) and motor-retarded unipolar depression (n = 25) and one group of non-hospitalized healthy individuals (n = 28). Motor activity was measured by wrist actigraphy, and analytical approaches using linear and non-linear variability and irregularity measures were undertaken. In between-group comparisons, the schizophrenia group showed more irregular activity patterns than depression cases and healthy individuals. The schizophrenia and mania cases were clinically similar with respect to high prevalence of psychotic symptoms. Although they could not be separated by a formal statistical test, the schizophrenia cases showed more normal amplitudes in morning to evening mean activity and activity variability. Schizophrenia constituted an independent entity in terms of motor activation that could be distinguished from the other diagnostic groups of psychotic and non-psychotic affective disorders. Despite limitations such as small subgroups, short recordings and confounding effects of medication/hospitalization, these results suggest that detailed temporal analysis of motor activity patterns can identify similarities and differences between prevalent functional psychiatric disorders. For this purpose, irregularity measures seem particularly useful to characterize psychotic symptoms and should be explored in larger samples with longer-term recordings, while searching for underlying mechanisms of motor activity disturbances.

Actigraphy as an objective intra-individual marker of activity patterns in acute-phase bipolar disorder: a case series.

BACKGROUND: Actigraphy could be an objective alternative to clinical ratings of motor activity in bipolar disorder (BD), which is of importance now that increased activity and energy are added as cardinal symptoms of (hypo)mania in the DSM-5 and commonly used rating scales give inadequate information about motor symptoms. To date, most actigraphy studies have been conducted in groups and/or used mean activity levels as the variable of interest. The novelty of this case series is therefore to indicate the potential of actigraphy and non-parametric analysis as an objective and personalized marker of intra-individual activity patterns in different phases of BD. To our knowledge, this is the first case series that provides an objective assessment of non-linear dynamics in within-person activity patterns during acute BD episodes. RESULTS: We report on three cases of bipolar I disorder with 24-h actigraphy recordings undertaken during the first few days of two or more separate admissions for an acute illness episode, including admissions for individuals in different phases of BD, or with different levels of severity in the same phase of illness. For each recording, we calculated mean activity levels over 24 h, but especially focused on key measures of variability and complexity in activity. Intra-individual activity patterns were found to be different according to phase of illness, but showed consistency within the same phase. With increasing psychotic symptoms, there was evidence of a lower overall level and greater irregularity in activity. As such, sample entropy (a measure of irregularity) may have particular utility in characterizing mania and psychotic symptoms, while assessment of the distribution of rest versus activity over 24 h may distinguish between phases of BD within an individual. CONCLUSIONS: This case series indicates that objective, intra-individual, real-time recordings of patterns of activity may have clinical impact as a valuable adjunct to clinical observation and symptom ratings. We suggest that actigraphy combined with detailed mathematical analysis provides a biological variable that could become an important tool for developing a personalized approach to diagnostics and treatment monitoring in BD.

Right unilateral electroconvulsive therapy does not cause more cognitive impairment than pharmacologic treatment in treatment-resistant bipolar depression: A 6-month randomized controlled trial follow-up study.

OBJECTIVES: Electroconvulsive therapy is an effective treatment for bipolar depression, but there are concerns about whether it causes long-term neurocognitive impairment. METHODS: In this multicenter randomized controlled trial, in-patients with treatment-resistant bipolar depression were randomized to either algorithm-based pharmacologic treatment or right unilateral electroconvulsive therapy. After the 6-week treatment period, all of the patients received maintenance pharmacotherapy as recommended by their clinician guided by a relevant treatment algorithm. Patients were assessed at baseline and at 6 months. Neurocognitive functions were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and autobiographical memory consistency was assessed using the Autobiographical Memory Interview-Short Form. RESULTS: Seventy-three patients entered the trial, of whom 51 and 26 completed neurocognitive assessments at baseline and 6 months, respectively. The MATRICS Consensus Cognitive Battery composite score improved by 4.1 points in both groups (P = .042) from baseline to 6 months (from 40.8 to 44.9 and from 41.9 to 46.0 in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively). The Autobiographical Memory Interview-Short Form consistency scores were reduced in both groups (72.3% vs 64.3% in the algorithm-based pharmacologic treatment and electroconvulsive therapy groups, respectively; P = .085). CONCLUSIONS: This study did not find that right unilateral electroconvulsive therapy caused long-term impairment in neurocognitive functions compared to algorithm-based pharmacologic treatment in bipolar depression as measured using standard neuropsychological tests, but due to the low number of patients in the study the results should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00664976.

Variability of activity patterns across mood disorders and time of day.

BACKGROUND: Few actigraphy studies in mood disorders have simultaneously included unipolar (UP) and bipolar (BD) depression or BD mixed states as a separate subgroup from mania. This study compared objectively measured activity in UP, BD depression, mania and mixed states and examined if patterns differed according to time of day and/or diagnostic group. METHODS: Eighty -eight acutely admitted inpatients with mood disorders (52 UP; 18 mania; 12 BD depression; 6 mixed states) underwent 24 hours of actigraphy monitoring. Non-parametric analyses were used to compare median activity level over 24 h (counts per minute), two time series (64-min periods of continuous motor activity) in the morning and evening, and variability in activity across and within groups. RESULTS: There was no between-group difference in 24-h median level of activity, but significant differences emerged between BD depression compared to mania in the active morning period, and between UP and mania and mixed states in the active evening period. Within-group analyses revealed that UP cases showed several significant changes between morning and evening activity, with fewer changes in the BD groups. CONCLUSIONS: Mean activity over 24 hours has limited utility in differentiating UP and BD. In contrast, analysis of non-linear variability measures of activity at different times of day could help objectively distinguish between mood disorder subgroups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01415323 , first registration July 6, 2011.

A pilot study to determine whether combinations of objectively measured activity parameters can be used to differentiate between mixed states, mania, and bipolar depression.

BACKGROUND: Until recently, actigraphy studies in bipolar disorders focused on sleep rather than daytime activity in mania or depression, and have failed to analyse mixed episodes separately. Furthermore, even those studies that assessed activity parameters reported only mean levels rather than complexity or predictability of activity. We identified cases presenting in one of three acute phases of bipolar disorder and examined whether the application of non-linear dynamic models to the description of objectively measured activity can be used to predict case classification. METHODS: The sample comprised 34 adults who were hospitalized with an acute episode of mania (n = 16), bipolar depression (n = 12), or a mixed state (n = 6), who agreed to wear an actiwatch for a continuous period of 24 h. Mean level, variability, regularity, entropy, and predictability of activity were recorded for a defined 64-min active morning and active evening period. Discriminant function analysis was used to determine the combination of variables that best classified cases based on phase of illness. RESULTS: The model identified two discriminant functions: the first was statistically significant and correlated with intra-individual fluctuation in activity and regularity of activity (sample entropy) in the active morning period; the second correlated with several measures of activity from the evening period (e.g. Fourier analysis, autocorrelation, sample entropy). A classification table generated from both functions correctly classified 79% of all cases based on phase of illness (χ 2 = 36.21; df 4; p = 0.001). However, 42% of bipolar depression cases were misclassified as being in manic phase. CONCLUSIONS: The findings should be treated with caution as this was a small-scale pilot study and we did not control for prescribed treatments, medication adherence, etc. However, the insights gained should encourage more widespread adoption of statistical approaches to the classification of cases alongside the application of more sophisticated modelling of activity patterns. The difficulty of accurately classifying cases of bipolar depression requires further research, as it is unclear whether the lower prediction rate reflects weaknesses in a model based only on actigraphy data, or if it reflects clinical reality i.e. the possibility that there may be more than one subtype of bipolar depression.

Sleep patterns as a predictor for length of stay in a psychiatric intensive care unit.

Systematic evaluations of the relationship between sleep patterns and length of stay in psychiatric intensive care units (PICUs) are lacking. The aims of the present study were to explore if sleep duration or night-to-night variations in sleep duration the first nights predict length of stay in a PICU. Consecutive patients admitted to a PICU were included (N=135) and the nurses registered the time patients were observed sleeping. In the three first nights, the mean sleep duration was 7.5 (±3.2)h. Sleep duration the first night correlated negatively with the length of stay for patients with schizophrenia. The mean difference in sleep duration from night one to night two were 3.3 (±3.0)h and correlated with length of stay for the whole group of patients, but especially for patients with schizophrenia. Patients of all diagnostic groups admitted to a PICU had pronounced intra-individual night-to-night variations in sleep duration. Stabilizing night-to-night variations of sleep duration might be a major goal in treatment.

Delayed sleep phase: An important circadian subtype of sleep disturbance in bipolar disorders.

BACKGROUND: Theoretical models of Bipolar Disorder (BD) highlight that sleep disturbances may be a marker of underlying circadian dysregulation. However, few studies of sleep in BD have reported on the most prevalent circadian sleep abnormality, namely Delayed Sleep Phase (DSP). METHODS: A cross-sectional study of 404 adults with BD who met published clinical criteria for insomnia, hypersomnia or DSP, and who had previously participated in a study of sleep in BD using a comprehensive structured interview assessment. RESULTS: About 10% of BD cases with a sleep problem met criteria for a DSP profile. The DSP group was younger and had a higher mean Body Mass Index (BMI) than the other groups. Also, DSP cases were significantly more likely to be prescribed mood stabilizers and antidepressant than insomnia cases. An exploratory analysis of selected symptom item ratings indicated that DSP was significantly more likely to be associated with impaired energy and activity levels. LIMITATIONS: The cross-sectional design precludes examination of longitudinal changes. DSP is identified by sleep profile, not by diagnostic criteria or objective sleep records such as actigraphy. The study uses data from a previous study to identify and examine the DSP group. CONCLUSIONS: The DSP group identified in this study can be differentiated from hypersomnia and insomnia groups on the basis of clinical and demographic features. The association of DSP with younger age, higher BMI and impaired energy and activity also suggest that this clinical profile may be a good proxy for underlying circadian dysregulation.

Actigraphically assessed activity in unipolar depression: a comparison of inpatients with and without motor retardation.

OBJECTIVE: To compare the activity patterns of inpatients with unipolar depression, who had been divided into groups with and without motor retardation prior to actigraphy monitoring. METHOD: Twenty-four-hour actigraphy recordings from 52 consecutively, acutely admitted inpatients with unipolar depression (ICD-10) were compared to recordings from 28 healthy controls. The patients, admitted between September 2011 and April 2012, were separated into 2 groups: 25 with motor retardation and 27 without motor retardation. Twenty-eight healthy controls were also included. Twenty-four-hour recordings, 9-hour daytime sequences, and 64-minute periods of continuous motor activity in the morning and evening were analyzed for mean activity, variability, and complexity. RESULTS: Patients with motor retardation had a reduced mean activity level (P = .04) and higher intraindividual variability, as shown by increased standard deviation (SD) (P = .003) and root mean square successive difference (RMSSD) (P = .025), during 24 hours compared to the patients without motor retardation. Both patient groups demonstrated significantly lower mean activity compared to healthy controls (P < .001) as well as higher SD (P < .02) and RMSSD (P < .001) and a higher RMSSD/SD ratio (P = .04). In the active morning period, the patients without motor retardation displayed significantly increased complexity compared to motor-retarded patients (P = .006). CONCLUSIONS: The patients with and without motor retardation differ in activity patterns. Findings in depressed inpatients without motor retardation closely resemble those of inpatients with mania.

Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders.

OBJECTIVES: Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Dwivedi et al., Arch Gen Psychiatry 2010;60:804-815; Zai et al., Prog Neuropsychopharmacol Biol Psychiatry 2012;34:1412-1418) and BDNF regulates the expression of the dopamine D3 receptor. OBJECTIVE: We examined the role of the BDNF and DRD3 genes in suicide. METHODS: We analysed four tag single-nucleotide polymorphisms (SNPs) in BDNF and 15 SNPs in the D3 receptor gene DRD3 for possible association with suicide attempt history in our Canadian sample of Schizophrenia (SCZ) patients of European ancestry (N = 188). RESULTS: In this sample, we found a possible interaction between the BDNF Val66Met and DRD3 Ser9Gly SNPs in increasing the risk of suicide attempt(s) in our SCZ sample. Specifically, a larger proportion of SCZ patients who were carrying at least one copy of the minor allele at each of the Val66Met and Ser9Gly functional markers have attempted suicides compared to patients with other genotypes (Bonferroni P < 0.05). However, we could not replicate this finding in samples from other psychiatric populations. CONCLUSIONS: Taken together, the results from the present study suggest that an interaction between BDNF and DRD3 may not play a major role in the risk for suicide attempt, though further studies, especially in SCZ, are required.

Religious convictions in patients with epilepsy-associated affective disorders: a controlled study from a psychiatric acute department.

Patients with epilepsy often have different mood symptoms and behavioral trait characteristics compared to the non-epileptic population. In the present prospective study, we aimed to assess differences in behavioral trait characteristics between acutely admitted, psychiatric in-patients with epilepsy-associated depressive symptoms and gender/age-matched patients with major depression. Patients with epilepsy-associated depression had significantly higher scores for "religious convictions," "philosophical and intellectual interests" and "sense of personal destiny." These behavioral trait characteristics at admission or in clinical history should alert the psychiatrist and lead to closer examination for a possible convulsive disorder.

The effect of electroconvulsive therapy on neurocognitive function in treatment-resistant bipolar disorder depression.

OBJECTIVE: To compare the effects of right unilateral (RUL) electroconvulsive therapy (ECT) and algorithm-based pharmacologic treatment (APT) on neurocognitive function in treatment-resistant bipolar disorder depression. METHOD: Inpatients with DSM-IV-TR-diagnosed, treatment-resistant bipolar depression, who were acutely admitted to 1 of the 7 clinical study centers in Norway, were recruited from May 2008 to April 2011 into a prospective, randomized controlled, 6-week acute treatment trial. General neurocognitive function was assessed with the MATRICS Consensus Cognitive Battery (MCCB), and retrograde memory for autobiographical events was assessed with the Autobiographical Memory Interview-Short Form (AMI-SF) before and shortly after (mean = 23.5 days) a trial with either RUL brief-pulse ECT (mean dose = 233.3 mC) or APT. RESULTS: Seventy-three patients entered, and 39 (nECT = 19, nAPT = 20) completed. Both groups showed improvements in all MCCB domain scores, with no significant differences between the study groups (no interaction effect: F1,37 = 1.52, P = NS). Improvements in neurocognitive performance were significantly correlated with reductions in depression ratings posttreatment. The AMI-SF score was significantly lower (based on consistent answers from pre- to posttreatment) in the ECT group (72.9%) than in the APT group (80.8%, P = .025), indicating reduced consistency in autobiographical memory after ECT. CONCLUSIONS: General neurocognitive function was unaffected by RUL brief-pulse ECT treatment and positively related to improved mood in bipolar depression. Autobiographical memory consistency was reduced in patients treated with ECT. The results suggest that ECT can be used in treatment-resistant bipolar depression without compromising general neurocognitive function. The clinical relevance of reduced autobiographical memory consistency in the ECT group requires further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00664976.

Factors associated with a positive occupational outcome during long-term central stimulant treatment in adult ADHD.

There is a lack of long-term studies of central stimulant (CS) treatment in adult attention-deficit/hyperactivity disorder (ADHD), and studies on functional outcomes like occupational status are rare. The current study investigated occupational status in adult ADHD patients before and after long-term CS treatment (median duration of treatment 33 months) and aimed to identify variables associated with improvement in occupational status. The collection of data was based on a naturalistic, retrospective approach using the medical records of a sample of all 117 adult ADHD patients consecutively starting treatment with CS in a specific catchment area in Norway in the period 1997 to May 2005. Most patients did not improve in occupational status during long-term CS treatment. The improved group had significantly higher baseline ADHD symptoms as measured by the general adult ADD symptom checklist (83.7 vs. 76.2, p=0.024) and had a significantly shorter period from the first contact with adult psychiatry until they got the ADHD diagnosis (11.7 vs. 50.9 months, p=0.001). The results indicate that long-term CS treatment itself may have limited effect on occupational status in functionally impaired and highly comorbid patients with adult ADHD. A high baseline ADHD symptom level may be related to a superior outcome in occupational status.

Neurocognitive profiles in treatment-resistant bipolar I and bipolar II disorder depression.

BACKGROUND: The literature on the neuropsychological profiles in Bipolar disorder (BD) depression is sparse. The aims of the study were to assess the neurocognitive profiles in treatment-resistant, acutely admitted BD depression inpatients, to compare the neurocognitive functioning in patients with BD I and II, and to identify the demographic and clinical illness characteristics associated with cognitive functioning. METHODS: Acutely admitted BD I (n = 19) and BD II (n = 32) inpatients who fulfilled the DSM-IV-TR criteria for a major depressive episode were tested with the MATRICS Consensus Cognitive Battery (MCCB), the Wechsler Abbreviated Scale of Intelligence, the National Adult Reading Test, and a battery of clinical measures. RESULTS: Neurocognitive impairments were evident in the BD I and BD II depression inpatients within all MCCB domains. The numerical scores on all MCCB-measures were lower in the BD I group than in the BD II group, with a significant difference on one of the measures, category fluency. 68.4% of the BD I patients had clinically significant impairment (>1.5 SD below normal mean) in two or more domains compared to 37.5% of the BD II patients (p = 0.045). A significant reduction in IQ from the premorbid to the current level was seen in BD I but not BD II patients. Higher age was associated with greater neurocognitive deficits compared to age-adjusted published norms. CONCLUSIONS: A high proportion of patients with therapy-resistant BD I or II depression exhibited global neurocognitive impairments with clinically significant severity. The cognitive impairments were more common in BD I compared to BD II patients, particularly processing speed. These findings suggest that clinicians should be aware of the severe neurocognitive dysfunction in treatment-resistant bipolar depression, particularly in BD I. TRIAL REGISTRATION: NCT00664976.