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.

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.

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.

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.

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.

Risk factors related to lifetime suicide attempts in acutely admitted bipolar disorder inpatients.

OBJECTIVE: The main aim of this study was to assess possible clinical characteristics of acutely admitted bipolar I disorder (BD-I) and bipolar II disorder (BD-II) inpatients at high risk of suicide by comparing patients who had made one or several serious suicide attempts with patients who had not. METHODS: A total of 206 consecutive patients (mean age 42 ± 15 years; 54.9% women) with DSM-IV diagnosed BD-I (n = 140) and BD-II (n= 66) acutely admitted to a single psychiatric hospital department from November 2002 through June 2009 were included. Using a detailed retrospective questionnaire, patients with a history of a serious suicide attempt were compared to those with no history of a suicide attempt. RESULTS: Ninety-three patients (45.1%) had a history of one or more serious suicide attempts. These constituted 60 (42.9%) of the BD-I patients and 33 (50%) of the BD-II patients (no significant difference). Lifetime suicide attempt was associated with a higher number of hospitalizations due to depression (p < 0.0001), antidepressant (AD)-induced hypomania/mania (p = 0.033), AD- and/or alcohol-induced affective episodes (p = 0.009), alcohol and/or substance use (p = 0.002), and a family history of alcohol abuse and/or affective disorder (p = 0.01). Suicide attempt was negatively associated with a higher Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Positive Subscale score (p = 0.022) and more hospitalizations due to mania (p = 0.006). CONCLUSIONS: The lifetime suicide attempt rate in BD inpatients is high. Risk factors of suicide attempts were: (i) a predominant depressive course of illness, (ii) comorbid alcohol and substance use disorders, and (iii) a history of AD- and/or alcohol-induced affective episodes. Risk-reducing factors were a preponderant manic or psychotic course of the illness. These risk factors may be signs of a clinical subgroup at risk of suicidal behaviour, and seem to be important for suicide risk assessment in acutely admitted BD patients.

Pharmacological treatment and adherence one week prior to acute psychiatric admissions.

BACKGROUND AND AIMS: To describe use of and adherence to psychotropic medication 1 week prior to acute admission to a psychiatric inpatient department. METHODS: All acute inpatient admissions to a department serving a catchment area were included. RESULTS AND CONCLUSIONS: Of the 227 admissions, 158 were prescribed psychotropic medication and 129 of the 158 had taken at least 75% of the prescribed dose. Among 59 patients with affective disorders, 23 were not prescribed medication prior to admission and two refused medication, while the rest were adherent. CONCLUSION: The high adherence to medication 1 week prior to admission might be related to increased experience of serious symptoms. Lack of opportunity to receive pharmacological treatment is a major problem.

Short-term prediction of threatening and violent behaviour in an Acute Psychiatric Intensive Care Unit based on patient and environment characteristics.

BACKGROUND: The aims of the present study were to investigate clinically relevant patient and environment-related predictive factors for threats and violent incidents the first three days in a PICU population based on evaluations done at admittance. METHODS: In 2000 and 2001 all 118 consecutive patients were assessed at admittance to a Psychiatric Intensive Care Unit (PICU). Patient-related conditions as actuarial data from present admission, global clinical evaluations by physician at admittance and clinical nurses first day, a single rating with an observer rated scale scoring behaviours that predict short-term violence in psychiatric inpatients (The Brøset Violence Checklist (BVC)) at admittance, and environment-related conditions as use of segregation or not were related to the outcome measure Staff Observation Aggression Scale-Revised (SOAS-R). A multiple logistic regression analysis with SOAS-R as outcome variable was performed. RESULTS: The global clinical evaluations and the BVC were effective and more suitable than actuarial data in predicting short-term aggression. The use of segregation reduced the number of SOAS-R incidents. CONCLUSIONS: In a naturalistic group of patients in a PICU segregation of patients lowers the number of aggressive and threatening incidents. Prediction should be based on clinical global judgment, and instruments designed to predict short-term aggression in psychiatric inpatients. TRIAL REGISTRATIONS: NCT00184119/NCT00184132.

Acute Unstable Depressive Syndrome (AUDS) is associated more frequently with epilepsy than major depression.

BACKGROUND: Depressive disorders are frequent in epilepsy and associated with reduced seizure control. Almost 50% of interictal depressive disorders have to be classified as atypical depressions according to DSM-4 criteria. Research has mainly focused on depressive symptoms in defined populations with epilepsy (e.g., patients admitted to tertiary epilepsy centers). We have chosen the opposite approach. We hypothesized that it is possible to define by clinical means a subgroup of psychiatric patients with higher than expected prevalence of epilepsy and seizures. We hypothesized further that these patients present with an Acute Unstable Depressive Syndrome (AUDS) that does not meet DSM-IV criteria of a Major Depressive Episode (MDE). In a previous publication we have documented that AUDS patients indeed have more often a history of epileptic seizures and abnormal EEG recordings than MDE patients (Vaaler et al. 2009). This study aimed to further classify the differences of depressive symptoms at admittance and follow-up of patients with AUDS and MDE. METHODS: 16 AUDS patients and 16 age- and sex-matched MDE patients were assessed using the Symptomatic Organic Mental Disorder Assessment Scale (SOMAS), the Montgomery and Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Test (MMST), at day 2, day 4-6, day 14-16 and 3 months after admittance to a psychiatric emergency unit. Life events were assessed with The Social Readjustment Rating Scale (SRRS) and The Life Experience Survey (LES). We also screened for medication serum levels and illicit drug metabolites in urine. RESULTS: AUDS patients had significantly higher SOMAS scores (average score at admission 6.6 +/- 0.8), reflecting increased symptom fluctuation and motor agitation, and decreased insight and concern compared to MDE patients (2.9 +/- 0.7; p < 0.001). Degree of mood depression, cognition, life events, drug abuse and medication did not differ between the two groups. CONCLUSIONS: AUDS patients present with rapidly fluctuating mood symptoms, motor agitation and relative lack of insight and concern. Seizures, epilepsy and EEG abnormalities are overrepresented in AUDS patients compared to MDE patients. We suggest that the study of AUDS patients may offer a new approach to better understanding epilepsy and its association with depressive disorders. TRIAL REGISTRATION: NCT00201474.

The study protocol of the Norwegian randomized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolar disorder.

BACKGROUND: The treatment of depressive phases of bipolar disorder is challenging. The effects of the commonly used antidepressants in bipolar depression are questionable. Electroconvulsive therapy is generally considered to be the most effective treatment even if there are no randomized controlled trials of electroconvulsive therapy in bipolar depression. The safety of electroconvulsive therapy is well documented, but there are some controversies as to the cognitive side effects. The aim of this study is to compare the effects and side effects of electroconvulsive therapy to pharmacological treatment in treatment resistant bipolar depression. Cognitive changes and quality of life during the treatment will be assessed. METHODS/DESIGN: A prospective, randomised controlled, multi-centre six- week acute treatment trial with seven clinical assessments. Follow up visit at 26 weeks or until remission (max 52 weeks). A neuropsychological test battery designed to be sensitive to changes in cognitive function will be used. SETTING: Nine study centres across Norway, all acute psychiatric departments. SAMPLE: n = 132 patients, aged 18 and over, who fulfil criteria for treatment resistant depression in bipolar disorder, Montgomery Asberg Depression Rating Scale Score of at least 25 at baseline. INTERVENTION: INTERVENTION group: 3 sessions per week for up to 6 weeks, total up to 18 sessions. CONTROL GROUP: algorithm-based pharmacological treatment as usual. DISCUSSION: This study is the first randomized controlled trial that aims to investigate whether electroconvulsive therapy is better than pharmacological treatment as usual in treatment resistant bipolar depression. Possible long lasting cognitive side effects will be evaluated. The study is investigator initiated, without support from industry. TRIAL REGISTRATION: NCT00664976.

Age at onset of first episode and time to treatment in in-patients with bipolar disorder.

This study aimed to investigate the relationship between age at onset and time to first pharmacological treatment in patients with either bipolar I or II disorder. A total of 146 consecutive in-patients acutely admitted from the same catchment area were included. Patients were divided into four age groups: 0-12 years (23%); 13-18 years (32%); 19-29 years (26%); and > or =30 years (18%). Mean age at first affective episode was 20.2 years (s.d.=11.8). This represents a similar pattern to the age at onset seen in out-patients in the USA. Early age at onset predicted a longer time to first pharmacological treatment (rho =-0.695, P<0.01).

Symptoms of epilepsy and organic brain dysfunctions in patients with acute, brief depression combined with other fluctuating psychiatric symptoms: a controlled study from an acute psychiatric department.

BACKGROUND: In psychiatric acute departments some patients present with brief depressive periods accompanied with fluctuating arrays of other psychiatric symptoms like psychosis, panic or mania. For the purpose of the present study we call this condition Acute Unstable Depressive Syndrome (AUDS). The aims of the present study were to compare clinical signs of organic brain dysfunctions and epilepsy in patients with AUDS and Major Depressive Episode (MDE). METHODS: Out of 1038 consecutive patients admitted to a psychiatric acute ward, 16 patients with AUDS and 16 age- and gender-matched MDE patients were included in the study. Using standardized instruments and methods we recorded clinical data, EEG and MRI. RESULTS: A history of epileptic seizures and pathologic EEG activity was more common in the AUDS group than in the MDE group (seizures, n = 6 vs. 0, p = 0.018; pathologic EEG activity, n = 8 vs. 1, p = 0.015). Five patients in the AUDS group were diagnosed as having epilepsy, whereas none of those with MDE had epilepsy (p = 0.043). There were no differences between the groups regarding pathological findings in neurological bedside examination and cerebral MRI investigation. CONCLUSION: Compared to patients admitted with mood symptoms fulfilling DSM 4 criteria of a major depressive disorder, short-lasting atypical depressive symptoms seem to be associated with a high frequency of epileptic and pathologic EEG activity in patients admitted to psychiatric acute departments. TRIAL REGISTRATION: NCT00201474.

Substance use at admission to an acute psychiatric department.

Substance use is prevalent in patients with psychiatric disorders and may cause severe symptoms in addition to complicating the diagnosis of psychiatric disorders. The aims of the study were to find the prevalence in use of alcohol, drugs, benzodiazepines, hypnotics, opiates and stimulants, and to find the prevalence of substance use disorders at admission to an acute psychiatric department receiving all admissions from a catchment area. Patients were interviewed about use of medications and intoxicating substances during the last week before admission in 227 consecutive admissions. Urine samples were analysed with the liquid chromatography with mass spectrometry (LC-MS) method. Use of substances was determined from reported use and findings in urine samples. Diagnoses were set at discharge according to ICD-10 research criteria. In 81.9% of the admissions, the patient had used alcohol, drugs, benzodiazepines, hypnotics, opiates or stimulants prior to admission. More men used alcohol, cannabis and stimulants, whereas more women used benzodiazepines. In 31.7% of the admissions, 49.5% of men and 16.4% of women, the patients had a substance use disorder (ICD-10, F10-19). Patients with substance use disorders had a shorter stay in hospital than other patients, and patients with no psychiatric disorder other than substance use disorders had a median length of stay of 2 days. Most patients had used psychoactive substances before admission to the acute psychiatric department, and half of the men had a substance use disorder.

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.