Remission in schizophrenia spectrum disorders: A randomized trial of amisulpride, aripiprazole and olanzapine.

Schizophrenia is a serious mental disorder, and monitoring remission is a widely used measure of effectiveness of the treatment provided. It is very important to identify possible factors correlating with remission. In our substudy of BeSt InTro, a randomized controlled trial of three antipsychotic drugs, 126 patients with ICD-10 diagnoses F20-29 (F23 excluded) were randomized to one of the second-generation antipsychotic drugs amisulpride, aripiprazole or olanzapine. Remission rate was calculated at seven assessment points, with and without using the time criterion of six months included in the consensus remission criteria. Because of drop-out (n = 77), we had data for 49 patients at one-year follow-up. These data were used to calculate the one-year remission rate to 55 % (27/49), without taking into consideration the 6-month time criterion. When we applied the consensus remission criteria with the 6-month time criterion included, the one-year remission rate was calculated for 59 patients: 29 % (17/59). Antipsychotic drug naivety and low negative symptom load at baseline correlated highly with belonging to the remission group. Use of amisulpride was more probable to lead to remission than that of aripiprazole, but it was not more probable than the use of olanzapine (in per-protocol analyses). Negative symptoms showed the largest resistance to treatment. The lack of remission for the majority of the participants in this closely monitored antipsychotic drug trial is alarming and could act as a reminder that novel treatment principles are needed, especially targeted towards the negative symptoms in schizophrenia.

NMDAR dysfunction and the regulation of dopaminergic transmission in schizophrenia.

A substantial body of evidence implicates dysfunction in N-methyl-d-aspartate receptors (NMDARs) in the pathophysiology of schizophrenia. This article illustrates how NMDAR dysfunction may give rise to many of the neurobiological phenomena frequently associated with schizophrenia with a particular focus on how NMDAR dysfunction affects the thalamic reticular nucleus (nRT) and pedunculopontine tegmental nucleus (PPTg). Furthermore, this article presents a model for schizophrenia illustrating how dysfunction in the nRT may interrupt prefrontal regulation of midbrain dopaminergic neurons, and how dysfunction in the PPTg may drive increased, irregular burst firing.

Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders.

BACKGROUND: Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. METHODS: The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. RESULTS: The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. CONCLUSIONS: In our study, patients with schizophrenia - including the drug-naïve - have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

Association between cytokines and suicidality in patients with psychosis: A multicentre longitudinal analysis.

Suicide is a common cause of death in all phases of schizophrenia spectrum disorder, particularly in the youngest patients. Clinical measures have demonstrated limited value in suicide prediction, spurring the search for potential biomarkers. The causes of suicidal behaviour are complex, but the immune system seems to be involved as it reflects or even causes mental suffering. We aimed to identify cytokines with associations to suicidality in a sample of patients with symptoms of active psychosis. Patients with schizophrenia spectrum disorder (N = 144) participating in a semi-randomized antipsychotic drug trial (the BeSt InTro study) were assessed with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS) at eight visits across 12 months. The Clinical Global Impression for Severity of Suicidality scale (CGI-SS) was used for assessing suicidality. Serum concentrations of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, and IL-10 were measured using immunoassays. A logistic regression model was used to investigate the association between cytokine levels and suicidality. To enhance clinical significance, the CGI-SS scores were dichotomized into two groups before analyses: low (=1) and high (≥2) risk for suicidality. Both uni- and multi-variate analyses revealed an inverse correlation between IL-2 and IL-10 serum levels and suicidality, where lower cytokine concentrations of IL-2 and IL-10 were associated with higher suicidality scores. The results were consistent when adjusted for depression and substance use. These results indicate that inflammatory processes are linked to the risk of suicidality in patients with schizophrenia spectrum disorders.

Effects of deep brain stimulation and verbal suggestions on pain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: In Parkinson's disease (PD) patients, verbal suggestions have been shown to modulate motor and clinical outcomes in treatment with subthalamic deep brain stimulation (DBS). Furthermore, DBS may alleviate pain in PD. However, it is unknown if verbal suggestions influence DBS' effects on pain. METHODS: Twenty-four people with PD and DBS had stimulation downregulated (80-60 to 20%) and upregulated (from 20-60 to 80%) in a blinded manner on randomized test days: (1) with negative and positive suggestions of pain for down- and upregulation, respectively, and (2) with no suggestions to effect (control). Effects of DBS and verbal suggestions were assessed on ongoing and evoked pain (hypertonic saline injections) via 0-10 numerical rating scales along with motor symptoms, expectations, and blinding. RESULTS: Stimulation did not influence ongoing and evoked pain but influenced motor symptoms in the expected direction. Baseline and experimental pain measures showed no patterns in degree of pain. There was a trend toward negative suggestions increasing pain and positive suggestions decreasing pain. Results show significant differences in identical stimulation with negative vs positive suggestions (60% conditions AUC 38.75 vs 23.32, t(13) = 3.10, p < 0.001). Expectations to pain had small to moderate effects on evoked pain. Patients estimated stimulation level correctly within 10 points. CONCLUSION: Stimulation does not seem to influence ongoing and evoked pain, but verbal suggestions may influence pain levels. Patients appear to be unblinded to stimulation level which is an important consideration for future studies testing DBS in an attempted blind fashion.

Risk factors for mortality in patients admitted to a psychiatric acute ward: A prospective cohort study.

INTRODUCTION: Associations between psychiatric disorders and mortality have been extensively studied, but limited evidence exists regarding influence of clinical characteristics on mortality risk, at the time of acute psychiatric hospitalization. METHODS: A prospective total-cohort study included all patients consecutively admitted to Haukeland University Hospital's psychiatric acute ward in Bergen, Norway between 2005 and 2014 (n = 6125). Clinical interviews were conducted at the first admission within the study period, and patients were subsequently followed for up to 15 years in the Norwegian Cause of Death Registry. Competing risks regression models were used to investigate associations between clinical characteristics at first admission and the risk of natural and unnatural death during follow-up. RESULTS: The mean age at first admission and at time of death was 42.5 and 62.8 years, respectively, and the proportion of women in the sample was 47.2%. A total of 1381 deaths were registered during follow-up, of which 65.5% had natural, 30.4% unnatural, and 4.1% unknown causes. Higher age, male sex, unemployment, cognitive deficits, and physical illness were associated with increased risk of natural death. Male sex, having no partner, physical illness, suicide attempts, and excessive use of alcohol and illicit substances were associated with increased risk of unnatural death. CONCLUSION: Psychiatric symptoms, except suicide attempts, were unrelated to increased mortality risk. In the endeavor to reduce the increased mortality risk in people with mental disorders, focus should be on addressing modifiable risk factors linked to physical health and excessive use of alcohol and illicit substances.

Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies.

Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia.

Dopamine dysregulation in Parkinson's disease flattens the pleasurable urge to move to musical rhythms.

The pleasurable urge to move to music (PLUMM) activates motor and reward areas of the brain and is thought to be driven by predictive processes. Dopamine in motor and limbic networks is implicated in beat-based timing and music-induced pleasure, suggesting a central role of basal ganglia (BG) dopaminergic systems in PLUMM. This study tested this hypothesis by comparing PLUMM in participants with Parkinson's disease (PD), age-matched controls, and young controls. Participants listened to musical sequences with varying rhythmic and harmonic complexity (low, medium and high), and rated their experienced pleasure and urge to move to the rhythm. In line with previous results, healthy younger participants showed an inverted U-shaped relationship between rhythmic complexity and ratings, with preference for medium complexity rhythms, while age-matched controls showed a similar, but weaker, inverted U-shaped response. Conversely, PD showed a significantly flattened response for both the urge to move and pleasure. Crucially, this flattened response could not be attributed to differences in rhythm discrimination and did not reflect an overall decrease in ratings. For harmonic complexity, PD showed a negative linear pattern for both the urge to move and pleasure while healthy age-matched controls showed the same pattern for pleasure and an inverted U for the urge to move. This contrasts with the pattern observed in young healthy controls in previous studies, suggesting that both healthy aging and PD also influence affective responses to harmonic complexity. Together, these results support the role of dopamine within cortico-striatal circuits in the predictive processes that form the link between the perceptual processing of rhythmic patterns and the affective and motor responses to rhythmic music.

GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task.

A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2 *-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.

Seroprevalence of SARS-CoV-2 antibodies in a prospective cohort of patients admitted to an acute psychiatric ward in Norway during the initial months of the COVID-19 pandemic.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) spread around the world during the first part of 2020. The purpose of the study was to assess the prevalence of SARS-CoV-2 infection among patients acutely admitted to the Psychiatric Clinic, Haukeland University Hospital. METHODS: Serum tests to assess for antibodies to SARS-CoV-2 were administered at admission to the clinic together with a questionnaire on symptoms and demographical information. Further information was obtained from the medical records. RESULTS: The cumulative seroprevalence in the 266 participants was 0.75%, the cumulative reported cases in the Norwegian general population was 0.61% at the end of the inclusion period of the study. Twenty-five percent of participants had risk factors for a serious course of COVID-19. There was a low prevalence of cohabitation and only 20% had their main income derived from ordinary salaries (not welfare). CONCLUSION: The prevalence of SARS-CoV-2 infection in a sample of patients acutely admitted to the Psychiatric Clinic, Haukeland University Hospital, was comparable to reported cases in the general population. A possible link to governmental and municipal restrictions, general low workplace participation and cohabitation is discussed.

Seroprevalence of SARS-CoV-2 antibodies is comparable to the general population.Twenty-five percent of patients had elevated risk for a serious course of COVID-19 because of somatic conditions.Fifty-seven percent lived alone, 17% with one other person in the household.Twenty percent had regular salary as the main income source for the last three months before admission.

Prevalence and severity of freezing of gait in a Danish cohort of people with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a widespread neurodegenerative disorder characterised by wide range of symptoms. Freezing of gait (FoG), a transient feeling that the patient's feet are nailed to the floor, resulting in an inability to move, is a particularly distressful symptom. The assessment of FoG can be challenging. Often, clinicians are reliant on patients' subjective experiences and patient questionnaires such as the Freezing of Gait Questionnaire (FOGQ) and its updated version, the New FOGQ (NFOGQ).Until now, the NFOGQ has not been validated and piloted for use in Danish. Therefore, few attempts have been made to assess the prevalence and severity of FoG in Danish patients with PD. METHODS: This report describes a two-step process of adapting the NFOGQ into Danish and piloting its use among a cohort of patients with PD. A satisfactory translation (Danish NFOGQ) was produced and successfully piloted. RESULTS: The translation showed robust test-retest reliability after two weeks. Patients fully understood the questionnaire. Using the Danish NFOGQ in an online prevalence survey, we found that 35.7% of respondents had experienced FoG and that the prevalence correlated with disease duration. CONCLUSION: The Danish NFOGQ appears to be appropriate for assessing FoG in Danish patients with PD in both clinical and research settings. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Dog-assisted interventions for adults diagnosed with schizophrenia and related disorders: a systematic review.

Background: Many individuals diagnosed with schizophrenia and related disorders experience insufficient symptom relief from currently available treatment options. Researching additional venues should be prioritized. This systematic review, designed in accordance with PRISMA, examined the effect of targeted and structured dog-assisted interventions as a supplementary treatment. Methods: Randomized as well as non-randomized studies were included. Systematic searches were conducted in APA PsycInfo, AMED, CENTRAL, Cinahl, Embase, Medline, Web of Science, and in several sources covering "gray" (unpublished) literature. In addition, forward and backward citation searches were performed. A narrative synthesis was conducted. Quality of evidence and risk of bias were assessed in accordance with GRADE and RoB2/ROBINS-I criteria. Results: 12 publications from 11 different studies met eligibility criteria. Overall, studies showed diverging results. General psychopathology, positive and negative symptoms of psychosis, anxiety, stress, self-esteem, self-determination, lower body strength, social function, and quality of life were among the outcome measures with significant improvement. Most documentation for significant improvement was found for positive symptoms. One study indicated significant deterioration of non-personal social behavior. The risk of bias was high or serious for most of the outcome measures. Three outcome measures were associated with some concerns regarding risk of bias, and three with low risk of bias. Quality of evidence was graded low or very low for all outcome measures. Conclusions: The included studies indicate potential effects of dog-assisted interventions for adults diagnosed with schizophrenia and related disorders, mostly beneficial. Nevertheless, low number of participants, heterogeneity, and risk of bias complicate the interpretation of results. Carefully designed randomized controlled trials are needed to determine causality between interventions and treatment effects.

Long term outcomes and causal modelling of compulsory inpatient and outpatient mental health care using Norwegian registry data: Protocol for a controversies in psychiatry research project.

OBJECTIVES: Compulsory mental health care includes compulsory hospitalisation and outpatient commitment with medication treatment without consent. Uncertain evidence of the effects of compulsory care contributes to large geographical variations and a controversy on its use. Some argue that compulsion can rarely be justified and should be reduced to an absolute minimum, while others claim compulsion can more frequently be justified. The limited evidence base has contributed to variations in care that raise issues about the quality/appropriateness of care as well as ethical concerns. To address the question whether compulsory mental health care results in superior, worse or equivalent outcomes for patients, this project will utilise registry-based longitudinal data to examine the effect of compulsory inpatient and outpatient care on multiple outcomes, including suicide and overall mortality; emergency care/injuries; crime and victimisation; and participation in the labour force and welfare dependency. METHODS: By using the natural variation in health providers' preference for compulsory care as a source of quasi-randomisation we will estimate causal effects of compulsory care on short- and long-term trajectories. CONCLUSIONS: This project will provide valuable insights for service providers and policy makers in facilitating high quality clinical care pathways for a high risk population group.

Does drug use affect the efficacy of amisulpride, aripiprazole and olanzapine in patients with schizophrenia spectrum disorders? Results from a pragmatic, randomised study.

OBJECTIVES: Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use. METHODS: The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20-29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score. RESULTS: At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients. CONCLUSION: The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use.

A study of the reliability and validity of the Six-Spot Step Test Cognitive in ambulatory persons with Parkinson's disease.

INTRODUCTION: Although dual-task walking deficits challenge ambulatory function in persons with Parkinson's disease (PwPD), ambulation measures that incorporate cognitive dual-task loads seem scarce. In its construct and instruction, the Six-Spot Step Test Cognitive (SSSTcog) ensures an equal focus on cognitive and motor tasks. The present study investigated the construct validity and test-retest reliability of the SSSTcog in PwPD. METHODS: Seventy-eight PwPD were recruited from outpatient clinics. The SSSTcog was completed twice within the same day and again three to seven days later. In addition, the cognitive Timed "Up and Go" test (TUGcog) and the Mini-BESTest were also conducted on the last day. Reliability and validity were estimated using Bland-Altman statistics, the minimal difference (MD), Intraclass Correlation Coefficient (ICC), and Spearman's rank correlation coefficient (ρ). RESULTS: The SSSTcog was found reliable (ICC: 0.84-0.89; MD: 23.7%-30.2%) and showed moderate construct validity to the TUGcog (ρ = 0.62, p < 0.001). Weak correlations to the Mini-BESTest (ρ = -0.33, p < 0.003) indicated low construct validity. Significantly (p < 0.001) higher dual-task costs were seen when performing the SSSTcog (77.6%) compared to the TUGcog (24.3%). CONCLUSIONS: In PwPD, the SSSTcog showed promising construct validity, acceptable to excellent reliability, making it a valid measure of functional mobility, including cognitive dual-tasking. Higher dual-task cost for the SSSTcog indicated actual cognitive-motor interference while performing the test.

Antidepressive Effectiveness of Amisulpride, Aripiprazole, and Olanzapine in Patients With Schizophrenia Spectrum Disorders: A Secondary Outcome Analysis of a Pragmatic, Randomized Trial (BeSt InTro).

BACKGROUND: Depressive symptoms are frequent in schizophrenia and associated with a poorer outcome. Currently, the optimal treatment for depressive symptoms in schizophrenia remains undetermined. Amisulpride, aripiprazole, and olanzapine all have antidepressive pharmacodynamic properties, ranging from serotonergic affinities to limbic dopaminergic selectivity. Consequently, in a 12-month pragmatic, randomized clinical trial, we aimed to investigate differences in antidepressive effectiveness among amisulpride, aripiprazole, and olanzapine as a secondary outcome, measured by change in the Calgary Depression Scale for Schizophrenia sum score in patients within the schizophrenia spectrum. METHODS: Psychotic patients within the schizophrenia spectrum were included, and effectiveness was analyzed with latent growth curve modeling. RESULTS: Of the 144 patients, 51 (35%) were women, the mean age was 31.7 (SD 12.7), and 39% were antipsychotic naive. At inclusion, 68 (47%) participants had a Calgary Depression Scale for Schizophrenia sum score >6, indicating severe depressive symptoms. Across the 12-month follow-up, there was a depressive symptom reduction in all medication groups, but no statistically significant differences between the study drugs. Separate analyses of the subcohort with elevated depressive symptoms at inclusion also failed to find differences in depressive symptom reduction between study drugs. The reduction in depressive symptoms mainly occurred within 6 weeks after randomization. CONCLUSIONS: There was a reduction in depressive symptoms under treatment with amisulpride, aripiprazole, and olanzapine in acutely psychotic patients with schizophrenia spectrum disorder, but no differences between the drugs.

Early identification of treatment non-response in first-episode psychosis.

BACKGROUND: Approximately one-third of patients with psychotic disorders does not respond to standard antipsychotic treatments. Consensus criteria for treatment resistance (TR) may aid the identification of non-response and subsequent tailoring of treatments. Since consensus criteria require stability of clinical status, they are challenging to apply in first-episode psychosis (FEP). This study aims to investigate (a) if an adaptation of consensus criteria can be used to identify FEP patients with early signs of TR (no early clinical recovery-no-ECR) after 1 year in treatment and (b) to what extent differences in antipsychotic treatments differentiate between outcome groups. METHODS: Participants with FEP DSM-IV schizophrenia spectrum disorders were recruited during their first treatment. A total of 207 participated in the 1-year follow-up. Remission and recovery definitions were based on adaptations of the "Remission in Schizophrenia Working Group" criteria and TR on adaptations of the "Treatment Response and Resistance in Psychosis" (TRRIP) working group criteria. RESULTS: 97 participants (47%) could be classified as no-ECR, 61 (30%) as ECR, and 49 (23%) as with partial ECR (P-ECR). Statistically significant baseline predictors of no-ECR matched previously identified predictors of long-term TR. Only 35 no-ECR participants had two adequate treatment trials and met the full TRRIP criteria. 21 no-ECR participants were using the same medication over the follow-up year despite the lack of significant effects. CONCLUSION: The difference in the percentage of FEP participants classified as no-ECR versus TR indicates that we may underestimate the prevalence of early TR when using consensus criteria.

Depression trajectories and cytokines in schizophrenia spectrum disorders - A longitudinal observational study.

Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1ß and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.

Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness.

BACKGROUND: Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. METHODS: We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. RESULTS: We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. CONCLUSION: We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.