Cerebrospinal Fluid Pathologies in Schizophrenia-Spectrum Disorder-A Retrospective Chart Review.

BACKGROUND: The role of inflammatory processes in the etiology of schizophrenia is increasingly being investigated. A link between psychosis and inflammation measured with different biomarkers has been reported in the literature and needs to be further explored. To investigate the presence of inflammatory biomarkers in first-episode psychosis (FEP) we analyzed the largest available FEP cohort to date regarding routine CSF and blood diagnostics. METHODS: We report a retrospective analysis of clinical data from all inpatients that were admitted to our tertiary care hospital with a ICD-10 diagnosis of F2x (schizophrenia-spectrum) between January 1, 2008 and August 1, 2018 and underwent a lumbar puncture. RESULTS: A total of n = 314 FEP patients were included in our sample. 42.7% patients (134/314) showed cerebrospinal fluid (CSF) alterations. Oligoclonal bands in the CSF were present in 21.8% of patients (67/307) with 12.4% (27/217) of patients presenting OCBs type 2 or 3. 15.8% (49/310) of our cohort revealed signs of blood-brain-barrier (BBB) dysfunction with increased albumin ratios. Mean serum CRP levels were 2.4 mg/l (SD = 9.5). CRP elevation was present in 116/280 cases (41.4%). CONCLUSIONS: This large retrospective analysis on FEP cohort greatly enriches the clinical data available on this population and contributes to the discussion around inflammation in psychosis. Of note, even though several inflammatory alterations were found both in CSF and in blood tests, we found no evidence for a significant relationship between peripheral inflammation and inflammatory CSF. Furthermore, no significant relationship between CSF alterations and peripheral inflammation measured with CRP could be established.

Routine cerebrospinal fluid parameters as biomarkers in first-episode psychosis: A prospective observational study.

In recent years, multiple studies have investigated the role of biomarkers in first-episode psychosis (FEP) to facilitate early diagnosis, disease stratification, therapeutic choice and outcome prediction. Few studies have focused on cerebrospinal fluid (CSF) investigations. In this prospective observational study, 95 FEP inpatients were followed up for one year. A lumbar puncture was performed at index admission (baseline) to study the CSF parameters (glucose, total proteins, lactate dehydrogenase [LDH], and pleocytosis). At the baseline visit, the clinical assessment included prodromal (psychotic and non-psychotic) symptoms before the psychotic outbreak and psychopathology at admission. The SCID-I was administered to obtain a clinical diagnosis at baseline and at 12 months. The relationship between prodromal and psychopathology symptoms at the baseline visit was tested with multiple linear regression. Multinomial logistic regression was also used to explore the association between CSF biomarkers and longitudinal diagnoses at follow-up (schizophrenia/schizoaffective disorder vs unipolar/bipolar depression vs other psychoses). Higher CSF glucose was associated with depressive (Standardized beta = 0.27, p = 0.041) and disorganized/concrete symptoms (Standardized beta = 0.33, p = 0.023) and lower CSF LDH was associated with prodromal symptoms (Standardized beta = -0.25, p = 0.042). Lower LDH concentrations were also associated with social withdrawal (r = -0.342, p = 0.001). CSF glucose was a predictor of the long-term diagnosis (lower CSF concentrations were associated with schizophrenia or schizoaffective disorder diagnoses [OR = 0.88, CI95%: 0.77-0.99). Our study suggests that CSF biomarkers that involve bioenergetic systems are associated with prodromal symptoms and the phenotype of psychotic disorders during the early stages of the disease.

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol.

BACKGROUND: Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls. METHODS: We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME). DISCUSSION: This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options. TRIAL REGISTRATION: The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Cerebrospinal fluid flow cytometry distinguishes psychosis spectrum disorders from differential diagnoses.

Psychotic disorders are common and disabling mental conditions. The relative importance of immune-related mechanisms in psychotic disorders remains subject of debate. Here, we present a large-scale retrospective study of blood and cerebrospinal fluid (CSF) immune cell profiles of psychosis spectrum patients. We performed basic CSF analysis and multi-dimensional flow cytometry of CSF and blood cells from 59 patients with primary psychotic disorders (F20, F22, F23, and F25) in comparison to inflammatory (49 RRMS and 16 NMDARE patients) and non-inflammatory controls (52 IIH patients). We replicated the known expansion of monocytes in the blood of psychosis spectrum patients, that we identified to preferentially affect classical monocytes. In the CSF, we found a relative shift from lymphocytes to monocytes, increased protein levels, and evidence of blood-brain barrier disruption in psychosis. In fact, these CSF features confidently distinguished autoimmune encephalitis from psychosis despite similar (initial) clinical features. We then constructed machine learning models incorporating blood and CSF parameters and demonstrated their superior ability to differentiate psychosis from non-inflammatory controls compared to individual parameters. Multi-dimensional and multi-compartment immune cell signatures can thus support the diagnosis of psychosis spectrum disorders with the potential to accelerate diagnosis and initiation of therapy.

Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis.

OBJECTIVES: To report the neuropsychiatric features and frequency of NMDA receptor (NMDAR) and other neuronal immunoglobulin G antibodies in patients with first episode psychosis (FEP) and to assess the performance of reported warning signs and criteria for autoimmune psychosis (AP). METHODS: This was a prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed. RESULTS: One hundred five patients were included; their median age was 30 (range 14-75) years, and 44 (42%) were female. None had neuronal antibodies. Two of 105 (2%) had CSF pleocytosis, 4 of 100 (4%) had brain MRI abnormalities, and 3 of 73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled 2 sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and nonpsychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1,159 reported patients with FEP, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features). CONCLUSIONS: NMDAR antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurologic symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.

Cerebrospinal fluid findings in patients with psychotic symptoms-a retrospective analysis.

In current international classification systems (ICD-10, DSM5), the diagnostic criteria for psychotic disorders (e.g. schizophrenia and schizoaffective disorder) are based on symptomatic descriptions since no unambiguous biomarkers are known to date. However, when underlying causes of psychotic symptoms, like inflammation, ischemia, or tumor affecting the neural tissue can be identified, a different classification is used ("psychotic disorder with delusions due to known physiological condition" (ICD-10: F06.2) or psychosis caused by medical factors (DSM5)). While CSF analysis still is considered optional in current diagnostic guidelines for psychotic disorders, CSF biomarkers could help to identify known physiological conditions. In this retrospective, partly descriptive analysis of 144 patients with psychotic symptoms and available CSF data, we analyzed CSF examinations' significance to differentiate patients with specific etiological factors (F06.2) from patients with schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (F2). In 40.3% of all patients, at least one CSF parameter was out of the reference range. Abnormal CSF-findings were found significantly more often in patients diagnosed with F06.2 (88.2%) as compared to patients diagnosed with F2 (23.8%, p < 0.00001). A total of 17 cases were identified as probably caused by specific etiological factors (F06.2), of which ten cases fulfilled the criteria for a probable autoimmune psychosis linked to the following autoantibodies: amphiphysin, CASPR2, CV2, LGl1, NMDA, zic4, and titin. Two cases presented with anti-thyroid tissue autoantibodies. In four cases, further probable causal factors were identified: COVID-19, a frontal intracranial tumor, multiple sclerosis (n = 2), and neurosyphilis. Twenty-one cases remained with "no reliable diagnostic classification". Age at onset of psychotic symptoms differed between patients diagnosed with F2 and F06.2 (p = 0.014), with the latter group being older (median: 44 vs. 28 years). Various CSF parameters were analyzed in an exploratory analysis, identifying pleocytosis and oligoclonal bands (OCBs) as discriminators (F06.2 vs. F2) with a high specificity of > 96% each. No group differences were found for gender, characteristics of psychotic symptoms, substance dependency, or family history. This study emphasizes the great importance of a detailed diagnostic workup in diagnosing psychotic disorders, including CSF analysis, to detect possible underlying pathologies and improve treatment decisions.

Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment.

Objectives: Despite intensive research, schizophrenia and schizoaffective disorders continue to be theoretical constructs that describe clinical syndromes and no pathophysiologically defined diseases. Moreover, there are no clear biomarkers at hand. Therefore, these diagnoses are still set up based on clinical ICD-10/DSM-5 criteria and the exclusion of alcohol-/drug-associated, systemic or other brain organic causes.Methods: Recently, autoimmune encephalitis with psychotic symptoms caused by specific antineuronal antibodies has been identified as a rare, but potentially treatable differential diagnosis. However, these inflammatory brain diseases are not reliably detected by our current routine diagnostic workup in psychiatry. This qualitative review provides structured diagnostic and therapeutic support for clinical practice.Results: Disturbances of consciousness and orientation, catatonia, speech dysfunction, focal neurological signs, epileptic seizures/EEG abnormalities or autonomic dysfunction are warning signs in psychiatric patients which should always induce cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Currently established immunotherapy strategies are summarised, taking into account international expert advice.Conclusions: Guided by clinical warning signs, our qualitative review enables rapid and reliable diagnosis of definite autoimmune encephalitis. This is of high relevance for the affected individuals, since early and sufficiently intense immunotherapy often leads to a good prognosis despite severe illness.

Measuring Disturbance of the Endocannabinoid System in Psychosis: A Systematic Review and Meta-analysis.

Importance: The endocannabinoid system (ECS) is a lipid-based endogenous signaling system. Its relevance to psychosis is through the association between cannabis use and the onset and course of illness and through the antipsychotic properties of cannabidiol, a potential ECS enhancer. Objective: To conduct a systematic review and meta-analysis of the blood and cerebrospinal fluid (CSF) measures of the ECS in psychotic disorders. Data Sources: Web of Science and PubMed were searched from inception through June 13, 2018. The articles identified were reviewed, as were citations to previous publications and the reference lists of retrieved articles. Study Selection: Original articles were included that reported blood or CSF measures of ECS activity in patients with psychotic illnesses and in healthy controls. Data Extraction and Synthesis: PRISMA guidelines, independent extraction by multiple observers, and random-effects meta-analysis were used. Heterogeneity was assessed with the I2 index. Sensitivity analyses tested the robustness of the results. Main Outcomes and Measures: The clinical relevance of ECS modifications in psychotic disorders was investigated by (1) a quantitative synthesis of the differences in blood and CSF markers of the ECS between patients and healthy controls, and (2) a qualitative synthesis of the association of these markers with symptom severity, stage of illness, and response to treatment. Results: A total of 18 studies were included. Three individual meta-analyses were performed to identify the differences in ECS markers between people with schizophrenia and healthy controls. Five studies, including 226 patients and 385 controls, reported significantly higher concentrations of anandamide in the CSF of patients than controls (standardized mean difference [SMD], 0.97; 95% CI, 0.67-1.26; P < .001; I2 = 54.8%). In 9 studies, with 344 patients and 411 controls, significantly higher anandamide levels in blood were found in patients, compared with controls (SMD, 0.55; 95% CI, 0.05-1.04; P = .03; I2 = 89.6%). In 3 studies, involving 88 patients and 179 controls, a significantly higher expression of type 1 cannabinoid receptors on peripheral immune cells was reported in patients compared with controls (SMD, 0.57; 95% CI, 0.31-0.84; P < .001; I2 = 0%). Higher ECS tone was found at an early stage of illness in individuals who were antipsychotic naïve or free, and it had an inverse association with symptom severity and was normalized after successful treatment. Moderate to high level of heterogeneity in methods was found between studies. Conclusions and Relevance: Testing clinically relevant markers of the ECS in the blood and CSF of people with psychotic illness appears possible, and these markers provide useful biomarkers for the psychotic disorder; however, not all studies accounted for important variables, such as cannabis use. Trial Registration: PROSPERO identifier: CRD42018099863.

Increased peripheral levels of TARC/CCL17 in first episode psychosis patients.

BACKGROUND: Evidence for a link between the pathophysiology of schizophrenia and the immune system is mounting. Altered levels of chemokines in plasma have previously been reported in patients with schizophrenia under antipsychotic medication. Here we aimed to study both peripheral and central chemokine levels in drug-naïve or short-time medicated first episode psychosis (FEP) patients. METHOD: We analyzed nine chemokines in plasma and CSF from 41 FEP patients and 22 healthy controls using electrochemiluminescence assay. RESULTS: In plasma four chemokines; TARC/CCL17, eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 and in CSF one chemokine; IP-10/CXCL10 showed reliable detection in >50% of the cases. FEP patients displayed increased levels of TARC/CCL17 in plasma compared to healthy controls, 89.6 (IQR 66.2-125.8) pg/mL compared to 48.6 (IQR 28.0-71.7) pg/mL (p = 0.001). The difference was not attributed to confounding factors. Plasma TARC/CCL17 was not associated with PANSS, CGI or GAF scores, neither with cognitive functions. The chemokines eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 in plasma and IP-10/CXCL10 in CSF did not differ between FEP patients and controls. CONCLUSION: In line with a previous study showing that chronic patients with schizophrenia display increased plasma TARC/CCL17 levels, we here found an elevation in FEP patients suggesting a role of TARC/CCL17 in early stages of schizophrenia. The exact mechanism of this involvement is still unknown and future longitudinal studies as well as studies of central and peripheral chemokine levels would be of great interest.

Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis.

Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942-2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.71; 95% CI 0.33-1.09) and affective disorders (4 studies [298 patients]; SMD = 0.41; 95% CI 0.23-0.60, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.41; 95% CI 0.15-0.67, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.80; 95% CI 0.39-1.21, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.68; 95% CI 0.30-1.06), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = -0.62; 95% CI -1.13 to -0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.55; 95% CI 0.35-0.76; I2 = 1%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17-0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2-6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

Active NET formation in Libman-Sacks endocarditis without antiphospholipid antibodies: A dramatic onset of systemic lupus erythematosus.

Although neutrophil extracellular traps (NETs) have been highlighted in several systemic inflammatory diseases, their clinical correlates and potential pathological role remain obscure. Herein, we describe a dramatic onset of systemic lupus erythematosus (SLE) with clear-cut pathogenic implications for neutrophils and NET formation in a young woman with cardiac (Libman-Sacks endocarditis) and central nervous system (psychosis and seizures) involvement. Despite extensive search, circulating antiphospholipid autoantibodies, a hallmark of Libman-Sacks endocarditis, could not be detected. Instead, we observed active NET formation in the tissue of the mitral valve, as well as in the circulation. Levels of NET remnants were significantly higher in serially obtained sera from the patient compared with sex-matched blood donors (p = .0011), and showed a non-significant but substantial correlation with blood neutrophil counts (r = 0.65, p = .16). The specific neutrophil elastase activity measured in serum seemed to be modulated by the provided immunosuppressive treatment. In addition, we found anti-Ro60/SSA antibodies in the cerebrospinal fluid of the patient but not NET remnants or increased elastase activity. This case illustrates that different disease mechanisms mediated via autoantibodies can occur simultaneously in SLE. NET formation with release of cytotoxic NET remnants is a candidate player in the pathogenesis of this non-canonical form of Libman-Sacks endocarditis occurring in the absence of traditional antiphospholipid autoantibodies. The case description includes longitudinal results with clinical follow-up data and a discussion of the potential roles of NETs in SLE.

First-presentation with psychotic behavior to the Emergency Department: Meningitis or not, that is the question.

INTRODUCTION: Meningitis is a potentially life threatening medical emergency. Psychotic behavior may be a presenting feature in patients with meningitis. We aimed to determine the value of various clinical and laboratory features at ruling-out meningitis in the patient presenting with a first-episode of psychotic behavior. METHODS: Medical records of 159 subjects presenting to a tertiary academic hospital over a 6-month period with one or more psychotic features for the first time were prospectively gathered. Pathological cerebrospinal fluid findings as well as clinical and other laboratory findings were tabulated and discussed retrospectively. RESULTS: Cerebrospinal fluid was obtained in 153/159 (96.2%) subjects. Meningitis was confirmed in twenty-eight (18.3%) subjects. Of these, a) one or more clinical feature of meningitis (headache, neck stiffness, photophobia or focal neuropathy) was present in 21 subjects (75.0%), b) visual hallucinations in 15 subjects (53.6%), c) pyrexia >37.5 °C in 7 subjects (25.0%), d) CRP >10 mg/L in 21 subjects (75.0%), e) HIV seropositive status in 19 subjects (67.9%) and f) an absence of illicit substances on urinalysis in 23 subjects (82.1%). Various combinations of these variables, where the presence of ≥1 variable was regarded as positive, were unable to rule-out meningitis in all study subjects. CONCLUSION: The absence of these six parameters; alone or in various combinations, was unable to rule-out meningitis in all patients presenting to our ED with a first-episode of psychotic behavior. When the underlying etiology of psychotic behavior is not obvious, the clinician should adopt a low threshold to perform a lumbar puncture.

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis.

OBJECTIVE: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients. METHOD: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer. RESULTS: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. CONCLUSION: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.

Cytokines in cerebrospinal fluid of patients with schizophrenia spectrum disorders: New data and an updated meta-analysis.

Few studies have been conducted examining cytokines in cerebrospinal fluid of patients compared to healthy volunteers. The goals of this study were: 1) to report original data detailing cytokine levels in the cerebrospinal fluid (CSF) of 10 patients with a schizophrenia spectrum disorder (SSD) diagnosis and 10 healthy controls and 2) to conduct a meta-analysis of the available data on cytokine levels in the CSF of patients with SSD compared to healthy controls, including our new data. Cytokine concentrations were measured using the Q-plex Human Cytokine Screen array in CSF of 10 patients with SSD and 10 healthy volunteers. For the meta-analysis, an electronic PubMed and Google Scholar search without restrictions was conducted for articles that reported on cytokine levels in CSF in patients with an SSD compared to healthy controls. Our original data revealed statistically significant increases in levels of interleukin-8 (IL-8) and interleukin-1 beta (IL-1ß) in the CSF of patients with an SSD compared to healthy volunteers. Our meta-analysis showed statistically significant increases in interleukin-6 (IL-6) and IL-8 in patients compared to healthy volunteers. Effect sizes between treated and untreated patients for IL-6 were of similar magnitude. However, IL-6 levels were higher in early stage schizophrenia patients compared to chronic schizophrenia patients. Studies with larger sample sizes, comprehensive assessments and ideally in the context of a randomized controlled intervention to minimize the impact of confounding factors are needed to fully understand the role of cytokines and inflammatory markers in the pathophysiology and treatment of schizophrenia.

No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals.

Metabolism of the monoamines dopamine, serotonin and noradrenaline, is altered in the central nervous system of people with schizophrenia, and their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively, have been intensively studied as indirect measures of these neurotransmitters in cerebrospinal fluid (CSF). Regular tobacco smoking has been shown to alter neurotransmitter metabolism in the brain and studies have found CSF monoamine metabolite concentrations to be substantially lower in smokers. However, few studies investigating these monoamines in CSF have controlled for regular tobacco smoking. We investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders (n = 69) and healthy non-psychotic human volunteers (n = 200). After lumbar puncture CSF samples were analyzed with mass fragmentography. CSF HVA, 5-HIAA and MHPG concentrations did not significantly differ between smokers and non-smokers neither in patients, nor in healthy subjects, whereas back-length predicted HVA and 5-HIAA and antipsychotic medication MHPG concentrations. The results indicate that regular tobacco smoking has no significant effect on monoamine metabolite concentrations in CSF. This suggests that lack of controlling for regular tobacco smoking should not substantially violate the results in studies of the major monoamine metabolites in CSF.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity.

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Intrathecal Thyroid Autoantibody Synthesis in a Subgroup of Patients With Schizophreniform Syndromes.

Schizophreniform syndromes in combination with autoimmune thyroiditis and increased serum thyroid antibodies lead healthcare practitioners to consider a diagnosis of Hashimoto's encephalopathy. To detect specific biomarkers, the authors analyzed whether intrathecal antithyroid antibody synthesis occurred in a subgroup of schizophreniform patients. In doing so, the authors analyzed thyroid antibodies in paired cerebrospinal fluid and serum samples from 100 schizophreniform patients. Increased antibody indices (AIs) for antithyroid peroxidase or antithyroglobulin autoantibodies in 13 schizophreniform patients were found. AIs were increased in 68% of the seropositive patients. These findings support the hypothesis that autoimmune processes may contribute to the pathophysiology in these patients.

Cerebrospinal fluid microglia and neurodegenerative markers in twins concordant and discordant for psychotic disorders.

Schizophrenia and bipolar disorder are debilitating psychiatric disorders with partially shared symptomatology including psychotic symptoms and cognitive impairment. Aberrant levels of microglia and neurodegenerative cerebrospinal fluid (CSF) markers have previously been found in schizophrenia and bipolar disorder. We aimed to analyze familial and environmental influences on these CSF markers and their relation to psychiatric symptoms and cognitive ability. CSF was collected from 17 complete twin pairs, nine monozygotic and eight dizygotic, and from one twin sibling. Two pairs were concordant for schizophrenia, and 11 pairs discordant for schizophrenia, schizoaffective disorder or bipolar disorder, and four pairs were not affected by psychotic disorders. Markers of microglia activation [monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14)], markers of ß-amyloid metabolism (AßX-38, AßX-40, AßX-42 and Aß1-42), soluble amyloid precursor proteins (sAPP-α and sAPP-ß), total tau (T-tau), phosphorylated tau (P-tau), and CSF/serum albumin ratio were measured in CSF using immunoassays. Heritability of the CSF markers was estimated, and associations to psychiatric and cognitive measurements were analyzed. Heritability estimates of the microglia markers were moderate, whereas several neurodegenerative markers showed high heritability. In contrast, AßX-42, Aß1-42, P-tau and CSF/serum albumin ratio were influenced by dominant genetic variation. Higher sCD14 levels were found in twins with schizophrenia or bipolar disorder compared to their not affected co-twins, and higher sCD14-levels were associated with psychotic symptoms. The study provides support for a significant role of sCD14 in psychotic disorders and a possible role of microglia activation in psychosis.