Thomas J. Raedler

Peptide Fingerprinting of Alzheimer's Disease in Cerebrospinal Fluid: Identification and Prospective Evaluation of New Synaptic Biomarkers

Background Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimers disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD. Methods and Findings Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimers disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho181-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. Conclusions The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.

The Face of Pain - A Pilot Study to Validate the Measurement of Facial Pain Expression with an Improved EMG Method

OBJECTIVE The purpose of this pilot study was to establish the validity of an improved facial electromyogram (EMG) method for the measurement of facial pain expression. BACKGROUND Darwin defined pain in connection with fear as a simultaneous occurrence of eye staring, brow contraction and teeth chattering. Prkachin was the first to use the video-based Facial Action Coding System to measure facial expressions while using four different types of pain triggers, identifying a group of facial muscles around the eyes. METHOD The activity of nine facial muscles in 10 healthy male subjects was analyzed. Pain was induced through a laser system with a randomized sequence of different intensities. Muscle activity was measured with a new, highly sensitive and selective facial EMG. RESULTS The results indicate two groups of muscles as key for pain expression. These results are in concordance with Darwins definition. As in Prkachins findings, one muscle group is assembled around the orbicularis oculi muscle, initiating eye staring. The second group consists of the mentalis and depressor anguli oris muscles, which trigger mouth movements. CONCLUSIONS The results demonstrate the validity of the facial EMG method for measuring facial pain expression. Further studies with psychometric measurements, a larger sample size and a female test group should be conducted.

No Effects of Antidepressants on Negative Symptoms in Schizophrenia

Abstract Negative symptoms are common in schizophrenia, but often difficult to differentiate from depression. They are associated with long-term impairment and do not respond well to current treatment approaches. Even though antidepressants are commonly prescribed in schizophrenia, their beneficial effect is still under debate. In the present study, we aimed to investigate the effect of serotonergic versus noradrenergic antidepressant add-on therapy on negative symptoms in schizophrenia. Fifty-eight patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and with predominant negative symptoms were randomized in a double-blind design to add-on treatment with citalopram, reboxetine, or placebo for 4 weeks. Analysis of covariance with repeated-measures design was used to compare improvement between treatment groups in scores of the Positive and Negative Syndrome Scale and the Hamilton Rating Scale for Depression. A &khgr;2 test was used to compare responder rates between treatment groups. Repeated-measures analysis of covariance revealed no differences between treatment groups over time (treatment × time, not statistically significant) for Positive and Negative Syndrome Scale subscales. Although a subgroup analysis in subjects fulfilling the criteria for minor depression was suggestive of higher responder rates in the citalopram group compared with reboxetine, the results did not reach significance level. Our findings do not support a beneficial effect of adjunctive antidepressant treatment on negative symptoms in schizophrenia. However, depressive symptoms are reduced in patients with minor depression by citalopram but not reboxetine, which is in line with previous findings.

Variability of the in vivo metabolism of clozapine.

Objectives: Clozapine, the gold standard of antipsychotic treatment in treatment-refractory patients with schizophrenia, is metabolized in vivo to clozapine-N-oxide and N-desmethylclozapine (NDMC = norclozapine). N-desmethylclozapine is an active metabolite of clozapine and combines unique pharmacological properties. Because little is known about the rate of metabolic conversion of clozapine in vivo, we assessed the association between clozapine dose and plasma levels for clozapine and NDMC. Methods: Plasma levels of clozapine and NDMC were measured in 485 blood samples from 108 patients with schizophrenia treated with clozapine. %NDMC, the ratio of NDMC to total clozapine (NDMC + clozapine), was used as a measure of the in vivo metabolism of clozapine. Results: Daily clozapine doses correlated significantly with clozapine levels and NDMC levels, whereas %NDMC showed a weaker negative correlation with clozapine dose. The mean %NDMC value was 37.0% ± 16.8%, with high variability between subjects. Repeated measurements in subjects treated with the same dose of clozapine showed a high within-subject variability of %NDMC. Conclusions: Our results suggest a high degree of between-subject and within-subject variability in the metabolism of clozapine in vivo. Direct administration of NDMC may be preferable to reliably achieve sufficient plasma levels of this compound.

Guidelines for the Pharmacotherapy of Schizophrenia in Adults.

Objective: The present guidelines address the pharmacotherapy of schizophrenia in adults across different stages, phases, and symptom domains. Method: Guidelines were developed using the ADAPTE process, which takes advantage of existing guidelines. Six guidelines were identified for adaptation, with recommendations extracted from each. For those specific to the pharmacotherapy of schizophrenia in adults, a working group selected between guidelines and recommendations to create an adapted guideline. Results: Recommendations can be categorized into 6 areas that include 1) first-episode schizophrenia, 2) acute exacerbation, 3) relapse prevention and maintenance treatment, 4) treatment-resistant schizophrenia, 5) clozapine-resistant schizophrenia, and 6) specific symptom domains. For each category, recommendations are made based on the available evidence, which is discussed and linked to other established guidelines. Conclusions: In most cases, evidence-based recommendations are made that can be used to guide current clinical treatment and decision making. Notably, however, there is a paucity of established evidence to guide treatment decision making in the case of clozapine-resistant schizophrenia, a subsample that represents a sizable proportion of those with schizophrenia.

Risperidone in the treatment of acute schizophrenia.

Introduction: Atypical antipsychotics have proven efficacy and tolerability in the treatment of schizophrenia. While a lot is known about maintenance treatment with atypical antipsychotics, less is known about their role in the management of acute psychotic decompensations. To evaluate the efficacy of the atypical antipsychotic risperidone, we conducted an open-label observational study among admissions to a secure unit. Method: Treatment with risperidone was offered to acutely psychotic schizophrenic patients with the requirement of a minimum score of ≥4 on 2 items of the PANSS positive symptoms subscale. Subjects were treated with 4 to 8 mg risperidone in divided doses (mean dose 5.7 ± 1.5 mg/d). Benzodiazepines and anticholinergics were allowed as comedications. Clinical Global Impression ratings and Positive and Negative Syndrome Scale ratings were obtained weekly for 4 weeks. Results: Forty-eight subjects (25 males, 23 females; mean age 36.9 ± 13.4 years, range 18 to 68 years) participated in this study. The mean duration of treatment was 13.4 ± 9.7 days (range 1 to 31 days). Risperidone was well tolerated, and 26 (54%) patients completed the study. Reasons for discontinuation were need of intramuscular antipsychotic medication (8 subjects), switch to a different antipsychotic (11 subjects), side effects (1 subject), and noncompliance (2 subjects). Treatment with risperidone reduced the mean CGI score from 5.9 to 4.8 (P < 0.001). Likewise, the total PANSS score improved from 110.9 to 86.0 (P < 0.001) with similar reductions in all subscales. Discussion: Our results demonstrate that risperidone is an effective and well-tolerated medication for the pharmacologic management of acutely psychotic schizophrenic subjects.

Canadian Treatment Guidelines for Individuals at Clinical High Risk of Psychosis

Objective: Young people who are at clinical high risk (CHR) of developing psychosis are often help seeking and have significant distress and dysfunction. There are limited guidelines for the assessment and treatment for this population. The aim of this guideline was to develop treatment recommendations for this at-risk group. Method: A systematic search was conducted for published guidelines for CHR. All current guidelines for schizophrenia were reviewed for treatment guidelines on individuals at CHR. The recommendations adopted were primarily drawn from the European Psychiatric Association (EPA) guidance on the early intervention in clinical high-risk states of psychoses and the 2014 National Institute for Health and Care Excellence (NICE) guidelines on the treatment and management of those at CHR for psychosis. Results: After the guideline development process described, 9 recommendations were developed based on the quality of evidence, appropriateness for the Canadian health care system, and clinical expert consensus. Conclusions: Assessment by an expert in the field was the first recommendation. It was recommended that treatment follow a staged approach with psychological treatments being the first-line treatment and pharmacotherapy reserved for adults, those who did not respond to psychological interventions, and those who had more severe symptoms.

Canadian Guidelines for the Pharmacological Treatment of Schizophrenia Spectrum and Other Psychotic Disorders in Children and Youth

Objective: Schizophrenia spectrum and other psychotic disorders often have their onset in adolescence. The sequelae of these illnesses can negatively alter the trajectory of emotional, cognitive, and social development in children and youth if left untreated. Early and appropriate interventions can improve outcomes. This article aims to identify best practices in the pharmacotherapy management of children and youth with schizophrenia spectrum disorders. Methods: A systematic search was conducted for published guidelines for schizophrenia and schizophrenia spectrum disorders in children and youth (under age 18 years). Recommendations were drawn from the National Institute for Health and Care Excellence guidelines on psychosis and schizophrenia in children and youth (2013 and 2015 updates). Current guidelines were adopted using the ADAPTE process, which includes consensus ratings by a panel of experts. Results: Recommendations identified covered a range of issues in the pharmacotherapy management of children and youth with schizophrenia spectrum disorders. Further work in this area is warranted as we continue to further understand their presentation in the developing brain. Conclusions: Canadian guidelines for the pharmacotherapy management of children and youth with schizophrenia spectrum disorders are essential to assist clinicians in treating this vulnerable population. Ongoing work in this area is recommended.

Proteomics as a New Tool for Biomarker-Discovery in Neuropsychiatric Disorders

Despite recent advances in our understanding of the neurobiology of neuropsychiatric disorders, most neuropsychiatric disorders remain clinical diagnoses that are based on the presence of a typical symptom-constellation as well as a typical time-course. Technical and laboratory examinations are frequently used to exclude other CNS-etiologies, such as tumor, infection, intoxication or epilepsy. However, only few biomarkers exist to assist in the differential diagnosis of neuropsy-chiatric disorders.