Walter de Millas

Rationale and Baseline Characteristics of PREVENT: A Second-Generation Intervention Trial in Subjects At-Risk (Prodromal) of Developing First-Episode Psychosis Evaluating Cognitive Behavior Therapy, Aripiprazole, and Placebo for the Prevention of Psychosis

Antipsychotics, cognitive behavioral therapy (CBT), and omega-3-fatty acids have been found superior to control conditions as regards prevention of psychosis in people at-risk of first-episode psychosis. However, no large-scale trial evaluating the differential efficacy of CBT and antipsychotics has been performed yet. In PREVENT, we evaluate CBT, aripiprazole, and clinical management (CM) as well as placebo and CM for the prevention of psychosis in a randomized, double-blind, placebo-controlled trial with regard to the antipsychotic intervention and a randomized controlled trial with regard to the CBT intervention with blinded ratings. The hypotheses are first that CBT and aripiprazole and CM are superior to placebo and CM and second that CBT is not inferior to aripiprazole and CM combined. The primary outcome is transition to psychosis. By November 2010, 156 patients were recruited into the trial. The subjects were substantially functionally compromised (Social and Occupational Functioning Assessment Scale mean score 52.5) and 78.3% presented with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition axis I comorbid diagnosis. Prior to randomization, 51.5% of the participants preferred to be randomized into the CBT arm, whereas only 12.9% preferred pharmacological treatment. First, assessments of audiotaped treatment sessions confirmed the application of CBT-specific skills in the CBT condition and the absence of those in CM. The overall quality rating of the CBT techniques applied in the CBT condition was good. When the final results of the trial are available, PREVENT will substantially expand the current limited evidence base for best clinical practice in people at-risk (prodromal) of first-episode psychosis.

P50 sensory gating and smoking in the general population

P50 gating is a major functional biomarker in research on schizophrenia and other psychiatric conditions with high smoking prevalence. It is used as endophenotype for studying nicotinic systems genetics and as surrogate endpoint measure for drug development of nicotinic agonists. Surprisingly, little is known about P50 gating in the general population and the relationship to smoking‐related characteristics. In this multicenter study at six academic institutions throughout Germany, n = 907 never‐smokers (NS < 20 cigarettes/lifetime), n = 463 light smokers (LS) with Fagerström Test for Nicotine Dependence (FTND) ≥ 4 and n = 353 heavy smokers (HS, FTND < 4) were randomly selected from the general population. As part of a standardized protocol for investigating the genetics of nicotine dependence (ND), an auditory P50 paradigm was applied. The main outcome measure was P50‐amplitude difference followed by time‐frequency analyses and functional imaging (sLORETA). Reduced P50 gating was found in HS compared to NS with LS taking an intermediate position—correlating with the degree of ND. sLORETA and time‐frequency analyses indicate that high‐frequency oscillations in frontal brain regions are particularly affected. With growing age, P50 gating increased in (heavy) smokers. This is the first large‐scale study (normative sample data) on P50 sensory gating and smoking in the general population. Diminished gating of P50 and associated high‐frequency oscillations in the frontal brain region are indications of a deficient inhibitory cortical function in nicotine‐dependent smokers. The suitability and application of sensory P50 gating as functional biomarker with regard to genetic and pharmacological studies is discussed.

Predictors for symptom re-exacerbation after targeted stepwise drug discontinuation in first-episode schizophrenia: Results of the first-episode study within the German research network on schizophrenia

BACKGROUND After a first episode in schizophrenia guidelines recommend antipsychotic maintenance treatment (MT) for at least 1year. Recent RCTs on subsequent targeted intermittent treatment (IT) after stepwise drug discontinuation yielded noticeably higher relapse rates than during MT also in first-episode patients. Nevertheless, about 50% of patients remain stable under IT. Given the potential adverse effects of antipsychotics and the preference of many patients to discontinue drugs, valid predictors for the feasibility of IT are urgently needed to support decision making. METHODS Based on a one-year RCT phase comparing MT with IT in first-episode patients after 1year of MT, conducted within the German Research Network on Schizophrenia (GRNS), predictors for deterioration under IT in 19 feasible patients were identified by logistic regression analysis. RESULTS Deterioration occurred in 10 patients (52.6%). Univariate analyses indicated a lower PANSS positive score after acute treatment as well as after one year of MT as significant predictors; in multivariate logistic regression, in addition to the lower PANSS positive score after acute treatment, reaching enduring remission and having had a deterioration both during MT evolved as significant predictors and indicate a higher risk for deterioration. CONCLUSIONS Although limited by the small sample size, our findings suggest that patients who show a favorable response and full and enduring symptom remission during antipsychotic treatment, as well as those with marked deterioration despite MT should rather be recommended to remain on treatment because they are at higher risk for symptom re-exacerbation after (stepwise) drug discontinuation.

The German multi-centre study on smoking-related behavior-description of a population-based case-control study.

Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND‐related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The German multi‐centre study ‘Genetics of Nicotine Dependence and Neurobiological Phenotypes’, which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: ‘Nicotine—Molecular and Physiological Effects in CNS’, was intended to overcome some of these inherent problems of current genetic studies of ND. The multi‐centre study is a population‐based case‐control study of smokers and never‐smokers (n = 2396). The study was unique worldwide because it was the first large‐scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper.

Psychological and hormonal features of smokers at risk to gain weight after smoking cessation--results of a multicenter study

Preclinical and clinical data suggest modulating effects of appetite-regulating hormones and stress perception on food intake. Nicotine intake also interferes with regulation of body weight. Especially following smoking cessation gaining weight is a common but only partially understood consequence. The aim of this study was to examine the interaction between smoking habits, the appetite regulating hormone leptin, negative affectivity, and stress vulnerability on eating behavior in a clinical case-control study under standardized conditions. In a large population-based study sample, we compared leptin and cortisol plasma concentrations (radioimmunoassay) between current tobacco smokers with high cognitive restraint and disinhibition in eating behavior and smokers scoring low in both categories as assessed with the Three Factor Eating Questionnaire (TFEQ; Stunkard & Messick, 1985). As a measure for smoking effects on the stress axis, the saliva cortisol concentrations were compared before and after nicotine smoking. Additionally, stress perception was assessed with the Perceived Stress Scale (PSS), symptoms of depression and anxiety with the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI). In smokers showing high cognitive restraint and disinhibition we found significantly higher leptin concentrations than in the group of smokers scoring low in both categories. Furthermore there was a significant group difference in saliva cortisol concentrations after nicotine intake. Smokers showing high cognitive restraint and disinhibition were also characterized by significantly higher scores in the STAI, the PSS and the BDI. Our results suggest that smokers with a pathological eating behavior show an impaired neuroendocrine regulation of appetite and are prone to experience higher levels of stress and negative affectivity. This interaction of behavioral and neuroendocrinological factors may constitute a high risk condition for gaining weight following smoking cessation.

Oxazepam versus Clomethiazol in Alcohol Withdrawal Treatment

The pharmacological management of the alcohol withdrawal syndrome associated with alcohol dependence is heterogeneous; however, according to the guidelines, clomethiazol is the standard medication in Germany. Benzodiazepines offer another safe possibility of treating alcohol withdrawal. In a retrospective study, alcohol-dependent patients treated either with oxazepam (n = 141) or clomethiazol (n = 357) were assessed with respect to the course of treatment and withdrawal symptoms. The results showed that under oxazepam treatment, there were fewer days with severe alcohol withdrawal symptoms and less severe adverse events, but patients receiving clomethiazol treatment had a more severe course of alcohol dependence. Oxazepam is a safe, efficient and cheap drug for the treatment of alcohol withdrawal symptoms, but controlled studies are needed to compare its effectiveness with that of clomethiazol.

Apparent motion perception in patients with paranoid schizophrenia

Impaired perceptual inference has been suggested to be at the core of positive symptoms in schizophrenia. Apparent motion (AM) is a visual illusion in which perceptual inference gives rise to the experience of a single object moving back and forth when two spatially separated objects are flashed in alternation. Here, we investigated the strength of AM perception in patients with paranoid schizophrenia. Patients were less susceptible to the illusion as indicated by a lower probability of motion perception at the individual’s optimal presentation frequency for AM. In addition, the probability of AM perception was inversely related to delusional conviction in the patient group. These results suggest that schizophrenia may be associated with a reduced susceptibility to visual phenomena that commonly rely on perceptual inference.

Clinical high risk for psychosis: gender differences in symptoms and social functioning

Schizophrenia is a heterogeneous disorder that presents differently in men and women: men show a higher propensity to negative symptoms, lower social functioning, earlier age at onset and co‐morbid substance abuse, whereas women display more affective symptoms. It is unknown whether these differences extend to subjects at high risk (HR) of psychosis. Thus, the aim of the present study was to address this question.

Detection of visual events along the apparent motion trace in patients with paranoid schizophrenia

Dysfunctional prediction in sensory processing has been suggested as a possible causal mechanism in the development of delusions in patients with schizophrenia. Previous studies in healthy subjects have shown that while the perception of apparent motion can mask visual events along the illusory motion trace, such motion masking is reduced when events are spatio-temporally compatible with the illusion, and, therefore, predictable. Here we tested the hypothesis that this specific detection advantage for predictable target stimuli on the apparent motion trace is reduced in patients with paranoid schizophrenia. Our data show that, although target detection along the illusory motion trace is generally impaired, both patients and healthy control participants detect predictable targets more often than unpredictable targets. Patients had a stronger motion masking effect when compared to controls. However, patients showed the same advantage in the detection of predictable targets as healthy control subjects. Our findings reveal stronger motion masking but intact prediction of visual events along the apparent motion trace in patients with paranoid schizophrenia and suggest that the sensory prediction mechanism underlying apparent motion is not impaired in paranoid schizophrenia.

Negative schemata about the self and others and paranoid ideation in at-risk states and those with persisting positive symptoms

The objective of this study is to test the conflicting theories concerning the association of negative self and other schemata and paranoid ideation.