M.Z. received scientific grants from the German Research Foundation and Servier. Speaker and travel grants were provided from Otsuka, Servier, Lundbeck, Roche, Ferrer and Trommsdorff.

The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study.

We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher’s exact test was performed to compare categorical variables. Wilcoxon’s rank-sum test was used to compare continuous variables between cohorts.

Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005–3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3–12.3] versus 15.9 [15.1–17.2], p < 0.001) and international normalised ratio (0.8 [0.73–0.90] versus 1.3 [1.2–1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls.

In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.

Perinatal exposure to alcohol (PEA) induces general developmental and specific neuropsychiatric disturbances in association with disturbed synaptic plasticity and functions of the amino acid neurotransmitter glutamate.

We were interested in effects of ethanol during the terminal neurodevelopmental differentiation on glutamatergic neurotransmission.

To establish an animal model based on vapor chamber exposure and to assess the expression of vGluT1, EAAT1 to 4, NMDA receptor (NR) subunits 1, 2A to D and NR binding with 3H-labeled MK 801.

After delivery, female Wistar Han outbred rats (N = 4) and their pups were exposed until postnatal day 8 (P8). At the age of 5 months, the animals were behaviorally characterized. Both, at P8 and after the testing we performed in situ-hybridizations receptor binding assays.

PEA-pubs showed a pronounced and highly significant retardation of body weight and length. Behavioral testing revealed no differences in locomotion and anxiety (open field and elevated plus maze) as well as T-maze-learning, but significantly impaired hippocampus-dependent spatial learning (MWM). We observed significant inductions of vGluT1, EAAT1, EAAT3, NR2A, 2B, 2C and 2D, as well as trends of increased NR1 mRNA. NR binding was found increased in hippocampus (P8) and parietal cortex (P8 and 5M).

The observed inductions of glial glutamate transporters validate previous in vitro data. Altered glutamatergic neurotransmission in general might be considered a molecular correlate of the learning deficit in our PEA model. This further supports the glutamatergic theory of PEA and suggests new targets for therapeutic interventions.

Anxiety is a core symptom of schizophrenia which elicits significant subjective burden of disease and contributes to treatment resistance in schizophrenia. Anxious syndromes might be attributed to incompletely remitted delusions, the negative syndrome, depressive episodes, panic attacks, social phobia, avoidance after hospitalization and down-tapering of benzodiazepine medication. Previous treatment attempts involved several strategies of combination and augmentation.

Pregabalin, an antagonist at the α2δ-subunit of voltage-gated Ca2+-channels, modulates several neurotransmitter systems and was found able to alleviate anxiety in depression and other mental disorders.

In schizophrenia, this treatment option has not been evaluated before.

Here, we report a case series of 11 schizophrenic patients who suffered from treatment-resistant anxiety and received augmentation with pregabalin.

This observational investigation reveals that augmentation with pregabalin was able to significantly reduce scores on the Hamilton anxiety scale; furthermore, we observed improvements of psychotic positive and negative symptoms and mood as assessed by PANSS, SANS and CDSS. After augmentation, both a complete discontinuation of concomitant benzodiazepine (BZD) treatment as well as a dose reduction of antipsychotics could be achieved. We did not observe pharmacokinetic interactions or adverse events.

These observations suggest that treating anxious syndromes in schizophrenia with pregabalin can be effective and tolerable. Further investigations should differentiate schizophrenic sub-syndromes of anxiety and evaluate benefits and risks of pregabalin in comparison to placebo and active competitors.

The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-Methyl-D-aspartate (NMDA)-receptors (NR). Several therapeutic strategies address NR function and effects of antipsychotic agents on NR expression have been described.

The partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract behavioural effects of NR antagonists, but effects of APZ on NR expression have not been investigated.

To evaluate effects of APZ on NR mRNA and protein expression

We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kg body weight. Expression of the NR subunits NR1, NR2A, NR2B, NR2C and NR2D was assessed by semiquantitative radioactive in situ-hybridization, and in parallel receptor binding using 3H-MK-801 receptor autoradiography.

Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months) and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses and time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40 mg-group and after 4 months in the 10 mg-group.

The effects of APZ converge in enhanced NMDA-receptor expression and a shift of subunit-composition towards adult-type receptors. Our results confirm regulatory connections between dopaminergic, serotonergic and glutamatergic neurotransmission with relevance for cognitive and negative symptoms of schizophrenia.

Cognitive deficits impair social and vocational rehabilitation in schizophrenic patients but little is known to which extend these symptoms are perceived by psychiatrists and how they influence antipsychotic treatment. Therefore, an online survey was performed in four European countries (Germany, Greece, Italy and Spain).

The survey involving 744 psychiatrists and assessed demographic characteristics including vocational status, presenting symptomatology, cognitive dysfunction severity, and current antipsychotic treatement. Methodology is described in full detail by Gorwood (2010).

Out of 3,996 patients, 29% were clinically assessed as having mild, 54% moderate and 17% severe cognitive dysfunction. In the mild dysfunction group, mean time since diagnosis was 9.7 years, 12.0 years in the moderate dysfunction group, and 17.0 years in the severe dysfunction group, and majority were outpatients (74.7%, 57.9% and 56.7%, respectively). The respective mean number of previous episodes was 5.1, 6.2 and 7.2 (6.0 for the total sample). Full or part time employment was reported in 32,2%, 19.1% and 11.8% of the patients, respectively. Olanzapine was the most frequently used antipsychotic in the mild group (21.0%) and severe group (24.9%), and risperidone in the moderate group (23.0%). Ziprasidone was used in 10.2%, 0.8% and 7.1% of subjects.

Cognitive dysfunction is frequently perceived by psychiatrist in every day clinical practice and severely interferes with the vocational status. Major associations between specific antipsychotics and the levels of cognitive impairment were not observed. Irrespective of the level of cognitive dysfunction, > 50% of subjects were outpatients.

Patients with psychotic disorders often suffer from intercurrent major depressive episodes (MDEs). Case reports suggested successful antidepressive treatment with duloxetine, a selective dual reuptake inhibitor of serotonin and norepinephrine (SSNRI). We initiated this open prospective clinical trial in order to evaluate efficacy, safety and tolerability of this approach.

Patients with a psychotic lifetime diagnosis suffering from mildly severe MDEs were treated with duloxetine over a period of 6 weeks. We evaluated effects on mood, monitored the psychotic psychopathology and assessed side effects, basal clinical and pharmacological parameters.

Twenty patients were included and experienced a significant improvement of their MDE during the observation period (CDSS: Calgary Depression Scale for Schizophrenia, HAMD: Hamilton Depression scale). Psychotic positive symptoms remained stably absent while negative syndrome and global psychopathology considerably improved (PANSS: Positive and Negative Syndrome Scale). In general, the treatment was well tolerated, serum prolactin levels stayed unchanged, but pharmacokinetic interactions with a number of antipsychotic agents were observed.

This open prospective evaluation revealed antidepressive efficacy of duloxetine in patients with co-morbid psychotic disorders. With regard to the psychotic disorder, the treatment appears to be safe and well tolerable. Further investigations should involve a randomized control group.

To explore safety, tolerability, treatment response and hospitalizations in adult patients with schizophrenia treated with long-acting injectable risperidone (RLAI) or oral antipsychotic standard of care (oAP) in routine clinical practice.

Prospective one-year open-label non-interventional study exploring flexible doses of RLAI and oAPs. Primary outcome was the number of hospitalizations from baseline to endpoint. Additional outcomes were changes in the Clinical Global Impression of Schizophrenia (CGI-SCH), patient functioning (Global Assessment of Functioning) and treatmentemergent adverse events (TEAEs).

The intent-to-treat analysis included 561 patients on RLAI and 522 patients on oAPs (44% female gender, mean age (±SD) 42.2±13.1 years). Demographics and baseline characteristics were comparable, yet RLAI-treated patients had higher disease severity, lower baseline functioning and more substance abuse. The number of hospitalizations did not differ between the two groups while median duration of hospitalization was significantly shorter with RLAI (12.3 vs 20.6 days). Positive, negative, cognitive symptoms, disease severity, patient functioning and medication satisfaction improved significantly better with RLAI than oAPs. The most frequently reported TEAEs (=2% in any group) for RLAI and oral APs were increase of body weight (5.0%; 5.6%), psychotic disorder (2.7%; 4.0%), schizophrenia (2.5%; 3.1%), anxiety (2.3%; 2.7%), insomnia (0.9%; 3.1%) and somnolence (0.4%; 2.5%), respectively.

This one-year non-interventional study supports results of recent randomized controlled trials that treatment with RLAI is associated with less days spent in hospital, better symptomatic and functional outcomes and higher patient satisfaction with medication compared to oral APs.

Recent metaanalyses have reported conflicting results on the efficacy of long-acting compared to oral antipsychotics in the prevention of relapse in patients with schizophrenia.

2-year international randomized active controlled, open-label, rater-blinded study evaluating time to relapse, relapse rates, psychotic symptoms (PANSS) and treatment-emergent adverse events (TEAEs) in recently diagnosed patients with schizophrenia (≥1-5 years) treated with a monotherapy of paliperidone palmitate (PP) compared to investigators’ choice of oral antipsychotics (oAPs), i.e. aripiprazole, olanzapine, quetiapine, paliperidone ER, risperidone or haloperidol.

715 patients (58.4% male, mean age 32.5±10.4 years, 86.2% paranoid schizophrenia, no significant differences in baseline characteristics) entered the 2-year study period (352 PP, 363 oAPs). Time to relapse was significantly longer with PP compared to oAPs (mean±SE: 616±10.9 vs 603±13.1 days, p=0.019). Relapse rates were significantly lower with PP vs oAPs (14.8% vs 20.9%; p=0.032), reflecting a relative risk reduction of 29.2%. Reduction of psychotic symptoms in PANSS was significantly superior with PP at treatment day 8 (p=0.021) and showed a trend in favor of PP at endpoint (p=0.074). TEAEs reported in ≥5% in any group (PP vs oAPs) were weight increase (15.9% vs 17.4%), headache (11.1% vs 8.5%), insomnia (9.7% vs 8.0%), schizophrenia (8.2% vs 9.6%), nasopharyngitis (7.1% vs 5.0%), injection site pain (6.8% vs 0%), anxiety (5.7% vs 4.4%), tremor (5.1% vs 2.2%) and suicidal ideation (4.5% vs 5.5%).

In this randomized active controlled 2-year study PP was significantly delaying time to relapse and reducing relapse rates compared to investigators’ choice of oral APs.

Epidemiological studies estimated that amongst patients with schizophrenia a large subgroup of up to 25% also suffers from comorbid obsessive compulsive symptoms (OCS). The association between these comorbid OCS and neuropsychological impairment remains unclear and somewhat contradictory. Longitudinal approaches which investigate the stability of OCS related cognitive deficits are missing.

37 patients with schizophrenia and comorbid OCS and 43 schizophrenia patients without OCS were assessed with a comprehensive cognitive test-battery and compared at baseline and again 12 months later.

Schizophrenia patients with comorbid OCS showed significant pronounced deficits with increasing effect sizes over the 12 month assessment period in specific cognitive areas such as visuo-spatial perception and visual memory (WAIS-R block design, Rey-Osterrieth Complex Figure Test), executive functioning (perseveration in the Wisconsin card sorting test) and cognitive flexibility (Trail making test B). These cognitive domains correlated with OCS severity and are known to be candidate domains in obsessive compulsive disorder (OCD).

OCS in schizophrenia is associated longitudinally stable specific cognitive deficits. Prospective studies involving patients with at risk mental states for psychosis are necessary to decipher the interaction of cognitive impairment and the clinical manifestation of schizophrenia and OCS. This might facilitate the definition of patients at high risk for OCS, an early detection of subclinical levels, therapeutic interventions and clinical monitoring.

Patients with psychosis display the so-called ‘Jumping to Conclusions’ bias (JTC) – a tendency for hasty decision-making in probabilistic reasoning tasks. So far, only a few studies have evaluated the JTC bias in ‘at-risk mental state’ (ARMS) patients, specifically in ARMS samples fulfilling ‘ultra-high risk’ (UHR) criteria, thus not allowing for comparisons between different ARMS subgroups.

In the framework of the PREVENT (secondary prevention of schizophrenia) study, a JTC task was applied to 188 patients either fulfilling UHR criteria or presenting with cognitive basic symptoms (BS). Similar data were available for 30 healthy control participants matched for age, gender, education and premorbid verbal intelligence. ARMS patients were identified by the Structured Interview for Prodromal Symptoms (SIPS) and the Schizophrenia Proneness Instrument – Adult Version (SPI-A).

The mean number of draws to decision (DTD) significantly differed between ARM -subgroups: UHR patients made significantly less draws to make a decision than ARMS patients with only cognitive BS. Furthermore, UHR patients tended to fulfil behavioural criteria for JTC more often than BS patients. In a secondary analysis, ARMS patients were much hastier in their decision-making than controls. In patients, DTD was moderately associated with positive and negative symptoms as well as disorganization and excitement.

Our data indicate an enhanced JTC bias in the UHR group compared to ARMS patients with only cognitive BS. This underscores the importance of reasoning deficits within cognitive theories of the developing psychosis. Interactions with the liability to psychotic transitions and therapeutic interventions should be unravelled in longitudinal studies.

Metamemory describes the monitoring and knowledge about one's memory capabilities. Patients with schizophrenia have been found to be less able in differentiating between correct and false answers (smaller confidence gap) when asked to provide retrospective confidence ratings in previous studies. Furthermore, higher proportions of very-high-confident but false responses have been found in this patient group (high knowledge corruption). Whether and how these biases contribute to the early pathogenesis of psychosis is yet unclear. This study thus aimed at investigating metamemory function in the early course of psychosis.

Patients in an at-risk mental state for psychosis (ARMS, n = 34), patients with a first episode of psychosis (FEP, n = 21) and healthy controls (HCs, n = 38) were compared on a verbal recognition task combined with retrospective confidence-level ratings.

FEP patients showed the smallest confidence gap, followed by ARMS patients, followed by HCs. All groups differed significantly from each other. Regarding knowledge corruption, FEP patients differed significantly from HCs, whereas a statistical trend was revealed in comparison of ARMS and FEP groups. Correlations were revealed between metamemory, measures of positive symptoms and working memory performance.

These data underline the presence of a metamemory bias in ARMS patients which is even more pronounced in FEP patients. The bias might represent an early cognitive marker of the beginning psychotic state. Longitudinal studies are needed to unravel whether metacognitive deficits predict the transition to psychosis and to evaluate therapeutic interventions.