Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

BACKGROUND: Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS: A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS: Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION: The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING: German Federal Ministry of Education and Research.

[Acute Psychotic Disorders]. / Akute psychotische Störungsbilder.

Acute psychotic disorders (APS) are characterized by an acute onset as well as a wide array of symptoms including affective, psychotic, and psychomotor symptoms. They occur independently of substance use or organic disorders. In most cases, patients recover fully and without residues within a short period of time. However, APS tend to show a relapsing course, and transitions into other psychiatric disorders (schizophrenia, bipolar disorder) may occur.

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

Response to Agomelatine Treatment is Independent of Smoking Status and Dosage: Results From the AGOPSYCH Study.

INTRODUCTION: Cigarette smoking influences response to antidepressant treatment. It accelerates the metabolism of several cytochrome P450 (CYP) subtypes, including CYP1A2, and therefore bears the risk of pharmacokinetic interactions with psychotropic drugs using that pathway. Agomelatine is a substrate of CYP1A2; the association between nicotine use and agomelatine dosage, however, has never been studied before. METHODS: Smoking habits were correlated with agomelatine doses and treatment outcomes in a sample of 27 patients with lifetime diagnoses within the schizophrenia spectrum who received agomelatine treatment in addition to their stable antipsychotic treatment regimen because of depressive symptoms. RESULTS: No interactions were found between smoking status and agomelatine dosage, and treatment outcomes did not differ between smokers and nonsmokers. DISCUSSION: Agomelatine efficacy appears to be independent of dosage and smoking status, pointing toward mechanisms beyond mere dose-response relationships. Further research will be necessary to validate these findings.

Reduced activity and connectivity of left amygdala in patients with schizophrenia treated with clozapine or olanzapine.

Obsessive-compulsive symptoms (OCS) in patients with schizophrenia are a common co-occurring condition, often associated with additional impairments. A subgroup of these patients develops OCS during treatment with second-generation antipsychotics (SGAs), most importantly clozapine and olanzapine. So far, little is known about possible neural mechanism of these SGAs, which seem to aggravate or induce OCS. To investigate the role of SGA treatment on neural activation and connectivity during emotional processing, patients were stratified according to their monotherapy into two groups (group I: clozapine or olanzapine, n = 20; group II: amisulpride or aripiprazole, n = 20). We used an fMRI approach, applying an implicit emotion recognition task. Group comparisons showed significantly higher frequency and severity of comorbid OCS in group I than group II. Task specific activation was attenuated in group I in the left amygdala. Furthermore, functional connectivity from left amygdala to right ventral striatum was reduced in group I. Reduced amygdala activation was associated with OCS severity. Recent literature suggests an involvement of an amygdala-cortico-striatal network in the pathogenesis of obsessive-compulsive disorder. The observed differential activation and connectivity pattern of the amygdala might thus indicate a neural mechanism for the development of SGA-associated OCS in patients with schizophrenia. Further neurobiological research and interventional studies are needed for causal inferences.

Neurocognitive Effects of Agomelatine Treatment in Schizophrenia Patients Suffering From Comorbid Depression: Results From the AGOPSYCH Study.

BACKGROUND: Cognitive impairment in schizophrenia is highly disabling and remains one of the major therapeutic challenges. Agomelatine (AGO), an agonist at melatonergic MT1/MT2 receptors and antagonist at 5-HT2C receptors, increases dopamine and norepinephrine in the prefrontal cortex and may therefore have the potential of improving neurocognition in patients with schizophrenia. METHODS: Twenty-seven patients with schizophrenia and comorbid depression were treated with AGO in addition to stable doses of antipsychotic drugs. Cognitive abilities were assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) at study entry and after 12 weeks of AGO treatment after the intention-to-treat principle. RESULTS: We observed statistically significant yet clinically negligible increases of the MCCB composite score and the reasoning/problem solving subscore. Patients with unimpaired sleep at baseline showed greater improvements over time than those with sleep disturbances. Changes on the MCCB were not correlated with other psychometric variables. CONCLUSIONS: Despite statistically significant, cognitive improvements after 12 weeks of AGO treatment were clinically irrelevant. Our findings may be limited by baseline properties of the study sample and the study design. In particular, lacking a control group, it cannot be ruled out that improvements were unrelated to AGO treatment. That is why randomized controlled trials are needed to validate the relevance of AGO as a cognitive enhancer in schizophrenia.

Early cognitive basic symptoms are accompanied by neurocognitive impairment in patients with an 'at-risk mental state' for psychosis.

AIM: Patients with an increased risk for psychosis ('at-risk mental state' (ARMS)) present various neurocognitive deficits. Not least because of differences in identifying the ARMS, results of previous studies are inconsistent. In most studies ARMS-patients are classified by the experience of attenuated psychotic symptoms (APS) and/or brief limited intermittent psychotic symptoms (BLIPS). Few studies additionally assessed cognitive basic symptoms (BS). A comprehensive assessment in the very early stage of the ARMS is missing. METHODS: In the present study we characterized ARMS-patients for cognitive BS (ARMS-BS), APS and BLIPS (ARMS-A/B) according to the Early Recognition Inventory based on IRAOS (ERIraos). Furthermore, we assessed neurocognitive deficits using the MATRICS consensus cognitive battery for schizophrenia with a primary hypothesis regarding working memory performance. Groups of 38 ARMS-patients and 38 healthy controls were matched for age, gender, education and premorbid verbal intelligence. RESULTS: Between-group comparisons revealed significant poorer working memory performance in addition to lower verbal learning and problem solving, slower processing speed and lower global neurocognitive functioning in ARMS-patients as compared to controls. ARMS-BS did not differ from ARMS-A/B. CONCLUSIONS: These results underscore the presence of cognitive limitations in patients only presenting with cognitive BS. Knowledge of these early cognitive deviations supports the inclusion of early ARMS-stages into a comprehensive concept of the psychosis risk state. Therapeutic interventions already applied at this stage might prevent deterioration of constraints. Longitudinal and interventional studies investigating the interaction of cognitive BS and neurocognitive as well as metacognitive deficits are warranted.

Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype.

Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12-15 Hz) and slow (9-12 Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.

Aberrant activity and connectivity of the posterior superior temporal sulcus during social cognition in schizophrenia.

Schizophrenia is associated with significant impairments in social cognition. These impairments have been shown to go along with altered activation of the posterior superior temporal sulcus (pSTS). However, studies that investigate connectivity of pSTS during social cognition in schizophrenia are sparse. Twenty-two patients with schizophrenia and 22 matched healthy controls completed a social-cognitive task for functional magnetic resonance imaging that allows the investigation of affective Theory of Mind (ToM), emotion recognition and the processing of neutral facial expressions. Moreover, a resting-state measurement was taken. Patients with schizophrenia performed worse in the social-cognitive task (main effect of group). In addition, a group by social-cognitive processing interaction was revealed for activity, as well as for connectivity during the social-cognitive task, i.e., patients with schizophrenia showed hyperactivity of right pSTS during neutral face processing, but hypoactivity during emotion recognition and affective ToM. In addition, hypoconnectivity between right and left pSTS was revealed for affective ToM, but not for neutral face processing or emotion recognition. No group differences in connectivity from right to left pSTS occurred during resting state. This pattern of aberrant activity and connectivity of the right pSTS during social cognition might form the basis of false-positive perceptions of emotions and intentions and could contribute to the emergence and sustainment of delusions.

Agomelatine for the Treatment of Major Depressive Episodes in Schizophrenia-Spectrum Disorders: An Open-Prospective Proof-of-Concept Study.

BACKGROUND: Depressive episodes in schizophrenia constitute a major clinical problem, and treatment success is often limited by treatment-emergent side effects. Agomelatine, an agonist at melatonergic MT1/MT2 receptors and 5-HT2C receptor antagonist, is a new antidepressant with a novel mode of action which constitutes a potential therapeutic option for depression in schizophrenia. METHODS: Twenty-seven patients with lifetime diagnoses within the schizophrenia spectrum and comorbid depression were treated with agomelatine in addition to stable doses of antipsychotic agents. Severity of depression and other psychopathological domains (positive/negative symptoms, general psychopathology, psychosocial performance) was assessed regularly by means of standardized rating scales during a 6-week acute treatment phase as well as after a 6-week extension phase. Moreover, safety measures (electrocardiograms, laboratory counts, neurological and non-neurological side effects, sleep quality, sexual functioning) were monitored on a regular basis. RESULTS: Depressive symptoms improved significantly during the 6-week acute treatment phase. In parallel, a significant improvement of negative symptoms, global psychopathology, and psychosocial performance was observed, whereas positive symptoms remained stable. Agomelatine was mostly well tolerated with predominantly mild and self-limiting side effects. However, pharmacokinetic interactions with antipsychotic agents were observed. Interestingly, the quality of sleep did not improve significantly, pointing toward mechanisms that do not depend on resynchronization of circadian rhythms. CONCLUSIONS: Agomelatine appears to be safe and efficacious in treating depressive symptoms in patients with schizophrenia. The risk of pharmacokinetic interactions with antipsychotic agents warrants the need of therapeutic drug monitoring, and regular recording of vital signs seems necessary. Further randomized trials will have to confirm these findings.

Bias against disconfirmatory evidence in the 'at-risk mental state' and during psychosis.

Prior studies have confirmed a bias against disconfirmatory evidence (BADE) in schizophrenia which has been associated with delusions. However, its role in the pathogenesis of psychosis is yet unclear. The objective was to investigate BADE for the first time in subjects with an at-risk-mental-state for psychosis (ARMS), patients with a first episode of psychosis without antipsychotic treatment (FEP) and healthy controls (HC). A standard BADE test presenting written scenarios was employed. In addition, psychometric rating scales and a neuropsychological test battery were applied. A three-staged image was revealed. FEP-patients showed a significant BADE compared to the other groups. The performance of ARMS-patients lay in between HC and FEP-patients. A trend towards significance became evident for a bias against confirmatory evidence (BACE) in FEP-patients. Results were not attributable to antipsychotic or other medication or depressive symptoms. Correlations with delusions reached medium effect sizes but failed significance after Bonferroni-corrections. These results provide evidence for aberrations in evidence integration in the pathogenesis of psychosis and contribute to our knowledge of metacognitive functioning which can be used for (meta-)cognitive intervention in psychosis.

Investigating the efficacy of an individualized metacognitive therapy program (MCT+) for psychosis: study protocol of a multi-center randomized controlled trial.

BACKGROUND: Psychological interventions are increasingly recommended as adjunctive treatments for psychosis, but their implementation in clinical practice is still insufficient. The individualized metacognitive therapy program (MCT+; www.uke.de/mct_plus ) represents a low-threshold psychotherapeutic approach that synthesizes group metacognitive training (MCT) and cognitive behavioral therapy for psychosis, and addresses specific cognitive biases that are involved in the onset and maintenance of psychosis. It aims to "plant the seed of doubt" regarding rigid delusional convictions and to encourage patients to critically reflect, extend and change their approach to problem solving. Its second edition also puts more emphasis on affective symptoms. A recent meta-analysis of metacognitive interventions (MCT, MCT+) indicate small to moderate effects on positive symptoms and delusions, as well as high rates of acceptance. Nonetheless, no long-term studies of MCT+ involving large samples have been conducted. METHODS: The goal of the present multi-center, observer-blind, parallel-group, randomized controlled trial is to compare the efficacy of MCT+ against an active control (cognitive remediation; MyBrainTraining(©)) in 328 patients with psychosis at three time points (baseline, immediately after intervention [6 weeks] and 6 months later). The primary outcome is change in psychosis symptoms over the 6-month follow-up period as assessed by the delusion subscale of the Psychotic Symptom Rating Scale. Secondary outcomes include jumping to conclusions, other positive symptoms of schizophrenia, depressive symptoms, self-esteem, quality of life, and cognitive insight. The study also seeks to elucidate mediating factors that promote versus impede symptom improvement across time. DISCUSSION: This is the first multi-center randomized controlled trial to test the efficacy of individualized MCT+ in a large sample of patients with psychosis. The rationale for the trial, the design, and the strengths and limitations of the study are discussed. TRIAL REGISTRATION: The trial is registered through the German Clinical Trials Register ( www.drks.de ) as DRKS00008001 . Registered 6 May 2015.

Reduced activation in the ventral striatum during probabilistic decision-making in patients in an at-risk mental state.

BACKGROUND: Patients with schizophrenia display metacognitive impairments, such as hasty decision-making during probabilistic reasoning - the "jumping to conclusion" bias (JTC). Our recent fMRI study revealed reduced activations in the right ventral striatum (VS) and the ventral tegmental area (VTA) to be associated with decision-making in patients with schizophrenia. It is unclear whether these functional alterations occur in the at-risk mental state (ARMS). METHODS: We administered the classical beads task and fMRI among ARMS patients and healthy controls matched for age, sex, education and premorbid verbal intelligence. None of the ARMS patients was treated with antipsychotics. Both tasks request probabilistic decisions after a variable amount of stimuli. We evaluated activation during decision-making under certainty versus uncertainty and the process of final decision-making. RESULTS: We included 24 AMRS patients and 24 controls in our study. Compared with controls, ARMS patients tended to draw fewer beads and showed significantly more JTC bias in the classical beads task, mirroring findings in patients with schizophrenia. During fMRI, ARMS patients did not demonstrate JTC bias on the behavioural level, but showed a significant hypoactivation in the right VS during the decision stage. LIMITATIONS: Owing to the cross-sectional design of the study, results are constrained to a better insight into the neurobiology of risk constellations, but not prepsychotic stages. Nine of the ARMS patients were treated with antidepressants and/or lorazepam. CONCLUSION: As in patients with schizophrenia, a striatal hypoactivation was found in ARMS patients. Confounding effects of antipsychotic medication can be excluded. Our findings indicate that error prediction signalling and reward anticipation may be linked to striatal dysfunction during prodromal stages and should be examined for their utility in predicting transition risk.

Increased orbitofrontal cortex activation associated with "pro-obsessive" antipsychotic treatment in patients with schizophrenia.

BACKGROUND: Patients with schizophrenia have an approximately 10-fold higher risk for obsessive-compulsive symptoms (OCS) than the general population. A large subgroup seems to experience OCS as a consequence of second-generation antipsychotic agents (SGA), such as clozapine. So far little is known about underlying neural mechanisms. METHODS: To investigate the role of SGA treatment on neural processing related to OCS in patients with schizophrenia, we stratified patients according to their monotherapy into 2 groups (group I: clozapine or olanzapine; group II: amisulpride or aripiprazole). We used an fMRI approach, applying a go/no-go task assessing inhibitory control and an n-back task measuring working memory. RESULTS: We enrolled 21 patients in group I and 19 patients in group II. Groups did not differ regarding age, sex, education or severity of psychotic symptoms. Frequency and severity of OCS were significantly higher in group I and were associated with pronounced deficits in specific cognitive abilities. Whereas brain activation patterns did not differ during working memory, group I showed significantly increased activation in the orbitofrontal cortex (OFC) during response inhibition. Alterations in OFC activation were associated with the severity of obsessions and mediated the association between SGA treatment and co-occurring OCS on a trend level. LIMITATIONS: The main limitation of this study is its cross-sectional design. CONCLUSION: To our knowledge, this is the first imaging study conducted to elucidate SGA effects on neural systems related to OCS. We propose that alterations in brain functioning reflect a pathogenic mechanism in the development of SGA-induced OCS in patients with schizophrenia. Longitudinal studies and randomized interventions are needed to prove the suggested causal interrelations.

Metamemory in schizophrenia: retrospective confidence ratings interact with neurocognitive deficits.

Prior studies with schizophrenia patients described a reduced ability to discriminate between correct and false memories in terms of confidence compared to control groups. This metamemory bias has been associated with the emergence and maintenance of delusions. The relation to neuropsychological performance and other clinical dimensions is incompletely understood. In a cross-sectional study, metamemory functioning was explored in 32 schizophrenia patients and 25 healthy controls. Metamemory was assessed using a verbal recognition task combined with retrospective confidence level ratings. Associations of metamemory performance with six neuropsychological domains (executive functioning/problem solving, speed of processing, working memory, verbal and visual learning, and attention/vigilance) and psychopathological measures were analyzed. Results revealed a significantly smaller discrepancy between confidence ratings for correct and incorrect recognitions in the patient group. Furthermore, patients showed significantly lower recognition accuracy in the metamemory task and marked deficits in all neuropsychological domains. Across all participants, metamemory performance significantly correlated with executive functioning and working memory. No associations with delusions were found. This data confirms prior findings of metamemory biases in schizophrenia. Selective neuropsychological abilities seem to be modulating factors of metamemory functioning. Longitudinal studies in at risk mental state and first-episode patients are needed to reveal causal interrelations.

Antipsychotic treatment modulates glutamate transport and NMDA receptor expression.

Schizophrenia patients often suffer from treatment-resistant cognitive and negative symptoms, both of which are influenced by glutamate neurotransmission. Innovative therapeutic strategies such as agonists at metabotropic glutamate receptors or glycin reuptake inhibitors try to modulate the brain's glutamate network. Interactions of amino acids with monoamines have been described on several levels, and first- and second-generation antipsychotic agents (FGAs, SGAs) are known to exert modulatory effects on the glutamatergic system. This review summarizes the current knowledge on effects of FGAs and SGAs on glutamate transport and receptor expression derived from pharmacological studies. Such studies serve as a control for molecular findings in schizophrenia brain tissue and are clinically relevant. Moreover, they may validate animal models for psychosis, foster basic research on antipsychotic substances and finally lead to a better understanding of how monoaminergic and amino acid neurotransmissions are intertwined. In the light of these results, important differences dependent on antipsychotic substances, dosage and duration of treatment became obvious. While some post-mortem findings might be confounded with multifold drug effects, others are unlikely to be influenced by antipsychotic treatment and could represent important markers of schizophrenia pathophysiology. In similarity to the convergence of toxic and psychotomimetic effects of dopaminergic, serotonergic and anti-glutamatergic substances, the therapeutic mechanisms of SGAs might merge on a yet to be defined molecular level. In particular, serotonergic effects of SGAs, such as an agonism at 5HT1A receptors, represent important targets for further clinical research.

Neurocognitive capabilities modulate the integration of evidence in schizophrenia.

Previous studies have demonstrated a cognitive bias in the integration of disconfirmatory evidence (BADE) in patients with schizophrenia. This bias has been associated with delusions. So far, it is unclear how the integration of evidence is associated with neurocognitive capabilities. In the current study, 31 patients with schizophrenia and 29 healthy controls, matched on age, gender, education and premorbid verbal intelligence, underwent a BADE task. Written scenarios of three consecutive sentences each were presented, which progressively reduced the ambiguity of situations. Participants were asked to rate the plausibility of four possible interpretations and adjust their ratings in response to the provided sentences. Psychometric rating scales and a neuropsychological test battery were applied. Patients displayed a bias in the integration of confirmatory, but not disconfirmatory evidence and a liberal acceptance of belief formation. Correlation analyses revealed no associations of evidence integration with the severity of positive symptoms, but with neurocognitive domains, especially with processing speed, executive functioning, vigilance and working memory. In conclusion, patients with schizophrenia show a bias in evidence integration. Neurocognitive functioning emerged as a modulatory factor that should be considered in further research. Studies investigating BADE in earlier stages of psychosis will be necessary to reveal causal relationships.

Reduced activation in ventral striatum and ventral tegmental area during probabilistic decision-making in schizophrenia.

Patients with schizophrenia suffer from deficits in monitoring and controlling their own thoughts. Within these so-called metacognitive impairments, alterations in probabilistic reasoning might be one cognitive phenomenon disposing to delusions. However, so far little is known about alterations in associated brain functionality. A previously established task for functional magnetic resonance imaging (fMRI), which requires a probabilistic decision after a variable amount of stimuli, was applied to 23 schizophrenia patients and 28 healthy controls matched for age, gender and educational levels. We compared activation patterns during decision-making under conditions of certainty versus uncertainty and evaluated the process of final decision-making in ventral striatum (VS) and ventral tegmental area (VTA). We replicated a pre-described extended cortical activation pattern during probabilistic reasoning. During final decision-making, activations in several fronto- and parietocortical areas, as well as in VS and VTA became apparent. In both of these regions schizophrenia patients showed a significantly reduced activation. These results further define the network underlying probabilistic decision-making. The observed hypo-activation in regions commonly associated with dopaminergic neurotransmission fits into current concepts of disrupted prediction error signaling in schizophrenia and suggests functional links to reward anticipation. Forthcoming studies with patients at risk for psychosis and drug-naive first episode patients are necessary to elucidate the development of these findings over time and the interplay with associated clinical symptoms.