Lower Emotion Regulation Competencies Mediate the Association between Impulsivity and Craving during Alcohol Withdrawal Treatment.

There is evidence that craving mediates the relationship between Impulsive Personality Traits (IPTs) and relapse during the treatment of an Alcohol Use Disorder (AUD). To provide tailored interventions, a deeper understanding of the relation between IPTs and craving, namely mediating processes, is important. Based on previous literature, we proposed that lower emotion regulation competencies mediate the relation between attentional as well as non-planning IPTs and craving. To investigate these interrelations, we used data from the baseline assessment (n = 320) of the SmartAssistEntz project (pre-registered in the German Clinical Trials Register [DRKS00017700]). Inpatients with a primary AUD diagnosis were interviewed using standardized self-report measures (IPTs: BIS-15, emotion regulation competencies: ERSQ, craving: OCDS-G short version) during their withdrawal treatment. Indirect effects were calculated using the SPSS macro PROCESS v3.5. Attentional as well as non-planning, but not motor, IPTs were associated with craving. Emotion regulation competencies mediated the relationship between attentional as well as non-planning IPTs and craving. Given their mediating role in the present study, it is interesting to investigate if addressing emotion regulation competencies can mitigate the negative influences of attentional and non-planning IPTs. The direct effect of attentional IPTs implicates alternate mediating processes, which should also be investigated in future research.

Association of impulsivity with quality of life and well-being after alcohol withdrawal treatment.

OBJECTIVES: Impulsivity is related to a higher risk of relapse in alcohol use disorders. However, besides drinking behavior, other recovery outcomes like physical and mental health-related quality of life are at least as important. The present study aimed to fill a research gap regarding the association of different impulsivity facets with health-related quality of life and well-being in alcohol use disorder. METHODS: Individuals with a primary alcohol use disorder diagnosis (n = 167) were interviewed with standardized self-report measures at the progressed stage of their withdrawal treatment and 6 weeks thereafter. Multiple regression models were calculated to examine the association of impulsivity, craving, and drinking patterns with health-related quality of life and well-being 6 weeks after withdrawal treatment, as well as the predictive role of impulsivity assessed during withdrawal for these two outcomes. RESULTS: Craving was associated with health-related quality of life and well-being 6 weeks after withdrawal. Likewise, non-planning and attentional impulsivity were associated with well-being 6 weeks after withdrawal. Motor impulsivity during withdrawal treatment predicted health-related quality of life 6 weeks thereafter. CONCLUSION: Impulsivity seems to be negatively related to health-related quality of life and well-being in the first weeks after alcohol withdrawal treatment, probably to a higher extent than drinking patterns, but differentiating between its facets seems to be important. These findings emphasize the importance of treatment approaches aiming at reduced impulsivity in the early recovery process.

[Obsessive-compulsive symptoms in psychotic disorders: pathogenesis and treatment]. / Zwangssymptome bei psychotischen Störungen: Pathogenese und Therapie.

BACKGROUND: Comorbid disorders often occur in psychoses from the schizophrenia spectrum and are an additional burden for patients' quality of life, render treatment and rehabilitation prognosis more difficult and can also contribute to suicidal ideation. Specifically, obsessive-compulsive syndrome (OCS) and OC disorder (OCD) have been reported. OBJECTIVE: What is known about the epidemiology and pathogenesis and which conclusions can be drawn regarding the diagnostics and treatment? MATERIAL AND METHODS: This review evaluated current reports on comorbid OCS during different stages of psychotic disorders, starting with the at-risk mental state (ARMS) via the first manifestation and up to chronic courses. The focus was on pharmacological and psychotherapeutic consequences. RESULTS: Patients with ARMS suffer much more often from OCS than the general population. The prevalence is even higher in patients with a first manifestation of psychosis. During the chronic courses ca. 30% of patients are affected by comorbid OCS and 12% fulfill the diagnostic criteria of a OCD. The pathogenesis can most likely be explained by a genetic disposition in the glutamatergic system, shared structural and functional abnormalities of cortical and subcortical structures, pharmacological influences and psychosocial stressors. CONCLUSION: Clozapine and other antipsychotics may induce or aggravate OCS in a dose-dependent manner. In order to alleviate symptoms clozapine should be reduced to a minimally sufficient level. This can be attempted through combination, for example with dopaminergic antipsychotics. In general, serotonergic antidepressants can be added. Cognitive behavioral therapy should be offered to every patient with comorbid OCS. For future research multimodal longitudinal studies investigating the efficacy of interventions and aimed at the subjective level will be important.

[Validity of the "Structured Inventory of Malingered Symptomatology" [SIMS] in the Assessment of Healthy Individuals and Patients with Psychiatric Disorders Outside the Forensic Context]. / Validität des "Strukturierten Fragebogens Simulierter Symptome" [SIMS] bei gesunden Probanden und Patienten mit psychiatrischen Erkrankungen außerhalb eines forensischen Kontexts.

OBJECTIVE: Assessment of the rate of false-positive results of the Structured Inventory of Malingered Symptomatology (SIMS) in healthy controls and authentic patients outside the forensic or rehabilitative context. METHODS: Beyond the SIMS scores, further variables (PANSS, Hamilton scale, MMSE) were obtained. SIMS scores of healthy individuals were compared with the SIMS scores of the different groups of patients. Additionally, correlations between the SIMS scores and other variables were investigated. RESULTS: Patients with psychotic disorders (n=30) or depressive episodes (n=32) more frequently achieved SIMS scores >16 as compared to healthy controls. In comparison, patients with amnestic disorders (n=15) had inconspicuous SIMS scores. Depressed patients with positive SIMS results were significantly more likely to be diagnosed with another psychiatric disorder and the scores of these patients on the Hamilton scale were correlated with positive results on 2 subscales of the SIMS (NI, AF). CONCLUSION: If this instrument is to applied in clinical practice in the future, further validation of the SIMS is necessary. The specificity of the SIMS seems to be context-related.

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.

[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.

Obsessive-compulsive symptoms in psychotic disorders: longitudinal associations of symptom clusters on between- and within-subject levels.

Obsessive-compulsive symptoms (OCS) are frequently reported in patients with schizophrenia and have been associated with subjective distress and higher impairment. Recent studies suggest fluctuation in co-occurring OCS and associations with the course of psychotic symptoms. Current evidence is limited by few studies with long assessments intervals and a sole focus on between-subject comparisons. The aim of this study was to specifically investigate co-variation of symptom domains over time within individuals. Patients with a psychotic disorder (n = 56) and un-affected siblings (n = 49) completed monthly assessments of clinical and subclinical symptoms over 6 months. Mixed-model multilevel analyses examined the variability and relationship between OCS and positive, negative, and depressive symptoms on the between- and within-subject level. Symptom domains were associated across subjects and assessment times, in patients and siblings, with the strongest association between OCS and (subclinical) positive symptoms. Within-subjects, substantial variability and co-variation of all symptom domains was found. Particularly, between-subject differences in positive symptoms and within-subject change in depressive symptoms predicted subsequent OCS in patients 1 months later. This is the first prospective study disaggregating between and within-subject associations between co-occurring OCS and symptom cluster of psychosis. Differences on these two levels suggest different underlying mechanisms. The association between depressive symptoms and subsequent increase/decrease of OCS within patients may have important treatment implications.

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.

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.

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.

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.

Obsessive-compulsive symptoms and overall psychopathology in psychotic disorders: longitudinal assessment of patients and siblings.

The course of obsessive-compulsive symptoms (OCS) and its association with alterations in other clinical variables in patients with psychotic disorders is insufficiently known. Patients (n = 602) and unaffected siblings (n = 652) from the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study were investigated at baseline and after 3 years. Participants were assigned to four groups based on the course of OCS over time: no-OCS, persistent OCS, initial OCS and de novo OCS. In addition to cross-sectional comparisons, longitudinal associations between changes in OCS and symptoms of schizophrenia and general functioning were investigated. Patients with co-occurring OCS reported significantly higher severity of psychotic and affective symptoms as well as lower overall functioning compared to patients without OCS. These differences were stable over time for patients reporting persistent OCS. Subsequent repeated measure analysis revealed significant interaction effects for groups reporting changes in their OCS. Whereas the group with remission of initial OCS showed significant improvement in positive symptoms, emotional distress and functioning, the de novo group showed no significant change in these variables, but rather reported stable higher psychopathology. Similar results were found on a subclinical level in siblings. Patients with co-occurring OCS present a more severe clinical picture, especially if symptoms persist over time. The remission of OCS was associated with overall improvement, whereas individuals with de novo OCS already reported higher clinical impairment before OCS onset. More research is needed to elucidate causal pathways and to develop effective interventions for persistent comorbid OCS.

Health-related quality of life in outpatients with schizophrenia: factors that determine changes over time.

PURPOSE: The objective of this study was to analyze the clinical factors associated with changes in HRQoL in outpatients with schizophrenia using both generic and condition-specific HRQoL scales. METHODS: Adult outpatients with schizophrenia at least 18 years of age who did not have an acute psychotic exacerbation in the 3 months prior to baseline were recruited. PANSS dimensions were calculated based on Lindenmayer et al.'s five factors. HRQoL data were assessed by patients using the Schizophrenia Quality of Life Scale (SQLS), the Short Form-36 (SF-36), and the EuroQol-5 Dimension (EQ-5D) questionnaires. RESULTS: Out of the 1345 patients included at baseline, 1196 (89%) were evaluated at 12 months. Regression models showed that the factor most consistently associated with HRQoL at endpoint was change in the PANSS negative symptoms score. A decrease in the PANSS negative symptoms score from baseline to 1 year was associated with a decrease in HRQoL during the same period. There were also significant associations of the change in PANSS excitatory factor with all the HRQoL scales except the SF-36 PCS. Female gender was associated with a decrease in all HRQoL ratings. There was also a relationship between years since onset and HRQoL. The longer the time since illness onset, the larger the decrease in HRQoL. CONCLUSIONS: This study has found that, in outpatients with schizophrenia, changes in negative and excitement symptoms may have a greater an association with HRQoL than changes in positive, cognitive and depressive symptoms.

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.

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.

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.

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.

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.

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.

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.