Panayiota G. Michalopoulou

Facial fear processing and psychotic symptoms in schizophrenia: functional magnetic resonance imaging study

BACKGROUND The recognition of negative facial affect is impaired in people with schizophrenia. The neural underpinnings of this deficit and its relationship to the symptoms of psychosis are still unclear. AIMS To examine the association between positive and negative psychotic symptoms and activation within the amygdala and extrastriate visual regions of patients with schizophrenia during fearful and neutral facial expression processing. METHOD Functional magnetic resonance imaging was used to measure neural responses to neutral and fearful facial expressions in 11 patients with schizophrenia and 9 healthy volunteers during an implicit emotional task. RESULTS No association between amygdala activation and positive symptoms was found; the activation within the left superior temporal gyrus was negatively associated with the negative symptoms of the patients. CONCLUSIONS Our results indicate an association between impaired extrastriate visual processing of facial fear and negative symptoms, which may underlie the previously reported difficulties of patients with negative symptoms in the recognition of facial fear.

Modafinil combined with cognitive training: Pharmacological augmentation of cognitive training in schizophrenia

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

The effects of a single dose of oxytocin on working memory in schizophrenia

Fig. 1. Effects of oxytocin on Digits Backward score. Oxytocin significantly increasedmean Digits Backward score. *Denotes significant difference fromplacebo at p b 0.016. Error bars represent ±1 standard error. Cognitive impairment associated with schizophrenia (CIAS) is related to the functional outcome of the illness. Oxytocin (OT), a “social” neuropeptide, has recently been linked with “non-social” cognition, such as cognitive flexibility, spatial and episodic memory (Chini et al., 2014) and with immediate and short-term verbal memory in schizophrenia (Feifel et al., 2012). Working memory (WM) is a central cognitive deficit of schizophrenia and a target domain for the development of new CIAS treatments (Barch and Smith, 2008). In the present study, we investigated the effects of a single OT dose on WM. We included the Digit Span (DS) as secondary outcomemeasure in a study implemented in our laboratory (Averbeck et al., 2012). DSmeasures twoWM components: a) information storage and maintenance (Digits Forward — DF) and b) information maintenance plus manipulation, i.e. the “executive component” of WM (Digits Backward — DB), which is more sensitive to WM deficits in schizophrenia (Kim et al., 2004). We also included Digit Symbol Coding (DSC), a processing speed test. The design details can be found elsewhere (Averbeck et al., 2012). Briefly, we conducted a double-blind placebo-controlled, crossover study. Twenty-one participants who met DSM-IV criteria for schizophrenia (mean illness duration 15.57 ± 6.61 years, NART IQ 100.79 ± 9.59, education years 12.19 ± 2.7) and were male, 18–50 years old (mean age 38.19 ± 8.04), clinically stable for one year prior to study entry (PANSS total score 58.86 ± 15.13), on atypical (n = 19) or lowdoses of typical (n = 2) antipsychotics (daily mean chlorpromazine equivalent 469.81 ± 351.44) were included in the study and were randomly allocated to a single intranasal dose of 24 IU OT (Syntocinon, Novartis) or saline placebo [n1 = 11 received placebo and n2 = 10 OT during the first visit — 7 or 8 days between the two visits (mean= 7.33 ± 0.48)]. There were no significant differences in demographic and clinical measures between n1 and n2 groups. Testing began 50 min after OT/placebo administration. No adverse events occurred. We used repeated measures ANOVA with drug as the within and order of drug administration as the between subject factor (alpha level = 0.05). Effect sizes were measured using Cohens formula for one sample comparisons (Cohens dz). We found a significant main effect of drug on DB [F (1, 19) = 7.354, p = 0.014] (DB under placebo = 5.38 ± 2.42 and under OT = 5.90 ± 2.55). Post-hoc analysis (paired t-tests, p after Bonferroni correction = 0.016) showed significant DB improvement under OT, irrespective of the visit OT was taken [t (20) =−2.75, p = 0.012, Cohens dz = 0.6] (Fig. 1). No significant order effect [F (1, 19)= 0.814, p= 0.378] or drug × order interaction [F (1, 19) = 1.272, p = 0.273] was found. No significant main effect of drug [F (1, 19) = 0.188, p = 0.669], order [F (1, 19) = 0.968, p = 0.338] or drug × order interaction [F (1, 19) = 1.340, p = 0.066] was

Can cognitive deficits differentiate between schizophrenia with and without obsessive–compulsive symptoms?

BACKGROUND The frequent occurrence of obsessive-compulsive symptoms (OCS) in the course of schizophrenia and their impact on the functional outcome of the illness underlie the suggestion that the presence of OCS represents a separate subtype of schizophrenia, with a distinct clinical presentation and prognosis and specific neurobiological characteristics. This study investigated whether the presence of OCS in schizophrenia is associated with worse cognitive functioning in the domains of processing speed, executive functions and visuospatial memory. We also explored whether the degree of impairment in any of these cognitive domains could predict group membership (i.e. Schizophrenia with OCS [Sch-OCS] and Schizophrenia without OCS) and if there was a relationship between cognitive functioning and severity of OCS within the Sch-OCS group. METHODS Forty patients with schizophrenia, 20 with and 20 without OCS, individually matched for age, gender, years of education and severity of psychotic symptoms and 20 healthy controls underwent a comprehensive neuropsychological assessment. RESULTS Only lower performance in processing speed discriminated patients with OCS from patients without OCS. Processing speed impairment not only classified patients in OCS or non-OCS group but was also independent of the severity of OCS symptoms. CONCLUSIONS The notion of additive effects of both schizophrenia and OCD on the structural and functional integrity of the brain circuits that support cognitive functions warrants further investigation in longitudinal neuropsychological and neuroimaging studies with larger samples and sufficient variation in the severity of OCS.

Differential diagnosis of obsessive-compulsive symptoms from delusions in schizophrenia: A phenomenological approach

Several studies suggest increased prevalence-rates of obsessive-compulsive symptoms (OCS) and even of obsessive-compulsive disorder (OCD) in patients with schizophrenic disorders. Moreover, it has been recently proposed the existence of a distinct diagnostic sub-group of schizo-obsessive disorder. However, the further investigation of the OCS or OCD-schizophrenia diagnostic comorbidity presupposes the accurate clinical differential diagnosis of obsessions and compulsions from delusions and repetitive delusional behaviours, respectively. In turn, this could be facilitated by a careful comparative examination of the phenomenological features of typical obsessions/compulsions and delusions/repetitive delusional behaviours, respectively. This was precisely the primary aim of the present investigation. Our examination included seven features of obsessions/delusions (source of origin and sense of ownership of the thought, conviction, consistency with ones belief-system, awareness of its inaccuracy, awareness of its symptomatic nature, resistance, and emotional impact) and five features of repetitive behaviours (aim of repetitive behaviours, awareness of their inappropriateness, awareness of their symptomatic nature, and their immediate effect on underlying thought, and their emotional impact). Several of these clinical features, if properly and empathically investigated, can help discriminate obsessions and compulsive rituals from delusions and delusional repetitive behaviours, respectively, in patients with schizophrenic disorders. We comment on the results of our examination as well as on those of another recent similar investigation. Moreover, we also address several still controversial issues, such as the nature of insight, the diagnostic status of poor insight in OCD, the conceptualization and differential diagnosis of compulsions from other categories of repetitive behaviours, as well as the diagnostic weight assigned to compulsions in contemporary psychiatric diagnostic systems. We stress the importance of the feature of mental reflexivity for understanding the nature of insight and the ambiguous diagnostic status of poor insight in OCD which may be either a marker of the chronicity of obsessions, or a marker of their delusionality. Furthermore, we criticize two major shortcomings of contemporary psychiatric diagnostic systems (DSM-IV, DSM-V, ICD-10) in their criteria or guidelines for the diagnosis of OCD or OCS: first, the diagnostic parity between obsessions and compulsions and, second, the inadequate conceptualization of compulsions. We argue that these shortcomings might artificially inflate the clinical prevalence of OC symptoms in the course of schizophrenic disorders. Still, contrary to a recent proposal, we do not exclude on purely a priori grounds the possibility of a concurrence of genuine obsessions along with delusions in patients with schizophrenia.

Drugs under early investigation for the treatment of bipolar disorder

Introduction: Despite the availability of several treatment options for bipolar disorder (BD), patients suffer from chronic, subsyndromal symptoms, quite frequent polarity shifts, cognitive impairment and poor community function. Overall, the current treatment outcomes for BD highlight the need to develop targeted, more effective and safe treatments. Areas covered: This review focuses on compounds currently under investigation for BD, covering compounds tested through animal studies to those in Phase II clinical trials over the past 5 years. These drugs concern all phases of BD treatment, that is, mania, depression, maintenance, and cognitive dysfunction. Expert opinion: Limitations exist in applying valid preclinical bipolar models and study designs. Research emphasis is given mainly on bipolar depression, with few compounds showing some evidence of efficacy. Non-effectiveness in current studies of mania and maintenance treatment reflects the need for novel compounds. Glycogen synthase kinase 3, casein kinase 1, inositol monophosphatase inhibition, histone deacetylase inhibition pathways are known targets that should proceed from preclinical to the clinical trial level.

Psychotic (delusional) depression and suicidal attempts: A systematic review and meta-analysis

It still remains unclear whether psychotic features increase the risk of suicidal attempts in major depressive disorder. Thus, we attempted, through a systematic review coupled with a meta‐analysis, to elucidate further whether unipolar psychotic depression (PMD) compared to non‐PMD presents higher levels of suicidal attempts.

Summary of the 1st Schizophrenia International Research Society Conference oral sessions, Venice, Italy, June 21-25, 2008: The rapporteur reports

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. A wide range of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversies about early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology and neurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiology and for use as targets in drug studies. Young investigators in the field were awarded travel grants to participate in the congress and one of their roles was to summarize the oral sessions and subsequent discussions. The reports that follow are the culmination of this work produced by 30 young investigators who attended the congress. It is hoped that these summaries will be useful synopses of what actually occurred at the congress for those who did not attend each session or were unable to be present. The abstracts of all presentations, as submitted by the authors a few months prior, were previously published as supplement 2 to volume 102/1-3, June 2008.

Psychotic (delusional) depression and completed suicide: a systematic review and meta-analysis

BackgroundIt remains unclear whether psychotic features increase the risk of completed suicides in unipolar depression. The present systematic review coupled with a meta-analysis attempts to elucidate whether unipolar psychotic major depression (PMD) compared to non-PMD presents higher rates of suicides.MethodsA systematic search was conducted in Scopus, PubMed, and “gray literature” for all studies providing data on completed suicides in PMD compared to non-PMD, and the findings were then subjected to meta-analysis. All articles were independently extracted by two authors using predefined data fields.ResultsNine studies with 33,873 patients, among them 828 suicides, met our inclusion criteria. PMD compared to non-PMD presented a higher lifetime risk of completed suicides with fixed-effect pooled OR 1.21 (95% CI 1.04–1.40). In a sub-analysis excluding a very large study (weight = 86.62%), and comparing 681 PMD to 2106 non-PMD patients, an even higher pooled OR was found [fixed-effect OR 1.69 (95% CI 1.16–2.45)]. Our meta-analysis may provide evidence that the presence of psychosis increases the risk of suicide in patients suffering from severe depression. The data are inconclusive on the contribution of age, mood congruence, comorbidity, and suicide method on PMD’s suicide risk. The lack of accurate diagnosis at the time of suicide, PMD’s diagnostic instability, and the use of ICD-10 criteria constitute the main study limitations.ConclusionsThe presence of psychosis in major depression should alert clinicians for the increased risk of completed suicide. Thus, the implementation of an effective treatment both for psychotic depression and patients’ suicidality constitutes a supreme priority.

The Effects of a Combined Intervention for Cognition in Schizophrenia On Cogstate Schizophrenia Battery

Background Cognitive impairment in schizophrenia is a strong predictor of the functional outcome and no effective treatments are available. MATRICS Consensus Cognitive Battery (MCCB) is approved by the FDA as outcome measure for trials of cognitive-enhancing drugs in schizophrenia. CogState Schizophrenia Battery (CSB) provides a briefer cognition assessment with minimal practice effects and a strong correlation between the CSB and MCCB composite scores. We tested the sensitivity of CSB as a cognitive outcome measure in a clinical trial in schizophrenia, where a cognitive-enhancing drug and cognitive training were combined. Methods 49 participants with schizophrenia were enrolled in a double-blind, placebo-controlled study. Participants were randomised to modafinil (200mg/day) or placebo and underwent a cognitive training program for 10 weekdays. CSB was administered twice at baseline to minimise practice effects, at the last day of the intervention and two weeks after the completion of the intervention. Results There was a significant time effect at the end of the intervention on the CSB composite score (p=0.042). There was no significant treatment effect on CSB composite score at the end of the intervention (p=0.686) or at follow up (p=0.120). Conclusions Multiple administrations of CSB were well tolerated by participants. The significant time effects on the composite score may suggest the operation of practice effects. Several factors could have contributed to the lack of treatment effects on CSB, such as the burden of multiple neuropsychological testing in a relatively brief study, the duration of modafinil treatment and also the intensive nature of cognitive training.