The importance of pro-social processing, and ameliorating dysfunction in schizophrenia. An FMRI study of oxytocin.

Schizophrenia is often a severe and debilitating mental illness, frequently associated with impairments in social cognition that hinder individuals' abilities to relate to others and integrate effectively in society. Oxytocin has emerged as a putative therapeutic agent for treating social deficits in schizophrenia, but the mode of action remains unclear. This placebo-controlled crossover study aimed to elucidate the neural underpinnings of oxytocin administration in patients with schizophrenia. 20 patients with schizophrenia were examined using functional magnetic resonance imaging under oxytocin (40 IU) or placebo nasal spray. Participants performed a stochastically rewarded decision-making task that incorporated elements of social valence provided by different facial expressions, i.e. happy, angry and neutral. Oxytocin attenuated the normal bias in selecting the happy face accompanied by reduced activation in a network of brain regions that support mentalising, processing of facial emotion, salience, aversion, uncertainty and ambiguity in social stimuli, including amygdala, temporo-parietal junction, posterior cingulate cortex, precuneus and insula. These pro-social effects may contribute to the facilitation of social engagement and social interactions in patients with schizophrenia and warrant further investigation in future clinical trials for social cognitive impairments in schizophrenia.

The effect of training intensity on implicit learning rates in schizophrenia.

Cognitive impairments in learning and memory are core symptoms of schizophrenia, associated with reduced self-reported quality of life. The most effective treatment of cognitive impairments is drill and practice cognitive training. Still, to date no study has investigated the effect of varying the frequency of training on cognitive outcomes. Here we utilized a verbal memory based language learning task, tapping into implicit cognitive processes, to investigate the role of training intensity on learning rates in individuals with schizophrenia. Data from 47 participants across two studies was utilized, one with a daily training regimen over 5 days and the other with a more intensive schedule of 5 sessions delivered over 2 days. The primary outcome measure was the change in implicit learning performance across five sessions, quantified with the Matthews Correlation Coefficient (MCC). Participants in the daily training group showed improved performance compared to the intensive group only at session 4. This is the first study to show that implicit learning rates are influenced by training intensity, with daily sessions outperforming a more intensive regimen; a period of consolidation overnight may be necessary to optimize cognitive training for individuals with schizophrenia.

The preclinical discovery and development of agomelatine for the treatment of depression.

INTRODUCTION: Under the treatment of commonly used antidepressants, many patients with major depressive disorder (MDD) do not achieve remission. All previous first-line treatments for depression have focused on the enhancement of monoaminergic activity. Agomelatine was the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission. AREAS COVERED: The aim of this case history is to describe the discovery strategy and development of agomelatine. The pharmacodynamic profile of the drug is briefly presented. The article summarizes (a) the preclinical behavioral data on agomelatine's effects on depressive-like behavior, anxiety, and circadian rhythmicity disruptions, and (b) the results of early preclinical studies on safety, efficacy in MDD, and the risk-benefit pharmacological profile. Furthermore, the article examines findings of post-marketing research on safety, efficacy, and cost-effectiveness of the drug. EXPERT OPINION: There is now evidence supporting the clinical efficacy and safety profile of agomelatine in the acute-phase treatment of MDD. Agomelatine may be more effective in specific subgroups of MDD patients, those with severe anxiety symptoms or disturbed circadian profiles. Its antidepressant and anxiolytic activities are due to synergy between its melatonergic and 5-hydroxytryptaminergic effects. Since its discovery, novel compounds acting on the melatonergic system have been under investigation for the treatment of MDD.

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

BACKGROUND: It 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. METHODS: A 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. RESULTS: Nine 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. CONCLUSIONS: The 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.

Calibration and cross-validation of MCCB and CogState in schizophrenia.

RATIONALE: Cognitive impairment associated with schizophrenia is a key predictor of functional outcomes. The FDA-accepted MATRICS Consensus Cognitive Battery (MCCB) is held to be the gold standard measure but there are concerns about its ease of administration, reliance on language causing problems with translation and possible practice effects. The CogState Schizophrenia Battery (SB) is suggested as a non-language-based alternative but there is no substantial, independent comparison. OBJECTIVES: The objective of this study was to assess the reliability and validity of these two assessment batteries. METHODS: One hundred forty-three participants with DSM-IV schizophrenia and schizoaffective disorder were recruited into three similar studies. Each study administered MCCB and SB tests on consecutive days (baseline 1 and 2) and follow-up 3-4 weeks later. RESULTS: Batteries' test-retest reliability was similar: SB composites correlated r = 0.66-0.78 between baselines, MCCB domains r = 0.69-0.90. Baseline 2 and follow-up SB composites correlated r = 0.65-0.80 and MCCB domains r = 0.62-0.87. MCCB tasks' practice effects (Glass' ∆ = 0.02-0.46) exceeded SB's (Glass' ∆ = 0.02-0.34). While the batteries' total scores correlated strongly (r = 0.79-0.82), apparently equivalent cognitive domains on each battery (e.g. psychomotor-attention) correlated r = 0.22-0.60, indicating substantial differences between some supposed counterparts. CONCLUSIONS: Clinical trials using either battery would benefit from initial practice sessions to ameliorate practice effects but the SB may be more suitable to measure change in the absence of repeated baselines. The MCCB domains' better correlations with social skills performance suggest that it may have an advantage for measuring cognition in relation to functional outcome.

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.

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.

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 one's 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.

Treating impaired cognition in schizophrenia: the case for combining cognitive-enhancing drugs with cognitive remediation.

Cognitive impairment is a well-documented feature of schizophrenia and represents a major impediment to the functional recovery of patients. The therapeutic strategies to improve cognition in schizophrenia have either used medications (collectively referred to as 'cognitive-enhancing drugs' in this article) or non-pharmacological training approaches ('cognitive remediation'). Cognitive-enhancing drugs have not as yet been successful and cognitive remediation has shown modest success. Therefore, we may need to explore new therapeutic paradigms to improve cognition in schizophrenia. The optimal approach may require a combination of cognitive-enhancing drugs with cognitive remediation. We review the available data from animal and human studies that provide the conceptual basis, proof-of-concept and illustrations of success of such combination strategies in experimental and clinical paradigms in other conditions. We address the major design issues relevant to the choice of the cognitive-enhancing drugs and cognitive remediation, as well as the timing and the duration of the intervention as will be relevant for schizophrenia. Finally, we address the practical realities of the development and testing of such combined approaches in the real-world clinical situation and conclude that while scientifically attractive, there are several practical difficulties to be overcome for this approach to be clinically feasible.

It's not what you say but the way that you say it: an fMRI study of differential lexical and non-lexical prosodic pitch processing.

BACKGROUND: This study aims to identify the neural substrate involved in prosodic pitch processing. Functional magnetic resonance imaging was used to test the premise that prosody pitch processing is primarily subserved by the right cortical hemisphere.Two experimental paradigms were used, firstly pairs of spoken sentences, where the only variation was a single internal phrase pitch change, and secondly, a matched condition utilizing pitch changes within analogous tone-sequence phrases. This removed the potential confounder of lexical evaluation. fMRI images were obtained using these paradigms. RESULTS: Activation was significantly greater within the right frontal and temporal cortices during the tone-sequence stimuli relative to the sentence stimuli. CONCLUSION: This study showed that pitch changes, stripped of lexical information, are mainly processed by the right cerebral hemisphere, whilst the processing of analogous, matched, lexical pitch change is preferentially left sided. These findings, showing hemispherical differentiation of processing based on stimulus complexity, are in accord with a 'task dependent' hypothesis of pitch processing.

The effects of reality distortion syndrome on salient stimuli processing in patients with schizophrenia: an fMRI study.

Schizophrenia is associated with interpersonal difficulties related to impairments in the processing of facial emotional expressions. The aim of the present study was to identify brain regions associated with reality distortion syndrome reduction in a group of patients with schizophrenia during processing of emotionally salient stimuli. We used functional magnetic resonance imaging to measure cerebral blood oxygenation changes during an implicit emotional task in 11 patients with schizophrenia, who were scanned twice with an interval of 6-8 weeks. We found that reality distortion syndrome reduction was associated with increases in the activation of the affective division of the anterior cingulate and lateral prefrontal cortices. Our findings may indicate that changes in the activation of these regions during processing of emotionally salient stimuli may represent neural markers of patients' symptomatic improvement.

Cognitive decline and dementia in elderly medical inpatients remain underestimated and underdiagnosed in a recently established university general hospital in Greece.

The aim of this study was to report the prevalence of cognitive decline as well as its recognition rates in elderly inpatients in a general hospital in Greece. Two hundred randomly selected patients, 65 years old and over, hospitalized in surgery and internal medicine departments, were assessed for cognitive decline in a period of 12 months by means of structured clinical interview for DSM-IV axis-I disorders, clinical version (SCID-IV), mini-mental state examination (MMSE) and the clock drawing test (CDT). During the next 12 months the liaison calls were evaluated and the two periods were compared. During the first screening period, when psychiatric assessment was performed, 61 patients (30.5%) were diagnosed to present cognitive decline. During the second period, there were only 20 liaison calls from the same departments for patients over 65 years of age, from which 15 patients were found to present cognitive decline. Comparison between the two periods showed significant underestimation of cognitive decline. In the general hospital the cognitive decline of elderly inpatients remains still under-recognized.

Obsessive-compulsive disorder associated with parietal white matter multiple sclerosis plaques.

We report the case of a patient who developed obsessive-compulsive symptoms after being diagnosed with multiple sclerosis. In this patient, obsessive-compulsive symptoms deteriorated with the emergence of a right parietal white matter multiple sclerosis plaque. The involvement of parietal white matter abnormalities in the pathophysiology of obsessive-compulsive disorder remains largely unexplored. Our case report raises the possibility that parietal lobe white matter microstructure plays a role in mediating obsessions and compulsions through disruptions of the functional connectivity between cortical-cortical and/or cortical-subcortical brain regions implicated in the pathophysiology of obsessive-compulsive disorder.

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.

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.