Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation.

161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF-α.

Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ (F(2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ (F(2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls.

The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Rumination is a significant cognitive symptom of depression. As rumination is strongly related to altered memory function we selected two genes previously described as important candidates for both depression and memory processing to assess their contribution to rumination. Based on a possible functional role for cAMP-dependent protein kinase in the mechanism of action antidepressants, we studied the association between G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding (CREB) protein genes and rumination in two independent European samples.

We genotyped an exonic SNP (rs2070995) in GIRK2 gene and a promoter SNP (rs2253206) in CREB gene of 611 individuals from Budapest and 1174 individuals from Manchester. Rumination was measured by Ruminative Response Scale (RRS) of Response Style Questionnaire. Generalized linear models (GLMs) were performed for single marker associations. Likelihood ratio tests were used for interactions between genetic markers on RRS.

Single marker associations did not provide any significant individual effect of the two SNPs on rumination. However, interaction analyses revealed a strongly significant interaction between the rs2070995 and rs2253206 on RRS in both European samples (pBudapest=0.00099; pManchester=0.0027). Homozygous TT individuals for rs2070995 in interaction with homozygous GG for rs2253206 scored significantly higher on RRS compared with other genotypes.

Our results suggest that two key post-receptor signalling proteins, GIRK2 and CREB, interact with each other in regulating the process of rumination which may have relevance for depression and its treatment.

These studies were supported by the Sixth Framework Programme of the EU, LSHM-CT-2004-503474, HRF T03298/2000.

There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents but have been found to be anti-inflammatory and also decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that adjunctive Ondansetron is efficacious against schizophrenia symptoms. We carried out a feasibility study in schizophrenia patients (within 5 years of first diagnosis) to explore the adjunctive use of simvastatin and ondansetron on positive, negative and general psychopathology.

This was a 12 week rater blind placebo controlled study. All to gather 36 patients with DSM-IV diagnosis of schizophrenia were recruited, 12 in each arm. Patients were assessed at baseline and at 12 weeks using PANSS, CGI, GAF and AIMS.

Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared to treatment as usual (TAU) on PANSS total score, although, this was not statistically significant. In the secondary analyses, no significant differences were seen on CGI, GAF and AIMS.

Anti-inflammatory treatments have shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared to treatment as usual. This study has led to a larger SMRI-funded, double blind, randomized control trial.

Immune mechanisms have been implicated in the pathogenesis of schizophrenia. This has lead to clinical trials of re-purposing drugs with off-target anti-inflammatory actions. They include the antibiotic minocycline and simvastatin (HMP-Co reductase inhibitor), which decrease microglial activation, and ondansetron a 5-HT3-receptor antagonist that has limited effects on cytokine production. This presentation will address their efficacy and mechanism of action.

1) Update on trials with minocycline including our own positive finding on negative symptoms (PMID: 16959472)

2) Present new results with ondansetron and simvastatin summarised below.

Ondansetron (8mg) and simvastatin (40mg) vs placebos in 2x2 design (PMID: 23782463). Patients aged 18-65, stable treatment, DSM IV schizophrenia-related diagnosis. PANSS and cognition at 0,3,6 months.

The four cells of the 2x2 design contained 302 patients. The interaction between ondansetron and simvastatin was significant at p=.006 reflecting the lower scores in the 3 active treatment groups than in the P+P group. Ondansetron improved verbal (p=.007) and visual list learning (p=.02) with no other treatment effects on cognition.

Minocycline appears to benefit negative symptoms in early psychosis with a minor effect on cognition. Simvastatin had limited effects in our patients with established schizophrenia but its anti-inflammatory effects could be worth investigating in early psychosis. Ondansetron has a significant effect on new learning, which might be expected from its 5-HT3 antagonist properties. This may underlie a benefit on negative symptoms reported by others and us.

One influential view is that vulnerability to major depressive disorder (MDD) is associated with a proneness to experience negative emotions in general. In contrast, blame attribution theories emphasise the importance of blaming oneself rather than others for negative events. Our previous exploratory study provided support for the attributional hypothesis that patients with remitted MDD show no overall bias towards negative emotions, but a selective bias towards emotions entailing self-blame relative to emotions that entail blaming others. More specifically, we found a decreased proneness for contempt/disgust towards others relative to oneself (i.e. self-contempt bias). Here, we report a definitive test of the competing general negative versus specific attributional bias theories of MDD.

We compared a medication-free remitted MDD (n = 101) and a control group (n = 70) with no family or personal history of MDD on a previously validated experimental test of moral emotions. The task measures proneness to specific emotions associated with different types of self-blame (guilt, shame, self-contempt/disgust, self-indignation/anger) and blame of others (other-indignation/anger, other-contempt/disgust) whilst controlling for the intensity of unpleasantness.

We confirmed the hypothesis that patients with MDD exhibit an increased self-contempt bias with a reduction in contempt/disgust towards others. Furthermore, they also showed a decreased proneness for indignation/anger towards others.

This corroborates the prediction that vulnerability to MDD is associated with an imbalance of specific self- and other-blaming emotions rather than a general increase in negative emotions. This has important implications for neurocognitive models and calls for novel focussed interventions to rebalance blame in MDD.

The authors have not supplied their declaration of competing interest.

A high proportion of patients with remitted major depressive disorder (MDD) will experience recurring episodes, whilst some develop resilience and remain in recovery. The neural basis of resilience to recurrence is elusive. Abnormal resting-state connectivity of the subgenual cingulate cortex (sgACC) was previously found in cross-sectional studies of MDD, suggesting its potential pathophysiological importance. The current study aimed to investigate whether resting-state connectivity to a left sgACC seed region distinguishes resilient patients from those developing recurring episodes.

A total of 47 medication-free remitted MDD patients and 38 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. Over 14 months, 30 patients remained resilient whilst 17 experienced a recurring episode.

Attenuated interhemispheric left-to-right sgACC connectivity distinguished the resilient from the recurring-episode and control groups and was not correlated with residual depressive symptoms.

The current study revealed a neural signature of resilience to recurrence in MDD and thereby elucidates the role of compensatory adaptation in sgACC networks.

Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown.

In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms.

We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05).

Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision-making abnormalities in depression.

Major depressive disorder (MDD) is associated with abnormalities in financial reward processing. Previous research suggests that patients with MDD show reduced sensitivity to frequency of financial rewards. However, there is a lack of conclusive evidence from studies investigating the evaluation of financial rewards over time, an important aspect of reward processing that influences the way people plan long-term investments. Beck's cognitive model posits that patients with MDD hold a negative view of the future that may influence the amount of resources patients are willing to invest into their future selves.

We administered a delay discounting task to 82 participants: 29 healthy controls, 29 unmedicated participants with fully remitted MDD (rMDD) and 24 participants with current MDD (11 on medication).

Patients with current MDD, relative to remitted patients and healthy subjects, discounted large-sized future rewards at a significantly higher rate and were insensitive to changes in reward size from medium to large. There was a main effect of clinical group on discounting rates for large-sized rewards, and discounting rates for large-sized rewards correlated with severity of depressive symptoms, particularly hopelessness.

Higher discounting of delayed rewards in MDD seems to be state dependent and may be a reflection of depressive symptoms, specifically hopelessness. Discounting distant rewards at a higher rate means that patients are more likely to choose immediate financial options. Such impairments related to long-term investment planning may be important for understanding value-based decision making in MDD, and contribute to ongoing functional impairment.

Negative biases in emotional processing are well recognised in people who are currently depressed but are less well described in those with a history of depression, where such biases may contribute to vulnerability to relapse.

To compare accuracy, discrimination and bias in face emotion recognition in those with current and remitted depression.

The sample comprised a control group (n = 101), a currently depressed group (n = 30) and a remitted depression group (n = 99). Participants provided valid data after receiving a computerised face emotion recognition task following standardised assessment of diagnosis and mood symptoms.

In the control group women were more accurate in recognising emotions than men owing to greater discrimination. Among participants with depression, those in remission correctly identified more emotions than controls owing to increased response bias, whereas those currently depressed recognised fewer emotions owing to decreased discrimination. These effects were most marked for anger, fear and sadness but there was no significant emotion × group interaction, and a similar pattern tended to be seen for happiness although not for surprise or disgust. These differences were confined to participants who were antidepressant-free, with those taking antidepressants having similar results to the control group.

Abnormalities in face emotion recognition differ between people with current depression and those in remission. Reduced discrimination in depressed participants may reflect withdrawal from the emotions of others, whereas the increased bias in those with a history of depression could contribute to vulnerability to relapse. The normal face emotion recognition seen in those taking medication may relate to the known effects of antidepressants on emotional processing and could contribute to their ability to protect against depressive relapse.

Both past depressive episodes and the personality trait of depressive rumination are strong risk factors for future depression. Depression is associated with abnormal emotional processing, which may be a neurobiological marker for vulnerability to depression. A consistent picture has yet to emerge as to how a history of depression and the tendency to ruminate influence emotional processing. The aim of this study was to investigate the relationship between rumination, past depression and neural responses when processing face emotions.

The Ruminative Responses Scale (RRS) was completed by 30 remitted depressives and 37 controls who underwent functional magnetic resonance imaging (fMRI) scanning while viewing happy, sad, fearful and neutral faces.

The remitted depressives showed overall reductions in neural responses to negative emotions relative to the controls. However, in the remitted depressives, but not the controls, RRS scores were correlated with increased neural responses to negative emotions and decreased responses to happiness in limbic regions.

Automatic emotion processing biases and rumination seem to be correlated to aspects of vulnerability to depression. However, remission from depression may be maintained by a general suppression of limbic responsiveness to negative emotion.

Generalized anxiety disorder (GAD) is under-researched despite its high prevalence and large impact on the healthcare system. There is a paucity of functional magnetic resonance imaging (fMRI) studies that explore the neural correlates of emotional processing in GAD. The present study investigated the blood oxygen level dependent (BOLD) response to processing positive and negative facial emotions in patients with GAD.

A total of 15 female GAD patients and 16 female controls undertook an implicit face emotion task during fMRI scanning. They also performed a face emotion recognition task outside the scanner.

The only behavioural difference observed in GAD patients was less accurate detection of sad facial expressions compared with control participants. However, GAD patients showed an attenuated BOLD signal in the prefrontal cortex to fearful, sad, angry and happy facial expressions and an attenuated signal in the anterior cingulate cortex to happy and fearful facial expressions. No differences were found in amygdala response.

In contrast with previous research, this study found BOLD signal attenuation in the ventrolateral and medial prefrontal cortex and the anterior cingulate cortex during face emotion processing, consistent with a hypothesis of hypo-responsivity to external emotional stimuli in GAD. These decreases were in areas that have been implicated in emotion and cognition and may reflect an altered balance between internally and externally directed attentional processes.

Drug-related stimuli reliably induce craving in experimental paradigms, yet are rarely cited by drug users as major precipitants of relapse. We examined the motivational significance of drug cues in opiate dependence, by exploring their impact on central attentional processes.

Fourteen methadone-maintained subjects and 14 matched controls were studied. Subjects performed a novel active visual oddball task, consisting of opiate-related and matched neutral pictures, some of which (the oddballs) included a white cup. Subjects were fitted with a 32-channel electrode cap. The P300 for each stimulus category was identified using temporal principal components analysis.

The P300 elicited by opiate stimuli was significantly larger than that elicited by neutral stimuli in the methadone-maintained group but not in the controls. There was also a non-significant trend for the opiate stimuli to elicit larger P300s than the oddball stimuli in the addicted group.

These results suggest that drug cues acquire motivational salience and automatically capture attentional resources in opiate addicts, even when engaged in a non-drug-related task. Enhanced P300s to drug cues may provide an important biological marker of crucial psychological mechanisms relevant to addiction.