J.F.W. Deakin

Response inhibition and impulsivity: an fMRI study

Aggressive, suicidal and violent behaviour have been associated with impulsive personality and difficulty in inhibiting responses. We used functional magnetic resonance imaging (fMRI) of the whole brain to examine the neural correlates of response inhibition in 19 normal subjects as they performed a Go/NoGo task. Subjects completed Eysencks Impulsivity Scale, Barratts Impulsivity Scale (BIS) and behavioural impulsivity tasks. Associations between blood oxygen level dependent (BOLD) response, trait impulsivity, task performance and National Adult Reading Test (NART) IQ were investigated. Neural response during response inhibition was most prominent in the right lateral orbitofrontal cortex. Responses were also seen in superior temporal gyrus, medial orbitofrontal cortex, cingulate gyrus, and inferior parietal lobule, predominantly on the right side. Subjects with greater scores on impulsivity scales and who made more errors had greater activation of paralimbic areas during response inhibition, while less impulsive individuals and those with least errors activated higher order association areas. Exploratory factor analysis of orbital activations, personality measures and errors of commission did not reveal a unitary dimension of impulsivity. However, the strong association between posterior orbital activation and Eysencks impulsivity score on a single factor suggests that greater engagement of right orbitofrontal cortex was needed to maintain behavioural inhibition in impulsive individuals. Lower IQ was more important than impulsivity scores in determining errors of commission during the task. Neuroimaging of brain activity during the Go/NoGo task may be useful in understanding the functional neuroanatomy and associated neurochemistry of response inhibition. It may also allow study of the effects of physical and psychological interventions on response inhibition in clinical conditions such as antisocial personality disorder.

Neuronal effects of acute citalopram detected by pharmacoMRI

RationaleSerotonin (5-hydroxytryptamine, 5-HT) is implicated in the aetiology and treatment of a variety of psychiatric disorders. A limitation of research has been the necessity to use indirect measures of 5-HT function.MethodWe describe a method of analysing pharmacoMRI data using SPM and apply it to the direct i.v. infusion of selective 5-HT reuptake inhibitor, citalopram, in 12 healthy volunteers. Scanning took place on a 1.5-T Philips MRI scanner.ResultsAreas implicated in depression and its treatment were observed to have increasing signal with respect to time. These areas included the caudate, the amygdala, the hippocampus, the striatum and the thalamus.ConclusionDirect pMRI using i.v. citalopram opens new ways of investigating 5-HT mechanism in depression and its treatment.

EPA-0380 – Effects of agomelatine and escitalopram on emotional detachment, emotional processing and motivation during a 9-week treatment in healthy volunteers

Dysfunctions of the emotion processing circuitry are associated with Major Depressive Disorder (MDD) and can be modulated by antidepressants like selective serotonin reuptake inhibitors (SSRIs). Moreover, motivation, pleasure or interest are important neuropsychological states of emotional life, and are known to be impaired in MDD patients. Under SSRIs, some patients report decreases in motivation and/or in emotional responsiveness commonly described as emotional detachment (Corruble E et al , 2013) and having significant impact on drug compliance and quality of life. The antidepressant agomelatine displays a unique neurochemical profile, different from SSRIs, being a MT1/MT2 receptors agonist and a 5HT2C receptors antagonist (De Bodinat C et al , 2010). Data from healthy volunteers and patients suggest that agomelatine is associated with less emotional detachment as compared to SSRIs notably with a more specific action in the facial expression recognition task (Harmer CJ et al , 2011), lower scores on scales for blunting (Corruble E et al , 2013), and absence of sexual dysfunction (Montejo AL et al , 2010). Here, the effects of two antidepressants, agomelatine (25 and 50mg) and escitalopram (10–20mg) on emotional detachment, emotional processing, motivation and sexual function were assessed during a 9-week randomised, double-blind, placebo-controlled, parallel-designed study in healthy male and female volunteers aged between 18-45 years. A battery of neuropsychological and motivation tasks/questionnaires available in the literature were used. Investigating antidepressant effects on key psychological processes in healthy volunteers allows elucidation of the direct actions of antidepressants unconfounded by changes in mood symptoms. The study is on progress.

Therapeutic Trials of Minocycline, Ondansetron and Simvastatin in Schizophrenia

Objectives 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. Aims 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. Methods 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. Results 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. Conclusions 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.

EPA-1435 - Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: Pilot study

Objectives 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. Methods 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. Results 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. Conclusions 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.

EPA-0931 - Acute ketamine challenge effects on visual information processing: implications for psychosis

Introduction Ketamine, a NMDA antagonist, replicates both cognitive and psychotic features of schizophrenia when administered to healthy volunteers. In this study, we aimed to test whether the administration of IV ketamine would replicate with cognitive and electrophysiological patterns that was observed in schizophrenia patients and schizotypal individuals. Methtods 44 healthy volunteers were randomised to receive IV infusion of ketamine or placebo. A 64 channel EEG kit was used to obtain eventrelated potentials in response to a working memory (WM) task. The two groups were compared in respect to their performance task as well as the amplitude of the P1 and P300 ERPs. Results The psychiatric scales scores (BPRS, CADSS) were significantly increased in the ketamine group when compared to saline. While there was no difference in terms of reaction times to the task, accuracy in the ketamine group worsened significantly with increase in working memory load than in controls. Ketamine significantly increased the P1 but lead to a decrease in P300. Conclusion In this study acute NMDA antagonism induced a WM deficit that was associated with visual processing and memory abnormalities. Specifically, ketamine increased the amplitude of the P1 potential and reduced the P300 amplitude. In addition P1 but not P300 predicted performance on the WM task. These effects could be mediated ketamine-induced acute glutamate release in the visual cortex, enhancing neuronal responses to visual stimuli and increasing the signal-to-noise ratio which in turn disrupted higher order cognitive function.

PW01-19 - Rumination is influenced by a genetic interaction between GIRK2 receptor and CREB in two independent European samples

Objectives 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. Methods 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. Results 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 (p Budapest =0.00099; p Manchester =0.0027). Homozygous TT individuals for rs2070995 in interaction with homozygous GG for rs2253206 scored significantly higher on RRS compared with other genotypes. Conclusion 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.