Stephen Cooper

The cardiovascular and respiratory health of people with schizophrenia

Objective:  To examine the cardiovascular and respiratory health of people with severe mental illness (SMI) and compare findings with the Health Surveys for England.

5-hydroxyindoleacetic acid in cerebrospinal fluid and prediction of suicidal behaviour in schizophrenia

Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) are associated with suicidal behaviour in patients with depressive illness, but studies of the relation between CSF 5-HIAA and suicide in schizophrenia have been inconclusive and have not included long-term follow-up. In a prospective study, we measured 5-HIAA in CSF taken from 30 schizophrenic patients in a drug-free state, and followed these patients for 11 years. 10 patients made suicide attempts during follow-up. Suicide attempters had significantly lower concentrations of CSF 5-HIAA at initial evaluation than non-attempters (mean [SE] 6.7 [2.2] vs 23.6 [5.6] ng/ml, p < 0.05). Our findings provide further evidence of the relation between serotoninergic dysfunction and suicide, and suggest a role for drugs with serotoninergic effects in schizophrenia.

Impact of persistent substance misuse on 1-year outcome in first-episode psychosis

BACKGROUND Substance misuse is a common comorbid problem in people presenting with first-episode psychosis and is associated with a poor short-term outcome. AIMS The aim of this study is to examine differences in baseline characteristics and 1-year outcome between individuals with first-episode psychosis who have never misused substances, those who stop misusing substances after initial presentation and those who persistently misuse substances over the 1-year assessment period. METHOD Patients were recruited to the Northern Ireland First Episode Psychosis Study (n = 272). Clinical assessments were performed at baseline and at 1 year (n = 194) and data were collected from the case notes. RESULTS Individuals with persistent substance misuse had more severe depression, more positive symptoms, poorer functional outcome and greater rates of relapse at 1 year than those who stopped and those who had never misused substances. There were no differences in outcome between people who had never misused substances and those who stopped misusing after presentation. CONCLUSIONS These results support assertive intervention targeted at comorbid substance misuse in individuals with first-episode psychosis.

Acute and chronic tryptophan depletion differentially regulate central 5-HT1A and 5-HT2A receptor binding in the rat

RationaleTryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized.ObjectiveThe aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan (TRP), central TRP and 5-HT and brain 5-HT1A and 5-HT2A receptor binding in the rat.MethodsTRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand binding and in-vitro receptor autoradiography.ResultsFree-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD compared to controls. ATD significantly reduced 5-HT1A binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT1A binding (frontal cortex, remaining cortex and hippocampus) or 5-HT2A binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT2A binding or postsynaptic 5-HT1A binding. Furthermore, 3-week CTD did not significantly alter 5-HT1A binding but significantly increased cortical 5-HT2A binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT2A-receptor binding.ConclusionATD-induced reduction in somatodendritic 5-HT1A autoreceptor binding may represent an intrinsic ‘homeostatic response’ reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT2A receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.

Influence of 5-HT2C receptor and leptin gene polymorphisms, smoking and drug treatment on metabolic disturbances in patients with schizophrenia.

BACKGROUND Obesity and metabolic syndrome are significant problems for patients taking antipsychotic drugs. Evidence is emerging of genetic risk factors. AIMS To investigate the influence of two candidate genes, smoking and drug treatment on obesity and metabolic syndrome in patients with schizophrenia. METHOD Patients (n=134) were assessed for measures of obesity, other factors contributing to metabolic syndrome, and two genetic polymorphisms (5-HT(2C) receptor -759C/T and leptin -2548A/G). RESULTS Neither genotype nor smoking was significantly associated with measures of obesity. However, both leptin genotype and smoking were significantly associated with metabolic syndrome. Significant interaction occurred between the genetic polymorphisms for effects on obesity, whereby a genotype combination increased risk. Drug treatment showed significant effects on measures of obesity and triglyceride concentrations; risperidone was associated with lower values than olanzapine or clozapine. CONCLUSIONS The findings suggest interacting genetic risk factors and smoking influence development of metabolic syndrome in patients on antipsychotic drugs.

The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland.

Low plasma folate and its derivatives have been linked with depressive disorders in studies dating back over 30 years. A thermolabile variant (677C>T) of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with low serum folate. The present study aimed to explore whether the thermolabile variant of MTHFR is associated with a vulnerability to depressive episodes. MTHFR C677T genotype frequencies in a cohort of patients (mean age 48 years) with depressive disorder (n = 100) were compared with those in age- and sex-matched controls. Serum levels of folate, homocysteine and vitamin B12 were also compared between groups. The thermolabile variant of MTHFR was significantly more common in the group with a history of depressive disorder (P= 0.03). Serum levels of folate, homocysteine and vitamin B12 did not differ significantly between groups. A MTHFR C677T genotype is associated with increased risk of depressive episodes in this homogenous patient population.

Anomalies of cerebral asymmetry in schizophrenia interact with gender and age of onset: a post-mortem study

In a post-mortem study of cerebral asymmetry in schizophrenia it was found that asymmetry of the length from the frontal pole to the central sulcus measured dorsally over the external surface of the brain on both hemispheres, showed a gender x diagnosis interaction (p = 0.002). Female controls had a left-greater-than-right asymmetry, and the male controls had a right-greater-than-left asymmetry. This pattern was reversed in schizophrenia. The converse effect was observed on a similar measure of the occipito-parietal lobes (p = 0.028). Significant changes were not seen in measures taken around the lateral surface of the hemispheres. Further, within the patient group, the frontal lobe asymmetry was related to age of onset such that leftward asymmetrical brains were associated with a later age of onset than rightward asymmetrical brains (p = 0.0463 for the females; p = 0.0162 for the males). The occipito-parietal asymmetry was not related to age of onset. We conclude that the asymmetry of the relative distribution of tissue between frontal and posterior regions of the hemispheres is altered in schizophrenia. The findings also suggest that there is an interaction between gender and cerebral asymmetry that is critical in determining age of onset.

Risk of postnatal depression after emergency delivery

Aim:  To identify whether women having emergency delivery are at increased risk of developing postnatal depression (PND).

Anterior cingulate and subgenual prefrontal blood flow changes following tryptophan depletion in healthy males.

In healthy humans, there is an apparent dissociation between cognitive and affective consequences of reduced brain serotonin (5-HT), as rapid tryptophan depletion (RTD) causes alterations in a consistent constellation of cognitive processes in the general absence of mood deterioration. This study aimed to investigate possible neural mechanisms underlying this relative dissociation by measuring the effects of reduced 5-HT on regional cerebral blood flow (rCBF). A total of 16 healthy, euthymic male subjects (mean age 39±9 years) without a personal or family history of affective disorder had mood ratings and single photon emission computed tomography scans with the rCBF tracer 99mTc-HMPAO under reduced 5-HT (RTD) and control conditions. Across individuals, modest positive and negative changes in subjective happiness associated with RTD were significantly correlated with change of rCBF in a cluster comprising subgenual (affective) anterior cingulate cortex (ACC) and associated regions (Brodmanns area (BA) 25, posterior BA11 and 47, caudate nucleus and ventral striatum; SPM99 p<0.05, corrected). The covariation was such that increasing sadness was associated with increased rCBF and vice versa. Independent of mood change, RTD was associated with reduced rCBF in the dorsal (cognitive) ACC (BA32; SPM99 p<0.05, corrected). The subgenual prefrontal cortex and dorsal ACC are important components of the ventral and dorsal neural systems that regulate and integrate affective and cognitive functions. The results therefore suggest that the dissociation between affective and cognitive consequences of RTD may possibly be attributable to differential effects of reduced 5-HT on these neural systems.

Childhood Trauma and Hippocampal and Amygdalar Volumes in First-Episode Psychosis

OBJECTIVE A history of childhood trauma is common in individuals who later develop psychosis. Similar neuroanatomical abnormalities are observed in people who have been exposed to childhood trauma and people with psychosis. However, the relationship between childhood trauma and such abnormalities in psychosis has not been investigated. This study aimed to explore the association between the experience of childhood trauma and hippocampal and amygdalar volumes in a first-episode psychosis (FEP) population. METHODS The study employed an observational retrospective design. Twenty-one individuals, who had previously undergone magnetic resonance imaging procedures as part of the longitudinal Northern Ireland First-Episode Psychosis Study, completed measures assessing traumatic experiences and were included in the analysis. Data were subject to correlation analyses (r and r (pb)). Potential confounding variables (age at FEP and delay to scan from recruitment) were selected a priori for inclusion in multiple regression analyses. RESULTS There was a high prevalence of lifetime (95%) and childhood (76%) trauma in the sample. The experience of childhood trauma was a significant predictor of left hippocampal volume, although age at FEP also significantly contributed to this model. There was no significant association between predictor variables and right hippocampal volume. The experience of childhood trauma was a significant predictor of right and total amygdalar volumes and the hippocampal/amygdalar complex volume as a whole. CONCLUSIONS The findings indicate that childhood trauma is associated with neuroanatomical measures in FEP. Future research controlling for childhood traumatic experiences may contribute to explaining brain morphology in people with psychosis.