Needs of forensic psychiatric patients with schizophrenia in five European countries.

AIMS: The purpose was to compare the frequency of needs of patients with schizophrenia in forensic services across five European countries as assessed by both the patients and their care staff. METHODS: Patients with schizophrenia and a history of significant interpersonal violence were recruited from forensic psychiatric services in Austria, Germany, Italy, Poland and England. Participants' needs were assessed using the Camberwell Assessment of Needs-Forensic Version (CANFOR). Multiple linear regression analyses were used to identify predictors of numbers of needs. RESULTS: In this sample, (n = 221) the most commonly reported need according to patients (71.0%) and staff (82.8%) was the management of psychotic symptoms. A need for information was mentioned by about 45% of staff and patients. Staff members reported a significantly higher number of total needs than patients (mean 6.9 vs. 6.2). In contrast, staff members reported a significantly lower number of unmet needs than patients (mean 2.0 vs. 2.5). Numbers of total needs and met needs differed between countries. Unmet needs as reported by patients showed positive associations with the absence of comorbid personality disorder, with higher positive symptom scores and lifetime suicide or self-harm history. Significant predictors of unmet needs according to staff were absence of comorbid personality disorder and higher positive as well as negative symptom scores according to PANSS. CONCLUSIONS: Staff rated a significantly higher number of total needs than patients, while patients rated more unmet needs. This indicates that patients' self-assessments of needs yield important information for providing sufficient help and support.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

BACKGROUND: A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. METHODS: This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. RESULTS: The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. CONCLUSIONS: The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort.

In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.

Predictive validity of the HCR-20 for inpatient aggression: the effect of intellectual disability on accuracy.

BACKGROUND: People with intellectual disability (ID) account for a large proportion of aggressive incidents in secure and forensic psychiatric services. Although the Historical, Clinical, Risk Management 20 (HCR-20) has good predictive validity in inpatient settings, it does not perform equally in all groups and there is little evidence for its efficacy in those with ID. METHOD: A pseudo-prospective cohort study of the predictive efficacy of the HCR-20 for those with ID (n = 109) was conducted in a UK secure mental health setting using routinely collected risk data. Performance of the HCR-20 in the ID group was compared with a comparison group of adult inpatients without an ID (n = 504). Analysis controlled for potential covariates including security level, length of stay, gender and diagnosis. RESULTS: The HCR-20 total score was a significant predictor of any aggression and of physical aggression for both groups, although the area under the curve values did not reach the threshold for a large effect size. The clinical subscale performed significantly better in those without an ID compared with those with. The ID group had a greater number of relevant historical and risk management items. The clinicians' summary judgment significantly predicted both types of aggressive outcomes in the ID group, but did not predict either in those without an ID. CONCLUSIONS: This study demonstrates that, after controlling for a range of potential covariates, the HCR-20 is a significant predictor of inpatient aggression in people with an ID and performs as well as for a comparison group of mentally disordered individuals without ID. The potency of HCR-20 subscales and items varied between the ID and comparison groups suggesting important target areas for improved prediction and risk management interventions in those with ID.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Striatal dopamine synthesis capacity in twins discordant for schizophrenia.

BACKGROUND: Elevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia. METHOD: In vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs. RESULTS: Striatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic. CONCLUSIONS: Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.

Genetic overlap between episodic memory deficits and schizophrenia: results from the Maudsley Twin Study.

BACKGROUND: Visual and verbal episodic memory deficits are putative endophenotypes for schizophrenia; however, the extent of any genetic overlap of these with schizophrenia is unclear. In this study, we set out to quantify the genetic and environmental contributions to variance in visual and verbal memory performance, and to quantify their genetic relationship with schizophrenia. METHOD: We applied bivariate genetic modelling to 280 twins in a classic twin study design, including monozygotic (MZ) and dizygotic (DZ) pairs concordant and discordant for schizophrenia, and healthy control twins. We assessed episodic memory using subtests of the Wechsler Memory Scale - Revised (WMS-R). RESULTS: Genetic influences (i.e. heritability) contributed significantly to variance in immediate recall of both verbal memory and visual learning, and the delayed recall of verbal and visual memory. Liability to schizophrenia was associated with memory impairment, with evidence of significant phenotypic correlations between all episodic memory measures and schizophrenia. Genetic factors were the main source of the phenotypic correlations for immediate recall of visual learning material; both immediate and delayed recall of verbal memory; and delayed recall of visual memory that, for example, shared genetic variance with schizophrenia, which accounted for 88% of the phenotypic correlation (rph=0.41) between the two. CONCLUSIONS: Verbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition. The inclusion of these endophenotypes in genetic association studies may improve the power to detect susceptibility genes for schizophrenia.

Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis?

BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.

A functional MRI study of verbal fluency in adults with bipolar disorder and their unaffected relatives.

BACKGROUND: Individuals with a history of bipolar disorder demonstrate abnormalities of executive function, even during euthymia. The neural architecture underlying this and its relationship with genetic susceptibility for illness remain unclear. METHOD: We assessed 18 remitted individuals with bipolar disorder, 19 of their unaffected first degree relatives and 19 healthy controls using functional magnetic resonance imaging (fMRI) and a paced verbal fluency task with two levels of difficulty. RESULTS: Bipolar patients made significantly more errors in the easy level of the verbal fluency task than their relatives or controls. Analysis of variance of fMRI data demonstrated a significant main effect of group in a large cluster including retrosplenial cortex and adjacent precuneate cortex (x=7, y=-56, x=15). All three groups showed deactivation in these areas during task performance relative to a neutral or rest condition. Group differences comprised a lesser amount of deactivation in unaffected relatives compared with controls in the easy condition [F(2, 55)=3.42, p=0.04] and in unaffected relatives compared with bipolar patients in the hard condition [F(2, 55)=4.34, p=0.018]. Comparison with the control group indicated that both bipolar patients and their relatives showed similar deficits of deactivation in retrosplenial cortex and reduced activation of left prefrontal cortex. CONCLUSIONS: Bipolar disorder may be associated with an inherited abnormality of a neural network incorporating left prefrontal cortex and bilateral retrosplenial cortex.

Genetic modelling of childhood social development and personality in twins and siblings with schizophrenia.

BACKGROUND: Abnormalities in early social development and personality are present in patients with schizophrenia and their unaffected relatives. This study aimed to establish the degree to which these childhood and adolescent developmental abnormalities are genetically determined. METHOD: We used a combined twin and family study design (n=531) to assess childhood and adolescent social adjustment and schizotypal personality traits in 98 twin pairs (n=196) varying in their zygosity and concordance for schizophrenia and 156 sibling clusters (n=335) varying in their concordance for schizophrenia. RESULTS: Schizophrenia was significantly associated with childhood and adolescent deficits in social adjustment and personality, with additive genetic effects being the main source of these phenotypic correlations. CONCLUSIONS: Abnormalities of social adjustment and personality are present in children and adolescents who later develop schizophrenia, reflecting the influence of common genetic risk.

Altered connections on the road to psychopathy.

Psychopathy is strongly associated with serious criminal behaviour (for example, rape and murder) and recidivism. However, the biological basis of psychopathy remains poorly understood. Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of > or = 25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003), an indirect measure of microstructural integrity, in the UF of psychopaths compared with age- and IQ-matched controls. We also found, within psychopaths, a correlation between measures of antisocial behaviour and anatomical differences in the UF. To confirm that these findings were specific to the limbic amygdala-OFC network, we also studied two 'non-limbic' control tracts connecting the posterior visual and auditory areas to the amygdala and the OFC, and found no significant between-group differences. Lastly, to determine that our findings in UF could not be totally explained by non-specific confounds, we carried out a post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala-OFC limbic network underpin the neurobiological basis of psychopathy.

Twins discordant for schizophrenia: psychopathology of the non-schizophrenic co-twins.

OBJECTIVE: Patients with schizophrenia are more likely to suffer from mood and anxiety disorders compared with the general population. We explored the aetiology of this comorbidity using a twin study design. METHOD: We applied an additive genetic + unique environment (AE) random effects model in the analysis of 35 non-schizophrenic co-twins from pairs discordant for schizophrenia, and 131 control twins. RESULTS: Non-schizophrenic co-twins had significantly increased rates of depression (P = 0.006) and anxiety disorders (P = 0.021) compared with the control twins. CONCLUSION: Our results provide evidence for a familial association between schizophrenia and anxiety and depression. This could reflect common aetiological factors contributing to each of the disorders. Future studies should attempt to investigate the relative genetic and environmental contribution to the shared risk factors for schizophrenia, mood and anxiety disorders.

The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

No association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder.

The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.

The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women.

Women have an increased risk of developing Alzheimer's Dementia (AD) compared to men. It has been postulated that this risk may be modulated by a reduction in the neuroprotective effects of estrogen on the brain in the early postmenopausal period. This view is supported by, for example, findings that ovariectomy in younger women (i.e. prior to menopause) significantly increases the risk for the development of memory problems and AD in later life. However, the biological basis underlying these cognitive changes is still poorly understood. Our aim in the current study was to understand the interactive effects of acute, pharmacological-induced menopause (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD) on brain functioning. To this end we used fMRI to study encoding during a Delayed Match to Sample (DMTS) (visual working memory) task. We report a relative attenuation in BOLD response brought about by scopolamine in regions that included bilateral prefrontal cortex and the left parahippocampal gyrus. Further, this was greater in women post-GnRHa than in women whose ovaries were functional. Our results also indicate that following pharmacological-induced menopause, cholinergic depletion produces a more significant behavioural deficit in overall memory performance, as manifest by increased response time. These findings suggest that acute loss of ovarian hormones exacerbate the effects of cholinergic depletion on a memory-related, behavioural measure, which is dependent on fronto-temporal brain regions. Overall, our findings point to a neural network by which acute loss of ovarian function may interact to negatively impact encoding.

Brain MRI abnormalities in schizophrenia: same genes or same environment?

BACKGROUND: Structural brain volume abnormalities are among the most extensively studied endophenotypes in schizophrenia. Bivariate genetic model fitting (adjusted to account for selection) was used to quantify the genetic relationship between schizophrenia and brain volumes and to estimate the heritability of these volumes. METHOD: We demonstrated by simulation that the adjusted genetic model produced unbiased estimates for endophenotype heritability and the genetic and environmental correlations. The model was applied to brain volumes (whole brain, hippocampus, third and lateral ventricles) in a sample of 14 monozygotic (MZ) twin pairs concordant for schizophrenia, 10 MZ discordant pairs, 17 MZ control pairs, 22 discordant sibling pairs, three concordant sibling pairs, and 114 healthy control subjects. RESULTS: Whole brain showed a substantial heritability (88%) and lateral ventricles substantial common environmental effects (67%). Whole brain showed a significant genetic correlation with schizophrenia, whereas lateral ventricles showed a significant individual specific correlation with schizophrenia. There were significant familial effects for hippocampus and third ventricle, but the analyses could not resolve whether these were genetic or environmental in origin (around 30%each). CONCLUSIONS: Using genetic model fitting on twin and sibling data we have demonstrated differential sources of covariation between schizophrenia and brain volumes, genetic in the case of whole brain volume and individual specific environment in the case of lateral ventricles.