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Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume.
A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, ‘at risk mental state’ or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry.
We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance).
Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.
The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of in vivo dopamine synthesis and release, and putative synaptic levels.
We focused on the role of dopamine postsynaptic regulation using [123I] iodobenzamide (IBZM) SPECT. We compared D2/3 receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia.
The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI −0.11 to 0.11; F = 0.00, df = 1, 69; p = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = −0.01(binding ratio); 95% CI −0.01 to −0.004; F = 11.5, df = 1, 69; p = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores.
Medication-naïve patients with recent-onset schizophrenia have similar D2/3 receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release.
In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing.
This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).
A statistical model, which described the concentration–time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.
The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann–Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.
Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
While recent research points to the potential benefits of clinical intervention before the first episode of psychosis, the logistical feasibility of this is unclear.
To assess the feasibility of providing a clinical service for people with prodromal symptoms in an inner city area where engagement with mental health services is generally poor.
Following a period of liaison with local agencies to promote the service, referrals were assessed and managed in a primary care setting. Activity of the service was audited over 30 months.
People with prodromal symptoms were referred by a range of community agencies and seen at their local primary care physician practice. Over 30 months, 180 clients were referred; 58 (32.2%) met criteria for an at risk mental state, most of whom (67.2%) had attenuated psychotic symptoms. Almost 30% were excluded due to current or previous psychotic illness, of which two-thirds were in the first episode of psychosis. The socio-demographic composition of the 'at risk' group reflected that of the local population, with an over-representation of clients from an ethnic minority. Over 90% of suitable clients remained engaged with the service after 1 year.
It is feasible to provide a clinical service for people with prodromal symptoms in a deprived inner city area with a large ethnic minority population.
There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.
To investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.
Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.
Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.
Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.
Declaration of interest
R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.
Subtle abnormalities in frontal white matter have been reported in
To assess whether impaired integrity of white matter tracts is associated
with bipolar disorder and genetic liability for the disorder.
A total of 19 patients with psychotic bipolar I disorder from multiply
affected families, 21 unaffected first-degree relatives and 18 comparison
individuals (controls) underwent diffusion tensor imaging. Whole brain
voxel-based analyses compared fractional anisotropy between patients and
relatives with controls, and its relationship with a quantitative measure
of genetic liability.
Patients had decreased fractional anisotropy compared with controls in
the genu of the corpus callosum, right inferior longitudinal fasciculus
and left superior longitudinal fasciculus. Increased genetic liability
for bipolar disorder was associated with reduced fractional anisotropy
across distributed regions of white matter in patients and their
Disturbed structural integrity within key intra- and interhemispheric
tracts characterises both bipolar disorder and genetic liability for this
We analysed Stroop (neuropsychological screening test) measures of response
inhibition in 18 twin pairs discordant for bipolar I disorder compared with
17 healthy control pairs, as well as 40 singletons with bipolar disorder
with psychotic features and a family history of psychosis, 46 of their
first-degree relatives without bipolar disorder or psychosis and 48
controls. In both studies, individuals with bipolar disorder showed Stroop
deficits and their first-degree relatives showed intact performance. In the
twin patients, an interference score was associated with depressive
symptoms. Having a first-degree relative with bipolar disorder, even a
familial, psychotic form, did not confer risk for enhanced susceptibility to
interference in our studies.
People with prodromal symptoms have a very high risk of developing psychosis.
To use functional magnetic resonance imaging to examine the neurocognitive basis of this vulnerability.
Cross-sectional comparison of regional activation in individuals with an ‘at-risk mental state’ (at-risk group: n=17), patients with first-episode schizophreniform psychosis (psychosis group: n=10) and healthy volunteers (controls: n=15) during an overt verbal fluency task and an N-back working memory task.
A similar pattern of between-group differences in activation was evident across both tasks. Activation in the at-risk group was intermediate relative to that in controls and the psychosis group in the inferior frontal and anterior cingulate cortex during the verbal fluency task and in the inferior frontal, dorsolateral prefrontal and parietal cortex during the N-back task.
The at-risk mental state is associated with abnormalities of regional brain function that are qualitatively similar to, but less severe than, those in patients who have recently presented with psychosis.
We assessed premorbid functioning during childhood and adolescence in 50 people with schizophrenia from multiply affected families, 39 of their unaffected siblings, 69 people with schizophrenia with no family history of psychosis, 67 of their unaffected siblings and 83 controls. People with schizophrenia had poorer premorbid social and academic adjustment and exhibited a decline between childhood and adolescence compared with controls. Unaffected siblings from multiply affected families also had poor academic functioning in adolescence, with a decline between childhood and adolescence. This may represent a familial (presumed genetic) effect.
Background. Electrophysiological endophenotypes are far less explored in bipolar disorder as compared to schizophrenia. No previous twin study of event-related potentials (ERPs) in bipolar illness has been reported. This study uses a twin design and advanced genetic model fitting analyses aiming to (1) assess and quantify the relationship of a range of ERP components with bipolar disorder with psychotic features, and (2) examine the source of the relationship (due to genetic or environmental factors).
Method. P300, P50 suppression and mismatch negativity (MMN) were recorded in 10 discordant monozygotic (MZ) bipolar twin pairs, six concordant MZ bipolar twin pairs and 78 control twin pairs. Statistical analyses were based on structural equation modelling.
Results. Bipolar disorder was significantly associated with smaller P300 amplitude and decreased P50 suppression. Genetic correlations were the main source of the associations, estimated to be −0·33 for P300 amplitude and 0·46 for P50 ratio. Individual-specific environmental influences were not significant. MMN and P300 latency were not associated with the illness.
Conclusions. The results provide supporting evidence that P300 amplitude and P50 suppression ratio are ERP endophenotypes for bipolar disorder.
Dimensional structures are established for many psychiatric diagnoses, but dimensions have not been compared between diagnostic groups.
To examine the structure of dimensions in psychosis, to analyse their correlations with disease characteristics and to assess the relative contribution of dimensions v. diagnosis in explaining these characteristics.
Factor analysis of the OPCRIT items of 191 Maudsley Family Study patients with schizophrenia, mood disorders with psychosis, schizoaffective disorder, and other psychotic illnesses, followed by regression of disease characteristics from factor scores and diagnosis.
Five factors were identified (mania, reality distortion, depression, disorganisation, negative); all were more variable in schizophrenia than in affective psychosis. Mania was the best discriminator between schizophrenia and affective psychosis; the negative factor was strongly correlated with poor premorbid functioning, insidious onset and worse course. Dimensions explained more of the disease characteristics than did diagnosis, but the explanatory power of the latter was also high.
Kraepelinian diagnostic categories suffice for understanding illness characteristics, but the use of dimensions adds substantial information.
Aunque la investigatión recieñte senala los beneficios potenciales de la interventión clínica antes del primer episodio de psicosis, la viabilidad logística de esto no esta clara.
Evaluar la viabilidad de proporcionar un servicio clínico para personas con síntomas prodrómicos en un área urbana deprimida donde el compromiso con los servicios de salud mental es malo por lo general.
Después de un periodo de enlace con agencias locales para promover el servicio, se evaluó y trató las derivaciones en un entomo de atención primaria. La actividad del servicio se auditó durante 30 meses.
Diversas agencias comunitarias derivaron a las personas con síntomas prodrómicos. Se vio a estas personas en la consulta de su médico de atención primaria local. Durante 30 meses, derivaron a 180 clientes; 50 (32,%) cumplían los criterios para estado mental de riesgo, teniendo la mayoría de ellos (67,2%) síntomas psicóticos atenuados. Se excluyó casi al 30% debido a enfermedad psicótica actual o anterior; dos tercios de ellos estaban en el primer episodio de psicosis. La compositión sociodemográfica del grupo “en situation de riesgo” reflejaba la de la población local, con una sobre-representación de clientes de una minoría étnica. Más del 90% de los clients apropiados mantenía el compromiso con el servicio después de 1 año.
Es posible proporcionar un servicio clínico para personas con síntomas pródromicos en un área urbana deprimida deficitaria con una gran población de minoría ertnica.
We report cognitive performance of a group of individuals who are likely to have transmitted liability to psychosis to their offspring. Out of 230 relatives of patients with psychosis, 27 met our criteria for a presumed obligate carrier, that is a non-psychotic individual who had a parent or a sibling as well as an offspring with psychosis. The presumed obligate carriers showed impairments in verbal memory and in visuospatial manipulations, suggesting that these individuals transmit vulnerability for psychosis to their offspring in terms of a disability to recall verbal information and an impaired capacity to perceive spatial relations.
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