Service users taking long-acting injectable antipsychotics (LIAs) may experience recurrence of symptoms as they approach trough levels within a steady-state cycle. Limited research exists around symptom variation between peak-to-trough plasma concentrations of LIA inter-dose intervals. Different LIAs have variable rates of change in dopamine receptor occupancy during this peak-to-trough variation due to differing elimination half-lifes. It is unclear what rate of change in D2 blockade is tolerated by patients at present, which this trial aims to determine through observing symptom severity differences during peak-to-trough variation.

A real-world observational longitudinal cohort study is proposed. Inclusion criteria would be working-age adults (18–65 years) who have received five consecutive and timely LIA administrations of a consistent drug and dose. The study would exclude anyone with significant hepatic or renal impairment, anyone on concurrent oral antipsychotic medication or anyone deemed not to yet be within steady-state plasma levels of their LIA medication.

Serum assays for drug level will be obtained at both peak and trough concentrations during an LIA cycle. Expected timings for peak levels will be determined by derived tmax values from existing pharmacokinetic literature for individual drugs. Trough levels will be taken within 24 hours of the next LIA administration being due. Plasma drug concentrations will then be used to calculate expected striatal D2 blockade using EC50 values and maximal occupancy for individual drugs derived from existing PET scan data.

Symptom severity will be assessed by completing Positive and Negative Symptom Scores (PANSS) questionnaires with service users at the time of both peak and trough plasma concentrations of LIA. The difference in these scores will then be plotted alongside the difference in expected D2 blockade derived from plasma drug concentrations.

We hypothesize that the rate of D2 occupancy change would correlate with symptom severity differences in an exponential manner, in that drugs with shorter elimination half-life would have greater difference in symptom severity between peak and trough. We expect that service users would be able to tolerate such change to a degree without significant emergence of symptoms; the trial aims to determine the threshold for what most service users can tolerate, which may then assist in guiding how to effectively reduce and discontinue medications.

This outlines a research protocol to monitor response to pharmacokinetic variation within inter-dose intervals of LIA medication, which may ultimately aid service users in reducing and discontinuing antipsychotics.

Psychotic experiences and negative symptoms (PENS) are common in non-clinical populations. PENS are associated with adverse outcomes, particularly when they persist. Little is known about the trajectories of PENS dimensions in young people, nor about the precursory factors associated with these trajectories.

We conducted growth mixture modelling of paranoia, hallucinations, and negative symptoms across ages 16, 17, and 22 in a community sample (N = 12 049–12 652). We then described the emergent trajectory classes through their associations with genome-wide polygenic scores (GPS) for psychiatric and educational phenotypes, and earlier childhood characteristics.

Three trajectory classes emerged for paranoia, two for hallucinations, and two for negative symptoms. Across PENS, GPS for clinical help-seeking, major depressive disorder, and attention deficit hyperactivity disorder were associated with increased odds of being in the most elevated trajectory class (OR 1.07–1.23). Lower education GPS was associated with the most elevated trajectory class for hallucinations and negative symptoms (OR 0.77–0.91). Conversely for paranoia, higher education GPS was associated with the most elevated trajectory class (OR 1.25). Trajectory class associations were not significant for schizophrenia, obsessive-compulsive disorder, bipolar disorder, or anorexia GPS. Emotional/behaviour problems and life events in childhood were associated with increased odds of being in the most elevated trajectory class across PENS.

Our results suggest latent heterogeneity in the development of paranoia, hallucinations, and negative symptoms in young people that is associated with specific polygenic scores and childhood characteristics.

Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22–31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging.

We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal–Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational.

Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex.

In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.

Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.

We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.

In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14–0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = −0.22; 95% CI −0.37 to −0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.

Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Stressful life events (SLEs) are associated with psychotic experiences. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences.

To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences.

Self- and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting.

SLEs correlated with positive psychotic experiences (r = 0.12–0.14, all P<0.001). Modest heritability was shown for psychotic experiences (25–57%) and dependent SLEs (32%). Genetic influences explained the majority of the modest covariation between dependent SLEs and paranoia and cognitive disorganisation (bivariate heritabilities 74–86%). The relationship between SLEs and hallucinations and grandiosity was explained by both genetic and common environmental effects.

Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive psychotic experiences.

Schneider's first-rank symptoms are given particular weight when making a diagnosis of schizophrenia, but the nuclear syndrome, characterised by one or more first-rank symptoms, has been found previously to have no heritability.

To estimate the heritability of the nuclear syndrome.

A total of 224 twin pairs (106 monozygotic, 118 same-gender dizygotic) were ascertained from the Maudsley Twin Register in London via probands with any psychosis. Lifetime-ever first-rank symptoms were rated using the OPCRIT checklist. Probandwise concordance rates were calculated for the nuclear syndrome and a heritability estimate was derived from biometric model fitting.

Probandwise concordance rates were 13/49 (26.5%) for monozygotic and 0/45 to 2/46 (0.0–4.3%) for dizygotic pairs. The heritability estimate for the best-fitting model was 71% (95% CI 57–82).

These results indicate that the nuclear syndrome shows substantial heritability, although this is slightly lower than that for schizophrenia as defined by the DSM and ICD systems.

Symptomatology in psychoses can be summarised as quantitative symptom dimensions, but their genetic basis is unknown.

To investigate whether genes make an important contribution to symptom dimensions.

A total of 224 probandwise twin pairs (106 monozygotic, 118 same-gender dizygotic) where probands had psychosis were ascertained from the Maudsley Twin Register in London. Factor analysis was performed on lifetime symptoms rated on the Operational Checklist for Psychotic Disorders (OPCRIT). Correlations of dimension scores within monozygotic and dizygotic pairs concordant for Research Diagnostic Criteria psychoses were performed. Relationships between dimension scores and genetic loading for psychoses were assessed using logistic regression.

Patterns of familial aggregation consistent with a genetic effect were found for the disorganised dimension and for some measures of the negative, manic and general psychotic dimensions. Disorganised dimension scores were related significantly to genetic loading for psychoses.

The disorganised dimension, and possibly other symptom dimensions, may be useful phenotypes for molecular genetic studies of psychoses.

Abnormalities presumed to occur during foetal life have been associated with schizophrenia. Polydactyly is a developmental abnormality but no previous association has been reported between Polydactyly and functional psychotic illness.

Individuals with both Polydactyly and a functional psychosis were ascertained during a study of familial schizophrenia.

Five such individuals were ascertained in the course of assessing 234 individuals with familial psychosis, giving a rate of Polydactyly in the sample of around 10 times the general population rate.

This study provides preliminary evidence that Polydactyly is over-represented in individuals with familial schizophrenia and related psychotic illnesses.

Schizophrenia is associated with expanded CAG/CTG trinucleotide repeats. We wished to determine whether the presence of such expansions correlated with specific subsyndromes or other clinical features of schizophrenia.

Seventy patients from England and Wales and 44 patients from Portugal with a DSM–III–R diagnosis of schizophrenia were rated on the opcrit checklist Patients' maximum CAG/CTG repeat length was measured using repeat expansion detection (RED). Significant differences were sought for repeat lengths in subjects categorised according to dimensional and categorical schizophrenia subsyndromes, affective episodes, individual symptoms, and a range of demographic variables.

Maximum CAG/CTG repeat length did not differ significantly for any of the clinical or demographic variables studied.

There are no subsyndromes or other clinical features of schizophrenia associated with CAG/CTG repeat expansion. Therefore, the identification of the gene(s) that contain expanded CAG/CTG repeats and which are associated with schizophrenia is unlikely to be facilitated at present by using any subsyndromes of schizophrenia as phenotypes.