Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood.

Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research.

As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant.

We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation.

DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

An evaluation of the benefits of ECT in patients with schizophrenia who received ECT in Cardiff & Vale UHB, in order to:

• ⋅ Investigate the effectiveness of ECT as a treatment for schizophrenia

• ⋅ Inform future clinical practice

• ⋅ Identify clear outcome measures for use in future research

Schizophrenia is a severe and debilitating mental illness, for which pharmacological treatment is often ineffective. ECT is seldom used for schizophrenia, despite encouraging evidence for its efficacy. Current guidance in the UK is inconsistent, as RCPsych contemplates the use of ECT in schizophrenia in certain cases, while NICE does not. This confusion warrants the need for further evaluation of ECT as a treatment for schizophrenia.

Eight suitable patients were identified, and a retrospective chart review was conducted in relation to the following outcomes:

• • What was the main indication for ECT, and was the issue resolved

• • Change in clinical rating scales

• • Concordance with medication before and after treatment

• • Length of hospital stay before and after treatment, over one year

• • Mental Health Act status after treatment for those treated on section

• • Was the level of observation reduced following treatment

Initial indication for treatment was completely resolved in seven out of eight cases. All patients improved in overall symptomatic score (mean improvement = 59.5%). Five patients (62.5%) improved above the threshold of clinically significant response. At the commencement of treatment, three (37.5%) patients were refusing all medication, three (37.5%) had poor concordance and two (25%) were fully concordant. At treatment endpoint, all were fully concordant. Average length of hospital stay remained unchanged: 30 weeks during the year before ECT, and 33 weeks during the year after ECT. Of six patients treated under Section 3, four (66.7%) had their section lifted within six months. Observation level was reduced in all cases that had been placed under continuous observation.

ECT improved all outcomes except admission duration. These results provide support for the consideration of ECT as a meaningful treatment option for schizophrenia.

Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.

To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.

We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.

Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015–0.017), with carriers being 7.5–7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.

This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.

Schizophrenia is a highly heritable disorder with undetermined neurobiological causes. Understanding the impact on brain anatomy of carrying genetic risk for the disorder will contribute to uncovering its neurobiological underpinnings.

To examine the effect of rare copy number variants (CNVs) associated with schizophrenia on brain cortical anatomy in a sample of unaffected participants from the UK Biobank.

We used regression analyses to compare cortical thickness and surface area (total and across gyri) between 120 unaffected carriers of rare CNVs associated with schizophrenia and 16 670 participants without any pathogenic CNV. A measure of cortical thickness and surface area covariance across gyri was also compared between groups.

Carrier status was associated with reduced surface area (β = −0.020 mm2, P < 0.001) and less robustly with increased cortical thickness (β = 0.015 mm, P = 0.035), and with increased covariance in thickness (carriers z = 0.31 v. non-carriers z = 0.22, P < 0.0005). Associations were mainly present in frontal and parietal areas and driven by a limited number of rare risk alleles included in our analyses (mainly 15q11.2 deletion for surface area and 16p13.11 duplication for thickness covariance).

Results for surface area conformed with previous clinical findings, supporting surface area reductions as an indicator of genetic liability for schizophrenia. Results for cortical thickness, though, argued against its validity as a potential risk marker. Increased structural thickness covariance across gyri also appears related to risk for schizophrenia. The heterogeneity found across the effects of rare risk alleles suggests potential different neurobiological gateways into schizophrenia's phenotype.

Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance.

To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).

In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.

Younger age at onset (odds ratio 0.94, P = 7.79 × 10−13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10−4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10−3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.

People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.

Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.

We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.

We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.

Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.

CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.

None.

There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.

Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.

Neither genetic measure was associated with season or month of birth within the UKBB sample.

As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.

Electroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but widely held concerns about memory problems may limit its use.

To find out whether repeated or maintenance courses of ECT cause cumulative cognitive deterioration.

Analysis of the results of 10 years of cognitive performance data collection from patients who have received ECT. The 199 patients had a total of 498 assessments, undertaken after a mean of 15.3 ECT sessions (range 0–186). A linear mixed-effect regression model was used, testing whether an increasing number of ECT sessions leads to deterioration in performance.

The total number of previous ECT sessions had no effect on cognitive performance. The major factors affecting performance were age, followed by the severity of depression at the time of testing and the number of days since the last ECT session.

Repeated courses of ECT do not lead to cumulative cognitive deficits. This message is reassuring for patients, carers and prescribers who are concerned about memory problems and confusion during ECT.

A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.

To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.

We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.

We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10−4).

We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.

Magnetic seizure therapy, in which seizures are elicited with a high-frequency magnetic field, is under development as a new treatment for major depressive disorder. Its use may be justified if it produces the antidepressant effects of electroconvulsive therapy (ECT), coupled with limited cognitive side-effects.

To evaluate the usefulness of a new 100 Hz magnetic seizure therapy device.

We induced seizures with 100 Hz magnetic transcranial stimulation in 11 patients with major depressive disorder during one session of a regular course of ECT. Recovery times after seizures induced by magnetic seizure therapy and ECT were compared.

Seizures could be elicited in 10 of the 11 patients. Stimulation over the vertex produced tonic-clonic activity on 9 out of 11 occasions. Stimulation over the prefrontal midpoint elicited seizures on 3 out of 7 occasions. The mean duration of magnetically induced seizures was 31.3s, ranging from 10 to 86s. All patients had an exceptionally quick recovery of orientation: mean of 7 min 12s (s.d.=2 min 7 s, range 4 min 20s to 9 min 41 s). The recovery times were on average 15 min 35s shorter with magnetic seizure therapy than with ECT in the same patients (paired-samples t-test: P<0.0001). Patients reported feeling less confused after magnetic seizure therapy. Side-effects were confined to myoclonic movements, associated with the use of etomidate.

The new 100Hz magnetic stimulator elicits seizures in the majority of patients when administered over the vertex. Magnetic seizure therapy was associated with shorter recovery times and less confusion following treatment. Subsequent work will be required to assess the safety and effectiveness of magnetic seizure therapy in the treatment of depression.

Brain-derived neurotrophic factor (BDNF) influences neuronal survival, proliferation and plasticity Three family-based studies have shown association of the common Valine (Val) allele of the Val66Met polymorphism of the BDNF gene with susceptibility to bipolar disorder.

To replicate this finding.

We genotyped the Val66Met polymorphism in our UK White bipolar case-control sample (n=3062).

We found no overall evidence of allele or genotype association. However, we found association with disease status in the subset of 131 individuals that had experienced rapid cycling at some time (P=0.004). We found a similar association on re-analysis of our previously reported family-based association sample (P<0.03, one-tailed test).

Variation at the Val66Met polymorphism of BDNF does not play a major role in influencing susceptibility to bipolar disorder as a whole, but is associated with susceptibility to the rapid-cycling subset of the disorder.

A randomised controlled trial was conducted in an acute treatment setting to examine the effectiveness of compliance therapy, a brief pragmatic intervention targeting treatment adherence in psychotic disorders, based on motivational interviewing and recent cognitive approaches to psychosis.

Seventy-four patients with psychotic disorders according to DSM–III–R criteria recruited from consecutive admissions to an acute in-patient unit, received 4–6 sessions of either compliance therapy or non-specific counselling, and were followed-up over 18 months. The principal outcome measures were observer-rated compliance, attitudes to treatment, insight and social functioning.

Significant advantages were found for the compliance therapy group post-treatment on measures of insight, attitudes to treatment and observer-rated compliance which were retained over the follow-up period. Global social functioning improved relatively more over time in the compliance therapy group compared with the control group. Survival in the community prior to readmission was significantly longer in the compliance therapy group.

The results support the effectiveness of compliance therapy in improving functioning and community tenure after an acute psychotic episode.

Non-compliance rates with antipsychotic medication can be high, and the personal and societal costs are considerable. A new psychological intervention, compliance therapy seeks to improve compliance and patient outcomes and reduce treatment costs.

A randomised controlled study examined the cost-effectiveness of compliance therapy compared to nonspecific counselling over 18 months for 74 people with psychosis admitted as inpatients at the Maudsley Hospital. Bivariate and multivariate analyses were conducted to test for differences and to explore inter-patient cost variations.

Compliance therapy is more effective and is no more expensive. Consequently, compliance therapy is more cost-effective than non-specific counselling at six, 12 and 18 months.

There are compliance, outcome and cost-effectiveness arguments in favour of compliance therapy in preference to non-specific counselling.