Copy number variants (CNVs) are large changes in the structure of DNA. Certain rare CNVs are associated with elevated chance of neurodevelopmental conditions and difficulties (NDs), including autism spectrum disorder (ASD) and intellectual disability, alongside various physical health complications. Currently, CNV testing in children with NDs is only recommended under limited circumstances, in part because their impact on outcomes and prognosis remains unknown. We aimed to investigate whether individuals with NDs in childhood, with and without rare pathogenic CNVs, differ in terms of functional outcomes in early adulthood.

Pathogenic CNV carriers were identified in the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort of individuals born in 1991–1992. Individuals with the following childhood NDs were identified through parent-reported diagnostic interviews and questionnaires, and assessment with the child: Attention Deficit Hyperactivity-Disorder (ADHD), ASD, reading difficulties, coordination difficulties, language difficulties, and chronic tics. Outcomes were measured at age 25 and included: presence of an emotional disorder, being in receipt of sickness/disability benefit, ability to make and maintain friendships, not being in education, employment, or training (NEET), and self-reported life satisfaction. We will use logistic regression to measure the association between carrying a pathogenic CNV and each functional outcome in ALSPAC. Sensitivity analyses will be conducted on all large (>250kb), rare (<1%) CNVs, as opposed to only pathogenic CNVs.

983 individuals with probable NDs (39.4% female, n = 387) were identified in ALSPAC, including 495 people with ASD, 163 with ADHD, 16 with Tourette's syndrome, 210 with reading difficulties, 295 with language difficulties, and 166 with coordination difficulties. Many individuals met criteria for more than one ND.

43 (4.4%) of individuals with an ND carried a pathogenic CNV. CNV carrier status amongst individuals with a ND was not associated with sex (4.4% of females vs 4.4% of males, OR = 1.007 [0.539–1.882] p = 0.981). Analysis of CNV carrier status on outcomes in NDs will be conducted between February and April 2024.

Evidence in support of poorer outcomes in CNV carriers could suggest that neurodiverse young people with CNVs may benefit from intervention to improve outcomes, and thus more individuals may benefit from genetic testing. Conversely, evidence indicating that CNVs do not impact outcomes may suggest that current clinical guidelines are appropriate within the current research landscape, and that further research is needed to understand the impact of carrying a pathogenic CNV in young people with NDs.

Digital Mental Health Interventions (DMHIs) that meet the definition of a medical device are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The MHRA uses procedures that were originally developed for pharmaceuticals to assess the safety of DMHIs. There is recognition that this may not be ideal, as is evident by an ongoing consultation for reform led by the MHRA and the National Institute for Health and Care Excellence.

The aim of this study was to generate an experts’ consensus on how the medical regulatory method used for assessing safety could best be adapted for DMHIs.

An online Delphi study containing three rounds was conducted with an international panel of 20 experts with experience/knowledge in the field of UK digital mental health.

Sixty-four items were generated, of which 41 achieved consensus (64%). Consensus emerged around ten recommendations, falling into five main themes: Enhancing the quality of adverse events data in DMHIs; Re-defining serious adverse events for DMHIs; Reassessing short-term symptom deterioration in psychological interventions as a therapeutic risk; Maximising the benefit of the Yellow Card Scheme; and Developing a harmonised approach for assessing the safety of psychological interventions in general.

The implementation of the recommendations provided by this consensus could improve the assessment of safety of DMHIs, making them more effective in detecting and mitigating risk.

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.