Depressive symptoms are highly prevalent in first-episode psychosis (FEP) and worsen clinical outcomes. It is currently difficult to determine which patients will have persistent depressive symptoms based on a clinical assessment. We aimed to determine whether depressive symptoms and post-psychotic depressive episodes can be predicted from baseline clinical data, quality of life, and blood-based biomarkers, and to assess the geographical generalizability of these models.

Two FEP trials were analyzed: European First-Episode Schizophrenia Trial (EUFEST) (n = 498; 2002–2006) and Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) (n = 404; 2010–2012). Participants included those aged 15–40 years, meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for schizophrenia spectrum disorders. We developed support vector regressors and classifiers to predict changes in depressive symptoms at 6 and 12 months and depressive episodes within the first 6 months. These models were trained in one sample and externally validated in another for geographical generalizability.

A total of 320 EUFEST and 234 RAISE-ETP participants were included (mean [SD] age: 25.93 [5.60] years, 56.56% male; 23.90 [5.27] years, 73.50% male). Models predicted changes in depressive symptoms at 6 months with balanced accuracy (BAC) of 66.26% (RAISE-ETP) and 75.09% (EUFEST), and at 12 months with BAC of 67.88% (RAISE-ETP) and 77.61% (EUFEST). Depressive episodes were predicted with BAC of 66.67% (RAISE-ETP) and 69.01% (EUFEST), showing fair external predictive performance.

Predictive models using clinical data, quality of life, and biomarkers accurately forecast depressive events in FEP, demonstrating generalization across populations.

Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).

We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.

Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.

Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.

We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.

Giant coronary artery aneurysms and myocardial fibrosis after Kawasaki disease may lead to devastating cardiovascular outcomes. We characterised the vascular and myocardial outcomes in five selected Kawasaki disease patients with a history of giant coronary artery aneurysms that completely regressed.

Five patients were selected who had giant coronary artery aneurysm in early childhood that regressed when studied 12–33 years after Kawasaki disease onset. Coronary arteries were imaged by coronary CT angiography, and coronary artery calcium volume scores were determined. We used endocardial strain measurements from CT imaging to assess myocardial regional wall function. Calprotectin and galectin-3 (gal-3) as biomarkers of inflammation and myocardial fibrosis were measured by enzyme-linked immunosorbent assay.

The five selected patients with regressed giant coronary artery aneurysms had calcium scores of zero, normal levels of calprotectin and gal-3, and normal appearance of the coronary arteries by coronary computed tomography angiography. CT strain demonstrated normal peak systolic and diastolic strain patterns in four of five patients. In one patient with a myocardial infarction at the time of Kawasaki disease diagnosis at the age of 10 months, CT strain showed altered global longitudinal strain, reduced segmental peak strain, and reduced diastolic relaxation patterns in multiple left ventricle segments.

These patients illustrate that regression of giant aneurysms after Kawasaki disease is possible with no detectable calcium, normal biomarkers of inflammation and fibrosis, and normal myocardial function. Individuals with regressed giant coronary artery aneurysm still require longitudinal surveillance to assess the durability of this favourable outcome.

Schizophrenia is a chronic psychiatric illness with periods of remission and relapse. Patients vary in the frequency and severity of relapse, time until relapse and time in remission. Discontinuation of antipsychotic medication is by far the most important reason for relapse. A possible method to optimize medication adherence is to treat patients with long-term, depot medication rather than oral medication.

Primary objective is to compare all cause discontinuation rates in patients with schizophrenia randomized to either one of the two depot medications (aripiprazole depot or paliperidone palmitate) with patients randomized to either one of the two oral formulations of the same medication (aripiprazole or paliperidone) over an 19 month follow-up period.

Pragmatic, randomized, open label, multicenter, multinational comparative trial consisting of a 19 month treatment period. Patients aged 18 years or older, having experienced the first psychosis 1-7 years ago, currently meeting DSM-IV-R criteria for schizophrenia. Patients are randomized 1:1:1:1 to paliperidone palmitate, aripiprazole depot, oral aripiprazole or oral paliperidone. The primary outcome is all cause discontinuation.

In the Intent to Treat sample (n=511), no difference was found in time to ACD between the combined oral and combined depot treatment arms, nor between the four individual treatment arms.

Even though the scientific evidence comparing oral and depot medication has been inconsistent, most studies were conducted in rigorous clinical settings, which may have biased those results. In contract, given the pragmatic, open label design of the current trial, the results may be more representative of common daily practice.

No significant relationships.

Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

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.

Prof Mucci has been a consultant and/or advisor to or has received honoraria from Gedeon Richter Bulgaria, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer and Pierre Fabre.

Genotype-first and within-family studies can elucidate factors that contribute to psychiatric illness. Combining these approaches, we investigated the patterns of influence of parental scores, a high-impact variant, and schizophrenia on dimensional neurobehavioral phenotypes implicated in major psychiatric disorders.

We quantitatively assessed cognitive (FSIQ, VIQ, PIQ), social, and motor functioning in 82 adult individuals with a de novo 22q11.2 deletion (22 with schizophrenia), and 148 of their unaffected parents. We calculated within-family correlations and effect sizes of the 22q11.2 deletion and schizophrenia, and used linear regressions to assess contributions to neurobehavioral measures.

Proband-parent intra-class correlations (ICC) were significant for cognitive measures (e.g. FSIQ ICC = 0.549, p < 0.0001), but not for social or motor measures. Compared to biparental scores, the 22q11.2 deletion conferred significant impairments for all phenotypes assessed (effect sizes −1.39 to −2.07 s.d.), strongest for PIQ. There were further decrements in those with schizophrenia. Regression models explained up to 37.7% of the variance in IQ and indicated that for proband IQ, parental IQ had larger effects than schizophrenia.

This study, for the first time, disentangles the impact of a high-impact variant from the modifying effects of parental scores and schizophrenia on relevant neurobehavioral phenotypes. The robust proband-parent correlations for cognitive measures, independent of the impact of the 22q11.2 deletion and of schizophrenia, suggest that, for certain phenotypes, shared genetic variation plays a significant role in expression. Molecular genetic and predictor studies are needed to elucidate shared factors and their contribution to psychiatric illness in this and other high-risk groups.

Structural brain abnormalities have consistently been found in schizophrenia, with increased familial risk for the disease associated with these abnormalities. Some brain volume changes are progressive over the course of the illness.

To investigate whether these progressive brain volume changes are mediated by genetic or disease-related factors.

We carried out a 5-year follow-up study in monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia (DISC) and healthy comparison (HC) twin pairs using brain magnetic resonance imaging. A total of 92 participants completed the study (DISC: 9 MZ and 10 DZ; HC: 14 MZ and 13 DZ). Percentage volume changes of the whole brain and cerebral gray and white matter were estimated. Structural equation modeling was applied to estimate contributions of additive genetic and common and unique environmental factors.

Significant decreases over time in whole brain volume was found in patients with schizophrenia and their unaffected co-twins compared with control twins. Bivariate structural equation modeling using cross-trait/cross-twin correlations revealed significant additive genetic influences on the correlations between schizophrenia liability and progressive whole brain (66%; 95% confidence interval [CI], 51%-100%), frontal lobe (76%; 95% CI, 54%-100%), and temporal lobe (79%; CI, 56%-100%) volume change.

The progressive brain volume loss found in patients with schizophrenia and their unaffected co-twins is at least partly attributable to genetic factors related to the illness.

Quetiapine immediate release (quetiapine IR) improves PANSS total, positive, negative and general psychopathology scores in schizophrenia. This study (D1444C00132) evaluated the efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) in patients with acute schizophrenia.

This was a 6-week, double-blind, randomised study (n=588) comparing quetiapine XR (400, 600 or 800 mg/day) and quetiapine IR (400 mg/day) with placebo. Efficacy was assessed using ANCOVA analyses of the change from baseline to study endpoint (Day 42) for: PANSS total score; positive, negative and general psychopathology subscale scores; and aggression and depression cluster scores (modified ITT population, LOCF). Changes in individual PANSS item scores were assessed post hoc.

At Day 42, there were statistically significant reductions (ie two-sided p-value <0.05) versus placebo with all doses of quetiapine XR for the change in PANSS total, positive, general psychopathology and aggression cluster scores. Changes in negative and depression cluster scores were statistically significant versus placebo for quetiapine XR 600 mg/day and 800 mg/day. There was statistically significant separation from placebo with quetiapine XR 600 mg/day and 800 mg/day for the change in 6/7 PANSS positive items, 5/7 negative items, and 12/16 general psychopathology items. For those items with no statistically significant separation from placebo, baseline scores were generally low.

Once-daily quetiapine XR is effective across a broad range of symptoms in acute schizophrenia, including positive and negative symptoms, as well as symptoms of general psychopathology, aggression and depression.

To evaluate efficacy and tolerability of quetiapine sustained release (SR) in a 6-week study (D1444C00132).

588 patients with acute schizophrenia (PANSS total ≥70; CGI-S ≥4) were randomised to fixed-dose quetiapine SR 400, 600 or 800 mg/day (once-daily), quetiapine immediate release (IR) 400 mg/day (200 mg twice-daily; 5-day dose-escalation schedule), or placebo. Quetiapine SR doses: 400, 600 mg reached by Day 2; 800 mg by Day 3. Primary endpoint: change from baseline to Day 42 in PANSS total score (LOCF; ANCOVA). Other assessments: PANSS response rate (% patients with ≥30% reduction in total score from baseline); CGI-I response rate (% patients with rating ≤3); CGI-S; AEs.

446 patients (76%) completed the study (similar across groups). LS mean change from baseline in PANSS total score at Day 42 showed significant improvement versus placebo (-18.8): -24.8 (p=0.03), -30.9 (p<0.001), and -31.3 (p<0.001), quetiapine SR 400, 600, and 800 mg, respectively; -26.6 (p=0.004), quetiapine IR. Statistical separation from placebo at Day 42 for: change from baseline in CGI-S (quetiapine SR 600 and 800 mg; IR); PANSS and CGI-I response rates (all active treatments). Most common AEs with quetiapine: somnolence and dizziness. There were no unexpected AEs with quetiapine SR. Incidence of EPS-related AEs was similar to placebo. Two quetiapine SR and two IR patients discontinued due to AEs in Week 1.

Once-daily quetiapine SR (400-800 mg) was effective versus placebo in patients with acute schizophrenia. Rapid dose escalation was well tolerated, with a therapeutically effective dose reached by Day 2.

To evaluate safety, tolerability and overall effectiveness of a titrated- versus fixed-dose switching strategy from risperidone to aripiprazole in a general practice setting.

This 12-week, multicentre, open-label study included patients with schizophrenia (DSM-IV-TR) experiencing insufficient efficacy and/or safety/tolerability issues while receiving risperidone for ≥6 weeks. Patients were randomized to titrated- or fixed-dose switching regimens.

Discontinuations due to AEs were similar between titrated- and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Titrated- and fixed-dose groups showed improvements (Week 12) in mean PANSS Total scores (–14.8 vs. –17.2; LOCF), mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF), ASEX scores (–1.5 vs. –1.9 from baseline; OC), serum prolactin levels (−48.7 vs. −48.5 from baseline; OC) and SWN scores (+8.6 vs. +10.3 from baseline; p=0.223; OC). POM scores indicated a preference for aripiprazole compared with risperidone using either regimen. Both strategies showed improvements (titrated-dose vs. fixed-dose; Week 12; LOCF) in social cognition as indicated by decreased GEOPTE patient (–5.3 vs. –6.1), caregiver (–5.4 vs. –9.9) and index scores (–5.1 vs. –9.8).

Switching to aripiprazole from risperidone can be effectively and safely achieved in a general practice setting through a slow down-titration of risperidone and either a titrated- or fixed-dose switching strategy for aripiprazole.

Data from two, identically designed, placebo-controlled, randomised, double-blind clinical trials (D1444C00132+D1444C00133) for once-daily extended-release quetiapine fumarate (QTP-XR) were pooled and analysed.

Evaluate dose response, efficacy and safety for QTP-XR in schizophrenia.

Post-hoc analysis of data from patients receiving QTP-XR 400, 600, 800 mg/day or placebo. Endpoints: least squares means (LSM) change from baseline to Day 42 in PANSS total and positive and negative subscale scores. No corrections for multiplicity were performed. Adverse events (AEs) were recorded.

914 patients were included; PANSS scores were assessed in the MITT population (n = 889). LSM change from baseline in PANSS total score diverged significantly from placebo at: Day 14 for QTP-XR 800 mg/day (-15.3 vs -12.1 for placebo; p = 0.018); Day 21 for 600 mg/day (-17.3 vs -14.2; p = 0.039); Day 42 for 400 mg/day (-19.2 vs -15.4; p = 0.033).

Jonckheere-Terpstra analysis of change in PANSS total score at Day 42 showed a significant QTP-XR dose response (p = 0.0196; p < 0.001 with placebo). PANSS positive scores diverged by Day 21 for both QTP-XR 800 (-5.7 vs -4.8; p = 0.049) and 600 mg/day (-5.8 vs -4.8; p = 0.046). PANSS negative scores diverged by Day 21 (-4.0 vs -3.2; p = 0.040) and 42 (-4.8 vs -3.6; p = 0.009) for QTP-XR 800 and 600 mg/day, respectively. AEs occurred in 59.4%, 66.5%, 62.1% and 56.2% of patients in the QTP-XR 800, 600, 400 mg/day and placebo groups, respectively. Most common AEs were somnolence, dry mouth, sedation, insomnia, dizziness, headache, constipation and nausea.

QTP-XR was generally well tolerated and demonstrated efficacy that increased with dose in schizophrenia.

Financial support: AstraZeneca.

Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.

This is a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. 210 treatment-seekers with DSM-IV diagnosis of cocaine dependence consented and enrolled. 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants attended the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy once per week. The primary outcome was the increase in weekly percentage of non-use days. Secondary outcomes included: decrease in the weekly median log of urine benzoylecgonine, subgroup analyses of balancing factors and co-morbid conditions, self-report of alcohol use, addiction severity, craving, and risk behaviors for HIV.

125 participants completed 12 weeks of treatment (60%). The GEE regression analysis showed that for the total sample, the difference between modafinil groups and placebo in the weekly percentage of cocaine non-use days over the 12-week treatment period was not statistically significant (p=0.95). A post-hoc analysis showed a significant effect for modafinil, only in the subgroup of cocaine patients without alcohol dependence. Modafinil 200mg also showed significant effects of an increase in the total number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04).

These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing craving.

Psychiatric Patients show abnormalities in volumes of several subcortical structures. Recently wider usage of automated segmentation methods in research of these abnormalities based on MR images has become possible. However manual segmentation is still considered to be the gold standard.

To compare differences in hippocampus volumes between manual segmentation and 2 packages for automatic segmentation (FSL and FreeSurfer).

To explore the overlap and differences between different segmentation methods used for segmentation of subcortical structures.

Structural MR brain scans were aquired from 98 subjects (53 schizophrenia patients, 45 controls). Volumes of left and right hippocampus were measured after manual, FreeSurfer and FSL segmentations. Differences between volumes from different methods were tested by the t-test (using R). In addition percent volume differences, Pearson correlations, Bland-Altman plots and Cronbach’s alpha were computed.

Both automatic methods yielded significantly larger hippocampal volumes than the manual segmentation. FreeSurfer volumes showed a higher correlation and lower percent volume difference with manual segmentation than FSL. Bland-Altman plots and Cronbach’s alpha showed only limited agreement between manual and both automatic methods.

Although volumes acquired by FreeSurfer appeared to be more related to manual segmentation, clear superiority of either of automatic methods could not be demonstrated. Therefore, all three methods seem to measure other aspects of hippocampus volume. An useful approach would be to compare effect-size of the difference between patients and healthy controls using different segmentation methods. We are currently pursuing this in a larger sample.

Peer relationships play a critical role in the development of adolescents, not only for the acquisition of social skills but also for the sense of personal identity and competence. Thus the quality of peer relationships influences actual and future mental health of the adolescent.

SEYLE (Saving and Empowering Young Lives in Europe) is a randomized controlled trial, funded by the EU, evaluating interventions for mental health promotion and suicide prevention. The study comprised 12,395 high-school students from 11 European countries.

We investigated the differences on psychological problems between students with poor and good peer relationships.

1,195 adolescents (mean age 15.3 ± 0.6; 68% females) from the Molise region constituted the Italian sample. Adolescents were identified as with poor peer relationships if they never or just sometimes get along with people of their age, feel that peers like having them in the group and feel that peers were kind and helpful. Psychometric measures were used to assess mental health problems such as depression (Beck Depression Inventory II), anxiety (Zung Self-Assessment Anxiety Scale), well-being (WHO-5) and suicidal ideation (Paykel Suicide Scale).

Adolescents who reported poor peer relationships scored significantly higher (p < .005) on the scales assessing depression, anxiety and suicidal ideation and significantly lower (p < .001) on the WHO-5.

Particularly in adolescence peer relationships may influence psychological well-being and vice versa mental health influences the openness to the others. So promoting mental health and contemporary improve social skills could lead adolescents to a better life.