One aim of personalized medicine is to determine which treatment is to be preferred for an individual patient, given all patient information available. Particularly in mental health, however, there is a lack of a single objective, reliable measure of outcome that is sensitive to crucial individual differences among patients.

We examined the feasibility of quantifying the total clinical value provided by a treatment (measured by both harms and benefits) in a single metric. An expert panel was asked to compare 100 pairs of patients, one from each treatment group, who had participated in a randomized clinical trial (RCT) involving interpersonal psychotherapy (IPT) and escitalopram, selecting the patient with the preferred outcome considering both benefits and harms.

From these results, an integrated preference score (IPS) was derived, such that the differences between any two patients' IPSs would predict the clinicians' preferences. This IPS was then computed for all patients in the RCT. A second set of 100 pairs was rated by the panel. Their preferences were highly correlated with the IPS differences (r=0.84). Finally, the IPS was used as the outcome measure comparing IPT and escitalopram. The 95% confidence interval (CI) for the effect size comparing treatments indicated clinical equivalence of the treatments.

A metric that combines benefits and harms of treatments could increase the value of RCTs by making clearer which treatments are preferable and, ultimately, for whom. Such methods result in more precise estimation of effect sizes, without increasing the required sample size.

To test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438).

We examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections.

Significant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts.

Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.

Psychosis, and in particular auditory verbal hallucinations (AVHs), are associated with adversity exposure. However, AVHs also occur in populations with no need for care or distress.

This study investigated whether adversity exposure would differentiate clinical and healthy voice-hearers within the context of a ‘three-hit’ model of vulnerability and stress exposure.

Samples of 57 clinical and 45 healthy voice-hearers were compared on the three ‘hits’: familial risk; adversity exposure in childhood and in adolescence/adulthood.

Clinical voice-hearers showed greater familial risk than healthy voice-hearers, with more family members with a history of psychosis, but not with other mental disorders. The two groups did not differ in their exposure to adversity in childhood [sexual and non-sexual, victimisation; discrimination and socio-economic status (SES)]. Contrary to expectations, clinical voice-hearers did not differ from healthy voice-hearers in their exposure to victimisation (sexual/non-sexual) and discrimination in adolescence/adulthood, but reported more cannabis and substance misuse, and lower SES.

The current study found no evidence that clinical and healthy voice-hearers differ in lifetime victimisation exposure, suggesting victimisation may be linked to the emergence of AVHs generally, rather than need-for-care. Familial risk, substance misuse and lower SES may be additional risk factors involved in the emergence of need-for-care and distress.

Resting cerebral blood flow (rCBF) in striatum and thalamus is increased in medicated patients with psychosis, but whether this is caused by treatment or illness pathology is unclear. Specifically, effects of partial dopamine agonism, sex, and clinical correlates on rCBF are sparsely investigated. We therefore assessed rCBF in antipsychotic-naïve psychosis patients before and after aripiprazole monotherapy and related findings to sex and symptom improvement.

We assessed rCBF with the pseudo-Continuous Arterial Spin Labeling (PCASL) sequence in 49 first-episode patients (22.6 ± 5.2 years, 58% females) and 50 healthy controls (HCs) (22.3 ± 4.4 years, 63% females) at baseline and in 29 patients and 49 HCs after six weeks. RCBF in striatum and thalamus was estimated with a region-of-interest (ROI) approach. Psychopathology was assessed with the positive and negative syndrome scale.

Baseline rCBF in striatum and thalamus was not altered in the combined patient group compared with HCs, but female patients had lower striatal rCBF compared with male patients (p = 0.009). Treatment with a partial dopamine agonist increased rCBF significantly in striatum (p = 0.006) in the whole patient group, but not significantly in thalamus. Baseline rCBF in nucleus accumbens was negatively associated with improvement in positive symptoms (p = 0.046), but baseline perfusion in whole striatum and thalamus was not related to treatment outcome.

The findings suggest that striatal perfusion is increased by partial dopamine agonism and decreased in female patients prior to first treatment. This underlines the importance of treatment effects and sex differences when investigating the neurobiology of psychosis.

Chemical weapons exercise an enduring and often powerful psychological effect. This had been recognized during the First World War when it was shown that the symptoms of stress mimicked those of mild exposure to gas. Debate about long-term effects followed the suggestion that gassing triggered latent tuberculosis.

A random sample of 103 First World War servicemen awarded a war pension for the effects of gas, but without evidence of chronic respiratory pathology, were subjected to cluster analysis using 25 common symptoms. The consistency of symptom reporting was also investigated across repeated follow-ups.

Cluster analysis identified four groups: one (n=56) with a range of somatic symptoms, a second (n=30) with a focus on the respiratory system, a third (n=12) with a predominance of neuropsychiatric symptoms, and a fourth (n=5) with a narrow band of symptoms related to the throat and breathing difficulties. Veterans from the neuropsychiatric cluster had multiple diagnoses including neurasthenia and disordered action of the heart, and reported many more symptoms than those in the three somatic clusters.

Mild or intermittent respiratory disorders in the post-war period supported beliefs about the damaging effects of gas in the three somatic clusters. By contrast, the neuropsychiatric group did not report new respiratory illnesses. For this cluster, the experience of gassing in a context of extreme danger may have been responsible for the intensity of their symptoms, which showed no sign of diminution over the 12-year follow-up.

Access to evidence-based psychological treatment is a challenge worldwide. We assessed the effectiveness of a fully automated aviophobia smartphone app treatment delivered in combination with a $5 virtual reality (VR) viewer.

In total, 153 participants from the Dutch general population with aviophobia symptoms and smartphone access were randomized in a single-blind randomized controlled trial to either an automated VR cognitive behavior therapy (VR-CBT) app treatment condition (n = 77) or a wait-list control condition (n = 76). The VR-CBT app was delivered over a 6-week period in the participants' natural environment. Online self-report assessments were completed at baseline, post-treatment, at 3-month and at 12-month follow-up. The primary outcome measure was the Flight Anxiety Situations Questionnaire (FAS). Analyses were based on intent-to-treat.

A significant reduction of aviophobia symptoms at post-test for the VR-CBT app compared with the control condition [p < 0.001; d = 0. 98 (95% CI 0.65–1.32)] was demonstrated. The dropout rate was 21%. Results were maintained at 3-month follow-up [within-group d = 1.14 (95% CI 0.46–1.81)] and at 12-month follow-up [within-group d = 1.12 (95% CI 0.46–1.79)]. Six participants reported adverse effects of cyber sickness symptoms.

This study is the first to show that fully automated mobile VR-CBT therapy delivered in a natural setting can maintain long-term effectiveness in reducing aviophobia symptoms. In doing so, it offers an accessible and scalable evidence-based treatment solution that can be applied globally at a fraction of the cost of current treatment alternatives.

Impulsivity is a central symptom of borderline personality disorder (BPD) and its neural basis may be instantiated in a frontoparietal network involved in response inhibition. However, research has yet to determine whether neural activation differences in BPD associated with response inhibition are attributed to attentional saliency, which is subserved by a partially overlapping network of brain regions.

Patients with BPD (n = 45) and 29 healthy controls (HCs; n = 29) underwent functional magnetic resonance imaging while completing a novel go/no-go task with infrequent odd-ball trials to control for attentional saliency. Contrasts reflecting a combination of response inhibition and attentional saliency (no-go > go), saliency processing alone (oddball > go), and response inhibition controlling for attentional saliency (no-go > oddball) were compared between BPD and HC.

Compared to HC, BPD showed less activation in the combined no-go > go contrast in the right posterior inferior and middle-frontal gyri, and less activation for oddball > go in left-hemispheric inferior frontal junction, frontal pole, superior parietal lobe, and supramarginal gyri. Crucially, BPD and HC showed no activation differences for the no-go > oddball contrast. In BPD, higher vlPFC activation for no-go > go was correlated with greater self-rated BPD symptoms, whereas lower vlPFC activation for oddball > go was associated with greater self-rated attentional impulsivity.

Patients with BPD show frontoparietal disruptions related to the combination of response inhibition and attentional saliency or saliency alone, but no specific response inhibition neural activation difference when attentional saliency is controlled. The findings suggest a neural dysfunction in BPD underlying attention to salient or infrequent stimuli, which is supported by a negative correlation with self-rated impulsiveness.

Genomewide association studies (GWASs) on antidepressant efficacy have yielded modest results. A possible reason is that response is influenced by other factors, which possibly interact with genetic variation. We used a GWAS model to predict antidepressant response, by including predictors previously known to affect response, such as quality of life (QoL). We also evaluated the association between genes, previously implicated in gene–environment (G × E) interactions, and response using an enrichment analysis.

We examined a sample of 1426 depressed patients from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: 774 responders, 652 non-responders and 418 865 single nucleotide polymorphisms (SNPs) were analysed. First, in a GWAS model, we investigated whether genetic variations interact with patients' levels of QoL to predict response, after controlling for demographic characteristics, severity and population stratification. Second, we conducted an enrichment analysis exploring whether candidate genes that have emerged from prior G × E interaction studies on depression are associated with treatment response.

The GWAS model, with QoL as a moderator, yielded one SNP (rs520210) associated with response in the NEDD4L gene (p = 3.64 × 10−8). In the Caucasian sample only, we observed a drop in significance for this SNP. The enrichment analysis showed that SNPs within serotonergic genes contained more significant markers that predicted response, compared with a random set of genes in the genome.

Our findings point to possible target genes, which are proposed for further independent replication. Our enrichment analysis provides further support, in a genomewide context, of the role of serotonergic genes in influencing antidepressant response.

Hospital-based biobanks are being increasingly considered as a resource for translating polygenic risk scores (PRS) into clinical practice. However, since these biobanks originate from patient populations, there is a possibility of bias in polygenic risk estimation due to overrepresentation of patients with higher frequency of healthcare interactions.

PRS for schizophrenia, bipolar disorder, and depression were calculated using summary statistics from the largest available genomic studies for a sample of 24 153 European ancestry participants in the Mass General Brigham (MGB) Biobank. To correct for selection bias, we fitted logistic regression models with inverse probability (IP) weights, which were estimated using 1839 sociodemographic, clinical, and healthcare utilization features extracted from electronic health records of 1 546 440 non-Hispanic White patients eligible to participate in the Biobank study at their first visit to the MGB-affiliated hospitals.

Case prevalence of bipolar disorder among participants in the top decile of bipolar disorder PRS was 10.0% (95% CI 8.8–11.2%) in the unweighted analysis but only 6.2% (5.0–7.5%) when selection bias was accounted for using IP weights. Similarly, case prevalence of depression among those in the top decile of depression PRS was reduced from 33.5% (31.7–35.4%) to 28.9% (25.8–31.9%) after IP weighting.

Non-random selection of participants into volunteer biobanks may induce clinically relevant selection bias that could impact implementation of PRS in research and clinical settings. As efforts to integrate PRS in medical practice expand, recognition and mitigation of these biases should be considered and may need to be optimized in a context-specific manner.

The transition from military service to civilian life is a high-risk period for suicide attempts (SAs). Although stressful life events (SLEs) faced by transitioning soldiers are thought to be implicated, systematic prospective evidence is lacking.

Participants in the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) completed baseline self-report surveys while on active duty in 2011–2014. Two self-report follow-up Longitudinal Surveys (LS1: 2016–2018; LS2: 2018–2019) were subsequently administered to probability subsamples of these baseline respondents. As detailed in a previous report, a SA risk index based on survey, administrative, and geospatial data collected before separation/deactivation identified 15% of the LS respondents who had separated/deactivated as being high-risk for self-reported post-separation/deactivation SAs. The current report presents an investigation of the extent to which self-reported SLEs occurring in the 12 months before each LS survey might have mediated/modified the association between this SA risk index and post-separation/deactivation SAs.

The 15% of respondents identified as high-risk had a significantly elevated prevalence of some post-separation/deactivation SLEs. In addition, the associations of some SLEs with SAs were significantly stronger among predicted high-risk than lower-risk respondents. Demographic rate decomposition showed that 59.5% (s.e. = 10.2) of the overall association between the predicted high-risk index and subsequent SAs was linked to these SLEs.

It might be possible to prevent a substantial proportion of post-separation/deactivation SAs by providing high-risk soldiers with targeted preventive interventions for exposure/vulnerability to commonly occurring SLEs.

Obsessive–compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms.

We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning.

A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear mixed models demonstrated that OCS in patients treated with clozapine were associated with significantly worse wellbeing scores, independently of depression and psychotic symptoms, but OCS did not impair general functioning. Obsessional thinking and hoarding behaviour, but not compulsions, were significantly associated with the impact on wellbeing, which may be attributable to the ego-syntonic nature of the compulsions.

Given the frequent occurrence of OCS and their negative impact on wellbeing, we encourage clinicians to routinely assess and treat OCS in patients who are taking clozapine.

Several multivariate algorithms have been developed for predicting psychosis, as attempts to obtain better prognosis prediction than with current clinical high-risk (CHR) criteria. The models have typically been based on samples from specialized clinics. We evaluated the generalizability of 19 prediction models to clinical practice in an unselected adolescent psychiatric sample.

In total, 153 adolescent psychiatric patients in the Helsinki Prodromal Study underwent an extensive baseline assessment including the SIPS interview and a neurocognitive battery, with 50 participants (33%) fulfilling CHR criteria. The adolescents were followed up for 7 years using comprehensive national registers. Assessed outcomes were (1) any psychotic disorder diagnosis (n = 18, 12%) and (2) first psychiatric hospitalization (n = 25, 16%) as an index of overall deterioration of functioning.

Most models improved the overall prediction accuracy over standard CHR criteria (area under the curve estimates ranging between 0.51 and 0.82), although the accuracy was worse than that in the samples used to develop the models, also when applied only to the CHR subsample. The best models for transition to psychosis included the severity of positive symptoms, especially delusions, and negative symptoms. Exploratory models revealed baseline negative symptoms, low functioning, delusions, and sleep problems in combination to be the best predictor of psychiatric hospitalization in the upcoming years.

Including the severity levels of both positive and negative symptomatology proved beneficial in predicting psychosis. Despite these advances, the applicability of extended psychosis-risk models to general psychiatric practice appears limited.

Contrasting the well-described effects of early intervention (EI) services for youth-onset psychosis, the potential benefits of the intervention for adult-onset psychosis are uncertain. This paper aims to examine the effectiveness of EI on functioning and symptomatic improvement in adult-onset psychosis, and the optimal duration of the intervention.

360 psychosis patients aged 26–55 years were randomized to receive either standard care (SC, n = 120), or case management for two (2-year EI, n = 120) or 4 years (4-year EI, n = 120) in a 4-year rater-masked, parallel-group, superiority, randomized controlled trial of treatment effectiveness (Clinicaltrials.gov: NCT00919620). Primary (i.e. social and occupational functioning) and secondary outcomes (i.e. positive and negative symptoms, and quality of life) were assessed at baseline, 6-month, and yearly for 4 years.

Compared with SC, patients with 4-year EI had better Role Functioning Scale (RFS) immediate [interaction estimate = 0.008, 95% confidence interval (CI) = 0.001–0.014, p = 0.02] and extended social network (interaction estimate = 0.011, 95% CI = 0.004–0.018, p = 0.003) scores. Specifically, these improvements were observed in the first 2 years. Compared with the 2-year EI group, the 4-year EI group had better RFS total (p = 0.01), immediate (p = 0.01), and extended social network (p = 0.05) scores at the fourth year. Meanwhile, the 4-year (p = 0.02) and 2-year EI (p = 0.004) group had less severe symptoms than the SC group at the first year.

Specialized EI treatment for psychosis patients aged 26–55 should be provided for at least the initial 2 years of illness. Further treatment up to 4 years confers little benefits in this age range over the course of the study.