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Selection bias is a concern in studies on psychotic disorders due to high dropout rates and many eligibility criteria for inclusion. We studied how representative the first-episode psychosis study sample in the Turku Early Psychosis Study (TEPS) was.We screened 3772 consecutive admissions to the clinical psychiatric services of Turku Psychiatry, Finland, between October 2011 and June 2016. A total of 193 subjects had first-episode psychosis and were suitable for TEPS. Out of 193 subjects, 101 participated (PA) and 92 did not participate (NPA) in TEPS due to refusal or contact problems. We retrospectively used patient register data to study whether NPA and PA groups differed in terms of clinical outcomes during 1-year follow-up.In overall sample, the NPA group had a significantly higher rate of discontinuation of clinical treatment than the PA group (48.9 % vs 29.7 %, p = 0.01). In the hospital-treated subsample chi-square tests did not indicate statistically significant differences between the NPA and PA groups in the rate of involuntary care (69.7 % vs 62.7 %, p = 0.34), coercive measures (36.0 % vs 22.7 %, p = 0.06), and readmissions during the follow-up (41.5 % vs 33.8 %, p = 0.31), respectively.The differences in clinical outcomes and treatment characteristics in the non-participating and participating groups were relatively modest. The results do not support a major sample selection bias that would complicate the interpretation of results in this first-episode psychosis study.

Background Secure attachment is important in maintaining an individual’s health and well-being. Attachment disturbances increase the risk for developing psychiatric disorders such as affective disorders. Yet, the neurobiological correlates of human attachment are poorly understood at the neurotransmitter level. We investigated whether adult attachment style is linked to functioning of the opioid and serotonergic systems in the human brain. Methods We used positron emission tomography with radioligands [11C]carfentanil and [11C]MADAM to quantify mu opioid receptor (n = 39) and serotonin transporter (n = 37) availability in volunteers with no current psychiatric disorders. Attachment style was determined according to the Dynamic-Maturational Model of Attachment and Adaptation with the structured Adult Attachment Interview. Results Secure attachment was associated with higher mu opioid receptor availability in the hippocampus, amygdala, thalamus, and prefrontal cortex when compared with insecure (i.e., avoidant or ambivalent groups combined) attachment. In contrast, attachment style was not associated with serotonin transporter availability. Conclusions Our results provide preliminary in vivo evidence that the opioid system may be involved in the neurocircuits associated with individual differences in adult attachment behavior. The results suggest that variation in mu opioid receptor availability may be linked with the individuals’ social relationships and psychosocial well-being and thus contributes to risk for psychiatric morbidity.

Background Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research.

Background Functional recovery of patients with clinical and subclinical psychosis is associated with clinical, neuropsychological and developmental factors. Less is known about how these factors predict functional outcomes in the same models. We investigated functional outcomes and their predictors in patients with first-episode psychosis (FEP) or a confirmed or nonconfirmed clinical high risk of psychosis (CHR-P vs. CHR-N). Methods Altogether, 130 patients with FEP, 60 patients with CHR-P and 47 patients with CHR-N were recruited and extensively examined at baseline (T0) and 9 (T1) and 18 (T2) months later. Global Assessment of Functioning (GAF) at T0, T1 and T2 and psychotic, depression, and anxiety symptoms at T1 and T2 were assessed. Functional outcomes were predicted using multivariate repeated ANOVA. Results During follow-up, the GAF score improved significantly in patients with FEP and CHR-P but not in patients with CHR-N. A single marital status, low basic education level, poor work situation, disorganization symptoms, perceptual deficits, and poor premorbid adjustment in patients with FEP, disorganization symptoms and poor premorbid adjustment in patients with CHR-P, and a low basic education level, poor work situation and general symptoms in patients with CHR-N predicted poor functional outcomes. Psychotic symptoms at T1 in patients with FEP and psychotic and depression symptoms at T1 and anxiety symptoms at T2 in patients with CHR-P were associated with poor functioning. Conclusions In patients with FEP and CHR-P, poor premorbid adjustment and disorganization symptomatology are common predictors of the functional outcome, while a low education level and poor work situation predict worse functional outcomes in patients with FEP and CHR-N. Interventions aimed at improving the ability to work and study are most important in improving the functioning of patients with clinical or subclinical psychosis.

BackgroundFunctional recovery of patients with clinical and sub-clinical psychosis is associated with clinical, neuropsychological and developmental factors. Less is known how these factors predict functional outcome in same models.AimWe investigated functional outcome and its predictors in patients with first-episode psychosis (FEP) or confirmed vs. non-confirmed clinical high risk to psychosis (CHR-P vs. CHR-N).MethodsAltogether, 130 FEP, 60 CHR-P and 47 CHR-N patients were recruited and extensively examined at baseline (T0) and at 9 (T1) and 18 (T2) months after baseline. Global Assessment of Functioning (GAF) at T0, T1 and T2, and psychotic, depression and anxiety symptoms at T1 and T2 were assessed. Functional outcome was predicted in multivariate repeated ANOVA.ResultsDuring follow-up, GAF improved significantly in FEP and CHR-P but not in CHR-N patients. In FEP, single marital status, low basic education, poor work situation, disorganised symptoms, perceptual deficits and poor premorbid adjustment, in CHR-P, disorganised symptoms and poor premorbid adjustment and in CHR-N, low basic education, poor work situation and general symptoms predicted poor functional outcome. In FEP, psychotic symptoms at T1 and in CHR-P, psychotic and depression symptoms at T1 and anxiety symptoms at T2 associated with poor functioning.DiscussionIn FEP and CHR-P patients, poor premorbid adjustment and disorganised symptomatology are common predictors for functional outcome, while poor education and work situation predict poor functional outcome in FEP and CHR-N patients. Interventions aimed to improve studying and ability to work are most important in improving functioning of patients with clinical or subclinical psychosis.

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (ρ = 0.20) and disorganization (ρ = 0.23), and with worse verbal performance (ρ = −0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [11C]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (VT) of [11C]PBR28 was lower in patients compared to controls (p = 0.026; Cohen’s d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.

Background Bullying as a specific subtype of adverse life events is a major risk factor for poor mental health. Although many questionnaires on bullying are available, so far none covers bullying retrospectively throughout school and working life. To close this gap, the Bullying Scale for Adults (BSA) was designed. Methods Based on data of 622 participants from five European countries collected in the prospective multicenter Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study, we investigated whether the BSA is a reliable and valid measurement for bullying and whether there is a difference across different diagnostic groups of early mental disorders (recent onset depressive/ psychotic patients, patients at clinical high-risk of psychosis) and healthy controls. Results Bullying experiences were significantly less frequent in healthy controls than in patient groups, with no significant differences between the three clinical groups. The BSA exhibited a high item scale discrimination (r > .3) and very good internal consistency (Cronbach's α = .93). Four factors were identified: 1. Sexual harassment, 2. Emotional Abuse, 3. Physical Abuse, 4. Problems at school. The highly significant correlation between bullying, and childhood adversities and trauma (r = .645, p Discussion The BSA is the first validated questionnaire that, in retrospective, reliably records various aspects of bullying (incl. its consequences) not only throughout childhood but also working life. It can be used to assess bullying as a transdiagnostic risk factor of mental disorders in different mental disorders, esp. psychosis and depression.

Background Attrition rates and sampling bias in controlled clinical studies are a concern when evaluating the relevance of the results to a specific patient population in a real-life clinical / treatment setting. Dropout rates in studies on psychotic disorders are high and many eligibility criteria may lead to bias in study samples. We wanted to analyze how representative are the patient samples typically included in first-episode psychosis studies such as the Turku Early Psychosis (TEPS) study by using a platform of 3772 consecutive admissions to clinical psychiatric services of Turku Psychiatry. Methods TEPS study was started in 2011 as a part of a larger study on psychosis treatment processes in Turku Psychiatric services. Each patient, inpatient and outpatient, went through initial clinical screening by the treatment group which was followed by a structured evaluation if the screen for first-episode psychosis was positive. Between Oct 2011 and June 2016 there were 195 patients with first-episode psychosis (FEP) suitable to the TEPS study. Of them 102 were willing and 93 were not willing to participate or were not reached in a baseline structured evaluation. Using patient records, we compared if these two groups differed in terms of clinical variables, treatment or prognosis during a 1-year follow-up. Time of hospital stay, involuntary vs. voluntary admission, coercive measures during the hospital care, re-hospitalizations and drop-out from the clinical care during the follow-up were used as outcomes. Results Non-participating (NTP) group had higher rate of involuntary care than participating (TP) group (70 % vs 62 %) as well as higher rate of coercion during the treatment and higher rate of re-admissions during the follow-up than the TP group (36 % vs 22 % and 41 % vs 34 %, respectively) but these differences did not reach statistical significance. During the one-year follow-up NTP group had a significantly higher rate of dropping out from the clinical care than participating TP group (48 % vs 30 %, p=0.01). NTP group had also higher rate of dropping out of clinical treatment mainly because of patient non-adherence (33 % vs 16 %, p=0.03). Discussion Nearly half (47 %) of the intent-to-study FEP patients were not reached or declined to participate in our study. Non-participating patients had a slightly more severe illness and poorer treatment adherence during one-year follow-up. The clinical differences were not as marked as we expected. E.g. involuntary care, inpatient care and more coercion during the follow-up were not significantly different between NTP and TP groups. Nevertheless, the data suggest considerable differences between participating and non-participating patients with first-episode psychosis which should be taken in to account when evaluating the generalizability of the results for an unselected group of psychotic patients in ‘real-life’ clinical care.

Background Childhood adverse experiences (CAE) are associated with clinical psychiatric disorders and symptoms, and with volumetric abnormalities in the amygdala-hippocampus complex (AmHiC) and frontal lobe (FroL) in adulthood. Aim To study whether CAE are associated with reduced AmHiC and FroL and whether these structures mediate the effect of CAE on social anxiety and depression. Method In seven European centres, 374 patients with recent onset of psychosis (n = 127), clinical high-risk to psychosis (n = 119) or recent onset of depression (n = 128) were scanned with MRI and their FroL and AmHiC volumes were measured. They all completed self-report scales for assessment of CAE, social anxiety and depression. Results Of the CAE domains, physical abuse was associated specifically with reduced grey and white matter volumes of FroL and AmHiC in psychotic and high-risk patients. After controlling intracranial volume, PhyAb associated significantly with FroL and its grey matter volume in high-risk patients only. In mediation analyses, the effect of physical abuse on social anxiety was mediated via reduced FroL grey mater volume in high-risk patients. In them, when the effects of AmHiC and depression were controlled, the effect of physical abuse on social anxiety was mediated via FroL grey matter volume reduction. Conclusions Childhood physical abuse is associated with reduced frontal lobe and amygdala-hippocampus complex volume in adult subjects with psychotic symptoms. Reduced frontal lobe and amygdala-hippocampus complex volume mediate the effect of physical abuse on social anxiety in high-risk patients. The effect of physical abuse on depression-independent social anxiety is mediated via reduced frontal lobe.

Structural and functional abnormalities of the amygdala in schizophrenia have been well documented. Post-mortem studies suggest that the lateral nucleus is particularly affected in schizophrenia. It is not known whether the amygdala subnuclei are differently affected at the time of the first-episode psychosis or already at high-risk state. 75 first-episode psychosis patients (FEP), 45 clinical high-risk patients (CHR) and 76 population controls participated in this cross-sectional case-control study. Participants underwent T1-weighted 3T MRI scans, from which the amygdala was segmented using a newly developed automated algorithm. Because early adverse events increase risk for psychosis and affect the amygdala, we also tested whether experiences of childhood maltreatment associate with the putative amygdala subnuclei abnormalities. Compared to the population controls, FEP had smaller volumes of the lateral, and basal nuclei. In CHR, only the lateral nucleus was significantly smaller compared to the control subjects. Experience of childhood maltreatment was inversely associated with lateral nucleus volumes in FEP but not in CHR. These results show that the lateral and basal nuclei of the amygdala are already affected in FEP. These volumetric changes may reflect specific cellular abnormalities that have been observed in post-mortem studies in schizophrenia in the same subnuclei. Decreased volume of the lateral nucleus in CHR suggest that a smaller lateral nucleus could serve as a potential biomarker for psychosis risk. Finally, we found that the lateral nucleus volumes in FEP may be sensitive to the effects of childhood maltreatment.

The endocannabinoid system (ECS) has a widespread neuromodulatory function in the central nervous system and is involved in important aspects of brain function including brain development, cortical rhythms, plasticity, reward, and stress sensitivity. Many of these effects are mediated via the cannabinoid CB1 receptor (CB1R) subtype. Animal studies convincingly show an interaction between the ECS and sex hormones, as well as a sex difference of higher brain CB1R in males. Human in vivo studies of sex difference have yielded discrepant findings. Gender differences in CB1R availability were investigated in vivo in 11 male and 11 female healthy volunteers using a specific CB1R tracer [18F]FMPEP-d2 and positron emission tomography (PET). Regional [18F]FMPEP-d2 distribution volume was used as a proxy for CB1R availability. In addition, we explored whether CB1R availability is linked to neuropsychological functioning. Relative to females, CB1R availability was on average 41% higher in males (p = 0.002) with a regionally specific effect larger in the posterior cingulate and retrosplenial cortices (p = 0.001). Inter-subject variability in CB1R availability was similar in both groups. Voxel-based analyses revealed an inverse association between CB1R availability and visuospatial working memory task performance in both groups (p A CB1R sex difference with a large effect size was observed and should be considered in the design of CB1R-related studies on neuropsychiatric disorders. The behavioural correlates and clinical significance of this difference remain to be further elucidated, but our studies suggest an association between CB1R availability and working memory.

Background The amygdala volume is reduced already in the first episode of psychosis. The amygdala is a key region in emotional processing, and its volume reduction has been associated with severity of childhood adversity in psychotic patients. Since the amygdala is comprised of separate subnuclei with distinct anatomy and function we wanted to study whether these effects are present in some subnuclei more than others in first episode of psychosis. Methods We studied amygdala subnuclei volumes in 68 first-episode psychosis (FEP) patients (mean age = 27.1 ± 6.2, 35 females) and 65 healthy controls (mean 28.9 ± 6.5, 33 females) randomly selected from the general population. Subjects underwent a T1-weighted MRI with 1mm isotropic resolution (Philips Ingenuity 3T). The subnuclei volumes were generated with a new automated algorithm in FreeSurfer. Childhood adversity was measured using the Trauma and Distress Scale Scores (TADS). Baseline group differences in the amygdala subnuclei volumes were tested using repeated measures general linear model. The analyses were restricted to the four largest subnuclei: the lateral, basal, accessory basal, and the corticoamygdaloid transition area with volumes > 100 mm3. There were no differences between hemispheres nor group by hemisphere interactions so left and right hemispheres were averaged. All group comparisons were corrected for age, sex, and total intracranial volume. Association between the volumes and the TADS scores in the FEP group were also corrected for cumulative exposure to antipsychotic medication. Results We found that amygdala subnuclei were smaller in the FEP patients than in the the controls with regional specifity (subnucleus ROI*Group p = 0.015). In the FEP, the most robust reductions were in the lateral nucleus (Bonferroni corrected p = 0.036, β = -64.15). No statistically significant difference was observed in the basal nucleus, the accessory basal nucleus or the corticoamygdaloid transition area. The FEP patients had in average higher TADS total score (19.00 ± 13.56) compared to the HC (7.68 ± 7.07) (p < 0.001, t = 5.84). We found that particularly the TADS physical abuse score (FEP(n)=63, HC(n)=59) associated significantly differently with some subnuclei in patients and control group (ROI*Group*Physical abuse p = 0.016). The difference was significant only in the lateral nucleus (Group*Physical abuse p = 0.048, β = -34.97). However, there was an overall nonsignificant trend of the negative association between lateral nucleus volume and all TADS scores in the FEP. Similar trend was not seen in the controls. Discussion We show that the amygdala subnuclei are differently affected already in the first episode of psychosis. Compared to the controls, the FEP patients had smaller lateral nucleus volume, but not basal, accessory basal nucleus or corticoamygdaloid transition area. The lateral nucleus volume was also negatively associated with childhood traumatic experiences, particularly physical abuse in the FEP patients. These findings suggest the involvement of the lateral nucleus of amygdala in the association between childhood traumatic experiences and psychotic disorders. This is well in agreement with studies suggesting that the lateral nucleus of the amygdala is associated with fear learning, recovery from fear and regulation of fear expression.