Relation between self-perceived stress, psychopathological symptoms and the stress hormone prolactin in emerging psychosis.

BACKGROUND: Psychosocial stress and the stress hormone prolactin are assumed to play an important role in the pathogenesis of schizophrenia and related psychoses, and have been frequently observed to be increased in antipsychotic-naïve patients with a clinical high risk for psychosis (CHR-P) or first episode of psychosis (FEP). The aim of this study was to further elucidate the relationships between self-perceived stress, psychopathological symptoms and prolactin levels in these patients. METHODS: In this cross-sectional study, 45 healthy controls, 31 CHR-P patients and 87 FEP patients were recruited from two different study centers. Prolactin was measured under standardized conditions between 8 and 10 am. All patients were antipsychotic-naïve and not taking any prolactin influencing medication. Self-perceived stress during the last month was measured with the perceived stress scale (PSS-10) immediately before blood taking. RESULTS: Both CHR-P and FEP patients showed significantly higher levels of self-perceived stress and prolactin than controls. Hyperprolactinemia (i.e. prolactin levels above the reference range) was observed in 26% of CHR-P and 45% of FEP patients. Self-perceived stress was significantly positively associated with affective symptoms, but not with other symptoms. There was no significant association between self-perceived stress and prolactin levels. CONCLUSION: Our results confirm that CHR-P and FEP patients have higher stress levels than healthy controls and frequently have hyperprolactinemia, independent of antipsychotic medication. However, although it is well established that prolactin increases in response to stress, our results do not support the notion that increased prolactin levels in these patients are due to stress.

Sex differences in cognitive functioning of patients at-risk for psychosis and healthy controls: Results from the European Gene-Environment Interactions study.

BACKGROUND: Sex differences in cognitive functioning have long been recognized in schizophrenia patients and healthy controls (HC). However, few studies have focused on patients with an at-risk mental state (ARMS) for psychosis. Thus, the aim of the present study was to investigate sex differences in neurocognitive performance in ARMS patients compared with HC. METHODS: The data analyzed in this study were collected within the multicenter European Gene-Environment Interactions study (11 centers). A total of 343 ARMS patients (158 women) and 67 HC subjects (33 women) were included. All participants completed a comprehensive neurocognitive battery. Linear mixed effects models were used to explore whether sex differences in cognitive functioning were present in the total group (main effect of sex) and whether sex differences were different for HC and ARMS (interaction between sex and group). RESULTS: Women performed better in social cognition, speed of processing, and verbal learning than men regardless of whether they were ARMS or HC. However, only differences in speed of processing and verbal learning remained significant after correction for multiple testing. Additionally, ARMS patients displayed alterations in attention, current IQ, speed of processing, verbal learning, and working memory compared with HC. CONCLUSIONS: Findings indicate that sex differences in cognitive functioning in ARMS are similar to those seen between healthy men and women. Thus, it appears that sex differences in cognitive performance may not be specific for ARMS, a finding resembling that in patients with schizophrenic psychoses.

Gender differences of patients at-risk for psychosis regarding symptomatology, drug use, comorbidity and functioning - Results from the EU-GEI study.

BACKGROUND: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis. METHODS: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews. RESULTS: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing. CONCLUSIONS: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful.

Clinical and functional long-term outcome of patients at clinical high risk (CHR) for psychosis without transition to psychosis: A systematic review.

BACKGROUND: Research on patients at clinical high risk (CHR) for psychosis has so far mainly focused on those with transition to frank psychosis (CHR-T patients). However, the majority of CHR patients do not transition (CHR-NT patients) and relatively little information is available on their clinical and functional outcome. METHODS: We conducted a systematic review on clinical and functional long-term outcome of CHR-NT patients. Studies were included if they had an average follow-up period of at least 24 months and reported on long-term outcome of CHR-NT patients in one or more of the following domains: (non-)remission from CHR, prevalence of clinical symptoms and/or clinical diagnoses (axis I and II), and psychosocial functioning. RESULTS: Ten publications from seven different single or multicenter studies with average follow-up durations of 2-7.5 years could be included. At the last follow-up assessment 28-71% of CHR-NT patients were not remitted from their CHR and 22-82% still had at least one clinical diagnosis. Approximately half of CHR-NT patients presented with poor psychosocial outcome at 2-year and 6-year follow-up. CONCLUSIONS: The results suggest that, in the long-term, the majority of CHR-NT patients are not in full clinical remission and seem to suffer from one or more clinical disorders and psychosocial impairments. Since relatively few studies could be identified, further research is required to better understand the trajectories and clinical needs of CHR-NT patients.

Gender differences in first self-perceived signs and symptoms in patients with an at-risk mental state and first-episode psychosis.

AIM: Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self-perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. METHODS: ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models. RESULTS: One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported "unusual anxiety, fears" and men (at a trend level) "social withdrawal" as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported "increased worrying/anxiety" and (sub-threshold) "hallucinations", independent of diagnostic group. Problems with "thinking, concentration" were reported more frequently by men in the ARMS group only. CONCLUSION: Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub-threshold) positive and affective symptoms.

Exploring the predictive power of the unspecific risk category of the Basel Screening Instrument for Psychosis.

AIM: Ultrahigh risk (UHR) criteria, consisting of brief limited intermittent psychotic symptoms (BLIPS), attenuated psychotic symptoms (APS) and genetic risk and deterioration (GRD) syndrome are the most widely used criteria for assessing the clinical high-risk state for psychosis (CHR-P). The Basel Screening Instrument for Psychosis (BSIP) includes a further risk category, the unspecific risk category (URC). However, little is known about the predictive power of this risk category compared to other risk categories. METHODS: Two hundred CHR-P patients were detected as part of the Früherkennung von Psychosen (FePsy) study using the BSIP. Transition to psychosis was assessed in regular intervals for up to 7 years. RESULTS: Patients meeting only the URC criterion (n = 40) had a significantly lower risk of transition to psychosis than the UHR group (including BLIPS, APS and GRD) (HR 0.19 [0.05; 0.80] (P = 0.024). Furthermore, the URC only risk group had a lower transition risk than the APS without BLIPS group (P = 0.015) and a trendwise lower risk than the BLIPS group (P = 0.066). However, despite the lower transition risk in the URC only group, there were still two patients (5%) in this group with a later transition to psychosis. CONCLUSIONS: The URC includes patients who have a lower risk of transition than those included by the UHR categories and thereby increases the sensitivity of the BSIP. This offers the possibility of a stratified intervention, with these subjects receiving low intensity follow-up and treatment.

Plasma and serum brain-derived neurotrophic factor (BDNF) levels and their association with neurocognition in at-risk mental state, first episode psychosis and chronic schizophrenia patients.

Objectives: Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive processes. Since cognitive deficits are a core feature of psychotic disorders, the investigation of BDNF levels in psychosis and their correlation with cognition has received increased attention. However, there are no studies investigating BDNF levels in individuals with an at-risk mental state (ARMS) for psychosis. Hence, the aims of the present study were: (1) assessing peripheral BDNF levels across different (potential) stages of psychosis; (2) investigating their association with cognition.Methods: Plasma and serum BDNF levels and neuropsychological performance were assessed in 16 ARMS, six first-episode psychosis (FEP), and 11 chronic schizophrenia (CS) patients. Neuropsychological assessment covered intelligence, verbal memory, working memory, attention and executive functioning.Results: Both plasma and serum BDNF levels were highest in CS, intermediate in FEP and lowest in ARMS. Multiple regression analysis revealed a significant positive association of plasma BDNF levels with planning ability across all groups.Conclusions: The lower peripheral BDNF levels in ARMS compared to FEP and CS might point towards an important drop of this neurotrophin prior to the onset of frank psychosis. The associations of peripheral BDNF with planning-abilities match previous findings.

The relationship between negative symptoms and cognitive functioning in patients at clinical high risk for psychosis.

Negative symptoms and neurocognitive performance have been reported to be negatively associated in patients with emerging psychosis. However, most previous studies focused on patients with frank psychosis and did not differentiate between subdomains of negative symptoms. Hence, we aimed to elucidate the specific relationship between negative symptoms and cognitive functioning in patients at clinical high risk (CHR) for psychosis. Data from 154 CHR patients collected within the prospective Früherkennung von Psychosen (FePsy) study were analyzed. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and cognitive functioning with an extensive neuropsychological test battery. Regression analyses revealed significant negative associations between negative symptoms and cognitive functioning, particularly in the domains of nonverbal intelligence and verbal fluency. When analyzing each negative symptom domain separately, alogia and asociality/anhedonia were significantly negatively associated with nonverbal intelligence and alogia additionally with verbal fluency. Overall, our results in CHR patients are similar to those reported in patients with frank psychosis. The strong negative association between verbal fluency and negative symptoms may be indicative of an overlap between these constructs. Verbal fluency might have a strong influence on the clinical impression of negative symptoms (particularly alogia) and vice versa.

Evaluating verbal learning and memory in patients with an at-risk mental state or first episode psychosis using structural equation modelling.

BACKGROUND: Verbal learning and memory are impaired not only in patients with a first episode of psychosis (FEP) but also-to a lower extent-in those with an at-risk mental state for psychosis (ARMS). However, little is known about the specific nature of these impairments. Hence, we aimed to study learning and memory processes in ARMS and FEP patients by making use of structural equation modelling. METHODS: Verbal learning was assessed with the California Verbal Learning Test (CVLT) in 98 FEP patients, 126 ARMS patients and 68 healthy controls (HC) as part of the Basel early detection of psychosis (FePsy) study. The four-factorial CFA model of Donders was used to estimate test performance on latent variables of the CVLT and growth curve analysis was used to model the learning curve. The latter allows disentangling initial recall, which is strongly determined by attentional processes, from the learning rate. RESULTS: The CFA model revealed that ARMS and FEP patients were impaired in Attention Span, Learning Efficiency and Delayed Memory and that FEP patients were additionally impaired in Inaccurate Memory. Additionally, ARMS-NT, but not ARMS-T, performed significantly worse than HC on Learning Efficiency. The growth curve model indicated that FEP patients were impaired in both initial recall and learning rate and that ARMS patients were only impaired in the learning rate. CONCLUSIONS: Since impairments were more pronounced in the learning rate than the initial recall, our results suggest that the lower scores in the CVLT reported in previous studies are more strongly driven by impairments in the rate of learning than by attentional processes.

Can neuropsychological testing facilitate differential diagnosis between at-risk mental state (ARMS) for psychosis and adult attention-deficit/hyperactivity disorder (ADHD)?

BACKGROUND: Patients with an at-risk mental state (ARMS) for psychosis and patients with attention-deficit/hyperactivity disorder (ADHD) have many overlapping signs and symptoms and hence can be difficult to differentiate clinically. The aim of this study was to investigate whether the differential diagnosis between ARMS and adult ADHD could be improved by neuropsychological testing. METHODS: 168 ARMS patients, 123 adult ADHD patients and 109 healthy controls (HC) were recruited via specialized clinics of the University of Basel Psychiatric Hospital. Sustained attention and impulsivity were tested with the Continuous Performance Test, verbal learning and memory with the California Verbal Learning Test, and problem solving abilities with the Tower of Hanoi Task. Group differences in neuropsychological performance were analyzed using generalized linear models. Furthermore, to investigate whether adult ADHD and ARMS can be correctly classified based on the pattern of cognitive deficits, machine learning (i.e. random forests) was applied. RESULTS: Compared to HC, both patient groups showed deficits in attention and impulsivity and verbal learning and memory. However, in adult ADHD patients the deficits were comparatively larger. Accordingly, a machine learning model predicted group membership based on the individual neurocognitive performance profile with good accuracy (AUC = 0.82). CONCLUSIONS: Our results are in line with current meta-analyses reporting that impairments in the domains of attention and verbal learning are of medium effect size in adult ADHD and of small effect size in ARMS patients and suggest that measures of these domains can be exploited to improve the differential diagnosis between adult ADHD and ARMS patients.

Early detection of psychosis: helpful or stigmatizing experience? A qualitative study.

AIM: Despite the large scientific debate concerning potential stigmatizing effects of identifying an individual as being in an at-risk mental state (ARMS) for psychosis, studies investigating this topic from the subjective perspective of patients are rare. This study assesses whether ARMS individuals experience stigmatization and to what extent being informed about the ARMS is experienced as helpful or harmful. METHODS: Eleven ARMS individuals, currently participating in the follow-up assessments of the prospective Basel Früherkennung von Psychosen (FePsy; English: Early Detection of Psychosis) study, were interviewed in detail using a semistructured qualitative interview developed for this purpose. Data were analysed using Interpretative Phenomenological Analysis. RESULTS: Most individuals experiencing first symptoms reported sensing that there was 'something wrong with them' and felt in need of help. They were relieved that a specific term was assigned to their symptoms. The support received from the early detection centre was generally experienced as helpful. Many patients reported stigmatization and discrimination that appeared to be the result of altered behaviour and social withdrawal due to the prepsychotic symptoms they experienced prior to contact with the early detection clinic. CONCLUSIONS: The results suggest that early detection services help individuals cope with symptoms and potential stigmatization rather than enhancing or causing the latter. More emphasis should be put on the subjective experiences of those concerned when debating the advantages and disadvantages of early detection with regard to stigma. There was no evidence for increased perceived stigma and discrimination as a result of receiving information about the ARMS.

The Frankfurt Complaint Questionnaire for self-assessment of basic symptoms in the early detection of psychosis-Factor structure, reliability, and predictive validity.

OBJECTIVES: Patients with schizophrenia often experience subtle disturbances in several domains of information processing-so-called basic symptoms (BS). BS are already present before onset of frank psychosis and can be assessed by interviews but also by the self-administered Frankfurt Complaint Questionnaire (FCQ). We investigated the factor structure, reliability, and predictive validity for transition to psychosis of the FCQ, comparing previously proposed factor solutions containing 1, 2, 4, and 10 factors. METHODS: Confirmatory factor analysis was used in a sample of 117 at-risk mental state and 92 first-episode psychosis participants of the Basel FePsy (early detection of psychosis) study. RESULTS: Although all factor models fitted to the data, the 2- or 4-factor solutions performed best among the models that used at least half of the FCQ items, suggesting the covariance between FCQ items is best explained by 2 to 4 underlying factors. No FCQ-scale predicted transition to psychosis. CONCLUSION: We could confirm a 2- to 4-factor structure of the FCQ in a sample of at-risk mental state and first-episode psychosis patients using confirmatory factor analysis. Contrary to interview-assessed cognitive-perceptive BS, self-assessed BS do not seem to improve prediction of psychosis. This result reinforces reports of poor correspondence between interview- and questionnaire-assessed BS.

Sex differences in prolactin levels in emerging psychosis: Indication for enhanced stress reactivity in women.

BACKGROUND: Hyperprolactinemia is a known side effect of antipsychotics. In recent reports it has also been shown in antipsychotic-naïve at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. Prolactin is not only involved in reproduction and lactation, but is also synthesized in response to stress. As stress is thought to play an important role in the onset and relapse of schizophrenia, the aim of this study was to further elucidate the influence of prolactin in emerging psychosis. METHODS: The data analysed in this study were collected within the prospective Früherkennung von Psychosen (FePsy) study. Blood sample collection took place under standardized conditions between 8 and 10am after an overnight fast and 30minutes of rest. All patients were antipsychotic-naïve and did not take any prolactin influencing medication. RESULTS: Our sample consisted of 116 antipsychotic-naïve ARMS and 49 FEP patients. Hyperprolactinemia was shown in 32% of ARMS and 35% of FEP patients. After correction for the normal biological variation between the sexes, we still found higher average prolactin levels in female than in male patients (ß=0.42; t=2.47; p=0.01) but no difference in prolactin levels between ARMS and FEP patients (ß=-0.05; t=-0.30; p=0.76). The survival analysis revealed no significant predictive value for prolactin levels to predict transition to psychosis. CONCLUSION: Our findings support a possible role of prolactin in emerging psychosis and it could be speculated that stress, which can induce hyperprolactinemia, has a stronger effect on women than on men in emerging psychosis.

Correlations between self-rating and observer-rating of psychopathology in at-risk mental state and first-episode psychosis patients: influence of disease stage and gender.

AIM: Research findings on the correlations between self-rating and observer-rating of schizophrenic psychopathology are inconsistent and have rarely considered first-episode psychosis (FEP) and at-risk mental state (ARMS) for psychosis patients. This study investigates these correlations in ARMS and FEP patients and how they are moderated by disease stage and gender. METHODS: In the Basel Früherkennung von Psychosen (FePsy) study, positive and negative psychotic and affective symptoms were rated in 126 ARMS and 94 FEP patients using two observer- and three self-rating scales. The agreement between self-rating and observer-rating and the moderating influence of disease stage and gender was quantified using Pearson correlation and multiple regression models. RESULTS: Correlations between self- and observer-rated subscales covering the same symptom dimension were low and mostly non-significant except for one correlation of positive and one of negative symptoms. There was no moderating influence of disease stage and gender on the correlations between self-rating and observer-rating except for one higher association in positive symptoms in FEP compared to ARMS and in women compared to men. However, these significant interaction effects did not withstand correction for multiple testing. CONCLUSIONS: This study suggests that the agreement between self-rating and observer-rating in FEP and ARMS patients is rather low, similar across symptom dimensions, and only partially dependent on disease stage and gender. However, low correlations between self-rating and observer-rating do not necessarily indicate that these patients have difficulties reporting their symptoms. They could also have occurred because the scales did not exactly cover the same symptom dimensions.

Aberrant Current Source-Density and Lagged Phase Synchronization of Neural Oscillations as Markers for Emerging Psychosis.

BACKGROUND: Converging evidence indicates that neural oscillations coordinate activity across brain areas, a process which is seemingly perturbed in schizophrenia. In particular, beta (13-30 Hz) and gamma (30-50 Hz) oscillations were repeatedly found to be disturbed in schizophrenia and linked to clinical symptoms. However, it remains unknown whether abnormalities in current source density (CSD) and lagged phase synchronization of oscillations across distributed regions of the brain already occur in patients with an at-risk mental state (ARMS) for psychosis. METHODS: To further elucidate this issue, we assessed resting-state EEG data of 63 ARMS patients and 29 healthy controls (HC). Twenty-three ARMS patients later made a transition to psychosis (ARMS-T) and 40 did not (ARMS-NT). CSD and lagged phase synchronization of neural oscillations across brain areas were assessed using eLORETA and their relationships to neurocognitive deficits and clinical symptoms were analyzed using linear mixed-effects models. RESULTS: ARMS-T patients showed higher gamma activity in the medial prefrontal cortex compared to HC, which was associated with abstract reasoning abilities in ARMS-T. Furthermore, in ARMS-T patients lagged phase synchronization of beta oscillations decreased more over Euclidian distance compared to ARMS-NT and HC. Finally, this steep spatial decrease of phase synchronicity was most pronounced in ARMS-T patients with high positive and negative symptoms scores. CONCLUSIONS: These results indicate that patients who will later make the transition to psychosis are characterized by impairments in localized and synchronized neural oscillations providing new insights into the pathophysiological mechanisms of schizophrenic psychoses and may be used to improve the prediction of psychosis.