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.

No associations between medial temporal lobe volumes and verbal learning/memory in emerging psychosis.

Grey matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naïve ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Früherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naïve patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures.

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.

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.

Outcome of individuals "not at risk of psychosis" and prognostic accuracy of the Basel Screening Instrument for Psychosis (BSIP).

BACKGROUND: We aimed to determine the prognostic accuracy of the Basel Screening Instrument for Psychosis (BSIP) in terms of specificity, sensitivity, positive and negative predictive value by following up individuals that were initially not considered to be at increased risk of psychosis based on the BSIP. Moreover, clinical characteristics of these individuals were examined given the relative lack of such information in the literature. METHODS: As part of the "Früherkennung von Psychosen" (FePsy) study, 87 individuals were screened with the BSIP. Of these, 64 were classified at baseline as being in an at-risk mental state (ARMS+) for psychosis using the BSIP and followed up at regular time intervals for at least 2 years to determine a putative transition to psychosis. Twenty-three individuals were classified at baseline as not being in an at-risk mental state (ARMS-) using the BSIP and re-assessed after 4 years. Sensitivity, specificity, positive and negative predictive value of the BSIP were computed. Clinical characteristics of the ARMS- group were analysed descriptively. RESULTS: During the follow-up period, none of the ARMS- individuals, but 21 of ARMS+ had developed psychosis. Sensitivity of the BSIP was 1.0, specificity was 0.35. The majority of ARMS- individuals showed depressive disorders or anxiety disorders and varying levels of functioning. CONCLUSIONS: The BSIP has good prognostic accuracy for detecting the prodromal phase of psychosis with an excellent sensitivity and a specificity similar to other risk instruments and the advantage of a relatively short duration. Depressive and anxiety symptoms commonly develop in ARMS- individuals.

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.

Individualized metacognitive therapy for delusions: A randomized controlled rater-blind study.

BACKGROUND: Theory-driven interventions targeting specific factors that contribute to delusions are receiving increased interest. The present study aimed to assess the efficacy of individualized metacognitive therapy (MCT+), a short manualized intervention that addresses delusion-associated cognitive biases. METHODS: 92 patients with current or past delusions were randomized to receive 12 twice-weekly sessions of either MCT+ or a control intervention within a randomized controlled rater-blind design. Psychopathology and cognitive biases were assessed at baseline, 6 weeks and 6 months. ANCOVAs adjusted for baseline scores were used to assess differences between groups regarding outcome variables. Both per-protocol and intention-to-treat analyses were conducted. RESULTS: At 6 weeks, there was a significant difference in favor of MCT+ regarding decrease in delusion severity and improvement of self-reflectiveness (medium effect size), and a trend-wise difference regarding probability thresholds to decision. These effects increased, when only patients attending a minimum of 4 therapy sessions were considered. Control group patients subsequently showed further improvement while patients in the MCT+ group remained stable, such that there were no differences between groups at the 6-month follow-up. LIMITATIONS: Lower attendance rates in the control group possibly leading to unequal therapeutic effort; lower baseline delusion severity in the MCT+ group. CONCLUSIONS: The result pattern suggests that MCT+ led to earlier improvement in delusions and cognitive biases compared to the control intervention. The absence of a long-term effect might reflect floor effects in the MCT+ group, but may also indicate the need for further measures to promote sustainability of MCT+ effects.

[Why and how to treat psychosis earlier?] / Pourquoi et comment soigner plus précocement les troubles psychotiques ?

Chronic psychosis, as for instance schizophrenia, usually begins in young adulthood and may cause severe disability. It causes a mean loss of life expectancy of 22 years. Actual models of psychosis do not trace the beginning of psychosis to the first franc psychotic episode only, but to earlier symptoms. In a classical health system only considering the first psychotic episode, the mean duration of untreated illness (DUI) can last several years. Yet this DUI has a direct impact on the prognosis of the disease. Actual international recommendations prescribe to early detect and treat at risk mental states of psychosis, thus reducing DUI. Such an attitude also helps the patient to integrate care in a moment where she/he is fully in condition to consent and to adhere. Generalist practitioners are crucial actors of early detection. We describe here simple and standardized tools helping early detection of high-risk mental states of psychosis in primary care and the appropriate attitude to do it properly. Numerous countries have developed early detection and treatment centers for psychosis. It has been established that such interventions clearly decrease the risk of transition towards chronic psychosis and improve the prognosis. These recent data about early detection and intervention in psychosis are a major step forward in psychiatry practice. It is now necessary to largely develop such actions in France.

Neural oscillations in antipsychotic-naïve patients with a first psychotic episode.

OBJECTIVES: In chronic schizophrenic psychoses, oscillatory abnormalities predominantly occur in prefrontal cortical regions and are associated with reduced communication across cortical areas. Nevertheless, it remains unclear whether similar alterations can be observed in patients with a first episode of psychosis (FEP), a state characterised by pathological features occurring in both late prodromal patients and initial phases of frank schizophrenic psychoses. METHODS: We assessed resting-state electroencephalographic data of 31 antipsychotic-naïve FEP patients and 29 healthy controls (HC). We investigated the three-dimensional (3D) current source density (CSD) distribution and lagged phase synchronisation (LPS) of oscillations across small-scale and large-scale brain networks. We additionally investigated LPS relationships with clinical symptoms using linear mixed-effects models. RESULTS: Compared to HC, FEP patients demonstrated abnormal CSD distributions in frontal areas of the brain; while decreased oscillations were found in the low frequencies, an increase was reported in the high frequencies (P < 0.01). Patients also exhibited deviant LPS in the high frequencies, whose dynamics changed over increasing 3D cortico-cortical distances and increasing psychotic symptoms. CONCLUSIONS: These results indicate that in addition to prefrontal cortical abnormalities, altered synchronised neural oscillations are also present, suggesting possible disruptions in cortico-cortical communications. These findings provide new insights into the pathophysiological mechanisms of emerging schizophrenic psychoses.