Clinical Factors Influencing Improvement in Disorganization in Clinical High-Risk for Psychosis: Preliminary Findings From a 2-Year Follow-Up.

Antipsychotic (AP) prescription in clinical high risk for psychosis (CHR-P) subjects remains a divisive issue. Although official guidelines currently discourage AP treatment in CHR-P, it is common in clinical practice, especially for psychosis prevention. The aim of this study was to investigate whether baseline AP need (especially in high-dose) indexes a CHR-P subgroup with poorer prognosis and differs from AP-naïve subjects in terms of sociodemographic, clinical, and outcome parameters across a 2-year follow-up. CHR-P participants were treated within an "Early Intervention in Psychosis" program and completed the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale both at baseline and every 12 months. Individuals with baseline AP prescription were included in the high-dose or low-dose CHR-P-AP+ subgroup. The others were grouped as AP-naïve. Cox regression analyses and mixed-design ANOVA were performed. 180 CHR-P individuals were enrolled (32 high-dose, 60 low-dose, and 88 AP-naïve). Compared to AP-naive, CHR-P AP+ subgroups showed older age and more severe clinical presentation. High-dose subgroup also had grater functioning decline at entry and poorer functional recovery at follow-up. No inter-group differences in psychosis transition and symptomatic remission were found. Significant improvement in clinical outcomes were found over time in all subgroups. Baseline AP prescription was specifically associated with a more relevant improvement in PANSS total score, and in negative and disorganized symptoms. Our results suggest that baseline AP need is an important prognostic parameter in CHR-P and should be considered in risk/benefit calculators.

Despite recommendations that young people at clinical high risk (CHR) for psychosis receive stepped treatment, few programs have published details of their clinical models or outcomes. This study describes the preliminary effectiveness of a risk calculator-informed stepped care model used at the Yale PRIME Clinic, a specialized outpatient clinic for young people at CHR. Seventy-one individuals (ages 12-25) at CHR enrolled in Yale's PRIME Clinic during the first four years of the treatment program. Participants completed clinical assessments at six timepoints over two years of treatment within a care model informed by an empirically grounded psychosis risk calculator. Linear mixed-effect models were fit to examine changes in clinical symptoms over time, and sensitivity analyses evaluated differences in clinical trajectories between completers and non-completers. Individuals engaged in treatment demonstrated significant and sustained improvements in positive, negative, general, disorganized, and depressive symptoms. Improvements in positive symptoms emerged by 6 months and continued to improve across most subsequent timepoints (6, 12, and 24 months). Pattern mixture analyses suggested that clinical trajectories did not significantly differ between completers and non-completers, though non-completers possessed more heterogeneous trajectories. A stepped care model informed by individualized risk calculator scores was feasible for delivery in a specialized outpatient setting, and was associated with broad symptom improvement for young people at CHR. Further controlled studies with blinded raters are needed to further confirm the efficacy of stepped care models and isolate the active components of treatment. Participants at clinical high risk for psychosis experienced significant reductions in attenuated psychotic symptoms and improvements in mood while enrolled in a risk-calculator-informed stepped care treatment model.Participants who disengaged from treatment did not have significantly different clinical trajectories than those who remained in care.The results suggest preliminary evidence for the feasibility of implementing a risk-calculator-informed stepped care model.

Auditory P300 as a predictor of short-term prognosis in subjects at clinical high risk for psychosis

Suicidal ideation has high rates among individuals at Clinical High Risk for Psychosis (CHR-P). CHR-P mental states are currently defined as attenuated psychotic symptoms, brief intermittent psychotic symptoms, or genetic risk and functioning deterioration syndrome. However, the relationship between psychotic experiences and suicidality in CHR-P subjects is still not fully understood. Research emphasizes the need to address suicidality in CHR-P individuals due to its incidence and severe socio-economic impact. This study aimed to assess the baseline prevalence and 2-year incidence rates of suicidal thinking and behaviors in an Italian CHR-P sample, investigate the stability of suicidal ideation over 2 years, and examine its associations with treatment outcomes, sociodemographic characteristics, and clinical factors. CHR-P participants were treated in an "Early Intervention in Psychosis" program and completed the PANSS and the GAF scale at baseline and every 12 months. 180 CHR-P individuals were enrolled (92 with suicidal ideation [SI+]). SI+ subjects had a higher baseline prevalence of past suicide attempts. Over 2 years, a decrease in suicidal ideation severity was observed in the total group. Longitudinal improvement in disorganized symptoms was a key predictor of the decrease in suicidal ideation. Participants with a history of suicide attempts were more likely to attempt again. Addressing disorganization is crucial for suicide prevention in the CHR-P population. Continuous risk monitoring and preventive actions are needed for those with past suicide attempts.

BackgroundBeneficial effects of N-acetyl-cysteine (NAC) on negative symptoms in chronic schizophrenia have been reported in two studies. A recent study in early psychosis from our group, did not report significant improvement in negative symptoms (potentially linked to the modest baseline levels) but showed improvement in cognition (i.e. processing speed) and an increase in the brain antioxidant glutathione (GSH) levels, indicating good target engagement.1 Indeed, research in animal models highlights the critical role of redox regulation by brain GSH for white matter maturation and maintenance. Given the strong evidence of white matter (WM) alterations in schizophrenia as well as the current lack of etiological treatments, redox dysregulation is an interesting target. The current study aims at investigating the impact of NAC, a precursor of GSH, the main antioxidant in the brain, on WM integrity in patients in the early psychosis phase. We focused on the fornix bundle that has been shown to be impaired in an animal model of oxidative stress2 (i.e. impaired GSH synthesis) as well as in early psychosis patients.3MethodsWM diffusion properties were estimated using generalized fractional anisotropy (gFA) computed from diffusion spectrum imaging (DSI) brain scans acquired in patients who received either NAC (n=10; mean age=25.3 ± 5.7; males/females 9/1) or placebo (n=10; mean age=24.8 ± 7.9; males/females 5/5) as add-on treatment over 6-months. GSH levels were measured in the medial prefrontal cortex using Magnetic Resonance Spectroscopy (MRS).ResultsA non-parametric longitudinal voxel-based analysis limited to the fornix revealed a time x treatment interaction which reached significance in the body of the fornix (corrected p<.04) with NAC patients showing an increase in gFA over 6-month of treatment. Importantly, improvement of gFA (i.e. increase) in the fornix of early psychosis patients (NAC and placebo) correlated with increase in cerebral GSH levels (r=.67; p<.005).DiscussionThis study is the first to assess the effect of NAC on WM integrity as assessed by diffusion weighted-imaging in the early phase of psychosis. WM alterations appear early in the illness and become widespread in a more chronic phase of the disease.4 To the best of our knowledge there is currently no approved medication for schizophrenia that show significant effect on WM integrity. In this study, effects of NAC on WM integrity in the fornix were significant despite the limited sample size. This is a small-scale proof of concept study, which was very demanding for early psychosis patients and needs replication in a larger study. Its potential properties to counteract WM deficits may be even more important in individuals at clinical high risk for psychosis. As NAC add-on treatment is safe with no side effects, this study paves the way for preventive approach at the early stages of psychosis.

Recent stressful life events (SLE) are a risk factor for psychosis, but limited research has explored how SLEs affect individuals at clinical high risk (CHR) for psychosis. The current study investigated the longitudinal effects of SLEs on functioning and symptom severity in CHR individuals, where we hypothesized CHR would report more SLEs than healthy controls (HC), and SLEs would be associated with poorer outcomes. The study used longitudinal data from the EU-GEI High Risk study. Data from 331 CHR participants were analyzed to examine the effects of SLEs on changes in functioning, positive and negative symptoms over a 2-year follow-up. We compared the prevalence of SLEs between CHR and HCs, and between CHR who did (CHR-T) and did not (CHR-NT) transition to psychosis. CHR reported 1.44 more SLEs than HC (p < 0.001), but there was no difference in SLEs between CHR-T and CHR-NT at baseline. Recent SLEs were associated with poorer functioning and more severe positive and negative symptoms in CHR individuals (all p < 0.01) but did not reveal a significant interaction with time. CHR individuals who had experienced recent SLEs exhibited poorer functioning and more severe symptoms. However, as the interaction between SLEs and time was not significant, this suggests SLEs did not contribute to a worsening of symptoms and functioning over the study period. SLEs could be a key risk factor to becoming CHR for psychosis, however further work is required to inform when early intervention strategies mitigating against the effects of stress are most effective.

The "early intervention" paradigm in psychiatry holds significant promise for preventing psychosis. Recent evidence showed that individuals at clinical high risk for psychosis (CHR-P) with antipsychotic (AP) prescription at baseline have higher psychosis transition rates compared with those without AP, although the underlying cause remains unclear. In this article, we reviewed international guidelines on early intervention in CHR-P people, paying specific attention to clinical recommendations on AP treatment. Then, we comment on these suggestions in the light of recent empirical evidence examining AP prescription in CHR-P populations within "real-world" clinical settings. This search was conducted on PubMed/MEDLINE, PsycINFO, EMBASE, and Google, looking for both "Guidelines AND CHR-P OR UHR OR Early Psychosis." International guidelines generally recommend not using AP as first-line treatment, but only when psychosocial interventions have failed. CHR-P people with AP drug showed high prevalence rates and had more severe clinical picture at entry. Is this a "warning signal" for potentially higher psychosis transition risk? Is it a direct AP iatrogenic effect? Is it possible to detect specific CHR-P subgroup that may benefit from AP? These are the questions that this article seeks to explore. The current framework for identifying CHR-P subjects has defined psychometric criteria mainly based on positive symptoms. In our opinion, this is reductive, especially for evaluating therapeutic outcomes and prognosis. A more comprehensive assessment considering quality of life, psychiatric comorbidity, persistent negative symptoms, subjective experience of CHR-P psychopathology, and social/personal recovery is thus needed.

Youth at clinical high risk (CHR) for psychosis often demonstrate significant negative symptoms, which have been reported to be predictive of conversion to psychosis and a reduced quality of life but treatment options for negative symptoms remain inadequate. Therefore, we conducted a systematic review and network meta-analysis of all intervention studies examining negative symptom outcomes in youth at CHR for psychosis. The authors searched PsycINFO, Medline, Embase, CINAHL, and EBM from inception to December 2016. Studies were selected if they included any intervention that reported follow-up negative symptoms in youth at CHR for psychosis. Treatment comparisons were evaluated using both pairwise and network meta-analyses. Due to the differences in negative symptom scales the effect sizes were reported as the standardized mean difference (SMD). Of 3027 citations, 32 studies met our inclusion criteria, including a total of 2463 CHR participants. The null hypothesis was not rejected for any of the 11 treatments. N-methyl-D-aspartate-receptor (NMDAR) modulators trended toward a significant reduction in negative symptoms compared to placebo (SMD = -0.54; 95% CI = -1.09 to 0.02; I2 = 0%, P = .06). In respective order of descending effectiveness as per the treatment hierarchy, NMDAR modulators were more effective than family therapy, need-based interventions, risperidone, amisulpride, cognitive behavioral therapy, omega-3, olanzapine, supportive therapy, and integrated psychological interventions. Efficacy and effectiveness were not confirmed for any negative symptom treatment. Many studies had small samples and the majority were not designed to target negative symptoms.

Disorganization is a nuclear dimension of psychosis, especially in schizophrenia. Despite its relevant association with poor prognosis and negative outcomes, it is still under-investigated compared to positive and negative symptoms, in particular at the onset of illness. This study explored disorganization in youth at Clinical High Risk for Psychosis (CHR-P) over a 2-year period. A sample of 180 CHR-P participants (50% males; 51.1% with baseline second-generation antipsychotic medication) recruited within a specialized CHR-P service completed the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale. Across the follow-up, we examined key associations of disorganization with other domains of psychopathology, functioning, and treatment response using Spearman’s rank correlation coefficients and linear regression analyses. Our results showed a significant longitudinal reduction in disorganization severity levels across the follow-up. This decrease was significantly associated with improvements in negative symptoms and daily functioning, with a shorter duration of untreated psychiatric symptoms, and with baseline equivalent dose of antipsychotic medication. No significant longitudinal associations with other treatment component of the PARMS program were found. Our findings suggest a longitudinal improvement in disorganization dimension in CHR-P individuals, especially in the context of early interventions targeting reduction in the duration of untreated psychiatric symptoms and favoring a prompt antipsychotic therapy.

The possible association between the duration of untreated prodromal symptoms (DUPrS) and cognitive functioning in individuals at clinical high risk (CHR) for psychosis remains underexplored. To investigate the intricate interplay between DUPrS, cognitive performance, and conversion outcomes, shedding light on the potential role of DUPrS in shaping cognitive trajectories and psychosis risk in individuals at CHR for psychosis. This cohort study of individuals at CHR for psychosis was conducted at the Shanghai Mental Health Center in China from January 10, 2016, to December 29, 2021. Participants at CHR for psychosis typically exhibit attenuated positive symptoms; they were identified according to the Structured Interview for Prodromal Syndromes, underwent baseline neuropsychological assessments, and were evaluated at a 3-year clinical follow-up. Data were analyzed from August 25, 2021, to May 10, 2023. Duration of untreated prodromal symptoms and cognitive impairments in individuals at CHR for psychosis. The primary study outcome was conversion to psychosis. The DUPrS was categorized into 3 groups based on percentiles (33rd percentile for short [≤3 months], 34th-66th percentile for median [4-9 months], and 67th-100th percentile for long [≥10 months]). The DUPrS, cognitive variables, and the risk of conversion to psychosis were explored through quantile regression and Cox proportional hazards regression analyses. This study included 506 individuals (median age, 19 [IQR, 16-21] years; 53.6% [n = 271] women). The mean (SD) DUPrS was 7.8 (6.857) months, and the median (IQR) was 6 (3-11) months. The short and median DUPrS groups displayed poorer cognitive performance than the long DUPrS group in the Brief Visuospatial Memory Test-Revised (BVMT-R) (Kruskal-Wallis χ2 = 8.801; P = .01) and Category Fluency Test (CFT) (Kruskal-Wallis χ2 = 6.670; P = .04). Quantile regression analysis revealed positive correlations between DUPrS rank and BVMT-R scores (<90th percentile of DUPrS rank) and CFT scores (within the 20th-70th percentile range of DUPrS rank). Among the 506 participants, 20.8% (95% CI, 17.4%-24.5%) converted to psychosis within 3 years. Cox proportional hazards regression analysis identified lower educational attainment (hazard ratio [HR], 0.912; 95% CI, 0.834-0.998), pronounced negative symptoms (HR, 1.044; 95% CI, 1.005-1.084), and impaired performance on the Neuropsychological Assessment Battery: Mazes (HR, 0.961; 95% CI, 0.924-0.999) and BVMT-R (HR, 0.949; 95% CI, 0.916-0.984) tests as factors associated with conversion. The finding of this cohort study suggest the intricate interplay between DUPrS, cognitive performance, and conversion risk in individuals at CHR for psychosis. The findings emphasize the importance of considering both DUPrS and cognitive functioning in assessing the trajectory of these individuals.

Reliability and validity of the Calgary Depression Scale for Schizophrenia (CDSS) in youth at clinical high risk for psychosis

The moderating role of lifetime social engagement on the relationship between C-reactive protein and negative symptoms among young adults at clinical high risk for psychosis.

Background and HypothesisNegative symptom trajectory in clinical high risk (CHR) for psychosis is ill defined. This study aimed to better characterize longitudinal patterns of change in negative symptoms, moderators of change, and differences in trajectories according to clinical subgroups. We hypothesized that negative symptom course will be nonlinear in CHR. Clinical subgroups known to be more severe variants of psychotic illness—deficit syndrome (DS), persistent negative syndrome (PNS), and acute psychosis onset—were expected to show more severe baseline symptoms, slower rates of change, and less stable rates of symptom resolution. Study DesignLinear, curvilinear, and stepwise growth curve models, with and without moderators, were fitted to negative symptom ratings from the NAPLS-3 CHR dataset (N = 699) and within clinical subgroups. Study ResultsNegative symptoms followed a downward curvilinear trend, with marked improvement 0–6 months that subsequently stabilized (6–24 months), particularly among those with lower IQ and functioning. Clinical subgroups had higher baseline ratings, but distinct symptom courses; DS vs non-DS: more rapid initial improvement, similar stability of improvements; PNS vs non-PNS: similar rates of initial improvement and stability; transition vs no transition: slower rate of initial improvement, with greater stability of this rate. ConclusionsContinuous, frequent monitoring of negative symptoms in CHR is justified by 2 important study implications: (1) The initial 6 months of CHR program enrollment may be a key window for improving negative symptoms as less improvement is likely afterwards, (2) Early identification of clinical subgroups may inform distinct negative symptom trajectories and treatment needs.

Brain changes associated with negative symptoms in clinical high risk for psychosis: A systematic review

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