Neurocognition and NMDAR co-agonists pathways in individuals with treatment resistant first-episode psychosis: a 3-year follow-up longitudinal study.

This study aims to determine whether 1) individuals with treatment-resistant schizophrenia display early cognitive impairment compared to treatment-responders and healthy controls and 2) N-methyl-D-aspartate-receptor hypofunction is an underlying mechanism of cognitive deficits in treatment-resistance. In this case‒control 3-year-follow-up longitudinal study, n = 697 patients with first-episode psychosis, aged 18 to 35, were screened for Treatment Response and Resistance in Psychosis criteria through an algorithm that assigns patients to responder, limited-response or treatment-resistant category (respectively resistant to 0, 1 or 2 antipsychotics). Assessments at baseline: MATRICS Consensus Cognitive Battery; N-methyl-D-aspartate-receptor co-agonists biomarkers in brain by MRS (prefrontal glutamate levels) and plasma (D-serine and glutamate pathways key markers). Patients were compared to age- and sex-matched healthy controls (n = 114). Results: patient mean age 23, 27% female. Treatment-resistant (n = 51) showed lower scores than responders (n = 183) in processing speed, attention/vigilance, working memory, verbal learning and visual learning. Limited responders (n = 59) displayed an intermediary phenotype. Treatment-resistant and limited responders were merged in one group for the subsequent D-serine and glutamate pathway analyses. This group showed D-serine pathway dysregulation, with lower levels of the enzymes serine racemase and serine-hydroxymethyltransferase 1, and higher levels of the glutamate-cysteine transporter 3 than in responders. Better cognition was associated with higher D-serine and lower glutamate-cysteine transporter 3 levels only in responders; this association was disrupted in the treatment resistant group. Treatment resistant patients and limited responders displayed early cognitive and persistent functioning impairment. The dysregulation of NMDAR co-agonist pathways provides underlying molecular mechanisms for cognitive deficits in treatment-resistant first-episode psychosis. If replicated, our findings would open ways to mechanistic biomarkers guiding response-based patient stratification and targeting cognitive improvement in clinical trials.

The co-occurrence of manic and depressive dimensions in early psychosis: a latent transition analysis.

BACKGROUND: Frequently associated with early psychosis, depressive and manic dimensions may play an important role in its course and outcome. While manic and depressive symptoms can alternate and co-occur, most of the studies in early intervention investigated these symptoms independently. The aim of this study was therefore to explore the co-occurrence of manic and depressive dimensions, their evolution and impact on outcomes. METHODS: We prospectively studied first-episode psychosis patients (N = 313) within an early intervention program over 3 years. Based on latent transition analysis, we identified sub-groups of patients with different mood profiles considering both manic and depressive dimensions, and studied their outcomes. RESULTS: Our results revealed six different mood profiles at program entry and after 1.5 years follow-up (absence of mood disturbance, co-occurrence, mild depressive, severe depressive, manic and hypomanic), and four after 3 years (absence of mood disturbance, co-occurrence, mild depressive and hypomanic). Patients with absence of mood disturbance at discharge had better outcomes. All patients with co-occurring symptoms at program entry remained symptomatic at discharge. Patients with mild depressive symptoms were less likely to return to premorbid functional level at discharge than the other subgroups. Patients displaying a depressive component had poorer quality of physical and psychological health at discharge. CONCLUSIONS: Our results confirm the major role played by mood dimensions in early psychosis, and show that profiles with co-occurring manic and depressive dimensions are at risk of poorer outcome. An accurate assessment and treatment of these dimensions in people with early psychosis is crucial.

Substance-use disorders, personality traits, and sex differences in institutionalized adolescents.

BACKGROUND: Substance-use disorder (SUD) was found to be an aggravating factor to delinquency and is closely related to personality disorders (PDs). OBJECTIVES: The aim of this study was to investigate sex differences in the relationship between PD traits and SUD in adolescents institutionalized in child welfare and juvenile justice institutions. METHODS: PD traits were measured dimensionally in a sample of 282 boys (69 with an SUD diagnosis) and 143 girls (45 with an SUD diagnosis) from child welfare and juvenile-justice institutions. RESULTS: Logistic regressions showed that antisocial, borderline, and paranoid personality traits were positively associated with SUD, while obsessive compulsive personality traits were negatively related with SUD. Additionally, in institutionalized girls, self-defeating personality traits were associated with less risk of SUD. CONCLUSION: This study provides a relative evidence for sex specificities in the relation between PD traits and SUD.

Interactions between mood and paranoid symptoms affect suicidality in first-episode affective psychoses.

BACKGROUND: Suicide prevention is a major challenge in the treatment of first-episode affective psychoses. The literature reports that combinations of manic, depressive and paranoid symptoms, which may interact, are associated with an increased risk of suicide. The present study investigated whether interactions between manic, depressive and paranoid symptoms affected suicidality in first-episode affective psychoses. METHODS: We prospectively studied 380 first-episode psychosis patients enrolled in an early intervention programme and diagnosed with affective or non-affective psychoses. We compared intensity and presence of suicidal thoughts and occurrence of suicide attempts over a three-year follow-up period and investigated the impact of interactions between manic, depressive and paranoid symptoms on level of suicidality. RESULTS: At 12 months follow-up, we observed a higher level of suicidal thoughts and higher occurrence of suicide attempts among the affective psychoses patients compared to non-affective psychoses patients. Combined presence of either depressive and paranoid symptoms, or manic and paranoid symptoms, was significantly associated with increased suicidal thoughts. However, the combination of depressive and manic symptoms showed a significant negative association with suicidal thoughts. CONCLUSIONS: This study suggests that paranoid symptoms combined with either manic or depressive symptoms are associated with an increased risk of suicide in first-episode affective psychoses. Detailed assessment of these dimensions is therefore warranted in first-episode affective patients and integrated treatment should be adapted to increased suicidal risk, even if patients do not display full-blown depressive or manic syndromes.

The differential impact of duration of untreated psychosis on functioning and quality of life: A threshold analysis.

AIM: Reduction of duration of untreated psychosis (DUP) remains a key goal of early intervention programs. While a significant body of literature suggests that a short DUP has a positive impact on outcome, little is known regarding the threshold above which various dimensions of outcome are impaired. In this study, we explore the DUP threshold that best discriminates subgroups with poorer outcome regarding global functioning and quality of life after 3 years of treatment. METHOD: A total of 432 patients were followed-up prospectively over 3 years. Several hypothetical cut-off points for DUP were tested in order to maximize differences in effect size for quality of life and general functioning. RESULTS: While a DUP cut-off of 86 weeks defined two subpopulations with a difference of greatest effect size in quality of life after 3 years, it is already at a cut-off of 3 weeks of DUP that two subpopulations with a difference in global functioning of the greatest effect size was reached. CONCLUSION: DUP seems to have a differential impact on the various components of outcome, and in particular on quality of life and global functioning. Our data suggest that aiming at very short DUP is justified, but that DUP over 3 weeks are still compatible with good quality of life after 3 years of treatment.

Grouping affective psychoses in early intervention: Justification for specific treatment guidelines.

The concept of affective psychosis regroups psychotic disorders with mood syndrome. Previous studies provided evidence to support a dichotomy between affective and non-affective psychoses although questions remain regarding the utility and validity of such a category to develop clinical guidelines. The aim of this study is to explore similarities and differences within affective psychoses to question whether strategies would apply to all the diagnoses falling under this umbrella term. Using Bayesian model comparison methods, we explored the homogeneity of the characteristics of first-episode affective patients (N = 77) treated in a specialized 3-year early intervention in psychosis programme. Our analysis revealed affective psychoses display many similarities regarding socio-demographic variables, the course of positive and manic symptoms over three years, and outcome at discharge. Our results did not support the heterogeneous model. However, despite no significant differences in the course of symptoms with the major depressive disorder group, the schizoaffective disorder group displayed a more severe clinical picture at the beginning of the programme and a poorer functional outcome than the two other groups. Absence of clear boundaries and the several similarities within affective psychoses suggest they can usefully be grouped to define treatment strategies that are easily legible by clinicians.

Subtyping based on premorbid profile: A strategy to personalize treatment in first-episode affective psychosis.

AIM: Premorbid history may have a major influence on the way patients cope with the onset of psychosis. This issue has been widely studied in the context of early intervention in schizophrenia but considerably less is known regarding affective psychosis. Our first goal was to investigate if subgroups could be identified among affective psychosis patients based on premorbid factors. Our second goal was to compare these subtypes according to the evolution of mood symptoms and outcomes at the end of the program. METHODS: We conducted a 3-year prospective study on a sample of 74 adults aged 18-35 with a first episode of affective psychosis. Latent class analysis (LCA) was used to reveal distinct exploratory subgroups within affective psychosis patients. RESULTS: Three distinct subgroups could be distinguished. One with later onset of psychosis mainly including women with more severe depressive symptoms in the first 6 months contrasting with two other subgroups with more severe manic symptoms all along the follow-up and earlier onset of psychosis, with or without many serious antecedents. The subgroup with many serious antecedents was more likely to require several hospitalizations, less likely to achieve recovery, especially regarding professional integration and return to premorbid general functioning. CONCLUSIONS: This study provides further evidence of poor functional recovery in the early phase of affective psychosis and shows that premorbid characteristics allow the identification of subgroups with distinct outcome which may require specification of treatment.

Exploring the clinical relevance of a dichotomy between affective and non-affective psychosis: Results from a first-episode psychosis cohort study.

AIM: Defining diagnosis is complex in early psychosis, which may delay the introduction of an appropriate treatment. The dichotomy of affective and non-affective psychosis is used in clinical setting but remains questioned on a scientific basis. In this study, we explore the clinical relevance of this dichotomy on the basis of clinical variables in a sample of first-episode psychosis patients. METHOD: We conducted a prospective study in a sample of 330 first-episode psychosis treated at an early intervention program. Affective and non-affective psychosis patients were compared on premorbid history, baseline data, outcomes and course of symptoms over the 3 years of treatment. RESULTS: Affective psychosis patients (22.42%) were more likely to be female, and had a shorter duration of untreated psychosis. The longitudinal analyses revealed that positive symptoms remained higher over the entire follow-up in the non-affective sub-group. A higher degree of variability of manic symptoms and a significantly better insight after 6 months were observed in the affective sub-group. No difference was observed regarding depressive and negative symptoms. At discharge, only the environmental quality of life and insight recovery were better in affective psychosis. CONCLUSIONS: Our study suggests that despite marginal differences at baseline presentation, these sub-groups differ regarding outcome, which may require differentiation of treatment and supports the utility of this dichotomy.

Evidence of mediation of severity of anxiety and depressive symptoms between abuse and positive symptoms of psychosis.

BACKGROUND: Considerable evidence on general population suggests that an "Affective pathway to psychosis", involving depression and anxiety dimensions, mediates the abuse-psychosis association. However, this has never been tested in Early Psychosis (EP) patients. We aim at testing whether severity of depressive and anxiety mediates the abuse-positive symptoms dyad in an EP prospective sample. METHODS: 330 EP subjects aged 18-35 were assessed for psychopathology after 2, 6, 12, 18, 24, 30, and 36 months of treatment. Abuse was considered as facing at least one experience of physical, sexual, or emotional abuse before age 16. Positive psychotic symptoms and anxiety were measured with the Positive and Negative Syndrome Scale and depressive symptoms with the Montgomery-Asberg Depression Rating Scale. Mediation analyses were performed to study whether the abuse-positive symptom's link was mediated by depressive, anxiety, and a combination of anxiety/mood symptoms. RESULTS: Among the 330 EP patient included, 104 (31.5% of the total) were exposed to abuse. Analyses across the 36 months of follow-up showed that depression and anxiety partially mediated 26.7% of the total effect of the abuse-positive symptoms association (indirect effects (IE) = 0.392 and 0.421 respectively), while the combined anxiety/mood model mediated 28.9% (IE = 0.475). Subanalyses at two and 36 months revealed a consistent role of depression, while that of anxiety was only present at baseline. CONCLUSION: Our work confirms a mediating role of mood and anxiety in the association between abuse and positive symptoms during the first three years of treatment.

Dynamics between insight and medication adherence in first-episode psychosis: Study of 3-year trajectories.

BACKGROUND: While specialized early intervention programs represent the gold standard in terms of optimal management of first-episode psychosis (FEP), poor medication adherence remains a predominant unmet need in the treatment of psychosis. In this regard, an interaction between insight and adherence in FEP patients has been hypothesized but has been challenged by multiple pitfalls. METHODS: Latent profile analysis and trajectory modeling techniques were used to evaluate insight and adherence of 331 FEP patients engaged at the beginning, middle, and end of a 3-year specialized early psychosis program. A Bayesian model comparison approach was used to compare scores of clinical, functional, and socioeconomic outcomes at the end point of the study. RESULTS: Nearly one-third of the patients maintain a high level of insight and adherence during the entire program. At the end of the 3-year follow-up, more than three-quarters of patients are considered adherent to their medication. Patients with low levels of insight and adherence at the beginning of the program improve first in terms of adherence and then of insight. Furthermore, patients with high levels of insight and adherence are most likely to reach functional recovery and to experience an increase in environmental quality of life. CONCLUSIONS: Latent FEP subpopulations can be identified based on insight and adherence. Medication adherence was the first variable to improve, but a gain in insight possibly plays a role in the reinforcement of adherence.

Symptom dimensions stability over time in recent onset psychosis: A prospective study.

BACKGROUND: The factorial structure of schizophrenia symptoms has been much debated but little is known on its degree of unicity, specificity as well as its dynamic over time. Symptom differentiation is a phenomenon according to which patients' symptoms could differentiate from one another during illness to form more independent, distinct dimensions. On the contrary, symptom dedifferentiation is an increase in the correlations between those symptoms over time. The goal of this study was to investigate symptom differentiation or dedifferentiation over time in recent onset psychosis using the Positive and Negative Syndrome Scale. METHODS: A confirmatory factor analysis model based on the consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia was estimated on seven different time points over a three-year period. A general factor capturing common variance between every symptom was also included. Explained common variance was computed for the general factor and each specific factor. RESULTS: Three hundred and sixty-two recent onset psychosis patients were assessed. Results showed no evidence for either symptom differentiation or dedifferentiation over time. Specific symptoms accounted for >70 % of the variance suggesting a high degree of specificity of the symptomatology. CONCLUSIONS: Overall, this study adds support for a highly multidimensional approach to clinical symptom assessment with an explicit focus on depression. The premise behind the staging approach being inherently one-dimensional, implications for further research is discussed.

Personality disorder among youth with first episode psychotic mania: An important target for specific treatment?

AIM: Personality disorder is a common co-occurrence ('comorbidity') among patients with bipolar disorder and appears to affect outcome negatively. However, there is little knowledge about the impact of this comorbidity in the early phases of bipolar disorder. We examined the prevalence and effect of personality disorder co-occurrence on outcome in a cohort of youth with first episode mania with psychotic features. METHODS: Seventy-one first episode mania patients, aged 15-29, were assessed at baseline, 6, 12, and 18 months as part of a randomized controlled trial of olanzapine and chlorpromazine as add-on to lithium in first episode mania with psychotic features. The current study involved secondary analysis of trial data. RESULTS: A co-occurring clinical personality disorder diagnosis was present in 16.9% of patients. Antisocial and narcissistic personality disorders were the most common diagnoses. Patients with co-occurring personality disorder had higher rates of readmission to hospital, lower rates of symptomatic recovery and poorer functional levels at 6 months, but these differences disappeared after 12 and 18 months. CONCLUSIONS: In the early phase of bipolar disorder, patients with personality disorder comorbidity display delayed symptomatic and functional recovery and increased likelihood to need hospital readmissions. These observations suggest that routine assessment for personality disorder and specific interventions are important in order to improve short-term treatment efficacy in this subgroup.

Time of exposure to social defeat stress during childhood and adolescence and redox dysregulation on long-lasting behavioral changes, a translational study.

Traumatic events during childhood/early adolescence can cause long-lasting physiological and behavioral changes with increasing risk for psychiatric conditions including psychosis. Genetic factors and trauma (and their type, degree of repetition, time of occurrence) are believed to influence how traumatic experiences affect an individual. Here, we compared long-lasting behavioral effects of repeated social defeat stress (SD) applied during either peripuberty or late adolescence in adult male WT and Gclm-KO mice, a model of redox dysregulation relevant to schizophrenia. As SD disrupts redox homeostasis and causes oxidative stress, we hypothesized that KO mice would be particularly vulnerable to such stress. We first found that peripubertal and late adolescent SD led to different behavioral outcomes. Peripubertal SD induced anxiety-like behavior in anxiogenic environments, potentiated startle reflex, and increased sensitivity to the NMDA-receptor antagonist, MK-801. In contrast, late adolescent SD led to increased exploration in novel environments. Second, the long-lasting impact of peripubertal but not late adolescent SD differed in KO and WT mice. Peripubertal SD increased anxiety-like behavior in anxiogenic environments and MK-801-sensitivity mostly in KO mice, while it increased startle reflex in WT mice. These suggest that a redox dysregulation during peripuberty interacts with SD to remodel the trajectory of brain maturation, but does not play a significant role during later SD. As peripubertal SD induced persisting anxiety- and fear-related behaviors in male mice, we then investigated anxiety in a cohort of 89 early psychosis male patients for whom we had information about past abuse and clinical assessment during the first year of psychosis. We found that a first exposure to physical/sexual abuse (analogous to SD) before age 12, but not after, was associated with higher anxiety at 6-12 months after psychosis onset. This supports that childhood/peripuberty is a vulnerable period during which physical/sexual abuse in males has wide and long-lasting consequences.

A narrative review of intervention in first-episode affective psychoses.

While first-episode schizophrenia has received extensive attention in the literature, few studies have focused on the first episode of affective psychoses. Considering the lack of structured data regarding this diagnostic grouping commonly used in clinical settings, our aim was to scope the literature on first-episode affective psychoses to consolidate current knowledge and to identify areas to be targeted in future studies. We also planned to investigate the relevance of the "affective psychosis" concept regarding diagnostic categories and specific needs of intervention. We conducted a search on the Embase, Medline, PubMed, PsycINFO and Web Of Science databases until October 2020. We selected studies and synthesized the key findings into a narrative review regarding major topics of early intervention research: diagnostic categorization, premorbid factors, intervention, duration of untreated illness, neurobiology and neurocognition. After screening 961 titles and abstracts and 193 full-text papers, we selected 77 studies for inclusion. Our results showed heterogeneity in diagnosis-related grouping under the concept of affective psychoses, especially variability regarding the inclusion of schizoaffective disorder. Nonetheless, this concept still encompasses patients with different psychopathological and neurocognitive profiles from the non-affective patients requiring specialized intervention. This study thus provided support for the relevance of this concept as well as a need for further investigation.

Six months functional response to early psychosis intervention program best predicts outcome after three years.

BACKGROUND: Not all patients respond well to early interventions for their psychosis. The present study's goal was to evaluate whether patients' responses in the first six months of treatment in a specialised three-year programme could predict final outcomes. METHODS: 206 early psychosis patients were assessed at baseline, using a large set of sociodemographic and clinical variables, and then monitored for 36 months. Among those variables, changes in their Global Assessment of Functioning (GAF) scores during the first six months were used to predict outcomes after three years. RESULTS: Changes in GAF scores during the first six months were the only variables that predicted every symptom of functional outcome. GAF scores were also always the first or second most important predictor for every outcome. This finding held for both high- and low-functioning patients at baseline. CONCLUSIONS: Predicting poor long-term outcomes after only six months should help clinicians to improve treatments.

Rate and predictors of disengagement in an early psychosis program with time limited intensification of treatment.

BACKGROUND: Service disengagement is a frequent problem in early intervention in psychosis. The goal of this study was to evaluate the rate and variables associated with service disengagement in a three year specialized program that allows treatment intensification on a case to case basis. METHODS: 328 early psychosis patients were assessed at baseline on a large set of socio-demographic and clinical variables and were followed-up over 36 months. Patients who left the program for reasons related to engagement with care were compared to patients who completed the program. RESULTS: Rates of disengagement were low (6.3%). Patients with lower socio-economic status, who committed offences during the program or with a diagnosis of Schizophreniform/brief psychotic disorder were more likely to disengage from the program. CONCLUSIONS: The engagement strategies implemented in the context of our early intervention programs have allowed to keep disengagements to a relatively low level. In this context, only 3 variables emerged to guide adaptation of the intervention in order to improve this already good engagement rate.