Longitudinal inference of multiscale markers in psychosis: from hippocampal centrality to functional outcome.

Multiscale neuroscience conceptualizes mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales. We leverage this framework to propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impairments in episodic memory and social cognition, which lead to more severe negative symptoms and lower functional outcome. As psychosis represents a heterogeneous collection of biological and behavioral alterations that evolve over time, we further predict this disease progression for a subtype of the patient sample, with other patients showing normal-range performance on all variables. We sampled data from two cross-sectional datasets of first- and multi-episode psychosis, resulting in a sample of 163 patients and 119 non-clinical controls. To address our proposed disease progression model and evaluate potential heterogeneity, we applied a machine-learning algorithm, SuStaIn, to the patient data. SuStaIn uniquely integrates clustering and disease progression modeling and identified three patient subtypes. Subtype 0 showed normal-range performance on all variables. In comparison, Subtype 1 showed lower episodic memory, social cognition, functional outcome, and higher negative symptoms, while Subtype 2 showed lower hippocampal-cortical connectivity and episodic memory. Subtype 1 deteriorated from episodic memory to social cognition, negative symptoms, functional outcome to bilateral hippocampal-cortical dysconnectivity, while Subtype 2 deteriorated from bilateral hippocampal-cortical dysconnectivity to episodic memory and social cognition, functional outcome to negative symptoms. This first application of SuStaIn in a multiscale psychiatric model provides distinct disease trajectories of hippocampal-cortical connectivity, which might underlie the heterogeneous behavioral manifestations of psychosis.

Enlarged pituitary gland volume: a possible state rather than trait marker of psychotic disorders.

BACKGROUND: Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders. METHODS: The study included 751 participants (174 with schizophrenia, 114 with schizoaffective disorder, 167 with psychotic bipolar disorder, and 296 healthy controls) across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Structural magnetic resonance images were obtained, and pituitary gland volumes were measured using the MAGeT brain algorithm. Linear mixed models examined between-group differences with controls and among patient subgroups based on diagnosis, as well as how pituitary volumes were associated with symptom severity, cognitive function, antipsychotic dose, and illness duration. RESULTS: Mean pituitary gland volume did not significantly differ between patients and controls. No significant effect of diagnosis was observed. Larger pituitary gland volume was associated with greater symptom severity (F = 13.61, p = 0.0002), lower cognitive function (F = 4.76, p = 0.03), and higher antipsychotic dose (F = 5.20, p = 0.02). Illness duration was not significantly associated with pituitary gland volume. When all variables were considered, only symptom severity significantly predicted pituitary gland volume (F = 7.54, p = 0.006). CONCLUSIONS: Although pituitary volumes were not increased in psychotic disorders, larger size may be a marker associated with more severe symptoms in the progression of psychosis. This finding helps clarify previous inconsistent reports and highlights the need for further research into pituitary gland-related factors in individuals with psychosis.

Five Years of Youth Engagement with Kids Help Phone Canada (Part 1): Phone, Chat, Text, and Peer-to-Peer Service Usage Nationally, Provincially, and Over Time.

Background: Child and youth mental health problems represent a substantial burden of illness in Canada, with appropriate services only inconsistently available. Charitable organizations, such as Kids Help Phone (KHP), are, therefore, crucial to filling system gaps by offering 24/7 phone, chat, texting, and peer-to-peer services. Methods: We describe the services provided by KHP, the volume of use for each service, and compare usage across Canada's provinces and territories for a 5-year period from January 2018 to December 2022. Trends seen during the COVID-19 pandemic are highlighted. Results: More than 1.5 million total number of conversations were held across texting, chat, and phone services over 5 years. Considerable growth is demonstrated between 2018 and 2022, and many of the highest peaks in volume occurred in March or April of 2020, the onset of the COVID-19 pandemic. The highest proportional volumes were consistently from the northern territories. Discussion: KHP cannot provide specialized or repeat services, nor can it alone meet the scale of unmet youth mental health needs across the country. Nonetheless, KHP plays a pivotal role in the Canadian mental health system. Efforts to understand the role that KHP and other e-mental health services like it play within the national mental health landscape should be intensified to aid in understanding unmet needs, identify system gaps, and make needed enhancements.

Five Years of Youth Engagement with Kids Help Phone Canada (Part 2): Issues Discussed Over Phone, Chat, Text, and Peer-to-Peer Services by Age Range.

Background: There is substantial unmet need for child and youth mental health problems in Canada. Charitable organizations, such as Kids Help Phone (KHP), are critical to filling system gaps, offering 24/7 e-mental health services outside the formal health care system. Methods: For the 5-year period from January 2018 to December 2022, we describe issues discussed by young people accessing KHP's services, and examine variations across different service platforms and age groups. Results: The most discussed issues across all service platforms and age groups were anxiety/stress, depression/sadness, and relationships. Suicide was most frequently discussed over text and Live Chat compared with other services, and was proportionally most discussed by young people 10-13 years of age on the phone and text services compared with other age ranges. Sexual abuse and violence were most frequently discussed by children 0-5 and 6-9 years of age across services. Discussion: Our analysis provides a unique snapshot into the concerns faced by children and youth across Canada, as well as the issues for which KHP is seen as an accessible place to seek support. Our findings can guide the future development of health promotion activities, and assist in new service development.

Dynamic association of the first identifiable symptom with rapidity of progression to first-episode psychosis.

BACKGROUND: Rapid progression from the first identifiable symptom to the onset of first-episode psychosis (FEP) allows less time for early intervention. The aim of this study was to examine the association between the first identifiable symptom and the subsequent speed of illness progression. METHODS: Data were available for 390 patients attending a catchment-based early intervention service for FEP. Exposure to non-psychotic and subthreshold psychotic symptoms was retrospectively recorded using semi-structured interviews. Outcomes following the onset of the first identifiable symptom were (1) time to onset of FEP and (2) symptom incidence rate (i.e. number of symptoms emerging per person-year until FEP onset). These outcomes were respectively analyzed with Cox proportional hazards and negative binomial regressions. RESULTS: After Bonferroni correction, having a subthreshold psychotic (v. non-psychotic) symptom as the first symptom was not associated with time to FEP onset [hazard ratio (HR) = 1.39; 95% CI 0.94-2.04] but was associated with higher symptom incidence [incidence rate ratio (IRR) = 1.92; 95% CI 1.10-3.48]. A first symptom of suspiciousness was associated with shorter time to FEP onset (HR = 2.37; 95% CI 1.38-4.08) and higher symptom incidence rate (IRR = 3.20; 95% CI 1.55-7.28) compared to other first symptoms. In contrast, a first symptom of self-harm was associated with lower symptom incidence rate (IRR = 0.06; 95% CI 0.01-0.73) compared to other first symptoms. Several associations between symptoms and illness progression were moderated by the age at symptom onset. CONCLUSIONS: Appreciating the content and timing of early symptoms can identify windows and treatment targets for early interventions in psychosis.

A multidimensional approach for differentiating the clinical needs of young people presenting for primary mental health care.

OBJECTIVES: There is an ongoing necessity to match clinical interventions with the multidimensional needs of young people. A key step toward better service planning and the design of optimal models of care is to use multidimensional assessment to understand the clinical needs of those presenting to primary mental health care. METHODS: 1284 people aged 12-25 years presenting to primary youth mental health services completed an online assessment at service entry. Latent class analysis was conducted for seven scales assessing anxiety, depression, psychosis, mania, functioning (indexed by Work and Social Adjustment Scale), and suicidality. RESULTS: A three-class solution was identified as the optimal solution. Class 1 (n = 305, 23.75%), an early illness stage group, had low and mixed symptomatology with limited functional impairment, class 2 (n = 353, 27.49%) was made up of older persons with established depression and functional impairment, and class 3 (n = 626, 48.75%) had very high and complex needs, with functional impairment, suicidality, and at-risk mental states (psychosis or mania). Additional differentiating characteristics included psychological distress, circadian disturbances, social support, mental health history, eating disorder behaviours, and symptoms of post-traumatic stress disorder. CONCLUSIONS: A large proportion of help-seeking young people present with symptoms and functional impairment that may exceed the levels of care available from basic primary care or brief intervention services. These subgroups highlight the importance of multidimensional assessments to determine appropriate service pathways and care options.

Examining the psychobiological response to acute social stress across clinical stages and symptom trajectories in the early psychosis continuum.

The stress-vulnerability model has been repeatedly highlighted in relation to the risk, onset and course of psychosis, and has been independently studied in clinical high-risk (CHR) and first-episode psychosis (FEP) populations. Notable in this literature, however, is that there are few studies directly comparing markers of stress response across progressive stages of illness. Here we examined the psychobiological response to the Trier Social Stress Test in 28 CHR (mean age 19.1) and 61 FEP (age 23.0) patients, in order to understand the stage(s) or trajectories in which differences in subjective stress or physiological response occur. The overall clinical sample had greater perceived stress and blunted cortisol (FEP + CHR, n = 89, age 21.7) compared with healthy controls (n = 45, age 22.9). Additional analyses demonstrated elevated heart rate and systolic blood pressure in FEP compared with CHR, but there were no further differences in physiological parameters (cortisol, heart rate, or blood pressure) between stage- or trajectory-based groups. Together, this suggests that individual stress response markers may differentially emerge at particular stages en route to psychosis - and demonstrates how stage-based analyses can shed light on the emergence and evolution of neurobiological changes in mental illness.

"The more things change "? Stability of delusional themes across 12 years of presentations to an early intervention service for psychosis.

PURPOSE: While the prevalence of delusional themes appears to be consistent across geographic contexts, little is known about the relative prevalence of such themes within a given setting over periods of time. We therefore investigated delusional themes across 12 years of presentation to a catchment-based early intervention service for first episode psychosis (FEP). METHODS: Systematically collected data from 500 patients at an early intervention service for FEP were analyzed. Four cohorts of 3 years each, from 2006 to 2017, were used to compare the frequency of delusion themes across cohorts. We also integrated into the analysis baseline sociodemographic factors such as gender, age, and highest level of education and clinical factors such as anxiety, depression, suicidality, hallucinations, and primary diagnosis (affective or non-affective psychosis). RESULTS: Sex and education level were stable across cohorts, while patient age varied (p = 0.047). Clinical anxiety, depression, and suicidality at entry were also stable. Across cohorts, the proportion of patients with affective versus non-affective diagnosis differed (p = 0.050), with no differences in global rating of delusion severity or theme prevalence except for delusions of guilt or sin (p = 0.001). This single theme difference was not correlated with age or diagnosis. CONCLUSION: Our study suggests relatively stable prevalence of delusion themes across cohorts of individuals experiencing FEP. This demonstrates the potential utility of studying thematic content both for understanding delusions in clinical populations and in research. Future explorations of the relationships between delusion themes and across individual patient episodes should be conducted.

Age- and sex-specific associations between risk scores for schizophrenia and self-reported health in the general population.

PURPOSE: The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. METHODS: Participants were from the population-based Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. RESULTS: For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18-65 years; 55.7-56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with - 0.10 of mental health and - 0.08 of physical health, whereas at age 65, it was associated with - 0.21 and - 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with - 0.19 of physical health among female and - 0.11 among male individuals. CONCLUSION: There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health.

Delusional content at initial presentation to a catchment-based early intervention service for psychosis.

BACKGROUND: During a psychotic episode, patients frequently suffer from severe maladaptive beliefs known as delusions. Despite the abundant literature investigating the simple presence or absence of these beliefs, there exists little detailed knowledge regarding their actual content and severity at the onset of illness. AIMS: This study reports on delusions during the initiation of indicated treatment for first-episode psychosis (FEP). METHOD: Data were systematically collected from a sample of 636 patients entering a catchment-based early intervention service for FEP. The average severity and frequency of each delusional theme at baseline was reported with the Scale for the Assessment of Positive Symptoms. Delusional severity (globally and per theme) was examined across a number of sociodemographic and clinical variables. RESULTS: Delusions were present in the vast majority of individuals experiencing onset of FEP (94%), with persecutory (77.7%) being the most common theme. Persecutory delusions remained consistent in severity across diagnoses, but were more severe with older age at onset of FEP. No meaningful differences in delusional severity were observed across gender, affective versus non-affective psychosis, or presence/absence of substance use disorder. Globally, delusion severity was associated with anxiety, but not depression. Delusions commonly referred to as passivity experiences were related to hallucinatory experiences. CONCLUSIONS: This community sample offers a rare clinical lens into the severity and content of delusions in FEP. Although delusional severity was consistent across certain sociodemographic and clinical variables, this was not always the case. Future research should now consider the course of delusion themes over time.

Altered hippocampal centrality and dynamic anatomical covariance of intracortical microstructure in first episode psychosis.

Hippocampal circuitry has been posited to be fundamental to positive symptoms in psychosis, but its contributions to other factors important for outcome remains unclear. We hypothesized that longitudinal changes in the hippocampal circuit and concomitant changes of intracortical microstructure are altered in first episode psychosis (FEP) patients and that such changes are associated with negative symptoms and verbal memory. Longitudinal brain scans (2-4 visits over 3-15 months) were acquired for 27 FEP and 29 age- and sex-matched healthy controls. Quantitative T1 maps, sensitive to myelin content, were used to sample the microstructure of the hippocampal subfields and output circuitry (fimbria, alveus, fornix, mammillary bodies), and intracortical regions. Dynamic anatomical covariance in pair-wise regional trajectories were assessed for each subject, and graph theory was used to calculate a participation coefficient metric that quantifies the similarity/divergence between hippocampal and intracortical microstructure. The mean participation coefficient of the hippocampus was significantly reduced in FEP patients compared with controls, reflecting differences in output hippocampal regions. Importantly, lower participation coefficient of the hippocampal circuit was associated with worse negative symptoms, a relationship that was mediated by changes in verbal memory. This study provides evidence for reduced hippocampal centrality in FEP and concomitant changes in intracortical anatomy. Myelin-rich output regions of the hippocampus may be an important biological trigger in early psychosis, with cascading effects on broader cortical networks and resultant clinical profiles.

Early intervention in psychiatry: scotomas, representativeness, and the lens of clinical populations.

Evidence supporting early intervention in mental health has gained prominence in recent years, with services for first episode psychosis having led the way. Despite this momentum, however, the extent to which rapidly accumulating data has been collected in samples resembling real-world clinical populations remains unclear. Kline et al. compare and contrast two groups experiencing a first episode of psychosis: research participants, and a clinical sample receiving early intervention services at the same health centre. They find key differences-including the underrepresentation of vulnerable groups and surprisingly little overlap between the two samples-that should prompt reflection about blind spots, filters between research and clinical care, and how to tie the generation of evidence to practice-based research.

Baby or bathwater? Referrals of "non-cases" in a targeted early identification intervention for psychosis.

PURPOSE: To explore the unintended impact of a targeted case identification (TCI) campaign for first episode psychosis (FEP) on people not experiencing FEP ("non-cases") with respect to referral patterns and reasons for being a non-case. METHODS: Sources of referral, reasons for being a non-case, and subsequent referral destinations of non-cases were examined before and after a TCI. RESULTS: Following the TCI, a greater proportion of non-cases lived outside the study catchment area. A smaller proportion was referred by the parent hospital's emergency room or had a substance-induced psychosis. CONCLUSIONS: TCIs for FEP may have unintended effects, with implications for early case identification and early intervention services.

Dysplasticity, metaplasticity, and schizophrenia: Implications for risk, illness, and novel interventions.

In this paper, we review the history of the concept of neuroplasticity as it relates to the understanding of neuropsychiatric disorders, using schizophrenia as a case in point. We briefly review the myriad meanings of the term neuroplasticity, and its neuroscientific basis. We then review the evidence for aberrant neuroplasticity and metaplasticity associated with schizophrenia as well as the risk for developing this illness, and discuss the implications of such understanding for prevention and therapeutic interventions. We argue that the failure and/or altered timing of plasticity of critical brain circuits might underlie cognitive and deficit symptoms, and may also lead to aberrant plastic reorganization in other circuits, leading to affective dysregulation and eventually psychosis. This "dysplastic" model of schizophrenia can suggest testable etiology and treatment-relevant questions for the future.

Sub-threshold mental illness in adolescents: within and beyond DSM's boundaries.

As researchers, clinicians and health systems strive to understand and improve mental health and well-being in youth, the parameters by which mental illness itself is defined have increasingly become the topic of inquiry. In the March 2015 issue of SPPE, Roberts et al. (Soc Psychiatry Psychiatr Epidemiol 50(3):397-406, 2015) integrate DSM diagnostic criteria with impairment in adolescents, showing that the latter is more frequent in full-syndrome disorders but still relevant for sub-threshold conditions, which have higher overall prevalence. These findings shift the focus away from specific diagnostic criteria and thresholds, and towards the backdrop of distress and impairment in young people. They also have implications for staging models and clinical services for youth mental health, particularly for prevention and early intervention efforts.

An analysis of financial hardship faced by patients with First Episode Psychosis, and their families, in an Indian setting.

BACKGROUND: The economic burden of psychotic disorders is not well documented in LMICs like India, due to several bottlenecks present in Indian healthcare system like lack of adequate resources, low budget for mental health services and inequity in accessibility of treatment. Hence, a large proportion of health expenditure is paid out of pocket by the households. OBJECTIVE: To evaluate the direct and indirect costs incurred by patients with First Episode Psychosis and their families in a North Indian setting. METHOD: Direct and Indirect costs were estimated for 87 patients diagnosed at AIIMS, New Delhi with first-episode psychosis (nonaffective) in the first- and sixth month following diagnosis, and the six months before diagnosis, using a bespoke questionnaire. Indirect costs were valued using the Human Capital Approach. RESULTS: Mean total costs in month one were INR 7991 ($107.5). Indirect costs were 78.3% of this total. Productivity losses was a major component of the indirect cost. Transportation was a key component of direct costs. Costs fell substantially at six months (INR 2732, Indirect Costs 61%). Respondents incurred substantial costs pre-diagnosis, related to formal and informal care seeking and loss of income. CONCLUSION: Families suffered substantial productivity loss. Care models and financial protection that address this could substantially reduce the financial burden of mental illness. Measures to address disruption to work and education during FEP are likely to have significant long-term benefits. Families also suffered prolonged income loss pre-diagnosis, highlighting the benefits of early and effective diagnosis.

Trajectories of Adolescent Media Use and Their Associations With Psychotic Experiences.

Importance: Adolescent media use is thought to influence mental health, but whether it is associated with psychotic experiences (PEs) is unclear. Objective: To examine longitudinal trajectories of adolescent media use and their associations with PEs at 23 years of age. Design, Setting, and Participants: This cohort study included participants from the Québec Longitudinal Study of Child Development (1998-2021): children who were born in Québec, Canada, and followed up annually or biennially from ages 5 months through 23 years. Data were analyzed between January 2023 and January 2024. Exposures: Participants reported their weekly amount of television viewing, video gaming, computer use, and reading at ages 12, 13, 15, and 17 years. Main Outcome and Measures: Lifetime occurrence of PEs was measured at 23 years of age. Covariables included sociodemographic, genetic, family, and childhood characteristics between ages 5 months and 12 years. Results: A total of 1226 participants were included in the analyses (713 [58.2%] female, 513 [41.8%] male). For each media type, latent class mixed modeling identified 3 group-based trajectories, with subgroups following trajectories of higher use: television viewing, 128 (10.4%); video gaming, 145 (11.8%); computer use, 353 (28.8%); and reading, 140 (11.4%). Relative to lower video gaming, higher video gaming was preceded by higher levels of mental health and interpersonal problems at age 12 years. Adjusting for these risk factors mitigated the association between higher video gaming and PEs at age 23 years. The curved trajectory of computer use (189 [15.4%] participants), characterized by increasing levels of use until age 15 years followed by a decrease, was associated with higher PEs (estimated difference, +5.3%; 95% CI, +1.5% to +9.3%) relative to lower use (684 [55.8%] participants). This association remained statistically significant after covariable adjustment. Conclusions and Relevance: This study found that longitudinal trajectories of media use during adolescence were modestly associated with PEs at age 23 years, likely reflecting the influence of shared risk factors. Understanding the environmental determinants and psychosocial functions of media use during adolescence may help better integrate digital technologies in the prevention and management of PEs.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.

AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.