Pre-onset subthreshold psychotic symptoms are associated with differential treatment delays before a first episode of psychosis: Initial evidence and implications.

BACKGROUND: Help-seeking and treatment delays are increasingly critical areas of study in mental health services. The duration of untreated psychosis (DUP), or the time between illness onset and initiation of treatment, is a predictor of symptom remission and functioning for a first episode of psychosis (FEP). The World Health Organization recommends that specialized treatment for psychosis be initiated within the first three months of FEP onset. As a result, research has focused on factors that are associated with threshold-level DUP, while the experience of subthreshold psychotic symptoms (STPS) prior to a FEP may also complicate and present barriers to accessing care for young people. We therefore examine the possibility that STPS can impact DUP and its components. METHOD: Using a follow-back cross-sectional design, we sought to describe duration of untreated illness, length of prodrome, DUP, help-seeking delay, referral delay, and number of help-seeking contacts among FEP patients who did and did not have STPS prior to psychosis onset. RESULTS: We found that patients who experienced STPS had a longer median duration of untreated illness, prodrome length, DUP, and help-seeking delay compared to patients who did not have such symptoms. Referral delay did not differ substantially between the two groups. Importantly, treatment delays were extremely lengthy for many participants. CONCLUSIONS: Pre-onset STPS are associated with help-seeking delays along the pathway to care even during a FEP. Examining early signs and symptoms may help to improve and tailor interventions aimed at reducing treatment delays and ultimately providing timely care when the need arises.

Pre-onset sub-threshold psychotic symptoms and cortical organization in the first episode of psychosis.

Individuals with sub-threshold psychotic symptoms (STPS) are considered at clinical high risk for psychosis (CHR). Imaging studies comparing CHR and patients shortly after a first episode of psychosis (FEP) support progressive cortical thinning by illness stage. However, at least 30% of FEP patients deny pre-onset STPS, suggesting no history of CHR. This calls into question the generalizability of previous imaging findings. To better understand the physiology of early psychosis symptomology, we investigated the relationship between pre-onset STPS and cortical thickness (CT) among FEP patients, examining regional CT and structural covariance (SC). Patients (N = 93) were recruited from PEPP-Montreal, a FEP clinic at the Douglas Mental Health University Institute. The Circumstances of Onset and Relapse Schedule was administered to retrospectively identify patients who recalled at least one of nine expert-selected STPS prior to their FEP (STPS+, N = 67) and to identify those who did not (STPS-, N = 26). Age and sex-matched healthy controls (HC) were recruited (N = 84) for comparison. Participants were scanned between one and three times over the course of two years. CT values of 320 scans (143 HC, 123 STPS+, 54 STPS-) that passed quality control were extracted for group analysis. Linear mixed effects models accounting for effects of age, sex, education, and mean thickness were applied for vertex-wise, group comparisons of cortical thickness and SC. Multiple comparison corrections were applied with Random Field Theory (p-cluster = 0.001). Compared to controls, only STPS- patients exhibited significantly reduced CT in a cluster of the right ventral lateral prefrontal cortex. The vertex with the highest t-statistic within this cluster was employed as a seed in the subsequent SC analysis. After RFT-correction, STPS+ patients exhibited significantly stronger SC between the seed and right pars orbitalis compared to STPS- patients, and HC exhibited significantly stronger SC between the seed and right middle temporal gyrus compared to STPS- patients. Our results revealed patterns of SC that differentiated patient subgroups and patterns of cortical thinning unique to STPS- patients. Our study demonstrates that the early course of sub-threshold psychotic symptoms holds significance in predicting patterns of CT during FEP.

Short duration of untreated psychosis enhances negative symptom remission in extended early intervention service for psychosis.

OBJECTIVE: To test whether duration of untreated psychosis (DUP) < 3 months, recommended by the World Health Organization/International Early Psychosis Association, enhances the effects of an extended early intervention service (EEIS) on symptom remission. METHOD: We examined data from a randomized controlled trial in which patients who received 2 years of treatment in EIS for psychosis were subsequently randomized to either 3 years of EEIS or 3 years of regular care (RC). Using a DUP cut-off ≤ 12 weeks (approximately < 3 months), patients were split into two groups. Length of positive, negative and total symptom remission were the outcomes. RESULTS: Patients (N = 217) were mostly male (68%) with schizophrenia spectrum disorder (65%); 108 (50%) received EEIS (58 had DUP ≤12 weeks; 50 had DUP >12 weeks). Interaction between treatment condition (EEIS vs. RC) and DUP cut-off ≤ 12 weeks was only significant in multiple linear regression model examining length of negative symptom remission as the outcome (adjusted ß = 36.88 [SE = 15.88], t = 2.32, P = 0.02). EEIS patients with DUP ≤12 weeks achieved 25 more weeks of negative symptom remission than EEIS patients with DUP >12 weeks. CONCLUSION: Having a short DUP may be critical in deriving long-term benefits from EIS for psychosis, including EEIS settings. This work empirically supports policy recommendations of reducing DUP <3 months.

Medication adherence in first episode psychosis: the role of pre-onset subthreshold symptoms.

OBJECTIVE: The experience of pre-onset subthreshold psychotic symptoms (STPS, signifying a clinical high-risk state) in first episode psychosis (FEP) predicts poorer outcomes during treatment, possibly through differential adherence to medication. We explored whether adherence differs between FEP patients with and without pre-onset STPS. METHODS: Antipsychotic medication adherence was compared in 263 STPS+ and 158 STPS- subjects in a specialized early intervention program for FEP. Data were gathered from a larger observational study conducted between 2003 and 2016. STPS status, sociodemographic, and baseline clinical variables were tested as predictors of non-adherence using univariate and multivariate logistic regressions. Time to onset of non-adherence was analyzed using Kaplan-Meier curves. The same predictors were tested as predictors of time to onset of non-adherence using Cox regression models. RESULTS: Medication non-adherence was higher in STPS+ participants (78.9% vs. 68.9%). STPS status (OR 1.709), substance use disorder (OR 1.767), and milder positive symptoms (OR 0.972) were significant baseline predictors of non-adherence. Substance use disorder (HR 1.410), milder positive symptoms (HR 0.990), and lack of contact between the clinical team and relatives (HR 1.356) were significant baseline predictors of time to non-adherence. CONCLUSION: FEP patients who experience pre-onset STPS are more likely to be non-adherent to antipsychotic medication over 2 years of intervention. FEP programs should routinely evaluate pre-onset symptomatology to deliver more personalized treatments, with emphasis on engaging both patients and family members from the beginning of care.

Linking persistent negative symptoms to amygdala-hippocampus structure in first-episode psychosis.

Early persistent negative symptoms (PNS) following a first episode of psychosis (FEP) are linked to poor functional outcome. Reports of reduced amygdalar and hippocampal volumes in early psychosis have not accounted for heterogeneity of symptoms. Age is also seldom considered in this population, a factor that has the potential to uncover symptom-specific maturational biomarkers pertaining to volume and shape changes within the hippocampus and amygdala. T1-weighted volumes were acquired for early (N=21), secondary (N=30), non-(N=44) PNS patients with a FEP, and controls (N=44). Amygdalar-hippocampal volumes and surface area (SA) metrics were extracted with the Multiple Automatically Generated Templates (MAGeT)-Brain algorithm. Linear mixed models were applied to test for a main effect of group and age × group interactions. Early PNS patients had significantly reduced left amygdalar and right hippocampal volumes, as well as similarly lateralized negative age × group interactions compared to secondary PNS patients (P<0.017, corrected). Morphometry revealed decreased SA in early PNS compared with other patient groups in left central amygdala, and in a posterior region when compared with controls. Early and secondary PNS patients had significantly decreased SA as a function of age compared with patients without such symptoms within the right hippocampal tail (P<0.05, corrected). Significant amygdalar-hippocampal changes with age are linked to PNS after a FEP, with converging results from volumetric and morphometric analyses. Differential age trajectories suggest an aberrant maturational process within FEP patients presenting with PNS, which could represent dynamic endophenotypes setting these patients apart from their non-symptomatic peers. Studies are encouraged to parse apart such symptom constructs when examining neuroanatomical changes emerging after a FEP.

Impact of Mental Health Services on Resilience in Youth with First Episode Psychosis: A Qualitative Study.

The purpose of this qualitative study is to understand how mental health and related services support and hinder resilience in young people diagnosed with first-episode psychosis. Seventeen youth between the ages of 18-24 were recruited and 31 in-depth interviews were conducted. Findings illustrated that informational and meaning making, instrumental, and emotional supports were experienced positively (i.e., resilience-enhancing); whereas services with ghettoizing, engulfing, regulating, and out of tune practices were experienced negatively (i.e., resilience-hindering). These results demonstrate how various types of service-related practices influence resilience in youth and can inform future planning of services for psychosis.

Interplay of hippocampal volume and hypothalamus-pituitary-adrenal axis function as markers of stress vulnerability in men at ultra-high risk for psychosis.

BACKGROUND: Altered hypothalamus-pituitary-adrenal (HPA) axis function and reduced hippocampal volume (HV) are established correlates of stress vulnerability. We have previously shown an attenuated cortisol awakening response (CAR) and associations with HV specifically in male first-episode psychosis patients. Findings in individuals at ultra-high risk (UHR) for psychosis regarding these neurobiological markers are inconsistent, and assessment of their interplay, accounting for sex differences, could explain incongruent results. METHOD: Study participants were 42 antipsychotic-naive UHR subjects (24 men) and 46 healthy community controls (23 men). Saliva samples for the assessment of CAR were collected at 0, 30 and 60 min after awakening. HV was determined from high-resolution structural magnetic resonance imaging scans using a semi-automatic segmentation protocol. RESULTS: Cortisol measures and HV were not significantly different between UHR subjects and controls in total, but repeated-measures multivariate regression analyses revealed reduced cortisol levels 60 min after awakening and smaller left HV in male UHR individuals. In UHR participants only, smaller left and right HV was significantly correlated with a smaller total CAR (ρ = 0.42, p = 0.036 and ρ = 0.44, p = 0.029, respectively), corresponding to 18% and 19% of shared variance (medium effect size). CONCLUSIONS: Our findings suggest that HV reduction in individuals at UHR for psychosis is specific to men and linked to reduced post-awakening cortisol concentrations. Abnormalities in the neuroendocrine circuitry modulating stress vulnerability specifically in male UHR subjects might explain increased psychosis risk and disadvantageous illness outcomes in men compared to women.

Transforming youth mental health: a Canadian perspective.

In most mental illnesses, onset occurs before the age of 25 and the earliest stages are critical. The youth bear a large share of the burden of disease associated with mental illnesses. Yet, Canadian youths with mental health difficulties face delayed detection; long waiting lists; inaccessible, unengaging services; abrupt transitions between services; and, especially in remoter regions, even a complete lack of services. Responding to this crisis, the Canadian Institutes of Health Research announced a 5-year grant that was awarded to ACCESS, a pan-Canadian network of youths, families, clinicians, researchers, policymakers, community organisations and Indigenous communities. Using strategies developed collaboratively by all stakeholders, ACCESS will execute a youth mental healthcare transformation via early detection, rapid access and appropriate, high-quality care. The project includes an innovative, mixed-methods service research component. Similar in many respects to other national youth mental health initiatives, ACCESS also exhibits important differences of scale, scope and approach.

The long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release in patients with schizophrenia.

OBJECTIVE: To evaluate the long-term clinical benefit and effectiveness of switching to once-daily quetiapine extended release (XR) from an oral antipsychotic in patients with schizophrenia. Reasons for switching included insufficient efficacy, tolerability, and/or non-acceptability. The primary endpoint was the percentage of patients achieving an improvement in Clinical Global Impression - Clinical Benefit (CGI-CB) scale scores. RESEARCH DESIGN AND METHODS: A 24-week, international, multicentre, open-label, prospective study ( www.clinicaltrials.gov : NCT00640601). After a 7-14 day enrolment period (depending whether prior antipsychotic mono- or combination therapy), all patients received quetiapine XR 300 mg once daily (day 1), 600 mg/day (day 2), 600-800 mg/day (day 3) and 400-800 mg/day thereafter, with down-titration and discontinuation of prior antipsychotic by day 4. RESULTS: A total of 62% of patients completed the study and 56.9% (LOCF, ITT) achieved a significant improvement in CGI-CB (95% CI [0.51, 0.63]; p = 0.02). Switches due to insufficient efficacy showed a significant improvement (60%, 95% CI [0.51, 0.68]; p = 0.02), compared to 54.4% ([0.44, 0.64]; p = 0.38) and 52.4% ([0.36, 0.68]; p = 0.76) of switches due to insufficient tolerability and non-acceptability respectively (both p = ns). Patients previously on olanzapine and quetiapine IR showed a significant improvement in CGI-CB (62.6% [p = 0.02] and 61.2% [p = 0.04], respectively). Somnolence (18.0%) and dizziness (14.6%) were the main adverse events. Anticholinergic use decreased from 7.1 to 2.7%. Overall mean weight gain was 0.4 kg; 12.9% of patients experienced a weight gain of ≥7% and 15% experienced a clinically relevant shift in triglycerides from baseline. CONCLUSIONS: A majority of patients switched from other antipsychotics to quetiapine XR experienced clinical benefit. This was supported by all other efficacy outcomes regardless of the reason for switching. Safety data confirmed quetiapine XR was safe and well tolerated. The open-label design and lack of a placebo group represent limitations.

Types of smokers in a community sample of individuals with Type 2 diabetes: a latent class analysis.

AIMS: Despite the detrimental effects of smoking on their health, a high number of adults with Type 2 diabetes continue to smoke. Identifying distinct types of smokers within this population could help tailor and target intervention programmes. This study examined whether smokers with Type 2 diabetes could be classified into different profiles based on smoking habits, socio-economic characteristics and lifestyle factors. METHODS: A sample of adults with self-reported diabetes was selected from random-digit dialing. Analyses included 383 participants with Type 2 diabetes who were current smokers. Information related to smoking, socio-economic status, health and lifestyle was collected by phone interview at baseline and 1 year later. Latent class analysis was used to identify subgroups of smokers. RESULTS: We uncovered three meaningful classes of smokers: class 1, long-time smokers with long-standing diabetes (n = 105); class 2, heavy smokers with deprived socio-economic status, poor health and unhealthy lifestyle characteristics (n = 105); class 3, working and active smokers who were more recently diagnosed with diabetes (n = 173). Members of class 2 were significantly more likely to be disabled and depressed at baseline and 1 year later compared with other classes. CONCLUSIONS: Different profiles of smokers exist among adults with Type 2 diabetes, each suggesting different cessation treatment needs. Distinguishing between these types of smokers may enable clinicians to tailor their approach to smoking cessation.

A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants.

BACKGROUND: There is increasing acceptance of migration as a risk factor for schizophrenia and related disorders; however, the magnitude of the risk among second-generation immigrants (SGIs) remains unclear. Generational differences in the incidence of psychotic disorders among migrants might improve our understanding of the relationship between migration, ethnicity and psychotic disorders. This meta-analysis aimed at determining the risk of psychotic disorders among SGIs in comparison with non-migrants and first-generation immigrants (FGIs). METHOD: Medline, EMBASE and PsycINFO databases were searched systematically for population-based studies on migration and psychotic disorders published between 1977 and 2008. We also contacted experts, tracked citations and screened bibliographies. All potential publications were screened by two independent reviewers in a threefold process. Studies were included in the meta-analysis if they reported incidence data, differentiated FGIs from SGIs and provided age-adjusted data. Data extraction and quality assessment were conducted for each study. RESULTS: Twenty-one studies met all inclusion criteria. A meta-analysis of 61 effect sizes for FGIs and 28 for SGIs yielded mean-weighted incidence rate ratios (IRRs) of 2.3 [95% confidence interval (CI) 2.0-2.7] for FGIs and 2.1 (95% CI 1.8-2.5) for SGIs. There was no significant risk difference between generations, but there were significant differences according to ethno-racial status and host country. CONCLUSIONS: The increased risk of schizophrenia and related disorders among immigrants clearly persists into the second generation, suggesting that post-migration factors play a more important role than pre-migration factors or migration per se. The observed variability suggests that the risk is mediated by the social context.

Early intervention in psychosis: specialized intervention and early case identification.

Specialized early intervention (SEI) approach to treatment of a First Episode of Psychosis (FEP) consists of two equally important components, namely, a phase specific treatment program and early case identification. In this article we report a brief update on our knowledge about both aspects of SEI services. We then provide a description of a prototypical SEI service within the Canadian context, examine the pathways to care for patients with FEP and report on different methods of reducing delay in treatment. We also provide a description of a novel method of reducing delay in treatment using principles of academic detailing targeting all health care and educational services within a defined catchment area in combination with quick access to the SEI service.

The pathways to mental health care of first-episode psychosis patients: a systematic review.

BACKGROUND: Although there is agreement on the association between delay in treatment of psychosis and outcome, less is known regarding the pathways to care of patients suffering from a first psychotic episode. Pathways are complex, involve a diverse range of contacts, and are likely to influence delay in treatment. We conducted a systematic review on the nature and determinants of the pathway to care of patients experiencing a first psychotic episode.MethodWe searched four databases (Medline, HealthStar, EMBASE, PsycINFO) to identify articles published between 1985 and 2009. We manually searched reference lists and relevant journals and used forward citation searching to identify additional articles. Studies were included if they used an observational design to assess the pathways to care of patients with first-episode psychosis (FEP). RESULTS: Included studies (n=30) explored the first contact in the pathway and/or the referral source that led to treatment. In 13 of 21 studies, the first contact for the largest proportion of patients was a physician. However, in nine of 22 studies, the referral source for the greatest proportion of patients was emergency services. We did not find consistent results across the studies that explored the sex, socio-economic, and/or ethnic determinants of the pathway, or the impact of the pathway to care on treatment delay. CONCLUSIONS: Additional research is needed to understand the help-seeking behavior of patients experiencing a first-episode of psychosis, service response to such contacts, and the determinants of the pathways to mental health care, to inform the provision of mental health services.

Toward a model of cognitive insight in first-episode psychosis: verbal memory and hippocampal structure.

Our previous work has linked verbal learning and memory with cognitive insight, but not clinical insight, in individuals with a first-episode psychosis (FEP). The current study reassessed the neurocognitive basis of cognitive and clinical insight and explored their neural basis in 61 FEP patients. Cognitive insight was measured with the Beck Cognitive Insight Scale (BCIS) and clinical insight with the Scale to assess Unawareness of Mental Disorder (SUMD). Global measures for 7 domains of cognition were examined. Hippocampi were manually segmented in to 3 parts: the body, head, and tail. Verbal learning and memory significantly correlated with the BCIS composite index. Composite index scores were significantly associated with total left hippocampal (HC) volume; partial correlations, however, revealed that this relationship was attributable largely to verbal memory performance. The BCIS self-certainty subscale significantly and inversely correlated with bilateral HC volumes, and these associations were independent of verbal learning and memory performance. The BCIS self-reflectiveness subscale significantly correlated with verbal learning and memory but not with HC volume. No significant correlations emerged between the SUMD and verbal memory or HC volume. These results strengthen our previous assertion that in individuals with an FEP cognitive insight may rely on memory whereby current experiences are appraised based on previous ones. The HC may be a viable location among others for the brain system that underlies aspects of cognitive insight in individuals with an FEP.

Ethnic diversity and pathways to care for a first episode of psychosis in Ontario.

OBJECTIVE: To examine ethnic variations in the pathways to care for persons accessing early intervention (EI) services in Ontario. METHOD: The pathways to care and the duration of untreated psychosis were assessed for first-episode psychosis patients who entered specialized EI services in Ontario. The sample was assigned to the following ethnic classifications: the White (Caucasian), Black (African descent), and Asian (ancestry from the continent) groups, plus all the "other ethnicities" group. RESULTS: There were 200 participants: 78% were male; 61% from the White, 15% Black, 13% Asian, and 11% were from the other ethnicities group. At the first point of contact, more participants used nonmedical contacts (12%), such as clergy and naturopathic healers, than psychologists (8%) or psychiatrists (7%). There were no ethnic differences for duration of untreated psychosis (median 22 weeks) or for initiation of help seeking by family/friends (53%), police (15%), or self (33%). After adjusting for relevant clinical and demographic factors, the Asian and other ethnicities groups were 4 and 3 times (respectively) more likely than the White or Black groups (P = .017) to use emergency room services as the first point of contact in the pathways to care. Participants from the Asian group experienced less involuntary hospitalizations (P = .023) than all the other groups. Yet overall, there were many more similarities than significant differences in the pathways to care. CONCLUSION: EI services should monitor the pathways to care for young people of diverse ethnic backgrounds to address any disparities in accessing care.

Investigating cognitive deficits and symptomatology across pre-morbid adjustment patterns in first-episode psychosis.

BACKGROUND: Cognitive deficits in schizophrenia are well established and are known to be present during the first episode of a psychotic disorder. In addition, consistent heterogeneity within these impairments remains unexplained. One potential source of variability may be the level of pre-morbid adjustment prior to the onset of first-episode psychosis (FEP). METHOD: Ninety-four FEP patients and 32 healthy controls were assessed at baseline on several neuropsychological tests comprising six cognitive domains (verbal memory, visual memory, working memory, processing speed, reasoning/problem-solving and attention) and an abbreviated version of the full IQ. A global neurocognitive domain was also computed. Pre-morbid adjustment patterns were divided into three distinct groups: stable-poor, stable-good and deteriorating course. RESULTS: Based on a cut-off of 0.8 for effect size, the stable-poor pre-morbid adjustment group was significantly more impaired on most cognitive domains and full IQ compared to the deteriorating group, who were more severely impaired on all measures compared to the stable-good group. The type of cognitive deficit within each subgroup did not differ and the results indicate that a global neurocognition measure may reliably reflect the severity of cognitive impairment within each subgroup. CONCLUSIONS: Pre-morbid adjustment patterns prior to onset of psychosis are associated with severity but not type of cognitive impairment. Patients in the stable-poor group are generally more impaired compared to the deteriorating group, who are, in turn, more impaired than the stable-good group.

Delusions are associated with low self-reflectiveness in first-episode psychosis.

Previous work on chronic psychosis patients has suggested that low self-reflectiveness and overconfidence in judgments may be associated with delusions. In the present study we evaluated whether this extends to a first-episode psychosis sample. Thirteen actively delusional and 53 non-delusional participants with a first-episode psychosis completed the Beck Cognitive Insight Scale. Relative to non-delusional participants, delusional participants endorsed greater self-reflectiveness, though their confidence in their judgments was the same as non-delusional participants. These results suggest that the capacity to self-reflect and refrain from overconfidence may interact with delusions differentially across multiple phases of psychosis. The cognitive system involved in self-reflectiveness may be important for delusional thinking during a first-episode psychosis.

A multi-site Canadian perspective: examining the functional outcome from first-episode psychosis.

OBJECTIVE: To examine factors contributing to variance in functional outcome in first-episode psychosis (FEP) following 1 year of treatment. METHOD: Naturalistic 1-year follow-up of a FEP cohort (n = 200), from programs in four university centers in Ontario, Canada. Functional recovery was defined by 'Social and Occupational Functioning Assessment Scale' (SOFAS) score>60. Regression analysis examined the contribution of independent variables to variance in functional outcome. RESULTS: Twelve-month outcome measures were available for 76.5% of the original cohort. Of these, 70% reported being in school/work and in satisfactory relationships. The functional recovery rate was 51%, compared to 74% attaining symptomatic remission. The greatest contributors to variance in outcome were ongoing symptoms at 6 months and substance abuse comorbidity. CONCLUSION: After 1 year of treatment, FEP patients show high rates of symptomatic remission and relatively lower rates of functional recovery. Symptoms and substance abuse contribute to variance in outcome.

Long-term effects of a community intervention for early identification of first-episode psychosis.

OBJECTIVE: To assess whether an Early Case Identification Program (ECIP) for first-episode psychosis (FEP), which showed no significant short-term effects, has a delayed impact on duration of untreated psychosis (DUP). METHOD: Using a historical control design, FEP patients were assessed on clinical variables over three consecutive phases, 2 years prior, 2 years during and 3 years after implementation of the ECIP. Additional analyses were conducted on non-affective and schizophrenia spectrum psychoses cases only. RESULTS: There was no overall significant difference in DUP across the three phases. For cases treated within the first year of illness a nonsignificant reduction in DUP to less than 2 months observed during the active phase was sustained post-ECIP. CONCLUSION: In some jurisdictions community-wide early case detection may fail to have an immediate or delayed effect on DUP, especially for cases who normally present for treatment with DUP >1 year.