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.

The SPEAK study rationale and design: A linguistic corpus-based approach to understanding thought disorder.

AIM: Psychotic symptoms are typically measured using clinical ratings, but more objective and sensitive metrics are needed. Hence, we will assess thought disorder using the Research Domain Criteria (RDoC) heuristic for language production, and its recommended paradigm of "linguistic corpus-based analyses of language output". Positive thought disorder (e.g., tangentiality and derailment) can be assessed using word-embedding approaches that assess semantic coherence, whereas negative thought disorder (e.g., concreteness, poverty of speech) can be assessed using part-of-speech (POS) tagging to assess syntactic complexity. We aim to establish convergent validity of automated linguistic metrics with clinical ratings, assess normative demographic variance, determine cognitive and functional correlates, and replicate their predictive power for psychosis transition among at-risk youths. METHODS: This study will assess language production in 450 English-speaking individuals in Australia and Canada, who have recent onset psychosis, are at clinical high risk (CHR) for psychosis, or who are healthy volunteers, all well-characterized for cognition, function and symptoms. Speech will be elicited using open-ended interviews. Audio files will be transcribed and preprocessed for automated natural language processing (NLP) analyses of coherence and complexity. Data analyses include canonical correlation, multivariate linear regression with regularization, and machine-learning classification of group status and psychosis outcome. CONCLUSIONS: This prospective study aims to characterize language disturbance across stages of psychosis using computational approaches, including psychometric properties, normative variance and clinical correlates, important for biomarker development. SPEAK will create a large archive of language data available to other investigators, a rich resource for the field.

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.

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.

Anxiety in youth at clinical high risk for psychosis: A case study and conceptual model.

Some individuals identified as being at clinical high risk (CHR) for developing psychosis may suffer substantial anxiety due to a fear of transitioning to psychosis. This can be associated with catastrophic misinterpretation of normal mental experiences, such as a momentary lapse in attention, as markers for psychosis, fueled by hypervigilance for mental experiences that may be perceived as signs of impending psychosis. This anxiety may only worsen due to the self-stigma triggered by admission to a psychiatric CHR clinic, independent of whether or not the individual transitions to psychosis. Based on a clinical case study, we propose a cognitive model for this anxiety, an extension of Clark's model of panic. Our model accounts for causal factors of this distress, such as self-stigma and maladaptive core beliefs. It also includes maintaining factors such as hypervigilance for mental experiences and catastrophic misinterpretation of normal mental experiences as anomalous and portending eventual psychosis. We outline assessment and treatment guidelines and offer suggestions for how this model could be empirically validated. We suggest that treatment with this model, under the neural diathesis-stress framework, may have the potential to lower the risk of transition to psychosis and that assessment for such anxiety should be part of standard CHR care.

Pituitary volume and clinical trajectory in young relatives at risk for schizophrenia.

BACKGROUND: Stress and vulnerability likely interact to play a major role in psychosis. While much has been written about the neural diathesis-stress model in psychosis and its clinical risk states, little is known about HPA axis biomarkers in non-help-seeking individuals at familial high risk (FHR). We sought to prospectively measure pituitary volume (PV) in adolescents and young adults at FHR for schizophrenia and to follow their emerging sub-clinical psychotic symptoms and clinical trajectories. METHOD: Forty healthy controls and 38 relatives of patients with schizophrenia or schizoaffective disorder were identified in Pittsburgh, USA. PV was derived from baseline 1.5 T magnetic resonance imaging. Chapman's schizotypy scales were acquired at baseline, and structured clinical interviews for DSM-IV-TR Axis I diagnoses were attempted annually for up to 3 years. RESULTS: Seven individuals converted to psychosis. PV did not differ between FHR and control groups overall. Within the FHR group, PV was positively correlated with Chapman's positive schizotypy (Magical Ideation and Perceptual Aberration) scores, and there was a significant group × PV interaction with schizotypy. PV was significantly higher in FHR subjects carrying any baseline Axis I diagnosis (p = 0.004), and higher still in individuals who went on to convert to psychosis (p = 0.0007). CONCLUSIONS: Increased PV is a correlate of early positive schizotypy, and may predict trait vulnerability to subsequent psychosis in FHR relatives. These preliminary findings support a model of stress-vulnerability and HPA axis activation in the early phases of psychosis.

Positive lumbar extradural space pressure.

Specially selected soft Macintosh balloon indicators were attached to needles during five extradural and five spinal punctures. When the needle point entered the extradural space, the mean balloon pressure decreased suddenly from 24.9 (range 14-37) to 12.3 (10-16) mm Hg in the five extradural punctures and from 22.3 (17-28) to 13.7 (10-17) mm Hg in the five spinal punctures. In the five spinal punctures, the balloon pressure did not alter when the needle was advanced from the extradural to the subarachnoid space. Contrary to expectation, none of the balloons deflated when the needle point entered the extradural or subarachnoid spaces. The balloon pressure varied rhythmically in synchrony with respiration and cardiac pulsations. The final balloon pressure, extradural space pressure and subarachnoid pressure were equal. The results suggest that the extradural pressure is positive and of the same magnitude as the prevailing lumbar cerebrospinal fluid pressure. Jugular venous compression, ventilation with carbon dioxide and positive end-expiratory pressure (PEEP) produce a rapid increase in cerebrospinal fluid (CSF) pressure. These stimuli also produced a measurable increase in the lumbar extradural pressure. Jugular venous compression increased the mean lumbar extradural pressure by 6.8 (3-10) mm Hg and ventilation with carbon dioxide increased it by 10 (5-12.5) mm Hg. PEEP values of 5, 10, 15 and 20 cm H2O produced an immediate increase in extradural pressure of 1-2 mm Hg for every 5 cm H2O of PEEP. The lumbar extradural pressure increased rapidly with stimuli known to increase CSF pressure. Changes in spinal CSF pressure may be detected by measuring extradural pressure.

Epidural pressure and postdural puncture headache in the parturient.

Forty patients in whom the dura had been punctured accidentally and 10 patients who had received spinal anaesthesia required epidural blood patching for relief of severe postdural puncture headache (PDPH). Before injecting blood, the epidural pressure was measured, using an epidural catheter as a manometer. Mean epidural pressure in the left lateral position was 6.4 cm H(2)O (range 0.5-12 cm H(2)O). Epidural pressure was not related to the size of needle hole or prophylactic infusion of saline into the epidural space. In 5 patients with inadvertent dural tap, there was a statistically significant decrease (P<0.02) in epidural pressure from 14.9 cm H(2)O (range 11-22 cm H(2)O) before PDPH to 6.9 cm H(2)O (range 5-8.5 cm H(2)O) when they developed PDPH. The benefits of performing an epidural blood patch through a catheter placed in the epidural space are discussed.

Epidural pressure during infusion of saline in the parturient.

Epidural pressure was measured in 17 post-partum patients who were receiving prophylactic infusion of saline into the epidural space after an inadvertent dural tap. During the infusion, the mean (+/-SD) epidural pressure was 19.1 (+/-4.3) cm H(2)O. Four patients complained of severe interscapular pain during the infusion. The epidural pressure in these patients was higher than 24 cm H(2)O. Prophylactic infusion of saline into the epidural space failed to prevent postdural puncture headache in 10 patients.

Severe headache following an epidural 'top-up'.

Half an hour after a normal delivery under epidural analgesia, a patient was given a top-up of 10 ml 0.25% bupivacaine for suture of a small vaginal tear. The patient developed severe headache, nausea and vomiting immediately after the top-up. Initially these symptoms were attributed to a complication of epidural analgesia. However, a raised epidural pressure led to a diagnosis of hypertensive encephalopathy.

Epidural blood patch using a catheter. Diagnosis of an unrecognised dural tap.

Twenty five patients were treated with an epidural blood patch for persistent headache, following a known or suspected dural puncture. Fifteen to 20 ml blood was injected into the epidural space through a catheter inserted one space away from the dural puncture. The catheter technique was useful in confirming the clinical diagnosis of previously unrecognised dural tap in six patients with severe headache. It was possible to perform the blood patch single-handed.

Resin injection studies of the lumbar extradural space.

Two resin injection studies of the lumbar extradural space were performed to elucidate its size and shape. To counteract the lack of cerebrospinal fluid pressure in the cadaver, the subarachnoid space was filled with water. In group 1, the extradural injection of resin caused an immediate increase in subarachnoid pressure. The casts produced varied in thickness, but were situated predominantly in the dorsomedial and dorsolateral regions of the spinal canal. Thin anterior spread occurred in 40% of cases. In group 2, resin was injected to the subarachnoid space before the extradural injection of dyed resin. The resulting extradural casts were thinner than in group 1, but the distribution of resin was similar. The problems of interpreting resin casts are discussed in relation to the results obtained, with reasons for suggesting that the extradural space is only potential.