Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

Identifying Psychosis Episodes in Psychiatric Admission Notes via Rule-based Methods, Machine Learning, and Pre-Trained Language Models.

Early and accurate diagnosis is crucial for effective treatment and improved outcomes, yet identifying psychotic episodes presents significant challenges due to its complex nature and the varied presentation of symptoms among individuals. One of the primary difficulties lies in the underreporting and underdiagnosis of psychosis, compounded by the stigma surrounding mental health and the individuals' often diminished insight into their condition. Existing efforts leveraging Electronic Health Records (EHRs) to retrospectively identify psychosis typically rely on structured data, such as medical codes and patient demographics, which frequently lack essential information. Addressing these challenges, our study leverages Natural Language Processing (NLP) algorithms to analyze psychiatric admission notes for the diagnosis of psychosis, providing a detailed evaluation of rule-based algorithms, machine learning models, and pre-trained language models. Additionally, the study investigates the effectiveness of employing keywords to streamline extensive note data before training and evaluating the models. Analyzing 4,617 initial psychiatric admission notes (1,196 cases of psychosis versus 3,433 controls) from 2005 to 2019, we discovered that the XGBoost classifier employing Term Frequency-Inverse Document Frequency (TF-IDF) features derived from notes pre-selected by expert-curated keywords, attained the highest performance with an F1 score of 0.8881 (AUROC [95% CI]: 0.9725 [0.9717, 0.9733]). BlueBERT demonstrated comparable efficacy an F1 score of 0.8841 (AUROC [95% CI]: 0.97 [0.9580, 0.9820]) on the same set of notes. Both models markedly outperformed traditional International Classification of Diseases (ICD) code-based detection methods from discharge summaries, which had an F1 score of 0.7608, thus improving the margin by 0.12. Furthermore, our findings indicate that keyword pre-selection markedly enhances the performance of both machine learning and pre-trained language models. This study illustrates the potential of NLP techniques to improve psychosis detection within admission notes and aims to serve as a foundational reference for future research on applying NLP for psychosis identification in EHR notes.

Cerebellar transcranial magnetic stimulation in psychotic disorders: intermittent, continuous, and sham theta-burst stimulation on time perception and symptom severity.

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.

Medication Adherence in a Transdiagnostic First-Episode Psychosis Sample.

Objective: Medication adherence is an important component of treatment and has the potential to influence illness trajectory in individuals with first-episode psychosis (FEP). We sought to examine time to medication non-adherence as well as factors related to non-adherence in a real-world FEP clinic.Methods: We conducted a survival analysis to examine time to medication non-adherence using data extracted from medical records of patients admitted to a FEP clinic at an academic psychiatric hospital between May 2012 and October 2017 (n = 219). The risk pool included patients who were adherent during the first 6 months in the clinic (n = 122). Data were extracted for the entire length of participants' time in the clinic, up to 66 months. Pre-selected clinical and demographic variables of interest were extracted and entered into a Cox proportional hazards model.Results: Of the risk pool of 122 patients, 37 (30%) had documented non-adherence events. The risk of non-adherence was 0.35 (95% CI, 0.25-0.46) and 0.49 (95% CI, 0.37-0.63) at the 24- and 36-month time points, respectively, and plateaued after 36 months. Non-White race (adjusted HR = 3.69; P = .003; 95% CI, 1.57-8.70), lack of insight in the prior 6 months (adjusted HR = 3.24; P = .005; 95% CI, 1.43-7.35), and substance use in the prior 6 months (adjusted HR = 2.58; P = .022; 95% CI, 1.15-5.81) were significant predictors of non-adherence.Conclusions: Clinicians should consider efforts to strengthen therapeutic alliance with non-White patients, improve insight, and help patients reduce or cease substance use when supporting medication adherence in the FEP population.

Auditory hallucinations, childhood sexual abuse, and limbic gray matter volume in a transdiagnostic sample of people with psychosis.

Childhood sexual abuse (CSA) is a potentially unique risk factor for auditory hallucinations (AH), but few studies have examined the moderating effects of sex or the association of CSA with limbic gray matter volume (GMV) in transdiagnostic samples of people with psychotic disorders. Here we found that people with psychotic disorders reported higher levels of all surveyed maltreatment types (e.g., physical abuse) than healthy controls, but people with psychotic disorders with AH (n = 41) reported greater CSA compared to both those without AH (n = 37; t = -2.21, p = .03) and controls (n = 37; t = -3.90, p < .001). Among people with psychosis, elevated CSA was most pronounced among females with AH (sex × AH status: F = 4.91, p = .009), held controlling for diagnosis, medications, and other maltreatment (F = 3.88, p = .02), and correlated with the current severity of AH (r = .26, p = .03) but not other symptoms (p's > .16). Greater CSA among patients related to larger GMV of the left amygdala accounting for AH status, diagnosis, medications, and other maltreatment (t = 2.12, p = .04). Among people with psychosis, females with AH may represent a unique subgroup with greater CSA. Prospective high-risk studies integrating multiple measures of maltreatment and brain structure/function may help elucidate the mechanisms linking CSA with amygdala alterations and AH.

Test-retest reliability of the Childhood Trauma Questionnaire in psychotic disorders.

BACKGROUND: Childhood trauma is common and associated with worse psychiatric outcomes. Yet, clinicians may not inquire about childhood trauma due to a misconception that patients cannot provide reliable reports. The goal of this study was to examine the reliability of self-reports of childhood trauma in psychotic disorders. METHODS: We examined the test-retest reliability of the Childhood Trauma Questionnaire (CTQ) in schizophrenia (SZ, n = 19), psychotic bipolar disorder (BD, n = 17), and healthy control (HC, n = 28) participants who completed the CTQ on ≥2 occasions over variable time periods (mean 19.6 months). We calculated the intraclass correlation (ICC) for the total CTQ score, each of the five CTQ domains, and the minimization/denial subscale for the three groups. For any CTQ domains showing low test-retest reliability (ICC < 0.61), we also explored whether positive, negative, depressive, and manic symptom severity were associated with CTQ variability. RESULTS: We found high ICC values for the total CTQ score in all three groups (SZ 0.82, BD 0.85, HC 0.88). The ICC values for CTQ subdomains were also high with the exceptions of scores for sexual abuse in BD (0.40), emotional neglect in SZ (0.60), and physical neglect in BD (0.51) and HC (0.43). In exploratory analyses, self-reports of sexual abuse in BD were associated with greater severity of depressive symptoms (ß = 0.108, p = 0.004). CONCLUSIONS: Patients with SZ and BD can provide reliable self-reports of childhood trauma, especially related to physical and emotional abuse. The presence of psychosis should not deter clinicians from asking patients about childhood trauma.

Childhood maltreatment and its role in the development of pain and psychopathology.

Childhood maltreatment represents a form of trauma capable of altering fundamental neurobiological properties and negatively impacting neurodevelopmental processes. An outcome of childhood maltreatment is the emergence of psychopathology, which might become evident during childhood or adolescence, but might also project into adulthood. In this Review, we propose a biobehavioural framework in which childhood maltreatment and the associated aberrant neurobiological mechanisms and behavioural processes additionally lead to the onset of altered pain processing and, ultimately, the existence of pain syndromes. Considering that subpopulations of maltreated children show preserved function and minimal psychiatric or pain symptoms, compensatory mechanisms-perhaps instilled by robust psychosocial support systems-are also discussed. We present validated tools and experimental methods that could facilitate better comprehension of the interactions between childhood maltreatment, psychopathology, and pain. Such tools and approaches can in parallel be implemented to monitor abnormal pain-related processes and potentially guide early intervention strategies in cases of childhood maltreatment.

Impact of the COVID-19 Pandemic on the Employment and Educational Outcomes of Individuals in a First-Episode Psychosis Clinic.

OBJECTIVE: A central objective of early psychosis therapy is to restore social functioning (e.g., through employment and education). Employment and educational outcomes during the COVID-19 pandemic were examined in a well-defined cohort of patients receiving care in an early psychosis clinic. METHODS: Data were extracted from the electronic health records of 128 patients receiving care at McLean Hospital's first-episode psychosis (FEP) clinic between January 1 and September 21 in 2019 and 2020. Using a generalized linear model with a Gaussian distribution and robust standard errors, the authors compared the average changes in the weekly employment and education proportions before and after COVID-19 lockdowns with the same changes in 2019. RESULTS: Employment losses among patients with FEP were greater than among the general population and persisted through the end of follow-up. In 2020, average employment after a stay-at-home order was instituted was 33% lower than before the order compared with the change in employment during the same period in 2019. The effect was stronger among men and those who identified as non-White, were age <21 years, or did not have a college education. Although educational engagement recovered in the fall of 2020, it still remained below the 2019 levels. CONCLUSIONS: Employment disruptions were major and persistent among the FEP population, which might affect short- and long-term outcomes. Innovative approaches are needed to help patients transition to remote employment, file unemployment claims, and use online hiring platforms to ameliorate the indirect effects of the COVID-19 pandemic.

The Intersection Between Childhood Trauma, the COVID-19 Pandemic, and Trauma-related and Psychotic Symptoms in People With Psychotic Disorders.

INTRODUCTION: People with psychotic disorders may be disproportionately affected by the traumatic effects of the COVID-19 pandemic. Childhood trauma, which also increases vulnerability to subsequent stressors, is common in individuals with psychosis. In this study, we investigated the intersection of the pandemic, childhood trauma, and psychotic and trauma-related symptoms in individuals with psychotic disorders. METHODS: We administered a cross-sectional survey to 151 participants [47 schizophrenia (SZ), 53 psychotic bipolar disorder (BP)], 51 healthy control (HC)] during the COVID-19 pandemic. Participants were asked about exposure to the pandemic's impacts, childhood trauma, and post-traumatic stress, dissociative, and psychotic symptoms. RESULTS: BP reported greater negative impacts to emotional health than SZ and HC and to non-COVID physical health than HC. SZ reported less impact on work and employment during the pandemic. There were no other group differences in pandemic-related adversities. We also found that cumulative exposure to the pandemic's negative impacts was significantly associated with PTSD symptoms but not psychotic or dissociative symptoms. Moreover, the number of adversities an individual experienced during the pandemic was strongly associated with the cumulative number of traumatic experiences they had in childhood. DISCUSSION: Our results suggest that having a psychotic disorder does not, in and of itself, increase susceptibility to the pandemic's negative impacts. Instead, we provide evidence of a graded relationship between cumulative exposure to the pandemic's negative impacts and PTSD symptom severity, as well as a graded relationship between cumulative childhood traumatic experiences and the number pandemic adversities, across diagnoses.

Auditory hallucinations across the psychosis spectrum: Evidence of dysconnectivity involving cerebellar and temporal lobe regions.

BACKGROUND: Auditory hallucinations (AH) are typically associated with schizophrenia (SZ), but they are also prevalent in bipolar disorder (BD). Despite the large body of research on the neural correlates of AH in SZ, the pathophysiology underlying AH remains unclear. Few studies have examined the neural substrates associated with propensity for AH in BD. Investigating AH across the psychosis spectrum has the potential to inform about the neural signature associated with the trait of AH, irrespective of psychiatric diagnosis. METHODS: We compared resting state functional magnetic resonance imaging data in psychosis patients with (n = 90 AH; 68 SZ, 22 BD) and without (n = 55 NAH; 16 SZ, 39 BD) lifetime AH. We performed region of interest (ROI)-to-ROI functional connectivity (FC) analysis using 91 cortical, 15 subcortical, and 26 cerebellar atlas-defined regions. The primary aim was to identify FC differences between patients with and without lifetime AH. We secondarily examined differences between AH and NAH within each diagnosis. RESULTS: Compared to the NAH group, patients with AH showed higher FC between cerebellum and frontal (left precentral gyrus), temporal [right middle temporal gyrus (MTG), left inferior temporal gyrus (ITG), left temporal fusiform gyrus)], parietal (bilateral superior parietal lobules), and subcortical (left accumbens, left palldium) brain areas. AH also showed lower FC between temporal lobe regions (between right ITG and right MTG and bilateral superior temporal gyri) relative to NAH. CONCLUSIONS: Our findings suggest that dysconnectivity involving the cerebellum and temporal lobe regions may be common neurofunctional elements associated with AH propensity across the psychosis spectrum. We also found dysconnectivity patterns that were unique to lifetime AH within SZ or bipolar psychosis, suggesting both common and distinct mechanisms underlying AH pathophysiology in these disorders.

Diagnostic Stability of Primary Psychotic Disorders in a Research Sample.

Psychiatric diagnosis is often treated as a stable construct both clinically and in research; however, some evidence suggests that diagnostic change may be common, which may impact research validity and clinical care. In the present study we examined diagnostic stability in individuals with psychosis over time. Participants with a diagnosis of any psychotic disorder (n = 142) were assessed at two timepoints using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. We found a 25.4% diagnostic change rate across the total sample. People with an initial diagnosis of psychosis not otherwise specified and schizophreniform disorder had the highest rates of change, followed by those with schizophrenia and schizoaffective disorder; people with bipolar disorder had the lowest change rate. Most participants with an unstable initial diagnosis of schizophrenia, schizophreniform disorder, bipolar disorder, or psychosis not otherwise specified converted to a final diagnosis of schizoaffective disorder. Participants with an unstable initial diagnosis of schizoaffective disorder most frequently converted to a diagnosis of schizophrenia. Our findings suggest that diagnostic change is relatively common, occurring in approximately a quarter of patients. People with an initial diagnosis of schizophrenia-spectrum disorder were more likely to have a diagnostic change, suggesting a natural stability of some diagnoses more so than others.

Neural Abnormalities in Fear Generalization in Schizophrenia and Associations With Negative Symptoms.

BACKGROUND: Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simplest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning. METHODS: To measure generalization in schizophrenia, 37 individuals with a nonaffective psychotic disorder and 32 demographically matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging. Skin conductance and neural responses to conditioned (CS+), neutral (CS-), and generalization stimuli were measured. Explicit memory ratings reflecting successful generalization were also collected after the scanning, as well as measures of symptom severity. RESULTS: Compared with healthy control subjects, individuals with nonaffective psychotic disorders showed significant deficits in fear generalization across multiple measurements, with impairments in memory ratings and reductions in activation and deactivation of the salience and default networks, respectively, during fear generalization. Moreover, in the psychotic disorder group, greater behavioral and neural abnormalities in generalization were associated with higher levels of negative symptoms. CONCLUSIONS: Fear generalization is impaired in psychotic illness. Given that successful generalization relies on a dynamic balance between excitatory and inhibitory neurotransmission, these results reveal a potentially quantifiable mechanism linked to negative symptoms that can be investigated further in future human and experimental animal studies.

Dissociable Auditory Cortico-Cerebellar Pathways in the Human Brain Estimated by Intrinsic Functional Connectivity.

The cerebellum, a structure historically associated with motor control, has more recently been implicated in several higher-order auditory-cognitive functions. However, the exact functional pathways that mediate cerebellar influences on auditory cortex (AC) remain unclear. Here, we sought to identify auditory cortico-cerebellar pathways based on intrinsic functional connectivity magnetic resonance imaging. In contrast to previous connectivity studies that principally consider the AC as a single functionally homogenous unit, we mapped the cerebellar connectivity across different parts of the AC. Our results reveal that auditory subareas demonstrating different levels of interindividual functional variability are functionally coupled with distinct cerebellar regions. Moreover, auditory and sensorimotor areas show divergent cortico-cerebellar connectivity patterns, although sensorimotor areas proximal to the AC are often functionally grouped with the AC in previous connectivity-based network analyses. Lastly, we found that the AC can be functionally segmented into highly similar subareas based on either cortico-cerebellar or cortico-cortical functional connectivity, suggesting the existence of multiple parallel auditory cortico-cerebellar circuits that involve different subareas of the AC. Overall, the present study revealed multiple auditory cortico-cerebellar pathways and provided a fine-grained map of AC subareas, indicative of the critical role of the cerebellum in auditory processing and multisensory integration.

Return to College After a First Episode of Psychosis.

A first episode of psychosis (FEP) can derail a patient's educational goals, including attainment of a college education, and this can have lasting ramifications for socioeconomic and health outcomes. Despite this, few studies have examined return to college, which is an important index of real-world educational success after a FEP. In this study, we conducted a longitudinal medical record review of patients in a transdiagnostic outpatient FEP program and performed survival analysis, setting return to college as the endpoint, among the subset of patients whose college education was interrupted. We found that 82% (93/114) of college-enrolled FEP individuals experienced disruptions to their education after FEP, but that return to college also occurred in a substantial proportion (49/88, 56%) among those on leave who had follow-up data. In this sample, the median time to college return was 18 months. When separated by baseline diagnostic category, FEP patients with affective psychotic disorders (FEAP, n = 45) showed faster time to college return than those with primary psychotic disorders (FEPP, n = 43) (median 12 vs 24 mo; P = .024, unadjusted). When adjusted for having no more than 1 psychiatric hospitalization at intake and absence of cannabis use in the 6 months prior to intake (which were also significant predictors), differences by diagnostic category were more significant (hazard ratio 2.66, 95% CI 1.43-4.94, P = .002). Participation in education is an important outcome for stakeholders, and students with FEP can be successful in accomplishing this goal.

Two-year diagnostic stability in a real-world sample of individuals with early psychosis.

OBJECTIVES: Diagnostic shifts in first episode psychosis (FEP) are not uncommon. Many studies examining diagnostic stability use structured diagnostic interviews. Less is known about the stability of FEP diagnoses made clinically. METHODS: We conducted a retrospective chart review of patients enrolled in a transdiagnostic FEP clinic. For the 96 patients followed clinically at least 2 years, we compared diagnoses at intake and 24 months. RESULTS: Diagnostic stability was high for bipolar disorder (89%), schizoaffective disorder (89%), and schizophrenia (82%). Psychosis not otherwise specified (13%) was more unstable, with limited baseline differences that would enable clinicians to predict who would convert to a primary psychotic vs affective psychotic disorder. CONCLUSIONS: Our real-world clinical sample shows that FEP diagnoses, with the exception of unspecified psychosis, are diagnostically stable, even without structured diagnostic interviews.

Visual hallucinations associated with multimodal hallucinations, suicide attempts and morbidity of illness in psychotic disorders.

BACKGROUND: Visual hallucinations (VH) are a common, but understudied symptom of psychosis, experienced by individuals across diagnostic categories of psychotic and neuropsychiatric conditions. There are limited data on VH and associated clinical phenotypes in adult idiopathic psychotic disorders, which are needed to elucidate their relevance to psychotic illness paradigms. METHOD: In this cross-sectional study, we examined clinical risk factors for VH in a well-characterized sample of 766 patients with adult psychotic disorders across diagnostic categories of schizophrenia (n = 227), schizoaffective disorder (n = 210), and bipolar I disorder (n = 329). The Structured Clinical Interview for DSM-IV-TR was used for diagnosis and symptom measurements. RESULTS: The prevalence of VH was 26.1% (200/766). Multivariate logistic regression showed that VH were independently associated with the presence of hallucinations in other modalities, including auditory, tactile, olfactory, and gustatory hallucinations. History of a suicide attempt and catatonic behavior were also associated with VH. In addition, specific delusions were associated with VH, in particular, delusions of control, and religious, erotomanic and jealousy delusions. Diagnosis, negative symptoms, and family history of psychosis were not independent predictors of VH. CONCLUSIONS: Results showed the clinical and disease relevance of VH as they were associated with severe morbidity of illness, including suicide attempts and catatonic behavior. Findings also suggest a phenotype associated with hallucinations in other modalities and specific types of delusions. Based on our findings, VH may be a significant factor in assessing for suicidality and illness severity, warranting clinical attention and further study of underlying mechanisms.