Psychosis in Alzheimer Disease and Elevations in Disease-Relevant Biomarkers.

Importance: The emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology. Objective: To investigate the longitudinal dynamics of plasma tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) levels in association with the emergence of psychotic symptoms (delusions and hallucinations) in the context of AD. Design, Setting, and Participants: This cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Baseline analyses compared patients with mild cognitive impairment (MCI) and AD (both with psychosis [AD+P] and without psychosis [AD-P]) and participants who were cognitively unimpaired (CU). For the longitudinal analysis, participants with MCI and AD were subdivided into patients with evidence of psychosis at baseline (AD+P baseline) and patients free of psychosis at baseline who showed incidence of psychosis over the course of the study (AD+P incident). Study data were analyzed between June and November 2023. Exposures: Plasma p-tau181 and NfL measures in individuals with MCI and AD, both with and without psychosis. Main Outcomes and Measures: Plasma p-tau181 and NfL quantifications up to 48 months and concurrent assessments of presence or absence of delusions and hallucinations via the Neuropsychiatric Inventory (NPI) questionnaire. Results: The cohort included 752 participants with AD (mean [SD] age, 74.2 [7.7] years; 434 male [57.7%]). A total of 424 CU participants had a mean (SD) age of 75.4 (6.6) years of whom 222 were female (52.4%). In the longitudinal analysis of p-tau181 trajectories of the AD+P group, the group of patients who showed incidence of psychosis over the course of follow-up (AD+P incident) demonstrated an associated increase in plasma p-tau181 levels compared with the group of patients who had psychosis at baseline (AD+P baseline) and showed an associated decrease in plasma p-tau181 levels (F4, 117 = 3.24; P = .01). The mean slope of p-tau181 change was significantly different in AD+P incident and AD+P baseline groups (F5,746 = 86.76, P < .0001) and when only individuals with amyloid-ß positivity (Aß+), which was determined using positron emission tomography, were compared (F5,455 = 84.60, P < .001). Patients who experienced psychosis at any time had increased levels of NfL relative to those who never experienced psychosis. Conclusions and Relevance: Results of this cohort study suggest that the emergence of psychosis in AD was associated with elevations in plasma levels of p-tau181, highlighting the potential utility of plasma p-tau181 as a biomarker of neuropsychiatric illness in AD, which could have implications for predictive and treatment response strategies.

Sociodemographic and clinical correlates of hallucinations in patients entering an early intervention program for first episode psychosis.

Hallucinations are a core feature of psychosis, and their severity during the acute phase of illness is associated with a range of poor outcomes. Various clinical and sociodemographic factors may predict hallucinations and other positive psychotic symptoms in first episode psychosis (FEP). Despite this, the precise factors associated with hallucinations at first presentation to an early intervention service have not been extensively researched. Through detailed interviews and chart reviews, we investigated sociodemographic and clinical predictors in 636 minimally-medicated patients who entered PEPP-Montréal, an early intervention service for FEP, between 2003 and 2018. Hallucinations were measured using the Scale for the Assessment of Positive Symptoms (SAPS), while negative symptoms were assessed using the Scale for the Assessment of Negative symptoms (SANS). Depressive symptoms were evaluated through the Calgary Depression Scale for Schizophrenia (CDSS), and anxiety symptoms via the Hamilton Rating Scale for Anxiety (HAS). A majority (n = 381, 59.9 %) of the sample presented with clinically significant hallucinations (SAPS global hallucinations score ≥ 3) at program entry. These patients had an earlier age at onset, fewer years of education, and a higher severity of delusions, depression and negative symptoms than those without clinical-level hallucinations. These results suggest that individuals with clinically significant hallucinations at admission tend to be younger and have a greater overall symptom burden. This makes it especially important to monitor hallucinations alongside delusions, depression and negative symptoms in order to identify who might benefit from targeted interventions. The implications of these findings for early intervention and person-centered care are discussed.

Exploring Psychosis in Neurodegenerative Dementia: Connecting Symptoms to Neurobiology.

The following commentary discusses a review by Cressot et al. entitled: 'Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review'. The authors describe the epidemiology and phenomenology of psychosis across neurodegenerative dementias. Dementia with Lewy bodies had the highest reported prevalence of psychosis at 74% followed by Alzheimer's disease, 54% and frontotemporal degeneration, 42%. Detailed characterization of psychosis shows differences in the types of hallucinations and delusions by dementia type. These findings suggest that different types of dementia related pathology are associated with high rates of psychosis with more specific symptom profiles than previously appreciated. Understanding the differences and variety of psychotic experiences across dementia types may have diagnostic and therapeutic implications for treating hallucinations and delusions in populations suffering from neurodegenerative diseases.

Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review.

Background: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer's disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. Objective: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. Methods: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). Results: Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6-78.3%) and visual hallucinations (50-69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1-60.3% and 3.10-41.5%). Limited data were found regarding psychosis in the early stages of these disorders. Conclusions: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.

Neuropsychiatric Symptoms and Trajectories of Dependence and Cognition in a Sample of Community-dwelling Older Adults with Dementia.

BACKGROUND AND OBJECTIVES: Neuropsychiatric symptoms (NPS), including psychotic symptoms (hallucinations, illusions, delusions), agitation/aggression, and depressed mood, are common in individuals with Alzheimer's disease (AD) and predict poorer outcomes, including faster disease progression. We aimed to evaluate associations between NPS and cognition and dependence in a multi-ethnic sample of community-dwelling older adults with AD. METHODS: Predictors 3 (P3) is a cohort study of AD disease courses recruiting older adults aged 65 and above residing in upper Manhattan. A total of 138 of 293 participants had probable AD at the study baseline. We fit linear mixed models to examine longitudinal associations of time-varying NPS (psychotic symptoms, agitation/aggression, and depressed mood) with dependence and cognition, adjusted for race-ethnicity, sex, education, age, clinical dementia rating score, APOE-ε4, and comorbidity burden; separate interaction models were fit for age, Hispanic ethnicity, and sex. RESULTS: Psychotic symptoms were associated with faster rates of increasing dependence and declining cognition over time, agitation/aggression with faster rates of declining cognition, and depressed mood with faster rates of increasing dependence. Among psychotic symptoms, delusions, but not hallucinations or illusions, were associated with worse outcome trajectories. Depressed mood predicted an accelerated increase in dependence in males but not females. CONCLUSION: Our results confirm and extend prior results in clinic-based samples. The presence of NPS was associated with worse trajectories of dependence and cognition in this muti-ethnic sample of older adults with AD. Importantly, sex modified the association between depressed mood and dependence. Our results on NPS as predictors of differential AD progression in a community-dwelling, ethnically diverse sample serve to better inform the clinical care of patients and the future development of AD therapies.

Drug-induced delusion: A comprehensive overview of the WHO pharmacovigilance database.

INTRODUCTION: A number of prescribed medicines have been reported in cases of drug-induced delusion, such as dopaminergic agents or psychostimulants. But to this day, most studies are based on a limited number of cases and focus on a few drug classes, so a clear overview of this topic remains difficult. To address this issue, we provide in this article a comprehensive analysis of drug-induced delusion, based on the World Health Organization (WHO) pharmacovigilance database. METHODS: We performed a disproportionality analysis of this database using the information component (IC). The IC compares observed and expected values to find associations between drugs and delusion, using disproportionate Bayesian reporting. An IC0.25 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. RESULTS: Here we present an analysis of 4559 suspected drug-induced delusion reports in the WHO pharmacovigilance database. These results identified 66 molecules statistically associated with delusion and an extensive analysis of confounding factors and coprescriptions was performed, using full database as background with an IC0.25 > 0. The main drug classes involved were antidepressants, antiepileptics, dopaminergic agents, opioids, antiinfective agents, benzodiazepines, anti-dementia drugs and psychostimulants. CONCLUSION: These results will help clinicians identify potential suspected drugs associated with delusion and decide which drug to discontinue and eventually lead to a re-evaluation of drug labels for some molecules.

Delusions and the dilemmas of life: A systematic review and meta-analyses of the global literature on the prevalence of delusional themes in clinical groups.

We investigated the prevalence of persecutory, grandiose, reference, control, and religious delusions in adult clinical populations worldwide and whether they differed according to country characteristics or age, gender, or year of publication. 123 studies met inclusion criteria, across 30 countries; 102 (115 samples, n = 20,979) were included in the main random-effects meta-analysis of studies measuring multiple delusional themes (21 in a separate analysis of studies in recording a single theme). Persecutory delusions were most common (pooled point estimate: 64.5%, CI = 60.6-68.3, k = 106, followed by reference (39.7%, CI 34.5-45.3, k = 65), grandiose (28.2, CI 24.8-31.9, k = 100), control 21.6%, CI 17.8-26.0, k = 53), and religious delusions 18.3%, CI 15.4-21.6, k = 50). Data from studies recording one theme were broadly consistent with these findings. There were no effects for study quality or publication date. Prevalences were higher in samples exclusively with psychotic patients but did not differ between developed and developing countries, or by country individualism, power distance, or prevalence of atheism. Religious and control delusions were more prevalent in countries with higher income inequality. We hypothesize that these delusional themes reflect universal human dilemmas and existential challenges.

Gender differences in the young-onset persistent delusional disorder.

We conducted a retrospective chart review to examine the gender differences in young onset Persistent Delusional Disorder (PDD) subjects (N = 236) with onset of illness before the age of 30 years. Gender differences in marital and employment status were significant (p-0.001). Delusion of infidelity and erotomania were more common in females, while males had more body dysmorphic and persecutory delusions (X2-20.45, p-0.009). Males had more substance dependence (X2-21.31, p < 0.001), as well as a family history of substance abuse and PDD (X2-18.5, p < 0.01). To conclude, gender differences in PDD comprised some psychopathology, co-morbidity, and family history among those with young onset PDD.

Reasoning biases and delusional ideation in the general population: A longitudinal study.

BACKGROUND: Reasoning biases have been suggested as risk factors for delusional ideation in both patients and non-clinical individuals. Still, it is unclear how these biases are longitudinally related to delusions in the general population. We hence aimed to investigate longitudinal associations between reasoning biases and delusional ideation in the general population. METHODS: We conducted an online cohort study with 1184 adults from the German and Swiss general population. Participants completed measures on reasoning biases (jumping-to-conclusion bias [JTC], liberal acceptance bias [LA], bias against disconfirmatory evidence [BADE], possibility of being mistaken [PM]) and delusional ideation at baseline, and delusional ideation 7 to 8 months later. RESULTS: A greater JTC bias was associated with a greater increase in delusional ideation over the following months. This association was better described by a positive quadratic relationship. Neither BADE, LA nor PM were associated with subsequent changes in delusional ideation. CONCLUSIONS: This study suggests that jumping-to-conclusions predicts delusional ideation in the general population but that this association may follow a quadratic trajectory. While no other associations turned significant, future studies with shorter temporal distances may shed further light on the role of reasoning biases as risk factors for delusional ideation in non-clinical samples.

Prevalence of multisensory hallucinations in people at risk of transition to psychosis.

Hallucinations can occur in single or multiple sensory modalities. Greater attention has been paid to single sensory experiences with a comparative neglect of hallucinations that occur across two or more sensory modalities (multisensory hallucinations). This study explored how common these experiences were in people at risk of transition to psychosis (n=105) and considered whether a greater number of hallucinatory experiences increased delusional ideation and reduced functioning, both of which are associated with a greater risk of transition to psychosis. Participants reported a range of unusual sensory experiences, with two or three being common. However, when a strict definition of hallucinations was applied, in which the experience has the quality of a real perception and in which the person believes them to be real experiences, then multisensory experiences were rare and when reported, single sensory hallucinations in the auditory domain were most common. The number of unusual sensory experiences or hallucinations was not significantly associated with greater delusional ideation or poorer functioning. Theoretical and clinical implications are discussed.

The effects of the COVID-19 pandemic on hallucinations and delusions in youth at clinical high-risk for psychosis and outpatients with schizophrenia.

Although the COVID-19 pandemic has had detrimental effects on mental health in the general population, the impact on those with schizophrenia-spectrum disorders has received relatively little attention. Assessing pandemic-related changes in positive symptoms is particularly critical to inform treatment protocols and determine whether fluctuations in hallucinations and delusions are related to telehealth utilization and treatment adherence. In the current longitudinal study, we evaluated changes in the frequency of hallucinations and delusions and distress resulting from them across three-time points. Participants included: (1) outpatients with chronic schizophrenia (SZ: n = 32) and healthy controls (CN: n = 31); (2) individuals at clinically high risk for psychosis (CHR: n = 25) and CN (n = 30). A series of questionnaires were administered to assess hallucination and delusion severity, medication adherence, telehealth utilization, and protective factors during the pandemic. While there were no significant increases in the frequency of hallucinations and delusions in SZ and CHR, distress increased from pre-pandemic to early pandemic in both groups and then decreased at the third time point. Additionally, changes in positive symptom severity in SZ were related to psychiatric medication adherence. Findings suggest that positive symptoms are a critical treatment target during the pandemic and that ongoing medication services will be beneficial.

"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.

Prevalence, service use and clinical correlates of hallucinations and delusions in an out-patient population from India.

BACKGROUND: Despite the persistent public health problem of positive psychotic symptoms, understanding of symptom specific prevalence rates, clinical correlates and service utilisation are sparse. AIMS: The current study aimed to establish prevalence, clinical and service utilisation correlates of hallucinations and delusions in people accessing outpatient clinics in Tamil Nadu, India. METHODS: Secondary patient data from outpatient clinics, over a 12-month period, in 2016, was used for analysis (N = 917). Based on the presence of positive psychotic symptoms (PPSx), the sample was divided into four groups for analysis- hallucinations-only (H), delusions-only (D), both hallucinations and delusions (HD) and neither PPSx (N-PPSx). RESULTS: Findings indicate that the most prevalent PPSx were hallucinations (10.7%) however, barriers to service utilisation and clinical correlates were associated predominantly with the D and the HD group; as was severe work impairment. Yet, this group was most likely to remain with psychiatric services. Lastly, diagnostic challenges were apparent within the sample. CONCLUSIONS: The study revealed that despite more barriers to service utilisation, persons with PPSx remain in contact with services. Yet prognosis remains only moderate at best, indicating other mediating and underlying factors impeding recovery may be interplaying and, therefore, a need for enhanced biopsychosocial approaches.

Delusions with content related to COVID-19 pandemic, in non-infected psychiatric hospitalized patients: a six-case series.

We briefly present a case series of six patients hospitalized in the Department of Psychiatry, University General Hospital of Ioannina, between the first (starting March 23, 2020) and the second (starting November 7, 2020) lockdown in Greece who presented with COVID-19 - related delusional ideas. All patients had negative PCR prior to admission and no history of COVID-19 infection.The first three of our cases were admitted during the first lockdown, between March 23 and May 4, one involuntary and the other two voluntary. The first one was diagnosed with acute and transient psychosis (F23 - First Episode Psychosis) and the other two with psychotic depression (F32.3). Three additional patients were admitted voluntary after the end of the first lockdown. One was diagnosed with acute and transient psychosis (F23-First Episode Psychosis) and the other two were relapses of a known psychiatric disorder (Bipolar disorder F31.5 and Psychotic depression F32.3). At follow-up six months after discharge all patients were in remission following antipsychotic medication, among other medicines. These cases reveal that COVID-19 pandemic may have an impact on the delusional content of new or preexisting psychotic disorders during the COVID-19 pandemic.

Religious Fundamentalism, Delusions, and Conspiracy Beliefs Related to the COVID-19 Pandemic.

The widespread COVID-19 conspiracy theories are a problem in dealing with the pandemic, as their proponents tend not to adhere to public health regulations. The aim of this study was to analyse the relationships between religious fundamentalism, delusions, compliance with public health regulations, and religion-related conspiracy beliefs about the COVID-19 pandemic. The participants were 570 internet users aged 18-60. They responded to questions regarding sociodemographic variables, compliance with public health regulations, conspiracy beliefs concerning COVID-19, as well as the Revised Religious Fundamentalism Scale, and the Delusions Scale. The results indicated that people exhibiting more conspiracy beliefs were less likely to comply with public health regulations concerning the COVID-19 pandemic and showed more religious fundamentalism. Additionally, there was an indirect effect of religious fundamentalism on conspiracy beliefs through delusions. The results suggest that when formulating epidemiological messages, it is worth paying attention to the importance of rational thinking.

Jumping to Conclusions and Its Associations With Psychotic Experiences in Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder-The Danish High Risk and Resilience Study, VIA 11.

BACKGROUND: The jumping to conclusions (JTC) bias, ie, making decisions based on inadequate evidence, is associated with psychosis in adults and is believed to underlie the formation of delusions. Knowledge on the early manifestations of JTC and its associations with psychotic experiences (PE) in children and adolescents is lacking. DESIGN: Preadolescent children (mean age 11.9 y, SD 0.2) at familial high risk of schizophrenia (FHR-SZ, n = 169) or bipolar disorder (FHR-BP, n = 101), and controls (n = 173) were assessed with the Beads Task to examine JTC. The number of beads drawn before making a decision, "draws to decision" (DTD) was used as a primary outcome. PE were ascertained in face-to-face interviews. General intelligence was measured with Reynolds Intellectual Screening Test. RESULTS: Children at FHR-SZ took fewer DTD than controls (4.9 vs 5.9, Cohen's d = 0.31, P = .004). Differences were attenuated when adjusting for IQ (Cohen's d = 0.24, P = .02). Higher IQ was associated with a higher number of DTD (B = 0.073, P < .001). Current subclinical delusions compared with no PE were associated with fewer DTD in children at FHR-SZ (P = .04) and controls (P < .05). Associations between delusions and DTD were nullified when accounting for IQ. CONCLUSIONS: JTC marks familial risk of psychosis in preadolescence, not reducible to general intelligence. JTC is associated with subclinical delusions, but this may be an expression of intellectual impairment. Future studies should establish temporality between JTC and delusion formation and examine JTC as a target for early intervention.

Prevalence, clinical features, and risk factors of delusions in patients with delirium.

OBJECTIVES: Delirium may be divided into multiple subtypes with different pathological factors. This study aimed to focus on the delirium subtype in which delusions are conspicuous and explore its prevalence, clinical characteristics, and risk factors. METHODS: The subjects were 601 delirium cases referred to the department of psychiatry over 5 years at a general hospital. The Delirium Rating Scale-Revised-98 was used to assess the delusions in patients with delirium, and the features of delusions (delusional form, object, and content) were examined. Multiple regression analysis was applied to determine whether individual factors were associated with the delusions. RESULTS: A total of 78 patients with delirium experienced delusions (13.0%). Most were classified as delusion of reference, such as persecution or poisoning, and 84.3% of patients believed that the persecutors were medical staff members. Older age (p < 0.001), female gender (p < 0.001), and living alone (p < 0.001) were significantly associated with delusions in patients with delirium. CONCLUSIONS: The content of delusions was rooted in the distress caused by the patients' medical situation, and the features and risk factors of the delusions suggested a formal similarity with late paraphrenia and "lack-of-contact paranoia." Psychological interventions that consider the isolation, anxiety, and fear behind delusions may be necessary in the care and treatment of these patients.

["ZOOM effect". The TV sign in patients with dementia: Is there an increased incidence during pandemia due to a rise in isolation and virtuality?] / "Efecto ZOOM". El signo de la TV en pacientes con demencia: ¿Hubo un aumento en la incidencia durante la pandemia debido al mayor aislamiento y la virtualidad?

Delusional misidentification syndromes are misperceptions of external stimuli with an associated belief or elaboration that is held with delusional intensity. In the TV sign patient believes that the observed television events are occurring in a real three-dimensional space. It is one of the very rare forms of delusional misidentification syndrome in patients withdementia.Wereport7patientswithcognitiveimpairmentcaseswhohavepresentedTVsignduringtheCOVID-19 pandemic. Two patients had Alzheimer's dementia type diagnosis, 1 atypical Alzheimer dementia, 1 vascular dementia and 3 of them had mixed etiology (2 Alzheimer dementia + vascular and 1 dementia with Lewy bodies + vascular). Three presented other psychotic symptoms and 1 patient also had Capgras syndrome. These 7 cases series raise the possibility of an increase incidence of TV sign in patients with dementia during pandemia triggered by the rise in expo- sure to screen devices and a social isolation during this period.