White matter connectivity reductions in the pre‐clinical continuum of psychosis: A connectome study

Widespread white matter connectivity disruptions have commonly been reported in schizophrenia. However, it is questionable whether structural connectivity decline is specifically associated with schizophrenia or whether it extends along a continuum of psychosis into the healthy population. Elucidating brain structure changes associated with psychotic‐like experiences in healthy individuals is insofar important as it is a necessary first step towards our understanding of brain pathology preceding florid psychosis. High resolution, multishell diffusion‐weighted magnetic resonance images (MRI) were acquired from 89 healthy individuals. Whole‐brain white matter fibre tracking was performed to quantify the strength of white matter connections. Network‐based statistics were applied to white matter connections in a regression model in order to test for a linear relationship between streamline count and psychotic‐like experiences. A significant subnetwork was identified whereby streamline count declined with increasing psychotic‐like experiences. This network of structural connectivity reductions affected all cortical lobes, subcortical structures and the cerebellum and spanned along prominent association and commissural white matter pathways. A widespread network of linearly declining connectivity strength with increasing number of psychotic‐like experiences was identified in healthy individuals. This finding is in line with white matter connectivity reductions reported from early to chronic stages of schizophrenia and might therefore aid the development of tools to identify individuals at risk of transitioning to psychosis.     

Cognitive endophenotypes of psychosis within dimension and diagnosis

This study sought to characterize the psychosis phenotype, contrasting cognitive features within traditional diagnosis and psychosis dimension in a family sample containing both schizophrenia and psychotic bipolar I disorder. Seventy-six probands with psychosis [44 probands with schizophrenia, 32 probands with psychotic bipolar I disorder] and 55 first-degree relatives [30 relatives of schizophrenia probands, 25 relatives of bipolar probands] were recruited. Standardized clinical and neuropsychological measures were administered. No differences in cognitive performance emerged between probands with schizophrenia and probands with psychotic bipolar disorder, or between relatives of probands with schizophrenia and relatives of probands with bipolar disorder in the domains of working and declarative memory, executive function and attention. Relatives overall showed higher cognitive performance compared to probands, as expected. However, when we segmented the probands and relatives along a psychosis dimension, independent of diagnostic groups, results revealed lower cognitive performance in probands compared to relatives without psychosis spectrum disorders, whereas relatives with psychosis spectrum disorders showed an intermediate level of performance across all cognitive domains. In this study, cognitive performance did not distinguish either probands or their first-degree relatives within traditional diagnostic groups (schizophrenia and psychotic bipolar disorder), but distinguished probands and relatives with and without lifetime psychosis manifestations independent of diagnostic categories. These data support the notion that schizophrenia and psychotic bipolar disorder present a clinical continuum with overlapping cognitive features defining the psychosis phenotype.     

Fronto-Temporal Disconnection Within the Presence Hallucination Network in Psychotic Patients With Passivity Experiences

Psychosis, characterized by hallucinations and delusions, is a common feature of psychiatric disease, especially schizophrenia. One prominent theory posits that psychosis is driven by abnormal sensorimotor predictions leading to the misattribution of self-related events. This misattribution has been linked to passivity experiences (PE), such as loss of agency and, more recently, to presence hallucinations (PH), defined as the conscious experience of the presence of an alien agent while no person is actually present. PH has been observed in schizophrenia, Parkinson’s disease, and neurological patients with brain lesions and, recently, the brain mechanisms of PH (PH-network) have been determined comprising bilateral posterior middle temporal gyrus (pMTG), inferior frontal gyrus (IFG), and ventral premotor cortex (vPMC). Given that the experience of an alien agent is a common feature of PE, we here analyzed the functional connectivity within the PH-network in psychotic patients with (N = 39) vs without PE (N = 26). We observed reduced fronto-temporal functional connectivity in patients with PE compared to patients without PE between the right pMTG and the right and left IFG of the PH-network. Moreover, when seeding from these altered regions, we observed specific alterations with brain regions commonly linked to auditory-verbal hallucinations (such as Heschl’s gyrus). The present connectivity findings within the PH-network extend the disconnection hypothesis for hallucinations to the specific case of PH and associates the PH-network with key brain regions for frequent psychotic symptoms such as auditory-verbal hallucinations, showing that PH are relevant to the study of the brain mechanisms of psychosis and PE.     

Biology and recent brain imaging studies in affective psychoses

Psychosis is a cardinal symptom of schizophrenia, but also occurs in other psychiatric conditions, including mood disorders. In many instances, brain abnormalities in psychotic and mood disorders appear to be on a spectrum, with the most marked changes in schizophrenia, followed by psychotic mood disorders, followed by nonpsychotic mood disorders. Such observations are consistent with the notion that mood disorders and schizophrenia represent a continuum of disease. However, in some instances, cerebral changes with psychosis may be qualitatively different, rather than merely more severe than those seen in mood disorders, more consistent with the theory that they are discrete entities. We review brain imaging studies that have advanced our knowledge of psychosis in mood disorders, with respect to the continuum versus discrete entity hypotheses.     

Aberrant Coupling Within and Across the Default Mode,Task-Positive,and Salience Network in Subjects at Risk for Psychosis

The task-positive network (TPN) is anticorrelated with activity in the default mode network (DMN), and possibly reflects competition between the processing of external and internal information, while the salience network (SN) is pivotal in regulating TPN and DMN activity. Because abnormal functional connectivity in these networks has been related to schizophrenia, we tested whether alterations are also evident in subjects at risk for psychosis. Resting-state functional magnetic resonance imaging was tested in 28 subjects with basic symptoms reporting subjective cognitive-perceptive symptoms; 19 with attenuated or brief, limited psychotic symptoms; and 29 matched healthy controls. We characterized spatial differences in connectivity patterns, as well as internetwork connectivity. Right anterior insula (rAI) was selected as seed region for identifying the SN; medioprefrontal cortex (MPFC) for the DMN and TPN. The 3 groups differed in connectivity patterns between the MPFC and right dorsolateral prefrontal cortex (rDLPFC), and between the rAI and posterior cingulate cortex (PCC). In particular, the typically observed antagonistic relationship in MPFC-rDLPFC, rAI-PCC, and internetwork connectivity of DMN-TPN was absent in both at-risk groups. Notably, those connectivity patterns were associated with symptoms related to reality distortions, whereas enhanced connectivity strengths of MPFC-rDLPFC and TPN-DMN were related to poor performance in cognitive functions. We propose that the loss of a TPN-DMN anticorrelation, accompanied by an aberrant spatial extent in the DMN, TPN, and SN in the psychosis risk state, reflects the confusion of internally and externally focused states and disturbance of cognition, as seen in psychotic disorders.Key words: resting-state fMRI, schizophrenia, anticorrelated networks, functional connectivity, central executive network, anterior insula, prodrome, intrinsic connectivity, brain     

Schizophrenia‐like topological changes in the structural connectome of individuals with subclinical psychotic experiences

Schizophrenia is often regarded as a “dysconnectivity” disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population‐based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion‐weighted MRI. Whole‐brain structural connectomes were derived and a range of global and local GT‐metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair‐wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair‐wise connections illustrates that, at less severe stages of psychosis, white‐matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness. Hum Brain Mapp 36:2629–2643, 2015.© 2015 TheAuthors Human Brain Mapping Published by Wiley Periodicals, Inc .     

An investigation of the relationship between cortical connectivity and schizotypy in the general population

Recent neuroimaging investigations have identified a relationship between psychotic symptoms in schizophrenia and abnormal brain connectivity. On the basis of the continuum model of psychosis, it was hypothesized that schizotypal traits in healthy control participants would be associated with relatively impaired frontotemporal white matter health as assessed using diffusion tensor imaging. Twenty-one participants (12 women and 9 men aged 18 to 58 years) completed the Schizotypal Personality Questionnaire (SPQ) and underwent diffusion-weighted magnetic resonance imaging scanning as part of a larger study. White matter integrity for the major association fibre tracts was assessed using standard measures of diffusivity, specifically fractional anisotropy (FA) and axial and radial diffusivity. A series of negative binomial regressions yielded significant relationships between reduced FA in seven white matter tracts and increased scores on the SPQ cognitive-perceptual factor. These findings are consistent with research relating brain connectivity to the positive symptoms of schizophrenia, suggesting that the neurobiological bases of schizotypal personality in healthy controls may be analogous to the neurobiological bases of schizophrenia spectrum disorders.     

Duration of untreated psychosis: are we ignoring the mode of initial development?. An extensive naturalistic case study of phenomenal continuity in first-episode schizophrenia

Duration of untreated psychosis (DUP) might affect the course and treatment outcome in schizophrenia significantly. Looking for potential determinants of DUP, researchers have mostly assessed the initial untreated psychosis in terms of plain duration, not developmental content. The present study provides empirical contributions to the discussion of phenomenal continuity throughout the entire untreated illness by pointing out continuous trajectories from prodrome to psychosis. In a series of 19 first-episode DSM-IV schizophrenia patients, we explore prodromal and untreated psychotic phenomena, and the data indicate that symptoms considered intrinsic to core psychosis phenomenology had attenuated antecedents in the prodromes, increasing continuously until treatment, whereas symptoms considered not intrinsic to core psychosis were characterized by fluctuations. Mode of initial psychosis development is proposed as a tentatively informative concept, comprising duration and content aspects of the initial prodrome and untreated psychosis.     

Working memory predicts presence of auditory verbal hallucinations in schizophrenia and bipolar disorder with psychosis

Objective: The recent dramatic increase in research investigating auditory verbal hallucinations (AVHs) has broadened the former narrow focus on schizophrenia to incorporate additional populations that experience these symptoms. However, an understanding of potential shared mechanisms remains elusive. Based on theories suggesting a failure of top-down cognitive control, we aimed to compare the relationship between AVHs and cognition in two categorical diagnoses of psychosis, schizophrenia and psychotic bipolar disorder. Method: A total of 124 adults aged 21–60 participated, of whom 76 had present-state psychosis (schizophrenia, n = 53; bipolar disorder with psychosis, n = 23), and 48 were non-clinical controls. Diagnosis and hallucination presence was determined using the Structured Clinical Diagnostic Interview for DSM-IV TR. AVHs severity was assessed using the Positive and Negative Syndrome Scale. Participants also completed the MATRICS cognitive battery. Results: The bipolar disorder with psychosis group performed better than the schizophrenia group for cognitive domains of Processing speed, Attention, Working memory (WM), and Visual memory. Hierarchical binary logistic regression found that WM significantly predicted presence of AVHs in both psychotic groups, but diagnosis did not significantly increase the predictive value of the model. A hierarchical multiple linear regression found that schizophrenia diagnosis was the only significant predictor of hallucination severity. Conclusions: The findings of this study—the first, to our knowledge, to compare the relationship between AVHs and MATRICS domains across schizophrenia and bipolar disorder with psychosis—support theories that deficits in WM underly the genesis of AVHs. WM potentially represents a shared mechanism of AVHs across diagnoses, supporting dimensional classifications of these psychotic disorders. However, non-cognitive factors predictive of hallucination severity may be specific to schizophrenia.     

The Cardiff Anomalous Perceptions Scale (CAPS): a new validated measure of anomalous perceptual experience

The study describes the Cardiff Anomalous Perceptions Scale (CAPS), a new validated measure of perceptual anomalies. The 32-item CAPS measure is a reliable, self-report scale, which uses neutral language, demonstrates high content validity, and includes subscales that measure distress, intrusiveness, and frequency of anomalous experience. The CAPS was completed by a general population sample of 336 participants and 20 psychotic inpatients. Approximately 11% of the general population sample scored above the mean of the psychotic patient sample, although, as a group, psychotic inpatients scored significantly more than the general population on all CAPS subscales. A principal components analysis of the general population data revealed 3 components: "clinical psychosis" (largely Schneiderian first-rank symptoms), "temporal lobe disturbance" (largely related to temporal lobe epilepsy and related seizure-like disturbances) and "chemosensation" (largely olfactory and gustatory experiences), suggesting that there are multiple contributory factors underlying anomalous perceptual experience and the "psychosis continuum."     

Familial association of schizotypal traits with psychotic and affective disorders

The criteria for schizotypal personality disorder were developed on the basis of traits observed in biologic relatives of schizophrenic and borderline schizophrenic probands from the Danish adoption studies. In this review, the relationship between schizotypal personality disorder and the schizophrenic spectrum, affective disorders, and psychotic disorders is explored. A dimension of psychosis may overlap with the schizophrenia spectrum to yield chronic schizophrenia, with the affective disorders spectrum to yield psychotic affective disorder, or by itself lead to other psychotic disorders. Schizotypal personality disorder in this model is posited to represent schizophrenia spectrum disorder that does not overlap with psychosis, whereas nonpsychotic affective disorders represent the affective disorders that do not overlap with psychosis. Delusional disorder represents another psychotic disorder that is not specifically related to either schizophrenia or the affective disorders. Evidence suggests that the schizotypal personality disorder criteria, particularly those emphasizing the negative symptoms or deficit-like symptoms of this disorder, specifically identify a unique relationship to the schizophrenia spectrum.     

Ventral Anterior Cingulate Connectivity Distinguished Nonpsychotic Bipolar Illness From Psychotic Bipolar Disorder and Schizophrenia

Bipolar illness is a debilitating neuropsychiatric disorder associated with alterations in the ventral anterior cingulate cortex (vACC), a brain region thought to regulate emotional behavior. Although recent data-driven functional connectivity studies provide evidence consistent with this possibility, the role of vACC in bipolar illness and its pattern of whole brain connectivity remain unknown. Furthermore, no study has established whether vACC exhibits differential whole brain connectivity in bipolar patients with and without co-occurring psychosis and whether this pattern resembles that found in schizophrenia. We conducted a human resting-state functional connectivity investigation focused on the vACC seed in 73 remitted bipolar I disorder patients (33 with psychosis history), 56 demographically matched healthy comparison subjects, and 73 demographically matched patients with chronic schizophrenia. Psychosis history within the bipolar disorder group corresponded with significant between-group connectivity alterations along the dorsal medial prefrontal surface when using the vACC seed. Patients with psychosis history showed reduced connectivity (Cohen’s d = −0.69), whereas those without psychosis history showed increased vACC coupling (Cohen’s d = 0.8) relative to controls. The vACC connectivity observed in chronic schizophrenia patients was not significantly different from that seen in bipolar patients with psychosis history but was significantly reduced compared with that in bipolar patients without psychosis history. These robust findings reveal complex vACC connectivity alterations in bipolar illness, which suggest differences depending on co-occurrence of lifetime psychosis. The similarities in vACC connectivity patterns in schizophrenia and psychotic bipolar disorder patients may suggest the existence of common mechanisms underlying psychotic symptoms in the two disorders.Key words: bipolar illness, schizophrenia, connectivity, resting-state, medial prefrontal cortex     

Premorbid functioning in early-onset psychotic disorders

OBJECTIVE: To examine the premorbid characteristics of youths with early-onset psychotic disorders. METHOD: Subjects with early-onset psychotic disorders received an extensive diagnostic evaluation upon entry into the study, including a historic review of premorbid functioning using the Premorbid Adjustment Scale. RESULTS: Youths with schizophrenia (n = 27), bipolar disorder (n = 22), and psychosis not otherwise specified (NOS) (n = 20) were included. High rates of premorbid behavioral problems and academic difficulties were noted across all subjects. Youths with schizophrenia had higher rates of premorbid social withdrawal and global impairment. They also tended to have fewer friends. The psychosis NOS group had significantly higher rates of abuse histories and posttraumatic stress disorder. CONCLUSIONS: Premorbid abnormalities are common features of early-onset psychotic disorders. The social withdrawal and peer problems specific to youths with schizophrenia likely represent early manifestations of negative symptoms. The abuse histories in the psychosis NOS group may explain the atypical nature of their reported psychotic symptoms, which in many cases are likely posttraumatic phenomena.     

Prospective study of neurological abnormalities in offspring of women with psychosis: birth to adulthood

OBJECTIVE: The authors prospectively investigated neurological abnormalities in 75 young adult offspring of mothers with psychotic disorders and 91 offspring of comparison mothers with no psychosis history. They also studied the stability of these abnormalities from birth to adulthood. METHOD: Neurological abnormalities were previously studied in infancy and at 6 years of age. In this study, they were blindly assessed with a comprehensive neurological assessment scale at a mean age of 22.4 years in a 93.3% effective follow-up of the sample. RESULTS: In relation to the comparison subjects (N=88) and offspring of mothers with affective psychosis (N=22), the adult offspring of mothers with schizophrenia (N=28) had significantly more neurological abnormalities. More soft signs, primitive reflexes, involuntary movements, and cranial nerve abnormalities characterized a subgroup (32%) among these offspring. The offspring of mothers with affective psychosis were not different from comparison subjects. The extension of schizophrenia and affective psychosis risk groups to include additional maternal "spectrum cases" (N=10 and N=14, respectively) generally yielded similar results. Neurological abnormalities at 22 years were significantly associated with neurological abnormalities at age 6, but not in infancy, among the total high-risk group, offspring of mothers with schizophrenia, and comparison offspring. CONCLUSIONS: High levels of neurological abnormalities are found in a substantial proportion of offspring of mothers with schizophrenia but not offspring of mothers with affective psychosis. This suggests that familial risk for schizophrenia is associated with neurodevelopmental disturbance that is manifest throughout life and belongs to a different biological continuum from that of affective psychosis.     

The role of top-down control in different phases of a sensorimotor timing task: a DCM study of adults and adolescents

The ability to precisely coordinate motor control to regularly-paced sensory stimuli requires an ability often called ‘mental timekeeping’, a distinct form of cognitive function. A consistent feature among conceptual models of the internal clock mechanism is an element of ‘top-down’ cognitive control. Although lesion and fMRI studies have provided indirect evidence supporting the role of the prefrontal cortex in exerting top-down influence over lower-level sensory and motor regions, little direct evidence exists. We investigated changes in Dynamic Causal Modeling (DCM)-measured top-down control of sensorimotor timing during different phases of a unimanual, auditory-paced finger-tapping task in a cohort of healthy adults and adolescents. The brain regions examined were organized into a network of excitatory connections between bilateral dorso- and ventrolateral prefrontal cortices and motor and auditory cortices. This baseline connectivity changed depending on whether participants listened passively to the pacing cue, synchronized their regular interval finger tapping with the cue, or continued tapping in absence of the cue. Subjects who performed better at maintaining the prescribed tapping pace in the absence of the auditory cue relied more on top-down control of the motor and sensory regions, while those with less accurate performance relied more on sensory driven, bottom-up control of the motor cortex. No significant maturational effects were observed in either the behavioral or DCM path weight data. Both right and left prefrontal cortex were found to exert control over timing behavioral accuracy, but there were distinctly lateralized roles with respect to optimal performance.     

Major self-mutilation in the first episode of psychosis

Major self-mutilation (MSM) is a rare but catastrophic complication of severe mental illness. Most people who inflict MSM have a psychotic disorder, usually a schizophrenia spectrum psychosis. It is not known when in the course of psychotic illness, MSM is most likely to occur. In this study, the proportion of patients in first episode of psychosis (FEP) was assessed using the results of a systematic review of published case reports. Histories of patients who had removed an eye or a testicle, severed their penis, or amputated a portion of a limb and were diagnosed with a schizophrenia spectrum psychosis were included. A psychotic illness was documented in 143 of 189 cases (75.6%) of MSM, of whom 119 of 143 (83.2%) were diagnosed with a schizophrenia spectrum psychosis. The treatment status of a schizophrenia spectrum psychosis could be ascertained in 101 of the case reports, of which 54 were in the FEP (53.5%, 95% confidence interval = 43.7%-63.2%). Patients who inflict MSM in FEP exhibited similar symptoms to those who inflict MSM later in their illness. Acute psychosis, in particular first-episode schizophrenia, appears to be the major cause of MSM. Although MSM is extremely uncommon, earlier treatment of psychotic illness may reduce the incidence of MSM.     

Is there an association between duration of untreated psychosis and 24-month clinical outcome in a first-admission series?

OBJECTIVE: The authors examined the duration of untreated psychosis, defined as the interval from first psychotic symptom to first psychiatric hospitalization, in a county-wide sample of first-admission inpatients who had received no previous antipsychotic medication. Differences between diagnostic groups in 24-month illness course and clinical outcomes as well as relationships between outcomes and duration of untreated psychosis were evaluated. METHOD: The data were derived from subjects in the Suffolk County Psychosis Project who were diagnosed at 24-month follow-up according to DSM-IV as having schizophrenia or schizoaffective disorder (N=155), bipolar disorder with psychotic features (N=119), or major depressive disorder with psychotic features (N=75). Duration of untreated psychosis was derived from the Structured Clinical Interview for DSM-III-R, medical records, and information from significant others. Measures at 24-month follow-up included consensus ratings of illness course, Global Assessment of Functioning Scale scores for the worst week in the month before interview, and current affective and psychotic symptoms. RESULTS: The median duration of untreated psychosis was 98 days for schizophrenia, 9 days for psychotic bipolar disorder, and 22 days for psychotic depression. Duration of untreated psychosis was not significantly associated with 24-month illness course or clinical outcomes in any of the diagnostic subgroups. CONCLUSIONS: Although these findings require replication in other epidemiologically based first-admission samples, at face value they do not support the suggestion of a psychotoxic effect of prolonged exposure to untreated psychosis.     

Validity and usefulness of the Wisconsin Manual for Assessing Psychotic-like Experiences.

The Wisconsin Manual for Assessing Psychotic-like Experiences is an interview-based assessment system for rating psychotic and psychotic-like symptoms on a continuum of deviancy from normal to grossly psychotic. The original manual contained six scales, assessing thought transmission, passivity experiences, thought withdrawal, auditory experiences, personally relevant aberrant beliefs, and visual experiences. A seventh scale assessing deviant olfactory experiences was subsequently added. The rating scales have good interrater reliability when used by trained raters. Cross-sectional studies indicated that the frequency and deviancy of psychotic-like experiences are elevated among college students who were identified, hypothetically, as psychosis prone by other criteria. Psychotic-like experiences of moderate deviancy in college students successfully predicted the development of psychotic illness and poorer overall adjustment 10 years later. The manual is useful for identifying psychosis-prone individuals and is recommended for use in linkage and treatment outcome studies. The present article provides an interview schedule for collecting information required for rating psychotic-like experiences.     

Distinct and opposite profiles of connectivity during self‐reference task and rest in youth at clinical high risk for psychosis

Self‐reference is impaired in psychotic disorders such as schizophrenia, associated with disability, and closely related to characteristic patterns of aberrant brain connectivity. However, at present, it is unclear whether self‐reference is impacted in pathogenesis of the disorder. Alterations in connectivity during a self‐reference task or resting‐state in the psychosis risk (i.e., prodromal) period may yield important clues for biomarker development, as well as for novel treatment targets. This study examined a task‐based and resting‐state functional magnetic resonance imaging in individuals at clinical high risk (CHR) for psychosis (n = 22) and healthy control unaffected peers (n = 20). The self‐reference task comprised three task conditions where subjects were asked if an adjective was relevant to themselves (self), a designated other individual (other), or to evaluate the word's spelling (letter). Connectivity analyses examined medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), regions commonly found in conjunction analyses of self‐reference, during both the self‐reference task and rest. In task connectivity analyses, CHR individuals exhibited decreased mPFC–PCC connectivity when compared to controls. In resting‐state analyses, CHR participants showed greater mPFC–PCC connectivity. Taken together, results suggest that psychosis‐like alterations in mPFC–PCC connectivity is present prior to psychosis onset across both task and rest.     

Loneliness and the psychosis continuum: a meta-analysis on positive psychotic experiences and a meta-analysis on negative psychotic experiences

Abstract

There is an increase in interest in the relationships between loneliness and psychosis. The notion of psychosis continuum implies that psychotic experiences extend from clinical populations with psychotic disorders to non-clinical populations. This meta-analytic review aimed to examine the respective associations of loneliness with positive and negative psychotic experiences along the psychosis continuum. A systematic database search was conducted and a total of 30 studies were included in the first meta-analysis and 15 studies were included in the second meta-analysis. There was a medium association between loneliness and positive psychotic experiences (r?=?0.302, p?<?0.001). In particular, the association between loneliness and paranoia was robust (r?=?0.448, p?<?0.001). The second meta-analysis revealed a medium association between loneliness and negative psychotic experiences (r?=?0.347, p?<?0.001). The associations between loneliness and both positive and negative psychotic experiences were found to be smaller among clinical than non-clinical samples. The above findings provided evidence for the associations between loneliness and the two core dimensions of psychotic experiences along the phenomenological continuum. Future research should examine the dynamics of these relationships in both clinical and non-clinical samples, preferably using a single-symptom approach.