Association between cannabis use and symptom dimensions in schizophrenia spectrum disorders: an individual participant data meta-analysis on 3053 individuals

Background: The association between cannabis use and positive symptoms in schizophrenia spectrum disorders is well documented, especially via meta-analyses. Yet, findings are inconsistent regarding negative symptoms, while other dimensions such as disorganization, depression, and excitement, have not been investigated. In addition, meta-analyses use aggregated data discarding important confounding variables which is a source of bias. Methods: PubMed, ScienceDirect and PsycINFO were used to search for publications from inception to September 27, 2022. We contacted the authors of relevant studies to extract raw datasets and perform an Individual Participant Data meta-analysis (IPDMA). Inclusion criteria were: psychopathology of individuals with schizophrenia spectrum disorders assessed by the Positive and Negative Syndrome Scale (PANSS); cannabis-users had to either have a diagnosis of cannabis use disorder or use cannabis at least twice a week. The main outcomes were the PANSS subscores extracted via the 3-factor (positive, negative and general) and 5-factor (positive, negative, disorganization, depression, excitement) structures. Preregistration is accessible via Prospero: ID CRD42022329172. Findings: Among the 1149 identified studies, 65 were eligible and 21 datasets were shared, totaling 3677 IPD and 3053 complete cases. The adjusted multivariate analysis revealed that relative to non-use, cannabis use was associated with higher severity of positive dimension (3-factor: Adjusted Mean Difference, aMD = 0.34, 95% Confidence Interval, CI = [0.03; 0.66]; 5-factor: aMD = 0.38, 95% CI = [0.08; 0.63]), lower severity of negative dimension (3-factor: aMD = -0.49, 95% CI [-0.90; -0.09]; 5-factor: aMD = -0.50, 95% CI = [-0.91; -0.08]), higher severity of excitement dimension (aMD = 0.16, 95% CI = [0.03; 0.28]). No association was found between cannabis use and disorganization (aMD = -0.13, 95% CI = [-0.42; 0.17]) or depression (aMD = -0.14, 95% CI = [-0.34; 0.06]). Interpretation: No causal relationship can be inferred from the current results. The findings could be in favor of both a detrimental and beneficial effect of cannabis on positive and negative symptoms, respectively. Longitudinal designs are needed to understand the role of cannabis is this association. The reported effect sizes are small and CIs are wide, the interpretation of findings should be taken with caution

Between-site reliability of startle prepulse inhibition across two early psychosis consortia

Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; between-site stability, however, has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling subjects studies were performed as part of quality assurance procedures in order to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) Consortium, 8 normal subjects traveled to each of the 8 NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy subjects were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multi-site studies, it is essential to institute quality assurance procedures early and establish between site reliability to assure comparable data across sites

Cognitive functioning and positive and negative symptoms in schizophrenia

Bibliography: p. 206-236.The first purpose of this study was to examine the relationship of cognitive functioning and positive and negative symptoms in schizophrenia. The second purpose was to determine whether there was a differential pattern of cognitive deficits associated symptoms. The third purpose was to see if cognitive functioning, negative symptoms and premorbid functioning were interrelated. Positive and negative symptoms were assessed and a battery of different cognitive tests were given. The sample consisted of fifty acutely ill schizophrenics who were assessed within the first week of their admission to a general hospital psychiatric ward. The data was analyzed using multiple regression analyses. Results of these analyses suggest that negative symptoms and not positive symptoms were associated with cognitive impairment. Furthermore, positive and negative symptoms were not differentially associated with specific patterns of cognitive deficits. Negative symptoms were associated with both tests of verbal ability and tests of visual-motor and visual spatial ability. Secondly, there were significant intercorrelations among negative symptoms, cognitive impairments, and poor premorbid functioning. The results were interpreted in terms of the concept that cognitive difficulties experienced by psychotic patients is a transient state that may fluctuate with changes in symptoms, whereas the deficits that are associated with negative symptoms are possible traits

Neuropsychology of the prodrome to psychosis in the NAPLS Consortium: Relationship to family history and conversion to psychosis

Context: Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions. Objectives: To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis. Design: Longitudinal study with 21?2 years of follow-up. Setting: Eight centers participating in the North American Prodrome Longitudinal Study. Participants: Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations. Main Outcome Measures: A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status. Results: Global ("composite") neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion. Conclusions: These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.This study was supported by the National Institute of Mental Health (grants R18 MH 43518, U01 MH081928, and P50 MH080272 to Dr Seidman; grant U01 MH066134 to Dr Addington; grants R01 MH60720 and K24 MH76191 to Dr Cadenhead; grant R01 MH65079 to DrCannon; grant K05MH01654 to DrMcGlashan; grants U01 MH066069 and P50 MH064065 to Dr Perkins; grant R18 MH 43518 to Dr Tsuang; grants RO1MH062066 and 5 U01MH081988 to DrWalker; grants U01MH74356, U01 MH082022, and R41 MH083436 to Dr Woods; and grant R01 MH061523 to Dr Cornblatt)

O10.2. DEFICIENT VISUAL ODDBALL STIMULUS PROCESSING PREDICTS PSYCHOSIS ONSET: RESULTS FROM THE NORTH AMERICAN PRODROME LONGITUDINAL STUDY

Abstract Background Clinical outcomes vary among young people with the psychosis risk syndrome (PRS), with approximately 20% of individuals progressing to a psychotic disorder over 2–3 years and 30% achieving clinical remission. The identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may enhance the accuracy of clinical outcome prediction in the PRS and help elucidate the pathogenic mechanisms of psychosis onset. Auditory P300 event-related potential (ERP) component amplitude reductions are well established in schizophrenia and reflect early attention-mediated information processing deficits. Recent studies employing auditory oddball tasks have shown that P300 amplitude deficits in PRS individuals are associated with later clinical outcomes, including both conversion to full-blown psychosis and remission from the at-risk state. The present study examined whether these effects extend to P300 in the visual modality using visual oddball task data collected as part of the North American Prodrome Longitudinal Study. Specifically, we evaluated whether visual P300 amplitudes are reduced in the PRS and predict future clinical outcomes. Methods 540 individuals meeting PRS criteria and 229 healthy individuals completed baseline EEG recording during a visual oddball task. Visual P300 subcomponents were measured in response to two stimulus types: (1) infrequent target stimuli, reflecting top-down allocation of attention (target P3b), and (2) infrequent non-target novel distractor stimuli, reflecting bottom-up orienting of attention (novelty P3a). P300 amplitudes of PRS participants who converted to psychosis (n=70) were compared with those of PRS non-converters who were followed clinically for 24 months and continued to be symptomatic (n=131) or fully remitted from the PRS (n=87). Results Group comparison effects did not differ by stimulus type. Visual P300 amplitudes were not significantly reduced in the PRS group relative to healthy individuals (p=.25). However, baseline target P3b and novelty P3a amplitudes were reduced in PRS individuals who later converted to psychosis relative to all PRS non-converters, including those who remitted (p=.006, d=.44) and those who remained symptomatic (p=.015, d=.37), as well as healthy individuals (p=.001, d=.44). Baseline P300 amplitudes were similar among healthy controls, PRS remitters, and PRS individuals who remained symptomatic (ps>.45). Moreover, visual P300 amplitudes differentiated future psychosis converters after accounting for PRS symptom severity. Finally, both target P3b and novelty P3a amplitudes predicted the time to psychosis onset in PRS participants (p=.03 and p=.02, respectively), such that more deficient P300 amplitudes were associated with shorter time to conversion. Discussion Baseline visual P300 amplitudes were reduced in future PRS converters relative to non-converters, with effect sizes comparable to those reported in previous auditory P300 studies of the PRS. Results implicate visual P300 as a neurophysiological vulnerability marker that predicts clinical outcomes among PRS individuals, including future transition to psychosis. Accordingly, together with prior auditory P300 studies, results suggest that P300 may have the potential to contribute to personalized early intervention in the PRS by distinguishing individuals with the greatest risk for psychotic illness, who require the most aggressive treatment, from those who may need minimal intervention

80. Auditory Target Processing Deficits in Individuals at Clinical High Risk for Psychosis

Abstract Background: Reductions in the auditory P300 event-related potential (ERP) component are well established in schizophrenia and reflect early attention-mediated auditory processing deficits. Two subcomponents of P300 are evident depending on oddball task conditions; P3b is elicited by infrequent target stimuli and reflects top-down attention allocation, whereas P3a is elicited by infrequent non-target novel distractor stimuli and reflects bottom-up orienting of attention. The present study examined whether auditory P300 abnormalities precede illness onset and are associated with future clinical status by assessing both target P3b and novel P3a in individuals at clinical high risk for psychosis (CHR) and healthy controls (HC) collected as part of the North American Prodrome Longitudinal Study. Methods: CHR (n = 552) and HC (n = 235) participants completed baseline EEG recording during an auditory oddball task. CHR participants were further categorized by clinical status after 24 months of study participation (n = 298) and included a subgroup who transitioned to psychosis (CHR-Transition; n = 73), a subgroup who did not transition but remained symptomatic (CHR-Symptomatic; n = 135), and a subgroup who did not transition and was in symptom remission (CHR-Remission; n = 90). Results: CHR participants had reduced target P3b and novel P3a amplitudes relative to HC (Ps < .001). There was also an effect of 24-month clinical status group on both P3b and P3a amplitudes (P < .001 and P = .006, respectively). Planned contrasts revealed that compared to HC, CHR participants had smaller target P3b amplitudes at baseline (P < .001). In addition, CHR-Transition participants had attenuated P3b amplitudes at baseline relative to all CHR participants who did not transition to psychosis (P = .037). Furthermore, both CHR-Transition and CHR-Symptomatic had smaller P3b amplitudes than both HC (Ps < .001) and CHR-Remission (P = .003 and P = .005, respectively), while P3b of CHR-Remission did not differ from HC at baseline (P > .05). In contrast, although CHR participants also had smaller novel P3a amplitudes than HC at baseline (P < .001), P3a did not differentiate CHR-Transition participants from CHR participants who did not transition within 24 months (P > .05). Despite CHR-Transition and CHR-Symptomatic having smaller P3a amplitudes than HC (P = .028 and P = .002, respectively), they did not differ from CHR-Remission (Ps > .05) at baseline. Moreover, target P3b predicted the time to psychosis onset in CHR participants over and above novel P3a amplitude (P = .024). Conclusion: Both target P3b and novel P3a are reduced in individuals identified to be at risk for developing a psychotic disorder, and P3b in particular appears sensitive to future transition to psychosis. Given this association with clinical outcomes, results implicate target P3b as a neurophysiological vulnerability marker for psychosis

F118. ARCHITECTURE OF PSYCHOSIS SYMPTOMS AND NEURAL PREDICTORS OF CONVERSION AMONG CLINICAL HIGH RISK INDIVIDUALS WITH AUTISM SPECTRUM DISORDER

Abstract Background: Individuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-). Methods: Clinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality. Results: In line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p<.01) and TASIT total score (t=-2.9, p=<.01), but groups did not differ in their psychotic symptoms on the SOPS (Positive: p=.72; Negative: p=.13; Disorganization: p=.13; General: p=.86). Groups did not differ in the rate at which they converted to psychosis (CHR/ASD+: 15.4%; CHR/ASD-: 11.1%; p=.50), and the Cannon risk score was equally predictive of 2-year conversion across groups (p=.39). EEG data revealed dissociable profiles regarding neural response to sensory stimuli in those who did versus did not convert to psychosis, depending on ASD status. P300 response over central electrodes to Novel visual stimuli was weaker in CHR- converters (n=71) than CHR- non-converters (n=220), but stronger in CHR/ASD+ converters (n=4) than CHR/ASD+ non-converters (n=10) (Novel Stimuli: Modality by ASD interaction, F=5.66, p=.02; Modality by ASD by Converter Interaction, F=3.57, p=.06). For both auditory and visual Target stimuli, P300 response over parietal electrodes did not differ between CHR/ASD- converters and non-converters; however, whereas CHR/ASD+ individuals who did not convert had amplitudes similar to all CHR/ASD- individuals, CHR/ASD+ converters had substantially greater auditory and visual P300 amplitudes (Target Stimuli: ASD by Converter interaction, F=12.12, p=.001). Discussion Individuals with ASD and CHR have greater social deficits than the general CHR population, but show similar psychotic symptoms and have similar risk for conversion to psychosis. Neural response to sensory stimuli is important for understanding risk for conversion, and differs among CHR individuals dependent on whether they have ASD. In particular, whereas all CHR individuals who do not convert share a common pattern of attenuated ERP amplitudes reflecting attention allocation to target and novel auditory and visual stimuli, CHR/ASD+ who convert have a unique pattern of globally heightened P300 responses to infrequent novel and target stimuli. These findings have two important implications: 1) individuals with ASD do convert to psychosis and have similar CHR symptom and risk profiles to non-ASD CHR patients clinically; 2) in CHR individuals with ASD in particular, examining neural markers of attention allocation to sensory stimuli may reveal important predictive clues about risk for conversion

Evidence of Slow Neural Processing, Developmental Differences and Sensitivity to Cannabis Effects in a Sample at Clinical High Risk for Psychosis From the NAPLS Consortium Assessed With the Human Startle Paradigm.

AbstractBiomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals.MethodsStartle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35.ResultsAt 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR&gt;NC) and non-users (NC&gt;CHR).DiscussionThis is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants