Research from JAMA Psychiatry — Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk — A Meta-analytical Stratification

Significance: Perceiving things that are not there and holding unfounded, bizarre beliefs (hallucinations and delusions, respectively) are psychotic symptoms that occur in particular syndromes including affective psychoses, paranoid states, and schizophrenia. We studied the emergence of this loss of contact with reality based on current models of normal brain function. Working with clinical individuals experiencing early psychosis and nonclinical individuals with high levels of psychosis proneness, we show that their visual perception is characterized by a shift that favors prior knowledge over incoming sensory evidence. Given that these alterations in information processing are evident early on in psychosis and even in association with subtle perceptual changes indicating psychosis proneness, they may be important factors contributing to the emergence of severe mental illnesses.

Background: Psychotic phenomena are common in the general population but are excluded from diagnostic criteria for mild to moderate depression and anxiety despite their co-occurrence and shared risk factors. We used item response theory modelling to examine whether the co-occurrence of depressive, anxiety and psychotic phenomena is best explained by: (1) a single underlying factor; (2) two separate, uncorrelated factors; (3) two separate yet linked factors; or (4) two separate domains along with an underlying ‘common mental distress’ (CMD) factor. We defined where, along any latent continuum, the psychopathological items contributed most information.Method: We performed a secondary analysis of cross-sectional, item-level information from measures of depression, anxiety and psychotic experiences in 6617 participants aged 13 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and 977 participants aged 18 years from the ROOTS schools-based sample. We replicated results from one sample in the other and validated the latent factors against an earlier parental measure of mental state.Results: In both cohorts depression, anxiety and psychotic items were best represented as a bi-factor model with a single, unitary CMD factor on which psychotic items conveyed information about the more severe end (model 4); residual variation remained for psychotic items. The CMD factor was significantly associated with the prior parental measure.Conclusions: Psychotic phenomena co-occur with depression and anxiety in teenagers and may be a marker of severity in a single, unitary dimension of CMD. Psychotic phenomena should be routinely included in epidemiological assessments of psychiatric morbidity, otherwise the most severe symptomatology remains unmeasured.

Importance Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear. Objective To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis. Design, Setting, and Participants In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication–naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied. Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017. Interventions A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo. Control participants were not given any drug. All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task. Main Outcomes and Measures Brain activation during verbal encoding and recall, indexed using the blood oxygen level–dependent hemodynamic response fMRI signal. Results Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 22.43 (4.95) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 25.35 (5.24) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 23.89 (4.14) years. Brain activation (indexed using the median sum of squares ratio of the blood oxygen level–dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group. Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, −0.027; interquartile range [IQR], −0.041 to −0.016; control: median, 0.020; IQR, −0.022 to 0.056;P < .001) and in the parahippocampal gyrus and midbrain during recall (placebo: median, 0.002; IQR, −0.016 to 0.010; control: median, 0.035; IQR, 0.015 to 0.039;P < .001). Within these 3 regions, activation in the CBD group was greater than in the placebo group but lower than in the control group (parahippocampal gyrus/midbrain: CBD: median, −0.013; IQR, −0.027 to 0.002; placebo: median, −0.007; IQR, −0.019 to 0.008; control: median, 0.034; IQR, 0.005 to 0.059); the level of activation in the CBD group was thus intermediate to that in the other 2 groups. There were no significant group differences in task performance. Conclusions and Relevance Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state. As these regions are critical to the pathophysiology of psychosis, the influence of CBD at these sites could underlie its therapeutic effects on psychotic symptoms. Trial Registration isrctn.org Identifier:ISRCTN46322781.

Since stability of DSM-IV diagnoses of disorders with psychotic features requires validation, we evaluated psychotic patients followed systematically in the McLean-Harvard International First Episode Project. We diagnosed 517 patients hospitalized in a first psychotic illness by SCID-based criteria at baseline and at 24 months to assess stability of specific DSM-IV diagnoses. Among 500 patients (96.7%) completing the study, diagnoses remained stable in 77.6%, ranking as follows: bipolar I disorder (96.5%) > schizophrenia (75.0%) > delusional disorder (72.7%) > major depressive disorder (MDD), severe, with psychotic features (70.1%) > brief psychotic disorder (61.1%) > psychotic disorder not otherwise specified (NOS) (51.5%) >> schizophreniform disorder (10.5%). Most changed diagnoses (22.4% of patients) were to schizoaffective disorder (53.6% of changes in 12.0% of subjects, from psychotic disorder NOS > schizophrenia > schizophreniform disorder = bipolar I disorder most recent episode mixed, severe, with psychotic features > MDD, severe, with psychotic features > delusional disorder > brief psychotic disorder > bipolar I disorder most recent episode manic, severe, with psychotic features). Second most changed diagnoses were to bipolar I disorder (25.9% of changes, 5.8% of subjects, from MDD, severe, with psychotic features > psychotic disorder NOS > brief psychotic disorder > schizophreniform disorder). Third most changed diagnoses were to schizophrenia (12.5% of changes, 2.8% of subjects, from schizophreniform disorder > psychotic disorder NOS > brief psychotic disorder = delusional disorder = MDD, severe, with psychotic features). These 3 categories accounted for 92.0% of changes. By logistic regression, diagnostic change was associated with nonaffective psychosis > auditory hallucinations > youth > male sex > gradual onset. Bipolar I disorder and schizophrenia were more stable diagnoses than delusional disorder or MDD, severe, with psychotic features, and much more than brief psychotic disorder, psychotic disorder NOS, or schizophreniform disorder. Diagnostic changes mainly involved emergence of affective symptoms and were predicted by several premorbid factors. The findings have implications for revisions of DSM and ICD.