Using a slightly different approach in a Korean sample, CHR converters were compared to non-converters, full remitters, and HC to assess for baseline neurocognitive differences among the groups and prediction of symptom abatement over a 12- to 24-month follow-up. At baseline, those whose prodromal symptoms subsequently remitted performed better on measures of verbal fluency and memory, immediate visual memory, and attention as compared to converters, and in fact performed equally to healthy controls in all cognitive domains. Over time, CHR remitters demonstrated improvement in semantic fluency while performance of non-remitting, non-converting CHR individuals declined despite the absence of significant baseline differences, implying that investigation of cognitive trajectories over time may clarify probability of transition.Neuroimaging studies investigating high-risk cohorts have found abnormalities in the white matter organization in the brains of CHR individuals as compared to HCs using diffusion tensor imaging , particularly in brain regions known to undergo significant changes from adolescence to adulthood such as the superior longitudinal fasciculus . However, to date no baseline differences between subsequent CHR converters and non-converters have been reported utilizing either DTI or volumetric techniques, though to date very few studies have reported on this comparison. Research using positron emission tomography to estimate dopamine synthesis capacity in the striatum found elevated dopamine synthesis capacity in the whole, associative and sensorimotor striatum,commercial marijuana vertical growing suggesting the presence of dopaminergic abnormalities that precede psychosis onset. These intriguing findings have potential implications for early initiation of anti-psychotic medications in these patients. Findings related to the predictive utility of neuroanatomic findings have been inconsistent, in part due to methodological differences.
Multivariate pattern classification has been used to classify converters and non-converters based on baseline group differences in gray matter volume in cerebellar, prefrontal, cingulate, and striatal structures, with classification algorithms attaining 80% accuracy in test cases. When an independent sample of CHR participants were then classified into low, intermediate, and high risk groups by the multivariate pattern analysis, low versus high risk group transition rates were 8 and 88% respectively, demonstrating fairly accurate conversion predictions from such neuroanatomic algorithms. However, while a recent review of the high-risk literature supports the notion of anatomic changes over time that distinguish CHR+ from CHR− individuals, reports of baseline and follow-up group differences are inconsistent. For example, various studies have found that CHR+ individuals demonstrate baseline volumetric abnormalities in several regions such as the interior frontal gyrus, prefrontal cortex, cerebellum, and cingulate cortex as compared to nonconverters, with particularly converging evidence for the insula and superior temporal gyrus. Converters also have been reported to evidence greater volumetric reductions over time in the insular cortex, superior temporal gyrus, and inferior frontal gyrus as compared to non-converters over a 1- to 4-year follow-up period. Cortical thickness abnormalities have also been investigated, with no significant whole-brain or region of interest differences found between converters and non-converters despite overall decreased cortical thickness in the right parahippocampal gyrus observed in CHRs as compared to controls. Importantly, findings from the NAPLS consortium in a sample of 135 controls and 274 CHR youth, 35 of whom converted, indicated no cortical thickness or volumetric group differences at baseline, but significantly greater rates of change in cortical thickness in superior frontal, middle frontal, and medial orbitofrontal regions within the right hemisphere in CHR+ versus CHR− and HC groups .
CHR+ individuals also evidenced greater expansion of the third ventricle over time as compared to CHR− and controls. These changes were not due to anti-psychotic medication exposure as both medicated and non-medicated converters showed similar rates of gray matter loss. Additionally, converters demonstrated stronger correlations between rates of right hemisphere cortical thickness reduction and levels of pro-inflammatory markers measured in blood plasma, although this association was present among the entire sample. This work highlights the need for more research on the role of neuroinflammatory factors in psychosis onset, and their temporal relationship to neurochemical and neuroanatomic changes. Various quantitative electroencephalogram parameters, such as resting EEG frequencies, have also been assessed for their utility in psychosis prediction. These include alpha , beta , theta , and delta activity. In the European Prediction of Psychosis Study study, variables of occipital-parietal alpha peakfrequency , frontal delta, and frontal theta power were included in a final model and analyzed for prognostic power. Three classes of participants emerged , with low and high-risk CHRs demonstrating statistically significant different rates of conversions. Additionally, CHR+ individuals were found to have higher frontal/central delta and theta and lower occipital-parietal alpha peak frequency, suggesting baseline resting EEG differences that can be used to predict later psychosis and potentially function as a point of individualized intervention. Resting state-EEG microstates, or transient patterns occurring during spontaneous mental operations, have also differentiated CHR patients from other symptomatic groups and HC. Schizophrenic and CHR patients significantly differed in their temporal microstates as compared to controls, as well as from each other. In particular, microstate class A, one of the four typical microstates that may be active during phonological processing, seemed to most prominently predict transition to psychosis in light of its correlation with positive symptom severity, though it may also simply be a proxy for anxiety and impaired stress tolerance. EEG-based event-related potential work has additionally revealed a promising biomarker via auditory mismatch negativity , an ERP component resulting from hearing a discordant sound among repeated standard sounds. In a comparison of CHR, FE, and HC individuals, HCs had significantly higher MMN amplitudes compared to FE and CHR groups, while CHR and FE groups did not differ. Within the CHR group, converters showed distinct profiles of lower MMN amplitudes at baseline compared to non-converters, a finding that was not accounted for by anti-psychotic medication. Further analysis suggested only one of two types of deviant MMN predicted psychosis when factoring in the time delay between ERP evaluation and conversion, highlighting more specific potential predictors for further evaluation.
Previous research has implicated stress and underlying neurohormonal factors in the etiology of schizophrenia, such that indicators of hypothalamic-pituitary-adrenal axis activity are elevated in individuals with psychotic-spectrum disorders and appear to be affected by both anti-psychotic medications that reduce psychotic symptoms and recreational substances that exacerbate such symptoms. The association between elevated cortisol and dopamine activity in high-risk populations further suggests a role of neurohormonal factors in the emergence of psychosis. Recently, two measures of HPA activity within a CHR cohort were examined. CHR individuals, particularly those who were unmedicated, demonstrated a smaller cortisol awakening response compared to healthy controls. No group differences were observed within daytime cortisol levels, nor were clinical symptoms significantly correlated with cortisol levels. However,mobile vertical grow rack the small sample size and confounds of medication plus psychosocial treatment throughout the study suggest notable limitations. To better assess the predictive power of neurohormonal factors, the NAPLS consortium investigated salivary cortisol levels and found significant correlations to baseline symptoms across positive, negative, general, and disorganized domains, with particular significance for dysphoric mood and impaired stress tolerance. Baseline cortisol levels among CHR+ patients were also found to be higher than that of CHR− or healthy control groups. Here too, effects were independent of anti-psychotic or other medication use. Therefore, the role of HPA axis dysfunction as a potential risk biomarker warrants additional attention, particularly given recent reviews highlighting the role of stress and impaired immune functioning in the etiology of psychosis. Despite the wealth of information we have accumulated from the CHR literature, several issues associated with the reliability and utility of the construct remain. One of the most prominent is the lack of specificity for determining later psychosis as opposed to other psychiatric disorders, broadly defined poor functioning, or brief psychotic symptoms that ultimately remit. As some suggest, this may be partially due to limited long-term follow-up, research definitions of conversion that typically are based on psychotic-level symptomatology at a single time point, and the diversity of research tools and analytic strategies used among research sites Variability in long-term outcome, specifically the high number of CHR individuals who do not convert to psychotic disorder, may also reflect access to effective intervention, sampling from heterogeneous help-seeking populations, and conversions occurring outside of study follow-up points. Much of the CHR research to date has focused on relatively short follow-up periods, thereby potentially missing some cases of conversion and confounding predictive algorithms. Some suggestions for increasing specificity have been proposed, such as including the COGDIS criterion into CHR criteria to increase the positive predictive power of conversion. For example, the incorporation of basic symptoms at baseline has indeed been shown to increase the likelihood of predicting schizophrenia over affective psychosis, although this meta-analysis has been criticized for the use of limited, potentially under powered studies. Regardless, the inclusion of basic symptoms does not address the full spectrum of outlined concerns. Many of the above arguments and challenges observed in CHR research put forth above became a part of the recent discussion and controversy regarding the inclusion of an Attenuated Psychosis Syndrome into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
Although the full debate is beyond the scope of the current article, we highlight several themes and point the reader in the direction of more comprehensive reviews of the topic. As put forth by the DSM psychotic disorders task force, the defined Attenuated Psychotic Symptoms syndrome significantly increases the likelihood of predicting future psychosis . However, as highlighted above, limitations to the current evidence base exist: the overwhelming presence of comorbid diagnoses, the range of non-psychotic psychiatric outcomes, and the decreased diagnostic reliability among community clinical settings outside of the research or academic domains. Therefore, continued investigation of the syndrome and its connection to other related disorders like Schizotypal Personality Disorder is necessary before inclusion into the DSM as a formal disorder. Recent research has continued to clarify the CHR state and long-term outcomes, finding that negative symptoms in CHR individuals predict deficits in functioning at baseline and follow-up, and that decreased functioning correlates with neurocognitive factors across all time points. In particular, premorbid social dysfunction appears to have some diagnostic specificity for predicting emergence of schizophrenia over other psychiatric outcomes, including other psychotic disorders. Additionally, the combination of clinical and neuropsychological variables such as IQ, verbal memory, or processing speed increases predictive power. Baseline differences in neuroanatomic structures have also been reported in CHR versus HC groups, with structural differences in the superior temporal gyrus and insula appearing in multiple studies. Progressive gray matter changes within several anatomic regions may be particularly relevant as predictors of psychosis outcome, although the implicated regions vary across studies. HPA axis dysfunction is also hypothesized to be relevant to psychosis risk; this possibility is supported by the finding of elevated baseline cortisol levels among CHR+ individuals. Lastly, most of the recent work conducted has focused on baseline predictors of psychosis, though it has also been suggested that the field should shift to assessing overall deterioration throughout study duration. Table 1 provides a summary of the clinical and neurocognitive prediction findings, while Table 2 summarizes neuroimaging, psychophysiological, and neurohormonal predictors of transition to psychosis. Despite this progress, findings across studies do not yet fully converge on common factors, highlighting the complex nature of schizophrenia and its etiology . Therefore, there are still many areas requiring clarification within the psychosis risk prediction literature. As with all budding research, many findings need to be replicated using larger sample sizes and extended longitudinal designs to confirm their validity and reliability; multi-site studies such as the NAPLS consortium may prove to be particularly useful here. It will also be imperative to pin down the timing and trajectories of suggested biomarkers in order to facilitate intervention. Although recent publications have highlighted promising interventions that seek to prevent psychosis emergence via symptom reduction, such as medications including Omega-3 fatty acids and glycine, psychosocial therapies, cognitive remediation training, and combined treatment approaches, this field is still in its infancy. Among other factors, potential regional/cultural variability in help-seeking behavior and health care programs has not yet been sufficiently addressed. Additionally, there continues to be a paucity of current research on the ethnic and cultural differences in CHR classification and outcomes, as well as whether distinct conversion predictors exist within ethnic groups as some have suggested. From a clinical standpoint, delays in obtaining access to care also present a substantial obstacle to receiving accurate early diagnosis and treatment.