Functional dysconnection in schizophrenia is underwritten by a pathophysiology of the glutamate neurotransmission that affects the excitation-inhibition balance in key nodes of the salience network. ...Physiologically, this manifests as aberrant effective connectivity in intrinsic connections involving inhibitory interneurons. In computational terms, this produces a pathology of evidence accumulation and ensuing inference in the brain. Finally, the pathophysiology and aberrant inference would partially account for the psychopathology of schizophrenia as measured in terms of symptoms and signs. We refer to this formulation as the 3-level hypothesis.
We tested the hypothesis in core nodes of the salience network (the dorsal anterior cingulate cortex dACC and the anterior insula) of 20 patients with first-episode psychosis and 20 healthy control subjects. We established 3-way correlations between the magnetic resonance spectroscopy measures of glutamate, effective connectivity of resting-state functional magnetic resonance imaging, and correlations between measures of this connectivity and estimates of precision (inherent in evidence accumulation in the Stroop task) and psychopathology.
Glutamate concentration in the dACC was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula, respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of subjects with first-episode psychosis. Furthermore, aberrant computational parameters of the Stroop task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the anterior insula correlated negatively with severity of social withdrawal.
These findings support a link between glutamate-mediated cortical disinhibition, effective-connectivity deficits, and computational performance in psychosis.
While both Attention deficit hyperactivity disorder (ADHD) and schizophrenia are considered to have neurodevelopmental origins with associated impairments in executive functioning, there is a paucity ...of clinical guidelines pertaining specifically to this comorbidity. We sought to summarize the existing literature on ADHD in early psychosis patients, focusing on issues that would be most relevant to clinical practice. For this narrative review, we completed a search on PubMed and PsycINFO with 22 papers meeting criteria for review. Overall, it appears that a diagnosis of ADHD in childhood increases the risk of the subsequent development of a primary psychotic disorder. This risk may be modified by higher rates of substance use and could be related to shared premorbid risk factors for both conditions, such as obstetrical complications. Stimulant use has been associated with the onset of psychotic symptoms in some individuals, but it is unclear whether certain subgroups are more susceptible. Despite the fact that these two conditions co-occur relatively frequently, there is currently a lack of objective diagnostic tests for ADHD specific to populations with primary psychotic disorders, and a paucity of evidence on whether stimulants are effective for ADHD symptoms in this sub-group. Future research is warranted to investigate whether stimulant treatment confers any additional risks for symptom exacerbation in individuals with primary psychotic disorders taking antipsychotic maintenance treatment.
Abstract
Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) ...cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (
n
= 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (
p
> 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.
Adversity is prevalent among people with psychotic disorders, especially those within the first 5 years of a psychotic disorder, called early phase psychosis. Although adversity can lead to many ...negative outcomes (e.g., posttraumatic stress symptoms), very few treatments for adversity-related sequelae have been tested with individuals with psychotic disorders, and even fewer studies have specifically tested interventions for people in early phase psychosis. Furthermore, people who misuse substances are commonly excluded from adversity treatment trials, which is problematic given that individuals with early phase psychosis have high rates of substance misuse. For the first time, this trial will examine the outcomes of an adapted 15-session prolonged exposure protocol (i.e., PE+) to observe whether reductions in adversity-related psychopathology occurs among people with early phase psychosis and comorbid substance misuse.
This study will use a multiple-baseline design with randomization of participants to treatment start time. Participants will complete baseline appointments prior to therapy, engage in assessments between each of the five therapy modules, and complete a series of follow-up appointments 2 months after the completion of therapy. Primary hypothesized outcomes include clinically significant reductions in (1) negative psychotic symptoms measured using the Positive and Negative Syndrome Scale, (2) adversity-related sequelae measured using the Trauma Symptom Checklist-40, and (3) substance use frequency and overall risk score measured with the Alcohol, Smoking, and Substance Involvement Screening Test. We also anticipate that clinically significant reductions in hopelessness and experiential avoidance, measured with the Beck Hopelessness Scale and Brief Experiential Avoidance Questionnaire, the theorized mechanisms of change of PE+, will also be observed. A secondary outcome is a hypothesized improvement in functioning, measured using the Clinical Global Impression and Social and Occupational Functioning Assessment scales.
The results of this treatment trial will contribute to the advancement of treatment research for individuals in early phase psychosis who have current substance misuse and a history of adversity, and the findings may provide evidence supporting the use of hopelessness and experiential avoidance as mechanisms of change for this treatment.
Clinicaltrials.gov, NCT04546178; registered August 28, 2020, https://clinicaltrials.gov/ct2/show/NCT04546178?term=NCT04546178&draw=2&rank=1.
Although approximately 1/3 of individuals with schizophrenia are Treatment Resistant (TR), identifying these subjects prospectively remains challenging. The Treatment Response and Resistance in ...Psychosis working group defines <20% improvement as an indicator of TR, though its utility in First Episode Schizophrenia (FES) remains unknown. In a prospective cohort of FES (n = 129) followed up for 5 years, we evaluated two improvement thresholds for ‘probable TR’; <20% and <50% based on positive, negative, and total symptoms. We ascertained (1) the ecological validity (i.e., the ability to identify an expected subgroup of 1/3rd of patients); (2) the predictive validity (i.e., ability to predict poor global functioning) and (3) the clinical utility (association with clozapine use at the 5th year). Using the criteria of a total symptom reduction of <50% or negative symptom reduction of <20% resulted in ‘probable TR’ rates of 37% and 33%, respectively. Using <20% positive or total symptoms criteria resulted in very low rates, indicating minimal utility in FES. <50% total symptom criterion best predicted the global functioning over 5 years. Clozapine use was only predicted by positive symptom criterion. Prospective characterization of TRS is possible at 6 months after FES through a time-based approach using a 50% threshold for symptom change in treatment-adherent patients.
Early response to antipsychotic medications is one of the most important determinants of later symptomatic and functional outcomes in psychosis. Glutathione and glutamate have emerged as promising ...therapeutic targets for patients demonstrating inadequate response to dopamine-blocking antipsychotics. Nevertheless, the role of these neurochemicals in the mechanism of early antipsychotic response remains poorly understood. Using a longitudinal design and ultrahigh field 7-T magnetic resonance spectroscopy (MRS) protocol in 53 subjects, we report the association between dorsal anterior cingulate cortex glutamate and glutathione, with time to treatment response in drug naive (34.6% of the sample) or minimally medicated first episode patients with schizophreniform disorder, schizophrenia, and schizoaffective disorder. Time to response was defined as the number of weeks required to reach a 50% reduction in the PANSS-8 scores. Higher glutathione was associated with shorter time to response (F = 4.86, P = 0.017), while higher glutamate was associated with more severe functional impairment (F = 5.33, P = 0.008). There were no significant differences between patients and controls on measures of glutamate or glutathione. For the first time, we have demonstrated an association between higher glutathione and favorable prognosis in FEP. We propose that interventions that increase brain glutathione levels may improve outcomes of early intervention in psychosis.
The prepsychotic phase of schizophrenia is not only important for indicated prevention strategies, but also crucial for developing mechanistic models of the emergence of frank psychosis (transition). ...This commentary highlights the work of Dukart and colleagues, published in this issue of the
, who sought to identify MRI-based anatomic endophenotypes of psychosis in a well-characterized sample of patients with at-risk mental state (ARMS) and first-episode psychosis (FEP). Conceptual and translational challenges in clarifying the neurobiology of transitional prepsychotic states are discussed. A role of intracortical myelin in the neurobiology of transition is proposed. Transition may not be an outcome of "progressive structural deficits"; it may occur due to inadequate compensatory responses in the predisposed. The need to revise our current "deficit-oriented" models of neurobiology of psychosis in the wake of burgeoning evidence indicating a dynamic process of cortical reorganization is emphasized.
Abstract
Background
Although a substantial proportion of individuals with schizophrenia fail to respond to first-line dopaminergic blocking medications and are Treatment Resistant (TR), identifying ...these subjects prospectively remains challenging. Though clinically defined only after multiple treatment trials, TR is suspected to reflect a stable neurobiological phenomenon that can be identified even at the first episode of schizophrenia (FES). Establishing clear expectations for symptom improvement following antipsychotic initiation would facilitate development of objective thresholds for determining lack of efficacy. The Treatment Response and Resistance in Psychosis (TRIPP; Howes et al, 2017) working group has recently published consensus guidelines which define lack of response as a <20% improvement in psychotic symptoms. However, given that most patients with FES respond robustly to antipsychotics (Robinson et al, 1999), FES specific criteria for prospective identification of TR are warranted. We examined two symptom improvement thresholds across positive and negative symptom domains at 6 months in FES to investigate poor response (PR) as a proxy measure of early TR. We then examined the baseline/early clinical features that best prospectively predicted PR+ status. Given the estimated prevalence of TR is approximately 33%, we hypothesized that a comparable number (ie, 1/3rd) of individuals with FES would meet PR criteria using less a 50% response threshold, rather than a more stringent 20% threshold for determining symptomatic response. Furthermore, we hypothesized that very early lack of response would be associated with PR at 6 months.
Methods
Data from a longitudinal naturalistic cohort study of patients treated at the Prevention and Early Intervention Program for Psychosis (PEPP) in London, Ontario, Canada collected between 2002 and 2007 were used for this analysis. Only individuals meeting criteria for a primary psychotic disorder that were medication compliant were included. Positive and negative symptoms of psychosis were assessed using the SAPS (Andreasen, 1983) and SANS (Andreasen, 1984) at baseline, and at months 1, 2, 3, and 6. Treatment was administered in a naturalistic setting and followed clinical guidelines for the treatment of FES.
Results
Applying a 20% and 50% symptom improvement threshold for defining PR resulted in 2.2% and 14% rates for positive symptom PR, 33% and 60.9% rates of negative symptom PR, and 12% and 37.0% rates of total symptom PR at 6 months. Logistic regression analyses demonstrated that poor premorbid functioning, having a longer duration of untreated illness, and limited overall treatment response at months one and two were significantly associated with being PR+ (<50% improvement in total symptoms) at 6 months.
Discussion
This is the first study to our knowledge to investigate the symptom response thresholds suggested by TRIPP in FES. Our results suggest that including negative symptoms (either alone, with a 20% criteria for improvement, or in addition to positive symptoms, with a 50% improvement threshold) is necessary to identify the expected proportion of TR subjects prospectively in a FES sample. We propose that failing to achieve at least a 50% improvement in total symptoms, or at least 20% change in negative symptom severity by 6 months may be an early clinical indicator of eventual TR. On an optimistic note, we speculate that it may be possible to determine clozapine-eligibility as early as 6 months by using this approach. However, further studies are warranted to investigate the utility of this symptom threshold criteria in larger samples of patients with FES.
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