Differentiating the Effect of Medication and Illness on Brain Volume Reductions in First-Episode Psychosis: A Longitudinal, Randomized, Triple-blind, Placebo-controlled MRI study

AbstractBackgroundPsychotic disorders are associated with reductions in brain volume, but the timing and causes of these reductions remain unclear. In particular, the effects of antipsychotic medication and illness have been difficult to disentangle due to a lack of prospective, longitudinal, randomized placebo-controlled designs.MethodsWe conducted a triple-blind randomised placebo-controlled trial where 62 antipsychotic naïve patients with first episode psychosis (FEP) received either an atypical antipsychotic or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n=27) was also recruited. Structural MRI scans were obtained at baseline, 3-months and 12-months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint.OutcomeFrom baseline to 3 months, we observed a significant group × time interaction in the pallidum, such that patients receiving atypical antipsychotics showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. In patients, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity, consistent with a neuroprotective effect of atypical antipsychotics. We additionally found preliminary evidence for illness-related volume reductions in prefrontal cortices at 12 months and putative antipsychotic-related neurotoxicity in cerebellum at both 3-months and 12-months.InterpretationOur findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotics may be primarily mediated through their effects on the basal ganglia.Trial registrationACTRN12607000608460.

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Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study

Neuropsychopharmacology ◽

10.1038/s41386-021-00980-0 ◽

2021 ◽

Author(s):

Sidhant Chopra ◽

Alex Fornito ◽

Shona M. Francey ◽

Brian O’Donoghue ◽

Vanessa Cropley ◽

...

Keyword(s):

Antipsychotic Medication ◽

Brain Volume ◽

First Episode Psychosis ◽

Common Finding ◽

First Episode ◽

Control Group ◽

Grey Matter Volume ◽

Long Term Effects ◽

Significant Group ◽

Episode Psychosis

AbstractChanges in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n = 27) was also recruited. Structural MRI scans were obtained at baseline, 3 months and 12 months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p < 0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.

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Network Constraints on Longitudinal Grey Matter Changes in First Episode Psychosis

10.1101/2022.01.11.22268989 ◽

2022 ◽

Author(s):

Sidhant Chopra ◽

Stuart Oldham ◽

Ashlea Segal ◽

Alexander Holmes ◽

Kristina Sabaroedin ◽

...

Keyword(s):

Volume Change ◽

Grey Matter ◽

Structural Connectivity ◽

First Episode Psychosis ◽

First Episode ◽

Control Group ◽

Grey Matter Volume ◽

Volume Changes ◽

Matter Volume ◽

Episode Psychosis

Background: Different regions of the brain's grey matter are connected by a complex structural network of white matter fibres which are responsible for the propagation of action potentials and the transport of trophic and other molecules. In neurodegenerative disease, these connections constrain the way in which grey matter volume loss progresses. Here, we investigated whether connectome architecture also shapes the spatial pattern of longitudinal grey matter volume changes attributable to illness and antipsychotic medication in first episode psychosis (FEP). Methods: We conducted a triple-blind randomised placebo-control MRI study where 62 young adults with first episode psychosis received either an atypical antipsychotic or placebo over 6-months. A healthy control group was also recruited. Anatomical MRI scans were acquired at baseline, 3-months and 12-months. Deformation-based morphometry was used to estimate illness-related and antipsychotic-related grey matter volume changes over time. Representative functional and structural brain connectivity patterns were derived from an independent healthy control group using resting-state functional MRI and diffusion-weighted imaging. We used neighbourhood deformation models to predict the extent of brain change in a given area by the changes observed in areas to which it is either structurally connected or functionally coupled. Results: At baseline, we found that empirical illness-related regional volume differences were strongly correlated with predicted differences using a model constrained by structural connectivity weights (ρ = .541; p < .001). At 3-months and 12-months, we also found a strong correlation between longitudinal regional illness-related (ρ > .516; p < .001) and antipsychotic-related volume change (ρ > .591; p < .001) with volumetric changes in structurally connected areas. These correlations were significantly greater than those observed across various null models accounting for lower-order spatial and network properties of the data. Associations between empirical and predicted volume change estimates were much lower for models that only considered binary structural connectivity (all ρ < .376), or which were constrained by inter-regional functional coupling (all ρ < .436). Finally, we found that potential epicentres of volume change emerged posteriorly early in the illness and shifted to the prefrontal cortex by later illness stages. Conclusion: Psychosis- and antipsychotic-related grey matter volume changes are strongly shaped by anatomical brain connectivity. This result is consistent with findings in other neurological disorders and implies that such connections may constrain pathological processes causing brain dysfunction in FEP.

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Pituitary volume in psychosis

The British Journal of Psychiatry ◽

10.1192/bjp.185.1.5 ◽

2004 ◽

Vol 185 (1) ◽

pp. 5-10 ◽

Cited By ~ 133

Author(s):

Carmine M. Pariante ◽

Konstantina Vassilopoulou ◽

Dennis Velakoulis ◽

Lisa Phillips ◽

Bridget Soulsby ◽

...

Keyword(s):

Hpa Axis ◽

Atypical Antipsychotics ◽

Antipsychotic Drugs ◽

First Episode Psychosis ◽

Magnetic Resonance Images ◽

First Episode ◽

Control Group ◽

Typical Antipsychotic ◽

The People ◽

Episode Psychosis

BackgroundPatients with psychosis have activation of the hypothalamic-pituitary-adrenal (HPA) axis during the acute phase of the psychosis. Whether this has any morphological consequences for the pituitary gland is currently unknown.AimsTo examine pituitary volume variation in people at different stages of psychotic disorder.MethodPituitary volume was measured using 1.5 mm, coronal magnetic resonance images in 24 people with first-episode psychosis, 51 with established schizophrenia and 59 healthy controls.ResultsCompared with the control group, the people with first-episode psychosis had pituitary volumes that were 10% larger, whereas those with established schizophrenia had pituitary volumes that were 17% smaller. In both of the groups with psychosis, there was no difference in pituitary volume between those receiving typical antipsychotic drugs and those receiving atypical antipsychotics.ConclusionsThe first episode of a psychosis is associated with a larger pituitary volume, which we suggest is due to activation of the HPA axis. The smaller pituitary volume in the group with established schizophrenia could be the consequence of repeated episodes of HPA axis hyperactivity.

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Brief psycho-education for caregivers of persons with first episode psychosis

Indian Journal of Positive Psychology ◽

10.15614/ijpp.v9i01.11741 ◽

2018 ◽

Vol 9 (01) ◽

Author(s):

Praful Prabhuappa Kapse ◽

Manisha Kiran

Keyword(s):

First Episode Psychosis ◽

First Episode ◽

Control Group ◽

Episode Psychosis ◽

Study Results ◽

Before And After ◽

Quasi Experimental ◽

Expressed Emotions ◽

Experimental Group ◽

Group Family

Caring for the persons with first episode psychosis is challenging and demanding. It may lead to the increased burden, expressed emotions among the caregivers. The numerous studies have shown that high burden and negative expressed emotions among caregivers can lead to early relapse in the patients with first episode psychosis. To evaluate the effects of the brief psychoeducation on the caregivers burden and expressed emotions. A quasi experimental - before and after with control group research design was adopted for the study. A total of 60 caregivers have participated in the study, of which 30 caregivers in experimental group and 30 caregivers in the control group. Family Burden Interview Schedule (Pai and Kapoor, 1981) and Attitude Questionnaire (Sethi et al., 1981) was used to assess caregiver's burden and expressed emotions. At end of the psychoeducation intervention, burden among caregivers and negative expressed emotions of the caregivers have significantly reduced. The positive expressed emotions have been increased. Study results demonstrates the importance of psychoeducation intervention in reducing the burden and negative expressed emotions.

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QUALITY OF INDIVIDUAL AND GROUP LEVEL INTERVENTIONS FOR FIRST EPISODE PSYCHOSIS AT THE TERTIARY PSYCHIATRIC HOSPITAL IN UGANDA.

10.31234/osf.io/hrygs ◽

2020 ◽

Author(s):

Emmanuel Kiiza Mwesiga ◽

Noeline Nakasujja ◽

Lawrence Nankaba ◽

Juliet Nakku ◽

Seggane Musisi

Keyword(s):

Psychiatric Hospital ◽

Psychotic Disorders ◽

First Episode Psychosis ◽

First Episode ◽

Group Level ◽

Group Interventions ◽

Episode Psychosis ◽

Essential Components ◽

The Individual

Introduction: Individual and group level interventions have the largest effect on outcomes in patients with the first episode of psychosis. The quality of these individual and group level interventions provided to first-episode psychosis patients in Uganda is unclear.Methods: The study was performed at Butabika National Psychiatric Teaching and referral hospital in Uganda. A retrospective chart review of recently discharged adult in-patients with the first episode of psychosis was first performed to determine the proportion of participants who received the different essential components for individual and group level interventions. From the different proportions, the quality of the services across the individual and group interventions was determined using the first-Episode Psychosis Services Fidelity Scale (FEPS-FS). The FEPS-FS assigns a grade of 1-5 on a Likert scale depending on the proportion of patients received the different components of the intervention. Results: The final sample included 156 first-episode psychosis patients. The median age was 27 years [IOR (24-36)] with 55% of participants of the female gender. 13 essential components across the individual and group interventions were assessed and their quality quantified. All 13 essential components had poor quality with the range of scores on the FEPS-FS of 1-3. Only one essential component assessed (use of single antipsychotics) had moderate quality.Discussion: Among current services at the National psychiatric hospital of Uganda, the essential for individual and group level interventions for psychotic disorders are of low quality. Further studies are required on how the quality of these interventions can be improved.

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Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis

Molecular Psychiatry ◽

10.1038/s41380-021-01197-9 ◽

2021 ◽

Author(s):

Meike Heurich ◽

Melanie Föcking ◽

David Mongan ◽

Gerard Cagney ◽

David R. Cotter

Keyword(s):

High Risk ◽

Psychotic Disorder ◽

Psychotic Disorders ◽

Clinical Symptoms ◽

First Episode Psychosis ◽

Specific Protein ◽

First Episode ◽

Clinical High Risk ◽

Blood Proteins ◽

Episode Psychosis

AbstractEarly identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways’ activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.

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Implementation of NAVIGATE Coordinated Specialty Care for First Episode Psychosis: the Michigan Experience

CNS Spectrums ◽

10.1017/s1092852920002928 ◽

2021 ◽

Vol 26 (2) ◽

pp. 177-178

Author(s):

Eric D. Achtyes ◽

Kari Kempema ◽

Zhehui Luo ◽

Katharine N. Thakkar ◽

Catherine Adams ◽

...

Keyword(s):

Mental Health ◽

Clinical Symptoms ◽

The United States ◽

First Episode Psychosis ◽

Specialty Care ◽

First Episode ◽

Control Group ◽

Evidence Based ◽

Block Grant ◽

Episode Psychosis

AbstractStudy ObjectivesCoordinated specialty care (CSC) is widely accepted as an evidence-based treatment for first episode psychosis (FEP). The NAVIGATE intervention from the Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) study is a CSC intervention which offers a suite of evidence-based treatments shown to improve engagement and clinical outcomes, especially in those with shorter duration of untreated psychosis (DUP). Coincident with the publication of this study, legislation was passed by the United States Congress in 2014–15 to fund CSC for FEP via a Substance Abuse and Mental Health Services Administration (SAMHSA) block grant set-aside for each state. In Michigan (MI) the management of this grant was delegated to Network180, the community mental health authority in Kent County, with the goal of making CSC more widely available to the 10 million people in MI. Limited research describes the outcomes of implementation of CSC into community practices with no published accounts evaluating the use of the NAVIGATE intervention in a naturalistic setting. We describe the outcomes of NAVIGATE implementation in the state of MI.MethodsIn 2014, 3 centers in MI were selected and trained to provide NAVIGATE CSC for FEP. In 2016 a 4th center was added, and 2 existing centers were expanded to provide additional access to NAVIGATE. Inclusion: age 18–31, served in 1 of 4 FEP centers in MI. Data collection began in 2015 for basic demographics, global illness (CGI q3 mo), hospital/ED use and work/school (SURF q3 mo) and was expanded in 2016 to include further demographics, diagnosis, DUP, vital signs; and in 2018 for clinical symptoms with the modified Colorado Symptom Inventory (mCSI q6 mo), reported via an online portal. This analysis used data until 12/31/19. Mixed effects models adjusted by age, sex and race were used to account for correlated data within patients.ResultsN=283 had useable demographic information and were included in the analysis. Age at enrollment was 21.6 ± 3.0 yrs; 74.2% male; 53.4% Caucasian, 34.6% African American; 12.9 ± 1.7 yrs of education (N=195). 18 mo retention was 67% with no difference by sex or race. CGI scores decreased 20% from baseline (BL) to 18 mo (BL=3.5, N=134; 15–18 mo=2.8, N=60). Service utilization via the SURF was measured at BL (N=172) and 18 mo (N=72): psychiatric hospitalizations occurred in 37% at BL and 6% at 18 mo (p<0.01); ER visits occurred in 40% at BL and 13% at 18 mo (p<0.01). 44% were working or in school at BL and 68% at 18 mo (p<0.01). 21% were on antipsychotics (AP) at BL (N=178) and 85% at 18 mo (N=13) with 8% and 54% on long acting injectable-AP at BL and 18 mo, respectively. Limitations include missing data and lack of a control group.ConclusionThe implementation of the NAVIGATE CSC program for FEP in MI resulted in meaningful clinical improvement for enrollees. Further support could make this evidence-based intervention available to more people with FEP.FundingSupported by funds from the SAMHSA Medicaid State Block Grant set-aside awarded to Network180 (Achtyes, Kempema). The funders had no role in the design of the study, the analysis or the decision to publish the results.

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Context-specific abnormalities of the central executive network in first-episode psychosis: relationship with cognition

Psychological Medicine ◽

10.1017/s0033291720004201 ◽

2020 ◽

pp. 1-10

Author(s):

Deepak K. Sarpal ◽

Goda Tarcijonas ◽

Finnegan J. Calabro ◽

William Foran ◽

Gretchen L. Haas ◽

...

Keyword(s):

Cognitive Control ◽

Psychotic Disorders ◽

First Episode Psychosis ◽

First Episode ◽

Cognitive State ◽

Cognitive States ◽

Episode Psychosis ◽

Dorsolateral Prefrontal ◽

Parietal Lobule ◽

Context Specific

Abstract Background Cognitive impairments, which contribute to the profound functional deficits observed in psychotic disorders, have found to be associated with abnormalities in trial-level cognitive control. However, neural tasks operate within the context of sustained cognitive states, which can be assessed with ‘background connectivity’ following the removal of task effects. To date, little is known about the integrity of brain processes supporting the maintenance of a cognitive state in individuals with psychotic disorders. Thus, here we examine background connectivity during executive processing in a cohort of participants with first-episode psychosis (FEP). Methods The following fMRI study examined background connectivity of the dorsolateral prefrontal cortex (DLPFC), during working memory engagement in a group of 43 patients with FEP, relative to 35 healthy controls (HC). Findings were also examined in relation to measures of executive function. Results The FEP group relative to HC showed significantly lower background DLPFC connectivity with bilateral superior parietal lobule (SPL) and left inferior parietal lobule. Background connectivity between DLPFC and SPL was also positively associated with overall cognition across all subjects and in our FEP group. In comparison, resting-state frontoparietal connectivity did not differ between groups and was not significantly associated with overall cognition, suggesting that psychosis-related alterations in executive networks only emerged during states of goal-oriented behavior. Conclusions These results provide novel evidence indicating while frontoparietal connectivity at rest appears intact in psychosis, when engaged during a cognitive state, it is impaired possibly undermining cognitive control capacities in FEP.

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Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis

Psychological Medicine ◽

10.1017/s0033291719002277 ◽

2019 ◽

Vol 50 (13) ◽

pp. 2182-2193 ◽

Cited By ~ 11

Author(s):

Kirsten B. Bojesen ◽

Bjørn H. Ebdrup ◽

Kasper Jessen ◽

Anne Sigvard ◽

Karen Tangmose ◽

...

Keyword(s):

Psychotic Disorders ◽

Poor Response ◽

First Episode Psychosis ◽

Anterior Cingulate ◽

First Episode ◽

Antipsychotic Treatment ◽

Resonance Spectroscopy ◽

Reference Levels ◽

Clinical Prognosis ◽

Episode Psychosis

AbstractBackgroundPoor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).MethodsThirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.ResultsBefore treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.ConclusionGlutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

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A-8 Developmental Cognitive Phenotypes in First-Episode Psychosis and Longitudinal Cognitive Change Following Antipsychotic Treatment

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab062.09 ◽

2021 ◽

Vol 36 (6) ◽

pp. 1030-1030

Author(s):

Milena Y Gotra ◽

Elmma Khalid ◽

Madison M Dykins ◽

Scot K Hill

Keyword(s):

Cognitive Ability ◽

Antipsychotic Medication ◽

Cognitive Change ◽

First Episode Psychosis ◽

First Episode ◽

Healthy Controls ◽

Significant Group ◽

Cognitive Improvement ◽

Episode Psychosis ◽

Chronic Psychosis

Abstract Objective The present study applied a developmentally based subgrouping procedure previously examined in chronic psychosis patients to a sample of first-episode psychosis (FEP) and examined change in cognition following treatment with antipsychotic medication. Method Medication naïve FEP patients (n = 119; age = 27.96; 63.9% male; 62.2% White, 32.8% Black, 5.0% Other) recruited during initial hospitalization were categorized into groups based on 1) estimated premorbid intellectual ability and 2) the discrepancy between predicted (modeled on 151 healthy controls) and current cognitive ability. Consistent with findings from chronic psychosis samples, groups were characterized as Preserved (n = 46; average premorbid, no discrepancy), Deteriorated (n = 44; average premorbid, significant discrepancy), and Compromised (n = 29, low premorbid and current cognitive ability). A mixed analysis of variance was used to examine change in a composite cognitive score derived from a comprehensive neuropsychological battery at baseline, 6 weeks, and 12 months. Results There was a significant group by time interaction [Figure 1; F(5.4142.4) = 2.81, p = 0.02] in which the Preserved group performed similar to healthy controls across all time points, the Compromised group demonstrated stable deficits after treatment, and the Deteriorated group diverged from the Compromised group at 6 weeks and 12 months. Discussion There is considerable cognitive heterogeneity in FEP at baseline and after initiation of antipsychotic medication. Findings of cognitive improvement in the Deteriorated group after treatment initiation suggests a differential response to antipsychotic medications that was not found in the Compromised or Preserved groups. Future work may benefit from examining medication and symptom severity as potential factors contributing to the unique change observed in the Deteriorated group.

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