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

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

10.1101/2020.03.18.20038471 ◽

2020 ◽

Author(s):

Sidhant Chopra ◽

Alex Fornito ◽

Shona M. Francey ◽

Brian O’Donoghue ◽

Vanessa Cropley ◽

...

Keyword(s):

Atypical Antipsychotics ◽

Psychotic Disorders ◽

Brain Volume ◽

First Episode Psychosis ◽

First Episode ◽

Control Group ◽

Grey Matter Volume ◽

Significant Group ◽

Episode Psychosis ◽

Prospective Longitudinal

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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Longitudinal Changes in Functional Connectivity in Antipsychotic-treated and Antipsychotic-naive Patients with First Episode Psychosis

10.1101/2021.04.13.21255375 ◽

2021 ◽

Author(s):

Sidhant Chopra ◽

Shona M. Francey ◽

Brian O’Donoghue ◽

Kristina Sabaroedin ◽

Aurina Arnatkeviciute ◽

...

Keyword(s):

Functional Connectivity ◽

First Episode Psychosis ◽

Common Finding ◽

First Episode ◽

Control Group ◽

Antipsychotic Treatment ◽

Long Term Effects ◽

Limbic Systems ◽

Episode Psychosis ◽

The Brain

AbstractBackgroundAltered functional connectivity (FC) is a common finding in resting-state functional Magnetic Resonance Imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotics may influence the temporal evolution of these disturbances, remains unclear. Here, we scanned first episode psychosis (FEP) patients who were and were not exposed to antipsychotic medication during the first six months of illness at baseline, three months, and 12 months, to characterize how FC changes over time and in relation to medication use.MethodsSixty-two antipsychotic-naïve patients with 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. A total of 202 rs-fMRI scans were obtained across three timepoints: baseline, 3-months and 12-months. Our primary aim was to differentiate patterns of FC in antipsychotic-treated and antipsychotic-naive patients within the first 3 months of treatment, and to examine associations with clinical and functional outcomes. A secondary aim was to investigate long-term effects at the 12-month timepoint.ResultsAt baseline, FEP patients showed widespread functional dysconnectivity in comparison to controls, with reductions predominantly affecting interactions between the default mode network (DMN), limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems, and some of these changes correlated with improved clinical outcomes. Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain. At the 12-month follow-up, antipsychotic treatment was associated with a prolonged increase of FC primarily in the DMN and limbic systems.Conclusions and RelevanceAntipsychotic-naïve FEP patients show widespread functional dysconnectivity at baseline, followed by an early normalization of DMN and paralimbic dysfunction in patients receiving a psychosocial intervention only. Antipsychotic exposure is associated with distinct FC changes, principally concentrated on thalamo-cortical and limbic networks.

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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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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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Brain volume change in first-episode psychosis: an effect of antipsychotic medication independent of BMI change

Acta Psychiatrica Scandinavica ◽

10.1111/acps.12677 ◽

2016 ◽

Vol 135 (2) ◽

pp. 117-126 ◽

Cited By ~ 7

Author(s):

K. N. Jørgensen ◽

R. Nesvåg ◽

S. Nerland ◽

L. Mørch-Johnsen ◽

L. T. Westlye ◽

...

Keyword(s):

Antipsychotic Medication ◽

Volume Change ◽

Brain Volume ◽

First Episode Psychosis ◽

First Episode ◽

Episode Psychosis

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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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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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