Summary

• Tandon et al (2024)¹ summarizes the findings from an expert panel of fifty schizophrenia researchers who surveyed the literature to generate a consensus publication on currently established findings in schizophrenia. The panel addressed the reproducibility of various neuroanatomical, pharmacological and functional changes that have been identified in the brains of patients with schizophrenia.
  • Neuroanatomical changes that have been supported by multiple independent studies with generally consistent findings included:
    • Total brain volume reductions with enlarged lateral and third ventricles
    • Reduced grey matter volume in the hippocampus, medial and superior temporal lobe, prefrontal cortex (PFC), anterior cingulate, and thalamus
    • Diffuse white matter abnormalities
    • Reduced functional connectivity between multiple brain networks  
    • Decreased activity of the PFC at rest and in response to cognitive activation
  • Changes in neuropharmacology that have also been well supported include:
    • Excess dopamine D₂ receptor activation in patients, which is supported by using agonists and antagonists to modulate psychotic symptoms
    • Abnormalities in glutamatergic and GABA-ergic neurotransmission, based on the occurrence of schizophrenia-like symptoms in healthy individuals given NMDA glutamatergic antagonists
  • While additional changes in both neuroanatomy and neuropharmacology have been documented, it is noteworthy that “Pathological-clinical linkages are inconsistent with limited replication” given the heterogeneity of the disorder
• Recent meta-analyses and selected neuroimaging studies have further characterized disease-related changes and the impact of antipsychotic medication.^2-5 
• The Disease Recovery Evaluation and Modification (DREaM) study characterized the impact of paliperidone palmitate (PP) and oral antipsychotic (OAP) treatments on cortical thickness, intracortical myelin (ICM), functional connectivity and microstructure.^6-8
  • Difference in cortical thickness were identified in select regions, with reductions occurring over 9 months in both groups, however differences between the treatment groups over time did not reach significance
  • ICM did not significantly change over time in the PP group, whereas the OAP group had a significant reduction from baseline, but the between-groups difference was non-significant at Day 92 or 260
  • Differences in functional connectivity and microstructure were observed in the frontal and temporal lobes of patients relative to healthy controls
    • Treatment with PP was more effective than OAPs in decreasing the abnormally high fronto-temporal and thalamo-temporal connectivity, and increasing the fronto-sensorimotor and thalamo-insular connectivity  
• This summary is not intended to provide an exhaustive examination of the neuroimaging literature in schizophrenia. The most recent consensus publications, meta-analyses and summaries of earlier original research and Johnson & Johnson funded studies are included as of April 15, 2025.

Neuroimaging Meta-analysis and selected Primary STUDIES

Recent Meta-Analyses

• Neuroimaging meta-analyses summarized by Howes et al 2023² have characterized a variety of differences in both the anatomy and functional activation in schizophrenia
  • More than 500 structural MRI studies comparing schizophrenia patients to health controls have consistently found significant increases in lateral and third ventricle volume and decreases in total brain and grey matter volume
    • To exclude the effect of antipsychotic medication use, 15 MRI studies compared drug-free patients to healthy controls and found lower grey matter volumes in 4 distinct regions (left fusiform gyrus, left inferior frontal gyrus, right superior temporal gyrus, and left supramarginal gyrus)
  • Longitudinal effects are also present over the course of the disease with larger absolute effect sizes for lower grey matter volume in patients with chronic schizophrenia vs first-episode patients
    • Longitudinal studies adjusting for antipsychotic exposure suggest that treatment is unlikely to account for the excess volume changes.^9,10
• du Plessis et al 2023³ used machine learning to characterize two distinct neuroanatomical change signatures in schizophrenia and correlated these signatures with antipsychotic treatment.  
  • Signature 1, described as lower grey matter volumes in the thalamus, nucleus accumbens, medial temporal, medial prefrontal/frontal, and insular cortices, remained stable over time and differences were not influenced by treatment effects
  • Signature 2, characterized as larger basal ganglia and internal capsule with normal cortical anatomy, differences increased over time and were significantly associated with greater symptom reduction, suggesting these may be treatment responsive changes
• Andreasen et al 2013⁵ evaluated 202 first-episode patients with schizophrenia from the Iowa Longitudinal Study to determine the impact of time spent in relapse, number of relapses, and antipsychotic treatment intensity on brain volume measures.
  • Patients with ≥2 magnetic resonance imaging scans and ≥5 years of follow-up were included in this study, with a mean follow-up duration of 7 years
  • Greater relapse duration was associated with significant brain tissue loss, with the largest effect on the frontal lobe and white matter
  • No significant brain volume changes were associated with the number of relapses
  • Antipsychotic treatment intensity was significantly associated with total brain volume loss as well as reduction in specific regions
  • These associations do not confirm the causality of these factors to neuroanatomical changes as the regression analysis cannot completely disentangle the possibility that patients with more severe disease also had longer relapse duration and required greater treatment intensity.
• van Haren et al 2007⁴ compared focal brain changes in patients with schizophrenia (n=96) to those of healthy patients (n=113) in a 5-year longitudinal study using voxel-based morphometry.
  • Gray matter density was significantly decreased in the left superior frontal gyrus, left superior temporal gyrus, right caudate nucleus and right thalamus relative to those of healthy patients, while white matter density changes were not significant.
    • The number of hospitalizations was significantly associated with decreases in gray matter density in certain brain regions, however total duration of hospitalization could not explain these changes
  • Cumulative treatment with typical antipsychotics was significantly correlated with increased density in the right caudate nucleus and thalamus, and the left superior frontal gyrus.
    • However, after excluding one patient who received a larger dose of typical antipsychotic treatment relative to other patients, cumulative treatment was only correlated with the right caudate nucleus.

Neuroimaging STUDIES of paliperidone palmitate (Dream)

• Alphs et al 2022⁶ conducted The Disease Recovery Evaluation and Modification (DREaM) study to evaluate the effectiveness of paliperidone palmitate (PP) vs oral antipsychotics (OAP) in delaying time to first treatment failure in adults with recent-onset schizophrenia or schizophreniform disorder over a 9-month span.
  • The study was separated into three parts:
    • (1) 2-month tolerability testing period for 273 patients with recent-onset schizophrenia prior to potential PP initiation,
    • (2) adequately treated patients were randomized to either PP or OAPs for 9 months,
    • (3) re-randomization of the OAP group to either PP or OAP for a second 9-month treatment period.
  • An extended disease progression phase evaluated differences in groups who received PP/PP and OAP/OAP in the previous 18 months.
  • In Part II, the difference between the TtFTF in PP and OAP groups (PP: 29.5%, OAP: 24.8%; P=0.377) was not significant though numerical differences were observed in Part III (PP/PP: 14.3, OAP/: 15.8%; OAP/OAP: 28.6%; P=0.067) and the EDP phases (PP/PP: 28.6%, OAP/OAP: 44.4%; NNT=6; P=0.080)
• Wang et al 2023⁷ examined cortical thickness, gray-to-white matter contrast (GWC) and frontal lobe intracortical myelin (ICM).
  • Prior to randomization, ICM and GWC were not different between first-episode patients and healthy controls, however, specific neuroanatomical regions were found to be thinner in patients vs control
  • Both OAP and PP patients showed reductions in cortical thickness in specific regions after 9 months, with more widespread reduction in the OAP group. However, there was no significant difference in the longitudinal changes between treatment groups
• Tishler et al 2023⁸ evaluated ICM from 71 participants (PP=23 and OAP=48) through 9 months of treatment in the DREaM study.
  • At baseline, adjusted ICM fractions were not different between patients in each treatment arms
  • At Day 92, ICM was unchanged in the PP group and the OAP group demonstrated a significant decrease relative to baseline (P<0.001), however the difference in the change between the groups did not reach significance (P=0.147), likely due to small sample size.
  • ICM was not different between groups at Day 260
• Wang et al 2023¹¹ analyzed functionality and structural connectivity of 68 patients with recent onset of schizophrenia or schizophreniform disorder from the DREaM study.
  • In relation to healthy controls (HCs), patients with FES showed stronger functional connectivity (FC) with the frontal, parietal, and temporal lobes, but weaker somatosensory and thalamo-insula FC.
  • Stronger microstructural connectivity between the frontal and temporal lobes and the limbic system was observed at baseline relative to HCs.
  • Treatment with PP was more effective than OAPs in decreasing the abnormally high fronto-temporal and thalamo-temporal connectivity, and increasing the fronto-sensorimotor and thalamo-insular connectivity
  • Consistent with prior studies, widespread abnormalities in white-matter pathways were observed by fractional anisotrophy and mean diffusivity in the supratentorial and infratentorial regions.
    • PP treatment, but not OAPs resulted in significant reductions in FA values between the frontal and temporal lobes
    • Increased mean diffusivity was observed in both treatment groups, with 5 localized clusters showing a greater increase with PP vs OAPs