Hippocampal Structural Changes and Antipsychotic Medication in Schizophrenia Spectrum Disorder: A Systematic Review and Meta-Analysis of Longitudinal MRI Studies Highlighting Current Evidence Gaps.
Jul 2026· Current Neuropharmacology· Vol 24· 0 citations
Medicine
TL;DR
The pace of hippocampal volume change appears to differ between the early and chronic stages of schizophrenia, and the ability to draw firm conclusions regarding hippocampal volume changes across disease stages or their relationship with antipsychotic medication is limited.
Abstract
INTRODUCTION
The hippocampus is among the most affected brain structures in schizophrenia and plays a central role in the core pathology of psychotic disorders. Despite observations that hippocampal structural deficits emerge from the early stages of schizophrenia, it remains unclear how these changes progress over the disease course and how antipsychotic medication influences them.
Methods
We conducted a systematic review of longitudinal, volumetric MRI studies of patients with First-Episode Psychosis (FEP) and those at the Chronic stage (CH), and extracted data on hippocampal volume and antipsychotic medication exposure for meta-analysis. Both the review and the analysis conformed to PRISMA 2020 guidelines.
Results
Eighteen reports were included. Longitudinal analysis of the FEP group revealed no significant change in hippocampal volume over time (scan interval), likely due to substantial heterogeneity across studies. By contrast, the CH group exhibited a significantly faster, albeit subtle, reduction in hippocampal volume compared with Healthy Controls (HC). The meta-regression analysis revealed no significant associations between hippocampal volume reduction and any examined factors, including antipsychotic medication exposure, likely reflecting the small number of studies and the paucity of medication-related data.
Discussion
The pace of hippocampal volume change appears to differ between the early and chronic stages.
Conclusions
Substantial heterogeneity and insufficient available data in the current literature limit the ability to draw firm conclusions regarding hippocampal volume changes across disease stages or their relationship with antipsychotic medication. The pace of these changes may differ between the FEP and CH stages, but this observation should be interpreted cautiously. Further longitudinal MRI studies with more detailed and consistent reporting of medication-related variables are needed to clarify these relationships.
Associations between patterns of brain connectivity and brain structural features have transdiagnostic relevance to psychopathology. There is considerable evidence for disruptions to the hippocampus and temporoparietal brain systems in psychotic disorders. The present study examines structure–function relationships—specifically, the relation of hippocampal volume with patterns of temporoparietal effective connectivity—in youth at clinical high-risk for psychosis (CHR-P) and healthy controls (HCs). Participants at CHR-P and HCs completed clinical symptom measures and magnetic resonance imaging at baseline (n = 388, 42.5% female, age = 19.8 ± 4.2) in the second cohort of the North American Prodrome Longitudinal Study. Group Iterative Multiple Model Estimation established a common functional network of temporoparietal effective connectivity in the full sample. Next, supervised (assuming the CHR-P and HC groups represent classes) and unsupervised (data-driven) clustering procedures interrogated effective connectivity parameters relevant to subsamples. Mean difference tests by unsupervised cluster membership determined whether clusters formed based on temporoparietal effective connectivity differed in hippocampal volume. Clusters were also compared on representation of CHR-P and positive and negative symptom totals to determine whether unsupervised clustering recovered clinical features. Unsupervised clustering generated two clusters that differed significantly in right hippocampal volume and attenuated positive and negative symptoms with small-to-medium effect sizes. The cluster demonstrating reduced right hippocampal volume reported greater symptoms. Unsupervised clustering did not recover diagnostic groups. Findings are consistent with literature indicating the transdiagnostic relevance of hippocampal volume to organizational properties of brain functional networks and patterns of temporoparietal connectivity.
K. Aberizk, B. Ku, Hengyi Cao et al.· Brain Structure and Function· 0 citations
Abstract Attention-deficit/hyperactivity disorder (ADHD) affects 2.5% of adults and is associated with cognitive decline and dementia. The neurobiological mechanisms contributing to adverse outcomes in ADHD are poorly understood. ADHD-related brain alterations may persist into later life and interact with ageing-related processes, potentially increasing susceptibility to neuropathology. This preregistered systematic review synthesised neuroimaging findings in adults aged 35 years and older with clinical, symptomatic, or genetic risk for ADHD, and summarised cognitive and clinical correlates. A search of five databases produced 13 included studies. Risk of bias was assessed using the Newcastle-Ottawa Scale. Most studies (11/13) had low risk of bias. Compared to controls, ADHD groups exhibited alterations in fronto-striatal, fronto-parietal, and limbic systems implicated in executive control and attention. Middle-aged adults with clinical ADHD showed more widespread cortical structural differences, whereas older adults demonstrated abnormalities primarily in frontal regions, possibly reflecting attenuation of differences through ageing. Two functional studies in those with clinical ADHD reported frontal hypoactivation alongside parietal hyperactivation, consistent with compensatory recruitment. Among undiagnosed samples, there were interactions between genetic risk for ADHD and Alzheimer’s disease-related pathology affecting brain and cognitive outcomes. Overall, ADHD-associated neurobiological alterations appear to persist into older age. Longitudinal investigations are needed to clarify these relationships.
Natalia Docteur, Hayley G P Huston, Avery A Krupa et al.· Dialogues in Clinical Neuros...· 0 citations
CA was not consistently associated with hippocampal or amygdala volume alterations in PD and BD, and more consistent evidence emerged for reduced GMV in prefrontal regions, suggesting that neurobiological impact of CA may be more robustly captured at the cortical level.
T. Petrova, A. Tennifjord, D. Cavero et al.· medRxiv· 0 citations
PURPOSE
This systematic review investigates existing evidence regarding the structural and functional alterations of the anterior cingulate cortex (ACC) in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD), a neurodevelopmental disorder characterized by persistent inattention and hyperactivity-impulsivity.
MATERIALS AND METHODS
Following the PICO framework, inclusion criteria specified populations of children and adolescents aged under 18 years. The intervention comprised neuroimaging modalities assessing the ACC, compared against typically developing controls, with neuroimaging findings as the primary outcomes.
RESULTS
Structural MRI findings reported reduced gray matter volume, cortical thinning, and atypical sulcal morphology within the ACC. Functional MRI studies indicated diminished ACC activation during inhibitory control tasks, alongside selective hyperactivation potentially reflecting compensatory mechanisms. Resting-state analyses revealed hypo-connectivity between the ACC and regulatory regions-including the dorsolateral prefrontal cortex, cerebellum, and default mode network-with mixed connectivity patterns suggesting neurofunctional subtypes. Additionally, EEG studies demonstrated attenuated N2/P3 amplitudes and disrupted theta oscillations.
CONCLUSIONS
This review demonstrates a coherent neurobiological pattern in pediatric ADHD, characterized by both structural alterations (reduced ACC volume, thickness, and atypical folding) and functional dysregulation (abnormal activation, disrupted connectivity, and altered electrophysiological responses) across tasks probing inhibitory control, reward processing, and resting-state dynamics.
Tonia Salem, H. Harati, Marwa Summaka· Nordic Journal of Psychiatry· 0 citations
Schizophrenia is a severe psychiatric disorder marked by widespread brain abnormalities. Recent studies suggest that pathological changes may originate from focal 'epicenter' regions and subsequently spread to other brain areas strongly connected to them. Investigating drug-naïve first-episode schizophrenia (dn-FES) patients may help characterize early-stage regional functional abnormalities and their potential neurochemical underpinnings. Resting-state functional magnetic resonance imaging data were acquired from 50 dn-FES patients and 50 age- and sex-matched healthy controls (HCs). Static regional homogeneity (sReHo) and dynamic ReHo (dReHo) were compared between groups, and correlations with psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We further used the JuSpace toolbox to test whether spatial patterns of ReHo alterations were associated with specific neurotransmitter receptor/transporter densities. Compared with HCs, dn-FES patients showed reduced sReHo in the bilateral postcentral/precentral gyri, bilateral paracentral lobules and right supplementary motor area, and increased dReHo in the left lingual gyrus. sReHo in the right postcentral gyrus was inversely correlated with PANSS positive scores, whereas dReHo in the left lingual gyrus was negatively correlated with PANSS general scores. Schizophrenia-related sReHo alterations showed significant spatial associations with serotonergic, dopaminergic, noradrenergic and cholinergic systems, whereas dReHo alterations were associated with serotonergic, dopaminergic, cannabinoid and opioid systems. Taken together, this study identifies abnormal static and dynamic local functional connectivity in sensorimotor and visual regions in drug-naïve first-episode schizophrenia, and the spatial correspondence between these alterations and receptor/transporter distributions may offer insight into the molecular substrates associated with these functional abnormalities.
Ziyu Wang, Kangkang Xue, Yan Zhang et al.· Progress in Neuro-psychophar...· 0 citations
Metabolic syndrome (MS) is a frequent comorbidity in schizophrenia, yet the characteristics of white matter (WM) network alterations in this subgroup remain largely unknown. This study examined distinctive WM structural network disruptions in schizophrenia patients with comorbid MS and explored whether these alterations mediate the relationship between schizophrenia and metabolic abnormalities.
Twenty-six schizophrenia patients with MS (SZ-MS), twenty-two without MS (SZ-nMS), and twenty-four age- and sex-matched healthy controls (HC) underwent diffusion tensor imaging. Individual WM structural networks were constructed, and group differences in connectivity and topological organization were analyzed using network-based statistics and graph theory, controlling for age and sex.
Both SZ-MS and SZ-nMS patients exhibited reduced FA-weighted connectivity in prefrontal, parietal, and temporal cortices, thalamus, and hippocampus compared to HC. Relative to SZ-nMS, the SZ-MS group exhibited significant reduction in prefrontal FA-weighted connectivity. Topological metrics revealed global and nodal disruptions in both patient groups, notably in prefrontal cortex, bilateral thalamus, supramarginal gyrus, left precuneus, and right superior temporal gyrus. The SZ-MS group demonstrated greater nodal efficiency impairments in prefrontal and right superior temporal gyrus regions. Further exploratory analyses revealed that WM network metrics correlated with triglycerides, BMI, waist circumference, hip circumference, and fasting glucose. Additionally, reduced nodal efficiency in the right superior temporal gyrus exhibited a potential mediating pathway between SZ-MS and elevated BMI.
These findings indicate that SZ-MS patients display characteristic WM network disruptions, predominantly in prefrontal and right superior temporal areas. These alterations are associated with metabolic abnormalities, providing neuroimaging evidence that may clarify the neuropathological mechanisms connecting schizophrenia and metabolic dysfunction.
Ying Li, Qianqian Liu, Xinyue Chen et al.· Frontiers in Psychiatry· 0 citations
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