Treatment-resistant schizophrenia: Addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients

Matrone, Marta; Kotzalidis, Georgios D.; Romano, Andrea; Bozzao, Alessandro; Cuomo, Ilaria; Valente, Francesca; Gabaglio, Chiara; Lombardozzi, Ginevra; Trovini, Giada; Amici, Emanuela; Perrini, F; Persis, Simone De; Iasevoli, Felice; Filippis, Sergio De; Bartolomeis, Andrea de

doi:10.1016/j.pnpbp.2021.110493

Cited by 13 publications

(6 citation statements)

References 133 publications

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“…Thus, while patients with schizophrenia tend to have reduced Glu in the MCC, a subgroup of TRS may have higher levels in this region. This is somewhat consistent with a more recent study in TRS ( n = 41) that reported increased Glu in the ACC [ 45 ]. In summary, the Nakahara et al (2021) meta-analysis suggests that through every illness stage, even before onset of psychosis, Glx levels in the basal ganglia are increased, though the group differences are reduced in patients with antipsychotic treatment, consistent with longitudinal studies (see below).…”

Section: The Glutamatergic Synapse and The Nmda-r-hypofunction Model ...supporting

confidence: 93%

Glutamatergic dysfunction in Schizophrenia

Kruse

Bustillo

2022

Transl Psychiatry

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The NMDA-R hypofunction model of schizophrenia started with the clinical observation of the precipitation of psychotic symptoms in patients with schizophrenia exposed to PCP or ketamine. Healthy volunteers exposed to acute low doses of ketamine experienced mild psychosis but also negative and cognitive type symptoms reminiscent of the full clinical picture of schizophrenia. In rodents, acute systemic ketamine resulted in a paradoxical increase in extracellular frontal glutamate as well as of dopamine. Similar increase in prefrontal glutamate was documented with acute ketamine in healthy volunteers with 1H-MRS. Furthermore, sub-chronic low dose PCP lead to reductions in frontal dendritic tree density in rodents. In post-mortem ultrastructural studies in schizophrenia, a broad reduction in dendritic complexity and somal volume of pyramidal cells has been repeatedly described. This most likely accounts for the broad, subtle progressive cortical thinning described with MRI in- vivo. Additionally, prefrontal reductions in the obligatory GluN1 subunit of the NMDA-R has been repeatedly found in post-mortem tissue. The vast 1H-MRS literature in schizophrenia has documented trait-like small increases in glutamate concentrations in striatum very early in the illness, before antipsychotic treatment (the same structure where increased pre-synaptic release of dopamine has been reported with PET). The more recent genetic literature has reliably detected very small risk effects for common variants involving several glutamate-related genes. The pharmacological literature has followed two main tracks, directly informed by the NMDA-R hypo model: agonism at the glycine site (as mostly add-on studies targeting negative and cognitive symptoms); and pre-synaptic modulation of glutamatergic release (as single agents for acute psychosis). Unfortunately, both approaches have failed so far. There is little doubt that brain glutamatergic abnormalities are present in schizophrenia and that some of these are related to the etiology of the illness. The genetic literature directly supports a non- specific etiological role for glutamatergic dysfunction. Whether NMDA-R hypofunction as a specific mechanism accounts for any important component of the illness is still not evident. However, a glutamatergic model still has heuristic value to guide future research in schizophrenia. New tools to jointly examine brain glutamatergic, GABA-ergic and dopaminergic systems in-vivo, early in the illness, may lay the ground for a next generation of clinical trials that go beyond dopamine D2 blockade.

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Section: The Glutamatergic Synapse and The Nmda-r-hypofunction Model ...supporting

confidence: 93%

Glutamatergic dysfunction in Schizophrenia

Kruse

Bustillo

2022

Transl Psychiatry

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“…Moreover, low FA in the CST exists in patients with treatment-resistant schizophrenia and explains their poor performance in complex motor tasks [39]. Combined with the ndings of our study, it may be suggested the effects of IRS/CIRS on motor de cits may have already occurred during schizophrenia onset.…”

Section: Discussionsupporting

confidence: 59%

Correlation of Immune-Inflammatory Response System (IRS)/Compensatory Immune-Regulatory Reflex System (CIRS) with White Matter Integrity in First-Episode Patients with Schizophrenia

Gou,

Li,

Tong

et al. 2023

Mol Neurobiol

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Several studies have reported compromised white matter integrity, and that some in ammatory mediators may underlie this functional dysconnectivity in brain of patients with schizophrenia. The immune-in ammatory response system and compensatory immune-regulatory re ex system (IRS/CIRS) are novel biomarkers for exploring the role of immune imbalance in the pathophysiological mechanism of schizophrenia. This study aimed to explore the little-known area regarding the composite score of peripheral cytokines, the IRS/CIRS, and its correlation with white matter integrity and the speci c microstructures most affected in schizophrenia. First-episode patients with schizophrenia (FEPS, n = 94) and age-and sex-matched healthy controls (HCs, n = 50) were enrolled in this study. Plasma cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA), and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). The whole brain white matter integrity was measured by fractional anisotropy (FA) from diffusion tensor imaging (DTI) using a 3-T Prisma MRI scanner. The IRS/CIRS in FEPS was signi cantly higher than that in HCs (p = 1.5×10 − 5 ) and Cohen's d effect size was d = 0.74. FEPS had a signi cantly lower whole-brain white matter average FA (p = 0.032), which was negatively associated with IRS/CIRS (p = 0.029, adjusting for age, gender, years of education, BMI, and total intracranial volume), but not in the HCs (p > 0.05). Among the white matter microstructures, only the cortico-spinal tract was signi cantly correlated with IRS/CIRS in FEPS (r=-0.543, p = 0.0009). Therefore, elevated IRS/CIRS may affect the white matter in FEPS.

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“…However, antipsychotics’ effects on functional connectivity have been assessed also after amphetamine administrations as well as in animals that did not model psychotic disorders, as presented in Table 2 . Although the specific drug used to mirror psychosis in the preclinical setting may affect the variability of the results, it should be remembered that patients with schizophrenia also showed alterations in different brain pathways, as highlighted by PET studies [ 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 ]. Thus, the application of drugs capable to reproduce changes in different neurotransmitter systems, including the dopaminergic and glutamatergic ones, is relevant in terms of translatability and clinical implication, through the opportunity to explore the effects of antipsychotics on different backgrounds and by providing the basis for tailoring the therapeutic choice according to the patient-specific characteristics.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

Bartolomeis¹,

Simone²,

Ciccarelli³

et al. 2022

Biomedicines

Self Cite

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Schizophrenia is a severe mental illness characterized by alterations in processes that regulate both synaptic plasticity and functional connectivity between brain regions. Antipsychotics are the cornerstone of schizophrenia pharmacological treatment and, beyond occupying dopamine D2 receptors, can affect multiple molecular targets, pre- and postsynaptic sites, as well as intracellular effectors. Multiple lines of evidence point to the involvement of antipsychotics in sculpting synaptic architecture and remodeling the neuronal functional unit. Furthermore, there is an increasing awareness that antipsychotics with different receptor profiles could yield different interregional patterns of co-activation. In the present systematic review, we explored the fundamental changes that occur under antipsychotics’ administration, the molecular underpinning, and the consequences in both acute and chronic paradigms. In addition, we investigated the relationship between synaptic plasticity and functional connectivity and systematized evidence on different topographical patterns of activation induced by typical and atypical antipsychotics.

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Treatment-resistant schizophrenia: Addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients

Cited by 13 publications

References 133 publications

Glutamatergic dysfunction in Schizophrenia

Glutamatergic dysfunction in Schizophrenia

Correlation of Immune-Inflammatory Response System (IRS)/Compensatory Immune-Regulatory Reflex System (CIRS) with White Matter Integrity in First-Episode Patients with Schizophrenia

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

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