Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor

Guma, Elisa; Rocchetti, Jill; Devenyi, Gabriel A.; Tanti, Arnaud; Mathieu, Axel; Lerch, Jason P.; Elgbeili, Guillaume; Courcot, Blandine; Mechawar, Naguib; Chakravarty, M. Mallar; Giros, Bruno

doi:10.1016/j.neuroimage.2018.04.054

Cited by 28 publications

(22 citation statements)

References 74 publications

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“…In a preclinical study, Guma and colleagues [52], presented evidence that D2 receptors play a significant role in mediating antipsychotic induced structural changes, whereby volumetric reduction in cortical areas, hippocampus and thalamus, was induced by genetic deletion of D2 receptors.…”

Section: Discussionmentioning

confidence: 99%

Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment

Tronchin

Akudjedu

Ahmed

et al. 2020

Neuropsychopharmacol.

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The association of antipsychotic medication with abnormal brain morphometry in schizophrenia remains uncertain. This study investigated subcortical morphometric changes 6 months after switching treatment to clozapine in patients with treatment-resistant schizophrenia compared with healthy volunteers, and the relationships between longitudinal volume changes and clinical variables. 1.5T MRI images were acquired at baseline before commencing clozapine and again after 6 months of treatment for 33 patients with treatment resistant schizophrenia and 31 controls, and processed using the longitudinal pipeline of Freesurfer v.5.3.0. Two-way repeated MANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. Whereas no significant subcortical volume differences were found between patients and controls at baseline(F(8,52)=1.79; p= 0.101), there was a significant interaction between time, group and structure(F(7,143)=52.54, p<0.001). Corrected post-hoc analyses demonstrated that patients had significant enlargement of lateral ventricles (F(1,59)=48.89; p<0.001) and reduction of thalamus (F(1,59)=34.85; p<0.001), caudate (F(1,59)=59.35; p<0.001), putamen (F(1,59)=87.20; p<0.001) and hippocampus (F(1,59)=14.49; p<0.001) volumes. Thalamus and putamen volume reduction was associated with improvement in PANSS (r=0.42; p=0.021, r=0.39; p=0.033), SANS (r=0.36; p=0.049, r=0.40; p=0.027) and GAF (r=-0.39; p=0.038, r=-0.42; p=0.024) scores. Reduced thalamic volume over time was associated with increased serum clozapine level at follow-up (r=-0.44; p=0.010). Patients with treatment-resistant schizophrenia display progressive subcortical volume deficits after switching to clozapine despite experiencing symptomatic improvement. Thalamo-striatal progressive volumetric deficit associated with symptomatic improvement after clozapine exposure may reflect an adaptive response related to improved outcome rather than a harmful process.

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Section: Discussionmentioning

confidence: 99%

Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment

Tronchin

Akudjedu

Ahmed

et al. 2020

Neuropsychopharmacol.

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“…Notably, when chronically exposed to the same antipsychotics as wild-type mice, no additional basal ganglia volume increases were found. Taken together, these data strongly support that volume increases following antipsychotic exposure are mediated via the dopamine D 2 -like receptor (Guma et al, 2018(Guma et al, , 2019, rather than depending on the drug-class ('typical' vs. 'atypical' antipsychotic).…”

Section: Basal Ganglia Volume Increasessupporting

confidence: 52%

“…Both drugs, however, have low affinity toward dopamine D 2 -like receptors, whereas typical antipsychotics have high affinities (Creese et al, 1976;Kusumi et al, 2015;Jorgensen et al, 2016). Dopamine D 2 -like receptor knock-out mice also show striatal volume increases, mirroring the effects of chronic exposure (9 weeks) to different APDs (Guma et al, 2018(Guma et al, , 2019. Notably, when chronically exposed to the same antipsychotics as wild-type mice, no additional basal ganglia volume increases were found.…”

Section: Basal Ganglia Volume Increasesmentioning

confidence: 96%

“…Nevertheless, longitudinal studies on antipsychotic-naïve patients as well as meta-analyses studies have reported associations between antipsychotic exposure and volumetric increase in basal ganglia (Glenthoj et al, 2007;Ebdrup et al, 2013;Jorgensen et al, 2016;Huhtaniska et al, 2017;Di Sero et al, 2019). Studies on rodents have replicated the basal ganglia volume increase in response to antipsychotic treatment (Vernon et al, 2012), and investigations in dopamine D 2 or D 3 receptor knock-out-and wild-type mice provide evidence that this increase is likely to be mediated through D 2 -like receptors (Guma et al, 2018(Guma et al, , 2019.…”

Section: Introductionmentioning

confidence: 99%

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Striatal Volume Increase After Six Weeks of Selective Dopamine D2/3 Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients

et al. 2020

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“…MRI data were collected using 3D True-fast imaging with steady state precession (3D-true FISP) with the following parameters: matrix 128 × 128 × 64, image resolution 140 × 140 × 140 μm 3 , echo time (TE)/repetition time (TR) = 2.6 ms/800 ms. Eight radio-frequency (RF) angles (180, 0, 90, 270, 45, 225, 135, and 315 degree) were used to remove banding artifacts and the time of the whole sequence lasted for 40 min for each subject (16). Finally, root mean square (RMS) of the 8 angle acquisitions were calculated for each subject.…”

Section: Methodsmentioning

confidence: 99%

Deformation-based Morphometry MRI Reveals Brain Structural Modifications in Living Mu Opioid Receptor Knockout Mice

et al. 2018

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Mu opioid receptor (MOR) activation facilitates reward processing and reduces pain, and brain networks underlying these effects are under intense investigation. Mice lacking the MOR gene (MOR KO mice) show lower drug and social reward, enhanced pain sensitivity and altered emotional responses. Our previous neuroimaging analysis using Resting-state (Rs) functional Magnetic Resonance Imaging (fMRI) showed significant alterations of functional connectivity (FC) within reward/aversion networks in these mice, in agreement with their behavioral deficits. Here we further used a structural MRI approach to determine whether volumetric alterations also occur in MOR KO mice. We acquired anatomical images using a 7-Tesla MRI scanner and measured deformation-based morphometry (DBM) for each voxel in subjects from MOR KO and control groups. Our analysis shows marked anatomical differences in mutant animals. We observed both local volumetric contraction (striatum, nucleus accumbens, bed nucleus of the stria terminalis, hippocampus, hypothalamus and periacqueducal gray) and expansion (prefrontal cortex, amygdala, habenula, and periacqueducal gray) at voxel level. Volumetric modifications occurred mainly in MOR-enriched regions and across reward/aversion centers, consistent with our prior FC findings. Specifically, several regions with volume differences corresponded to components showing highest FC changes in our previous Rs-fMRI study, suggesting a possible function-structure relationship in MOR KO-related brain differences. In conclusion, both Rs-fMRI and volumetric MRI in live MOR KO mice concur to disclose functional and structural whole-brain level mechanisms that likely drive MOR-controlled behaviors in animals, and may translate to MOR-associated endophenotypes or disease in humans.

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Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor

Cited by 28 publications

References 74 publications

Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment

Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment

Striatal Volume Increase After Six Weeks of Selective Dopamine D2/3 Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients

Deformation-based Morphometry MRI Reveals Brain Structural Modifications in Living Mu Opioid Receptor Knockout Mice

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