Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia

Abstract

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P < 0.001), and reductions in thickness of the left inferior temporal cortex, left caudal middle frontal cortex, and the right temporal pole. Reductions in right caudate volume were associated with local reductions in NAA (P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.

Olanzapine, Risperidone and Clozapine prescribing is associated with increased risk for Alzheimer’s Disease reflecting antipsychotic-specific effects on microglial phagocytosis

“…These data support the notion that Olanzapine is unlikely to contribute to synaptic loss in schizophrenia as measured in vivo using SV2A selective positron emission tomography (PET) ( Onwordi et al, 2020 ). Of note, structural magnetic resonance imaging (sMRI) studies of individuals with treatment-resistant schizophrenia, provide evidence for cortical thinning and sub-cortical volume reductions relative to age-matched healthy controls after switching to Clozapine treatment ( Ahmed et al, 2015 , Krajner et al, 2022 ). Moreover, the cellular basis of such tissue loss cannot be established from these studies.…”

“…Aside from declines in cognitive performance and memory, dementia is also commonly associated with other behavioural and psychological symptoms, complicating its management (Cerejeira et al, 2012). It is estimated that up to 90% of AD patients will develop at least one symptom of psychosis in the course of their illness (Liperoti et al, 2008).…”

Resting-state functional MRI in treatment-resistant schizophrenia

“…In particular, although treatment with CLZ was associated with global cortical thinning and reductions in the medial PFC and the periventricular area volumes regardless of treatment response (Ahmed et al, 2015 ), other studies noted that larger temporal and prefrontal volumes and thinner frontal cortices before the initiation of treatment correlated with the improvement of symptoms post-treatment (Arango et al, 2003 ; Molina et al, 2003 , 2014 ). Treatment with CLZ was associated with a reduction in the caudate volume in correlation with clinical improvement (Scheepers et al, 2001 ; Tronchin et al, 2020 ) and further correlated with caudal N-acetylaspartate level reductions as studied by MR spectroscopy (Krajner et al, 2022 ). In addition, reductions of the thalamus and putamen volumes were associated with symptom improvement (Tronchin et al, 2020 ).…”

Synaptic dysfunction in schizophrenia

“…On the other hand, an important question is whether the effects of first-generation antipsychotics and second-generation antipsychotics on the synapse are different. Negative effects of both first-and second-generation antipsychotics on cortical thickness have been reported (Krajner et al, 2022;van Erp et al, 2018). However, the negative impacts of first-generation antipsychotics on cortical thickness appear to be greater (Ho et al, 2011;Thompson et al, 2009;van Erp et al, 2018).…”