Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment

Abstract

Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6-9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity.

What is the risk‐benefit ratio of long‐term antipsychotic treatment in people with schizophrenia?

“…Furthermore, brain volumetric changes do not seem to correlate with poor clinical response or outcomes. In patients treated with clozapine, both a grey matter decrement and a clinical improvement have been reported, whereas in other studies the opposite was found.…”

Cortical Alterations in Medication‐Overuse Headache

“…However, as discussed above, changes in gyrification have been related to early cortical development, so that the gyrification changes are more likely to precede the onset of the migraine, representing a promising candidate to predict response to treatment. In contrast, CT changes are much more dynamic over time, and previous studies have examined potential effects of environmental factors, experience‐related plasticity, and intake of psychotropic medication . While there are fewer data on the effect of simple analgesic on brain structure, studies in rat models have demonstrated effect of opioids on synaptic structure, and effects of triptans on brain connectivity .…”

“…In contrast, CT changes are much more dynamic over time, 22 and previous studies have examined potential effects of environmental factors, 47 experience-related plasticity, 48,49 and intake of psychotropic medication. [50][51][52] While there are fewer data on the effect of simple analgesic on brain structure, studies in rat models have demonstrated effect of opioids on synaptic structure, 53 and effects of triptans on brain connectivity. 54 These data in mouse models thus leave open the possibility that medication overuse alters CT, requiring the need for further longitudinal studies to better understand whether the observed altered thickness causes medication overuse or results from it.…”

NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure

“…cerebral cortex) volumes have been previously reported in rodents in which the duration of antipsychotic treatment varied from 1 to 2 months(Vernon et al, 2011) and in large cohorts of patients with schizophrenia(Haijma et al, 2013). On the other hand, evidence is emerging that gray matter loss in schizophrenia reflects the underlying disease process irrespective of clozapine treatment(Ahmed et al, 2015; Anderson et al, 2015). Therefore, the lack of frontal lobe volume changes in the clozapine-treated monkeys of the present study could also be explained, in part, by the absence of the underlying disease process (schizophrenia) in the animals.…”