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. 2020 Oct 15;88(8):649-656.
doi: 10.1016/j.biopsych.2020.03.007. Epub 2020 Mar 29.

Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder

Sophia Attwells  1 , Elaine Setiawan  2 , Pablo M Rusjan  2 , Cynthia Xu  2 , Celeste Hutton  2 , Dorsa Rafiei  2 , Benjamin Varughese  2 , Alan Kahn  3 , Stephen J Kish  4 , Neil Vasdev  2 , Sylvain Houle  5 , Jeffrey H Meyer  6
Affiliations

Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder

Sophia Attwells et al. Biol Psychiatry. .

Abstract

Background: Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO VT), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO VT in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder.

Methods: A total of 41 subjects with treatment-resistant major depressive disorder underwent one [18F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO VT. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS).

Results: Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO VT, showing a significant nonlinear relationship. At low TSPO VT values, there was no reduction in HDRS scores, but as TSPO VT values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO VT accounted for 84% and 92% of the variance, respectively.

Conclusions: Celecoxib administration in the presence of gliosis labeled by TSPO VT is associated with greater reduction of symptoms. Given the predictiveness of TSPO VT on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.

Keywords: Celecoxib; Gliosis; Major depressive disorder; Positron emission tomography; Translocator protein; Treatment response.

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Conflict of interest statement

SH and JHM have received operating grant funds from Janssen in the past 5 years. JHM has been a consultant to Lundbeck and Takeda, in the past 5 years. JHM is an inventor on five patents of blood and/or clinical markers to predict brain inflammation or to diagnose affective disorders, and a dietary supplement to reduce depressed mood post-partum. JHM is arranging collaborations with nutraceutical companies for the dietary supplement to prevent post-partum depression. SK has operating grant funds from US National Institutes of Health National Institute on Drug Abuse (DA04066) to measure microglial status in the brains of methamphetamine users, and from Jazz Pharmaceuticals for an unrelated study. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Flow Diagram of Study Participants
Flow of participants through the study. Abbreviations: PET, positron emission tomography.
Figure 2.
Figure 2.. Cumulative Mean Change in Hamilton Depression Rating Scale Scores Based on Regional Translocator Protein Total Distribution Volume
Cumulative mean change in 17-item HDRS scores based on regional TSPO VT demonstrated greater change in HDRS scores at TSPO VT values greater than 10 to 11. Black line represents the 4-parameter sigmoidal function (y=y0+(a/(1+exp(−(x-x0)/b)) that provides the best fit for the data [PFC: Adjusted R2=0.84, y=−3.55+(5.70/(1+exp(−(x-9.93)/−0.59)); ACC: Adjusted R2=0.92, ACC: y=−3.70+(5.54/(1+exp(−(x-8.84)/−0.079))]. a To address the effect of the rs6971 genotype on TSPO VT, its differential effect on TSPO VT was found applying a linear regression. Then, the MAB TSPO VT values were adjusted by adding the differential effect of genotype to the TSPO VT values. (Adjusted PFC TSPO VT=unadjusted TSPO VT+b1*genotype, where b1=4.490; and adjusted ACC TSPO VT=unadjusted TSPO VT+b1*genotype, where b1=4.559). Abbreviations: ACC, anterior cingulate cortex; HDRS, Hamilton Depression Rating Scale; MAB, mixed-affinity binder; PFC, prefrontal cortex; TSPO, translocator protein; vs., versus; VT, total distribution volume.
Figure 3.
Figure 3.. Cumulative Mean Percent Change in Hamilton Depression Rating Scale Scores Based on Regional Translocator Protein Total Distribution Volume
Cumulative mean change in 17-item HDRS scores based on regional TSPO VT demonstrated greater per cent change in HDRS scores at TSPO VT values greater than 10 to 11. Black line represents the 4-parameter sigmoidal function (y=y0+(a/(1+exp(−(x-x0)/b)) that provides the best fit for the data [PFC: Adjusted R2=0.82, y=14.11+(−27.28/(1+exp(−(x-9.88)/0.61)); ACC: Adjusted R2=0.91, ACC: y= −13.60+(25.59/(1+exp(−(x-8.84)/−0.067))]. a To address the effect of the rs6971 genotype on TSPO VT, its differential effect on TSPO VT was found applying a linear regression. Then, the MAB TSPO VT values were adjusted by adding the differential effect of genotype to the TSPO VT values. (Adjusted PFC TSPO VT=unadjusted TSPO VT+b1*genotype, where b1=4.490; and adjusted ACC TSPO VT=unadjusted TSPO VT+b1*genotype, where b1=4.559). Abbreviations: ACC, anterior cingulate cortex; HDRS, Hamilton Depression Rating Scale; MAB, mixed-affinity binder; PFC, prefrontal cortex; TSPO, translocator protein; vs., versus; VT, total distribution volume.
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