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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases.J Neuropathol Exp Neurol. 2004; 63: 901-910
- Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms.Nat Rev Neurosci. 2007; 8: 57-69
- The COX-2/prostanoid signaling cascades in seizure disorders.Expert Opin Ther Targets. 2019; 23: 1-13
- Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain.Neuropathol Appl Neurobiol. 2009; 35: 306-328
- Translocator protein-18 kDa (TSPO) positron emission tomography (PET) imaging and its clinical impact in neurodegenerative diseases.Int J Mol Sci. 2017; 18: E785
- PK (“peripheral benzodiazepine”)—binding sites in the CNS indicate early and discrete brain lesions: Microautoradiographic detection of [3H]PK11195 binding to activated microglia.J Neurocytol. 1997; 26: 77-82
- Evaluation of the PBR/TSPO radioligand [18F]DPA-714 in a rat model of focal cerebral ischemia.J Cereb Blood Flow Metab. 2010; 30: 230-241
- Human immunodeficiency virus infection inhibits granulocyte-macrophage colony-stimulating factor-induced microglial proliferation.J Neurovirol. 2007; 13: 536-548
- The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders.J Neuropathol Exp Neurol. 2008; 67: 1001-1010
- Cellular sources and regional variations in the expression of the neuroinflammatory marker translocator protein (TSPO) in the normal brain.Int J Mol Sci. 2018; 19: E2707
- Comparison of [11C]PBR28 and [18F]FEPPA as CNS peripheral benzodiazepine receptor PET ligands in the pig.J Nucl Med. 2008; 49: 81P
- In-vivo imaging of microglial activation using a novel peripheral benzodiazepine receptor ligand, 18F-FEPPA and animal PET following 6-OHDA injury of the rat striatum; A comparison with 11C-PK11195.NeuroImage. 2008; 41: T94
- Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors.Nucl Med Biol. 2008; 35: 305-314
- Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography.J Cereb Blood Flow Metab. 2011; 31: 1807-1816
- The World Health Report 2001: Mental Health: New Understanding, New Hope.World Health Organization, Geneva, Switzerland2001
- Evaluation of outcomes with citalopram for depression using measurement-based care in STAR∗D: Implications for clinical practice.Am J Psychiatry. 2006; 163: 28-40
- Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes.JAMA Psychiatry. 2015; 72: 268-275
- Association of translocator protein total distribution volume with duration of untreated major depressive disorder: A cross-sectional study.Lancet Psychiatry. 2018; 5: 339-347
- PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects.EJNMMI Res. 2018; 8: 57
- Translocator protein (18kDa TSPO) binding, a marker of microglia, is reduced in major depression during cognitive-behavioral therapy.Prog Neuropsychopharmacol Biol Psychiatry. 2018; 83: 1-7
- Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: A positron emission tomography study.Biol Psychiatry. 2018; 83: 61-69
- Lower synaptic density is associated with depression severity and network alterations.Nat Commun. 2019; 10: 1529
- Targeting abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic.Nat Neurosci. 2007; 10: 1116-1124
- A rating scale for depression.J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
- Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice.Proc Natl Acad Sci U S A. 2001; 98: 1294-1299
- Cyclooxygenase-2 signalling pathway in the cortex is involved in the pathophysiological mechanisms in the rat model of depression.Sci Rep. 2017; 7: 488
- A randomized, double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in treatment of drug-naive depressed women: A pilot study.Iran J Pharmaceut Res. 2015; 14: 891-899
- Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: Randomized double-blind placebo-controlled study.J Affect Disord. 2012; 141: 308-314
- Clinical trial of adjunctive celecoxib treatment in patients with major depression: A double blind and placebo controlled trial.Depress Anxiety. 2009; 26: 607-611
- The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: Results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine.Mol Psychiatry. 2006; 11: 680-684
- An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28.J Cereb Bood Flow Metabolism. 2012; 32: 1-5
- Translocator protein (18 kDa) polymorphism (rs6971) explains in-vivo brain binding affinity of the PET radioligand [18F]-FEPPA.J Cereb Blood Flow Metab. 2012; 32: 968-972
- An inventory for measuring depression.Arch Gen Psychiatry. 1961; 4: 561-571
- Duloxetine in the treatment of major depressive disorder: A double-blind clinical trial.J Clin Psychiatry. 2002; 63: 225-231
- Duloxetine, 60 mg once daily, for major depressive disorder: A randomized double-blind placebo-controlled trial.J Clin Psychiatry. 2002; 63: 308-315
- Monoamine oxidase B total distribution volume in the prefrontal cortex of major depressive disorder: An [11C]SL25.1188 positron emission tomography study.JAMA Psychiatry. 2019; 76: 634-641
- Role of complex epigenetic switching in tumor necrosis factor-alpha upregulation in the prefrontal cortex of suicide subjects.Am J Psychiatry. 2018; 175: 262-274
- Abnormal protein and mRNA expression of inflammatory cytokines in the prefrontal cortex of depressed individuals who died by suicide.J Psychiatry Neurosci. 2018; 43: 376-385
- Altered neuro-inflammatory gene expression in hippocampus in major depressive disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2018; 82: 177-186
- Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys.J Nucl Med. 2018; 59: 1907-1912
- In Vivo Brain Imaging, Biodistribution, and Radiation Dosimetry Estimation of [11C]Celecoxib, a COX-2 PET Ligand, in Nonhuman Primates.Molecules. 2018; 23: E1929
- Large variation in brain exposure of reference CNS drugs: A PET study in nonhuman primates.Int J Neuropsychopharmacol. 2015; 18: pyv036
- Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans.Anesthesiology. 2005; 102: 409-415
- Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study.Biol Psychiatry. 2016; 80: 424-431
- Subcallosal cingulate deep brain stimulation for treatment-resistant depression: A multisite, randomised, sham-controlled trial.Lancet Psychiatry. 2017; 11: 839-849
Article Info
Publication History
Published online: March 28, 2020
Accepted:
March 11,
2020
Received in revised form:
March 5,
2020
Received:
October 24,
2019
Identification
Copyright
© 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Microglial Activation and Response to Anti-inflammatory Treatment in Major Depressive Disorder: Another Piece in the Inflammation–Mood Disorders PuzzleBiological PsychiatryVol. 88Issue 8
- PreviewThere is good news and bad news when it comes to our understanding of inflammation in the pathogenesis and treatment of major depressive disorder (MDD). The bad news is that, like the dexamethasone suppression test or the efficacy of antidepressants before it, inflammation is oversold as an answer to the mystery of depression and its treatment. The good news is that an unusually replicable set of findings (for psychiatry) increasingly paints a consistent picture of the ways in which inflammation is of value in understanding MDD.
- Full-Text
- Preview
