TY - JOUR
T1 - Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum
T2 - A preliminary PET study
AU - Conway, Charles R.
AU - Chibnall, John T.
AU - Cumming, Paul
AU - Mintun, Mark A.
AU - Gebara, Marie Anne I.
AU - Perantie, Dana C.
AU - Price, Joseph L.
AU - Cornell, Martha E.
AU - McConathy, Jonathan E.
AU - Gangwani, Sunil
AU - Sheline, Yvette I.
N1 - Funding Information:
The authors thank Jon Christenson and Lars Couture for image processing, Betsy Thomas, RN, for scheduling and assistance with obtaining scans, Thomas Zeffiro, MD, Ph.D., of Harvard University School of Medicine for image interpretation, Britt Gott, MS, for editing and formatting the text, and Sudha Patel, MD, for her assistance with clinical assessments. This study was funded by Bristol-Myers Squibb by an investigator-initiated, industry-sponsored (CRC) grant. Bristol-Myers Squibb did not have any involvement in data collection, analysis, interpretation, or any editorial involvement. Forest Pharmaceuticals provided cost-free escitalopram (Lexapro ™) for this study.
Funding Information:
CRC is on the speaker's bureau for Pfizer Pharmaceuticals, Merck, and Bristol-Myers Squibb. CRC is currently supported by funding from the National Institute of Mental Health K08 award (1K08MH078156) and YIS K24 award (9K24MH07951006). MAM is an employee of Avid Radiopharmaceuticals. YIS has received honoraria for speaking through Eli Lilly and Co. and has served as a consultant for Bristol-Myers Squibb. JEM has received honoraria for advisory and speaking with Avid Radiopharmaceuticals/Eli Lilly and Co. JTC, PC, MAG, DCP, JLP, MEC, and SG all have no financial relationships to disclose.
PY - 2014/3/30
Y1 - 2014/3/30
N2 - Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole's antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-l-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; 11 responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity.
AB - Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole's antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[18F]-fluoro-3,4-dihydroxy-l-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; 11 responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post-aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity.
KW - Aripiprazole
KW - Caudate
KW - Dopamine
KW - Positron emission tomography
KW - Treatment-resistant depression
UR - http://www.scopus.com/inward/record.url?scp=84894317267&partnerID=8YFLogxK
U2 - 10.1016/j.pscychresns.2014.01.003
DO - 10.1016/j.pscychresns.2014.01.003
M3 - Article
C2 - 24468015
AN - SCOPUS:84894317267
SN - 0925-4927
VL - 221
SP - 231
EP - 239
JO - Psychiatry Research - Neuroimaging
JF - Psychiatry Research - Neuroimaging
IS - 3
ER -