Original articleCerebral Blood Flow Changes After Treatment of Social Phobia with the Neurokinin-1 Antagonist GR205171, Citalopram, or Placebo
Section snippets
Screening
Participants were recruited through newspaper advertising. Initial screening included a brief telephone interview and social anxiety questionnaires returned by mail. Structured clinical diagnostic interviews (Structured Clinical Interview for DSM-IV [SCID]) (First et al 1998) were thereafter administered by a clinical psychologist and a public speaking behavioral test was performed. In addition, a psychiatrist (K.W.) administered the Mini International Neuropsychiatric Interview (MINI) (Sheehan
Treatment Procedure
The study was double blind. GlaxoSmithKline (Verona, Italy) supplied the study drugs for a 6-week treatment period. The NK1 group received a daily oral dose of 5 mg GR205171, which started after 14 days of placebo because of limited available safety data on repeated dosing. GR205171 was taken as 4 mL solution made up to 100 mL in orange juice. The SSRI group was treated with 40 mg citalopram (one tablet), starting with 20 mg (half tablet) during the first week. To maintain study blindness, the
PET Assessments
Investigations were performed using a 32-ring ECAT EXACT HR+ camera (Siemens/CTI, Knoxville, Tennessee). The camera enables acquisition of 63 contiguous planes of data with a distance of 2.46 mm, resulting in a total axial field of view of 155 mm.
Subjects were positioned in the scanner with the head gently fixated, and a venous catheter for tracer injections was inserted. Patients were instructed to prepare a 2.5-minute speech about a vacation or travel experience about 20 minutes before the
Pretreatment Evaluation
There were no significant differences between groups before treatment on any primary (.027 <F < 1.38; .27 <p < .93) or secondary (.22 <F < 3.20; .054 <p < .80) clinical outcome measure.
Response Rate
On day 42 (end of treatment), the numbers of CGI responders were 5 (41.7%) in the NK1 group, 6 (50%) in the citalopram group, and 1 (8.3%) in the placebo group (Figure 2). Eleven nonresponders (NK1/citalopram/placebo = 4/4/3) were “minimally improved” (CGI-I = 3), whereas 13 (NK1/citalopram/placebo = 3/2/8) were
Discussion
This study explored changes in rCBF following short-term treatment with the NK1 antagonist GR205171, compared with citalopram and placebo, in patients with social phobia. Posttreatment assessments (day 42) suggested that the NK1 and SSRI treatments reduced the neural response to public speaking in the MTL, including the perirhinal, entorhinal, and parahippocampal cortices, as well as the amygdala. This effect was also observed in responders as defined by the CGI-I, regardless of treatment
References (76)
- et al.
Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal gray on the behaviour of rats in the plus-maze test
Physiol Behav
(1996) The primate amygdala and the neurobiology of social behaviorImplications for understanding social anxiety
Biol Psychiatry
(2002)- et al.
The Liebowitz social anxiety scale as a self-report instrumentA preliminary psychometric analysis
Behav Res Ther
(2002) - et al.
Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions
Neuropeptides
(1994) - et al.
Patients with generalized social phobia direct their attention away from faces
Behav Res Ther
(2002) - et al.
Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism
Eur Neuropsychopharmacol
(2002) Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test
Pharmacol Biochem Behav
(1997)- et al.
Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia
Neurosci Lett
(2004) - et al.
GR205171A novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity
Regul Pept
(1996) Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?
Pharmacol Ther
(1999)
Substance P and its role in neural mechanisms governing learning, anxiety and functional recovery
Neuropeptides
Molecular targets in the treatment of anxiety
Biol Psychiatry
Substance P is involved in the sensitization of the acoustic startle response by footshocks in rats
Behav Brain Res
The retrosplenial cortex and emotionNew insights from functional neuroimaging of the human brain
Trends Neurosci
Development and validation of measures of social phobia scrutiny fear and social interaction anxiety
Behav Res Ther
Regional metabolic effects of fluoxetine in major depressionSerial changes and relationship to clinical response
Biol Psychiatry
Participation of GABAA receptors in the modulation of experimental anxiety by tachykinin agonists and antagonists in mice
Prog Neuropsychopharmacol Biol Psychiatry
Comparison of the functional blockade of rat substance P (NK1) receptors by GR205171, RP67580, SR140333 and NKP-608
Neuropharmacology
Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists
Trends Pharmacol Sci
The psychobiology of anxiolytic drugs. Part 1: Basic neurobiology
Pharmacol Ther
Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia
Biol Psychiatry
Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatmentAn fMRI study
Biol Psychiatry
Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat
Brain Res
Effects of central administration of tachykinin receptor agonists and antagonists on plus-maze behavior in mice
Eur J Pharmacol
Cerebral blood flow during anticipation of public speaking in social phobiaA PET study
Biol Psychiatry
A PET provocation study of generalized social phobia
Psychiatry Res
Functional brain imaging and pharmacotherapy in social phobiaSingle photon emission computed tomography before and after treatment with the selective serotonin reuptake inhibitor citalopram
Prog Neuropsychopharmacol Biol Psychiatry
The gerbil elevated plus-maze IIAnxiolytic-like effects of selective neurokinin NK1 receptor antagonists
Neuropsychopharmacology
Brain circuits involved in emotional learning in antisocial behavior and social phobia in humans
Neurosci Lett
Disability and quality of life in pure and comorbid social phobia. Findings from a controlled study
Eur Psychiatry
Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear fixed and mixed effect modeling approach
Nucl Med Biol
Cognitive neuroscience of human social behaviour
Nat Rev Neurosci
Attentional activation of the cerebellum independent of motor involvement
Science
Diagnostic and Statistical Manual of Mental Disorders
Drugs in development for social anxiety disorderMore to social anxiety than meets the SSRI
Expert Opin Investig Drugs
Sample size and statistical power in [15O]H2O studies of human cognition
J Cereb Blood Flow Metab
Pharmacotherapy of social anxiety disorder
EXACON-a Fortran 77 program for the exact analysis of single cells in a contingency table
Educ Psychol Meas
Cited by (191)
Meta-analysis of placebo group dropout in adult antidepressant trials
2020, Progress in Neuro-Psychopharmacology and Biological PsychiatryBrain neurokinin-1 receptor availability in never-medicated patients with major depression – A pilot study
2019, Journal of Affective DisordersAmygdala reactivity and connectivity during social and non-social aversive stimulation in social anxiety disorder
2018, Psychiatry Research - NeuroimagingAltered regional and integrated resting-state brain activity in general social anxiety disorder patients before and after group cognitive behavior therapy
2018, Psychiatry Research - NeuroimagingInhibition of substance P-induced defensive behavior via neurokinin-1 receptor antagonism in the central and medial but not basolateral nuclei of the amygdala in male Wistar rats
2017, Progress in Neuro-Psychopharmacology and Biological PsychiatryWithin-session effect of repeated stress exposure on extinction circuitry function in social anxiety disorder
2017, Psychiatry Research - Neuroimaging