Elsevier

Biological Psychiatry

Volume 58, Issue 2, 15 July 2005, Pages 132-142
Biological Psychiatry

Original article
Cerebral Blood Flow Changes After Treatment of Social Phobia with the Neurokinin-1 Antagonist GR205171, Citalopram, or Placebo

https://doi.org/10.1016/j.biopsych.2005.03.029Get rights and content

Background

Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia.

Methods

Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions. GR205171 was administered for 4 weeks preceded by 2 weeks of placebo. Before and after treatment, regional cerebral blood flow (rCBF) during a stressful public speaking task was assessed using oxygen-15 positron emission tomography. Response rate was determined by the Clinical Global Impression Improvement Scale.

Results

Patients improved to a larger extent with the NK1 antagonist (41.7% responders) and citalopram (50% responders), compared with placebo (8.3% responders). Within- and between-group comparisons showed that symptom improvement was paralleled by a significantly reduced rCBF response to public speaking in the rhinal cortex, amygdala, and parahippocampal-hippocampal regions. The rCBF pattern was corroborated in follow-up analyses of responders and subjects showing large state anxiety reduction.

Conclusions

Short-term administration of GR205171 and citalopram alleviated social anxiety. Neurokinin-1 antagonists may act like serotonin reuptake inhibitors by attenuating neural activity in a medial temporal lobe network.

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

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