One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: Investigation of neural correlates with BOLD MRI

Abstract

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.

Keywords

anxiety benzodiazepine CCK-4 fMRI lorazepam panic attacks

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References

Arce

Miller

Feinstein

Stein

Paulus

. (2006) Lorazepam dose-dependently decreases risk-taking related activation in limbic areas. Psychopharmacology 189: 105–116.

Bond

Lader

. (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47: 211–218.

Bradwejn J, Koszycki D and Shriqui C (1991) Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings. Arch Gen Psychiatry 48: 603–610.

Bradwejn

Koszycki

Paradis

Reece

Hinton

Sedman

. (1995) Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers. Biol Psychiatry 38: 742–746.

Charney

Woods

. (1989) Benzodiazepine treatment of panic disorders: a comparison of alprazolam and lorazepam. J Clin Psychiatry 50: 418–423.

Cloninger

. (1987) A systematic method for clinical description and classification of personality variants. A proposal. Arch Gen Psychiatry 44: 573–588.

De Montigny

. (1989) Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers. Preliminary findings. Arch Gen Psychiatry 46: 511–517.

Genovese

Lazar

Nichols

. (2002) Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 15: 870–878.

Hennel

. (1998) Image-based reduction of artifacts in multishot echo-planar imaging. J Magn Reson 134: 206–213.

10.

Koszycki

Zacharko

Le Medello

Bradwejn

. (1998) Behavioral, cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: a comparison of panickers and nonpanickers. Depress Anxiety 8: 1–7.

11.

Lecrubier

Sheehan

Weiller

. (1997) The MINI International Neuropsychiatric Interview (MINI), a short diagnostic structured interview: reliability and validity according to the CIDI. Eur Psychiatry 12: 224–231.

12.

Le Mellédo

Bradwejn

Koszycki

Bichet

Bellavance

. (1998) The role of the β-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms. Biol Psychiatry 44: 364–366.

13.

Nikou

Heitz

Armspach

Namer

Grucker

. (1998) Registration of MR/MR and MR/SPECT brain images by fast stochastic optimisation of robust voxel similarity measures. Neuroimage 8: 30–43.

14.

Oldfield

. (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9: 97–113.

15.

Paulus

Feinstein

Castillo

Simmons

Stein

. (2005) Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry 62: 282–288.

16.

Schunck

Erb

Mathis

. (2006) Functional magnetic resonance imaging characterization of CCK-4-induced panic attack and subsequent anticipatory anxiety. Neuroimage 31: 1197–1208.

17.

Shlik

Aluoja

Vasar

Podar

Bradwejn

. (1997) Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder. J Psychiatry Neurosci 22: 332–340.

18.

Sperling

Greve

Dale

. (2002) Functional MRI detection of pharmacologically-induced memory impairment. Proc Natl Acad Sci USA 99: 455–460.

19.

Spielberger

Gorsuch

Lushene

Vagg

Jacobs

. (1983) Manual for the State-trait Anxiety Inventory (Form Y). Palo Alto: Consulting Psychologists Press Inc.

20.

Van Megen

HJGM

Westenberg

HGM

den Boer

Kahn

. (1996) Review: Cholecystokinin in anxiety. Eur Neuropsychopharmacol 6: 263–280.

21.

Van Megen

HJGM

Westenberg

HGM

den Boer

Slaap

Scheepmakers

. (1997) Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacks. Psychopharmacology 129: 357–364.

22.

Zwanzger

Eser

Aicher

. (2003) Effect of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study. Neuropsychopharmacology 28: 979–984.