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Clinical Improvement With Fluoxetine Therapy and Noradrenergic Function in Patients With Panic Disorder

Jeremy D. Coplan, MD; Laszlo A. Papp, MD; Daniel Pine, MD; Jose Martinez, MA; Thomas Cooper, MA; Leonard A. Rosenblum, PhD; Donald F. Klein, MD; Jack M. Gorman, MD
Arch Gen Psychiatry. 1997;54(7):643-648. doi:10.1001/archpsyc.1997.01830190069007.
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Background:  Central noradrenergic (NA) dysregulation has provided a major theoretical framework for understanding the pathogenesis of panic disorder (PD). Using clonidine, an α2-adrenergic receptor agonist, as a probe of NA function, we investigated the hypothesis that the antipanic efficacy of the selective serotonin reuptake inhibitors may be associated with normalization of a putatively dysregulated NA system.

Methods:  We report further analyses on data from 17 subjects with PD and 16 healthy volunteers who underwent measurement of the plasma NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) immediately before and after oral clonidine administration. Thirteen patients with PD were rechallenged after 12 weeks during open fluoxetine hydrochloride treatment using the same clonidine paradigm; 13 healthy volunteers were rechallenged at 12 weeks, not having received treatment between challenges.

Results:  Patients with PD, compared with healthy volunteers, have markedly elevated plasma MHPG volatility during the first clonidine challenge. Volatility describes the magnitude of within-subject plasma MHPG oscillatory activity as assessed by the root of the mean square successive difference. A greater degree of clinical global improvement was predicted by a greater magnitude of basal MHPG reduction with fluoxetine treatment. Antipanic response to fluoxetine was accompanied by a significant decrease of MHPG volatility to volunteer levels. Volunteer MHPG volatility remained unchanged from the first to second clonidine challenge.

Conclusions:  Further evidence is provided for the hypothesis of NA dysregulation in PD as reflected by elevations of within-subject plasma MHPG volatility during clonidine challenge. Effective selective serotonin reuptake inhibitor—antipanic treatment in this clinical sample was paralleled by normalization of dysregulated NA function.

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