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.
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.
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.
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.
Coplan JD, Papp LA, Pine D, Martinez J, Cooper T, Rosenblum LA, Klein DF, Gorman JM. Clinical Improvement With Fluoxetine Therapy and Noradrenergic Function in Patients With Panic Disorder. Arch Gen Psychiatry. 1997;54(7):643-648. doi:10.1001/archpsyc.1997.01830190069007