Evidence for global reduction in brain cyclic adenosine monophosphate signaling in depression.

p p s w m c d s p u a p m o F ujita and coworkers, utilizing 11C-(R)-rolipram positron emission tomography, demonstrate that human subjects with major depression exhibit reductions in the enzyme phosphodiesterase-4 (PDE4) in a number of brain regions (1). PDE4, a cyclic adenosine monophosphate (AMP) phosphodiesterase, is an important regulator of cyclic AMP concentrations in the brain; it has been suggested as a molecular target for antidepressant drug discovery (2). The present study provides support for this premise and also suggests that global reductions in cyclic AMP signaling in the brain may be associated with major depression. The positron emission tomography ligand used in the study, rolipram, has been the subject of considerable preclinical and clinical investigation for antidepressant efficacy. Although numerous studies have supported its potential as an antidepressant, doselimiting nausea and emesis prevented its successful development. To date, it has proven difficult to dissociate therapeutic from significant side effects, but as pointed out by the authors, recent understanding of the roles of PDE4 subtypes and the discovery of allosteric inhibitors of PDE4 offer some new insights (3,4). Prior to this report by Fujita et al. (1), several lines of evidence have indirectly implicated cyclic AMP signaling in depression and its treatment. This includes preclinical studies of the neurochemical effects of proven antidepressants and postmortem examination of brains of patients with major depression (5,6). For example, repeated treatment of rodents with antidepressants that enhance noradrenergic or serotonergic neurotransmission increases markers in the brain indicative of increased cyclic AMP signaling, such as increased phosphorylation of cyclic AMP response element binding protein and increased expression of brain-derived neurotrophic factor. By contrast, postmortem studies of brains from patients with major depression or depressed suicide victims exhibit changes indicative of reduced cyclic AMP signaling. The major finding by Fujita et al. (1) is that 11C-(R)-rolipram binding is reduced by approximately 20% in 10 brain regions of 28 depressed subjects, including a number of cortical regions, cerebellum, and the caudate nucleus, compared with matched controls. A careful analysis of other contributing factors and possible alternative interpretations supports the central conclusion of global reductions in labeling by the PDE4 ligand in the subjects with major depression. It should be noted that earlier work has shown that rolipram binding is to two affinity states, termed the lowand high-affinity rolipram binding sites (LARBS, HARBS); under the conditions of the present study, it is likely that only the HARBS is being labeled (7). The HARBS, which has been associated with mediation of antidepressant effects on behavior, is observed only in the brain and is increased by antidepressant drug treatment (8). It is likely that the HARBS represents a conformation of PDE4 that is stabilized by certain posttranslational modifications and interactions with