Introduction

Research interest in the role of norepinephrine (NE) in the pathophysiology of mood and anxiety disorders and the therapeutic effects of antidepressant medications has waxed and waned over the past 50 years. After an intense round of research in the 1960s and 1970s, interest in NE decreased substantially in the decade between 1980 and 1990. This was due to various factors, including the introduction of selective serotonin (5-HT) reuptake inhibitors (SSRIs), the failure to find evidence of a NE deficiency in depressed or anxious patients, and the disappointing results of studies of NE receptor agonists and antagonists as treatment for major depression.

The reawakening of interest in the role of NE in depression and antidepressant effects was fueled by results from neurotransmitter depletion studies 1–7 and the clinical development of selective NE reuptake inhibitors (NRIs) such as reboxetine. Neurotransmitter depletion studies showed that the therapeutic effects of SSRIs could be transiently reversed by rapid depletion of 5-HT but not by depletion of NE.1–3,7 Conversely, the therapeutic effects of the NRI (desipramine) could be transiently reversed by depletion of NE but not by depletion of 5-HT.1–3,7 These key studies strongly suggest that antidepressants do not simply work by enhancing neurotransmission through a single final monoamine common pathway.

Unfortunately, progress has been slowed by the lack of available methods for direct measurement of central nervous system (CNS) NE function in living humans.