Introduction

Researchers introduced the first antidepressants, tricyclic antidepressants and monoamine oxidase inhibitors, in the late 1950s to treat depression. It was the finding that chlorpromazine was an effective antipsychotic agent that led researchers to comb the shelves of drug companies for look-alike compounds to treat psychosis. They came upon imipramine, which was found to lack antipsychotic properties. However, astute clinicians, in particular, Doctor Roland Kuhn in Switzerland, noted that patients who were both depressed and psychotic improved in their depression on imipramine although their psychosis was unaffected. The year after the report by Kuhn, Sigg reported on the peripheral adrenergic effects of imipramine in laboratory animals. Among his findings was that there was an enhancement and prolongation of the vasopressor response to norepinephrine. This effect occurred with acute but not chronic treatment. Interestingly, without any direct evidence, he hypothesized that, based on the peripheral effects of imipramine on the adrenergic system, it exerted its antidepressant effect by sensitization of central adrenergic synapses. Thus, we have known for over 40 years that antidepressants interact with noradrenergic systems. This chapter will review the evolution of our knowledge of the interactions of antidepressants and other drugs with the noradrenergic system. This overview will focus on antidepressants.

Temporal overview

The 1950s and 1960s

Aside from the 1950s and 1960s giving birth to rock and roll, this era gave birth to modern day psychopharmacology when researchers took advantage of the clinical insights made when patients were treated with psychotropic drugs.