The neurobiology and pharmacology of depression: A comparative overview of serotonin selective antidepressants
Background. Over the past decade, targeted drug design has led to significant advances in the pharmacological management of depression. A serendipitous approach to drug discovery has therefore been replaced by the development of drugs acting on predetermined neurobiological targets recognised to be involved in the pathology of depressive illness. The first of these 'designer drugs'. were the selective serotonin (5-HT) reuptake inhibitors (SSRls), followed more recently by venlafaxine and nefazodone which, in addition to 5-HT uptake, also target noradrenaline (NA) uptake and 5-HT, receptors, respectively.
Methods. This paper reviews the biochemistry and pharmacology of depression. From this foundation. the relevance of 5-HT selectivity is discussed followed by a comparison of the clinical pharmacology and pharmacokinetics of 5-HT-selective antidepressants.
Results. Despite their common actionon synaptic 5-HT uptake, structural heterogeneity among the group allows differences to be observed in kinetic and pharmacological parameters, viz. plasma half-life (T1/2), liver metabolism, protein binding, receptor affinities and selectivity ratios. This not only leads to different attributes which assist in the successful management of a particular patient. but will also predict subtle differences in drug interaction risks and in side-effect profiles of clinical relevance.
Conclusion. 5-HT selective antidepressants may be more dissimilar than similar, and these differences can allow the clinician to identify clinically reliable determinates predicting side-effects and, possibly, to identify suitable patients for a particular drug.