title: Designing a new generation of antidepressant drugs.
abstract: Although longer-term adaptive changes in receptor sensitivity may better explain the delayed onset of action of antidepressants, the mechanism based on acutely elevated noradrenaline (NA) and serotonin (5-HT) synaptic levels remains the basis for new drug design. The dual action concept, which postulates that effects on both NA and 5-HT are more advantageous than a selective action on serotonin reuptake (SSRI), has been used to design new antidepressants such as venlafaxine and mirtazapine. Both drugs enhance NA and 5-HT neurotransmission with little affinity for receptors mediating tricyclic-like side effects. Mirtazapine, the prototype noradrenergic and specific serotonergic antidepressant (NaSSA), specifically enhances 5-HT1 neurotransmission and blocks 5-HT2 and 5-HT3 receptors, and in contrast to venlafaxine lacks SSRI-like and adverse cardiovascular side effects. The unique pharmacological action of mirtazapine is a result of implementation of two concepts: dual action as a basis of efficacy combined with receptor-specific action as a basis of tolerability.
authors.affiliation: NV Organon, Oss, The Netherlands.
authors.forename: R M
authors.initials: RM
authors.lastname: Pinder
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000737:chemistry / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D000068736:Duloxetine Hydrochloride; D006801:Humans; D008803:Mianserin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000078764:Milnacipran; D000078785:Mirtazapine; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D003511:Cyclohexanols; D003521:Cyclopropanes; D000068736:Duloxetine Hydrochloride; D008803:Mianserin; D000078764:Milnacipran; D000078785:Mirtazapine; D008996:Monoamine Oxidase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; D000069470:Venlafaxine Hydrochloride