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.
MeSH terms
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Adrenergic Uptake Inhibitors / chemistry
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Adrenergic Uptake Inhibitors / pharmacology*
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Adrenergic alpha-Antagonists / chemistry
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Adrenergic alpha-Antagonists / pharmacology*
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Animals
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Antidepressive Agents / chemistry
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Antidepressive Agents / pharmacology*
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Antidepressive Agents, Second-Generation / chemistry
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Antidepressive Agents, Second-Generation / pharmacology
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Antidepressive Agents, Tricyclic / pharmacology
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Cyclohexanols / chemistry
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Cyclohexanols / pharmacology
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacology
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Drug Design*
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Duloxetine Hydrochloride
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Humans
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Mianserin / analogs & derivatives
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Mianserin / chemistry
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Mianserin / pharmacology
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Milnacipran
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Mirtazapine
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Monoamine Oxidase Inhibitors / pharmacology
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Rats
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Receptors, Adrenergic, alpha-1 / drug effects
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Receptors, Adrenergic, alpha-2 / drug effects
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Receptors, Serotonin / drug effects
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Selective Serotonin Reuptake Inhibitors / chemistry
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Selective Serotonin Reuptake Inhibitors / pharmacology*
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Venlafaxine Hydrochloride
Substances
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Adrenergic Uptake Inhibitors
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Adrenergic alpha-Antagonists
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Antidepressive Agents
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Antidepressive Agents, Second-Generation
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Antidepressive Agents, Tricyclic
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Cyclohexanols
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Cyclopropanes
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Monoamine Oxidase Inhibitors
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Receptors, Adrenergic, alpha-1
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Receptors, Adrenergic, alpha-2
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Receptors, Serotonin
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Serotonin Uptake Inhibitors
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Thiophenes
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Mianserin
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Venlafaxine Hydrochloride
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Duloxetine Hydrochloride
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Mirtazapine
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Milnacipran