title: Pharmacology of rapid-onset antidepressant treatment strategies.
abstract: Although selective serotonin reuptake inhibitors (SSRIs) block serotonin (5-HT) reuptake rapidly, their therapeutic action is delayed. The increase in synaptic 5-HT activates feedback mechanisms mediated by 5-HT1A (cell body) and 5-HT1B (terminal) autoreceptors, which, respectively, reduce the firing in 5-HT neurons and decrease the amount of 5-HT released per action potential resulting in attenuated 5-HT neurotransmission. Long-term treatment desensitizes the inhibitory 5-HT1 autoreceptors, and 5-HT neurotransmission is enhanced. The time course of these events is similar to the delay of clinical action. The addition of pindolol, which blocks 5-HT1A receptors, to SSRI treatment decouples the feedback inhibition of 5-HT neuron firing and accelerates and enhances the antidepressant response. The neuronal circuitry of the 5-HT and norepinephrine (NE) systems and their connections to forebrain areas believed to be involved in depression has been dissected. The firing of 5-HT neurons in the raphe nuclei is driven, at least partly, by alpha1-adrenoceptor-mediated excitatory inputs from NE neurons. Inhibitory alpha2-adrenoceptors on the NE neuroterminals form part of a feedback control mechanism. Mirtazapine, an antagonist at alpha2-adrenoceptors, does not enhance 5-HT neurotransmission directly but disinhibits the NE activation of 5-HT neurons and thereby increases 5-HT neurotransmission by a mechanism that does not require a time-dependent desensitization of receptors. These neurobiological phenomena may underlie the apparently faster onset of action of mirtazapine compared with the SSRIs.
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville 32610-0383, USA. blier@psych.med.ufl.edu
authors.forename: P
authors.initials: P
authors.lastname: Blier
mesh_terms: D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use; D017660:Autoreceptors / Q000187:drug effects / Q000378:metabolism; D003511:Cyclohexanols / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008803:Mianserin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000078785:Mirtazapine; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D010869:Pindolol / Q000494:pharmacology / Q000627:therapeutic use; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D044302:Receptor, Serotonin, 5-HT1B; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride
chemical_list: D000929:Antidepressive Agents, Tricyclic; D017660:Autoreceptors; D003511:Cyclohexanols; D008803:Mianserin; D000078785:Mirtazapine; D009638:Norepinephrine; D010869:Pindolol; D044302:Receptor, Serotonin, 5-HT1B; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C470302:HTR1B protein, human