Neurobiology of Serotonin Norepinephrine Reuptake Inhibitors

A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

Serotonin-dopamine reuptake inhibitor | Psychology …

Because most antidepressants increase monoamine levels within hours but clinical response can take weeks, investigators have searched for the adaptive changes in various brain areas that temporally correspond with the clinical data. A chronic increase in the synaptic concentration of NE and 5-HT with antidepressants is associated with changes in β-adrenergic and 5-HT receptor density and/or sensitivity.6,76-80 These changes are common to most antidepressants, irrespective of whether they are NRIs, SSRIs, or SNRIs, and therefore are more likely to reflect the underpinnings of shared therapeutic81-83 or side effect profiles.

Side effects of selective serotonin reuptake inhibitors include loss of sex drive, headache, nausea, and sleep disturbances.

A serotonin-dopamine reuptake inhibitor ..

This could occur as a result of decreased serotonin re-uptake (from tricyclic antidepressants), decreased serotonin metabolism (from monoamine oxidase inhibitors), or excessive adminstration of serotonin precursors or agonists (trazodone, L-tryptophan, 5-HTP).Certain street drugs may cause serotonin syndrome.

The SNRIs as an antidepressant class exhibit affinity toward both 5-HT and NE transporter molecules, but their selectivity differs among members of the class, possibly leading to differences in their effects on central and peripheral targets. Recent advances in pharmacogenomics demonstrate that polymorphisms of gene loci involved in monoamine signaling pathways are associated with changes in the efficacy, safety, and tolerability of SNRIs.119,120,122-124,133 As this area of investigation matures, it may be possible to select patients who will be more likely to respond to specific classes of drugs based on the presence of certain genes or biomarkers. Until such time, data suggest that there are theoretical reasons why medications with a broader profile of effects on monoamine systems may have a slight advantage over the more neurotransmitter-selective compounds. PP

Serotonin, depression, and aggression: The problem of brain energy

Depletion studies suggest that the 5-HT and NE effects of antidepressants may be independent of each other. For example, depleting 5-HT causes a rapid MDD return in depressed patients who have responded to fluoxetine, fluvoxamine, MAOIs, and imipramine but not in those who have responded to desipramine, nortriptyline, or bupropion.4,69,70 Depleting NE and D causes a rapid MDD return in those depressed patients who have improved on desipramine and mazindol but not on fluoxetine.68,71 The selectivity seen in neurotransmitter depletion studies argue against a single monoamine as being responsible for the therapeutic actions of antidepressants.68,71 Noteworthy in these studies, symptoms of MDD appeared within ~5–24 hours after depletion; furthermore, patients recovered rapidly (within 48 hours) after testing was concluded.4,68,69,71 Neither 5-HT nor NE depletion resulted in MDD symptoms in nondepressed volunteers.72,73 In a randomized, double-blind, crossover trial, Shansis and colleagues72 examined the effect of tryptophan on mood, memory, attention, and induced anxiety in 12 healthy male volunteers. None of these parameters was affected by 5-HT depletion. Likewise, NE depletion in eight healthy volunteers failed to provoke symptoms of depression.73 Additionally, patients who were experiencing an MDD episode did not experience worsened symptoms with 5-HT or NE depletion.74

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While “downstream” changes in neuroplasticity may be the final changes mediating antidepressant efficacy, neurotransmitter depletion studies in humans suggest that the initial effects on NE and 5-HT may be necessary for the therapeutic effects of many current drugs.4,67,68 Selective depletion of 5-HT4,68 causes a rapid MDD relapse in depressed patients having had therapeutic responses to and maintained on serotonergic antidepressants. The relapse is qualitatively similar to before treatment MDD and correlates with the time course of monoamine depletion, and patients improve rapidly as monoamine content returns to baseline levels. Although similar results have been demonstrated with NE depletion in responders to noradrenergic antidepressants, it is important to note that similar studies have not yet been conducted with SNRI antidepressants.