Dual serotonin-norepinephrine reuptake inhibitors

In the past decade, other antidepressants have been introduced. Many of these act, at least in part, via serotonin-mediated mechanisms and, as such, have been tested in the treatment of one or more anxiety disorders. These additional antidepressants include two dual serotonin-norepinephrine reuptake inhibitors (SNRIs),... 

A controlled trial of duloxetine (Cymbalta)—like venlafaxine a dual serotonin-norepinephrine reuptake inhibitor—in the treatment of GAD is currently underway. Anecdotal data suggests that nefazodone (Serzone) and mirtazapine (Remeron) may be effective in the treatment of GAD, though no controlled data is available. In addition, recent concerns regarding nefazodone and liver toxicity have limited this medication s utility. Please refer to Chapter 3 for more information regarding these antidepressants. 

Venlafaxine (Effexor, Effexor XR). Venlafaxine, a dual serotonin-norepinephrine reuptake inhibitor, has only recently been used to treat ADHD with a few case reports suggesting it may provide modest benefit for both inattention and impulsivity. Effexor XR is generally well tolerated, though it can elevate blood pressure somewhat at higher doses. This should be monitored especially when venlafaxine is coadministered with a stimulant. Controlled trials are needed. 

Kirwin JL, Goren JL. Duloxetine a dual serotonin-norepinephrine reuptake inhibitor for treatment of major depressive disorder. Pharmacotherapy 2005 25 396-410. 

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... 

Dual serotonin- norepinephrine reuptake inhibitors Duloxetine 40-80 mg/day (1 or 2 doses) Once approved, will become first-line therapy. Most adverse events diminish with time so support patient during initial period of use... 

Duloxetine (Scheme 57.11) is an antidepressant drug that acts as a dual serotonin-norepinephrine reuptake inhibitor, the (5)-enantiomer being twice as potent as its counterpart. Both (/ )- and (5)-duloxetine have been prepared from ester (/ )-48, which in turn has been obtained by the DKR of the (3-hydroxynitrile rac-Al using CAL-B and Ru catalyst 3a. ... 

Although the SSRIs provided a tremendous advantage over the TCAs in terms of tolerability, an effect on norepinephrine also has some theoretical advantages. For example, some authors have suggested that dual reuptake inhibitors may be more likely to lead to remission (Thase et al. 2001). As the name of the class implies, these agents affect the reuptake of both serotonin and norepinephrine, while having very little effect on muscarinic, histaminic or Hj, or aj-adrenergic receptors. Hence these medications share many of the tolerability and safety benefits of the SSRIs. Currently, two serotonin-norepinephrine reuptake inhibitors (SNRIs) are available in the United States venlafaxine and duloxetine. 

FIGURE 7—1. Shown here is the icon of a dual reuptake inhibitor, which combines the actions of both a serotonin reuptake inhibitor (SRI) and a norepinephrine reuptake inhibitor (NRI). In this case, three of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6—27) were removed. Both the SRI portion and the NRI portion of the TCA remain however the alpha, antihistamine, and anticholinergic portions are removed. These serotonin/norepinephrine reuptake inhibitors are called SNRIs or dual inhibitors. A small amount of dopamine reuptake inhibition (DRI) is also present in some of these agents, especially at high doses. 

Serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g. duloxetine, venlafaxine and desvenlafax-ine) inhibit the reuptake of both serotonin and norepinephrine and are referred to as dual inhibitors or selective serotonin norepinephrine inhibitors . The SNRIs lack of anticholinergic side effects results in a distinct advantage over traditional TCAs [13,77,78]. For example, duloxetine is a potent, balanced inhibitor of serotonin and norepinephrine reuptake [79]. Venlafaxine inhibits serotonin reuptake at lower dosages and inhibits both serotonin and norepinephrine reuptake at higher dosages [70,80]. 

DUAL SELECTIVE SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SSNRIs)... 

Additional dual 5HT-NE reuptake inhibitors include sibutramine, which is approved for the treatment of obesity but not depression. Tramadol is a kappa opiate agonist approved for the treatment of pain, but it also has serotonin and norepinephrine reuptake inhibitor properties. Dual reuptake inhibitors in clinical testing as antidepressants include milnacipran and duloxetine. 

SNRI (dual serotonin and norepinephrine reuptake inhibitor) may be classified as an antidepressant, but it is not just an antidepressant... 

As milnacipran Is a more potent norepinephrine reuptake Inhibitor than a serotonin reuptake Inhibitor, some patients may require dosing at the higher end of the dosing range to obtain robust dual SNRI actions... 

SNRI dual serotonin and norepinephrine reuptake inhibitor... 

Thiophene seems to be very popular in Li Lilly drugs. Its dual selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for depression, duloxetine (Cymbalta), contains a thiophene. And its atypical antipsychotic drug olanzapine (Zyprexa) has a fused thiophene as its core structure. 

In the 1980s the Boots company developed the serotonin- and norepinephrine-reuptake inhibitor sibutramine for reduction of severe overweight. [242, 244] Sibutramine has a dual function to increase the feeling of satiety and to enhance metabolism. In 1997, the drug was launched under the trade name Meridia , however after an unfavourable risk/benefit assessment and the consequent ban by the European Medicines Agency (EM A) and the FDA, it was ultimately suspended by Abbott in 2010. 

Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake indicated for depression and painful diabetic neuropathy, is expected to become first-line therapy for SUI. Duloxetine is thought to facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase. 

Venlafaxine is a dual reuptake inhibitor of both serotonin and norepinephrine with equal potency for both transporters. 

Thase ME, Tran PV, Curtis W, Pangallo B, Mallinckrodt C, Detke MJ. Cardiovascular profile of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. J Clin Psychopharmacol 2005 25 132-40. 

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