Serotonin-norepinephrine reuptake inhibitor

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of major depression and other mood disorders. They are also sometimes used to treat anxiety disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD) and chronic neuropathic pain. They act upon two neurotransmitters in the brain that are known to play an important part in mood, namely, serotonin and norepinephrine. This can be contrasted with the more widely-used selective serotonin reuptake inhibitors (SSRIs), which act only on serotonin.

Mode of action

Activity on norepinephrine reuptake is thought necessary for an antidepressant to be effective on neuropathic pain, a property shared with the older tricyclic antidepressants but not with the SSRIs. Fact|date=November 2007

It has been theorized that depression corresponds with a reduction in communication and connectivity between neurons in the hippocampus. Neurons pass information to each other by means of neurotransmitters, which pass across the narrow synapses between the cells. After interacting with receptors on a postsynaptic neuron, most of the neurotransmitter is reabsorbed by the presynaptic cell in a process called reuptake.Antidepressants increase the number of neurotransmitters active in the synapse, thereby enhancing neuronal activity downstream. Via an effect on NMDA receptors, this causes neuronal growth and synapse formation which have been shown in animal models to correlate with the relief of depression.cite journal |author=Reid IC, Stewart CA |title=How antidepressants work: new perspectives on the pathophysiology of depressive disorder |journal=The British Journal of Psychiatry: the journal of mental science |volume=178 |issue= |pages=299–303 |year=2001 |pmid=11282807|doi= 10.1192/bjp.178.4.299] Modern antidepressants usually achieve this effect by blocking the transporter proteins that reabsorb certain neurotransmitters, hence the name "reuptake inhibitors". The result is that more of the neurotransmitter is left in the synaptic cleft, so it has a greater effect on the target neuron.

SNRIs were developed more recently than SSRIs, and there are relatively few of them. Their efficacy as well as their tolerability appear to be somewhat better than the SSRIs', apparently owing to their compound effect. Fact|date=November 2007

Adverse effects

As with the SSRIs, abrupt discontinuation of SNRI-medication usually leads to a discontinuation syndrome which could include states of anxiety and further symptoms. It is therefore recommended to slowly taper down the dose under the supervision of a psychopharmacologist when discontinuing SNRIs. Due to the effects of increased norepinephrine synaptic activity, these drugs are contraindicated in patients with hypertension, heart disease, or risk of stroke. Fact|date=November 2007

ide effects and drug interactions

Because one of the actions of the SNRIs is to block the reuptake of serotonin as the SSRIs do, it has many of the same side effects. The most common include nausea, drowsiness, headache, changes in appetite, vivid dreams, and sexual side effects. There are two common sexual side effects: diminished interest in sex (libido) and difficulty reaching climax (orgasm). These drugs typically do not cause problems with erection, but the sexual side effects are the most common reason people stop taking this type of antidepressant even if it is working well.

Activity at the norepinephrine transporter can sometimes cause anxiety, activation, and elevated blood pressure, leading to the recommendation that everyone who takes these medications should have their blood pressure monitored.

SNRIs should be taken with caution when using St John's wort. [cite book | title=2006 Lippincott's Nursing Drug Guide |last=Karch |first=Amy |year= 2006 |publisher=Lippincott Williams & Wilkins |location=Philadephia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo |isbn= 1-58255-436-6 ] , and should never be taken with MAOI antidepressants.

NRIs currently available

*venlafaxine (tradenames Effexor XR, Effexor) is the first and most commonly used SNRI. Although it also works on dopamine somewhat at high dosages, the majority of its effect is on serotonin and norepinephrine.

*desvenlafaxinecite journal |author=Deecher DC, Beyer CE, Johnston G, "et al" |title=Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor |journal=J. Pharmacol. Exp. Ther. |volume=318 |issue=2 |pages=657–65 |year=2006 |month=August |pmid=16675639 |doi=10.1124/jpet.106.103382 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16675639] (tradename Pristiq) is the active metabolite of venlafaxine and is believed to work in the same manner. It was introduced by Wyeth in May 2008.

*sibutramine (tradenames Meridia, Reductil) is an SNRI which failed to show antidepressant activity in animal tests, but instead has been widely marketed as an appetite suppressant drug for weight loss.

*nefazodone (tradename Serzone) is an antidepressant with efficacy similar to SSRIs, but without the sexual side effects. In fact, Serzone at times may act similarly to Wellbutrin in its neutral or at times positive effect on function. It has been discontinued in several countries due to rare cases of liver failure. The tradename "Serzone" has been discontinued, however generic nefazodone is currently available (May 6). However, the liver failure is rare, and a simple blood test every 6 months to assess liver enzyme levels is sufficient. Nefazodone has an active metabolite which at higher doses (> 250 mg/day) can increase anxiety. One of the benefits nefazodone has over Effexor and Cymbalta is its enhanced sedation when taken at bedtime.Verify source|date=November 2007

*milnaciprancite journal |author=Nonogaki K, Nozue K, Kuboki T, Oka Y |title=Milnacipran, a serotonin and norepinephrine reuptake inhibitor, induces appetite-suppressing effects without inducing hypothalamic stress responses in mice |journal=Am. J. Physiol. Regul. Integr. Comp. Physiol. |volume=292 |issue=5 |pages=R1775–81 |year=2007 |month=May |pmid=17218444 |doi=10.1152/ajpregu.00527.2006 |url=http://ajpregu.physiology.org/cgi/pmidlookup?view=long&pmid=17218444] (tradename Dalcipran/ Portugal; Ixel/ France) has shown to be significantly effective in the treatment of depression and Fibromyalgia syndrome (FMS). Although it has not yet been approved by the Food and Drug Administration (FDA) for use in the United States, it has been commercially available in Europe and Asia for several years.

*desipramine (tradenames Norpramine, Pertofraneis) is technically a tricyclic antidepressant, and is usually categorized as such. Like an SNRI it works on both serotonin and norepinephrine transporters, but because it also interacts with cholinergic and histamine receptors, leading to the characteristic side effects associated with blockade of these receptors, it lacks the specificity that the serotonin norepinephrine specific reuptake inhibitors have.

*duloxetinecite journal |author=Iyengar S, Webster AA, Hemrick-Luecke SK, Xu JY, Simmons RM |title=Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats |journal=J. Pharmacol. Exp. Ther. |volume=311 |issue=2 |pages=576–84 |year=2004 |month=November |pmid=15254142 |doi=10.1124/jpet.104.070656 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15254142] (tradename Cymbalta) by Eli Lilly and Company, also inhibits serotonin reuptake and has been approved for the treatment of depression and neuropathic pain in August 2004.

*bicifadine by DOV Pharmaceutical inhibits the reuptake of serotonin and norepinephrine (and dopamine to a lesser extent) but rather than being developed for the already crowded antidepressant market, it is being researched as a non-opioid, non-NSAID analgesic drug.

Please note that some of the above medications may not be considered "true" SNRIs; refer to specific peer-reviewed scientific journals for more in-depth coverage on classifications and pharmaco-kinetics.

ee also

*Serotonin-noradrenaline-dopamine reuptake inhibitor
*Noradrenergic and specific serotonergic antidepressant

References