Serotonin–norepinephrine reuptake inhibitors



Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs used in the treatment of major depression and other mood disorders. They are sometimes also used to treat anxiety disorders, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.

SNRIs act upon and increase the levels of two neurotransmitters in the brain that are known to play an important part in mood, these being serotonin and norepinephrine. This can be contrasted with the more widely-used selective serotonin reuptake inhibitors (SSRIs) which only act on serotonin.

Overview of SNRIs

 * Venlafaxine (Effexor) - The first and most commonly used SNRI. It was introduced by Wyeth in 1994. The reuptake effects of venlafaxine are dose dependent. At low doses (<150 mg/day) it acts only on serotonergic transmission. At moderate doses (>150 mg/day) it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day) it also affects dopaminergic neurotransmission.


 * Desvenlafaxine (Pristiq) - The active metabolite of venlafaxine. It is believed to work in a similar manner, though some evidence suggests lower response rates compared to venlafaxine and duloxetine. It was introduced by Wyeth in May 2008.


 * Duloxetine (Cymbalta, Yentreve) - By Eli Lilly and Company, has been approved for the treatment of depression and neuropathic pain in August 2004. Duloxetine is contraindicated in patients with heavy alcohol use or chronic liver disease, as duloxetine can increase the levels of certain liver enzymes which can lead to acute hepatitis or other diseases in certain at risk patients. Currently, the risk of liver damage appears only to be for patients already at risk, unlike the antidepressant nefazodone which, though rare, can spontaneously cause liver failure in healthy patients.  Duloxetine is also approved for Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), chronic musculoskeletal pain, including chronic osteoarthritis pain and chronic low back pain (as of October, 2010), and is one of the only three medicines approved by the FDA for Fibromyalgia.


 * Milnacipran (Dalcipran, Ixel, Savella) - Shown to be significantly effective in the treatment of depression and fibromyalgia. The Food and Drug Administration (FDA) approved milnacipran for treatment of fibromyalgia in the United States of America in January 2009, however it is currently not approved for depression in that country. Milnacipran has been commercially available in Europe and Asia for several years.


 * Levomilnacipran (F2695) - The levo- isomer of milnacipran. Under development for the treatment of depression in the United States and Canada.


 * Sibutramine (Meridia, Reductil) - An SNRI, which, instead of being developed for the treatment of depression, was widely marketed as an appetite suppressant for weight loss purposes.


 * Bicifadine (DOV-220,075) - By DOV Pharmaceutical, potently 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.


 * SEP-227162 - An SNRI under development by Sepracor for the treatment of depression.


 * LY 2216684 - An SNRI under development by Eli Lilly for the treatment of depression.

Pharmacology
SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in an increase in the extracellular concentrations of serotonin and norepinephrine and therefore an increase in neurotransmission. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for NE than serotonin.

Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs.

Comparison to SSRIs
The SNRIs were developed more recently than the SSRIs and as a result there are relatively few of them. However, the SNRIs are among the most widely used antidepressants today. In 2009 Cymbalta and Effexor were the 11th and 12th most prescribed branded drugs in the United States. This translates to the 2nd and 3rd most common antidepressants, behind Lexapro (#5). In some studies, SNRI's demonstrated slightly higher antidepressant efficacy than the SSRIs (response rates 63.6% versus 59.3%). However, in one study escitalopram had a superior efficacy profile to venlafaxine. It is not clear what the reasons were for this unexpected anomaly. The side effects of SNRIs are reported to be slightly less severe in comparison to the SSRIs as well. One of the major complaints that many users of SSRIs have is the negative sexual side effects that can be very difficult to treat. . Although SNRIs can have similar side effects, many of them can have the opposite effect of increased libido. Wellbutrin has had official studies done, and Strattera and Savella have commonly been reported as increasing libido in both men and women, even though studies have contradicted these reports. However, the individuals who reported increased sexual functioning also tended to report increased anxiety, heart rate, blood pressure, and other negative effects associated with adrenaline increase.

Side effects
Because the SNRIs and SSRIs both act similarly to elevate serotonin levels, they subsequently share many of the same side effects, though to varying degrees. The most common include loss of appetite, weight, and sleep. There may also be drowsiness, dizziness, fatigue, headache, mydriasis, nausea/vomiting, sexual dysfunction, and urinary retention. There are two common sexual side effects: diminished interest in sex (libido) and difficulty reaching climax (anorgasmia), which are usually somewhat milder with the SNRIs in comparison to the SSRIs. Nonetheless, sexual side effects account for lack of compliance with both SSRIs and SNRIs.

While tricyclic antidepressants also produce similar sexual side effects as SNRIs, discontinuation of TCAs is more often due to the other side effects (like cardiovascular effects). Also Amitriptyline (a TCAs) is more commonly associated with orthostatic hypotension.

Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. People at risk for hypertension and heart disease should have their blood pressure monitored.

Discontinuation syndrome
As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or "discontinuation syndrome", which could include states of anxiety and other symptoms. It is therefore recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs. Accordingly, as tramadol is related to venlafaxine, the same conditions apply. This is likely due to venlafaxine's relatively short half-life and therefore rapid clearance upon discontinuation.

Contraindications
Due to the effects of increased norepinephrine levels and therefore higher adrenergic activity, pre-existing hypertension should be controlled before treatment with SNRIs and blood pressure periodically monitored throughout treatment. Duloxetine has also been associated with cases of hepatic failure and should not be prescribed to patients with chronic alcohol use or liver disease.

SNRIs should be taken with caution when using St John's wort as the combination can lead to the potentially fatal serotonin syndrome. They are contraindicated with dextromethorphan, tramadol, cyclobenzaprine, meperidine/pethidine, and propoxyphene as well. They should also never be taken within 14 days of any other antidepressant, especially the monoamine oxidase inhibitors (MAOIs).