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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, and fibromyalgia syndrome (FMS), and for the relief of menopausal symptoms.
SNRIs are potent inhibitors of serotonin (5-Hydroxytryptamine, 5-HT) and norepinephrine (NE, noradrenalin) reuptake. These neurotransmitters are known to play an important role in mood. These can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin alone.
The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane proteins that are responsible for the reuptake of serotonin and norepinephrine. Balanced dual inhibition of monoamine reuptake can possibly offer advantages over other antidepressants drugs by treating a wider range of symptoms. SNRIs are second-generation agents, such as selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs). Over the past two decades, second-generation agents have gradually replaced first-generation agents, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) as the drugs of choice for the treatment of MDD. This is mainly because of their improved tolerability and safety profile.
In 1952 iproniazid, an antimycobacterial agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis. Researchers noted that patients given iproniazid became cheerful, more optimistic, and more physically active. Soon after its development, iproninazid and related substances were shown to slow enzymatic breakdown of norepinephrine, serotonin and dopamine via inhibition of mitochondrial enzyme monoamine oxidase. For this reason this class of drugs became known as MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine became the first clinically useful TCA. Imipramine was found to affect numerous neurotransmitter systems and to block reuptake of norepinephrine and serotonin from the synapse, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects and significant safety and toxicity issues.
Throughout the 1960s and 1970s the catecholamine hypothesis of emotion and its relation to depression was of wide interest and that the decreased levels of certain neurotransmitters, such as norepinephrine, serotonin, and dopamine might play a role in the pathogenesis of depression. This led to the development of fluoxetine, the first SSRI. The improved safety and tolerability profile of the SSRIs in patients with MDD, compared with TCAs and MAOIs, represented yet another important advance in the treatment of depression.
Since the late 1980s SSRIs have dominated the antidepressant drug market. Today there is increased interest in antidepressant drugs with broader mechanisms of action that may offer improvements in efficacy and fewer adverse effects. In 1993 a new drug was introduced to the US market called venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines. These substances are unrelated to TCA and other SSRIs. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine in the central nervous system. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition. See timeline in figure 1.
Monoamines are connected to the pathophysiology of depression. Symptoms are thought to appear because concentrations of neurotransmitters for example norepinephrine and serotonin are insufficient. Medications to treat symptoms of depression effect the transmission of serotonin, norepinephrine and/or dopamine. Older and more unselective antidepressants like TCAs and MAOIs, act by inhibiting the reuptake or metabolism, of norepinephrine and/or serotonin in the brain which concludes higher neurotransmitters concentrations. Antidepressants that have dual mechanisms of action, inhibit both serotonin and norepinephrine reuptake, in some cases with weak effect on dopamine reuptake. Antidepressants have effects on variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle, leading to decreased cardiac conduction and cardiotoxicity. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression. Drugs that selectively block the reuptake of serotonin and/or norepinephrine have shown to be effective in treating depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity 
TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood. TCAs have dual inhibition effects on norepinephrine reuptake transporters and serotonin reuptake transporters. Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for norepinephrine reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites.
In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport. Norepinephrine interacts with postsynaptic α- and β-adrenergic receptor subtypes and presynaptic α2-autoreceptors. The α2-receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system. Formation of norepinephrine is reduced by autoreceptors through the ratelimiting enzyme tyrosine hydroxylase, by decreasing the expression of cyclic AMP-mediated phosphorylation-activation of the enzyme. α2-receptors also cause decreased intracellular cyclic AMP expression which is resulted in smooth muscle relaxation or decreased secretion. TCAs activate a negative-feedback mechanism through its effects on presynaptic receptor mediation. Probable explanation of effects on decreased neurotransmitter release is that as the receptors activate, inhibition of neurotransmitter release occurs, including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents. Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release. However, repeated administration of TCAs finally results in decreased responses of α2-receptors. This desensitization of these responses may be caused due to increased exposure to the endogen norepinephrine or from prolonged occupation of the norepinephrine transport itself caused by allosteric effect. This adaptation allows the presynaptic synthesis and secration of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Overall inhibition of norepinephrine reuptake induced by TCAs, lead to decreased rates of neuron firing (mediated through α2-autoreceptors), metabolic activity, and release of neurotransmitters.
TCAs do not block dopamine transport but might facilitate dopamine effects indirectly by transport-inhibition of dopamine into noreadrenergic terminals in cerebral cortex. Because of multiple effects on different receptors, TCAs have poor tolerability which could result in adverse effects and increased risk of toxicity.
Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin and are a widely used group of antidepressants. With increased receptors selectivity compared to TCAs, undesired effects like poor tolerability are avoided. Serotonin is synthesized from an amino acid called L-tryptophan. Active transport system regulates the uptake of tryptophan across the blood–brain barrier. Serotonergic pathways are classified into two main ways in the brain; the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord. The reuptake blocking of SSRIs into the presynaptic terminal results in increased concentration of serotonin in the synaptic cleft, just like the TCAs, but with much less additional effects. Altering the serotonin concentrations to higher levels influence symptoms of anxiety which coexist with depression, leading to improvement of depression symptoms.
There are two major regions in the brain where noradrenergic neurons are located. These regions are called locus coeruleus and the lateral tegmental. With administration of selective NRIs, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft. This results in activation of α2-adrenoreceptors, as discussed in section 5.1. Assays have shown that selective NRIs have insignificant penchant for muscarinic-cholinergic, α1- and α2-adrenergic or H1-histaminergic receptors.
Agents with dual serotonin and norepinephrine reuptake inhibition (SNRIs) are sometimes called nontricyclic serotonin and norepinephrine reuptake inhibitors. Clinical studies suggest that compounds which increase the concentration in the synaptic cleft of both norepinephrine and serotonin are more successful than single acting agents in the treatment of depression. Dual reuptake inhibitors have low affinity at neuronal receptors of the other neurotransmitters which results in a low adverse effects, compared with the TCAs. Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRI alone, which give the impression that synergism is an efficient property in mediating antidepressant activity. Between the nontricyclic SNRIs there are several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions and the half-life of the nontricyclic SNRIs. Combination of mechanisms of action in a single active agent is an important development in psychopharmacology.
Several reuptake inhibitors contain an aryloxypropanamine scaffold. This structural motif has potential for high affinity binding to biogenic amine transports. Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring. Selective NRIs contain a substituent in 2’-position of the aryloxy ring but SSRIs contain a substituent in 4’-position of the aryloxy ring. Atomoxetine, nisoxetine and reboxetine all have a substitution group in the 2’-position and are selective NRIs while compounds that have a substitution group in the 4’-position (like fluoxetine and paroxetine) are SSRIs. Duloxetine contains a phenyl group fused at the 2’- and 3’-positions, therefore it has dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters. The nature of the aromatic substituent also has a significant influence on the activity and selectivity of the compounds as inhibitors of the serotonin or the norepinephrine transporters.
Venlafaxine and desvenlafaxine contain a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring provides more potent inhibitory effect of norepinephrine uptake and improves the selectivity for norepinephrine over the serotonin transporter. Effects of chloro, methoxy and trifluoromethyl substituents in the aromatic ring of cycloalkanol ethylamine scaffold were tested. The results showed that the strongest electron-withdrawing m-trifluoromethyl analogue exhibited the most potent inhibitory effect of norepinephrine and the most selectivity over serotonin uptake. WY-46824, a piperazine-containing derivative, has shown norepinephrine and dopamine reuptake inhibition. Further synthesis and testing identified WAY-256805, a potent norepinephrine reuptake inhibitor that exhibited excellent selectivity and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
Milnacipran is structurally different from other SNRIs. The SAR of milnacipran derivatives at transporter level is still largely unclear and is based on in vivo efficacy that was reported in 1987. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity. Researches on different secondary amides in substitution groups R6 and R7 showed that π electrons play an important role in the interaction between transporters and ligands. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters. Studies have shown that when introducing a 2-methyl group in substituent R3 the potency at norepinephrine and serotonin transporters are almost abolished. Methyl group in substituent group R1 and R2 also abolished the potency at norepinephrine and serotonin transporters. Researchers found out that when replacing one of the ethyl groups of milnacipran with an allyl moiety increases the norepinephrine potency. The pharmacophore of milnacipran derivatives is still largely unclear.
The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran resides in the 1S,2R isomer and substitution of the phenyl group in the 1S,2R isomer has negative impact on norepinephrine concentration. Milnacipran has low molecular weight and low lipophilicity. Because of these properties milnacipran exhibits almost ideal pharmacokinetics in humans such as high bioavailability, low inter-subject variability, limited liver enzyme interaction, moderate tissue distribution and a reasonably long elimination half-life. Milnacipran´s lack of drug-drug interactions via cytochrome P450 enzymes is thought to be an attractive feature because many of the central nervous system drugs are highly lipophilic and are mainly eliminated by liver enzymes.
The application of an aryloxypropanamine scaffold has generated a number of potent MAOIs. Before the development of duloxetine, the exploration of aryloxypropanamine SAR resulted in the identification of fluoxetine and atomoxetine. The same motif can be found in reboxetine where it is constrained in a morpholine ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur to give arylthiomethyl morpholine. Some of the arylthiomethyl morpholine derivatives maintain potent levels of serotonin and norepinephrine reuptake inhibition. Dual serotonin and norepinephrine reuptake inhibition resides in different enantiomers for arylthiomethyl morpholine scaffold. Possible drug candidates with dual serotonin and norepinephrine reuptake inhibitory activity have also been derived from piperazine, 3-amino-pyrrolidine and benzylamine templates.
Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity is more effective than SSRIs in treating MDD. Results showed that serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared to SSRIs in treating MDD  and have less side effects. Serotonergic-noradrenergic antidepressant drugs used to treat MDD compared to SSRIs and mirtazapine seem to be less expensive than other drugs for example in the UK. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms.
Data from clinical trials have indicated that SNRIs might have pain relieving properties. The pain perception and transmission in the central nervous system have not been fully elucidated however, extensive data support a role of serotonin and norepinephrine in the modulation of pain. This is also supported by data from clinical trials in humans in which antidepressants have been shown to reduce pain and functional impairment in central and neuropathic pain conditions. This property of SNRIs might be used to reduce doses of other pain relieving medication and lower frequency of limited efficacy, safety and tolerability issues. Clinical research data have shown in patients with GAD that the SNRI duloxetine is significantly more effective than placebo in reducing painful physical symptoms of GAD after short-term and long-term treatment. Findings suggested that painful physical symptoms reoccur with relapsing that indicate a need for ongoing treatment in patients with GAD and concurrent painful physical symptoms.
Bicifadine is a SNRI. Bicifadine is being developed for the treatment of acute and chronic pain. Clinical research have shown that bicifadine is effective in the treatment of acute dental pain and bunionectomy pain. Bicifadine has also been reported to be as effective as the standard of care in reducing chronic lower back pain.
|Active ingredient||Product name||Therapeutic use||Binding affinity|
|Venlafaxine||Efexor, Effexor||Treatment of major depressive disorder (MDD), including treatment-resistant cases, generalized anxiety disorder (GAD), chronic pain syndromes ||5-HT:7,8|
|Milnacipran||Savella, Ixel, Dalcipran, Toledomin||Treatment of pain and multiple symptoms associated with fibromyalgia syndrome, treatment of MDD ||5-HT:8,4|
|Duloxetine||Cymbalta, Ariclaim, Xeristar, Yentreve||Treatment of MDD and fibromyalgia ||5-HT:0,07|
|Levomilnacipran||Fetzima||Treatment of MDD in adults||5-HT:NA|
|Bicifadine||—||Under development ||5-HT:NA|
|Desvenlafaxine||Pristiq||Treatment of MDD in adults ||5-HT:NA|
|Sibutramine||Meridia, Reductil||Treatment of obesity ||5-HT:NA|
5-HT: Serotonin - NE: Norepinephrine - D: Dopamine - NA: Not available
SNRIs are approved for treatment of the following conditions:
SNRIs are delivered orally, usually in the form of gel capsules. The drugs themselves are usually a fine crystalline powder that diffuses into the body during digestion.
Dosages fluctuate depending on the SNRI used due to varying potencies of the drug in question as well as multiple strengths for each drug.
The disease for which SNRIs are mostly indicated, Major Depressive Disorder, is thought to be mainly caused by decreased levels of serotonin and norepinephrine in the synaptic cleft, causing erratic signaling. Due to the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depression symptoms, the following relations were determined: "Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life." 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 norepinephrine 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.
Recent studies have shown that depression may be linked to increased inflammatory response, thus attempts at finding an additional mechanism for SNRIs have been made. Studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia in addition to their effect on serotonin and norepinephrine levels. As such, it is possible that an additional mechanism of these drugs that acts in combination with the previously understood mechanism exist. The implication behind these findings suggests use of SNRIs as potential anti-inflammatories following brain injury or any other disease where swelling of the brain is an issue. However, it should be noted that, regardless of the mechanism, the efficacy of these drugs in treating the diseases for which they have been indicated has been proven, both clinically and in practice.
Most SNRIs function alongside primary metabolites and secondary metabolites in order to inhibit reuptake of serotonin, norepinepherine, and trace amounts of dopamine. For example, venlafaxine works alongside its primary metabolite O-desmethylvenlafaxine to strongly inhibit serotonin and norepinephrine reuptake in the brain. Recent evidence suggests that dopamine and norepinepherine behave in a cotransportational manner, due to dopamine's inactivation by norepinephrine reuptake in the prefrontal cortex, which largely lacks dopamine transporters. Therefore, SNRIs can increase dopamine neurotransmission in this part of the brain. Furthermore, because SNRIs are extremely selective, they have no measurable effects on unintended systems, such as on monoamine oxidase inhibition. Furthermore, studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia
Due to the effects of increased norepinephrine levels and, therefore, higher Noradrenergic 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. Patients suffering from coronary artery disease should avoid the use of SNRIs. Furthermore, due to some SNRIs' actions on obesity, patients with major eating orders such as anorexia nervosa or bulimia should not be prescribed SNRIs. Duloxetine and milnacipran are also contraindicated in patients with uncontrolled narrow-angle glaucoma, as they have been shown to increase incidence of mydriasis.
SNRIs should be taken with caution when using St John's wort, as the combination can lead to the potentially fatal serotonin syndrome. There is also a significant risk when combining SNRIs with dextromethorphan, tramadol, cyclobenzaprine, meperidine/pethidine, and propoxyphene. They should never be taken within 14 days of any other antidepressant, especially with monoamine oxidase inhibitors (MAOIs), as combinations of SNRIs with MAOIs can cause hyperthermia, rigidity, myoclonus, autonomic instability with fluctuating vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.
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, increase in suicidal thoughts, 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. 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.
Due to the extreme changes in noradrenergic activity produced from norepinephrine and serotonin reuptake inhibition, patients that are just starting an SNRI regimen are usually given lower doses than their expected final dosing to allow the body to acclimate to the drug's effects. As the patient continues along at low doses without any side-effects, the dose is incrementally increased until the patient sees improvement in symptoms without detrimental side-effects.
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. Therefore, it is 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. As such, 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.
Symptoms of SNRI overdose, whether it be a mixed drug interaction or the drug alone, vary in intensity and incidence based on the amount of medicine taken and the individuals sensitivity to SNRI treatment. Possible symptoms are as follows:
Overdose is usually treated symptomatically, especially in the case of serotonin syndrome, which requires treatment with cyproheptadine and temperature control based on the progression of the serotonin toxicity. Patients are often monitored for vitals and airways cleared to ensure that they are receiving adequate levels of oxygen. Another option is to use activated carbon in the GI tract in order to adsorb excess neurotransmitter. It is important to consider drug interactions when dealing with overdose patients, as separate symptoms can arise.
The SNRIs were developed more recently than the SSRIs[date missing] 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), the SSRI escitalopram. In some studies, SNRIs 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. 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, a norepinephrine-dopamine reuptake inhibitor (NDRI) and Savella, an SNRI, have been reported to increase libido in both men and women, although some studies have contradicted these reports. However, the individuals having reported increased libido also tended to report increased anxiety, heart rate, blood pressure, and other negative effects associated with adrenaline increase.
If a person has an abnormal level of certain neurotransmitters in their brain, it may result in having mood swings or a mood disorder. Serotonin is a neurotransmitter in the brain that is involved with sleep, moods, and emotional states. A slight imbalance of serotonin could result in depression. Norepinephrine is a neurotransmitter that is involved with learning, memory, and physical arousal. Like serotonin, an imbalance of norepinephrine may also result in depression.