Dual inhibition of serotonin and noradrenaline reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms.

Soon after its development, iproniazid and related substances were shown to slow enzymatic breakdown of serotonin, dopamine, and norepinephrine via inhibition of the enzyme monoamine oxidase.

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.

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.

In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition.

[10] Older and less selective antidepressants like TCAs and MAOIs inhibit the reuptake or metabolism of norepinephrine and serotonin in the brain, which results in higher concentrations of neurotransmitters.

Overall, inhibition of norepinephrine reuptake induced by TCAs leads to decreased rates of neuron firing (mediated through α2 autoreceptors), metabolic activity, and release of neurotransmitters.

[35] Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring.

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 both transporters.

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.

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.

[28] The structure activity relationship of milnacipran derivatives at the transporter level is still largely unclear and is based on in vivo efficacy that was reported in 1987.

[38] 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.

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.

[42] Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity are generally more effective than SSRIs, which act upon serotonin reuptake by itself.

Serotonergic-noradrenergic antidepressant drugs may have a modest efficacy advantage compared to SSRIs in treating major depressive disorder (MDD),[43] but are slightly less well tolerated.

This property of SNRIs might be used to reduce doses of other pain relieving medication and lower the frequency of safety, limited efficacy and tolerability issues.

[51] Based on the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depressive 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.

[53] Recent studies have shown that depression may be linked to increased inflammatory response,[54] 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[55] in addition to their effect on serotonin and norepinephrine levels.

[55][16][58][59][11][60] The half-life of venlafaxine is about 5 hours, and with once-daily dosing, steady-state concentration is achieved after about 3 days, though its active metabolite desvenlafaxine lasts longer.

[60] SNRIs are contraindicated in patients taking MAOIs within the last two weeks due to the increased risk of serotonin syndrome, which can be life-threatening.

[65] Other drugs and substances that should be avoided due to increased risk of serotonin syndrome when combined with an SNRI include: other anti-depressants, anti-convulsants, analgesics, antiemetic agents, anti-migraine medications, methylene blue, linezolid, Lithium, St. John's wort, ecstasy, and LSD.

[69] Because the SNRIs and SSRIs act in similar ways to elevate serotonin levels, they share many side effects, though to varying degrees.

The most common side effects include nausea/vomiting, sweating, loss of appetite, dizziness, headache, increase in suicidal thoughts, and sexual dysfunction.

[11][59][72] The two common sexual side effects are diminished interest in sex (libido) and difficulty reaching climax (anorgasmia), which are usually somewhat milder with SNRIs compared to SSRIs.

Other drugs that contribute to serotonin syndrome include MAO inhibitors, linezolid, tedizolid, methylene blue, procarbazine, amphetamines, clomipramine, and more.

[79] Studies have suggested caution when using SNRIs or SSRIs with high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or naproxen due to an increased risk of upper GI bleeding.

[90] Studies have shown correlations between pregnant women treated with SNRIs and risk of hypertensive disorders,[91] preeclampsia,[92] miscarriage,[93] seizures in children,[94] and many other adverse affects.

[100] Studies show that these factors also put the geriatric population at increased risk of adverse effects when treated with SNRIs but not with SSRIs.