FOCUS POINTS 1 Venlafaxine, milnacipran, and duloxetine block the reuptake of serotonin (5-HT) and norepinephrine (NE) with differing selectivity. Approximate potency ratios (5-HT:NE) are 1:1 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine.• When used at doses that cause inhibition of the reuptake of both 5-HT and NE, treatment with all three serotonin and norepinephrine reuptake inhibitors (SNRIs) produce higher rates of response and remission from major depression than the selective serotonin reuptake inhibitors (SSRIs). 1 SNRIs are effective in treating a variety of anxiety disorders. Efficacy of SNRIs and SSRIs in anxiety is comparable. 1 SNRIs are effective in the treatment of chronic pain, whereas SSRIs are generally not useful. ' Venlafaxine seems t o be the least well-tolerated SNRI, combining a high level of serotonergic adverse effects (nausea, sexual dysfunction, w i t h d r a w a l problems) with dose-dependent hypertension. In contrast, duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity. ABSTRACT The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaydne, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepineph-rine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. M three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.* Positive numbers: more selective uptake inhibition and binding for NE transporter than 5-HT transporter. Negative numbers: more selective for 5-HT transporter than NE transporter. Adapted with permission from the Journal of Clinical Psychiatry. Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. * Taken from a meta-analysis comparing milnacipran 100 mg/day (n=1,871) and SSRIs. 43 * 4 t Taken from a pooled analysis of venlafaxine (IR and XR) used at variable doses from 75-225 mg/day (n=851) and SSRIs (n=748). 45p46 t Taken from a comparative study of duloxetine 40 mg/day (data not shown) and 80 mg/day (n=91) and paroxetine 20 mg/day (n=87). 47 § Response rate is...

Depression is one of the most common psychological diseases with significant potential morbidity and mortality. Although the underlying pathophysiology of depression has not been clearly defined, preclinical and clinical evidence suggest disturbances in serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmission in the central nervous system. Virtually all currently available antidepressants act on one or more of the following mechanisms: inhibition of reuptake of 5-HT or NE (and DA), antagonism of inhibitory presynaptic 5-HT or NE receptors, or inhibition of monoamine oxidase. All of these mechanisms result in an enhanced neurotransmission of 5-HT and/or NE. Evidence for the involvement of NE in depression is abundant, and recent studies on neuronal pathways and symptoms highlight the specific role of NE in this disorder. NE plays a determinant role in executive functioning regulating cognition, motivation, and intellect, which are fundamental in social relationships. Social dysfunction is possibly one of the most important factors affecting the quality of life in depressed patients.

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