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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...

Recent epidemiological surveys conducted in general populations have found that the lifetime prevalence of depression is in the range of 10% to 15%. Mood disorders, as defined by the World Mental Health and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, have a 12-month prevalence which varies from 3% in Japan to over 9% in the US. A recent American survey found the prevalence of current depression to be 9% and the rate of current major depression to be 3.4%. All studies of depressive disorders have stressed the importance of the mortality and morbidity associated with depression. The mortality risk for suicide in depressed patients is more than 20-fold greater than in the general population. Recent studies have also shown the importance of depression as a risk factor for cardiovascular death. The risk of cardiac mortality after an initial myocardial infarction is greater in patients with depression and related to the severity of the depressive episode. Greater severity of depressive symptoms has been found to be associated with significantly higher risk of all-cause mortality including cardiovascular death and stroke. In addition to mortality, functional impairment and disability associated with depression have been consistently reported. Depression increases the risk of decreased workplace productivity and absenteeism resulting in lowered income or unemployment. Absenteeism and presenteeism (being physically present at work but functioning suboptimally) have been estimated to result in a loss of $36.6 billion per year in the US. Worldwide projections by the World Health Organization for the year 2030 identify unipolar major depression as the leading cause of disease burden. This article is a brief overview of how depression affects the quality of life of the subject and is also a huge burden for both the family of the depressed patient and for society at large.

Over 75% of depressed patients in primary care complain of painful physical symptoms such as headache, stomach pain, neck and back pain as well as non-specific generalized pain. The presence of such symptoms predicts a greater severity and a less favourable outcome of depression with a poorer health-related quality of life. World Health Organization data obtained in primary care centres worldwide show that 22% of all primary care patients suffer from persistent debilitating pain and that these patients are four times more likely to have co-morbid anxiety or depressive disorder than pain-free primary care patients. Not unexpectedly, the risk of depression is greater when the pain is more diffuse, as indicated by the number of painful sites, and has a greater effect on the quality of life. Certain depressive symptoms, such as low energy and sleep disturbances, are commonly found in patients with co-morbid pain, whereas the opposite is true for symptoms such as guilt and loneliness. Increasingly, major depression is seen as being composed of psychological, somatic and painful physical symptoms. In order to achieve full sustained remission it is necessary to treat symptoms in all three of these areas. The area of painful physical symptoms is unfortunately still poorly understood and clearly merits greater attention.

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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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