Most effective antidepressants directly or indirectly increase the synaptic concentrations of serotonin (5-HT) and/or norepinephrine (NE) by blocking the reuptake of one or both of the neurotransmitters. This property was initially discovered with the tricyclic antidepressants (TCAs). Their various additional interactions at different receptors and ion channels are not required for antidepressant action, but are responsible for the poor tolerability and toxicity in overdose of the early antidepressants.

The selective serotonin reuptake inhibitors are effective and well tolerated. Selective norepinephrine reuptake inhibitors, such as reboxetine, also have proven antidepressant activity. A selective action on one or the other of the principal monoamines thus appears to be sufficient for antidepressant activity. The idea that a dual action on both neurotransmitters might produce greater efficacy in certain patients led to the development of the serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants, which block the reuptake of both 5-HT and NE without the nonspecific, side-effect–inducing interactions of the TCAs. The three SNRIs—venlafaxine, milnacipran, and duloxetine—constitute a new class of antidepressants.

Antidepressant response rates rarely exceed 60% to 70% and remission rates are usually <50%. Although SNRIs clearly provide superior efficacy in certain populations, their use has not dramatically changed antidepressant therapy. The search for agents that are more effective, rapidly acting, and better tolerated continues. However, clinicians must find ways to better use the antidepressants that are available today. This supplement, based on a symposium held at the International Forum on Affective Disorders in Budapest in December 2007, discusses several everyday problems in the treatment of depression, with a focus on SNRIs.

In 2004, more people died in Europe from suicide than from road accidents. The lifetime prevalence of major depression is 20% for women and 10% for men. Depression is a leading cause of disability and decreased quality of life. In spite of this, numerous studies have shown that only ~50% of depressed patients are recognized as such in primary care. In a recent international survey of everyday management of depression we observed that only ~15% of patients became symptom-free following treatment. In spite of this low level of remission primary care physicians and psychiatrist only rarely increased the dose of antidepressant or switched to another medication as unanimously recommended by different guidelines. Numerous studies have demonstrated the importance of maintaining treatment for ≥6 months after remission is obtained in order to prevent relapse and recurrence. However, a recent study reported that only 19% of a cohort of patients in primary care continued treatment for 6 months as recommended. Antidepressants can be very effective but only when used correctly at adequate doses and for a sufficient duration. Although new improved antidepressants are obviously desirable, a greater recognition of depression and its treatment by the correct use of currently available antidepressant drugs could greatly improve the management of this major public health problem.

Full remission, defined as the absence of all significant symptoms of depression over at least 6 months, is the ultimate goal of antidepressant therapy. Remission takes time and studies have shown that remission rates continue to rise for at least 3 months after initial improvement. Depression is a recurrent condition with a cumulative probability of recurrence of 40% over 2 years and 70% over 5 years after the first depressive episode. In addition the risk of recurrence increases with each new depressive episode. Continuing antidepressant treatment beyond the acute response significantly decreases the risk of recurrence. A double-blind study with the serotonin norepinephrine reuptake inhibitor milnacipran, for example, has shown that patients in remission following treatment with milnacipran who continued the active treatment for a further 12 months had significantly less relapse (P<.05) than those switched to placebo. In spite of the importance of maintaining antidepressant therapy, many patients do not continue treatment. Among the principal reasons for this are side effects and worries of psychological or physical dependence. To reduce the risk of relapse, treatment with effective, well-tolerated antidepressants with few withdrawal effects should be pursued for at least 6 months and possibly longer in patients already experiencing relapse.

There is evidence that the serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine, milnacipran, and duloxetine, have probable superior antidepressant activity to most selective serotonin reuptake inhibitors (SSRIs), especially in more severe depression. Some patients, however, respond better than others to SNRIs. Several factors influencing response to milnacipran have been recently studied. The presence of certain polymorphisms related to noradrenergic neurotransmission has been shown to be related to different degrees or rapidity of response to milnacipran. In addition, patients with low pretreatment levels of plasma 3-methoxy-4-hydroxyphenylglycol have a better response to milnacipran. These recent genomic and neurochemical data confirm that milnacipran, in contrast to SSRIs and venlafaxine, has an impact on the noradrenergic system. Differences in metabolism determined by genetic variables in cytochrome P450 (CYP) 2D6 activity are a major determinant of venlafaxine levels to such an extent that genetically determined decreases in CYP 2D6 activity have been associated increased adverse effects. Milnacipran, which is not metabolized by the enzymes of the CYP system is not influenced by polymorphism of these enzymes. These preliminary data suggest that a patient's biochemical and pharmacogenetic characteristics may be useful in the future to help clinicians chose the most  effective antidepressant medication.

Comorbid chronic pain is common in depressed patients. It is predictive of a poor prognosis for depression and is a major risk factor for suicidal behavior. Depression and chronic pain may result from a common neurobiological dysfunction of monoamine cell bodies in the basal ganglia. Amitriptyline, which inhibits both serotonin and norepinephrine reuptake, is a preferred treatment of chronic pain although it is not officially indicated for this condition. Chronic pain can be modeled in animals where amitriptyline has been shown to be highly effective. Similar effects are obtained with the serotonin norepinephrine reuptake inhibitors milnacipran, duloxetine, and venlafaxine, whereas selective serotonin reuptake inhibitors (SSRIs) are only weakly active. Both animal and clinical studies of chronic pain show that dual-acting reuptake inhibitors are more active than selective norepinephrine reuptake inhibitors, which are, in turn, more active than SSRIs. A meta-analysis of placebo-controlled studies confirmed that dual-action antidepressants, but not SSRIs, were effective in reducing chronic lower-back pain. Milnacipran, duloxetine, and venlafaxine, have all been reported to be effective in a number of chronic pain conditions, including the treatment of fibromyalgia where their analgesic effects are independent of comorbid depression.

All three serotonin norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of both serotonin and norepinephrine but they do so with differing affinity ratios. Venlafaxine has a 30-fold higher affinity for serotonin than for norepinephrine while duloxetine has a 10-fold selectivity for serotonin. Milnacipran has a balanced (1:1) ratio of potency for inhibition of reuptake of the two neurotransmitters. The most frequent adverse event with SNRIs is nausea. Not unexpectedly, adverse effects related to a noradrenergic stimulation, such as dry mouth, sweating, and constipation, are found more frequently with SNRIs than with selective serotonin reuptake inhibitors. At true SNRI doses, venlafaxine is associated with dose-dependent cardiovascular phenomena (principally increased blood pressure), an effect which is less frequent with duloxetine and rare with milnacipran. Serious and potentially fatal hepatotoxity has been reported with duloxetine. This problem appears to be unique to duloxetine and not a characteristic of the SNRI class. There are differences in overdose toxicity between venlafaxine and the other SNRIs, possibly related to its increased cardiotoxicity.