In the past serendipity and good clinical observation were essential for the discovery of new drug treatments for mental disorders. Today, neurochemical and pharmacological research allows development of compounds starting from hypothesis on the origin of the disorders and the actions of available drugs. The new compounds are cleaner from the pharmacological point of view, more specific and therefore with less undesired effects. Venlafaxine is one of these drugs and provides antidepressant efficacy in a broad range of depressed patients, including the most severe ones, with a good safety and tolerability profile.

When selecting an antidepressant, a number of factors must be considered. These considerations are summarized under the mnemonic STEPS: Safety, Tolerability, Efficacy, Payment (eg, cost-effectiveness), and Simplicity of use. Venlafaxine is the first of a new class of antidepressants that selectively blocks the serotonin and noradrenaline uptake pumps without blocking muscarinic, histaminergic and adrenergic receptors or inhibiting sodium fast channels. Because venlafaxine avoids these mechanisms of action, it has a wide therapeutic index, an improved tolerability profile and a reduced risk of causing pharmacodynamically mediated drug-drug interactions when compared to tricyclic antidepressants (TCAs). In contrast to some other new antidepressants, venlafaxine also avoids effects on cytochrome P450 which are likely to cause clinically meaningful, pharmacokinetically mediated drug-drug interactions. The effects on the uptake pumps of both serotonin and noradrenaline appear to be responsible for some of venlafaxine's unique features in terms of antidepressant efficacy, including its ascending antidepressant dose-response curve and its apparent rapid onset of antidepressant action at the upper end of its clinically relevant dosing range. Venlafaxine is effective in a broad spectrum of patients, including outpatients and inpatients, those with and without melancholia, patients with symptoms of anxiety or agitation or retardation and patients with first time or recurrent episodes of major depression. An important factor when selecting an antidepressant is the simplicity of the dosing regimen and the ability to rapidly and confidently achieve the optimal dose for the patient. In this regard, venlafaxine can be initiated at a clinically effective dose from the beginning. If the patient fails to respond to this dose, there is evidence that increased antidepressant efficacy can be achieved by increasing the dose rather than having to resort to an augmentation strategy or switch to another class of antidepressants. In the immediate release form, venlafaxine has proven antidepressant efficacy when using a twice-or three-times-a-day schedule. A sustained release formulation is expected to be marketed soon and will permit once-a-day-dosing.

The benefits of an antidepressant with an early or rapid onset of action include a more rapid resolution of the debilitating symptoms of depression, a potential reduction in the risk of suicide and cost savings associated with a reduction in hospitalization. While these benefits are valuable, this promise has yet to be fulfilled by any antidepressant. Venlafaxine is a unique serotonin-noradrenaline reuptake inhibitor (SNRI) which produces rapid and prolonged desensitization of β-adrenergic receptors in preclinical studies after both acute and chronic administration of venlafaxine. Results from placebo-controlled and active comparator clinical studies provide evidence that venlafaxine may have an early onset of activity which is most apparent at higher dosages. The early onset is most apparent with rapid escalation of the venlafaxine dosage, and the incidence, therefore, of side effects tends to be higher early after initiating therapy with venlafaxine. Thus, venlafaxine may fill the long awaited need for an antidepressant with an early onset of action.

Venlafaxine is a serotonin-noradrenaline reuptake inhibitor (SNRI) that has no affinity for muscarinic, adrenergic or histaminergic receptors. In short-term trials, the adverse effects that occurred more often with venlafaxine than with placebo included nausea, somnolence, dizziness, dry mouth, and sweating. Rapid titration of the dose of venlafaxine to higher levels appeared, not unexpectedly, to be associated with an increased incidence of side effects. Side effects that appeared to be dose related included insomnia, nausea and sexual dysfunction. The incidence of nausea and dizziness was highest during the first 2 or 3 weeks of therapy and decreased rapidly thereafter. Somnolence also decreased over time. At high doses blood pressure increases were reported in a small percent of patients on venlafaxine and antidepressant drugs but were uncommon at the venlafaxine dose of 75–150 mg daily. Studies with venlafaxine in healthy volunteers indicate a low potential for drug-drug interactions. Overdoses have been reported in 14 of 3,082 patients administered venlafaxine in clinical trials, and no deaths were reported among these patients. Overdoses of venlafaxine induced mainly drowsiness and lethargy.

Venlafaxine is a selective serotonin norepinephrine reuptake inhibitor with no activity at muscarinic, histaminergic or adrenergic receptors. The antidepressant activity of venlafaxine has been demonstrated in placebo-controlled and active comparator-controlled clinical trials. Venlafaxine was effective in outpatients and hospitalized patients with major depression and in those with melancholia, agitated or retarded symptoms, and refractory or treatment-resistant depression. Venlafaxine was at least as effective as comparative antidepressants and was more effective than fluoxetine or imipramine in some trials. A positive dose-response relationship has been shown with venlafaxine. When doses of venlafaxine are titrated rapidly upward, an onset of antidepressant action has been detected within one week in some studies. Venlafaxine is well tolerated during short- and long-term treatment. The most common adverse effects are nausea, somnolence and dry mouth. The overall tolerability of venlafaxine appears to exceed that of tricyclic antidepressants and compares favorably with that of selective serotonin reuptake inhibitors. Venlafaxine is a novel antidepressant that is appropriate for first-line therapy in patients with major depression.