Venlafaxine (Effexor) is a novel antidepressant recently released to the American market. Its entry into the antidepressant market has been much heralded. The lay press has described the drug as "Prozac with a punch," and many patients were asking for it long before it was available. As the hoopla settles down, we are learning that venlafaxine is a potentially important drug with both advantages and disadvantages over other available antidepressants, including the selective serotonin reuptake inhibitors (SSRIs).Pharmacology
Venlafaxine is a phenylethylamine antidepressant that, unlike the SSRIs, strongly inhibits the reuptake of both serotonin and norepinephrine(Drug information on norepinephrine). At high doses (>375 mg per day), it also appears to impact the reuptake of dopamine(Drug information on dopamine) and this may be clinically significant in the treatment of depression. Venlafaxine's mechanism of action perhaps most closely resembles that of the tricyclics that also interfere with the reuptake of monamine neurotransmitters. However, unlike the tricyclics, venlafaxine has no significant affinity for muscarinic, alpha adrenergic or histaminergic receptors.
In addition to the monamine selectivity of venlafaxine, two other pharmacological parameters may distinguish venlafaxine from most other antidepressants. The first is that venlafaxine is rather weakly bound to protein. While the tricyclics and SSRIs tend to be highly bound to serum and tissue protein at levels of 85 percent or more, venlafaxine is only about 30 percent bound to albumin. As a result, venlafaxine is less likely to be displaced by other tightly protein-bound drugs such as oral contraceptives and phenytoin(Drug information on phenytoin) (Dilantin).
Another distinguishing pharmacological parameter of venlafaxine is that it appears to cause the rapid down-regulation of the beta adrenergic-linked cAMP system. Isoprotere-nol (Isaprel) typically induces an increase in cyclic adenosine(Drug information on adenosine) monophosphate (cAMP) in control animals, and chronic administration with antidepressants tends to inhibit cAMP production. The decreased sensitivity of the beta adrenergic system appears to be associated with onset of clinical antidepressant effects. At this time, venlafaxine is the only antidepressant known to produce this down-regulation of beta adrenergic-linked cAMP production in the rat pineal after a single dose. The clinical significance of this finding, if replicated, may be that venlafaxine would be expected to have an earlier onset of action. In fact, a number of premarketing controlled studies have suggested that venlafaxine may have significant antidepressant effects in the first two weeks of treatment (Schweizer and coworkers 1991; Khan 1991, Guelfi and coworkers 1992; Mendels and colleagues 1993). However, several antidepressants have looked promising as more rapidly acting agents in the premarketing literature only to be disappointing when further studied. At present it is unclear whether venlafaxine will distinguish itself as an antidepressant that truly acts more rapidly or whether it will follow suit with other antidepressants that have made this claim.Efficacy in Major Depression
The efficacy of venlafaxine in the treatment of major depression has been established by a number of placebo-controlled studies.
In a study by Schweizer and colleagues (1991), 90 percent of 224 outpatients treated with venlafaxine for major depression showed moderate to marked improvement with venlafaxine treatment compared to 79 percent of patients taking imipramine (Tofranil) and 53 percent of patients on placebo. Endpoint analysis suggested that only venlafaxine was statistically superior to placebo because of the higher attrition rate of the imipramine(Drug information on imipramine)-treated group (25 percent versus 16 percent in the venlafaxine-treated group). In an earlier six-week study, Schweizer and colleagues (1989) compared venlafaxine and placebo in 44 outpatients with major depression. They found that venlafaxine at doses up to 375 mg per day was more than twice as likely to induce a marked improvement in depressive symptoms than placebo. Cunningham and colleagues (1994) found that treatment with venlafaxine for six weeks in 225 patients with major depression resulted in more significant improvement in the venlafaxine-treated group (72 percent) than either trazodone (Desyrel) (60 percent) or placebo-treated groups. Venlafaxine also produced more improvement in the retardation and cognitive disturbance scales of the Hamilton Depression Rating Scale. Mendels and colleagues studied 312 depressed outpatients on doses ranging from 25 to 200 mg per day and found that the higher-dose group had a significantly better response rate on venlafaxine than placebo and that the lower-dose groups did not show a robust antidepressant effect. Finally, Khan demonstrated that venlafaxine was significantly better than placebo at doses ranging from 75 mg per day to 375 mg per day in 93 depressed outpatients treated for six weeks. Inpatients with more severe depressive episodes represent an important target population for antidepressant therapy. Thus far, two studies have suggested venlafaxine may be useful in severely depressed inpatients with melancholia. Guelfi and associates found venlafaxine, rapidly titrated up to the maximum dose of 375 mg per day, was superior to placebo in this population within the first week of treatment. In a more recently published study, Clerc and colleagues (1994) found venlafaxine superior to fluoxetine(Drug information on fluoxetine) in the treatment of 68 melancholic inpatients at four and six weeks. However, this was not a placebo-controlled study, and the data must be considered preliminary.
Maintenance protocols have demonstrated the expected finding that venlafaxine is also effective in preventing relapse in patients with recurrent depression. Entsuah and colleagues (1993) reported on 396 patients who responded to acute treatment with an antidepressant and were maintained on either placebo, imipramine, trazodone or venlafaxine for one year. Venlafaxine was superior to placebo and at least as effective as the other active compounds in preventing relapse of depression at six and 12 months.
Another possible indication for venlafaxine is in the treatment of refractory depression. Given its effect on both serotonin and norepinephrine, venlafaxine may be a reasonable option for treating patients who have not responded to other treatments. Nierenberg and colleagues (1993) studied venlafaxine in patients who had not responded to either three adequate antidepressant trials of different classes or two trials and one course of electroconvulsive therapy (ECT). In addition, patients also were required to have failed at least one attempt at augmentation. Of 82 patients who met criteria for major depression, about one-third of these refractory patients were judged to be full responders to venlafaxine treatment (Hamilton Depression Rating Scale score < 8). Approximately 80 percent of these responders maintained their improvement for at least six months. This was an open-label study, however, and double-blind studies are needed to confirm the findings.