Venlafaxine (Effexor) is a novel antidepressant recently released to the American market. Its entry into the antidepressant market has been much heralded. The laypress has described the drug as "Prozacwith a punch," and many patients were asking for it longbefore it was available. As the hoopla settles down, we are learningthat venlafaxine is a potentially importantdrug with both advantages and disadvantages over other availableantidepressants, including the selectiveserotonin reuptake inhibitors (SSRIs).

Pharmacology

Venlafaxine is a phenylethylamine antidepressant that, unlikethe SSRIs, strongly inhibits the reuptake of both serotonin andnorepinephrine. At high doses (>375 mg per day), it also appearsto impact the reuptake of dopamine and this may be clinicallysignificant in the treatment of depression. Venlafaxine's mechanismof action perhaps most closely resembles that of the tricyclicsthat also interfere with the reuptake of monamine neurotransmitters.However, unlike the tricyclics, venlafaxine has no significantaffinity for muscarinic, alpha adrenergic or histaminergic receptors.

In addition to the monamine selectivity of venlafaxine, two otherpharmacological parameters may distinguish venlafaxine from mostother antidepressants. The first is that venlafaxine is ratherweakly bound to protein. While the tricyclics and SSRIs tend tobe highly bound to serum and tissue protein at levels of 85 percentor more, venlafaxine is only about 30 percent bound to albumin.As a result, venlafaxine is less likely to be displaced by othertightly protein-bound drugs such as oral contraceptives and phenytoin(Dilantin).

Another distinguishing pharmacological parameter of venlafaxineis that it appears to cause the rapid down-regulation of the betaadrenergic-linked cAMP system. Isoprotere-nol (Isaprel) typicallyinduces an increase in cyclic adenosine monophosphate (cAMP) incontrol animals, and chronic administration with antidepressantstends to inhibit cAMP production. The decreased sensitivity ofthe beta adrenergic system appears to be associated with onsetof clinical antidepressant effects. At this time, venlafaxineis the only antidepressant known to produce this down-regulationof beta adrenergic-linked cAMP production in the rat pineal aftera single dose. The clinical significance of this finding, if replicated,may be that venlafaxine would be expected to have an earlier onsetof action. In fact, a number of premarketing controlled studieshave suggested that venlafaxine may have significant antidepressanteffects in the first two weeks of treatment (Schweizer and coworkers1991; Khan 1991, Guelfi and coworkers 1992; Mendels and colleagues1993). However, several antidepressants have looked promisingas more rapidly acting agents in the premarketing literature onlyto be disappointing when further studied. At present it is unclearwhether venlafaxine will distinguish itself as an antidepressantthat truly acts more rapidly or whether it will follow suit withother antidepressants that have made this claim.

Efficacy in Major Depression

The efficacy of venlafaxine in the treatment of major depressionhas 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 majordepression showed moderate to marked improvement with venlafaxinetreatment compared to 79 percent of patients taking imipramine(Tofranil) and 53 percent of patients on placebo. Endpoint analysissuggested that only venlafaxine was statistically superior toplacebo because of the higher attrition rate of the imipramine-treatedgroup (25 percent versus 16 percent in the venlafaxine-treatedgroup). In an earlier six-week study, Schweizer and colleagues(1989) compared venlafaxine and placebo in 44 outpatients withmajor depression. They found that venlafaxine at doses up to 375mg per day was more than twice as likely to induce a marked improvementin depressive symptoms than placebo. Cunninghamand colleagues (1994) found that treatment with venlafaxine forsix weeks in 225 patients with major depression resulted in moresignificant improvement in the venlafaxine-treated group (72 percent)than either trazodone (Desyrel) (60 percent)or placebo-treated groups. Venlafaxine also produced more improvementin the retardation and cognitive disturbance scales of the HamiltonDepression Rating Scale. Mendels and colleaguesstudied 312 depressed outpatients on doses ranging from 25 to200 mg per day and found that the higher-dose group had a significantlybetter response rate on venlafaxine than placebo and that thelower-dose groups did not show a robust antidepressant effect.Finally, Khan demonstrated that venlafaxine was significantlybetter than placebo at doses ranging from 75 mg per day to 375mg per day in 93 depressed outpatients treated for six weeks.Inpatients with more severe depressive episodes represent an importanttarget population for antidepressant therapy. Thus far, two studieshave suggested venlafaxine may be useful in severely depressedinpatients with melancholia. Guelfi and associatesfound venlafaxine, rapidly titrated up to the maximum dose of375 mg per day, was superior to placebo in this population withinthe first week of treatment. In a more recently published study,Clerc and colleagues (1994) found venlafaxine superior to fluoxetinein the treatment of 68 melancholic inpatients at four and sixweeks. However, this was not a placebo-controlled study, and thedata must be considered preliminary.

Maintenance protocols have demonstrated the expected finding thatvenlafaxine is also effective in preventing relapse in patientswith recurrent depression. Entsuahand colleagues (1993) reported on 396 patients who responded toacute treatment with an antidepressant and were maintained oneither placebo, imipramine, trazodone or venlafaxine for one year.Venlafaxine was superior to placebo and at least as effectiveas the other active compounds in preventing relapse of depressionat six and 12 months.

Another possible indication for venlafaxine is in the treatmentof refractory depression. Givenits effect on both serotonin and norepinephrine, venlafaxine maybe a reasonable option for treating patients who have not respondedto other treatments. Nierenberg and colleagues(1993) studied venlafaxine in patients who had not responded toeither three adequate antidepressant trials of different classesor two trials and one course of electroconvulsive therapy (ECT).In addition, patients also were required to have failed at leastone attempt at augmentation. Of 82 patients who met criteria formajor depression, about one-third of these refractory patientswere judged to be full responders to venlafaxine treatment (HamiltonDepression Rating Scale score < 8). Approximately 80 percentof these responders maintained their improvement for at leastsix months. This was an open-label study, however, and double-blindstudies are needed to confirm the findings.

Managing Side Effects

Given the relative specificity of venlafaxine on serotonin andnoradrenergic reuptake, some of the adverse effects that plaguethe tricyclic antidepressants are not seen with venlafaxine. Forexample, antimuscarinic effects such as constipation, blurredvision and urinary retention do not appear commonly in treatmentwith venlafaxine. Likewise, there is no alpha adrenergic blockadeto result in orthostatic hypotension. Finally, antihista-minicside effects such as weight gain and prominent sedation are uncommonwith venlafaxine treatment.

The relative lack of side effects in comparison to the tricyclicsdoes not mean, however, that patients have no difficulty toleratingthe drug. About 18 percent of patients taking venlafaxine in premarketingstudies dropped out. While generally well-tolerated, venlafaxineshares many side effects with the selective serotonin reuptakeinhibitors, as well as some that could be attributed to its norepinephrinereuptake.

Among the most common side effects of venlafaxine is nausea. Approximately37 percent of patients in premarketing studies complained of nausea,and it was by far the most common reason for patients to discontinuethe drug. However, as with the SSRIs, patients appear to adaptto this side effect in time. By about the fifth week of treatment,nausea complaints are no more evident on venlafaxine than on placebo.Thus, strategies for dealing with treatment-emergent nausea includecutting back the venlafaxine dose with more gradual titrationupward, taking the drug with food and reassuring the patient thatthe nausea will subside in time.

Insomnia and somnolence were the second and third most commonreasons for patients to discontinue the drug, with each contributingto about 3 percent of patients who discontinued. Approximately18 percent of patients taking venlafaxine complained of insomniaversus 10 percent of patients taking placebo. The insomnia istypically an initial insomnia, although middle interruptions alsooccur. As with the SSRIs, the insomnia sometimes responds to shiftingthe venlafaxine doses to earlier in the day and avoiding bedtimedoses.

Somnolence is an even more common side effect than insomnia, with23 percent complaining of this adverse effect compared to only9 percent of patients treated with placebo. Adaptation may alsooccur with somnolence, but patients seem to complain about itfor longer periods of time than they do the nausea. Also, somnolenceis clearly a dose-related side effect much more evident at higherdoses than at lower ones. Therefore, if somnolence becomes a problem,cutting back the dose and allowing time for adaptation will probablyhelp. Shifting the doses to later in the day and closer to bedtimeshould also be considered.

Venlafaxine shares many other side effects in common with theSSRIs including headaches, sexual dysfunction, agitation and perspiration.These side effects appear at about the same rate as existing SSRIs.One adverse effect not typically seen with the SSRIs but reportedwith venlafaxine is treatment-emergent hypertension.

Some patients treated with venlafaxine do show sustained increasesin blood pressure. The hypertension is probably noradrener-gicallymediated and related to dose. Less than 5 percent of patientson doses under 200 mg experience any increase in blood pressure,but 13 percent of patients on doses greater than 300 mg show treatment-emergenthypertension with an increase in diastolic pressure around 7 mmHg. Despite this increase, very few people discontinue venla-faxinesecondary to hypertension. Less than 1 percent of patients inpremarketing studies had a significant enough increase in bloodpressure to warrant stopping the medication.

Nevertheless, the incidence of treatment-emergent hypertensionwarrants the monitoring of blood pressure with each visit, particularlyin the first two months of therapy. While there are no specificcontraindications to treatment with venlafaxine, caution shouldbe exercised with some patients. For example, patients with advancedcongestive heart disease and a very low systolic ejection fractionmay be sensitive to even small increases in afterload inducedby venlafaxine. Such patients need not be excluded from venlafaxinetreatment but will require more vigilant monitoring.

Potential Drug Interactions

Venlafaxine generally shares the same potential for drug interactionsthat the SSRIs have. Because of the risk of patients developingpotential lethal serotonergic symptoms, venlafaxine should notbe used concurrently with a monamineoxidase inhibitor. The manufacturer recommends that venlafaxinebe discontinued two weeks before initiating an MAOI. This is comparableto the recommendations for paroxetine (Paxil) and sertraline (Zoloft).However, because the half-life of venlafaxine is considerablyshorter than that of any of the SSRIs, some investigators feelconfident in waiting only one week before starting treatment withan MAOI.

Another difference between the SSRIs and venlafaxine may be theirability to inhibit some hepatic enzymes. The SSRIs, particularlyparoxetine and fluoxetine, tend to saturate the IID6P-450 isoenzyme that is responsible for the metabolism of manydrug classes including the tricyclic antidepressants, phenothiazinesand carbamazepine (Tegretol). As a result, the serum levels ofthese other drugs may rise substantially when used concurrentlywith most SSRIs. Venlafaxine, on the other hand, seems to be considerablyless potent than even sertraline in saturating the IID6 enzyme.Thus, venlafaxine should be less likely to elevate the serum levelsof a number of important psychotropic drugs.

However, venlafaxine is metabolized by the P-450 system and drugssuch as cimetidine (Tagamet) that inhibit thesystem will raise venlafaxine serum levels. Thus, lower dosesof venlafaxine may be required when used concurrently with thesedrugs.

There is no known interaction between venlafaxine and such drugsas lithium, ethanol or the benzodiazepines.

Dosing

The half-life of venlafaxine (four hours) and its active metabolite(11 hours) is fairly short relative to some antidepressants suchas fluoxetine. The short half-life indicates the need for morefrequent dosing. Dosing tid generally does not appear to offeradvantages over bid dosing. Given the likelihood of greater compliancewith bid dosing, it makes sense to generally use this dosing regimen.However, at the highest doses, 300 to 400 mg per day, some patientsanecdotally appear to tolerate the tid regimen better. Unlikemany of the SSRIs, venlafaxine appears to have a linear dose responsecurve. Higher doses are associated with more efficacy, as wellas more side effects. The data would indicate that most patientswill respond to doses in the 75 mg to 225 mg per day range. Themost depressed, melancholic inpatients have frequently been treatedwith doses ranging from 300 mg to 400 mg per day.

Most patients can be started at 37.5 mg bid. There are severalexceptions to this regimen, however. One exception is patientswith extensive hepatic disease such as cirrhosis. Since venlafaxineis metabolized through the cytochrome P-450 system, patients withsevere liver disease should probably be started at half the usualstarting dose. Likewise, patients with significantly diminishedrenal function should also be started and maintained on smallerdoses of venlafaxine, since they will clear the drug less efficiently.The manufacturer does not suggest that reduced doses are requiredfor the elderly. However, many geriatric psychiatrists are startingtheir patients at 25 mg a day; this seems reasonable given thereduced hepatic and renal clearance of elderly patients.

A common approach to titrating the dose upward while allowingfor adaptation to side effects is to start at 37.5 mg bid fortwo weeks and then increase the dose by 75 mg per week until adose of 225 mg per day is achieved. This dosing schedule appearsto be adequate for most outpatients with mild to moderate depression;inpatients and outpatients with more severe depressive episodesmay require more rapid titration with doses in the 300 mg to 400mg range. In premarketing inpatient studies, the dose would sometimesbe increased to over 300 mg in just 7 days. The manufacturer,however, advises increasing the dose by no more than 75 mg everyfour days.

Venlafaxine appears to be a safe and effective medication forthe treatment of major depression. It may offer advantages overthe SSRIs in that it acts on several monoamine neurotransmittersystems instead of primarily acting on serotonin. There is someenticing but preliminary data on rapid onset of action and utilityin more severely depressed as well as refractory patients. Furthercontrolled studies are needed to determine if these findings canbe supported. The major disadvantages of venlafaxine at this timeare the split dosing, a side-effect profile that appears to beno better than the SSRIs and a general lack of experience withthe drug. Time will tell how important venlafaxine is in the rapidlygrowing antidepressants arsenal.

References:

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1. Venlafaxine would best fit into which one of the following classes of antidepressants?
a. Selective serotonin reuptake inhibitors
b. Tricyclic antidepressants
c. Selective serotonin norepinephrine reuptake inhibitors
d. Monoamine oxidase inhibitors
2. Potentially important pharmocological features of venlafaxine include:
a. Rapid down-regulation of beta-adrenergically linked cAMP
b. Low protein binding
c. Short half-life
d. All of the above
3. Serious interactions may occur when venlafaxine is used concurrently with
a. Monoamine oxidase inhibitors
b. Lithium
c. Alcohol
d. None of the above
4. The most common side effects of venlafaxine treatment are
a. Nausea, insomnia, and somnolence
b. Constipation, blurred vision and dry mouth
c. Sexual dysfunction and orthostasis
d. Asthenia, urinary frequency and hypertension
5. There is preliminary data on the utility of venlafaxine in all the following depressed populations except:
a. Patients with refractory depression
b. Outpatients with major depression
c. Inpatients with melancholic depression
d. Inpatients with atypical depression