Given the relative specificity of venlafaxine on serotonin and noradrenergic reuptake, some of the adverse effects that plague the tricyclic antidepressants are not seen with venlafaxine. For example, antimuscarinic effects such as constipation, blurred vision and urinary retention do not appear commonly in treatment with venlafaxine. Likewise, there is no alpha adrenergic blockade to result in orthostatic hypotension. Finally, antihista-minic side effects such as weight gain and prominent sedation are uncommon with venlafaxine treatment.
The relative lack of side effects in comparison to the tricyclics does not mean, however, that patients have no difficulty tolerating the drug. About 18 percent of patients taking venlafaxine in premarketing studies dropped out. While generally well-tolerated, venlafaxine shares many side effects with the selective serotonin reuptake inhibitors, as well as some that could be attributed to its norepinephrine(Drug information on norepinephrine) reuptake.
Among the most common side effects of venlafaxine is nausea. Approximately 37 percent of patients in premarketing studies complained of nausea, and it was by far the most common reason for patients to discontinue the drug. However, as with the SSRIs, patients appear to adapt to 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 include cutting back the venlafaxine dose with more gradual titration upward, taking the drug with food and reassuring the patient that the nausea will subside in time.
Insomnia and somnolence were the second and third most common reasons for patients to discontinue the drug, with each contributing to about 3 percent of patients who discontinued. Approximately 18 percent of patients taking venlafaxine complained of insomnia versus 10 percent of patients taking placebo. The insomnia is typically an initial insomnia, although middle interruptions also occur. As with the SSRIs, the insomnia sometimes responds to shifting the venlafaxine doses to earlier in the day and avoiding bedtime doses.
Somnolence is an even more common side effect than insomnia, with 23 percent complaining of this adverse effect compared to only 9 percent of patients treated with placebo. Adaptation may also occur with somnolence, but patients seem to complain about it for longer periods of time than they do the nausea. Also, somnolence is clearly a dose-related side effect much more evident at higher doses than at lower ones. Therefore, if somnolence becomes a problem, cutting back the dose and allowing time for adaptation will probably help. Shifting the doses to later in the day and closer to bedtime should also be considered.
Venlafaxine shares many other side effects in common with the SSRIs 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 reported with venlafaxine is treatment-emergent hypertension.
Some patients treated with venlafaxine do show sustained increases in blood pressure. The hypertension is probably noradrener-gically mediated and related to dose. Less than 5 percent of patients on doses under 200 mg experience any increase in blood pressure, but 13 percent of patients on doses greater than 300 mg show treatment-emergent hypertension with an increase in diastolic pressure around 7 mm Hg. Despite this increase, very few people discontinue venla-faxine secondary to hypertension. Less than 1 percent of patients in premarketing studies had a significant enough increase in blood pressure to warrant stopping the medication.
Nevertheless, the incidence of treatment-emergent hypertension warrants the monitoring of blood pressure with each visit, particularly in the first two months of therapy. While there are no specific contraindications to treatment with venlafaxine, caution should be exercised with some patients. For example, patients with advanced congestive heart disease and a very low systolic ejection fraction may be sensitive to even small increases in afterload induced by venlafaxine. Such patients need not be excluded from venlafaxine treatment but will require more vigilant monitoring.Potential Drug Interactions
Venlafaxine generally shares the same potential for drug interactions that the SSRIs have. Because of the risk of patients developing potential lethal serotonergic symptoms, venlafaxine should not be used concurrently with a monamine oxidase inhibitor. The manufacturer recommends that venlafaxine be discontinued two weeks before initiating an MAOI. This is comparable to the recommendations for paroxetine(Drug information on paroxetine) (Paxil) and sertraline(Drug information on sertraline) (Zoloft). However, because the half-life of venlafaxine is considerably shorter than that of any of the SSRIs, some investigators feel confident in waiting only one week before starting treatment with an MAOI.
Another difference between the SSRIs and venlafaxine may be their ability to inhibit some hepatic enzymes. The SSRIs, particularly paroxetine and fluoxetine(Drug information on fluoxetine), tend to saturate the IID6 P-450 isoenzyme that is responsible for the metabolism of many drug classes including the tricyclic antidepressants, phenothiazines and carbamazepine(Drug information on carbamazepine) (Tegretol). As a result, the serum levels of these other drugs may rise substantially when used concurrently with most SSRIs. Venlafaxine, on the other hand, seems to be considerably less potent than even sertraline in saturating the IID6 enzyme. Thus, venlafaxine should be less likely to elevate the serum levels of a number of important psychotropic drugs.
However, venlafaxine is metabolized by the P-450 system and drugs such as cimetidine (Tagamet) that inhibit the system will raise venlafaxine serum levels. Thus, lower doses of venlafaxine may be required when used concurrently with these drugs.
There is no known interaction between venlafaxine and such drugs as lithium(Drug information on 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 such as fluoxetine. The short half-life indicates the need for more frequent dosing. Dosing tid generally does not appear to offer advantages over bid dosing. Given the likelihood of greater compliance with bid dosing, it makes sense to generally use this dosing regimen. However, at the highest doses, 300 to 400 mg per day, some patients anecdotally appear to tolerate the tid regimen better. Unlike many of the SSRIs, venlafaxine appears to have a linear dose response curve. Higher doses are associated with more efficacy, as well as more side effects. The data would indicate that most patients will respond to doses in the 75 mg to 225 mg per day range. The most depressed, melancholic inpatients have frequently been treated with doses ranging from 300 mg to 400 mg per day.
Most patients can be started at 37.5 mg bid. There are several exceptions to this regimen, however. One exception is patients with extensive hepatic disease such as cirrhosis. Since venlafaxine is metabolized through the cytochrome P-450 system, patients with severe liver disease should probably be started at half the usual starting dose. Likewise, patients with significantly diminished renal function should also be started and maintained on smaller doses of venlafaxine, since they will clear the drug less efficiently. The manufacturer does not suggest that reduced doses are required for the elderly. However, many geriatric psychiatrists are starting their patients at 25 mg a day; this seems reasonable given the reduced hepatic and renal clearance of elderly patients.
A common approach to titrating the dose upward while allowing for adaptation to side effects is to start at 37.5 mg bid for two weeks and then increase the dose by 75 mg per week until a dose of 225 mg per day is achieved. This dosing schedule appears to be adequate for most outpatients with mild to moderate depression; inpatients and outpatients with more severe depressive episodes may require more rapid titration with doses in the 300 mg to 400 mg range. In premarketing inpatient studies, the dose would sometimes be increased to over 300 mg in just 7 days. The manufacturer, however, advises increasing the dose by no more than 75 mg every four days.
Venlafaxine appears to be a safe and effective medication for the treatment of major depression. It may offer advantages over the SSRIs in that it acts on several monoamine neurotransmitter systems instead of primarily acting on serotonin. There is some enticing but preliminary data on rapid onset of action and utility in more severely depressed as well as refractory patients. Further controlled studies are needed to determine if these findings can be supported. The major disadvantages of venlafaxine at this time are the split dosing, a side-effect profile that appears to be no better than the SSRIs and a general lack of experience with the drug. Time will tell how important venlafaxine is in the rapidly growing antidepressants arsenal.