Venlafaxine adverse effects

Cimetidine 800 mg daily for 5 days was found to reduce the oral clearance of venlafaxine 50 mg every 8 hours by 40%, and to increase the AUC by 62% in 18 healthy subjects. It had no effect on the formation or elimination of the major active metabolite of venlafaxine, O-desmethylvenla-faxine (ODV). The total level of venlafaxine with ODV was found to be increased by only 13%. Thus the overall pharmacological activity of the two was only slightly increased by cimetidine and no special precautions would seem to be necessary on concurrent use. However, the manufacturers of venlafaxine suggest that the elderly and those with hepatic impairment may possibly show a more pronounced effect, and such patients should be monitored more closely, for venlafaxine adverse effects. 

A number of non-hormonal therapies have been studied for symptomatic management of vasomotor symptoms, including antidepressants [e.g., selective serotonin reuptake inhibitors (SSRIs) and venlafaxine], herbal products (e.g., soy, black cohosh, and dong quai), and a group of miscellaneous agents (e.g., gabapentin, clonidine, and megestrol). The choice of therapy depends on the patient s concomitant disease states, such as depression and hypertension, and the risk for potential adverse effects. 

Pregabalin produced anxiolytic effects similar to lorazepam, alprazolam, and venlafaxine in acute trials. Sedation and dizziness were the most common adverse effects, and the dose should be tapered over 1 week upon discontinuation. 

Venlafaxine is generally well tolerated. The most common adverse effects include nausea, drowsiness, insomnia, dizziness, headache, and dry mouth. At higher doses, elevations in blood pressure have been observed. 

Perhaps a more benign adverse effect profile, particularly with regard to activation and sexual dysfunction, in contrast to the SSRIs and venlafaxine... 

Bupropion appears to be relatively free of adverse effects on sexual function, in contrast to the SSRIS or venlafaxine (168). 

Patients with cardiovascular disorders or those predisposed to anticholinergic adverse effects (e.g., elderly or diabetic patients) probably do best on drugs low in these effects (e.g., an SSRI, venlafaxine, or bupropion). 

The biotransformation of venlafaxine to its active metabolite, ODV, is dependent on CYP 2D6 (138, 306). The further elimination of ODV is dependent on CYP 3A3/4. Venlafaxine and ODV have approximate half-lives of 5 and 11 hours, respectively. Because venlafaxine and ODV have virtually identical pharmacological profiles, both are believed to contribute equally to the patient s overall response in terms of both efficacy and adverse effects ( 141). The 11-hour half-life of ODV is consistent with the fact that the immediate release formulation of venlafaxine is efficacious when administered twice daily. 

SSRIs and venlafaxine can cause of variety of sexual dysfunctions including delayed ejaculation, anorgasmia, and decreased libido ( Table 7-24). For two reasons, the adverse effect of these medications on sexual function was underestimated during the early clinical trials. First, such trials rely on spontaneous reporting by participants. Second, these adverse effects appear to take several weeks to develop. These adverse effects develop in approximately 30% to 40% of patients on adequate doses of SSRIs and venlafaxine. Although all manufacturers of these medications endeavor to suggest that their product is less likely to cause these effects, there is no compelling evidence to indicate that is true. Comparisons of rates across studies are not fair comparisons because they may differ based on how these problems were assessed. 

TABLE 7-25. Comparison of the placebo-adjusted incidence rate (%) of frequent adverse effects for fluoxetine, sertraline, paroxetine, venlafaxine, and nefazodone... 

TABLE 7-26. Placebo-adjusted, dose-dependent adverse effects of paroxetine, venlafaxine, and nefazodone (mg/d)... 

In contrast to decreased libido seen with SSRIs and venlafaxine, concerns about priapism invariably arise when trazodone is discussed. This adverse effect is rare, occurring in only 1 of 6,000 treated male patients (456, 457). If the patient is informed of this possibility and discontinues the drug promptly, priapism usually resolves without further intervention. Although earlier persistent cases were treated surgically, this approach carries a 50% chance of permanent impotence pharmacological intervention via direct injections into the cavernous bulbosa is preferable ( 458, 459). Using this approach, the chance of permanent impotence is low and depends on the duration of symptoms before treatment (460). This latter fact is another reason to fully inform the male patient on trazodone, so that early detection and intervention can be implemented. 

These adverse effects bear some similarity to those of the SSRIs. Although these adverse effects rarely require discontinuation, aggravation of psychosis and seizures caused by this agent do (427, 462, 463 and 464). In contrast to the SSRIs and venlafaxine, bupropion usually does not cause sexual dysfunction. As such, bupropion may be an alternative for patients bothered by these adverse effects (465). Bupropion may also be a useful antidote for SSRI-induced sexual dysfunction (4 53, 455, 466, 467). 

Venlafaxine is converted by CYP 2D6 to ODV, which is subsequently cleared by CYP 3A3/4 ( 501). ODV has virtually the same in vitro pharmacology as venlafaxine. Thus, the total of venlafaxine plus ODV is believed to be the relevant concentration determining clinical effect ( 137). Theoretically, venlafaxine should be relatively impervious to even substantial CYP 2D6 inhibition because ODV levels would decrease proportionate to the increase in venlafaxine levels such that the total level would remain the same. In contrast, the inhibition of CYP 3A3/4 would be potentially more clinically relevant because it should decrease ODV clearance and thus increase total levels. Nevertheless, such an interaction would not be expected to do more than increase the usual dose-dependent adverse effects of venlafaxine because of its wide therapeutic index. 

The adverse effects of SSRIs, venlafaxine, and nefazodone in children and adolescents are comparable with those in adults (see Chapter 7) and have been documented in both clinical trials and practice ( 35, 36, 119, 120 and 121 123). As in adults, isolated case reports have described behavioral activation in children and adolescents given SSRIs (133, 134). The significance of such reports in terms of a causal link to the drug is difficult because of their rare and anecdotal nature and because the patients are at increased risk for such behavioral disturbances relative to the general population as a result of their underlying psychiatric disorder. 

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture. 

SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in most patients. A dose-related increase in blood pressure has been seen more commonly with the immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation. 

Venlafaxine is a potent inhibitor of serotonin reuptake and a weaker inhibitor of norepinephrine transport such that at lower therapeutic doses it behaves like an SSRI. At high doses (more than 225 mg/d) it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine reuptake inhibition. Doses in the range of 300 mg/d or greater may confer broader therapeutic effects than SSRIs, but a careful titration up to these doses is needed to control adverse effects. 

There have been other reports of hyponatremia with SSRIs (38,39). Hyponatremia is probably more common with SSRIs than with tricyclic antidepressants and predominantly but not exclusively affects older patients. Most reports involve fluoxetine, but this might represent greater patient exposure. All SSRIs and venlafaxine can produce this adverse effect (SEDA-23,21 SEDA-25,14). According to published reports, the median time to the onset of hyponatremia is 13 days (range 3-120) and the presentation is of inappropriate secretion of antidiuretic hormone (38). Symptoms, such as lethargy and confusion, can be non-specific, so awareness of the possibility of SSRI-induced hyponatremia, particularly in elderly people, is needed. 

Venlafaxine Bicyclic cyclohexanol Serotonin and noradrenaline uptake inhibitor Nausea, sexual dysfunction, and cardiovascular adverse effects... 

Duloxetine has recently been marketed as an antidepressant in Europe. It inhibits the re-uptake of serotonin and noradrenaline, with minimal effects on other neurotransmitter mechanisms. It is therefore classified as a serotonin and noradrenaline re-uptake inhibitor (SNRI) and is grouped with venlafaxine. The adverse effect profile of duloxetine appears to be similar to that of the SSRIs and venlafaxine. In placebo-controlled trials the most common adverse effects were nausea (37%), dry mouth (32%), dizziness (22%), somnolence (20%), insomnia (20%), and diarrhea (14%). Sexual dysfunction has also been reported. Current data suggest that, unlike venlafaxine, duloxetine does not increase the blood pressure, but further post-marketing surveillance studies will be needed to confirm this (1). 

Raised liver enzymes have been rarely found in patients taking venlafaxine, and it appears that hepatitis may also be rare adverse effect (21). 

Psychodynamic supportive psychotherapy (n = 107) has been compared with psychotherapy plus medication (n = 101) in patients with major depressive disorder (93). The medications included venlafaxine, selective serotonin reuptake inhibitors, nortriptyline, and nortriptyline plus lithium. Lithium was used as an augmentation strategy in the patients who took lithium and nortriptyline (number not given). There were no differences in outcomes between the two treatment groups. No adverse effects specific to lithium were reported. 

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