At what concentration could venlafaxine (Efexor) be expected to have noradrenergic effects? It is s

Fråga: At what concentration could venlafaxine (Efexor) be expected to have noradrenergic effects? It is sometimes discussed that high doses of venlafaxine (300 mg/d) are required, is this true? What is the rationale behind the recommendation to maintain a dose of 375 mg daily for a maximum of four weeks? The patient is a somatically healthy woman suffering from relapsing depression. Treatment with venlafaxine has been partly successful but the prescribing doctor wishes to increase the dose to the highest recommended dose. If this works, why should the dose be reduced after four weeks? The patient has no other medications.

Sammanfattning: The noradrenergic effect of venlafaxine has been demonstrated in doses above 1.0 mg/kg in one study, in another study venlafaxine 150 mg/d has been shown to potentiate the venoconstrictor response to noradrenaline. It should be noted that there is a great variability in the metabolism of venlafaxine and thus plasma levels are of more concern than the dose given. If the blood pressure and plasma concentration are monitored and remain within normal limits a daily dose of 375 mg venlafaxine could be used for more than four weeks. However, the dose required to achieve effect is not necessarily the dose required to maintain the same.

Svar: Venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) inhibit reuptake of both serotonin and noradrenaline and exert a weak inhibition on dopaminergic uptake (1). Its pharmacological profile is thus that of a serotonin and noradrenergic reuptake inhibitor (SNRI) and is supposed to be different from both tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRI). Venlafaxine lacks anticholinergic, antiadrenergic, and antihistaminergic effects (2). The formation of ODV is catalyzed by CYP2D6, an iso-enzyme of the cytochrome P450 family (1). This enzyme is polymorphic and approximately seven percent of white Caucasians are poor metabolizers (3). To ensure that the given drug results in the anticipated plasma concentration therapeutic drug monitoring can be of value.

The notion that only very high doses of venlafaxine would yield noradrenergic effects is probably based on a paper by Harvey and co authors (4). In this study two different doses were investigated, 75 mg and 375 mg/d. It was shown that platelet serotonin uptake was inhibited by venlafaxine at both doses (4). Inhibition was competitive and related to increases in affinity (4). The platelet noradrenalin uptake was inhibited in the high dose group (4). This was showed indirectly through a blunted pressor response to tyramine in the high dose group (4). No other doses were investigated. In another study it has been shown that venlafaxine at a dose of 150 mg/d potentiates the venoconstrictor response to noradrenaline (2). In yet another study, also in healthy volunteers, the noradrenergic effect of venlafaxine was demonstrated at doses above 1.0 mg/kg (5).

It has been suggested that drugs with dual-action, ie SNRI have a more rapid onset of action than that of other available antidepressants (6). Moreover, it has been shown in a placebo-controlled study from the manufacturer that between 20 and 27% of the patients in a study responded to venlafaxine treatment (> 200mg/d) within the first two weeks (7). However, no increase in efficacy could be demonstrated (8).

The rationale to recommend that a dose of 375 mg/d should not be used for a longer duration of four weeks is probably based on the fact that most of the clinical trials ran for four weeks (9). There is a known risk of increased blood pressure when doses over 200 mg are used, especially in older patients (10). If plasma levels of the drug as well as blood pressure are monitored there is no evidence that a dose of 375 mg/d for more than four weeks is accompanied by an increased risk for severe adverse effects. In the American Physicians Desk Reference no such warning is present (11). The manufacturer recommends that if 375 mg/d works well that dose should be continued even after four weeks (9). However, the dose required to achieve effect is not necessarily the dose required to maintain the same.