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Michael E. Thase, Diane M. Sloan: Chapter 22. Venlafaxine and Desvenlafaxine, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition.

Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.427499. Printed

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Chapter 22. Venlafaxine and Desvenlafaxine

HISTORY AND DISCOVERY

The drug known as venlafaxine was first synthesized in the early 1980s and was found to block the uptake of serotonin (5-HT) and, with

lower potency, norepinephrine (NE), in rat brain synaptosomal preparations (Muth et al. 1986). Subsequently, it was shown to have in vivo

activity in animal models of depression and to have little affinity for muscarinic or histaminergic postsynaptic receptors (Bolden-Watson

and Richelson 1993; Muth et al. 1986). As such, venlafaxine was predicted to have a better tolerability profile than the tricyclic

antidepressants (TCAs). Several early randomized, controlled trials (RCTs) confirmed that venlafaxine had antidepressant effects

comparable to those of TCAs, with fewer side effects attributable to anticholinergic and antihistaminergic activity (see, for example, T. R.

Einarson et al. 1999). The initial formulation of venlafaxine—now known as venlafaxine immediate-release (IR)—was approved by the U.S.

Food and Drug Administration (FDA) for treatment of depression in 1994. An extended-release (XR) formulation was introduced a little

more than 3 years later. Generic formulations of venlafaxine IR began to be introduced in 2007.

O-desmethylvenlafaxine (ODV), or simply desvenlafaxine, the primary active metabolite of venlafaxine, was introduced in 2008 as

desvenlafaxine succinate, a sustained-release formulation for treatment of depression. Like venlafaxine, desvenlafaxine is classified as a

serotonin–norepinephrine reuptake inhibitor (SNRI) and has minimal effects on other neurotransmitter receptors. Desvenlafaxine was

developed in the hope of improving on the strengths of the parent drug. In vitro studies indicate that desvenlafaxine is somewhat more

potent for blockade of norepinephrine transporters than the parent drug; the succinate salt was chosen to enhance bioavailability (Deecher

et al. 2006). To date, desvenlafaxine’s efficacy has been established in a series of placebo-controlled RCTs of major depressive disorder

(MDD).

STRUCTURE–ACTIVITY RELATIONS

Venlafaxine and desvenlafaxine are bicyclic phenylethylamine compounds and are structurally and chemically unrelated to all other

available antidepressants and anxiolytics, including other antidepressants classified as SNRIs (Figure 22–1).

FIGURE 22–1. Chemical structure of venlafaxine hydrochloride.

PHARMACOLOGICAL PROFILE

As noted above, venlafaxine and desvenlafaxine inhibit the neuronal reuptake of 5-HT and NE in in vitro and ex vivo experimental paradigms

(Bolden-Watson and Richelson 1993; Muth et al. 1986; Owens et al. 1997). Venlafaxine and desvenlafaxine do not inhibit the enzyme

monoamine oxidase and have little or no in vitro affinity for muscarinic, cholinergic, histaminergic H1, and -adrenergic receptors

(Bolden-Watson and Richelson 1993; Muth et al. 1986).

PHARMACOKINETICS AND DISPOSITION

After oral administration, venlafaxine and desvenlafaxine are well absorbed from the gastrointestinal tract and undergo extensive first-pass

metabolism in the liver. Given that ODV is the only major metabolite of venlafaxine with relevant activity, desvenlafaxine has no active

metabolites. Coadministration with food decreases the rate but not the extent of absorption (Troy et al. 1997b). Peak plasma

concentrations are achieved within 2 hours for venlafaxine and within 3 hours for ODV following ingestion of the IR formulation (Troy et al.

1995b). Venlafaxine XR is absorbed more slowly than the IR formulation (peak plasma concentrations are achieved within 5.5 hours for

venlafaxine and within 9 hours for ODV), resulting in lower peak and higher trough plasma concentrations. The extent of absorption and

bioavailability of the two formulations of venlafaxine is comparable (Troy et al. 1997a). Steady-state plasma concentrations of both the

parent drug and ODV are reached within 3–4 days of therapy.

Venlafaxine exhibits linear kinetics over a dosage range of 75–450 mg/day (Klamerus et al. 1992). The same is true for ODV across a range

of 50–400 mg/day. Renal elimination is the primary route of excretion for both venlafaxine and ODV (S. R. Howell et al. 1993). Clearance of

ODV (half-life = 10 hours) is slower than that of venlafaxine (half-life = 4 hours); therefore, most patients treated with venlafaxine have

higher steady-state plasma concentrations of ODV than of the parent drug (Klamerus et al. 1992). Both venlafaxine and ODV are minimally

bound to plasma albumin at therapeutic concentrations (27% and 30%, respectively).

The recommended starting dosage of venlafaxine is 75 mg/day (either divided into two or three doses of the IR or once-daily dosing of the

XR formulation) for most therapeutic indications; a lower starting dosage may be used when treating the elderly or patients with a history

of tolerability problems. The IR formulation is available in 25-, 37.5-, 50-, 75-, 100-, and 150-mg tablets. The XR formulation is available in

37.5-, 75-, and 150-mg capsules; attempts to develop a larger dosage strength failed because some people found that the size of capsule

was too large to easily swallow. Once-daily dosing with the XR formulation achieves bioavailability (i.e., >90%) nearly equivalent to that of

twice-daily dosing with the IR formulation (Troy et al. 1997a). The XR formulation may be taken in either the morning or evening, and

bioavailability is not affected by coadministration with food (Troy et al. 1997a).

The recommended starting dose of desvenlafaxine is 50 mg/day. A larger (100-mg) capsule is also available.Print: Chapter 22. Venlafaxine and Desvenlafaxine http://www.psychiatryonline.com/popup.aspx?aID=427503&print=yes…

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The results of fixed-dose studies of venlafaxine suggest dose-dependent efficacy in MDD (Kelsey 1996; Khan et al. 1998; Rudolph et al.

1998c; Thase et al. 2006b). Perhaps most importantly, a large amount of data from RCTs suggests that patients who do not respond to

lower dosages often benefit from dosage increases (Costa e Silva 1998; Diaz-Martinez et al. 1998; Dierick et al. 1996; Mehtonen et al. 2000;

Thase et al. 2006b). As reviewed elsewhere (Thase 2006), there is relatively little evidence of a dose–response relationship in treatment of

anxiety disorders. Whereas the original form of venlafaxine was approved for treatment at doses of up to 375 mg/day (divided bid or tid),

the manufacturer “capped” the recommended maximum daily dosage of XR at 225 mg because of a lack of data on the safety and

tolerability of once-daily therapy at higher doses. Although some clinicians disregard this arbitrary restriction, it is true that the incidence of

elevated blood pressure during venlafaxine therapy is heavily dose dependent (Thase 1998), and if only for this reason, vigilance is

warranted when higher-dose therapy is indicated.

Less is known about the dose–response characteristics of desvenlafaxine. Early experiences with the compound in RCTs of MDD suggested

that dosages above 200 mg/day may convey no additional efficacy and have a significantly higher incidence of side effects (DeMartinis et

1. 2007; Septien-Velez et al. 2007). Although the full therapy development program has not yet been published, the minimum therapeutic

dosage is 50 mg/day, and dosages above 100 mg/day are not recommended by the manufacturer. Whether patients who do not respond to

50 mg/day will benefit from upward titration to higher dosages has not yet been demonstrated.

Clearance of venlafaxine and desvenlafaxine is reduced among patients with cirrhosis or severe renal disease (Troy et al. 1994); therefore,

dosing should be adjusted downward accordingly. In the absence of formal studies to inform such decisions, a 50% reduction in dosage and

slower titration (i.e., at least 7–10 days between adjustments) of both the parent drug and desvenlafaxine are generally recommended. In

otherwise healthy elders, adjustments in dosing of venlafaxine do not appear to be necessary (Klamerus et al. 1996). However, initiation of

treatment with a lower starting dose, and slower subsequent titration, is a sensible approach when treating frail elders or medically

complicated patients. Specific studies of desvenlafaxine in older, medically complex patients have not yet been undertaken.

MECHANISM OF ACTION

The mechanism of action of both venlafaxine and desvenlafaxine is believed to be inhibition of 5-HT and NE reuptake. From the beginning,

comparisons with the first medication to be considered a “dual reuptake inhibitor,” the TCA clomipramine, have been inevitable.

Venlafaxine is also a weak inhibitor of dopamine reuptake in vitro (Muth et al. 1986), although this effect probably is not clinically

significant at routine therapeutic doses. Consistent with this view are the results of one recent in vivo study of healthy volunteers, which

found essentially no blockade of the dopamine transporter with venlafaxine dosages of 75 and 150 mg/day (Shang et al. 2007).

There is good evidence that venlafaxine and desvenlafaxine are more potent inhibitors of 5-HT reuptake than of NE reuptake

(Bolden-Watson and Richelson 1993; Deecher et al. 2006; Vaishnavi et al. 2004). It has long been suggested that this relationship

underpins the ascending dose–response relationship of venlafaxine (Kelsey 1996; Thase 1996). Moreover, some argue that venlafaxine is

essentially an SSRI at the lowest therapeutic dosage (i.e., 75 mg/day) and that the noradrenergic effect is progressively recruited as the

dose is increased (Kelsey 1996). There are both experimental (Harvey et al. 2000) and clinical (Davidson et al. 2005; R. Entsuah and Gao

2002; Rudolph et al. 1998a; Thase 1998; Thase et al. 2006b) data that are consistent with such a relationship. Nevertheless, significant

effects on autonomic measures of noradrenergic function are evident at 37.5- and 75-mg/day dosages (Bitsios et al. 1999; Siepmann et al.

2007). Until it is possible to directly image NE transporter occupancy in vivo, this question cannot be definitively answered.

INDICATIONS AND EFFICACY

Venlafaxine XR is approved by the FDA for the treatment of MDD, generalized anxiety disorder (GAD), social anxiety disorder, and panic

disorder. Venlafaxine IR and desvenlafaxine are approved only for the treatment of MDD.

Although venlafaxine has not been formally approved for treatment of other psychiatric disorders, there is evidence that it also has efficacy

in other disorders that are responsive to SSRIs, including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and

premenstrual dysphoric disorder (PMDD). Given that desvenlafaxine is the active metabolite of venlafaxine, it is likely to be effective in

every disorder that is responsive to the parent drug.

Major Depressive Disorder

The antidepressant efficacy of venlafaxine has been established in a large number of placebo-controlled, randomized trials (Cunningham

1997; Guelfi et al. 1995; Khan et al. 1991; Mendels et al. 1993; Rudolph et al. 1998c; Schweizer et al. 1991; Shrivastava et al. 1994; Thase

1997), including studies focusing on depressed patients with associated symptoms of anxiety (Feighner et al. 1998; Khan et al. 1998;

Rudolph et al. 1998b). In published studies employing SSRIs as active comparators, venlafaxine therapy has been found to be comparable

or superior to therapy with fluoxetine (Alves et al. 1999; Clerc et al. 1994; Costa e Silva 1998; De Nayer et al. 2002; Dierick et al. 1996;

Keller et al. 2007a; Nemeroff and Thase 2007; Rudolph and Feiger 1999; Rudolph et al. 1998a; Schatzberg and Roose 2006; Silverstone and

Ravindran 1999; Tylee et al. 1997; Tzanakaki et al. 2000), sertraline (Mehtonen et al. 2000; Rush et al. 2006; Shelton et al. 2006; Sir et al.

2005), paroxetine (Ballus et al. 2000; McPartlin et al. 1998; Poirier and Boyer 1999), and citalopram (Allard et al. 2004). Results of two

studies comparing venlafaxine and escitalopram have yielded somewhat conflicting results (Bielski et al. 2004; Montgomery et al. 2004b),

with comparability in the latter study and trends favoring the SSRI in the former study, which employed rapid titration to maximum

FDA-approved doses (Bielski et al. 2004). A pooled analysis of these two trials also found a significant advantage for escitalopram among

the subset of patients with higher pretreatment depression severity (Montgomery and Andersen 2006). Comparative studies of

desvenlafaxine and SSRIs are under way, but results are not yet available.

Results from meta-analyses of early published and unpublished studies comparing venlafaxine and SSRIs provided some evidence that

venlafaxine may produce a significantly greater antidepressant response than fluoxetine and perhaps than SSRIs as a class (T. R. Einarson

et al. 1999; Smith et al. 2002; Stahl et al. 2002; Thase et al. 2001). In the meta-analysis by Thase et al. (2001), for example, the magnitude

of this effect was a 10% higher rate of remission (as defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for

Depression), which was comparable to the magnitude of the effect favoring the SSRIs over placebo. The advantage versus fluoxetine was

subsequently confirmed by an independent meta-analysis conducted by the Cochrane group (Cipriani et al. 2006), although this was not

observed in the largest prospective head-to-head RCT (Keller et al. 2007a), which examined the outcomes of 1,096 patients with recurrent

MDD across 10 weeks of double-blind therapy.

Results of the most comprehensive meta-analysis of RCTs comparing venlafaxine and SSRIs undertaken to date are consistent with the

hypothesis that venlafaxine therapy has significantly greater efficacy than fluoxetine alone and than the SSRIs as a class (Nemeroff et al.

2008). Working with individual patient data from all of the manufacturer-sponsored double-blind RCTs conducted worldwide (N = 34

studies), the antidepressant efficacy of venlafaxine, various SSRIs (fluoxetine, paroxetine, sertraline, citalopram, or fluvoxamine), and

placebo (9 studies) across up to 8 weeks of therapy were compared in more than 8,500 adults with MDD. The absolute difference in

remission rates was found to be 6%, favoring the SNRI (95% confidence interval = 3.8%–8.1%) (Figure 22–2). The difference was againPrint: Chapter 22. Venlafaxine and Desvenlafaxine http://www.psychiatryonline.com/popup.aspx?aID=427503&print=yes…

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statistically significant for the more numerous studies using fluoxetine as a comparator but not for the comparisons of the other SSRIs

individually. A secondary analysis utilizing the funnel plot method, which also included results of all other known comparative studies of

venlafaxine and SSRIs, yielded confirmatory results (Nemeroff et al. 2008). Although statistical significance was observed, the modest

magnitude of the difference across studies falls below the standard for clinical significance suggested by the Cochrane group (e.g., Cipriani

et al. 2006).

FIGURE 22–2. Rate differences for remission and 95% confidence intervals for venlafaxine versus selective serotonin reuptake inhibitors

(SSRIs).

Remission is defined as a 17-item Hamilton Rating Scale for Depression (Ham-D-17) score of 7 or less for 33 of the 34 studies. One study (4229; Allard

et al. 2004) did not use the Ham-D, and remission was defined as a Montgomery-Åsberg Depression Rating Scale score of 10 or less. Remission rate

differences for the individual studies ranged from –7% to 31%; differences numerically favored venlafaxine in 28 studies (although only 5 reached

statistical significance), with 6 studies numerically favoring the SSRIs.

Source. Reprinted from Nemeroff CB, Entsuah R, Benattia I, et al.: “Comprehensive Analysis of Remission (COMPARE) With Venlafaxine Versus SSRIs.”

Biological Psychiatry 63:424–434, 2008. Copyright 2008, Elsevier. Used with permission.

With respect to other newer antidepressants, two studies comparing venlafaxine and mirtazapine therapies (Benkert et al. 2006; Guelfi et

1. 2001) found trends favoring the latter compound early in the course of treatment but comparable efficacy at study endpoint.

Mirtazapine, which is a potent blocker of histamine and 5-HT2 receptors, also had a significant advantage in relief of insomnia in both of

these studies. One relatively large outpatient study contrasting bupropion, a norepinephrine–dopamine reuptake inhibitor (NDRI), and

venlafaxine XR found a comparable overall pattern of efficacy, with the NDRI having a significant advantage in terms of a lower incidence of

sexual side effects and a higher proportion of patients achieving remission at study endpoint (Thase et al. 2006a). The latter finding, which

was discrepant from levels of symptom reduction and response rates, may be attributable to the special nature of the study population (i.e.,

relatively younger, sexually active patients). A pair of studies contrasting venlafaxine and the other widely available SNRI, duloxetine,

found no differences in efficacy at either the primary or secondary study endpoints (Perahia et al. 2008). In the pooled data set of those

two studies, several tolerability indices favored venlafaxine early in the course of therapy, whereas there were fewer discontinuation

symptoms in the duloxetine group following cessation of study therapy.

Several studies have evaluated the utility of venlafaxine therapy in bipolar depression. In the first, a double-blind, placebo-controlled study,

the efficacy and safety of venlafaxine treatment were compared in 17 patients with bipolar II disorder and 31 patients with unipolar

depression (Amsterdam 1998). Patients were randomly assigned to 6 weeks of double-blind treatment with once- versus twice-daily

venlafaxine IR (up to 225 mg/day). Overall, similar efficacy was observed in unipolar and bipolar patients, although a more rapid reductionPrint: Chapter 22. Venlafaxine and Desvenlafaxine http://www.psychiatryonline.com/popup.aspx?aID=427503&print=yes…

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of symptoms was observed by week 2 of treatment among bipolar patients who completed the entire trial. No episodes of drug-induced

hypomania or rapid cycling were observed.

Vieta et al. (2002) compared therapy with venlafaxine or paroxetine in a double-blind study of 60 bipolar I patients taking concomitant

mood stabilizers. Results suggested comparable efficacy and tolerability, although the patients treated with venlafaxine had a higher rate of

treatment-induced mania (13%) than the group treated with paroxetine (3%).

Venlafaxine was contrasted with bupropion and sertraline in 174 bipolar I and II patients taking concomitant mood stabilizers (Post et al.

2006). Again, there was no difference in efficacy, but the rate of treatment-emergent affective switches was significantly higher for the

patients randomly assigned to the SNRI compared with those assigned to the other two antidepressants.

Venlafaxine is one of the preferred choices for patients who have not responded to other first-line antidepressants (Thase et al. 2000). Two

recent RCTs compared venlafaxine with other treatment options after nonresponse to an initial course of SSRI therapy (Baldomero et al.

2005; Rush et al. 2006). Despite a number of differences in design, these studies yielded almost identical results, with a modest numeric

advantage in remission rates for the SNRI versus a second trial within the SSRI class. Results were statistically significant in a larger study

(Baldomero et al. 2005), which was conducted in Spain, but did not reach significance in the smaller study, which was conducted in the

United States as part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project (Rush et al. 2006). Another study

within the STAR*D program contrasted the combination of venlafaxine and mirtazapine (n = 51) versus the monoamine oxidase inhibitor

(MAOI) tranylcypromine (n = 58) among MDD patients who had not responded to three consecutive prospective medication trials (McGrath

et al. 2006). Although the two strategies did not differ with respect to the primary outcome variable (remission rates were only 14% and

7% for the combination and MAOI strategies, respectively), patients treated with the combination strategy had significantly greater

symptom reduction and a higher study completion rate than patients treated with the MAOI.

Venlafaxine has not been studied in combination with antipsychotic medication for patients with psychotic depression. One study did,

however, compare double-blind therapy with either venlafaxine IR (300 mg/day) or fluvoxamine (300 mg/day) as monotherapies in 28

psychotically depressed patients (Zanardi et al. 2000). Findings strongly favored the group receiving fluvoxamine (response rates: 79% vs.

50%), although such an apparently large difference was not statistically significant in this small study. Regardless, venlafaxine should not

be thought of as a stand-alone therapy for patients with psychotic depression.

Earlier longer-term open-label trials suggested that venlafaxine had sustained efficacy across 12 months of continued therapy (Magni and

Hackett 1992; Tiller et al. 1992). Results of a pooled analysis of the extension phases of four randomized, double-blind, controlled studies in

outpatients with major depression demonstrated that the rate of relapse at 6 months and 1 year was significantly lower in the

venlafaxine-treated group than in the placebo-treated group (A. R. Entsuah et al. 1996). Double-blind, placebo-controlled studies

subsequently confirmed the efficacy of venlafaxine treatment for prevention of relapse during 6 months of continuation treatment (Simon

et al. 2004) and for prevention of recurrence during 12 months (Kocsis et al. 2007; Montgomery et al. 2004a) and 24 months (Keller et al.

2007b) of maintenance-phase therapy.

Generalized Anxiety Disorder

Venlafaxine XR was approved by the FDA for treatment of GAD on the basis of a series of placebo-controlled RCTs (Allgulander et al. 2001;

Davidson et al. 1999; Gelenberg et al. 2000; Nimatoudis et al. 2004; Rickels et al. 2000), including two trials that evaluated efficacy across 6

months of therapy (Allgulander et al. 2001; Gelenberg et al. 2000). Across studies, the efficacy of doses ranging from 75 mg/day to 225

mg/day was established versus placebo, with little evidence of dose–response relationships for both efficacy and tolerability.

To date, there have been no studies of higher-dose venlafaxine therapy for GAD. Only a handful of studies have been completed comparing

venlafaxine XR with other medications with established efficacy in GAD. Superiority to buspirone was found on some (but not all) measures

in the one study that was undertaken (Davidson et al. 1999). In the single study that compared venlafaxine XR with the benzodiazepine

diazepam (Hackett et al. 2003), the two treatments were comparably effective, although neither active therapy was statistically more

effective than placebo.

Two comparative studies have contrasted venlafaxine XR with SSRIs in GAD. In the first, a randomized but open-label trial comparing

venlafaxine XR and paroxetine in 60 outpatients, Kim et al. (2006) reported comparable efficacy and tolerability. In the second study (Bose

et al. 2008), a relatively large (N = 392) RCT, venlafaxine XR and escitalopram were contrasted. Overall, there were no significant

differences between the two therapies. However, venlafaxine XR was statistically significantly more effective than placebo on the primary

outcome measure (whereas escitalopram was not), and attrition due to side effects was significantly greater in the venlafaxine arm than in

the placebo arm (whereas the difference in attrition between the escitalopram and placebo arms was not statistically significant).

Social Anxiety Disorder

Venlafaxine XR was approved for treatment of social anxiety disorder on the basis of a series of RCTs that confirmed its efficacy and safety

relative to placebo across up to 6 months of double-blind therapy (Allgulander et al. 2004; Liebowitz et al. 2005a, 2005b; Rickels et al.

2004; Stein et al. 2005). As was the case in GAD, effective doses ranged from 75 mg/day to 225 mg/day, with little evidence of an

ascending dose–response relationship. In the two studies that included paroxetine as an active comparator, venlafaxine therapy was at

least as effective and as well tolerated as the SSRI (Allgulander et al. 2004; Liebowitz et al. 2005a).

Panic Disorder

Although promising results in panic disorder were apparent in an early placebo-controlled study utilizing the IR formulation (Pollack et al.

1996), the research that ultimately led to a formal FDA indication was largely delayed until after studies of the XR formulation were

completed in MDD, GAD, and social anxiety disorder. Antipanic efficacy was demonstrated in three placebo-controlled studies of

acute-phase therapy, including one 10-week flexible-dose study (Bradwejn et al. 2005) and two 12-week fixed-dose studies investigating

75 mg/day and 150 mg/day (Pollack et al. 2007a) or 75 mg/day and 225 mg/day (Pollack et al. 2007b). These studies, which incorporated

a 37.5-mg starting dose to minimize early side effects, established an effective dosage range of 75–225 mg/day. Two of the

placebo-controlled studies also included paroxetine (40 mg/day) as an active comparator (Pollack et al. 2007a, 2007b). Overall, two fixed

doses of venlafaxine XR (75 mg/day and 150 mg/day) were comparable to paroxetine in both efficacy and tolerability. In the single RCT

that included a fixed-dose 225-mg/day arm, the higher dose of venlafaxine therapy was significantly more effective than paroxetine on

several secondary outcome measures, including the proportion of patients who experienced complete relief from full symptom panic attacks

(70% vs. 58%) (Pollack et al. 2007b). Sustained efficacy was demonstrated in one longer-term study using a classic relapse prevention

design, in which patients who responded to 12 weeks of open-label therapy with venlafaxine XR (75–225 mg/day) were randomly allocated

to 6 additional months of double-blind therapy with either the active drug or placebo (Ferguson et al. 2007).

Other Anxiety DisordersPrint: Chapter 22. Venlafaxine and Desvenlafaxine http://www.psychiatryonline.com/popup.aspx?aID=427503&print=yes…

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Early studies of venlafaxine therapy of PTSD have been reviewed by Pae et al. (2007). Results of two large RCTs demonstrated the efficacy

of venlafaxine XR versus placebo (Davidson et al. 2006a, 2006b). The first trial, which enrolled 573 adults scoring at least 60 on the

Clinician-Administered PTSD Scale (CAPS-SX17), compared venlafaxine XR (range = 37.5–300 mg/day; mean dosage = 225 mg/day),

sertraline (range = 25–200 mg/day; mean dosage = 151 mg/day), and matching placebo across 12 weeks of double-blind treatment.

Venlafaxine XR therapy was significantly more effective than placebo, as measured by change in CAPS-SX17 scores and remission rates at

study endpoint, whereas sertraline was not. There were, however, no significant differences in efficacy between the two active therapies.

Final remission rates were 30%, 24%, and 20% for the SNRI, SSRI, and placebo groups, respectively. In the second study, which enrolled

329 adults meeting the same entry criteria, venlafaxine XR (mean dosage = 222 mg/day) was compared with placebo across up to 6

months of double-blind therapy. The efficacy of the SNRI was documented by significant effects on all primary and secondary outcome

measures, with final remission rates of 51% and 38% for the venlafaxine XR and placebo groups, respectively.

The results of an initial open-label case series (Rauch et al. 1996) suggested that venlafaxine would also be a useful treatment of OCD.

Indeed, results of a 12-week single-blind study indicated that venlafaxine might be at least as effective as clomipramine and significantly

better tolerated (Albert et al. 2002). However, the manufacturer did not pursue a large-scale registration program for this indication, and

the smaller-scale studies that have been performed do not reveal particular advantages as compared to approved SSRIs such as paroxetine

(see the review by Thase 2006).

Premenstrual Dysphoric Disorder

A randomized, double-blind, placebo-controlled study evaluated the efficacy of venlafaxine IR for the treatment of PMDD in 157 women

treated across four menstrual cycles (Freeman et al. 2001). Dosages ranged from 50 mg/day to 200 mg/day, with adjustments for adverse

events or lack of efficacy early in each cycle. Analysis of daily symptom rating scores revealed significantly greater improvement in the

venlafaxine group compared with the placebo group at endpoint in the primary factors of emotion, function, physical symptoms, and pain.

In a second small pilot study of intermittent (premenstrual) dosing, Cohen et al. (2004) treated 11 women with PMDD who had not

responded to a single-blind placebo lead-in. Nine of the 11 responded to the two 14-day courses of venlafaxine XR 75–112.5 mg/day. The

medication was well tolerated, and intermittent dosing was not associated with significant discontinuation symptoms. Further studies are

needed to ascertain the longer-term efficacy of venlafaxine treatment for PMDD.

Treatment of Children and Adolescents

Venlafaxine XR was being evaluated for treatment of MDD, GAD, and social anxiety disorder in pediatric populations at the time that

concerns about the potential for antidepressants to induce suicidal ideation and behaviors in children began to surface in 2003–2004.

Although the manufacturer chose not to pursue further formal indications in any pediatric disorder, results of the five completed studies

have been published and include a pair of studies in MDD (Emslie et al. 2007), two RCTs in GAD (Rynn et al. 2007), and one study in social

anxiety disorder (March et al. 2007). Results in the depression studies (pooled N = 334) were mixed: venlafaxine XR was significantly more

effective than placebo among participants ages 12–17 years but not among children ages 7–11 years. In the pooled data set, venlafaxine XR

therapy was associated with an increased risk of treatment-emergent suicidal and aggressive behaviors compared with placebo (Emslie et

1. 2007). In the pair of GAD studies (pooled N = 330), venlafaxine XR was significantly more effective than placebo in the pooled data set;

one study was unequivocally positive, but the second study failed to separate between drug and placebo on the primary dependent measure

(Rynn et al. 2007). In the social anxiety disorder study (N = 293), venlafaxine XR also was significantly more effective than placebo on both

primary and secondary outcome measures (March et al. 2007).

SIDE EFFECTS AND TOXICOLOGY

The side-effect profile of the IR formulation of venlafaxine was superior to the TCAs, although not quite as favorable as the SSRIs (Preskorn

1995). In the meta-analysis of Nemeroff et al. (2008), for example, 11% of the venlafaxine-treated patients withdrew from therapy

because of adverse events, compared with 9% of patients treated with SSRIs. As an SNRI, the tolerability profile of venlafaxine includes all

of the characteristic side effects associated with 5-HT uptake inhibition (i.e., nausea, insomnia, tremor, and sexual dysfunction) as well as

side effects attributable to NE reuptake inhibition (i.e., sweating and dry mouth). The major advantage of the XR formulation, aside from

permitting once-daily dosing, is a somewhat lower incidence of nausea during the first weeks of therapy (Cunningham 1997). To date, no

comparative study of venlafaxine and an SSRI has included a detailed assessment of sexual dysfunction. The results of studies focused on

detection of sexual dysfunction during antidepressant treatment suggest that venlafaxine and the SSRI are associated with similar risks

(Clayton et al. 2002; Kennedy et al. 2000; Montejo et al. 2001).

Like the SSRIs, venlafaxine does not affect cardiac conduction and does not lower the seizure threshold (at least at therapeutic doses).

Unlike the SSRIs, however, venlafaxine is associated with a small increase in pulse rate and a dose-dependent increased risk of elevated

blood pressure (Thase 1998). Experience with the IR formulation in studies of MDD indicated that the risk of sustained high blood pressure

increased from 3% to 7% at dosages of 100–225 mg/day and to 13% at dosages above 300 mg/day (Thase 1998). In the studies of the XR

formulation, which limited the maximum dosage to 225 mg/day, the increased risk was only 3% in patients with MDD and 0.5% in patients

with GAD. Nevertheless, the manufacturer continues to recommend that all patients receiving venlafaxine have regular monitoring of blood

pressure. In practice, it is prudent to record blood pressure prior to initiating venlafaxine therapy and to monitor serially if dosages above

225 mg/day are prescribed. More careful monitoring is warranted for patients with preexisting high blood pressure and for the elderly.

Similar to most other antidepressants, venlafaxine is classified as pregnancy Category C, indicating that there are no adequate and

well-controlled studies in pregnant women and that the drug should be used during pregnancy only if it is clearly needed. Results of a

multicenter case–control study evaluating pregnancy outcome following gestational exposure to venlafaxine (n = 150), SSRIs (n = 150), or

other drugs (n = 150) revealed no evidence that venlafaxine therapy increases the risk of major fetal malformations (A. Einarson et al.

2001).

As with other psychotropic medications, venlafaxine and its metabolites are excreted in human breast milk. Reports by Ilett et al. (1998,

2002) of the distribution of venlafaxine in human milk and its effects in breast-fed infants demonstrated that the mean infant dose

exposure was approximately 6%–7% of the maternal dose, which is below the 10% notional level of concern. No adverse effects were

noted in any of the infants (Ilett et al. 2002). Although these data support the use of venlafaxine in pregnant or breast-feeding women, the

findings are preliminary, and the available safety data remain limited. The decision to use venlafaxine in pregnancy or lactation should be

made on the basis of an individual risk–benefit assessment.

Precipitous withdrawal of venlafaxine can result in a characteristic “discontinuation” profile, including dizziness, dry mouth, insomnia,

nausea, nervousness, sweating, anorexia, diarrhea, somnolence, and sensory disturbances (Haddad 2001). Venlafaxine therapy therefore

should not be discontinued abruptly, and whenever possible, a taper schedule of no more than 75 mg/day/week is strongly recommended.

It is important to note that the discontinuation schedule used in clinical trials was based on only 6- to 12-week durations of treatment. InPrint: Chapter 22. Venlafaxine and Desvenlafaxine http://www.psychiatryonline.com/popup.aspx?aID=427503&print=yes…

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practice, longer tapering schedules may be required, depending on the dose, the duration of therapy, and the individual patient. Clinicians

should counsel patients about the possibility of adverse effects following abrupt discontinuation of treatment.

In the 13-plus years since its initial introduction, there has been extensive experience with venlafaxine overdose. A number of fatal

overdoses have been reported, primarily involving combinations of venlafaxine and other drugs and/or alcohol (Banham 1998; Kunsman et

1. 2000; Long et al. 1997; Parsons et al. 1996). In nonfatal overdoses, electrocardiogram changes (e.g., prolongation of QT interval, bundle

branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, altered level of consciousness (ranging from

somnolence to coma), serotonin syndrome, and seizures have been reported (C. Howell et al. 2007; Whyte et al. 2003). In an analysis of

fatal poisoning with antidepressants in the United Kingdom, Buckley and McManus (2002) used a statistic known as the fatal toxicity index

(FTI), which was defined by the number of overdose deaths per million prescriptions, to compare the relative risks of different

antidepressants. They found that venlafaxine had a significantly higher FTI than the SSRIs (13.2 vs. 0.7–3.0). The authors suggested that

these data could mean that venlafaxine should not be used as a first-line treatment for patients with suicidal ideation. However, many

nonpharmacological factors can contribute to the likelihood of a fatal overdose, particularly patient risk factors. In this regard, two studies

have documented that the patients who are selected for treatment with venlafaxine are at greater inherent suicide risk than are patients

selected for treatment with SSRIs (Mines et al. 2005; Rubino et al. 2007). Adjustment for these risk factors greatly reduced the difference

in FTI between venlafaxine and the SSRIs (Rubino et al. 2007). Although the potential for lethality in overdose certainly warrants ongoing

study, the current state of the evidence does not indicate that venlafaxine therapy should be avoided in patients at risk for suicidal

behavior.

DRUG–DRUG INTERACTIONS

Venlafaxine undergoes extensive metabolism in the liver by the cytochrome P450 (CYP) enzyme system, particularly by the CYP2D6

isoenzyme. Patients who are “poor CYP2D6 metabolizers,” whether genetically or by taking drugs that inhibit this enzyme, thus have

increased concentrations of the parent drug relative to ODV. Although it could be argued that this should not affect response, given that the

parent drug and ODV are nearly pharmacologically equipotent, poor metabolizers of CYP2D6 may be at greater risk for side effects

(McAlpine et al. 2007; Shams et al. 2006). Such patients thus could potentially be better candidates for therapy with desvenlafaxine than

the parent drug.

Despite being a substrate for CYP2D6, venlafaxine and ODV are among the weakest of inhibitors of this isoenzyme (Alfaro et al. 2000;

Amchin et al. 2001; Ball et al. 1997). In vitro and in vivo studies have shown that venlafaxine and ODV cause little or no inhibition of other

CYP isoenzymes, including 1A2, 2C9, 2C19, and 3A4 (Ball et al. 1997; Owen and Nemeroff 1998). Although it does not appear to have

significant affinity for CYP3A4, venlafaxine has been shown to decrease blood levels of the protease inhibitor indinavir, a substrate of

CYP3A4 (Levin et al. 2001). Neither the mechanism nor the clinical significance of this interaction is known, but it is of concern given the

critical nature of treatment with protease inhibitors.

As SNRIs, both venlafaxine and desvenlafaxine are contraindicated in patients taking MAOIs, because of the risk of serotonin syndrome.

This is as true for the newer transdermally delivered formulation of selegiline as it is with the older agents. As with cyclic antidepressants

and SSRIs, venlafaxine or desvenlafaxine treatment should not be initiated until 2 weeks after discontinuation of an MAOI, and MAOI

therapy should not be initiated until at least 7 days after discontinuation of venlafaxine or desvenlafaxine.

Venlafaxine and desvenlafaxine appear to have no clinically significant interactions with lithium (Troy et al. 1996), diazepam (Troy et al.

1995a), or alcohol (Troy et al. 1997c).

CONCLUSION

Venlafaxine, the first widely used member of the SNRI class, appears to be at least as effective as other first-line antidepressants and has

an overall safety profile that is closer to the SSRIs than the TCA. There is evidence of a modest efficacy advantage compared with fluoxetine

and perhaps to the SSRIs as a class, although to date a significant efficacy advantage has not been demonstrated against other specific

members of the class, most particularly escitalopram. Venlafaxine also has established efficacy for treatment of GAD, social anxiety

disorder, and panic disorder. Generic formulations of venlafaxine IR are now available, although the more heavily prescribed XR

formulation, which is patent-protected for several more years, offers the advantages of once-daily dosing and a lower incidence of nausea

during the first few weeks of therapy. ODV, the primary active metabolite of venlafaxine, was introduced as antidepressant (desvenlafaxine

succinate) in 2008. Desvenlafaxine offers several advantages over venlafaxine XR in terms of simpler dosing (e.g., lower starting dose,

lower minimum therapeutic dose, no active metabolite, and possibly less need for upward dosage titration); beyond this, however, the

relative merits of the two drugs have not yet been assessed. Both drugs have a low potential for cytochrome P450–mediated drug–drug

interactions and are associated with dose-dependent increases in blood pressure.

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