Venlafaxine efficacy

Alternatives to estrogen for hot flushes are shown in Table 31-6. Progesterone alone may be an option in women with a history of breast cancer or venous thrombosis, but side effects limit their use. For women with contraindications to hormone therapy, selective serotonin reuptake inhibitors and venlafaxine are considered by some to be first-line therapy, but efficacy of venlafaxine beyond 12 weeks has not been shown. 

There are three approved drugs, venlafaxine (16), duloxetine (17) and milnacipran (18), in the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Whereas milnacipran blocks 5-HT and NE reuptake with almost equal potency, venlafaxine and duloxetine block 5-HT reuptake preferentially [39-41]. Clinical evidence shows that SNRIs have comparable efficacy in the treatment of MDD compared with antidepressants in the SSRI class. An advantage with SNRIs appears to be the ability of alleviating chronic pain associated with, and independent of depression [42-44],... 

Structurally related to venlafaxine, PRC025 (29) and PRC050 (30) were reported to be triple reuptake inhibitors. Both exhibited antidepressant efficacy at 5 mg/kg in the rat FST [91]. 

The so-called atypical antidepressants such as venlafaxine and bupropion can be tried, but their safety and efficacy in treating patients with dementia have not been well studied. The older tricyclic antidepressants and monoamine oxidase inhibitors are not tolerated well by demented patients and should be avoided. Two possible exceptions are nortriptyline (Pamelor) and desipramine (Norpramin), but even these should be tried only after the newer antidepressants have proved ineffective. 

Lactation Venlafaxine and ODV are excreted in breast milk. Children Safety and efficacy have not been established. 

Taken together, the efficacy of antidepressants covers the spectrum of anxiety disorders, although there are important differences between drugs in the group (Table 3). Several new antidepressants have been marketed since the SS-RIs venlafaxine and mirtazapine are discussed later (Sects. 3.2.1.2 and 3.2.1.4) nefazodone, a serotonin reuptake inhibitor and postsynaptic 5-HT2 blocker showed promise in early studies but was recently withdrawn by its manufacturers reboxetine, a noradrenaline reuptake inhibitor (NARI) showed benefits in panic disorder in one published study (Versiani et al. 2002) and further evidence of its anxiolytic efficacy is awaited. 

There is a large evidence base for the antidepressant efficacy of venlafaxine, but fewer studies have been carried out in anxiety disorders. The best evidence is for GAD (Allgulander et al. 2001) and anxiety symptoms associated with depression (Silverstone and Ravindran 1999). Side-effects on initiation of therapy are similar to those of SSRIs, with nausea being the most common. Higher doses can cause raised blood pressure. A discontinuation syndrome similar to that seen with SSRIs has been reported. Toxicity causes cardiac conduction problems, seizures and coma, and venlafax-... 

Place in therapy Similar to venlafaxine, with less risk of increased blood pressure alternative in major depression in poor responders to other agents at least as effective as tricyclics, but with lower toxicity more efficacious than SSRls... 

Smith D, Dempster C, Glanville I, et al. Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and other antidepressants a meta-analysis. Br 1 Psych iatry 2002,180 396-404. 

Most child and adolescent studies published thus far have focused on the effects of the tricyclic antidepressants (TCAs) and, more recently, the SSRIs. A few open studies have also shown that monoamine oxidase inhibitors (MAOIs) can be used safely with children and adolescents (Ryan et ah, 1988b), but noncompliance with dietary requirements may present a significant problem for minors. Other antidepressants, including the heterocyclics (HTC) (e.g., amoxapine, maprotiline), buproprion, venlafaxine, and nefazodone, have been found to be efficacious for the treatment of depressed adults (APA, 2000), but they have not been well studied for the treatment of MDD in children and adolescents. Therefore, this chapter mainly describes the use of SSRIs and TCAs for youth with MDD. 

Currently, the antidepressants of choice are the SSRIs because they have been shown to be efficacious and safe for the treatment of children and adolescents with MDD, but further research on the other new antidepressants (e.g., bupropion, venlafaxine, nefazodone, mirtazapine) is needed. Patients should be treated with adequate doses for at least 6 weeks before declaring lack of response to treatment (treatment of nonresponders is described below) (AACAP, 1998 Hughes et ah, 1999 Fig. 36.1). 

For patients who do not respond to a specific antidepressant medication or who do not tolerate its side effects, other antidepressants of the same class or different classes (e.g., venlafaxine for a patient treated with a SSRI) can be tried. The few adult studies published thus far suggest that it is more efficacious to switch antidepressant classes than to stay within the same class, because of the probable heterogeneity in underlying depression mechanisms. Also, it has been suggested that severe depressions appear to respond better to antidepressants with both serotonergic and adrenergic properties (e.g., venlafaxine) (Poirier and Boyer, 1999). 

Social phobia also has a component of avoidance and has been successfully treated with the RlMAs brofaromine and moclobemide (Keck and McElroy 1997]. However, the SSRls and venlafaxine have also shown efficacy in social phobia (Gorman and Kent 1999 Keck and McElroy 1997], suggesting that further divisions of anxiety diagnostic categories may result from future pharmacological research. 

Several preliminary lines of research have started to suggest that antidepressants, once considered ineffective in generalized anxiety disorder, may be very efficacious [Gorman and Kent 1999]. In particular, venlafaxine has been effective in treating generalized anxiety disorder in both open-label and double-blind trials, and imipramine and paroxetine were as effective as a benzodiazepine in the long-term treatment of generalized anxiety disorder. 

Venlafaxine and milnacipran are two members of a new class of antidepressants that have selective effects on the reuptake of both serotonin and noradrenaline—serotonin noradrenaline reuptake inhibitors (SNRIs). In theory, based on the findings of B. M. Baron and colleagues [1988 and of J. C. Nelson and colleagues (1991), the combination of these two pharmacological actions should be associated with superior efficacy either in terms of rapid onset of action or extra efficacy at the end of treatment. 

TCAs in more serious forms of depression such as melancholic or psychotic depression. Some studies have suggested that the SSRls do not work as well as the TCAs in melancholic depression (Roose et al. 1994]. Likewise, one study has suggested that venlafaxine, a drug with a mechanism of action similar to that of the TCAs, was superior to fluoxetine in the treatment of inpatients with melancholic depression (Clerc et al. 1994]. Still, other metaanalyses have failed to find a difference in the efficacy of SSRls versus TCAs in serious forms of depression [Nierenberg 1994]. Nonetheless, given that most studies have employed TCAs, and some debate exists about the utility of SSRls in severe subtypes, it may be prudent to start with a TCA in most patients until the debate is further resolved. For patients who present a significant suicide risk or who have not been able to tolerate TCAs, the SSRls in combination with a standard antipsychotic appears an effective option. 

In contrast, a less extensive but still convincing database has identified important clinical differences in efficacy for antidepressants used to treat patients with atypical or comorbid depression. Individuals with atypical depression (distinct quality of mood, hyperphagia, hypersomnia, psychomotor retardation, rejection sensitivity, and such unusual atypical features as chocolate craving] have superior responses to monoamine oxidase inhibitors (MAOIs], selective serotonin reuptake inhibitors (SSRIs), and perhaps venlafaxine, and most do not respond well to tricyclic antidepressants (TCAs] (Davidson et al. 1982 Liebowitz et al. 1988 Quitkin et al. 1988, 1991). Despite these data, TCAs unfortunately have been the first choice for most atypical patients until SSRIs were introduced. 

TCAs derive their name from their chemical structure aU tricyclics have a three-ring nucleus. Currently, most clinicians are moving away from using TCAs as first-line drugs relative to the newer antidepressants, they tend to have more side effects, to require gradual titration to achieve an adequate antidepressant dose, and to be lethal in overdose. Some data suggest that TCAs may be more effective than SSRIs in the treatment of major depression with melancholic features (Danish University Antidepressant Group 1990 Perry 1996) however, many skilled clinicians and researchers continue to prefer the newer antidepressants, even for patients with melancholia, for the aforementioned reasons. Newer medications that affect both norepinephrine and serotonin (e.g., venlafaxine and mirtazapine) also may have superior efficacy in severely iU depressed patients or when remission is defined as the outcome (Thase et al. 2001). 

A critical review by Olver et al. (2001) on so-called third-generation antidepressants (venlafaxine, reboxetine, nefazodone, mirtazapine) covered 30 controlled therapeutic trials and a number of relapse prevention studies. Questions addressed were overall efficacy, speed of onset and safety but, according to this review, none of the third-generation antidepressants was specifically tested with respect to its potential effects on cognitive function in depressed patients. 

A meta-analysis of 32 controlled studies comparing venlafaxine with several SSRIs and other antidepressants (Smith et al., 2002) demonstrated some modest efficacy advantage for venlafaxine. Tolerability was considered comparable to that of the reference compounds but no information is provided on the effects of venlafaxine on cognitive function in depressed patients. 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Because of its sequential, concentration-dependent effects on 5-HT and NE uptake pumps, venlafaxine may offer a wider spectrum of efficacy than SSRIs. Because of its absence of effects on other neuroreceptors and fast Na channels, venlafaxine has a better safety and tolerability profile than do TCAs. 

The one study done to date with venlafaxine used a double-blind continuation design rather than a crossover design used with the SSRIs ( Table 7-21). Responders in the double-blind, placebo- and active-controlled acute efficacy phase could elect to remain on double-blind treatment for a 1-year follow-up phase ( 271). The treatment arms in these studies included venlafaxine, trazodone, imipramine, and placebo. At the end of 1 year, 18% of patients on venlafaxine had relapsed versus 32% on placebo. The difference between the venlafaxine and the placebo groups was smaller than that seen between the SSRIs and their respective placebo groups (Table 7-20), consistent with the difference in the design of these studies. 

As with venlafaxine, a double-blind continuation study has been done with nefazodone (see Jable 7-21). Patients who responded to nefazodone, imipramine, or placebo in the acute phase were offered the option of remaining on double-blind treatment for 1 year ( 272). Those patients who chose to participate were then followed up monthly to assess whether efficacy persisted. The relapse rate was 22% on placebo versus 10% on nefazodone and 7% on imipramine. The absolute difference in relapse rates between nefazodone and placebo was similar to that of venlafaxine versus placebo (i.e., 12% to 14%). Thus, maintenance treatment with nefazodone, as with venlafaxine and the SSRIs, reduced the risk of relapse when compared with placebo even when the comparison group had initially responded to placebo and remained on placebo for the maintenance period. 

Given their design differences, no direct comparison can be made between the relative relapse efficacy of SSRIs, venlafaxine, and nefazodone. The bottom line, however, is that both designs demonstrated that maintenance therapy for up to 1 year is important in reducing the risk of a depressive relapse after an initial response. 

A double-blind continuation study has been conducted with mirtazapine. As with venlafaxine and nefazodone, patients in this acute, double-blind, placebo- and active-controlled study with mirtazapine could remain on the double-blind treatment at the end of the initial 6-week efficacy trial and were then followed up for up to 1 year. There was a statistically significant lower risk of relapse (defined as HDRS > 16) on both mirtazapine (18%) and amitriptyline (28%) in comparison with placebo (53%), indicating that mirtazapine has maintenance efficacy (274). More recently, a 40-week, double-blind, placebo-controlled crossover study was performed with mirtazapine (275). Patients maintained on this drug had less than half the likelihood of relapsing than those patients switched to placebo (i.e., 19.7% versus 43.8%, p <0.01). 

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