Serotonin-Norepinephrine Reuptake Inhibitors
Several antidepressants have dual action at both serotonergic and noradrenergic receptors. The most notable are the serotonin/norepinephrine reuptake inhibitors, particularly extended-release venlafaxine (Wyeth’s Effexor XR) and milnacipran (bioMerieux-Pierre Fabre’s Ixel/Dalcipran, Asahi Kasei/Janssen-Kyowa’s Toledomin; available only in France and Japan). The noradrenergic and specific serotonergic antidepressants (NaSSAs) mirtazapine (Organon’s Remeron/Remergil), nefazodone (Bristol-Myers Squibb’s Serzone/Dutonin/Nefadar/Reseril), and reboxetine (Pfizer’s Vestra/Edronax) also fall into this class, but nefazodone is associated with severe liver dysfunction and reboxetine, a noradrenergic agent only, is used only minimally. The two most popular drugs in the serotonin/norepinephrine reuptake inhibitor class, extended-release venlafaxine and milnacipran, are discussed in detail in this section.
Mechanism Of Action
Like the selective serotonin reuptake inhibitors, the serotonin/norepinephrine reuptake inhibitors inhibit the serotonin reuptake transporter, and, like the older tricyclic antidepressants, they inhibit the norepinephrine reuptake transporter. However, the serotonin/norepinephrine reuptake inhibitors are considered an improvement on the tricyclic antidepressants because they do not affect the histamine, acetylcholine, and adrener-gic receptors and therefore do not cause the severe weight gain, dry mouth, and hypotension associated with tricyclic antidepressants. Because serotonin/norepinephrine reuptake inhibitors act on both serotonergic and noradrenergic systems, they are also called noradrenergic and specific serotonergic antidepressants. Venlafaxine is more potent in inhibiting serotonin than in inhibiting norepinephrine. Conversely, milnacipran is twice as potent in inhibiting norepinephrine reuptake as it is in inhibiting serotonin reuptake; hence, milnacipran is sometimes referred to as a norepinephrine/serotonin reuptake inhibitor.
Eli Lilly’s duloxetine (Eli Lilly’s Cymbalta/Yentreve/Ariclaim/ Xeristar) is newly launched in the United States and Europe and is in phase III trials in Japan. In most markets, it is approved for more than one indication outside of psychiatry. In the United States, duloxetine is approved for the treatment of major depression and pain caused by diabetic peripheral neuropathy — it is the first drug approved for diabetic peripheral neuropathy. In August 2004, the FDA gave duloxetine final approval as treatment for depression under the trade name Cymbalta. In September 2004, also under the name Cymbalta, the agency gave the antidepressant approval to treat pain caused by diabetic peripheral neuropathy. Lilly and Quintiles Transnational are in a five-year commitment to copromote duloxetine for depression in the United States. In Europe, duloxetine is approved for the treatment of major depression and SUI (Yentreve/Ariclaim).
Like all serotonin/norepinephrine reuptake inhibitors, duloxetine acts on both serotonergic and noradrenergic systems; studies by Lilly demonstrate that duloxetine inhibits serotonin and norepinephrine equally.
The labeling for duloxetine cites four randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There have been no studies to date evaluating the use of duloxetine for the treatment of minor depression; therefore, this section discusses only major depression trials.
Duloxetine proved significantly more effective than placebo and fluoxetine in an eight-week trial. In one eight-week, double-blind, multicenter study, patients (n = 173) with major depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were given 40-120 mg per day of duloxetine, 20 mg per day of fluoxetine, or placebo. The primary measure of efficacy was a reduction in the 17-item Hamilton Rating Scale for Depression (HAM-D) for depression. At end point, duloxetine was significantly better than placebo or fluoxetine. Furthermore, duloxetine-treated patients showed greater, statistically significant improvement on the 17-item HAM-D anxiety subscale relative to fluoxetine-treated patients. In this same trial, duloxetine’s side effects were similar to fluoxetine’s: duloxetine- and fluoxetine-treated patients reported similar frequency of nausea, dry mouth, insomnia, and sexual dysfunction. It is important to note that the purpose of the fiuoxetine treatment group was not to compare differences in efficacy between duloxetine and fiuoxetine but to assess the sensitivity of the study for detection of efficacy in the event that the duloxetine treatment failed to separate from placebo.
High doses of duloxetine were shown effective in a longer-term study, using 80-120mg/day of duloxetine (60mg/day is recommended in the drug’s labeling). In a 52-week, multicenter, open-label, multinational clinical trial, outpatients (n = 1,279) with major depression (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and having a Clinical Global Impressions-Severity of Illness Scale (Clinical Global Impressions-Spain) score greater than 3 at the first and second visits were monitored for one year. The primary end points of this study were the safety and efficacy of duloxetine at 40 mg twice daily and 60 mg twice daily. The secondary objectives were the efficacy of long-term duloxetine treatment and patient quality of life based on the Clinical Global Impressions-Spain, the 17-item HAM-D, the Beck Depression inventory (BDI), the Patient Global Impressions-Improvement Scale (PGI-Italy), and the Sheehan Disability Scale. At the end of the trial, the mean changes on all scales showed highly significant improvements in all assessment times. Treatment-emergent adverse events reported were nausea, insomnia, headache, somnolence, dry mouth, dizziness, constipation, sweating increase, anxiety, diarrhea, and fatigue. Events that led to discontinuation from the trial were nausea, somnolence, vomiting, hypomania, pregnancy, dizziness, insomnia, and hypertension.
Of the 1,039 patients in this study who did not have hypertension at baseline, 46 of these patients met criteria for sustained hypertension during the course of the study. Although 23 of these 46 patients returned to baseline blood pressure while taking duloxetine and 2 patients no longer met criteria for hypertension, 21 of these patients met the criteria for sustained blood pressure and did not return to their baseline pressure.
Duloxetine will not offer any advantages over currently available drugs in the area of sexual dysfunction. Because of its mechanism of action, which is similar to that of venlafaxine, the compound is likely to cause sexual dysfunction and to share venlafaxine’s delayed onset of action. In a long-term study that measured improvement of sexual dysfunction in patients receiving duloxetine or paroxetine, rates of acute sexual dysfunction were similar in paroxetine- and duloxetine-treated patients, and both groups had rates significantly higher than patients treated with placebo, as measured by the Arizona Sexual Experience questionnaire (ASEX). However, responses to certain questions on the ASEX showed that 70.9 % of patients receiving duloxetine experienced improvement over time in sexual function while only 57.6 % of patients taking paroxetine experienced improvement.
Venlafaxine (Wyeth’s Effexor/Effexor XR) was first approved for major depression in the United States in 1994. It has since received approvals for the treatment of generalized anxiety disorder and social anxiety disorder. It is now available in all the major markets except Japan, where it is in Phase III development for major depression in immediate-release and extended-release (XR; also called “once-daily”) formulations.
Venlafaxine blocks the uptake of serotonin and norepinephrine almost equally and has little effect on muscarinic, cholinergic, histaminergic, or noradrenergic receptors. It also has some dopaminergic activity, but the extent to which this activity translates into clinical benefit is unclear. Its mechanism of action in norepinephrine reuptake inhibition is like that of the tricyclic antidepressants, but because of its serotonergic component, its side-effect profile is more like that of the selective serotonin reuptake inhibitors.
Venlafaxine has not been evaluated in any large placebo-controlled trials for the treatment of minor depression, but it has been evaluated for the treatment of major depression. Extended-release venlafaxine, 75-225 mg/day, was compared with placebo in two placebo-controlled, short-term, flexible-dose studies in adult patients diagnosed with DSM-III-R major depression (n = 278) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition major depression (n = 191). Responses to treatment were evaluated using the MADRS, HAM-D, and Clinical Global Impressions scales, and in both the 8-week and 12-week studies, extended-release venlafaxine performed significantly better than placebo as measured on all three scales. The most common side effects in both trials were nausea, insomnia, and somnolence. The incidence of nausea was highest during the first two weeks of treatment.
The efficacy of extended-release venlafaxine has also been compared with that of other antidepressants. A meta-analysis of randomized, double-blind, controlled trials of extended-release venlafaxine, selective serotonin reuptake inhibitors, and tricyclic antidepressants found extended-release venlafaxine had higher response rates than either tricyclic antidepressants or selective serotonin reuptake inhibitors. An analysis of pooled data from eight comparable randomized, double-blind trials of venlafaxine, selective serotonin reuptake inhibitors, and placebo for major depression found remission rates were higher for venlafaxine than for the selective serotonin reuptake inhibitors or placebo.
Venlafaxine has some drawbacks. At doses greater than 200 mg/day, patients may experience sustained, dose-dependent increases in blood pressure; consequently, patients taking the higher doses of this agent require careful monitoring. Although the recommended dose range for venlafaxine is 75-250 mg per day (most patients with minor depression are prescribed 75-150 mg/day), some physicians will prescribe higher doses if necessary; patients taking these higher doses are at highest risk for increased blood pressure. Moreover, like the selective serotonin reuptake inhibitors, venlafaxine can disrupt sleeping patterns and cause sexual dysfunction. The most common side effect associated with venlafaxine is nausea. Approximately 10-20% of patients also report dizziness, headache, and dry mouth.
Milnacipran (bioMerieux-Pierre Fabre’s Dalcipran/Ixel, Asahi Kasei’s Toledomin) was approved for the treatment of depression in France in September 1997 and in Japan in October 2000. In the United States, milnacipran is in Phase III trials for fibromyalgia (these trials are being conducted by Cypress Bioscience). In January 2004, Cypress, Forest Laboratories, and Pierre Fabre entered into a development and marketing agreement for milnacipran in the United States. Although Cypress licensed the rights to develop and sell milnacipran for any indication, milnacipran will likely be developed and sold only for chronic pain indications (e.g., fibromyalgia, irritable bowel syndrome).
Milnacipran inhibits norepinephrine and serotonin reuptake at a ratio of approximately 2.5:1. This ratio is slightly lower in tricyclic antidepressants and serotonin/norepinephrine reuptake inhibitors and significantly lower in selective serotonin reuptake inhibitors.
No large, placebo-controlled trials have evaluated the efficacy of milnacipran in the treatment of minor depression, but the agent (20, 50, and lOOmg/day) has been compared with placebo in three double-blind trials with both outpatients and inpatients diagnosed with DSM-III or DSM-III-R major depression. In one study, which compared 50mg/day of milnacipran with placebo, response to treatment was evaluated using the MADRS and the 17-item HAM-D as the primary measure in inpatients (n = 58) with major depression. At the four-week end point, patients taking milnacipran experienced significant improvement as measured by the MADRS and the HAM-D. The second study, which compared 50 mg/day of milnacipran with placebo, measured response to treatment in depressed inpatients (n = 101). At the six-week end point, a significant difference between milnacipran and placebo was observed on the 17-item HAM-D. Although the difference on the MADRS favored milnacipran, the difference was not significant. In the third study, which compared 25, 50, and 100 mg/day of milnacipran with placebo, response to treatment was measured using the MADRS and the 17-item HAM-D in outpatients (n = 263) with major depression. At the eight-week end point, patients receiving 50 mg/day of milnacipran experienced significant improvement as measured by the MADRS and 17-item HAM-D; patients receiving 100 mg/day were significantly better only on the MADRS; and changes in patients receiving the lowest dose, 25 mg/day, were not significantly different from changes in patients receiving placebo.
Milnacipran has also been compared with the TCA imipramine and the selective serotonin reuptake inhibitors fluoxetine and fluvoxamine. In a meta-analysis of six clinical trials, 50 mg/day of milnacipran was found to be similar in efficacy to 100-150 mg/day of imipramine, although milnacipran was better tolerated (Briley M, 1998). In a meta-analysis of two studies comparing 50 mg/day of milnacipran with 20 mg/day of fluoxetine and 100 mg/day of fluvoxamine, milnacipran was found to be significantly more effective than the selective serotonin reuptake inhibitors on the MADRS and the HAM-D.
The side effects associated with milnacipran are similar to those of venlafaxine and are dose-dependent. Additional side effects specific to milnacipran — most likely because milnacipran is more potent than venlafaxine at inhibiting norepinephrine — are vertigo, increased sweating, hot flashes, and painful urination.