Combination Antidepressant Therapy More Effective for MDD Than Fluoxetine Alone
By Deborah Brauser
Medscape Medical News
December 23, 2009 — Mirtazapine used in combination with fluoxetine, venlafaxine, or bupropion is more effective and as well tolerated in treating major depressive disorder (MDD) as fluoxetine alone, according to results from a new double-blind comparison study published in the December issue of the American Journal of Psychiatry.
In fact, patients treated with these combinations had mean differences of 4.5 to 4.8 points on the Hamilton Depression Rating Scale (HAM-D) by day 42 compared with those treated with monotherapy.
"The study results, which add to a growing body of evidence, suggest that use of antidepressant combinations from treatment initiation may double the likelihood of remission compared with use of a single medication," write Pierre Blier, MD, PhD, University of Ottawa Institute of Mental Health Research, Ontario, Canada, and colleagues.
"Not only is remission the goal of treatment for major depression, but achieving it as early as possible is of critical importance," they add.
Past Remission Rates Needed Improvement
Although a response to a single antidepressant is generally obtained in about 50% to 75% of patients in a first trial, remission rates are generally only around 30% with a single agent, report the study authors.
"This is a disappointing result indicating that additional treatment measures must be taken in about two-thirds of patients," they write.
The current standard of care is drug substitution, with or without an elimination period. However, because it is accepted practice that an antidepressant drug trial should last at least 6 weeks, 2 consecutive attempts using different medications would require almost 3 months, with patients often stopping treatment during this period.
Although maintaining a first drug and then adding a second to obtain remission is another common approach, this method has not proven to be any more effective than drug substitution, and it still requires a first trial completion and delayed response or remission for most patients, note the authors.
Past studies have shown that MDD patients treated with mirtazapine and the selective serotonin reuptake inhibitor (SSRI) paroxetine showed more improvements than those treated with either drug alone.
Mirtazapine + Antidepressants Other Than SSRIs
In this study, Dr. Blier and his team sought to compare whether mirtazapine plus antidepressants other than SSRIs, given from treatment initiation on, could produce improvements superior to those from fluoxetine alone.
A total of 105 patients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria for MDD (and having a score of at least 18 on the HAM-D) were enrolled at 3 sites, including 1 in Florida and 2 in Canada. The patients were then randomly assigned to 4 groups and received a 20 mg/day dose of fluoxetine plus placebo (n = 28) or a 30 mg/day dose of mirtazapine plus the fluoxetine dose (n = 25), a 225 mg/day dose of venlafaxine (titrated in 14 days, n = 26), or a 150 mg/day dose of bupropion (n = 26).
Given mirtazapine's association with potential weight gain, "we selected more activating and weight-neutral antidepressant drugs...to combine with it," explain the study authors.
The patients' psychotropic drugs were discontinued after initial screening, but clonazepam, zopiclone, and zolpiderm were allowed to manage anxiety and other symptoms.
The primary outcome measure was a change in HAM-D score. Treatment response was defined as a sustained improvement of 50% or more, and remission was defined as a HAM-D score of 7 or less.
The investigators also used the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impressions (CGI) severity and improvement scales for their evaluations.
Mirtazapine + Venlafaxine Group Performs Best
Results at the end of the study showed that although the bupropion, fluoxetine, and venlafaxine combination groups had more patients that achieved a treatment response compared with the group treated with fluoxetine alone (65%, 68%, and 73% vs 54%, respectively), this was not found to be statistically significant.
However, all 3 combination groups did have significantly greater improvements on the HAM-D compared with those receiving monotherapy.
The proportion of patients achieving a sustained remission was also statistically different between the fluoxetine-only treatment group (25%) and both the fluoxetine combination (52%) and the venlafaxine combination (58%) groups. The 46% rate from the bupropion combination group was not deemed statistically different.
Montgomery-Asberg Depression Rating Scale score differences at day 42 between the patients treated with the fluoxetine monotherapy and those treated with the fluoxetine, bupropion, and venlafaxine combinations were 4.9, 4.6, and 5.8 points, respectively, none of which reached statistical significance.
There were also no significant differences between the treatment groups on the CGI severity and improvement scores.
For treatment-related adverse events, there were no significant changes in sitting systolic blood pressure or pulse in any of the groups. Although the monotherapy group did not experience significant increases in weight (mean, +0.1 kg), those in the combination groups did (fluoxetine, 3.1 kg; bupropion, 2.7 kg; venlafaxine, 2.2 kg; P < .001).
Other adverse events and drop-out rates were comparable among all groups.
"The combination of mirtazapine and venlafaxine seemed to perform particularly well; the group receiving this treatment achieved the highest remission rate, had the highest number of patients with a score of 1 [not at all] on the CGI severity scale, and had no dropouts attributed to lack of efficacy," report the authors.
Among all patients who had had a marked response, a blind discontinuation of 1 agent produced a relapse in about 40% of the cases.
Discontinuation Phase
A 6-month "discontinuation and prolongation phase" followed-up 66 of the patients. In this phase, those from both the fluoxetine combination and monotherapy groups switched to receiving fluoxetine only. The other 2 combination groups switched to receiving mirtazapine monotherapy.
Results from this part of the study showed that "about half the patients who initially received combination treatment with mirtazapine and fluoxetine or venlafaxine relapsed, compared with about a quarter of those who initially received fluoxetine monotherapy or combination treatment with mirtazapine and bupropion," report the study authors. About half of the relapses occurred within the first month of the prolongation.
"The observations in the prolongation phase have practical implications for the use of antidepressant combinations from treatment initiation," write the study authors. "Not only is the approach as well tolerated and more efficacious than monotherapy, but if a drug becomes intolerable due to side effects or if the combination becomes a financial burden, 1 drug could be stopped."
"In fact, more than half the patients in the 6-month prolongation did not relapse," they add.
Strong Data
"In a very well controlled fashion, the investigators have demonstrated the importance of combination therapy in the treatment of depression," said Elliott Richelson, MD, professor of psychiatry and pharmacology at the Mayo Clinic College of Medicine, Jacksonville, Florida, in an interview with Medscape Psychiatry. Dr. Richelson was not associated with this trial.
"The standard of care for treatment of depression is remission, which is total absence of any signs or symptoms of the depression," he added. "If you don't achieve remission, then it's likely that you're going to have a recurrence of full-blown depression down the road by several months or a year. The remission rates in this relatively short study were excellent. They're the levels you usually see in response."
Dr. Richelson said that good combination comparison studies of antidepressants are rare. "I think this is unique in that regard. Although each group only had about 20 patients, these are expensive, hard studies to do, and the data found here is strong."
He continued, "For years, [California psychopharmacologist] Dr. Steven Stahl has said that the combination of mirtazapine and venlafaxine is 'California rocket fuel,' but I wasn't aware of any controlled trial looking at that. The results here for that combination are quite impressive, as are the combinations with the other drugs in this study. Going forward, this is a good approach in everyday clinical practice to treat depression."
He said that he has only 1 minor caution: "Whenever you start 2 drugs at the same time, if you get a serious side effect such as a rash, you don't know which drug did it and you have to stop both. That's a rare event, but that's why in my practice I generally don't start 2 drugs at the same time. But given the importance of getting patients who are depressed into remission, I think this study gives us good guidance as to how to approach that."
This study was supported by Organon Pharmaceuticals. The study authors have reported financial relationships with Organon, Biovali, Lundbeck, Eli Lilly, Wyeth, and AstraZeneca. Dr. Richelson is a coinventor on patents that have been issued on potential antidepressant technology licensed to AstraZeneca.
Am J Psychiatry. Published online December 15, 2009.
