When one antidepressant does not provide enough relief from Depression, patients and clinicians often wonder whether combining two antidepressants might work better than using one medication alone. Combination strategies are common in psychiatry, especially for people with more severe or treatment-resistant Depression. But what does the research show?
Two widely cited studies published in the American Journal of Psychiatry explored a specific version of this question: what happens when treatment for Major Depressive Disorder (MDD) starts with two antidepressants instead of one. An early study led by Pierre Blier suggested that starting with two medications could improve remission rates. A larger trial, the CO-MED study led by A. John Rush, found that two combinations offered no advantage over a single medication from the outset. Newer pooled research has kept the question open.
Understanding these studies can help patients make informed decisions about Depression treatment, and appreciate why other evidence-based options, such as transcranial magnetic stimulation (TMS), may be worth discussing when medication alone is not enough. Medication changes should always be made with your prescriber, never on your own.
Why Consider Combining Antidepressants?
Most antidepressants act on neurotransmitter systems such as serotonin and norepinephrine, and different medications affect those systems in different ways. The CO-MED authors outlined several reasons a combination might work better as an initial treatment:
- It might affect a wider range of neurotransmitter systems
- It might benefit a broader range of patients, since some medications work for some people but not others
- A synergy between medications might produce a faster benefit, so fewer patients would drop out of treatment
- Other branches of medicine, such as asthma care, often start with combination treatment
However, using two antidepressants also carries trade-offs. In these trials, combinations were associated with weight gain, more side effects in some pairings, and, in CO-MED, extra care around drug interactions. At the time of CO-MED, treatment guidelines did not recommend combinations as a first treatment step, and the risk of serious or intrusive side effects had not been fully evaluated. Researchers therefore tested whether the potential benefits outweigh the risks.
The Blier Study (2010): Promising Early Results
In 2010, Dr. Pierre Blier and colleagues published a double-blind randomized trial examining whether antidepressant combinations started from the beginning of treatment were more effective than monotherapy.
Study design. The trial enrolled 105 adults with moderate-to-severe MDD at three sites in the United States and Canada. Participants were randomly assigned to one of four groups for six weeks:
- Fluoxetine alone
- Mirtazapine plus fluoxetine
- Mirtazapine plus venlafaxine
- Mirtazapine plus bupropion
The primary outcome was the change in the Hamilton Depression Rating Scale (HAM-D) score, with remission defined as a sustained score of 7 or less.
Key findings. All three combination groups improved significantly more than the fluoxetine-alone group on the HAM-D. Remission rates were 25% with fluoxetine alone, compared with 52% for mirtazapine plus fluoxetine, 58% for mirtazapine plus venlafaxine, and 46% for mirtazapine plus bupropion. The difference in remission was statistically significant for the fluoxetine and venlafaxine combinations but not for the bupropion combination. The authors concluded that starting treatment with two antidepressants might double the likelihood of remission compared with a single medication.
Two details deserve attention. First, response rates (at least a 50% improvement) were not significantly different among the groups, and neither was the time to response or remission, so the combinations produced more remissions within six weeks rather than a faster onset of benefit. Second, patients in all three combination groups gained weight over the six weeks (an average of about 2 to 3 kilograms), while patients on fluoxetine alone did not. The authors found the combinations otherwise as well tolerated as fluoxetine alone, and 15% of participants dropped out overall.
Why this study generated interest. Remission rates with a single antidepressant are often disappointingly low, and Blier’s team noted that leaving patients with residual symptoms makes a full relapse more likely. The trial suggested that combining medications early might improve outcomes. But important questions remained: the study was small, had no placebo group, used a 20 mg dose of fluoxetine that was not optimized, and lasted only six weeks. The next step was a larger test.
The CO-MED Trial (2011): A Larger Test
The Combining Medications to Enhance Depression Outcomes (CO-MED) trial was designed as a proof-of-concept study to test whether either of two combinations would produce higher remission rates at 12 weeks, and secondarily at seven months, than a single medication.
Study design. CO-MED enrolled 665 outpatients with chronic and/or recurrent, nonpsychotic MDD at six primary care and nine psychiatric care sites, a sample larger than many earlier antidepressant studies. Participants were randomly assigned to one of three groups:
- Escitalopram plus placebo
- Escitalopram plus bupropion
- Venlafaxine plus mirtazapine
Treatment followed a measurement-based approach to dosing, with a 12-week acute phase and follow-up through seven months. The trial was single-blind: participants did not know what the second medication was, but the physicians and research coordinators did.
Acute phase results (12 weeks). Remission rates were nearly identical: 38.8% for escitalopram alone, 38.9% for escitalopram plus bupropion, and 37.7% for venlafaxine plus mirtazapine. Response rates were also similar, ranging from 51.6% to 52.4%.
Long-term results (7 months). Remission rates ranged from 41.8% to 46.6% and response rates from 57.4% to 59.4%, again with no statistically significant differences among the groups.
Side effects. The venlafaxine-plus-mirtazapine group had a greater side effect burden than escitalopram alone, including more worsening side effects, at both 12 weeks and seven months (an average of 5.7 worsening adverse events compared with 4.7 at 12 weeks). The escitalopram-plus-bupropion group had modestly more side effects than escitalopram alone as well. Dropout rates did not differ among the groups, but only about 72% of all participants completed the full 12 weeks.
Why Did the Two Studies Reach Different Conclusions?
The apparent contradiction is not fully explained, and the CO-MED authors tested several possibilities directly. Several differences stand out:
- Size and length. Blier’s study enrolled 105 participants over six weeks; CO-MED enrolled 665 over 12 weeks and seven months. Smaller, shorter studies are more vulnerable to chance findings, and the CO-MED authors noted that six weeks may be too brief for fluoxetine to show its full benefit.
- The comparison group. Fluoxetine alone produced remission in 25% of Blier’s participants, while escitalopram alone produced remission in 38.8% of CO-MED participants. The combinations also performed differently across the studies: 46% to 58% in Blier, about 38% in CO-MED.
- Patients. About two-thirds of Blier’s participants had melancholic features, compared with about 20% in CO-MED, and CO-MED enrolled many more people with chronic Depression, along with many with anxious features and other co-occurring conditions. The CO-MED team analyzed whether chronicity or melancholia explained the gap and concluded that neither seemed to account for it.
- Dosing. CO-MED’s mean mirtazapine dose was about 20 mg a day, lower than Blier’s 30 mg. The authors checked the 86 participants who reached the higher venlafaxine and mirtazapine doses; their remission rate (33.7% at 12 weeks) did not suggest underdosing was the cause.
- Design and outcomes. The studies also used different rating scales and remission definitions, and Blier’s trial was double-blind while CO-MED was single-blind.
The CO-MED authors acknowledged limits of their own, including that their sample may not represent all outpatients with chronic or recurrent Depression, that clinicians were not blinded, and that their findings depend on the doses used. They also noted that they could not rule out an unknown baseline difference between the two groups of participants.
What Newer Research Shows
Both trials are now more than a decade old, so it is worth asking what pooled evidence says. A 2022 meta-analysis in JAMA Psychiatry by Henssler and colleagues combined 39 randomized trials involving 6,751 patients (published between 1977 and 2020). Overall, combining antidepressants was associated with better outcomes than monotherapy, with a small-to-moderate average advantage and no increase in dropouts. The advantage was clearest when a reuptake inhibitor (such as an SSRI or SNRI) was combined with an agent such as mirtazapine, and it did not extend to combinations involving bupropion.
That finding is not settled. A published critique argued that the meta-analysis may overstate the true benefit, pointing out that the pooled result sits alongside several large trials with negative results. In other words, the evidence on antidepressant combinations is mixed, and the answer may depend on which medications are paired and for which patients.
What Do These Studies Mean for Patients?
Taken together, the research does not support the idea that two antidepressants are automatically better than one. The largest single trial found no advantage from either combination as a first-step treatment, and the pooled evidence suggests any average benefit is modest and specific to certain pairings.
For most patients, treatment begins with a single medication because it is simpler, easier to assess, and associated with fewer side effects and interactions. It also leaves room to stop one drug if it becomes intolerable or a financial burden, an advantage Blier’s team noted for combinations as well.
It’s worth noting what these trials did not test. Both studied people starting treatment, not people who had already failed a medication, and neither tested what happens when a second medication is added after the first one fails. Blier’s team noted that it has not been proven that adding a drug is more effective than switching drugs. Whether a combination makes sense for a specific patient is an individual decision to make with a prescriber.
The Limitations of Medication Strategies
Even in the large CO-MED study, only about 39% of patients had remitted after 12 weeks, and fewer than half (41.8% to 46.6%) at seven months. Most participants therefore did not become fully well despite structured medication management. Blier’s group also noted that patients left with residual symptoms are more likely to relapse.
When TMS May Be a Next Step
At Mid City TMS, we frequently see patients who have tried one antidepressant, several medications, or even combination therapy without achieving adequate relief. TMS offers a different approach. Rather than acting through the bloodstream, TMS uses focused magnetic pulses to stimulate brain regions involved in mood regulation.
TMS is FDA-cleared for MDD and has been available since 2008, including for people whose Depression has not responded adequately to antidepressants. It is noninvasive and does not require medication. The most common side effects are mild headache or scalp discomfort. Because TMS is not systemic, it does not carry the weight gain, sexual side effects, or sedation associated with some medications, which is relevant given the weight gain seen with the combinations in Blier’s trial.
Medication Combinations and TMS: Not Mutually Exclusive
TMS can be used with or without antidepressant medication, and in routine practice it is commonly given alongside a patient’s current medications. In a retrospective review of 181 patients at UCLA, use of SSRIs, SNRIs, and other antidepressants was not significantly associated with how patients responded to a six-week TMS course, although that study was exploratory and its authors called for replication before drawing clinical conclusions. Whether and how to adjust any medication during TMS is a decision to make with your prescriber.
Bottom Line
The idea of combining two antidepressants is scientifically appealing, and an early study suggested that it might double remission rates. The much larger CO-MED trial did not confirm that benefit for two combinations used as a first step, and one of them added side effects. Newer pooled research suggests a modest advantage for some pairings but not others, and that conclusion is disputed.
For patients whose Depression persists despite one or more medication trials, a combination may be a reasonable conversation to have with a prescriber, but it is not a guaranteed solution. At Mid City TMS, we believe treatment decisions should be guided by the best available evidence. When medications, alone or in combination, have not led to full recovery, TMS is an FDA-cleared option worth discussing.
If you or a loved one continues to struggle with Depression despite antidepressant treatment, learn how Mid City TMS can help you explore whether TMS may be the next step and contact us today to schedule a consultation.
Sources
Blier, P., Ward, H. E., Tremblay, P., Laberge, L., Hébert, C., & Bergeron, R. (2010). Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study. American Journal of Psychiatry, 167(3), 281–288. https://doi.org/10.1176/appi.ajp.2009.09020186 (Original work published March 1, 2010)
Rush, A. J., Trivedi, M. H., Stewart, J. W., Nierenberg, A. A., Fava, M., Kurian, B. T., … Wisniewski, S. R. (2011). Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study. American Journal of Psychiatry, 168(7), 689–701. https://doi.org/10.1176/appi.ajp.2011.10111645 (Original work published July 1, 2011)