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Combining antidepressants tied to better outcomes than monotherapy

JAMA Psychiatry
Reuters Health - 24/02/2022 - Combination antidepressant therapy, particularly with an antagonist of presynaptic alph2-autoreceptors, may be an effective option for patients who don't respond to monotherapy and a possible first-line treatment for severe depression, researchers suggest. 

"Antidepressant combination therapy has been implemented as a possible second-step treatment in practice guidelines; however, in light of the solid evidence for specific combinations that our findings provide, we believe these should be favored over other second-step treatments that are less evidence-based, such as switching an antidepressant or increasing the dose," Dr. Christopher Baethge of the University of Cologne and Dr. Jonathan Henssler of Charite University Medicine in Berlin told Reuters Health in a joint email. 

"Beyond that," they said, "as we found indications of complementary mechanisms and synergistic effects in specific combinations, exceeding a mere 'higher dose - higher efficacy - lower tolerability' effect, we believe there is good reason to also consider these combinations as a first-line antidepressant treatment strategy in some severe cases of depression." 

As reported in JAMA Psychiatry, Dr. Baethge, Dr. Henssler and colleagues searched the literature from inception through 2020 for randomized clinical trials comparing combinations of antidepressants with antidepressant monotherapy in adults with acute depression. Ultimately, they included 39 trials involving 6,751 patients. 

The main outcome was efficacy measured as standardized mean difference (SMD). 

Combination treatment was significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31). 

Combining a reuptake inhibitor with an antagonist of presynaptic alpha2-autoreceptors was superior to other combinations (SMD = 0.37). 

Combining bupropion was not superior to monotherapy (SMD = 0.10). 

Numbers of dropouts and dropouts due to adverse events did not differ between combination therapy (odds ratio, 0.99) and monotherapy (OR, 1.17). 

Studies were heterogeneous, and less than half (38%) were considered to be at low risk of bias. Nevertheless, the results persisted across prespecified secondary outcomes (e.g., response, remission, change from baseline in rating scale scores) and sensitivity and subgroup analyses, including analyses restricted to studies with low risk of bias. 

Dr. Jonathan Alpert, Psychiatrist-in-Chief, Montefiore Medical Center in New York City pointed to a number of limitations in the meta-analysis, including that some of the studies: 

- Involved mianserin, which is not approved in the U.S., although has some limited use in the UK and other European countries and Australia. 

- Involved the combination of a tricyclic antidepressant (e.g., trimipramine or amitriptyline) and a monoamine oxidase inhibitor (e.g., phenelzine or isocarbazide), which, he said, "are rarely prescribed in contemporary practice as monotherapy, and even less so as combination treatment, given serious side-effects and drug interactions." 

"The bulk of remaining studies looked at the combination of mirtazapine with serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors," he noted. "This is a generally well-regarded combination, though mirtazapine has significant side-effects, including weight gain and drowsiness, which makes it difficult to tolerate for many patients, particularly younger patients or patients who already have elevated BMIs." 

Further, he said, the included studies "are exclusively short-term trials (4-12 weeks). In the absence of studies carried out longer, we cannot answer clinically important questions such as whether people tolerate and remain adherent to combinations as well as single-agent treatments in the longer run." 

In addition, he noted, "The study is limited to combination antidepressants. Other major classes -- particularly atypical antipsychotics (e.g., aripiprazole) -- are now widely used and FDA-approved as augmenting agents for antidepressants in the treatment of individuals with treatment-resistant unipolar depression." 

Dr. Alexandre Dombrovski, Associate Professor of Psychiatry at the University of Pittsburgh, also commented by email. "The findings are valid, clinically important and fairly presented." However, he noted, "we don't know if trying a monoamine reuptake inhibitor and an alpha2 autoreceptor antagonist consecutively would have been as effective." 

"Perhaps more important, while these studies in aggregate did not detect an increase in adverse effects or dropout with the alpha2/reuptake inhibitor combination over monotherapy, adverse effects reports and dropout in acute antidepressant trials are influenced by participants' mood: people who are getting better are less likely to complain." 

"Alpha2 agents are certainly not without adverse effects," he added. "We should consider revising guidelines nevertheless, but I would have a high threshold for using this combination as first-line therapy for the above reasons; this option should probably be promoted in the algorithm for non-responders." 

SOURCE: https://bit.ly/351eknE JAMA Psychiatry, online February 16, 2022. 

By Marilynn Larkin 

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