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Antidepressants, Part 1: 100 Years and Counting: Page 5 of 5

Antidepressants, Part 1: 100 Years and Counting: Page 5 of 5

Treatment modalities for depressionTable 1 – Treatment modalities for depression
FDA-approved medications for the treatment of MDDTable 2 – FDA-approved medications for the treatment of MDD
Additional FDA-approved indications for at least one antidepressantTable 3 – Additional FDA-approved indications for at least one antidep...
Four steps of the STAR*D algorithmTable 4 – Four steps of the STAR*D algorithm[2]


Augmentation: get by with a little help from a friend

When antidepressant monotherapy does not provide a satisfactory response to depressive symptoms, one strategy is to augment the antidepressant with another treatment modality. Options are numerous, and many are listed in Table 1. The first medication that was approved by the FDA as an augmentation agent for partial or nonresponse to antidepressant monotherapy was the atypical antipsychotic aripiprazole in 2007. Following this was the approval of quetiapine XR and an olanzapine-fluoxetine combination in 2009. In 2015, brexpiprazole was approved by the FDA as an adjunct to antidepressant monotherapy.

Although not FDA approved, many augmentation strategies and combination therapies (taking 2 antidepressants from different classes) have been used clinically for decades. These include augmentation with lithium, thyroid hormone, psychostimulants, and buspirone. In the 1980s, low doses of a TCA were slowly added to stable doses of an MAOI in patients who were partial responders, a practice that occasionally continues today. Other common antidepressant combinations include an SSRI/SNRI with bupropion, an SSRI/SNRI with a tricyclic antidepressant, and an SSRI/SNRI with nefazodone, trazodone, or mirtazapine. The clinician should be mindful of the pharmacokinetics and pharmacodynamics of the drugs, and choose combinations that have rational complementary mechanisms.

A recent review of augmenting antidepressants with nutraceuticals concluded that there is evidence of efficacy with S-adenosylmethionine (SAMe), L-methylfolate, omega-3 fatty acids, and vitamin D.9 SAMe and L-methylfolate are well established methyl-group donors in the metabolic synthesis of monoamines. The nutraceuticals do not require a prescription. St John’s wort (Hypericum perforatum) has been used for centuries to treat depression, and its mechanism of action appears to be that of a serotonin reuptake inhibitor.

Conclusion: from Coca-Cola to serotonin sub-receptor modulation

The past 100 years have been quite eventful in our understanding of depression and its treatment. However, much remains to be discovered, and it is time to move beyond the monoamine hypothesis of depression.

Part 1 of this article has provided a timeline of the progress made in the development of antidepressant medications since the early 1900s —and an overview of our current armamentarium of antidepressant medications and augmenting agents. Part 2 in the November issue will explore the pharmacokinetic and pharmacodynamic variables that differentiate antidepressants. In addition, the serotonin system is used as a model to explore medication targets to relieve depressive symptoms. Finally, an overview of antidepressants in the pipeline is provided.



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Dr. Miller is Medical Director, Brain Health, Exeter, NH.


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