Q&A: New and Emerging Options for the Treatment of Major Depressive Disorder

Course Director

Ian A. Cook, MD

Ian A. Cook, MD
David Geffen School of Medicine at UCLA
Semel Institute for Neuroscience and Human Behavior
UCLA Brain Research Institute
Los Angeles, California

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Part 1 of a 2-part series

Dr. Cook provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Current treatments available for major depressive disorder (MDD) are only partially effective. Although the pipeline of antidepressants is not very robust, some new agents have recently been approved, and there are research efforts underway to further expand upon the standard treatment options. Among the new and emerging therapies for MDD, the majority can be classified as monoaminergic agents, but novel treatments targeting the glutamate neurotransmitter and other systems are under investigation as well. In this activity, Dr. Ian A. Cook provides a concise overview of the latest advances and new directions in the treatment of MDD.


This activity is supported by an educational grant from Lilly USA, LLC. Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Ian A. Cook, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Allergan, Inc.; Aspect Medical Systems, Inc./Covidien; and NeuroSigma, Inc.
Grant/Research Support from Aspect Medical Systems, Inc./Covidien and NeoSync.
Speakers Bureau participant with Neuronetics.
Shareholder in NeuroSigma, Inc.
Other Financial or Material Support from NeuroSigma, Inc. in the form of royalties/patents.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What is the development status of the different newer monoaminergic treatment options for major depressive disorder (MDD)?

Dr. Cook: The past five decades have been an era where the monoamine neurotransmitters have really dominated the trends in psychopharmacology. The triad of norepinephrine, serotonin, and dopamine has been the primary foundation both for new drug development and for our conceptual models about psychiatric illnesses, as well as treatment.

When the SSRI [selective serotonin reuptake inhibitor] agents were introduced, there was traction for the idea that we could have agents that affected a single neurotransmitter system more or less purely, instead of, for example, the way that the tricyclic antidepressants had binding to targets in all three systems. As we ran historically through the SSRIs, there was a tendency for the selectivity to become greater and greater by design, with an even greater affinity for the serotonin reuptake transporter, and even less affinity for other targets.

In parallel with this, the idea of the dual-action reuptake inhibitors [serotonin-norepinephrine reuptake inhibitors (SNRI)] was marked by the introduction of products such as venlafaxine, duloxetine, and now desvenlafaxine, or products that had affinity at receptors as well as at the reuptake pumps, like vilazodone. A new dual reuptake SNRI agent, levomilnacipran, was approved by the US FDA in July of this year. Here the published data show efficacy greater than placebo, but how that compares with other agents is a question where we are still eagerly awaiting more data from clinical trials.1,2

Narrator: Similarly, another new antidepressant, vortioxetine, was also recently approved by the FDA.3 The approval was based on safety and efficacy data from six multicenter, randomized, double-blind trials of adult patients comparing vortioxetine with placebo. This agent is an inhibitor of serotonin reuptake, which is thought to be its key mechanism of action. It also acts as an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors. It is not yet clear how these additional actions may contribute to the agent’s antidepressant effect.

Dr. Cook: Newer compounds in the development pipeline include the triple reuptake inhibitors (TRIs) or other variations on that reuptake inhibition theme, as ways to alter neurotransmission to the synapse, or agents with affinity for dopaminergic targets.

Narrator: Amitifadine (EB-1010) is an example of a TRI currently undergoing phase 3 testing.4 Some of the other monoaminergic agents currently being evaluated in phase 3 trials include the D2 receptor partial agonist brexpiprazole (also called OPC-34712)5 and the selective norepinephrine transporter (NET) inhibitor edivoxetine (LY2216684).6 Many other agents are being evaluated in phase 2 and earlier clinical trials.

Dr. Cook: The field is, of course, eagerly awaiting the publication and presentation of those results.

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What is the rationale for targeting the glutamate neurotransmitter system in the treatment of depression, and is there any evidence to support the use of ketamine and other novel glutamatergic agents in patients with MDD?

Dr. Cook: Glutamate is arguably the most abundant neurotransmitter in the brain. It has excitatory activity at its main ionotropic receptors—the NMDA receptor, the AMPA receptor, and the kainate receptor. NMDA receptor (NMDAR) antagonists include agents like ketamine, riluzole, and memantine, along with compounds like amantadine, phencyclidine or PCP, and dextromethorphan, or DXM.

Several other compounds in this area are now in development. One is the NMDAR antagonist AZD6765, also now called lanicemine. Originally examined for use in treating stroke, there are now published data supporting its use as an intravenous agent for treatment-resistant depression.7 There's also a partial agonist at the glycine site on the NMDA receptor called GLYX-13, and this compound is in phase 2 trials now, after some early positive results were reported at meetings in late 2012.8,9

In addition to the ion channel ionotropic receptors for glutamate, there are also metabotropic glutamate receptors. These are G-protein–coupled receptors, and thus activate biochemical cascades intracellularly as opposed to opening ion channels with the NMDA and AMPA receptors. Some of these cascades actually appear to modulate the activity of the NMDA receptors. Here, again, there are a number of compounds which are in the pipeline in phase 1, phase 2, and phase 3 trials. And everyone is eagerly awaiting the clinical [trial] results.

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Are there any promising future treatments for MDD on the horizon that have novel mechanisms of action?

Dr. Cook: There's a great deal of evidence that major depression is marked by dysregulation of other body functions besides those that lead to our classic symptoms. These include things like blunted activity in the HPA axis or chronic elevation of inflammatory markers.

Efforts to target these phenomena have met with somewhat mixed results over the years. On the one hand, it has been reported that the administration of nonsteroidal anti-inflammatory agents have attenuated the effects of the SSRI antidepressants—and this has been found and reported both in animal models and in the data from the STAR*D study.10

On the other hand, the agent infliximab, which is an antagonist for the inflammatory cytokine TNF showed no benefit in a general depression population, but did show significant improvements over placebo in those individuals who had elevated biomarkers of inflammation at the start of the study,11 suggesting that an anti-inflammatory agent may have benefits when people have evidence of an inflammatory component to their depression.

Where does this leave the field? I think the most sensible way to think about this is that we may end up with a situation much like [the] one seen in the breast cancer world, where, for example, if one has a certain receptor expressed by the tumor, then treatments that target that receptor may be of great benefit. And if one doesn't have a tumor that's expressing that, then those treatments may not be of much value.

As we move further into the biomarker-guided treatment era, it may be important to recognize that biomarker data can help select the correct treatment for the patient, much as we have relied upon primarily clinical signs and symptoms in the past. But, of course, we have to have data before these can be made into firm treatment recommendations.

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  1. Asnis GM et al. J Clin Psychiatry. 2013;74:242-248. doi: 10.4088/JCP.12m08197.
  2. Montgomery SA et al. J Clin Psychiatry. 2013;74:363-369. doi:10.4088/JCP.12m08141.
  3. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204447Orig1s000ltr.pdf. Accessed October 3, 2013.
  4. http://clinicaltrials.gov/ct2/show/NCT01318434. Accessed October 3, 2013.
  5. http://clinicaltrials.gov/ct2/show/NCT01838681. Accessed October 3, 2013.
  6. http://clinicaltrials.gov/ct2/show/NCT01173601. Accessed October 3, 2013.
  7. Zarate CA Jr et al. Biol Psychiatry. 2013;74:257-264. doi:10.1016/j.biopsych.2012.10.019.
  8. Burgdorf J et al. Neuropsychopharmacology. 2013;38:729-742. doi:10.1038/npp.2012.246
  9. http://www.naurex.com/html/glyx13.html. Accessed October 3, 2013.
  10. Warner-Schmidt JL et al. Proc Natl Acad Sci USA. 2011;108:9262-9267. doi:10.1073/pnas.1104836108. Erratum in: Proc Natl Acad Sci USA. 2011;108:11297.
  11. Raison CL et al. JAMA Psychiatry. 2013;70:31-41. doi:10.1001/2013.jamapsychiatry.4.

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This activity is supported by an educational grant from Lilly USA, LLC.
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