Beyond the monoamines: The future of antidepressants


For close to 6 decades, since the approval of imipramine in 1959, all Food and Drug Administration-approved medications for depression worked through the monoamine system, in some ways altering the concentration of serotonin, norepinephrine, or dopamine within synapses or binding to post synaptic receptors. A conservative estimate has at least a third of patients with depression not adequately responsive to these monoaminergic medications.

Dr. Scott Aaronson is the director of clinical research programs at the Sheppard Pratt Health System in Baltimore.

Dr. Scott Aaronson

A host of medications in various stages of development might each offer unique additions to the current therapeutic paradigm. Compounds closest to market include N-methyl-D-aspartate (NMDA) blockers such as esketamine or rapastinel; opioid receptor partial agonists and antagonists, such as Alkermes 5461; and a GABAA receptor modulator, brexanolone. A further off, more speculative intervention involves the use of psychedelic drugs like psilocybin.

NMDA antagonists have gained the highest visibility after some promising results in early studies looking at intravenous ketamine, an anesthetic agent approved by the FDA in 1970 for treatment-resistant depression. This has led to several companies trying to develop a patentable NMDA antagonist for depression. The most likely first candidate is one of the enantiomers of ketamine, esketamine, which, because of higher binding affinity, can be dosed intranasally rather than intravenously. Studies are completed to establish efficacy in TRD2 [treatment-resistant depression] as well as acute suicidality3. Johnson & Johnson plans to submit these results for FDA approval this year.

Another promising NMDA antagonist, rapastinel, is wending its way through clinical trials – but should it be approved, its use might be limited by the requirement for intravenous delivery.

Despite only early evidence for efficacy in depression, the easy availability of ketamine for infusion has created a cadre of independent clinicians as well as some academic clinics offering intravenous ketamine infusions for those with difficult-to-treat depression and adequate finances to pay for off-label treatment (some insurance companies as well have supported its use). It is understandable to try to offer patients suffering with refractory illnesses anything the field has to offer, but the limitations on our knowledge, especially about the efficacy and safety of long-term use of ketamine for depression, need to be taken into account4. There is little to no regulation around providing intravenous ketamine, and clinicians and patients should be aware of the risks, take care in the administration of the drug, and watch for the potential of dissociation or substance abuse along with being clear about the likelihood of benefit being at best around 50%. As more evidence and experience are collected, NMDA antagonists might offer a unique efficacy profile within safe boundaries.

Opioid agonists have some antidepressant activity, but tolerance to it quickly develops – requiring users to take increasingly higher doses. Would a partial opioid agonist coupled with a pure opioid antagonist provide ongoing efficacy at a continuous dose with adequate safety? A combination medication containing buprenorphine, a mu- and kappa-opioid partial agonist, and samidorphan, a mu-opioid antagonist, is currently being reviewed by the FDA. The phase 3 studies are not yet published. However, the phase 2 published trial demonstrated efficacy at low doses (2 mg of buprenorphine with 2 mg of samidorphan) as an adjunctive medication in treatment-resistant depression5. While offering a novel mechanism of action and a reasonable safety profile seen in several poster presentations, though not published articles, the drug – should it receive approval – will require an intensive effort to educate practitioners and the public about the critical differences (especially with regard to risk/benefits of long-term use, abuse potential, and safety) between opiate agonism and opiate modulation/antagonism.

Brexanolone, an intravenous formulation of allopregnanolone, a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, has been studied for the treatment of postpartum depression6. Early development has focused on an intravenous delivery system and a unique target population of postpartum depression, but the novel concept of targeting GABAA receptors might prove fruitful with a wider population of depressed patients with inadequate responses to existing antidepressants. An oral formulation, SAGE-217, is in early clinical trials.

While much earlier in the development for FDA approval, psychedelics, particularly psilocybin, have been investigated for use in treatment-resistant depression. A small double-blind trial in terminal cancer patients showed that psilocybin had a remarkable palliative effect on depression and anxiety7. An open label study of treatment-resistant depressed patients demonstrated lasting benefit over 6 months after two doses of psilocybin8. A neuroimaging study supported the idea that changes in resting state functional connectivity in specific brain regions from exposure to psilocybin might account for alleviation in depressive symptoms9. These findings are preliminary, but they have sparked the commencement of a few phase 2 randomized trials for psychedelic drugs. It should be noted that all these trial to date – and those planned – require dosing to be done in a very controlled and supervised psychologically supportive environment.

Which of these treatments will make it to market? That remains unclear, but it is reassuring that so many different novel paradigms for addressing treatment-resistant depression are in development.

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