The focus on the pharmacological management of depression—since the introduction of the first antidepressants in the late 1950s—has been on the monoamine system.1 Medications targeting the monoamine neurotransmitters serotonin, norepinephrine, and dopamine have been the mainstay of biological therapies.1 Newer discoveries in the field of neuroscience are calling this approach into question. Most recently, a highly publicized paper declared the serotonin theory of depression unfounded.2 Depression is now generally considered to be a heterogenous disorder involving a variety of neurotransmitter pathways that vary between individuals.3 This complexity may explain the reported remission rates ranging from 30-50% with currently available antidepressants.4
In order to find an effective treatment, successive medication trials are often needed before a beneficial agent is found.4 Practice guidelines typically recommend a trial of 4 to 8 weeks, at a therapeutic dose of an antidepressant, before switching to another medication due to the delayed onset of action.1 The consequence of a potentially prolonged trial and error process—before having a treatment response—is that the longer the depression goes untreated, the more the likelihood of response diminishes and depression recurrence increases.5 Another limitation to currently available therapies is their side effect burden. Rates of switching from one antidepressant to another because of tolerability are reported from 5-39%.6
These issues are driving the urgent need for new agents, with novel mechanisms of actions, that may be more effective in greater numbers of patients, exhibit more rapid onset of action, and demonstrate better side effect profiles.
Antidepressants Targeting Glutamate and GABA: The Next Big Wave?
Glutamate and gamma-aminobutyric acid (GABA) have been implicated in the pathophysiology of major depressive disorder (MDD) and have assumed a prominent place in drug development pipelines.7,8 Glutamate is the most abundant excitatory neurotransmitter in the brain.7 Glutamate plays an important role in thinking, learning, and memory, as well as mood.9 The GABA system has been implicated in both anxiety and depression, and GABAergic deficit may be a shared pathophysiology with mood and anxiety disorders.10 Chronic stress and depression are associated with reduced glutamate and GABA functioning including pyramidal neuron atrophy, and changes in both glutamate and GABA neurons in the medial prefrontal cortex (PFC) and hippocampus.7
There are several newly approved therapies targeting these systems. An intranasal N-methyl-D-aspartate (NMDA) receptor antagonist modulating glutaminergic function has been approved for treatment resistant depression and depression with suicidal ideation.11 An intravenous neuro-steroid targeting the GABA-A receptors has been approved for postpartum depression.12 Each of these drugs provide rapid response within hours of administration in their respective indications,7,13,14 but both carry black box warnings for neurotoxic effects, most notably excessive sedation and loss of consciousness.11,12 In addition, the NMDA receptor antagonist carries a warning for abuse potential, and the neuro-steroid must be administered in a continuous 60-hour infusion. Both drugs are used under terms of FDA-mandated Risk Evaluation and Mitigation Strategies (REMS).11,12
The first oral antidepressant acting on the NMDA receptor was recently approved for depression. The medication is an NMDA receptor antagonist that increases glutamate levels. There is also an increase in serotonin levels via serotonin reuptake blockade and through activity in the dorsal raphe mediated by sigma-1-agonism. The medication is a combination of the NMDA antagonist agent, with bupropion to increase drug concentrations of the antagonist, which would otherwise be rapidly metabolized if administered alone.15 The bupropion also increases the availability of norepinephrine by inhibiting its reuptake and acts as an alpha-4-beta-2 nicotinic (nACh) antagonist.16 In a 6-week phase 3 trial there were no serious adverse events, eliminating the need for REMS supervision.15 The medication showed a statistically significant improvement over placebo at week 1, and a 39.5% remission rate after 6 weeks, which did not represent a substantially greater improvement, or more rapid response compared with monoamine-based therapies.15 This medication also demonstrated greater benefit than when compared to bupropion alone.
NMDA Receptor Antagonists in Phase 3 Development
A novel, once-daily oral NMDA receptor channel blocker with a unique binding profile,17 now in phase 3 development, has demonstrated encouraging results. In a 7-day, phase 2, placebo-controlled trial (n=62),18 improvements in the Montgomery-Åsberg Depression Scale (MADRS) score were evident by day 4 and were sustained through the final dose on day 7 and through day 14 (7 days after the final dose). Effect sizes for 25-mg and 50-mg doses were 0.7 to 1.0, indicating robust efficacy. The medication is an isomer of a currently approved opiate medication. However, there were no signs of dissociative psychomimetic effects as well as neurotoxic effects, opioid effects, or signs of withdrawal.18
Neuro-Steroid Analogs and GABA-A Receptor Modulators in Phase 3
An oral neuro-steroid targeting the GABA-A receptors is being studied as a once-a-day medication given for two weeks, along with standard antidepressant therapy. This is meant to provide rapid, sustainable improvement and can be taken on a short-term basis. A post hoc analysis of one study with this compound at a higher dose showed a statistically significant reduction in depression measured by Hamilton Depression Rating Scale (HAMD-17) at day 15, and a rapid onset of improvement at day 3 and day 8.14,19 The drug was well tolerated with no new safety signals.
In a longitudinal study with this compound, 725 patients with MDD were treated for 14 days after which patients who responded to the initial course could receive 14-day retreatments for up to 1 year.14 After the initial course, 71.6% of patients met response criteria (a ≥ 50% reduction in HAM-D), and 39.8% of patients with a HAM-D ≤ 7 were considered to be in remission.14 Among responders to the initial treatment, 44.5% did not require retreatment, 26.7% needed 1 retreatment, 13.4% required 2 retreatments, and 10.3% and 5.5% needed 3 and 4 retreatments, respectively. Retreatments were as effective and well tolerated as the initial course of treatment.14
The most common adverse events with this oral neuro-steroid were mild-to-moderate somnolence, dizziness, sedation, and tremor. There have been no reports of loss of consciousness.14,20,21
Future Prospects
Drugs targeting NMDA and GABA-A receptors represent an exciting advance in MDD therapeutics, offering the potential for more rapid response in a larger proportion of patients than is possible with monoamine-based therapies. In addition to NMDA and GABA-A, receptor targets of interest in drug development efforts for MDD include orexin, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin, and opioid receptors.22 Other biological processes implicated in the pathogenesis of MDD include inflammation, oxidative stress, metabolic dysfunction, mitochondrial dysfunction, and neuroendocrine dysfunction.22,23
For most of these targets and processes, potentially therapeutic compounds have not been identified or are in early-stages development.22,23 However, several approved cyclooxygenase inhibitors and biological therapies are being investigated in recognition of the correlation between MDD and inflammation, and next-generation monoamine drugs and atypical antipsychotics are also being studied.23 With an evolving understanding of the neurobiology of MDD, drug development pipelines will hopefully soon produce more promising additions to the MDD treatment armamentarium.
References
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2. Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry. 2022 Jul 20. doi: 10.1038/s41380-022-01661-0
3. Vasiliu O. Investigational drugs for the treatment of depression (part 1): monoaminergic, orexinergic, GABA-ergic, and anti-inflammatory agents. Front Pharmacol. 2022;13:884143. doi:10.3389/fphar.2022.884143
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5. Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344-353 doi:10.4088/jcp.07m03780
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12. Zulresso. Prescribing information. Sage Therapeutics, Inc; 2022.
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14. Walkery A, Leader LD, Cooke E, VandenBerg A. Review of allopregnanolone agonist therapy for the treatment of depressive disorders. Drug Design Devel Ther. 2021;15:3017-3026. doi:10.2147/DDDT.S240856
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16. Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther. 2000; 295(1):321-7.
17. Bettini E, Stahl SM, Martin SD, et al. Pharmacological comparative characterization of REL-1017 (esmethadone-HCl) and other NMDAR channel blockers in human heterodimeric N-methyl-D-aspartate receptors. Pharmaceuticals (Basel). 2022;15(8):997. doi: 10.3390/ph15080997
18. Fava M, Stahl S, Pani L, et al. REL-1017 (esmethadone) as adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial. Am J Psychiatry. 2022;179(2):122-131. doi:10.1176/appi.ajp.2021.21020197
19. Biogen. Biogen and Sage therapeutics present new analyses at psych congress further evaluating the efficacy and safety of zuranolone. Biogen. September 19, 2022. Accessed November 3, 2022. https://investors.biogen.com/news-releases/news-release-details/biogen-and-sage-therapeutics-present-new-analyses-psych-congress
20. Sage Therapeutics reports topline results from pivotal phase 3 MOUNTAIN Study of SAGE-217 in major depressive disorder. News release. Bloomberg US Edition. December 5, 2019. Accessed October 9, 2022. https://www.bloomberg.com/press-releases/2019-12-05/sage-therapeutics-reports-topline-results-from-pivotal-phase-3-mountain-study-of-sage-217-in-major-depressive-disorder
21. Sage Therapeutics and Biogen announce positive, one-year zuranolone 50 mg data in the ongoing open-label SHORELINE Study in. News release. Bloomberg US Edition. December 1, 2021. Accessed October 9, 2022. https://www.bloomberg.com/press-releases/2021-12-01/sage-therapeutics-and-biogen-announce-positive-one-year-zuranolone-50-mg-data-in-the-ongoing-open-label-shoreline-study-in
22. Elias E, Zhang AY, Manners MT. Novel pharmacological approaches to the treatment of depression. Life (Basel). 2022;12(2):196. doi:10.3390/life12020196