Time is the Enemy of Effective MDD Management

Patients with MDD who do not respond to treatment within 2 weeks of initiation are significantly less likely than rapid responders to achieve sustained remission and, if they do achieve remission outside the 2-week window, are more likely to relapse.¹ As with schizophrenia,² increased symptom duration and more frequent relapses in MDD lead to structural changes in the brain that are associated with greater functional impairment, and diminishing response over time to successive lines of antidepressant treatments.^3,4

It often takes longer than 2 weeks to even diagnose MDD, let alone establish an effective treatment regimen. MDD must be distinguished from bipolar depression (BD), which can be challenging.^5,6 Patients with bipolar disorder (BP) generally do not seek help during the manic phase of their illness, and BD is often difficult to distinguish from MDD.⁵ Observing a patient longitudinally to establish a diagnosis may represent a critical loss of time.

Establishing symptom control also takes patients outside the optimal 2-week response-time window. Clinical guidelines recommend a 4- to 8-week antidepressant trial to determine whether the agent prescribed is effective, with subsequent trials of other antidepressants if the first proves ineffective.⁷ Efficacy usually isn’t obtained with the first trial, as only 30 to 50% of clinical trial participants with MDD respond to a first monoamine-based antidepressant, and response rates are lower in actual clinical practice.⁸ After a failed trial, response rates decline with each successive drug trial. In the STAR*D trial (n=3671), response to a first antidepressant trial were only 38.6%, and declined to 13% by a fourth trial.⁹

Rapidly identifying patients with MDD, finding the best available treatment, and ultimately, having more rapid-acting treatments are each critical unmet needs in MDD management.

Diagnosis

Results from research on MDD biomarkers may eventually obviate the need for time-consuming longitudinal observation to differentiate between MDD and BD. Ren and colleagues assayed the expression of 14 proteins in 30 patients with MDD, 30 with BD, and 30 healthy controls.⁵ Nine proteins were differentially expressed between MDD and BD. Of these, B2RAN2 and endoglin levels were ≥1.36-fold higher in MDD than in BD and may be particularly useful for differentiating MDD from BD.⁵ 

In a subsequent study, Wu and colleagues compared demographic information and parameters assayed in the routine blood work of 160 adolescent patients hospitalized for MDD and 101 hospitalized for BD.⁶ Direct bilirubin, lactic dehydrogenase, free triiodothyronine, and C-reactive protein were each differentially expressed between the two groups and showed good diagnostic accuracy for establishing a differential diagnosis of MDD or BD.⁶ It is noteworthy that these 4 parameters were assayed during routine blood work that might be collected during an ordinary physical examination, rather than through costly tests that might require hospitalization. Convenient, timely diagnosis based on information obtained in a primary care setting might reduce the time to intervention. Research from this area is still emerging and not yet ready for everyday clinical use.

Treatment

Precision Prescribing

Until recently, there has been limited efficacy data to guide antidepressant prescribing. For example, the CO-MED trial (n=665),¹⁰ remission rates at 12 weeks were 37-38% in patients with MDD who received selective serotonin reuptake inhibitors (SSRI) monotherapy, bupropion plus an SSRI, or a serotonin-norepinephrine reuptake inhibitor (SNRI) plus a tetracyclic antidepressant. However, as with diagnosis, researchers have identified biomarkers and patient characteristics that may potentially help predict differential response between treatments.

In post-hoc analyses of CO-MED,¹¹ 143 patients with baseline interleukin 13 (IL-13) levels ≥20 pg/ml achieved remission at a higher rate on bupropion-SSRI (67%) than on SNRI-tetracyclic (43%) or SSRI monotherapy (24%). Patients with baseline IL-13 levels ≤20 pg/ml were more likely to experience remission with SSRI monotherapy (59%) than with bupropion-SSRI (38%).¹¹ In 106 patients with baseline c-reactive protein (CRP) levels <1 mg/L, remission was more common with SSRI monotherapy (57.1%) than with bupropion-SSRI (33.3%) treatment; but in patients with baseline CRP levels ≥1 mg/L, remission was more likely with the SSRI-bupropion combination (51.4%) than with SSRI monotherapy (29.7%).¹²

In addition to inflammatory biomarkers, additional patient factors associated with improved response to a combination regimen compared with SSRI monotherapy, included BMI ≥35¹³ and the presence of sub-threshold hypomanic symptoms .¹⁴  Without subtyping patients, drug selection would be conducted in the American Psychiatric Association (APA) recommended sequence of 4- to 8-week trials, with combination regimens often reserved for patients showing insufficient response to monotherapy.⁷ Precision prescribing may expedite effective treatment by increasing the likelihood that the first trial will be sufficient, even if that means administering early combination therapy.

New Drug Targets

Glutamate and gamma-aminobutyric acid (GABA) are the most plentiful excitatory and inhibitory neurotransmitters in the brain, respectively.¹⁵ An intranasal N-methyl-D-aspartate (NMDA) receptor antagonist that modulates glutaminergic function has been approved for patients with treatment-resistant depression and depression with suicidality¹⁶; and an intravenous neuroactive steroid (NAS) that modulates the GABA-A receptors is now available, but only for the treatment of postpartum depression (PPD).¹⁷ While each of these agents provides relief within hours of administration,^15,18-19 they also carry warnings for various issues including, excessive sedation and loss of consciousness.^16,17 The label for the NMDA receptor antagonist warns of abuse potential, and the neuroactive steroid must be administered in a continuous 60-hour infusion. Both drugs are only available under terms of Risk Evaluation and Mitigation Strategies (REMS).^16,17

A novel, once-daily oral NMDA receptor channel blocker is in late-stage development for the treatment of MDD. In a 7-day, phase 2, placebo-controlled trial (n=62),²⁰ this agent, given in combination with ongoing antidepressant therapy, led to significant improvements in the Montgomery-Åsberg Depression Scale (MADRS) score by day 4, which was sustained through day 14 (7 days after the last dose). Effect sizes for 25-mg and 50-mg doses were 0.7 and 1.0 respectively, indicating a large, clinically meaningful treatment effect.²⁰ However, in another phase 3 trial, the NMDA receptor channel blocker, given as once-daily monotherapy for 28 days, failed to meet its primary endpoint, a statistically significant improvement in MADRS score.²¹ Nonetheless, in both trials, there were no signs of the neurotoxic effects, opioid effects, or signs of withdrawal that limited use of the IV formulation, eliminating the need for an REMS.^20,21

A once-daily oral neuroactive steroid (NAS) targeting the GABA-A receptors is in phase 3 development for the treatment of MDD. In a longitudinal study with this compound as monotherapy,²² 725 patients were treated for 14 days, after which patients who responded to treatment could receive additional 14-day retreatments, as needed, for up to 1 year. At day 14, 71.6% of patients met response criteria (≥50% reduction in HAM-D score), and 39.5% of patients were in remission (HAM-D ≤ 7). During long-term follow-up, 44.5% of responders did not require another treatment, 26.7% needed a 2^nd treatment, 13.4% required a 3^rd treatment, 10.3% a 4^th, and 5.5% a 5^th. Retreatments were as effective and well tolerated as the first treatment. Serious adverse events, such as loss of consciousness, were not reported.²²

Conclusion

Novel drugs targeting glutaminergic and GABAergic function offer clinicians an opportunity to offer many of their patients meaningful symptom relief in a shorter time than seen with monoaminergic therapies. Improved diagnostics will hopefully continue to shorten the interval between presentation with symptoms and implementation of effective treatment. The continued evolution in understanding the neurobiology of MDD can help match patients with the right treatment on the first attempt, thereby decreasing the interval between diagnosis and symptom control. Finally, identification of new drug targets, and the development of new agents can help to provide rapid response and remission to patients with MDD.

References

1. 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
2. Andreasen NC, Liu D, Ziebell S, Vora A, Ho BC. Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. Am J Psychiatry. 2013; 170:609-615.
3. Oluboka OJ, Katzman MA, Habert J, et al. Functional recovery in major depressive disorder: providing early optimal treatment for the individual patient. Int J Neuropsychopharmacol. 2018. 21(2):128-144. doi: 10.1093/ijnp/pyx081
4. Zaremba D, Dohm K, Redlich R, et al. Association of brain cortical changes with relapse in patients with major depressive disorder. JAMA Psychiatry. 2018;75(5):484-492. doi:10.1001/jamapsychiatry.2018.0123
5. Ren J, Zhao G, Sun X, et al. Identification of plasma biomarkers for distinguishing bipolar depression from major depressive disorder by iTRAQ-coupled LC-MS/MS and bioinformatics analysis. Psychoneuroendocrinology. 2017;86:17-24. doi:10.1016/j.psyneuen.2017.09.005
6. Wu X, Niu Z, Zhu Y, et al. Peripheral biomarkers to predict the diagnosis of bipolar disorder from major depressive disorder in adolescents. Eur Arch Psychiatr Clin Neurosci. 2022;272(5):817-826. doi:10.1007/s00406-021-01321-4
7. Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd Ed. American Psychiatric Association; 2010. Accessed August 14, 2022. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf 
8. Saragoussi D, Touya M, Haro JM, et al. Factors associated with failure to achieve remission and with relapse after remission in patients with major depressive disorder in the PERFORM Study. Neuropysychiatr Dis Treat. 2017;13:2151-2165. doi:10.2147/NDT.S136343
9. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psych. 2006;163:(11)1905-1917. doi:10.1176/ajp.2006.163.11.1905
10. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168(7):689-701. doi:10.1176/appi.ajp.2011.10111645
11. Czysz AH, Mason BL, Li Q, Chin-Fatt C, Minhajuddin A, Carmody T, Trivedi MH. Comparison of inflammatory markers as moderators of depression outcomes: a CO-MED Study. J Affect Disord. 2021;295:1066-1071. doi:10.1016/j.jad.2021.08.116
12. Jha MK, Minhajuddin A, Gadad B, et al. Can c-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017;78:105-113. doi:10.1016/j.psyneuen.2017.01.023
13. Jha MK, Wakhlu S, Nronamraju N, Minhajuddin A, Greer T, Trevedi MH. Validating pre-treatment body mass index as moderator of antidepressant treatment outcomes: findings from CO-MED trial. J Affect Disord. 2018;234:34-37. doi:10.1016/j.jad.2018.02.089
14. Jha MK, Malchow AL, Grannemann BD, Rush AJ, Trivedi MH. Do baseline sub-threshold hypomanic symptoms affect acute phase antidepressant outcome in outpatients with major depressive disorder? Preliminary findings from the randomized CO-MED trial. Neuropsychopharmacology. 2018;43(11):2197-2203. doi:10.1038/s41386-018-0180-z
15. Duman RS, Sancacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102(1):75-90. doi:10.1016/j.neuron.2019.03013.
16. Spravato. Prescribing information. Janssen Pharmaceuticals, Inc; 2020.
17. Zulresso. Prescribing information. Sage Therapeutics, Inc; 2022.
18. Canuso CM, Ionescu DF, Li X, et al. Esketamine nasal spray for the rapid reduction of depressive symptoms in major depressive disorder with acute suicidal ideation or behavior. J Clin Psychopharmacol. 2021;41(5):516-524. doi:10.1097/JCP.0000000000001465
19. 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
20. 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
21. Relmada Therapeutics announces top-line results from phase 3 RELIANCE III trial for REL-1017 as a monotherapy for the treatment of major depressive disorder. PR Newswire. October 13, 2022. Accessed November 18, 2022. https://www.prnewswire.com/news-releases/relmada-therapeutics-announces-top-line-results-from--phase-3-reliance-iii-trial-for-rel-1017-as-a-monotherapy-for-the-treatment-of-major-depressive-disorder-301648190.html
22. Sage Therapeutics announces positive interim, topline zuranalone safety and tolerability data from open-label SHORELINE study in patients with MDD. Sage Therapeutics. October 15, 2020. Accessed November 18, 2022. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-positive-interim-topline-zuranolone