Only 30% to 50% of patients with major depressive disorder (MDD) respond to antidepressant medications in clinical trials, and response rates in clinical practice are even lower.¹ Failure to establish early response has serious consequences, as research suggests patients who do not respond to treatment within 2 weeks are less likely than rapid responders to experience stable response or remission.²

The expected onset of action is 4- to 6-weeks with currently available agents,³ which means response typically falls outside the desirable 2-week window. Because guidelines recommend an 8-week antidepressant trial to determine efficacy,^3,4 simply confirming that a drug is not effective and initiating a substitute agent would be expected to take the response time to more than 12 weeks, assuming the substitute agent is effective, which it may not be; response to antidepressants declines with each successive trial. In the STAR*D study,⁵ for example, 3671 patients with MDD received 1 to 4 antidepressant trials. Only 36.8% responded to the first drug, and response rates progressively declined with the second (30.6%), third (13.7%), and fourth (13.0%) trials.⁵

Higher response rates and more rapid onset of action remain critical unmet needs for patients with MDD. Addressing those needs requires more precise prescribing and greater insight into the neurobiology of MDD.

Precision Prescribing

The 2010 American Psychiatric Association guidelines stated that the effectiveness of antidepressants is similar between individual agents and that drug selection should therefore be based on tolerability, pharmacological considerations (eg, interaction potential), and factors such as cost and patient preference.³

Until recently, a limited understanding of MDD made precision prescribing based on patient characteristics difficult. The DSM-5 criteria for a diagnosis of MDD requires the presence of 5 of 9 core symptoms.⁶ By this standard, there are 227 possible MDD symptom profiles. However, MDD turned out to be much more complicated than originally thought. In the STAR*D study, a total of 1030 unique symptom profiles were identified in 3703 depressed patients.⁶

Studies such as the Combining Medications to Enhance Depression Outcomes (CO-MED) trial⁷ have begun to break down the clinical characteristics of MDD to allow for more precise prescribing. In the entire population (N=665), there were no significant differences in remission rates during 7 months of treatment between selective serotonin reuptake inhibitor (SSRI) monotherapy (38.8%), bupropion plus an SSRI (38.9%), and a serotonin and norepinephrine reuptake inhibitor (SNRI) plus the tetracyclic antidepressant mirtazapine (37.7%).⁷ As per the 2010 APA guidelines, there would be no efficacy-based criteria for selecting between these treatments based on the original CO-MED results.

However, analyses conducted after the primary study publication found that patients with high baseline levels of interleukin-13 (IL-13; ≥20 pg/mL) had higher remission rates on bupropion-SSRI (67%) than on SSRI monotherapy (24%), and SSRI monotherapy had a higher remission rate in patients with lower baseline IL-13 (59%).⁸ Patients with baseline C-reactive protein (CRP) levels less than 1 mg/L had higher remission rates with SSRI monotherapy (57.1%) than with the drug combinations, but patients with baseline CRP levels equal to or greater than 1 mg/L were most likely to remit on SSRI-bupropion (51.4%).⁹ Additional subanalyses found that patients with a BMI equal to or greater than 35 or subthreshold hypomanic symptoms did better on one of the combination regimens than on SSRI monotherapy.^10,11

In each CO-MED subpopulation, a refined understanding of the relationship between inflammation, physical variables, or symptom profiles allowed for higher remission rates than those achieved in the overall study population. Future research will further improve the precision with which currently available antidepressants are prescribed.

Novel Drug Targets for Rapid Response

Potential mechanisms implicated in the etiology of MDD include inflammation, oxidative stress, metabolic dysfunction, and mitochondrial dysfunction.¹² Prominent among potential mechanisms under consideration are dysregulation of the glutamate and gamma-aminobutyric acid (GABA) neurotransmitter systems.
Currently available antidepressants target at least 1 of 3 monoamines: serotonin, norepinephrine, and dopamine. However, these account for only a small proportion of the neurotransmitters in the brain and have a limited role relative to glutamate and GABA, providing specific inputs to the cerebral cortex.¹³ In contrast, glutamate and GABA are the primary excitatory and inhibitory neurotransmitters in the brain, respectively.¹³ Abnormalities in these neurotransmitter systems have been identified in patients with MDD, and accordingly, several new treatments are under development to target these systems.

Intravenous infusions of N-methyl-D-aspartate ionotropic glutamatergic receptor modulators such as esketamine and rapastinel have provided rapid relief in patients with treatment-resistant MDD, with onset of effect as early as 2-hours post-infusion,^13-15 and a GABA-A-receptor-positive allosteric modulator has been associated with significant reductions in depressive symptoms, evaluated using the 17-item Hamilton Rating Scale for Depression, after 2 weeks of once-daily oral treatment.¹⁶

These and other novel agents in the pipeline might eventually offer more rapid response than the 4 to 6 weeks required with currently available agents that target monoamine systems.

References:
1.    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
2.    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
3.    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
4.    Qaseem A, Snow V, Denberg TD, Forclea MA, Owens DK. Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;149(10):725-733. doi:10.7326/0003-4819-149-10-200811180-00007
5.    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
6.    Fried EI, Nesse RM. Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. J Affect Disord. 2015;172:96-102. doi:10.1016/j.jad.2014.10.010
7.    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
8.    Czysz AH, Mason BL, Li Q, et al. 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
9.    Jha MK, Minhajuddin A, Gadad BS, 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
10.    Jha MK, Wakhlu S, Dronamraju N, Minhajuddin A, Greer TL, Trivedi 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
11.    Jha MK, Malchow AL, Grannemann BD, Rush JA. 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
12.    Rosenblat JD, Lee Y, McIntyre RS. The effect of pharmacogenomic testing on response and remission rates in the acute treatment of major depressive disorder: A meta-analysis. J Affect Disord. 2018;241:484-491. doi:10.1016/j.jad.2018.08.056
13.    Duman RS, Sanacora 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.2019.03.013
14.    Preskorn S, Macaluso M, Mehra DOV, Zammit G, Moskal JR, Burch RM. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21(2):140-149. doi:10.1097/01.pra.0000462606.17725.93
15.    Singh JB, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80(6):424-431. doi:10.1016/j.biopsych.2015.10.018
16.    Suthoff E, Kosinski M, Arnaud A, et al. Patient-reported health-related quality of life from a randomized, placebo-controlled phase 2 trial of zuronalone in adults with major depressive disorder. J Affect Disord. 2022;308:19-26. doi:10.1016/j.jad.2022.03.068