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New Options Available for Treatment-Resistant Depression

Major depressive disorder (MDD) is one of the most common mood disorders seen in adults in the United States. Over the past 30 years, few new pharmacologic therapies have been developed for mood disorders, including depression. However, for patients who do not respond to conventional pharmacologic treatments for MDD, new answers for treatment-resistant depression have emerged in recent years that may help these patients.

According to the 2017 National Survey on Drug Use and Health, MDD is characterized by a minimum of 2 weeks of depressed mood, lack of interest, or loss of pleasure in activities where a person may have low energy, and/or problems with their self-worth, sleeping, eating, and concentrating. The reasons a person may have MDD are multiple, and include illness, substance use disorders, or side effects of medications.1

In 2017, 17.3 million adults in the United States (7.1% of the adult population) experienced MDD, with women (8.7%) having a greater prevalence of MDD than men (5.3%). Young adults between 18 years and 25 years old have the highest prevalence of MDD, at 13.1%, with depression also highest among adults who are multiracial (11.3%).1 

A recent study in JAMA Psychiatry by Hasin et al attempted to capture the prevalence of specifiers of MDD outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). These DSM-5 specifiers include “mixed” episodes of MDD such as those with mania or hypomania, while also removing a specifier for bereavement included in DSM-IV criteria. Both the DSM-IV and DSM-V cite mild, moderate, and severe cases of MDD as specifiers that are not well represented in national data.2 

In 36,309 adult participants from the National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC-III), Dr Hasin and colleagues found a 12-month prevalence of 10.4% and a lifetime prevalence of 20.6% for MDD. A higher 12-month prevalence was observed in young adults 18 years to 29 years old (odds ratio [OR], 3.0; 95% confidence interval, 2.48-3.55) and individuals with a low income (OR, 1.7; 95% CI, 1.49-2.04), and lower prevalence in men (OR, 0.5; 95% CI, 0.46-0.55) as well as individuals of African American (OR, 0.6; 95% CI, 0.54-0.68), Asian/Pacific Islander (OR, 0.6; 95% CI, 0.45-0.67), and Hispanic (OR, 0.7; 95% CI, 0.62-0.78) race. 

The researchers also found MDD was associated with comorbid psychiatric disorders such as specific phobia (adjusted OR, 2.1; 95% CI, 1.84-2.35) and generalized anxiety disorder (adjusted OR, 5.7; 95% CI, 4.98-6.50), and associated with substance abuse disorders such as alcohol (adjusted OR, 1.8; 95% CI, 1.63-2.01) and any drug (adjusted OR, 3.0; 95% CI, 2.57-3.55).

Economic Burden of MDD

The economic burden of MDD has increased within the last decade. In 2005, the economic burden was estimated at $173.2 billion, which increased to $210.5 billion in 2010—an increase of 21.5% mostly from higher direct medical costs and health care resource use (HCRU) associated with MDD. About $6.60 for every dollar spent on direct costs was spent on costs associated with comorbidities of MDD, the workplace, and costs related to suicide. “According to the findings, patients with MDD with more severe depression had higher overall work productivity impairment, higher direct and indirect costs, and higher HCRU compared with patients with less severe depression,” Wing Chow, PharmD, MPH, and colleagues wrote in a clinical brief published from The American Journal of Managed Care.3

MDD also carries significant behavioral health challenges, both financial and nonfinancial. Patients with MDD may have problems with their insurance, difficulty accessing providers of specialty behavioral health services, and care may be delivered in a fragmented fashion, which can serve as barriers to seeking treatment. They may also choose not to receive care based on perceptions of their illness by themselves or others, or distrust of providers. Even when cost is not a barrier to treatment, some patients may not seek treatment. In the case of one study that analyzed the behavior of Medicare beneficiaries when costs of behavioral health services were lowered, the cost-sharing reductions did not result in an increase of more behavioral health visits.4

Among patients with treatment-resistant depression, the costs can be even greater. In one study published in Psychiatric Research & Clinical Practice, patients hospitalized for treatment-resistant depression had significantly longer mean length of stay (7.4 vs 5.9 days; P<.001), significantly higher mean hospital costs ($8681 vs. $6632; P<.001), and significantly greater overall hospital costs, including all-cause readmissions ($12,370 vs. $9429; P<.001) compared with patients with MDD that was not treatment resistant.5

Treatment options for MDD

About two-thirds of US adults receive treatment for major depressive episodes every year, most commonly seeking help from a health professional and receiving medication (44%) as compared with seeing a health professional but not receiving medication (15%) or receiving medication only (6%).1 

Guidelines released by the American Psychiatric Association (APA) in 2010 and reaffirmed in 2015 recommend the use of tricyclic antidepressants; selective serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram; serotonin–norepinephrine reuptake inhibitor such as venlafaxine, desvenlafaxine, and duloxetine; antidepressants such as bupropion, nefazodone, trazodone, and mirtazapine; and monoamine oxidase inhibitors such as phenelzine, tranylcypromine, isocarboxazid, and selegiline in a transdermal formulation.6

“Although some studies have suggested superiority of one mechanism of action over another, there are no replicable or robust findings to establish a clinically meaningful difference. For most patients, the effectiveness of antidepressant medications is generally comparable between classes and within classes of medications,” the APA said in the guidelines.

The guidelines state the response rate for each medication is between 50% and 75%, and APA notes patients with more severe depression may benefit greater from treatment. Other treatment options for patients with MDD include psychosocial intervention such as cognitive behavioral therapy (CBT), and somatic treatment like electroconvulsive therapy (ECT), transcranial magnetic stimulation, and vagus nerve stimulation.

Research suggests cost-effectiveness of therapies like CBT compared with second-generation antidepressants are roughly equal. A model in one study found higher quality-adjusted-life years for CBT at 1 year and 5 years, with higher costs at 1 year that decreased by 5 years.7 

Cost differences between medications depend on the dose prescribed, whether the patient is taking a generic or brand name version of the medication, and if the patient is taking more than one medication. For example, Goodrx lists a 30-day supply of the generic form of fluoxetine (20 mg) at $4.00, while Prozac is listed at around $490 for the same dose and 30-day supply.

Treatment-resistant MDD

In 2019, the FDA approved Spravato (esketamine), a nasal spray developed by Janssen for patients with treatment-resistant depression who had failed other antidepressant medications.8 Tiffany Farchione, MD, acting director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research, said in a press release that the approval was made because there is a “long-standing need for additional effective treatments for treatment-resistant depression.” Esketamine is a Schedule III narcotic that had been misused for at least 40 years as a recreational drug, so the potential for misuse in patients as well as the risk of adverse events was known.

“Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment,” Dr. Farchione  said. “Because of safety concerns, the drug will only be available through a restricted distribution system and it must be administered in a certified medical office where the health care provider can monitor the patient.” 

However, further concerns about Spravato came after its approval.9 In a commentary published in The American Journal of Psychiatry, Alan F. Schatzberg, MD, questioned whether Spravato was needed after the initial dose, as the phase 3 study presented to the FDA as evidence for esketamine’s approval involved patients using the drug alongside an active antidepressant.10,11 “This question needs to be considered in the context of what ketamine is—an anesthetic agent that has been abused in this country and elsewhere in various formulations,” he said.

Esketamine is also significantly more expensive than other medications, with an initial announced list price of $32,400.12 

“Treatment-resistant forms of major depression are common and have large negative effects on patient quality of life, so new therapies are badly needed,” David Rind, MD, chief medical officer of the Institute for Clinical and Economic Review (ICER), stated in a press release. “It is hard to understand how a price exceeding usual cost-effectiveness thresholds is appropriate for a treatment that could be very widely used, particularly when that price is an order of magnitude higher than that of intravenous generic ketamine, a closely related therapy.”

Dr Schatzberg also raised questions in his commentary about the effectiveness of esketamine. “Do we have clear evidence of efficacy? Maybe? How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear. If patients lose response, should we increase the frequency of administration? This could be problematic. Can coming off the drug be problematic? Data suggest that it could be an issue,” he said. “Taken together, there are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice. Only time will tell how useful it will be.”

Recent data suggest longer-term safety and efficacy of esketamine may reflect earlier trials. In a phase 3, open-label study that evaluated use of Spravato in 802 patients with treatment-resistant depression for up to 1 year found that Spravato had improvements in depression as well as a “manageable safety profile,” with 9.5% of patients discontinuing because of treatment-related adverse events and 6.9% having serious treatment-related adverse events.13

“[F]or most patients, the findings suggested consistent benefits and acceptable tolerability of esketamine nasal spray treatment over a period of up to 1 year,” Ewa Wajs, MD, PhD, and colleagues wrote. 


  1. The National Institute of Mental Health Information Resource Center. Major depression: definitions [updated February 2019. Accessed November 10, 2020. 
  2. Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry. 2018;75(4):336–346. doi:10.1001/jamapsychiatry.2017.4602
  3. Chow W, Doane MJ, Sheehan J, Alphs L, Le H. Economic burden among patients with major depressive disorder: an analysis of healthcare resource use, work productivity, and direct and indirect costs by depression severity. Accessed November 6, 2020.
  4. Fz Fung V, Price M, Nierenberg AA, Hsu J, Newhouse JP, Cook BL. Assessment of behavioral health services use among low-income Medicare beneficiaries after reductions in coinsurance fees. JAMA Netw Open. 2020;3(10):e2019854. doi:10.1001/jamanetworkopen.2020.19854
  5. Lin J, Szukis H, Sheehan JJ, et al. Economic burden of treatment-resistant depression among patients hospitalized for major depressive disorder in the United States [Published online October 11, 2019].Accessed November 10, 2020. Accessed November 10, 2020. 
  6. Practice guideline for the treatment of patients with major depressive disorder, third edition. American Psychiatric Association. Accessed November 6, 2020.
  7. Ross EL, Vijan S, Miller EM, Valenstein M, Zivin K. The cost-effectiveness of cognitive behavioral therapy versus second-generation antidepressants for initial treatment of major depressive disorder in the United States. Ann Intern Med. 2019;171(11):785. doi:10.7326/m18-1480
  8. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic [Press release published March 5, 2019]. Accessed November 6, 2020.
  9. Caution urged over use of fast-acting version of ketamine for depression [Published June 11, 2019]. Accessed November 6, 2020.
  10. Schatzberg A. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019 Jun 1;176(6):422-424. doi:10.1176/appi.ajp.2019.19040423.
  11. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438. doi:10.1176/appi.ajp.2019.19020172 
  12. ICER Issues Final Report and Policy Recommendations on Esketamine for Treatment-Resistant Depression [Published June 20, 2019]. Accessed November 6, 2020.
  13. Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891.

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