How to Identify and Tackle Treatment-Resistant Depression in Geriatric Patients

March 17, 2021
Paul Gleason, PhD

If patients decline electroconvulsive therapy, psychiatrists still have many good options.


“The problem of treatment-resistant depression in later life [TRD-LL] is increasingly recognized but remains poorly characterized,” Randall Espinoza, MD, MPH, told the audience at the American Association of Geriatric Psychiatry Annual Meeting. According to Espinoza, estimates of its prevalence run from 6% up to 40% in geriatric patients with depression, depending on how treatment-resistant depression (TRD) is defined.

At a session titled “Beyond ECT – Neuromodulation and Interventional Psychiatry for Treatment Resistant Depression in Later Life,” Espinoza and his colleagues Aaron Kaufman, MD, and Ali Ashghar-Ali, MD, discussed the challenges of identifying and treating TRD in older patients, including the latest results from clinical research.

TRD is associated with increases in morbidity and mortality, including greater levels of pain and suicide. It leads to higher health care costs, lower quality of life, and reduced workplace productivity. TRD can be chronic and recurrent: 20% to 35% of patients have continuous depression for more than 1 year, and 25% to 40% of patients experience a recurrence within 2 years, and 60% have a recurrence after 5 years.1,2

Despite the prevalence of TRD, simply identifying it may be a challenge, Espinoza noted. He broke it down into 3 possible categories: 1) nonresponse to treatment and a high degree of functional impairment, 2) treatment resistant depression, which shows minimal to partial response to treatment, and 3) treatment refractory depression, which shows no response to treatment and symptoms unchanged or worsening.3 He noted that TRD may have a different epidemiology in older adult populations and may arise due to trauma, social adversity, and losses. Furthermore, treatment is complicated by brain aging and the fact that most clinical trials deliberately exclude older adults, which makes pharmacological options uncertain.

Espinoza also warned that TRD in older patients may be accompanied by significant comorbidities, including anxiety disorders, substance abuse, and cognitive and personality disorders.

In terms of treatment, Espinoza suggested that clinicians consider moving from the framing of “treatment-resistant” to a “difficult to treat” depression (DTD) model.3 The TRD model treats depression as a chronic rather than acute illness. To the biological emphasis of the TRD model, it would add a neurobiopsychosocial focus. Rather than judging progress according to cure or remission alone, it also emphasizes capability, recovery, and symptom management.

As Espinoza explained, “DTD captures not only acute phase treatment but also encourages a shift of focus to long-term treatment with the goals of improving overall function, quality of life, and optimization of treatment when full remission is no longer viable.”

Turning to more specific treatment options, Ashghar-Ali noted that “ECT remains [the] gold standard for neuromodulation intervention in older adults,” and noted clinicians have other options as well. He reviewed 2 studies of repetitive transcranial magnetic stimulation (RTMS)/DEEP TMS, which showed positive results.4,5

Ashghar-Ali also discussed ketamine. Although it is not approved by the US Federal Drug Administration (FDA) for treating TRD, ketamine has shown antidepressant effects.6 Esketamine, however, is FDA approved for treating depression. Ashghar-Ali noted that esketamine plus an antidepressant demonstrated a statistically significant treatment effects in patients aged 65 to 74 years (although not for patients aged more than 75 years).7 He concluded that esketamine might play a helpful role in treating TRD in patients during the 64 to 75 age band.

Kaufman considered the possible role of lithium augmentation. He discussed 1 study in which lithium augmentation had a high remission rate (63.6%) among elderly patients with treatment resistant depression, and another in which geriatric patients responded significantly better to lithium augmentation than nongeriatric patients.8,9 He noted that some evidence also existed for augmenting with atypical antipsychotics and stimulants.

Psychotherapy is also an option. Kaufman presented from a meta-analysis of psychotherapy in later-life depression that found large effects, when compared with waitlist controls.10 The evidence is strongest for problem-solving therapy, interpersonal psychotherapy, and cognitive behavioral therapy. Exercise, meditation, acupuncture, and Tai Chi had also been shown to help in a number of cases.

During the Question and Answer period, both Kaufman and Ashghar-Ali spoke to why treatments beyond ETC may be necessary.

“These are of course really challenging cases,” Kaufman said. Some patients may have trouble recalling the details of her medication and adherence history, and many do not trust ECT. “We’ve all had patients decline ETC and want to pursue alternatives,” Kaufman said further.

Alternately, said Ashghar-Ali, “a lot of people come to ECT with the assumption that it’s the only option left.”

But, Ashghar-Ali and Kaufman concluded, ECT is in fact only 1 option, and there are many others for clinicians and patients.


1. Benson C, Szukis H, Sheehan JJ, et al. An evaluation of the clinical and economic burden among older adult Medicare-covered beneficiaries with treatment-resistant depression. Am J Geriatr Psychiatry. 2020;28(3):350-362.

2. Pilon D, Joshi K, Sheehan JJ, et al. Burden of treatment-resistant depression in Medicare: a retrospective claims database analysis. PLoS One. 2019;14(10):e0223255.

3. Rush AJ, Aaronson ST, Demyttenaere K. Difficult-to-treat depression: a clinical and research roadmap for when remission is elusive. Aust N Z J Psychiatry. 2019;53(2):109-118.

4. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology. 2009;34(2):522-34.

5. Conelea CA, Philip NS, Yip AG, et al. Transcranial magnetic stimulation for treatment-resistant depression: naturalistic treatment outcomes for younger versus older patients. J Affect Disord. 2017;217:42-47.

6. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-6.

7. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-141.

8. Kok RM, Nolen WA, Heeren TJ. Outcome of late-life depression after 3 years of sequential treatment. Acta Psychiatr Scand. 2009;119(4):274-81.

9. Buspavanich P, Behr J, Stamm T, et al. Treatment response of lithium augmentation in geriatric compared to non-geriatric patients with treatment-resistant depression. J Affect Disord. 2019;251:136-140.

10. Huang AX, Delucchi K, Dunn LB, Nelson JC. A systematic review and meta-analysis of psychotherapy for late-life depression. Am J Geriatr Psychiatry. 2015;23(3):261-73.