Treatment Options in Late-Life Treatment-Resistant Depression

This article sheds light on the strengths and weaknesses of various approaches to TRD management in adults 60 years and older.

Depression is a major public health issue and is associated with significant morbidity, mortality, and economic burden. It is the third-greatest contributor to global disease burden1 and affects both low- and high-income countries, with a 12-month prevalence of 5.9% and 5.5%, respectively.2 There is a relative paucity of information on treatment of late-life treatment-resistant depression (TRD). We conducted a survey of the readership of Psychiatric Times to assess the general attitudes toward the prevalence of-and the existing treatment approaches toward-TRD in adults 60 years and older.

Here we present the results of that survey and discuss the strengths and weaknesses of various approaches to TRD management.

What the survey revealed

The online survey received 468 responses: 51.6% respondents identified as psychiatrists, 7.7% as psychologists, and 14% as other mental health professionals. The US was well represented, contributing 79.3% of responses: 25.1% came from the Northeast, 16.2% from the Southeast, 17.2% from the Midwest, 8.1% from the Southwest, and 12.7 from the West. The remaining 20.7% of responses came from 41 countries, including Australia, the UK, Canada, and India. Of the respondents, 36.4% had been practicing for more than 25 years. Approximately one-third were in their first decade of practice, and one-third were in their second decade of practice.

The Table shows the incidence of TRD as reported by survey takers. Figure 1 shows the percentages of patients with TRD, and Figure 2 shows the percentages of TRD patients 60 years and older in the respondents’ practices.

Question from survey: Please rate how helpful you would find the results of a large randomized study that compares the risks and benefits of augmentation and switching strategies for TRD in patients who are 60+ years old.

Most (71.7%) respondents stated that such a study would be “helpful,” and 61% would find it “extremely helpful.” Importantly, 76.6% of respondents believe their practice would benefit from the findings of such a study.

Question from survey: What treatment choices would you like to see in a randomized study for TRD in patients who are 60+ years old?

The most popular options were augmentation with aripiprazole (53.5%), augmentation with bupropion (49.2%), and augmentation with lithium (45.2%). Switching to bupropion and nortriptyline options were less popular, and each scored 28.4%.

Over one-third of respondents suggested alternative treatment options to be studied. The most common suggestions were psychotherapy; augmentation with antipsychotics; transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS); ECT; the addition of a second antidepressant, both typical (SSRI, SNRI, TCA, MAOI) and atypical (mirtazapine), and newer agents (vortioxetine); as well as methylphenidate and other stimulants, ketamine, and lamotrigine.

Several respondents suggested supplementation with thyroid hormone and, less frequently, folate and omega 3. Other drugs named were memantine, pramipexole, pindolol, nefazodone, buspirone, and glutaminergics. Finally, lifestyle measures such as exercise and various complementary and alternative practices, including acupuncture, were also suggested.


TRD: A significant problem in older adults

Up to 20% of patients with depression do not respond to 2 or more pharmacologically different agents. These patients reflect a significant portion of the mental health professions’ workload. The findings of this survey approximately mirror the literature values: the mode response to the TRD-workload question was 10% to 25% of patients.

Depression affects 7% of older adults, among whom it is the leading cause of disability and premature mortality.3-5 Depression in older adults is an important risk factor for all-cause dementia6 and is associated with higher utilization of health care services, caregiver burden, and suicide rates.7,8 In older adults, depression is more likely to follow a chronic or relapsing course, and 55% to 81% of older adults with MDD fail to respond to an SSRI or SNRI.9-10

The findings of our survey are more conservative. Older adults accounted for 10% to 55% of the total TRD workload in the practices of almost half of respondents.

TRD is clearly a significant issue in this population. While previous studies-including Sequenced Treatment Alternatives to Relieve Depression (STAR*D), Veterans Affairs Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D), Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT), and the International Study to Predict Optimized Treatment in Depression (iSPOT-D)-have explored treatment of TRD in young adults, there is a relative paucity of research in the management of TRD in older adults.11

There is growing concern about the heightened risks of cardiac arrest and falls and fractures associated with psychotropic medication in older adults.12,13 This demographic will continue to grow, which makes this a priority research area. This view was shared by 71.7% of survey respondents.

Treatment approaches

Approaches to TRD include:

• Dosage optimization

• Switching to a drug from a different class

• Augmentation with a nonstandard agent to the treatment regimen

• Non-pharmacological therapies, including psychotherapy, and interventional methods

Of the treatment approaches suggested by survey respondents, the most popular include aripiprazole, methylphenidate, ketamine, TMS, and pharmacogenetics.

A meta-analysis of 48 trials of augmentation agents in general TRD populations found that quetiapine, aripiprazole, thyroid hormone, and lithium were significantly more effective than placebo, notwithstanding tolerability issues with antipsychotics and lithium, and safety issues with thyroid hormone supplementation.14

In TRD in older adults, a double-blind randomized controlled trial (RCT) of aripiprazole to augment venlafaxine therapy afforded 12 weeks of sustained remission in almost half the participants assigned to the intervention group, with a number needed to treat of 6.6.10 In this group, aripiprazole was associated with mild and transient akathisia and parkinsonism, typically tremor, but not with cardiometabolic adverse effects, QTc prolongation, or increased suicidal ideation.10 In this same study, severe baseline anxiety and cognitive inflexibility were associated with reduced remission rates.15 These findings indicate that aripiprazole has good outcomes, tolerability, and safety in TRD in older adults.

The use of methylphenidate in treating depression has been explored following favorable findings in small trials involving palliative care patients and on review.16-18 Recently, in a double-blind RCT of citalopram, methylphenidate, and combination therapy to treat depression in geriatric patients, combination therapy yielded a greater rate of remission than either drug alone: time to remission was shorter with monotherapy, which was also associated with enhanced mood and general wellbeing.19 While 40% of patients in this trial had TRD, efficacy in this group was not analyzed separately. Case reports also support methylphenidate use in catatonic major depression and bipolar depression in the elderly when family members decline ECT.20,21 In both cases, methylphenidate use triggered breakthrough in catatonia that enabled the patient to consent to ECT as definitive treatment. Due to the lack of long-term follow up, it is unknown whether the antidepressant effect of methylphenidate is sustained.

The rapid antidepressant effect of ketamine has been widely covered in scientific publications and mainstream media. Where other antidepressants have a lag time to response, often resulting in poor compliance, ketamine infusions have significantly ameliorated symptoms within hours and sustained responses over days to weeks in trials against placebo22,23 and midazolam.24 Trials of repeat infusions have demonstrated sustained effects for 14 and 19 days after final infusion.25,26 The major downfalls of ketamine infusion therapy are significant dissociative effects, including perceptual disturbances-usually short-lived-and, in some patients, iatrogenic hemodynamic instability.27 More recent trials of intranasal ketamine have demonstrated fewer adverse effects and more rapid onset of action of less than 1 hour.28,29 This is a promising area of research. To our knowledge, there have been no studies on the use of ketamine in TRD in older adults.

TMS is a promising innovation in the management of depression. It is significantly more effective than placebo and has a greater effect size than antidepressants.30 TMS is also effective in TRD31-33: its efficacy is comparable to that of augmentation with atypical antipsychotics without the adverse-effect profile and it has favorable effects on cognition.34-36 When used in combination, TMS significantly potentiates antidepressant action.37 Furthermore, TMS is more cost-effective than further pharmacotherapy in TRD.38 TMS also appears to have a sustained effect: the longest-duration study reported that 58% of patients were in remission at 3-month follow-up.39 The few studies investigating TMS in older patients with depression suggest lesser effect than in younger patients.40,41 It may be that age-related structural brain changes are less responsive to stimulation.42

Pharmacogenetics were not mentioned by any survey respondents. This is notable given the increasing availability of such tests. It may suggest poor clinical utility of such products, or a lack of clinician awareness of recent RCTs.43


TRD is clearly a major burden to communities and health services. In the general adult population, there are a number of promising treatment strategies for TRD in development, including ketamine and pharmacogenetics. There is a clear need for a large randomized study that compares risks and benefits of augmentation and switching strategies in older adults. There is also a need for randomized trials comparing adjunct antipsychotic therapy and ECT; innovative treatments, including TMS, DBS, pharmacogenetic testing, anti-inflammatory adjunct therapy, and ketamine; and complementary and alternative medicines.


Dr Arandjelovic is a Medical Doctor and Researcher at the IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Victoria, Australia. Dr Eyre is an Adjunct Research Fellow at the IMPACT Strategic Research Centre; the College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia; and the Semel Institute for Neuroscience and Human Behaviour at UCLA. Dr Forbes is an Adjunct Research Fellow at the College of Medicine and Dentistry, James Cook University. Dr Lavretsky is Professor of Psychiatry at the Semel Institute in Los Angeles, where she directs the Late-Life Mood Stress and Wellness Research Program.


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