Revisiting the Management of Treatment-Resistant Depression

Pharmacologic Exhaustion

Sequential pharmacological treatments in treatment-resistant depression (TRD) yield increasingly modest outcomes, with cumulative remission rates declining substantially with each subsequent intervention. In the STAR*D trial, remission rates decreased sequentially from 36.8% to 30.6%, 13.7%, and 13.0% with each successive treatment step. Concurrently, relapse rates increased highlighting a fundamental limitation of standard monoaminergic pharmacotherapy. Recognizing the limitations of antidepressant switching, the CANMAT 2023 clinical guidelines recommend considering augmentation strategies after the first or second adequate antidepressant trial, suggesting Aripiprazole and Brexpiprazole as first-line agents. Augmentation strategies utilizing antipsychotics offer a modest statistical advantage over alternative agents. ¹ However, this benefit is frequently accompanied by a greater burden of adverse events, especially weight gain and akathisia.

Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic stimulation (rTMS) provides a critical alternative by targeting network-level pathology rather than acting on neurotransmitters. As a non-invasive neuromodulation technique with well-established efficacy, rTMS research has increasingly focused on its performance against active comparators and its optimal position within the TRD treatment algorithm. ² Although remission rates are lower in patients who have been exposed to a greater number of treatments across treatment modalities, ³ recent evidence suggests rTMS may be superior to some standard pharmacological strategies, including medication switching. In a head-to-head comparison, rTMS achieved significantly higher response (37.5%) and remission rates (27.1%) ⁴ than antidepressant switching. When benchmarked against antipsychotic augmentation, ⁵ rTMS demonstrated comparable efficacy while avoiding the metabolic and extrapyramidal risks inherent to antipsychotic use.

Although the lack of blinding in these studies introduces expectancy bias, it is not feasible to blind interventions in pragmatic comparative effectiveness trials. Despite this limitation, these findings generally reflect real-world clinical practice outcomes. The response to rTMS can be durable for 6 to 12 months, with one study indicating that 46.3% remain well after 12 months. ⁶ While maintenance rTMS has been explored to sustain treatment gains, more robust studies are necessary to define the optimal maintenance methodology. ⁷

Access to care remains a potential challenge due to variable funding structures across jurisdictions. In Canada, some provinces provide formal public funding, whereas access in other provinces relies on hospital budgets, philanthropy, or research grants to maintain public programs. ⁸ Patients unable to access public programs face financial obstacles at private, fee-for-service clinics. Several provinces have recently introduced new funding models over the last 4 years to improve public access. Additional challenges include staffing and equipment capacity limits in public programs, which can result in long wait times. Furthermore, services are predominantly concentrated in large urban centers. This distribution imposes travel and financial burdens on rural patients who require 30 daily treatments over 6 weeks under standard protocols. Accelerated protocols delivering multiple treatments per day may reduce the required number of days, although further data are needed to determine the durability and optimal strategy for acceleration. ⁹

While the CANMAT 2023 guidelines suggest considering rTMS after a switch or augmentation medication strategy fails, we propose positioning rTMS one step earlier, as an alternative to pharmacological augmentation. This recommendation is supported by emerging evidence of its similar or superior efficacy relative to antipsychotics, alongside expanding public access.

Ketamine and Esketamine

Ketamine and esketamine are glutamatergic agents that have emerged as promising treatments for TRD due to their rapid antidepressant effects and demonstrated efficacy. ¹⁰ In direct head-to-head trials, esketamine has demonstrated superiority over standard augmentation strategies in both acute and long-term outcomes, ¹¹ establishing it as a potent alternative for patients failing standard augmentation strategies. However, these agents provide rapid but initially transient antidepressant effects. Single ketamine infusions produce peak effects at day 7 but typically do not persist beyond one month without repeated dosing. Although a systematic review ¹² demonstrated maintained antidepressant effects with repeated treatments, data regarding optimal maintenance protocols remain lacking. Indefinite maintenance with intravenous (IV) ketamine may be unsustainable due to infusion and monitoring costs, while esketamine maintenance is limited by high acquisition costs.

While no direct comparisons between Esketamine and rTMS exist, a secondary analysis of individual patient data from two large clinical trials suggests both interventions are superior to initiating a new antidepressant medication, with rTMS potentially demonstrating greater symptom reduction. ¹³ The CANMAT 2023 guidelines position IN esketamine and IV ketamine as second-line adjunctive medications alongside agents such as Bupropion and lithium. Given the efficacy data, limited access, and high maintenance costs of esketamine, we recommend ketamine be considered a second-line interventional option following rTMS.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) demonstrates superior efficacy compared to both rTMS and ketamine, achieving remission rates up to 62%, ¹⁴ even in highly treatment-resistant populations, though this advantage varies by patient population and treatment setting. ECT is particularly efficacious in older adults, patients with psychotic features, and inpatient populations. Network meta-analyses indicate that bitemporal ECT (OR 8.91) and high-dose right unilateral ECT (OR 7.27) substantially outperform high-frequency left rTMS (OR 3.17) and bilateral rTMS (OR 4.92) in response rates. ¹⁵ Notably, ECT is also the only interventional treatment shown to reduce all-cause mortality and the risk of death by suicide in the year following hospital discharge. ¹⁶ It is accessible in most hospitals with inpatient psychiatry programs, though capacity and wait times can limit access to both acute and maintenance treatment.

In comparison against IV ketamine, ketamine was found non-inferior to ECT while avoiding ECT-associated cognitive adverse events. ¹⁷ However, this trial primarily included outpatients with less severe illness and excluded patients with psychotic features. ECT remains the treatment of choice for the severely ill patients pending studies clarifying the comparative effectiveness of IV ketamine in populations with high acuity and those receiving full courses of ECT.

Clinical Pearls

1. Prioritize ECT for acute and severely ill patients.

   In cases requiring urgent symptom resolution or with high acuity—such as inpatients, or patients with acute suicide risk, catatonia, or psychotic features—ECT is the treatment of choice. It should be prioritized rather than being delayed solely as a “last resort” following exhaustive, sequential medication failures.

2. Recognize pharmacologic exhaustion: Augmentation beats switching.

   Following two or more adequate antidepressant trials, initiating a third antidepressant yields diminishing returns. At this juncture, clinicians should consider either pharmacological augmentation or neurostimulation.

3. Position rTMS as an early alternative to atypical antipsychotics.

   Clinicians should evaluate rTMS as an alternative to atypical antipsychotic augmentation. While antipsychotics are widely accessible, rTMS provides comparable efficacy with a superior tolerability profile, avoiding the extrapyramidal and metabolic risks of long-term pharmacotherapy. rTMS can serve as an adjunctive treatment to a partially effective antidepressant or as monotherapy following the discontinuation of an ineffective agent. It should be offered alongside other augmentation strategies whenever systemic barriers such as regional availability, waitlists, and daily travel requirements permit.

4. Reserve ketamine/esketamine for select non-responders.

   Given the relative scarcity of long-term maintenance data and availability compared to established treatments like ECT, they should be positioned cautiously. These agents may be considered for patients who remain non-responsive to standard augmentation strategies (including rTMS) and who either refuse ECT or cannot tolerate its anesthetic and cognitive risks, provided the intervention is accessible.