Experimental Therapies for Treatment-Resistant Depression: Deciding When to Go to an Unproven or Experimental Therapy

Starting with the initial antidepressant trial, we recommend a measurement-based care (MBC) approach that relies on systematic assessments of symptom severity, side effects, and adherence (6). Such an approach allows for prospective assessments of inadequate response (<50% reduction in symptom severity) to antidepressant trials of adequate dose (lowest dose approved by the U.S. Food and Drug Administration [FDA]) and duration (six to eight weeks). When scores of symptom rating scales, such as the nine-item Patient Health Questionnaire (7) or the 16-item Quick Inventory of Depressive Symptomatology Self-Report Version (8), are not available, we recommend the use of a structured tool, such as the Massachusetts General Hospital—Antidepressant Treatment Response Questionnaire to ascertain the TRD status (9).

Presence of subthreshold hypomanic symptom among patients with major depressive disorder or unrecognized bipolar depression may reduce response to commonly used antidepressant medications (10). Hence, we recommend that clinicians revise or reconduct diagnostic assessments when evaluating TRD status. Finally, recent evidence shows that selective serotonin reuptake inhibitors are minimally effective for patients with major depressive disorder with evidence of systemic inflammation (11, 12). Thus, clinicians may use commercially available tests, such as high-sensitivity c-reactive protein (hsCRP), to personalize the selection of antidepressant medications and prevent failed antidepressant treatment trials (13).

Multiple studies have now demonstrated that ketamine and its s-enantiomer (esketamine) acutely reduce depressive symptom severity at subanesthetic doses when administered by either intravenous or intranasal route (14–17). Ongoing phase III clinical trials with TRD patients (trials NCT02417064, NCT02418585, NCT02422186, NCT02493868, and NCT02497287) will clarify the optimal dose, duration, and sustained benefit with repeated dosing of intranasal esketamine. Driven in part by the recent attention on ketamine as a novel antidepressant, the number of providers prescribing ketamine in an off-label fashion has increased rapidly over the last five years (18).

However, there are significant concerns with off-label ketamine use. Poorly monitored ketamine infusion has reportedly been associated with death (19). Additionally, although ketamine has poor oral bioavailability because of extensive first-pass metabolism (20), one in five providers in a recent survey by Wilkinson et al. reported administering ketamine by oral route for their patients with TRD (18). Intranasal administration of ketamine is also associated with variation in plasma levels of ketamine and its metabolites and was poorly tolerated by patients in a recent report (21). Thus, we recommend that off-label use of ketamine should be restricted to intravenous use and be conducted in a safe environment by trained professionals with easy access to higher-level care. On the basis of our experience, we have listed (see Box) some issues for clinicians to consider before, during, and after infusion when using intravenous ketamine in an off-label fashion.

Dopaminergic agents have gained recent attention in the treatment of depression because of the role of inflammation on anhedonia (12, 22, 23). Pramipexole, a dopamine receptor D2 and D3 agonist, has been shown to be effective in reducing depression (24) and to result in long-term improvement for patients with TRD (25, 26). Because higher doses might be needed to attain therapeutic response with pramipexole, Fawcett et al. recommended that clinicians start at low dosage, slow titration, and once-daily dosing at night to enhance tolerability (26).

Stimulants such as methylphenidate have also been used as augmentation strategies among patients with depression, with variable results (27, 28). These stimulants likely most benefit TRD patients with prominent anhedonia or fatigue (29, 30). When prescribing stimulants, clinicians should consider the risk of abuse potential, comorbid substance use disorder, undiagnosed bipolar or psychotic disorder, and seizure disorder. Although it is not a dopaminergic medication, modafinil may be considered as a treatment option for TRD patients, especially those with excessive sleepiness and fatigue (31–33). Thus, pramipexole, stimulants, and modafinil may be considered in the absence of adequate response to currently available antidepressants and in the presence of marked anhedonia, fatigue, or hypersomnia.

Nutritional deficiencies may contribute not only to symptoms of depression but also to reduced efficacy of antidepressant medications (34). Emerging evidence suggests a role for nutritional supplements in a subgroup of patients with TRD. Folate supplementation, either with folinic acid (15–20 mg/day) or l-methylfolate (15 mg/day), has been shown reduce symptom severity among TRD patients (35, 36). Other supplements with mixed results of efficacy include s-adenosyl methionine, omega−3 fatty acids, vitamin D, zinc, vitamin B12, and probiotics (37–40). Clinicians may consider personalizing the selection of nutritional supplements on the basis of markers of inflammation (hsCRP) or body mass index, which have been associated with better response to l-methylfolate (41, 42).

Other supplements that can be considered for TRD patients with elevated inflammatory and metabolic biomarkers include curcumin and leucine. In a recent study, patients with major depressive disorder who had elevated levels of leptin experienced a greater reduction in their depression severity with curcumin as compared with those with lower levels of leptin (43). Because leptin levels increase with obesity, curcumin supplementation may be useful for obese TRD patients. Leucine is another supplement that may be considered for TRD patients with markers of elevated inflammation (e.g., hsCRP), because it prevents the uptake of harmful kyneurinine metabolites across the blood-brain barrier (44). We recommend that, when prescribing nutritional supplements, clinicians remain vigilant regarding where these supplements are produced and the use of pharmaceutical-grade supplements. Additionally, when using the MBC approach, clinicians should monitor any side effects or improvement with these supplements and ensure that patients are not continued on ineffective treatments for too long.

Repetitive TMS (rTMS) is approved by the FDA for TRD, but fewer than one in four patients attain remission with the current paradigm of high-frequency (10Hz) stimulation over left dorsolateral prefrontal cortex (45). The availability of liquid-cooled magnets and higher powered devices has enabled the off-label use of alternative stimulation paradigms in clinical practice. In contrast to the FDA-approved rTMS stimulation paradigm, which takes 20–45 minutes, theta burst stimulation can be administered in less than five minutes. Additionally, a recent report suggests that intermittent theta burst stimulation delivered over multiple sessions resulted in marked reduction in depressive symptom severity among TRD patients who had failed to improve with electroconvulsive therapy, multiple medication trials, and psychotherapy (46). Another promising brain stimulation paradigm is the combination of off-label ketamine with rTMS. Although published literature has been sparse on this combination (47), it offers the potential to sustain the improvements with ketamine infusion.

Recent reports have highlighted the limitations of measuring only depressive symptom severity during the course of antidepressant treatment. In fact, persistent impairment across functional domains, such as work productivity, psychosocial function, quality of life, and nonwork-related daily activity, are associated with lower likelihood of attaining remission with antidepressant medications (48–51). Clinicians may consider using psychosocial interventions, systematically evaluated as part of an MBC approach, to reduce impairments in these functional domains. Augmentation of antidepressant treatment with exercise also improves psychosocial functioning and quality of life (52) and may be considered as a treatment strategy for TRD patients.

Depression is often comorbid with other medical conditions. Optimized treatment of these medical conditions, such as obstructive sleep apnea, may result in improved mood. In the context of comorbid inflammatory disorders, such as rheumatoid arthritis and psoriasis, use of anti-inflammatory medications has been associated with improvements in depressive symptom severity (53–55). A large meta-analysis conducted recently demonstrated the antidepressant potential of monoclonal antibodies against inflammatory cytokines (56). In fact, more recent studies of monoclonal antibodies against interleukin 17 (IL-17) have shown that improvement in depression severity is partly independent of changes in skin lesions among patients with psoriasis and moderate to severe depression (53).

The last decade has seen the emergence of several promising new treatments for patients with TRD. In the face of either refractoriness, intolerability, unavailability, or unaffordability of FDA-approved treatments, clinicians and patients now have several options available. When considering these options, clinicians must exercise caution to enhance diagnostic certainty, prevent adverse events, and minimize the suffering of patients. We strongly encourage a measurement-based care approach, because it will help document failure of previous treatments and ascertain the efficacy of experimental treatments.