Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

Depression is described as a highly burdensome, pervasive disorder for which a large proportion of patients do not achieve adequate benefit from standard treatments. The paper focuses on treatment-resistant depression (TRD), operationalised in the text as failure to achieve response to one or more adequate antidepressant trials, and highlights that, after decades of monoaminergic drug development, many patients remain symptomatic and therefore require new therapeutic strategies. Papakostas outlines a shift in research trajectories away from sole reliance on monoaminergic mechanisms towards agents acting on glutamatergic, cholinergic and opioid systems, as well as device-based and procedural therapies. The review updates an earlier overview of TRD from roughly five years prior, organising the discussion by drug class and addressing both pharmacological and device interventions with an emphasis on novel and rapidly acting approaches.

Glutamatergic modulators were a major focus. Ketamine, given most commonly as a subanaesthetic intravenous infusion (typically 0.5 mg kg-1 over 40 minutes), is reported to produce a rapid antidepressant effect within about 110 minutes that can persist for around 7 days in patients with TRD. A randomised, double-blind trial using midazolam as an active comparator (n = 73) found a large effect on Montgomery–Åsberg Depression Rating Scale (MADRS) scores for ketamine versus midazolam (Cohen's d = 0.81) at 24 hours, with sustained benefit for several days. Intranasal ketamine (50 mg) produced significant symptom reduction at 24 hours in an 18-completer proof-of-concept trial, although the effect was not significant at 72 hours. Safety data summarised include a pooled report in which 4 of 205 ketamine infusions were stopped due to adverse events and no persistent psychotomimetic effects or increased substance use were observed in a subgroup followed long term. Several other NMDA- and glutamate-targeting agents are reported. Lanicemine (AZD6765), a low-trapping NMDA blocker, produced rapid MADRS decreases within 80–110 minutes in small studies; in a larger adjunctive trial (n = 124) thrice-weekly infusions for 3 weeks produced a mean difference from placebo in MADRS of −5.5 (P < 0.02), and a 100 mg dose showed effects lasting up to 5 weeks after the last infusion, without significant psychotomimetic or dissociative side effects. Memantine trials were largely negative in depression. Riluzole showed antidepressant signals in small open-label and augmentation studies, but a double-blind trial following an open-label ketamine infusion (n = 42) found no difference between riluzole and placebo for prolonging ketamine response. NR2B-selective antagonist MK-0657 (oral) did not produce significant improvement on the MADRS in a small crossover trial (n = 21) though some secondary measures showed rapid benefits; a Phase II programme with CERC-301 (MK-0657) was noted as completed with results pending. Inhaled nitrous oxide produced rapid antidepressant effects within 2 hours in a crossover pilot (n = 20), with effects lasting at least 24 hours; reported response was 20% and remission 15% in that sample. Agents aimed at modulating NMDA glycine or AMPA receptor function are also reviewed. GLYX-13, a functional partial agonist at the NMDA-receptor glycine site, improved depressive symptoms within hours and effects were sustained for 1–2 weeks in a Phase IIa trial of TRD patients (n = 116) without observed psychotomimetic effects. AVP-786 (deuterated dextromethorphan plus low-dose quinidine) was described as entering Phase II testing. Org 26576, an AMPA positive allosteric modulator, was well tolerated in Phase I (n = 36) and Phase Ib (n = 54) studies, improved certain cognitive measures and showed larger symptomatic improvements than placebo; biomarker changes included increased growth hormone and decreased cortisol. Metabotropic glutamate receptor modulators are at earlier stages; antagonists of mGluR2/3 showed promising preclinical data, whereas basimglurant (mGluR5 antagonist) in a 9-week adjunctive, randomised trial (n = 333) produced consistent efficacy across endpoints but narrowly missed statistical significance on the clinician-rated MADRS (P = 0.061), with a sizable placebo response noted. Anticholinergic approaches included scopolamine, a competitive muscarinic antagonist, which produced rapid antidepressant and anxiolytic effects within about 3 days across unipolar and bipolar samples, with apparently larger effects in women and in treatment-naive patients; evidence on maintenance of benefit is limited. Nicotinic antagonists showed mixed results: mecamylamine augmented to citalopram showed superiority over placebo in incomplete responders, but the active enantiomer dexmecamylamine (TC-5214) failed to show benefit in Phase III trials that exhibited high placebo response rates. CP-601,927, an α4β2 partial agonist, was not superior to placebo in a Phase II trial, although a post hoc signal appeared in non-obese participants. Opioid-system modulation is represented by ALKS 5461, a combination of buprenorphine and samidorphan intended to produce functional κ-opioid antagonism while limiting μ-opioid-related abuse. A published study reported positive efficacy and safety data without evidence of abuse or withdrawal concerns; Phase III trials were ongoing at the time of the review. Among monoaminergic and catecholaminergic agents, vortioxetine (approved by the FDA in 2013) demonstrated superior antidepressant efficacy versus placebo in pooled analyses of multiple trials and showed advantages over agomelatine when used as a switch strategy after SSRI/SNRI failure. Lisdexamfetamine (LDX) augmentation trials in partially remitted patients did not find statistically significant benefit over placebo in Phase II and subsequently failed Phase III development. Edivoxetine (LY2216684) showed higher remission in a Phase II adjunctive trial (24.2% vs 11.8%, P = 0.044 by last observation carried forward) but failed to demonstrate efficacy in Phase III studies. Pramipexole produced modest, non-significant augmentation benefit in small trials and combination strategies did not show superiority while sometimes being poorly tolerated. Nutraceuticals and behavioural approaches yielded mixed findings. L-methylfolate augmentation produced divergent results: a 148-patient adjunctive trial showed no difference, whereas a smaller 75-patient trial reported efficacy at 15 mg day-1; post hoc work suggested inflammatory and genetic markers might predict response. SAMe augmentation (800 mg twice daily) showed greater response and remission than placebo in a 73-patient TRD sample. An exercise trial in SSRI non-remitters (n = 126) comparing high- versus low-dose exercise over 12 weeks did not show a statistically significant difference on primary depression outcomes overall, but a trend to higher remission (P ≈ 0.06) and subgroup benefits in men and women without family history of mental illness were reported. Hormonal and anti-inflammatory strategies provided selective signals. Repeated erythropoietin (EPO) administration in a double-blind, placebo-controlled trial (n = 39) did not reduce depression on the primary outcome but improved verbal memory and showed a benefit on one secondary depression measure. Testosterone trials after an initial positive report did not replicate augmentation effects in men. Anti-inflammatory treatment with infliximab (three intravenous infusions) improved depressive symptoms only in patients with elevated baseline inflammatory biomarkers (for example C-reactive protein) in a 60-patient randomised trial. Meta-analyses and pooled trials indicated adjunctive celecoxib (a COX-2 selective NSAID) is associated with improved antidepressant effects without increased NSAID-related adverse events. Device-based therapies are summarised with standard repetitive transcranial magnetic stimulation (rTMS) described as effective in TRD, albeit with smaller effect sizes and slower onset than electroconvulsive therapy (ECT). Deep TMS (dTMS), which uses an H-coil to reach deeper cortical regions, showed promising results: an open study (n = 29) reported a maintained response rate of 81% and remission rate of 71% over extended treatment, and a randomised, double-blind, multi-centre trial in 212 unmedicated TRD patients found significantly higher response (38.4% versus 21.4%) and remission (32.6% versus 14.6%) rates for active dTMS versus sham (P's ≤ 0.01), with effects persisting up to 4 months with maintenance therapy. The authors note the logistical burden of daily administration and challenges in sustaining long-term benefit.

Papakostas and colleagues interpret the body of evidence as indicating incremental progress in treating TRD, with several novel mechanisms showing promise but persistent limitations. They note that atypical antipsychotics have expanded their evidence base as adjunctive treatments and that olanzapine, aripiprazole and quetiapine are the only FDA-approved pharmacological adjuncts; however, tolerability concerns and slow onset of action limit their utility. The repeated failure of some Phase III programmes for catecholaminergic agents (for example LDX, edivoxetine) and for dexmecamylamine highlights an ongoing unmet need, while glutamatergic modulators and scopolamine represent more successful development of rapidly acting agents. Several important caveats are emphasised. Rapid-acting interventions often face exceptionally large placebo responses, limited durability of effect beyond a few days in many studies, and practical limitations related to intravenous administration. Device-based therapies such as rTMS and dTMS have favourable safety profiles compared with ECT but typically exhibit smaller effect sizes and slower clinical onset; daily treatment burden and challenges in maintaining long-term efficacy are additional concerns. The authors recommend better operationalisation of TRD in trials (for example, specifying degrees of resistance such as 1–3 failed trials versus ≥ 4), more head-to-head and blinded comparisons among devices, pharmacotherapies and ECT, and broader enrolment of difficult cases into clinical trials. Finally, Papakostas stresses the value of serendipity and clinical observation in drug discovery and advocates for combining innovation with biomarker-driven, target-engagement and neuroscience-informed approaches to advance antidepressant research. The ongoing NIMH-funded RAPID initiative is cited as an exemplar programme that will test low-field magnetic stimulation, a κ-opioid receptor antagonist (LY2456302), and ketamine dose-finding strategies, reflecting the translational priorities outlined by the authors.