University of Otago researchers are at the forefront of a promising new approach to tackling treatment-resistant depression (TRD), a condition affecting tens of thousands of New Zealanders. A landmark phase 2 clinical trial led by Professor Paul Glue has demonstrated that extended-release oral ketamine tablets, known as R-107, offer rapid and sustained relief with excellent tolerability. This innovation, developed in collaboration with New Zealand's Douglas Pharmaceuticals, could transform access to effective care by enabling at-home administration without the intense side effects associated with intravenous or nasal ketamine formulations.
The BEDROC trial, published in Nature Medicine in June 2024, marks a significant milestone for Otago's Department of Psychological Medicine and the broader higher education landscape in Aotearoa. With TRD impacting an estimated 100,000 Kiwis—roughly one-third of those with major depressive disorder—this research underscores the vital role of university-led clinical pharmacology in addressing national mental health challenges.
Understanding Treatment-Resistant Depression in New Zealand
Treatment-resistant depression, often abbreviated as TRD, is defined as major depressive disorder that fails to respond adequately to at least two different antidepressant medications taken at therapeutic doses for sufficient duration, typically six weeks or more. In New Zealand, depression affects about 5.4% of adults, equating to over 220,000 people, with TRD comprising 30-40% of cases. Recent surveys indicate one in seven adults experiences high psychological distress, exacerbating the burden on healthcare systems and individuals alike.
Traditional treatments like selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) provide relief for many, but for TRD patients, options are limited to electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or off-label ketamine. These carry logistical hurdles: clinic visits, monitoring for blood pressure spikes, and dissociative effects. Otago's work addresses these gaps head-on.
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The Science Behind Ketamine's Antidepressant Effects
Ketamine, originally an anesthetic, gained attention after a 2000 Yale study showed rapid symptom relief in TRD patients within hours—far faster than weeks for conventional antidepressants. It primarily acts on glutamate receptors, particularly NMDA, promoting synaptogenesis via brain-derived neurotrophic factor (BDNF) and reversing neural atrophy in depression.
Challenges with standard ketamine include short duration (days), dissociation ('K-hole'), hypertension, and abuse potential. Extended-release formulations like R-107 slow absorption, maintaining steady plasma levels to minimize peaks that cause side effects while sustaining therapeutic benefits. Otago's Professor Glue, tracking ketamine since Yale, pioneered this with Douglas Pharma since 2016, conducting meta-analyses and early trials.
Breaking Down the BEDROC Phase 2 Trial
The BEDROC trial innovatively started with an open-label phase: 231 TRD patients took 120mg R-107 daily for 5 days. Responders (MADRS score drop ≥50% to ≤12; 73%, n=168) were randomized to twice-weekly 30mg, 60mg, 120mg, 180mg, or placebo for 12 weeks. Most dosing occurred at home, mimicking real-world use.
- Highest dose (180mg): Significant MADRS improvement (-6.1 vs placebo, p=0.019)
- Relapse rates: Dose-dependent, 42.9% (180mg) vs 70.6% placebo
- Remission in enrichment: 57.1%; response 72.7%
NZ sites (Dunedin, Auckland, Christchurch, Rotorua) contributed substantially, highlighting Otago's clinical trial infrastructure.
Read the full Nature Medicine studySafety, Tolerability, and Patient Stories
Safety shone: No blood pressure changes, minimal dissociation (CADSS <1 double-blind), low sedation. Common mild AEs: headache, dizziness, anxiety. Completion rates high (56% 180mg vs 30% placebo). Patient Andrew Marshall shared: "I would probably not be alive today if I wasn't on this drug," crediting resilience during cancer.
Over 100 post-trial participants access funded supply via compassionate use, per Glue.
Ongoing Otago Trials: Ketamine + Psychotherapy
Building on BEDROC, Otago's Christchurch campus recruits for a trial led by Assoc Prof Ben Beaglehole: oral ketamine ± Behavioral Activation Therapy (BAT) for TRD. Aimed at 60 adults 18-65 with two failed antidepressants. 8 weeks twice-weekly ketamine, monitored 12 weeks. BAT boosts activity to sustain gains. Recruiting from Christchurch/Dunedin; email ben.beaglehole@otago.ac.nz.
Trial recruitment detailsOtago vs Existing Ketamine Options in NZ
NZ approves esketamine (Spravato®) nasal spray for TRD since 2020, but requires clinic supervision. IV ketamine off-label, costly (~$800/dose). R-107 promises home use, lower cost, better compliance. RANZCP guidelines support specialist ketamine use; Otago advances evidence for oral forms.
| Treatment | Route | Setting | Duration | Side Effects |
|---|---|---|---|---|
| Spravato | Nasal | Clinic | Weeks | Dissociation, BP rise |
| IV Ketamine | Infusion | Clinic | Days | High dissociation |
| R-107 | Oral tablet | Home | Weeks-months | Minimal |
Paul Glue's Legacy and Otago's Research Ecosystem
Prof Glue, Hazel Buckland Prof of Psychiatry, has 200+ ketamine pubs, cited 13k times. Collaborated with Douglas since 2016; meta-analyses, cancer patient trials. Finalist KiwiNet Awards 2025. Otago's ecosystem fosters such impact: funding from Health Research Council, trials in multiple campuses.
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Implications for New Zealand Mental Health Landscape
If Phase 3 succeeds (Tasman Therapeutics' ROCKET program, IND open FDA), R-107 could be first oral monotherapy for TRD, easing DHB burden. NZ$55M Douglas investment highlights pharma-uni synergy. Addresses youth distress surge (50% 15-24yo anxiety/depression).
University research drives policy; potential public funding post-approval.
Future Outlook: Phase 3 and Beyond
Tasman plans Phase 3 H2 2025; patents to 2037+. Otago's BAT trial ends 2026, informing combos. Broader: glutamate therapies, biomarkers for responders. NZ positions as ketamine hub.
Photo by Duskfall Crew on Unsplash
Careers in Psychiatric Research at NZ Universities
Otago exemplifies opportunities: clinical trials coordinators, psychopharm PhDs, postdocs. With TRD trials expanding, demand grows for researchers, nurses, data analysts. Research assistant jobs abound; career advice for thriving in academia. Internal links to university jobs, higher ed jobs.