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JAMA Psychiatry recently published phase 4 data that supports esketamine monotherapy for treatment-resistant depression (TRD).¹

Back on January 21, 2025, Johnson & Johnson announced that the US Food and Drug Administration (FDA) approved esketamine (SPREVATO) CIII nasal spray as the first monotherapy for adults with TRD.2 The approval followed the FDA’s Priority Review on esketamine for TRD and was based on a phase 4 randomized, double-blind, multicenter, placebo-controlled study that found esketamine alone provided a rapid, superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 weeks compared with placebo.

Among approximately 21 million US adults who live with major depressive disorder, a third do not respond to oral antidepressants alone.² Patients who do not respond to ≥ 2 oral antidepressants can now try esketamine, a non-selective, non-competitive antagonist of the N-methyl-D-aspartate receptor that targets glutamate.

The phase 4 study, led by Adam Janik, MD, from the department of neuroscience at Johnson & Johnson in San Diego, assessed the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD.¹

“In this first placebo-controlled, monotherapy randomized clinical trial, esketamine demonstrated rapid and robust efficacy at both 56- and 84-mg doses, with a clinically meaningful and statistically significant treatment effect, initially observed 24 hours after the first dose, representing substantial benefit compared to [oral antidepressants], which typically exhibit a delayed onset of effect,” Janik and colleagues wrote.¹

The team conducted this phase 4 study from November 2020 to January 2024 at 51 outpatient centers in the US. Participants (mean age, 45.4 years; 61% females) had major depressive disorder without psychotic features that met DSM-5 criteria. All patients experienced inadequate response (≤ 25% improvement) to ≥ 2 oral antidepressants during the current depressive episode and had a baseline mean MADRS total score of 37.3 (range, 28 – 50).

The primary endpoint was the change in the MADRS total score from baseline to day 28. The secondary endpoint was the change in MADRS total score from baseline to 24 hours post-first dose. Data was analyzed from March 1, 2024, to July 8, 2024.

In total, 378 patients participated in a 2-week antidepressant-free period before getting randomized 1:1:2 to fixed-dose intranasal esketamine (56 mg [n = 86] or 84 mg [n = 95]) or matching intranasal placebo (n = 197). Esketamine or placebo was administered twice weekly for 4 weeks.

At day 28, the least-square (LS) mean difference between esketamine and placebo was -5.1 (95% confidence interval [CI], -7.91 to -2.33) for 56 mg and -6.8 (95% CI, -9.48 to -4.07) for 84 mg (P < .001). Observed effect sizes were 0.48 for 56 mg and 0.63 for 84 mg.¹

Approximately 24 hours post-first dose, investigators observed a significant difference between esketamine and placebo: -3.8 (95% CI, -6.29 to -1.22; P = .004) for 56 mg and -3.4 (95% CI, -5.89 to -1.00; P = .006) for 84 mg.¹

Common treatment-emergent adverse events (TEAEs) for esketamine 56 mg and 84 mg included nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19%). Most adverse events were mild or moderate and resolved 2 hours post-dose. No patient on esketamine experienced a treatment-related serious adverse event.¹

“Results from this study strengthen the body of evidence for esketamine’s antidepressant efficacy and inform on the monotherapy treatment option for patients with TRD, particularly when [oral antidepressants] have inadequate efficacy but high adverse effect burden,” investigators concluded. “That the 84-mg dose, the most common in real-world practice, conferred a larger effect size without safety concerns supports the potential for starting esketamine monotherapy at this dose.”¹

References

1. Janik A, Qiu X, Lane R, et al. Esketamine Monotherapy in Adults With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online July 02, 2025. doi:10.1001/jamapsychiatry.2025.1317

2. Derman, C. FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression. HCPLive. January 21, 2025. https://www.hcplive.com/view/fda-approves-esketamine-first-monotherapy-treatment-resistant-depression. Accessed July 28, 2025.

Governance

Effective governance is fundamental to advancing migrant health equity by fostering trust, reducing systemic discrimination, and improving institutional accountability. Multi-stakeholder governance models that include government, civil society, and private actors have facilitated migrant inclusion and integration. These approaches are highly applicable with modifications to Iran’s context, particularly given its experience with refugee populations but need adaptation to address centralized decision-making structures. For instance, intersectoral collaboration in municipalities with limited health focus on migrants has contributed to reducing local health disparities [16, 17]. In Italy, coordinated governance across regional and national levels helped streamline healthcare access for undocumented groups [17, 18], demonstrating a model that is moderately applicable to Iran if implemented alongside decentralization reforms. These examples highlight the role of context specifically, political will and decentralization in activating mechanisms such as participatory governance and equity audits.

Germany’s introduction of inclusive language guidelines is a compelling example of how minor but intentional policy changes can shift provider behaviors and improve trust between migrants and health systems [9]. This low-cost intervention is highly applicable to Iran’s health system and could be rapidly implemented through Ministry of Health directives. Similarly, countries like Sweden and Canada, which rank highly on the Migrant Integration Policy Index MIPEX, show that inclusive governance frameworks lead to better health outcomes compared to exclusionary policies [19]. While these comprehensive models are aspirational for Iran, selected components could be adapted to local capacity.

In Iran, where registered refugees have free access to Primary Health Care PHC, but undocumented migrants face administrative barriers, inclusive policy reforms require intersectoral collaboration. For example, the “Health Houses for Refugees” initiative in Tehran a partnership between the Ministry of Health and UNHCR has improved PHC access for Afghan refugees, yet service gaps persist for irregular populations due to documentation requirements. This demonstrates that partnership models are highly applicable but require expansion to cover undocumented groups. Additionally, in Sistan-Baluchestan province, mobile health units targeting border communities have demonstrated how decentralized governance can extend care to hard-to-reach migrants, though funding constraints limit scalability. These localized solutions are highly applicable to other border regions but require sustainable financing mechanisms.

Financing

Financial barriers remain among the most pressing challenges faced by migrant populations, especially undocumented individuals who are typically excluded from public insurance schemes. Thailand’s Health Insurance Card Scheme HICS, which demonstrated that every dollar invested in migrant coverage yielded three dollars in savings through reduced emergency care usage [10], is highly applicable to Iran’s context and could build on existing humanitarian health financing structures. During the COVID-19 pandemic, targeted subsidies and co-pay waivers effectively mitigated financial barriers for migrant workers [20], representing a crisis-responsive model that is highly applicable to Iran’s emergency preparedness planning. Nigeria’s GIFSHIP program enhanced coverage among vulnerable groups [21], offering lessons that are moderately applicable to Iran but would require adaptation to local insurance frameworks.

For Iran, where registered refugees have limited but structured access to PHC, extending subsidized coverage through tiered or community-based insurance schemes could reduce disparities for undocumented populations and align with broader UHC objectives. Community-based insurance models are highly applicable given Iran’s PHC infrastructure but require pilot testing in provinces with high migrant density. The Imam Khomeini Relief Committee’s existing networks could serve as implementation platforms for such pilots.

Health workforce

Provider-level discrimination and lack of cultural competence are persistent barriers to equitable healthcare access for migrants. Implicit bias training programs, proven effective for sub-Saharan African migrant women [22, 23], are highly applicable to Iran’s health workforce and could be integrated into existing continuing education systems. Interventions that align with cultural beliefs such as co-designed perinatal mental health services, enhance service utilization and patient satisfaction. These participatory approaches are highly applicable to serving Afghanistan’s migrant populations in Iran but require investment in community engagement mechanisms.

A study in Nigeria underscored the importance of systemic reforms, noting that training, performance incentives, and infrastructure investment are essential to address workforce shortages in rural and migrant-heavy areas [24]. These findings are moderately applicable to Iran’s border provinces, where similar workforce challenges exist but require adaptation to local resourcing constraints. Integrating community health workers CHWs into formal systems has reduced care disparities, particularly in hard-to-reach or marginalized communities [25]. This strategy is highly applicable to Iran’s Behvarz network but would require additional training in migrant health needs and cultural sensitivity.

Health system information

Robust health information systems play a critical role in combating misinformation, promoting health literacy, and ensuring service continuity for mobile populations. Digital solutions like blockchain-based immunization records, successfully implemented for undocumented migrants elsewhere [26, 27], are highly applicable to Iran’s context but require investment in technological infrastructure and staff training. A mobile application in Colombia facilitated HIV testing and linkage to care among Venezuelan migrants, demonstrating an approach that is moderately applicable to Iran’s Afghan population but would need Dari/Pashto language adaptation [12].

In Malaysia, digital maternal health monitoring systems improved outcomes for migrant women [28], representing a model that is highly applicable to Iran’s PHC system but requires gender-sensitive design considerations. Guidelines promoting inclusive and non-stigmatizing language have been shown to build institutional trust [10], an intervention that is highly applicable and low-cost for Iran’s health facilities.

For Iran’s national electronic health record SIB system, incorporating flexible, low-barrier, multilingual access points e.g., Dari, Pashto, Arabic could significantly improve digital inclusion for migrant groups. This adaptation is highly applicable but requires coordination between the Ministry of Health and migrant community representatives to ensure cultural appropriateness.

Medical products, vaccines, and technologies

Legal and administrative exclusions often prevent migrants from accessing essential medicines and preventive services. Inclusive vaccination campaigns, achieving 90% coverage in Italy’s undocumented communities [27], are highly applicable to Iran and could leverage existing mobile health units in border provinces. Community-driven outreach using respondent-driven sampling, as implemented for HIV services in Colombia [11], is moderately applicable to Iran but requires adaptation to local epidemiological profiles and trust-building with hidden populations.

For Iran, mobile clinics and community health navigators could be strategically deployed in provinces with high migrant density, particularly to address vaccine hesitancy and access gaps during outbreaks or emergencies. This approach is highly applicable given Iran’s experience with Behvarz workers but needs additional training in migrant-specific health communication strategies.

Service delivery

Service delivery innovations that respond to local contexts have been pivotal in enhancing migrant health equity. Programs like Pronto Badante in Tuscany that improved eldercare access through peer networks [30] are moderately applicable to Iran’s context and could be adapted for migrant elderly care in urban centers. Adaptive leadership and integrated care systems utilizing real-time data dashboards [31, 32] are highly applicable to Iran’s hospital systems but require investments in health information technology.

Language barriers have been addressed through certified interpreters and AI-assisted translation, improving communication quality and reducing misdiagnosis [33, 38]. While interpreter services are highly applicable to Iran’s clinical settings, AI solutions are currently moderately applicable due to infrastructure limitations. In maternal health, culturally sensitive models using trained doulas and CHWs have improved birth outcomes among migrant women [23, 34]. These models are highly applicable to serving Afghanistan’s migrant women in Iran but require partnerships with community-based organizations.

Synthesis and policy implications

Across all domains, this review highlights that successful strategies share common mechanisms: trust-building, legal and financial inclusion, cultural alignment, and participatory governance. These mechanisms are not universally effective in isolation; they are activated by enabling contexts such as inclusive legislation, institutional collaboration, and system readiness. The realist lens thus offers a nuanced understanding of “what works, for whom, and under what conditions.”

For Iran, global strategies are most transferable when they: Leverage existing infrastructure, such as the Behvarz network, PHC system, or SIB digital record platform, address well-documented implementation challenges, including centralized governance, inconsistent migrant registration, and linguistic barriers, Align with sociopolitical and cultural norms, particularly in marginalized and border communities.

Iran’s contextual strengths like an expansive PHC system, a history of refugee engagement, and humanitarian partnerships create opportunities for adaptation. However, challenges remain, including fragmented governance, limited insurance integration for undocumented groups, and lack of sustained cultural responsiveness in mainstream services.

Key policy recommendations include

• Piloting inclusive insurance schemes for undocumented and migrants with temporary or limited legal status.

• Scaling up CHW networks with training in cultural competence and gender sensitivity.

• Investing in multilingual health communication and interpretation infrastructure.

• Enhancing digital inclusion through mobile outreach and telehealth for migrants.

• Institutionalizing anti-discrimination training and equity audits at provider levels.

Sustained political commitment, intersectoral coordination, and migrant community engagement are essential to institutionalizing these changes. Adopting a context-sensitive, equity-driven approach can help Iran move toward inclusive health system strengthening, ensuring that no population is left behind.