This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Background. Treatment-resistant depression (TRD) is a prevalent, high-burden disorder. Esketamine nasal spray (ESK-NS) has been approved for, T.R.D.; and efficacy has been observed in both clinical trials and real-world studies. However, observations integrating patients’ perspective on this treatment are limited. This multicentric Italian study explored experiences with ESK-NS in TRD patients, focusing on perceived therapeutic effects and overall satisfaction. Methods. A self-report survey was administered to 236 outpatients with TRD (55.1% females, 54.1 ± 14.1 years) treated with ESK-NS for at least three consecutive months within standard clinical care. Based on satisfaction levels, participants were classified as “unsatisfied” (10.2%), “partially satisfied” (19.1%), “satisfied” (44.4%), or “very satisfied” (26.3%), and compared for sociodemographic, clinical characteristics, and feedback on perceived benefits. Artificial intelligence (OpenAI) served to categorize responses to an open-ended question. Results. Enhanced quality of life was reported by 88.4% of participants. Significant differences emerged in earliest self-perceived benefits, most relevant effects, and impact on global functioning across groups. Specifically, “very satisfied” patients described the following: early improvements in depressed mood, suicidal thoughts, and restlessness; decreased suicidal thoughts among the most significant effects; and functional gains across all domains. OpenAI identified experiences of personal growth and rediscovery and a desire for tailored settings and approaches as recurring topics. Conclusions. Most patients reported a positive perception of ESK-NS treatment. The most satisfied participants highlighted significant benefits to depressed mood, suicidal thoughts, and overall functioning. Patient-reported experiences offer insights into different psychopathological dimensions, including functional outcomes and quality of life. Integrating these perspectives into clinical practice might assist treatment personalization, improving patients’ adherence and satisfaction.

Background/Objectives: Intranasal esketamine has emerged as an effective treatment for patients with treatment-resistant depression (TRD), providing rapid symptom relief when conventional antidepressant strategies fail. While its pharmacological efficacy has been demonstrated in randomized controlled trials, less attention has been paid to the organizational, relational, and multidisciplinary aspects that influence its real-world implementation and clinical effectiveness. While practical recommendations for intranasal esketamine services exist, an implementation-ready framework integrating psychiatry, nursing, and psychotherapy across treatment phases is still lacking. This narrative review synthesizes the clinical and real-world evidence and proposes a phase-based integration framework with explicit role delineation and measurable implementation/fidelity indicators. Methods: We conducted a narrative review informed by a structured literature search in major databases from inception to the most recent update. Search terms combined ‘esketamine’/‘Spravato’ with ‘treatment-resistant depression’, ‘nursing’, ‘psychotherapy’, ‘multidisciplinary’, and ‘implementation’. Outcomes prioritized in the synthesis included depressive symptom severity/response, relapse prevention, safety/tolerability, anhedonia, suicidality monitoring, functional outcomes, and patient-reported experience/retention. Based on this evidence, an integrated, phase-based multidisciplinary framework for esketamine treatment was developed. Results: Available evidence supports the efficacy of intranasal esketamine in reducing depressive symptoms in TRD, with growing real-world data confirming its effectiveness and safety. Beyond global symptom improvement, studies highlight benefits on clinically relevant domains such as anhedonia and suicidality trajectories, as well as meaningful patient-reported outcomes. However, the complexity of esketamine delivery requires structured clinical pathways. The proposed model delineates complementary roles for medical supervision, nursing care, and psychotherapy across pre-treatment assessment, induction and session delivery, post-session integration, and maintenance phases, emphasizing safety, continuity of care, and patient-centred monitoring. Conclusions: Intranasal esketamine represents not only a pharmacological innovation but also a treatment that necessitates an integrated multidisciplinary approach. A structured phase-based multidisciplinary approach may support safer, more acceptable delivery of intranasal esketamine and potentially improve retention and patient experience; however, prospective implementation and comparative studies are needed to evaluate clinical effectiveness, feasibility, and cost-effectiveness.