Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression

Medications used in neuropsychiatry are most commonly given orally or parenterally, but intranasal drug delivery (INDD) has been available for decades and is supported by a substantial animal literature and longstanding clinical use in other fields. INDD offers several theoretical and practical advantages for brain-targeted treatments, including rapid absorption from the intranasal vascular bed, avoidance of gastrointestinal degradation and first‑pass hepatic metabolism, and the potential to bypass the blood–brain barrier via olfactory pathways. Andrade sets out to review the applications and advantages of INDD in neuropsychiatry, and to focus in particular on the potential role of intranasal ketamine for acute management and maintenance therapy of refractory depression. The article synthesises examples of approved and experimental intranasal treatments and highlights gaps in evidence, especially regarding repeated‑dose and maintenance strategies for intranasal ketamine.

INDD fulfils several distinct clinical needs in neuropsychiatry. Local nasal action is useful in otorhinolaryngology and occasionally relevant to psychiatry when intranasal decongestants are required. Rapid systemic onset follows absorption from the richly vascularised nasal mucosa, which accounts for the fast peak blood levels and quick clinical effects reported with agents such as sumatriptan, intranasal lidocaine and nicotine nasal spray. A further advantage of INDD is the potential to deliver drugs to the central nervous system while bypassing the blood–brain barrier. Transport via the olfactory epithelium and cribriform plate underlies attempts to use intranasal insulin for cognitive disorders and experimental intranasal peptides that act on central receptor interactions; one such peptide reduced depressive‑like behaviour in rodents and showed target engagement in prefrontal cortex. INDD also improves bioavailability for molecules susceptible to digestive degradation, notably peptides. Desmopressin, intranasal insulin and oxytocin are cited as examples of treatments developed or tested using the intranasal route. Convenience and avoidance of parenteral administration are additional practical benefits; ketamine is discussed as an example in which intranasal administration could substitute for intravenous infusion in some patients. Intranasal oxytocin has been widely studied for social and cognitive domains but has yielded mixed findings. Small open or pilot studies have reported improvements in social functioning, repetitive behaviours and anxiety in autism, and some symptom or cognition benefits in schizophrenia and social anxiety. However, a randomised controlled trial failed to show efficacy in at least one context, and overall results do not produce straightforward, consistent conclusions. Evidence for intranasal ketamine comprises emergency‑care analgesic use, case reports, a small randomised controlled trial, and retrospective clinical series. Intranasal ketamine reduces pain in children and adults in emergency settings and has shown benefit in migraine. Case reports include a woman with autism who improved in mood and social function after multiple intranasal doses, and an individual case report of benefit in depression. The most rigorous controlled evidence cited is a randomised, double‑blind, saline‑controlled crossover trial in 20 patients with major depression (Lapidus and colleagues). In that study a single 50 mg intranasal dose produced a 7.6‑point greater improvement on the Montgomery–Åsberg Depression Rating Scale at 24 hours compared with saline, with response rates of 44% versus 6%. Anxiety scores also declined more with ketamine. The antidepressant separation, however, was not sustained at days 3 and 7. Adverse effects were few, mild and transient (derealisation/unreality), and there was a small transient increase in systolic blood pressure of about 7.6 mm Hg at 40 minutes. Maintenance data are sparse. Intravenous ketamine maintenance infusions are known to sustain benefit, but repeated‑dose intranasal strategies for depression have not been studied in controlled trials. A retrospective chart review of 12 treatment‑refractory bipolar youth with a ‘‘fear of harm’’ phenotype reported that intranasal ketamine (30–120 mg) given every 3–7 days was associated with improvements across anxiety, aggression, cognition, behaviour and sleep, and hypomanic symptoms attenuated. Dissociative adverse events were reported but resolved within an hour without intervention; many patients were able to reduce other medications and no patients discontinued treatment. One patient reportedly received maintenance intranasal ketamine for over 4 years. Andrade also reports an unpublished clinical case in which a 25‑year‑old man refractory to medication and electroconvulsive therapy remained well on intranasal ketamine 50–80 mg every 2–3 days for 26 months, but these observations are anecdotal and not reported as part of a controlled study. Practical pharmacokinetic considerations are noted: oral ketamine bioavailability is low (8%–17%) because of first‑pass metabolism, whereas sublingual bioavailability is higher (reported around 29%); oral ketamine has been used for chronic pain in some reports.

Andrade interprets INDD as a promising route for neuropsychiatric therapeutics because it can accelerate onset, improve bioavailability for certain molecules and potentially deliver agents directly to the brain. Intranasal ketamine is presented as an emerging alternative to intravenous administration for refractory depression, offering practical advantages and some early evidence of rapid antidepressant effect. At the same time, the author stresses important limitations: the controlled evidence base is limited to a small single‑dose randomised crossover trial and mainly uncontrolled case series and retrospective reports for repeated dosing. Reported benefits tend to be transient after a single intranasal dose, with separation from placebo not maintained beyond a few days in the cited trial. Safety data are likewise preliminary; adverse effects described in the literature and case series are generally mild and short‑lived but require systematic assessment in larger samples and with repeated dosing. Positioning these findings relative to earlier research, Andrade notes that other intranasal agents (for example oxytocin, intranasal insulin, and experimental peptides and neurosteroids) have generated mixed or preliminary results, underscoring both the potential of the route and the heterogeneity of outcomes across compounds and indications. The author therefore calls for appropriately designed parallel‑group randomised controlled trials to evaluate repeated intranasal ketamine dosing and formal trials of maintenance intranasal therapy in treatment‑refractory depression. The paper concludes that intranasal ketamine should remain an experimental intervention until results from such trials become available. Andrade emphasises the need for systematic efficacy and safety data to determine whether intranasal ketamine can be a viable maintenance strategy and to define optimal dosing, frequency and monitoring in clinical practice.