This article (2015) examines the advantages and applications of intranasal drug delivery, with a particular focus on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. The article contrasts intranasal delivery to oral and sublingual delivery methods, which are less effective with regards to their bioavailability, crossing of the blood-brain-barrier, and rapid onset of drug effects.
Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of 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.
Papers cited by this study that are also in Blossom
Murrough, J. W., Wan, L., Levitch, C. F. et al. · Journal of Clinical Psychiatry (2015)
Papers in Blossom that reference this study
Roelandt, G. H. J., Strous, J. F. M., Kamphuis, J. et al. · BJPsych Open (2026)
Huggins, C., Glue, P., Martin, D. et al. · Journal of Psychopharmacology (2018)
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.
Medications in neuropsychiatric practice are most commonly administered either orally or parenterally. Intranasal drug delivery (INDD) systems, however, have been available for decades; there is a large body of animal literature on the subject, this route of drug administration has long been used in several medical fields, and, more recently, INDD has gained importance even in neuropsychiatry. This article will examine INDD in neuropsychiatry with particular focus on the use of intranasal ketamine in the treatment of refractory depression.
INDD systems cater to different situations and needs that are not necessarily mutually exclusive (Table). These are briefly discussed below. Local action. In otorhinolaryngologic practice, medications have for long been administered intranasally (as drops or sprays) for local action. In neuropsychiatry, a patient may require a nasal decongestant if a stuffy nose results from the use of sildenafil or a tricyclic antidepressant drug.Rapid onset of action. INDD is associated with a fast onset of action. This is because there is quick drug absorption from the rich, intranasal vascular bed. Peak blood levels are rapidly attained.As examples, sumatriptan nasal spray 10 and intranasal lidocaine 11 both afford rapid relief from acute migraine. Nicotine nasal spray affords rapid relief from craving in nicotine-dependent individuals.Bypassing the blood-brain barrier. INDD can deliver drugs directly to the central nervous system, bypassing the blood-brain barrier. Absorption occurs through the olfactory epithelium, and transport through the cribriform plate, via the olfactory pathways, into the brain.An example is the use of insulin spray as an experimental treatment for cognitive decline and Alzheimer's disease.INDD can also be used to study brain functioning. For example, a peptide that interferes with the interaction between D 1 and D 2 receptors was shown to have antidepressant action in the forced swim test in rodents for up to 2 hours after intranasal administration. Inhibition of D 1 -D 2 receptor interaction was demonstrated in the prefrontal cortex.Improvement of bioavailability. INDD can improve bioavailability of drugs such as peptides that may be digested rather than absorbed after oral administration. Examples of approved and experimental treatments include desmopressin for pediatric 15 and geriatricenuresis, insulin for disorders of cognition, 13 and oxytocin for a variety of experimental indications (see below). Avoidance of parenteral administration. INDD can improve the convenience of drug administration, as with intranasally administered ketaminein place of intravenously infused ketamine for patients with refractory depression. Tablelists a few examples of INDD applications in neuropsychiatry; in this regard, ketamine and oxytocin are perhaps the best-studied agents. Aqueous (4%) lidocaine nasal drops have demonstrated rapid efficacy in episodes of acute migraine. 11 Intranasal ropiniroleand other intranasal treatments are being studied for Parkinson disease, and intranasal insulin and other treatments are being studied for mild cognitive impairment and early Alzheimer's disease.A neurosteroid, PH94B, was successfully trialled for social anxiety in women.INDD is also being studied for brain neoplasms.This list is not exhaustive.
Intranasal oxytocin may influence social relationships and has been much studied in this regard; notwithstanding the media hype over this so-called love hormone, research has not resulted in straightforward conclusions.There has been much investigation of the possible benefits of intranasal oxytocin for schizophrenia, 24 with improvements recorded in domains such as clinical symptom ratings 25 and social cognition.Intranasal oxytocin has also been studied for autism. For example, 15 children and adolescents with autism spectrum disorder showed improvement during 12 weeks of treatment in the domains of social functioning, repetitive behaviors, and anxiety; some improvements persisted as long as 3 months later.A randomized controlled trial, however, failed to demonstrate efficacy.Some benefits with intranasal oxytocin have also been recorded in social anxiety.Intranasal oxytocin is also being studied for the prevention of posttraumatic stress disorder in persons who experience trauma. 30
Intranasal ketamine attenuates pain in the emergency room in childrenand adults.Intranasal ketamine also reduces the severity of pain in migraine.Wink et alreported a 29-year-old woman with autism who was treated with intranasal ketamine (20-60 mg) on 12 dosing occasions across 6 weeks. She showed improvements in mood, social interactions, flexibility, tolerance of changes in routine, motivation, and concentration. Adverse events were mostly mild; the most prominent was headache, which lasted for up to 10 hours after a treatment. A case report also showed benefits with intranasal ketamine in depression.In a randomized, double-blind, saline-controlled, crossover trial conducted in 20 patients with major depression, Lapidus et alfound that a single intranasal dose of ketamine (50 mg) outperformed saline by 7.6 points on the Montgomery-Asberg Depression Rating Scale as assessed 24 hours after dosing; the response rate was 44% vs 6%, respectively. Anxiety ratings also decreased significantly more with ketamine. However, there was no significant separation between ketamine and saline at 3 and 7 days posttreatment. In this study, intranasal ketamine was well tolerated, with few, mild, and very transient adverse effects such as feelings of unreality. There was also a small and transient increase in systolic blood pressure (by 7.6 mm Hg at 40 minutes). Maintenance treatment with intravenous ketamine infusion maintains treatment gains.Because the antidepressant benefits of intranasal ketamine wear off within 3 days,might maintenance treatment with intranasal ketamine be a viable treatment strategy to extend treatment gains? Regrettably, this has not been investigated in the context of depression. However, in a retrospective chart review of 12 treatment-refractory bipolar youth (10 male; age, 6-19 years) with fear of harm phenotype, Papolos et al 36 reported that
■ Intranasal drug delivery (INDD) systems allow for improved bioavailability, avoidance of the inconvenience and discomfort of parenteral administration, rapid onset of therapeutic action, and bypassing of the blood-brain barrier. ■ INDD has been used for test, experimental, and approved indications to treat conditions such as migraine, acute and chronic pain, Parkinson disease, disorders of cognition, schizophrenia, social phobia, autism, and refractory depression. ■ Intranasal ketamine is emerging as a potential alternative to intravenous ketamine infusions for patients with refractory depression; at present, however, the data are limited, and so the treatment remains emphatically experimental. maintenance therapy with intranasal ketamine (30-120 mg) resulted in improvements in anxiety, aggression, fear of harm, cognition, behavior, sleep, and other symptoms. Interestingly, hypomanic symptoms also attenuated with intranasal ketamine. Adverse events were mostly dissociative in nature, and all remitted within an hour, without medical intervention. Intranasal ketamine dosing had to be repeated every 3-7 days to maintain the experienced benefits. In many patients, other medications could be tapered or discontinued. No patient dropped out of treatment, and, at the time of writing, 1 patient had been receiving maintenance intranasal ketamine for over 4 years. This author (Andrade, unpublished data) has personal experience with using intranasal ketamine in the dose of 50-80 mg per treatment occasion, once in 2-3 days, as maintenance therapy for a 25-year-old, medication-and electroconvulsive therapy-refractory, functionally impaired man with severe depression. The treatment has been ongoing for the past 26 months and keeps depression at bay only when punctually administered. It has been the only intervention to have helped the patient during a 10-year span of lifecrippling depressive illness. One hopes that there will soon be parallel-group, randomized controlled trials examining the safety and efficacy of repeated dosing with intranasal ketamine, followed by trials of its safety and efficacy during maintenance therapy in treatment-refractory depressed patients. Until data from such trials become available, intranasal ketamine will remain an experimental treatment.
1. The oral bioavailability of ketamine is only 8%-17% because of extensive first-pass metabolism 37,38 ; bioavailability is slightly higher, at 29%, when the drug is administered sublingually.Other reports have also been published.Oral ketamine has also been used to treat chronic pain.
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Andrade, C. · Journal of Clinical Psychiatry (2017)