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

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.

Abstract

“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.”

Author: Chittaranjan Andrade

Summary

ABSTRACT

Intranasal drug delivery systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier. They have found several applications in neuropsychiatry, including the treatment of depression.

Clinical Question

Intravenous ketamine infusion has been found safe and effective as a treatment for medication-refractory depression. However, repeated infusions are not a practical treatment strategy for maintenance therapy.

Introduction

Intranasal drug delivery systems (INDD) have been used for decades in several medical fields, including neuropsychiatry, and have gained importance in neuropsychiatry.

Why Deliver Drugs Intranasally?

INDD is associated with a fast onset of action. Drugs such as sumatriptan and lidocaine afford rapid relief from acute migraine.

INDD can deliver drugs directly to the central nervous system, bypassing the blood-brain barrier. This method is used to treat cognitive decline and Alzheimer’s disease, and to study brain functioning.

INDD improves bioavailability of drugs such as desmopressin and insulin, which may be digested rather than absorbed after oral administration.

Table 2 lists a few examples of intranasal drugs being studied in neuropsychiatry, including ketamine, oxytocin, lidocaine, ropinirole, insulin, mild cognitive impairment, and early Alzheimer’s disease.

Intranasal Oxytocin

Intranasal oxytocin may influence social relationships and has been studied in this regard. It has been shown to improve social functioning and repetitive behaviors in persons with autism spectrum disorder, but a randomized controlled trial failed to demonstrate efficacy.

Intranasal Ketamine

Intranasal ketamine reduces pain in the emergency room in children and adults, and improves mood, social interactions, flexibility, tolerance of changes in routine, motivation, and concentration in a 29-year-old woman with autism. It also reduces anxiety ratings and decreases depression in 20 patients with major depression.

Maintenance treatment with intravenous ketamine infusion maintains treatment gains. Intranasal ketamine may be a viable treatment strategy to extend treatment gains in patients with refractory depression, but the data are limited.

Intranasal ketamine decreased anxiety, aggression, fear of harm, cognition, behavior, sleep, and other symptoms in patients, and allowed other medications to be tapered or discontinued.

This author uses intranasal ketamine as maintenance therapy for a 25-year-old man with severe depression. It has been ongoing for 26 months and keeps depression at bay.

There will soon be trials examining the safety and efficacy of repeated dosing with intranasal ketamine in treatment-refractory depressed patients.

Parting Notes

Ketamine has been used to treat depression and anxiety in both oral and sublingual forms. It is well tolerated and shows rapid and sustained improvement in mood, cognition, and sleep in 20 outpatients (77%). Inhalational drug delivery systems deliver drugs to the lungs and are used in medicine to treat schizophrenia and bipolar disorder. They are contraindicated in the presence of acute respiratory disease and in patients at risk of bronchospasm.

Ketamine is a new treatment option for therapy-resistant depression, with a promising safety and tolerability profile. It has also been shown to be effective in enhancing remission and improving quality of life in patients with bipolar disorder and major depressive disorder. PubMed 7 – 11 – Nasal obstruction as a common side-effect of sildenafil citrate. Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial. PubMed 12 to 17 provide references for studies on nicotine replacement therapy for smoking cessation, long-acting intranasal insulin detemir for mild cognitive impairment or early-stage Alzheimer’s disease dementia, and a peptide with antidepressant-like effect for nocturnal enuresis. A systematic review of inhaled intranasal therapy for central nervous system neoplasms: an emerging therapeutic option. Intranasal oxytocin may enhance relationships: research imperatives, clinical policy, and ethical considerations.

Intranasal oxytocin administration enhances controlled social cognition in patients with schizophrenia and a randomized controlled trial of oxytocin as an adjunct to risperidone in youth with social anxiety disorder. PubMed 30 – 35 are references to studies on the use of intranasal ketamine for the treatment of pain in children, adults, and adolescents, as well as references to a case report on the use of intranasal ketamine for the treatment of depression.

Ketamine has been used to treat bipolar disorder in children. It has analgesic and sedative properties. PubMed 38, 39, Rolan P, Lim S, Sunderland V, et al. The absolute bioavailability of racemic ketamine from a novel sublingual formulation. Daily oral ketamine for the treatment of depression and anxiety in hospice patients: a 28-day open-label proof-of-concept trial. PubMed 40, 41. PubMed 42, 43, 44, 45, 46, 47, Keating GM, Messina JC, Mahmoud RA, Djupesland PG. Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care.