Opinion
EDITORIAL
The Promise of Intranasal Esketamine
as a Novel and Effective Antidepressant
Daniel S. Quintana, PhD; Nils Eiel Steen, MD, PhD; Ole A. Andreassen, MD, PhD
Nearly one-third of people with major depressive disorder are
considered to have treatment-resistant depression (TRD).1 This
diagnosis is a serious health concern due to its consequences
for each affected individual
and its associated economic
Related article burden on society owing to
the prevalence of TRD.1,2 De-
spite the large public health influence, the principal mecha-
nisms of action of pharmacologic agents used for the treat-
ment of depression have remained largely unaltered since
the introduction of selective serotonin-reuptake inhibitors in
the 1980s. Moreover, current treatments are associated with
delayed efficacy onset and inadequate remission rates. The
N-methyl- D -aspartate receptor antagonist ketamine has
emerged as a promising therapeutic agent, with intravenous ad-
ministration demonstrating rapid antidepressant effects and
striking response rates.3 In this issue of JAMA Psychiatry, Daly
and colleagues4 present intriguing findings from the first clini-
cal trial of intranasal esketamine hydrochloride (the more po-
tent S-enantiomer of ketamine) adjunctive to oral antidepres-
sants in TRD, reporting on its efficacy, safety, and dose response.
This study is of considerable interest primarily due to
2 aspects. First, the results show that esketamine has a sig-
nificant effect on depressive symptoms (Montgomery-
Ǻsberg Depression Rating Scale) already after 1 week of treat-
ment (twice-weekly administrations), which is substantially
faster than current treatments.5 The doses used, 28 to 84 mg,
also showed a significant dose-response relationship. Few
studies have investigated the duration of the effect, but here
the improvement in depressive symptoms appeared to be
sustained with reduced dosing frequency for up to 2 months,
at least in the open-label phase of the trial. The study was a
randomized, double-blind trial including 67 participants with
TRD who continued their existing antidepressant treatment.
Treatment-resistant depression was defined as inadequate re-
sponse to 2 or more antidepressants. It is also of interest that
a relatively low percentage of participants (5%) discontinued
treatment during the double-blind phase due to adverse ef-
fects. As the authors conclude, the findings are encouraging
and should lead to investigations in larger trials.
The second novel aspect of the current study4 is the use
of intranasal drug delivery, which is receiving increasing at-
tention in psychiatry.6 The previous reports of the antidepres-
sant effect of ketamine were based mainly on intravenous
administration, 7 which limits the use of the drug as an
outpatient depression treatment. Conversely, intranasal de-
livery offers the advantage of patient self-administration, and
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thus wider general use. Intranasal administration also in-
creases bioavailability compared with oral administration, due
to the avoidance of first-pass liver metabolism.6 Esketamine
is a good candidate for intranasal delivery because of its
relatively low molecular weight (238 Daltons), providing more
favorable nasal mucosa absorption. In broad terms, there are
2 drug transport routes from the nasal cavity to the central
nervous system compartment. The nondirect systemic route
capitalizes on capillary networks that blanket the nasal cav-
ity, which drain into the systemic circulatory system and then
across the blood brain barrier. Although the possibility is specu-
lative, a direct nose-to-brain delivery route bypassing the
blood-brain barrier is also plausible via olfactory and trigemi-
nal nerve fibers that innervate the upper posterior region of
the nasal cavity.6 Animal studies using a variety of radio-
tracer molecules have shown that intranasal deposition
increases central molecule concentrations via olfactory and
trigeminal nerve transport.
Intranasal delivery has several advantages compared with
oral and intravenous administration routes. First, with in-
creased bioavailability, lower doses can be administered, which
can limit adverse effects. Second, self-administration is rela-
tively straightforward compared with intravenous adminis-
tration. Another more general benefit is the potential for
the pharmaceutical industry to develop and market non-
patented compounds in tandem with novel delivery technolo-
gies, such as spray formulations designed to enhance nasal
mucosa absorption or optimized nasal spray devices. This
can facilitate the development and repurposing of older,
nonpatented drug compounds into commercially interesting
products. For instance, research is exploring the intranasal
administration of oxytocin to improve social cognition using
a novel intranasal exhalation delivery system device,8 which
may have applications for psychiatric disorders character-
ized by social dysfunction.
Despite the benefits of intranasal delivery, there are limi-
tations that should be considered, regardless of the adminis-
tered drug compounds. First, nasal cavity physiology can
present several drug delivery challenges. For instance,
mucosal inflammation, nasal polyps, and septal deviation can
limit nasal mucosa absorption and consequently reduce bio-
availability. Second, poor self-administration practices may
reduce efficacy. For example, spray deposition onto the nasal
vestibule epithelium, which is more likely to occur if the pa-
tient does not sufficiently insert the nasal spray nozzle into the
nostril, would have little opportunity for absorption. Exces-
sive sniffs during nasal administration can also increase medi-
(Reprinted) JAMA Psychiatry Published online December 27, 2017 E1
 Opinion Editorial

cation loss via nostril drip down, as large sniffs can constrict
the nasal valve, forming a barrier to the upper regions of the
nasal cavity. Excessive sniffs can also increase throat drip down
to the gastrointestinal tract, as sniffs can draw the medica-
tion down the floor of the nasal cavity to the oropharynx.6
Regardless of administration modality, esketamine should
be used with caution in psychiatric populations, because it can
induce psychotic-like symptoms.9 In fact, it is regarded as a
model drug for schizophrenia, inducing both positive and nega-
tive symptoms, a finding that contributed to the N-methyl-D-
aspartate hypothesis of psychosis.9 It is therefore reassuring
to learn that no psychotic symptoms were observed in the re-
ported trial; however, patients with psychotic disorders or ma-
jor depressive disorder with psychosis were excluded from the
study. One of the 3 most common adverse effects was percep-
tual changes or dissociative symptoms, which fits with the
known effect of ketamine and should be further clarified be-
fore starting routine use in clinical practice. Moreover, sev-
eral issues related to long-term use, including the potential
for addiction and adverse effects (somatic and cognitive), need
to be carefully assessed in forthcoming studies. The rapid
effects of esketamine are likely related to its effect on synap-
tic potentiation, 10 which may facilitate the reduction of
negative thinking and the prevention of negative spirals of
depressive thoughts. Further studies examining the psycho-
logical factors underlying the putative effects of esketamine
could lead to a better understanding of the disease mecha-
nisms of depression.
Given the early stages of research in esketamine treat-
ment of depression, it is important to be cautious. However,
the results of the study by Daly and colleagues4 demonstrate
the considerable promise of combining a compound with
rapid antidepressant effects with intranasal delivery. We
look forward to further research developments of intranasal
esketamine as a novel treatment for depression given the
crucial need for better antidepressants.

ARTICLE INFORMATION
Author Affiliations: NORMENT-KG Jebsen Centre
for Psychosis Research, Division of Mental Health
and Addiction, Oslo University Hospital & Institute
of Clinical Medicine, University of Oslo, Oslo,
Norway.
Corresponding Author: Ole A. Andreassen, MD,
PhD, NORMENT-KG Jebsen Centre for Psychosis
Research, TOP Study, Bldg 49, Division of Mental
Health and Addiction, Oslo University Hospital &
Institute of Clinical Medicine, University of Oslo,
Ullevål, Kirkeveien 166, PO Box 4956, Nydalen,
0424 Oslo, Norway (o.a.andreassen@medisin
.uio.no).
Published Online: December 27, 2017.
doi:10.1001/jamapsychiatry.2017.3738
Conflict of Interest Disclosures: Dr Andreassen
has received speaker’s honorarium from Lundbeck.
Drs Quintana and Andreassen are coinventers on
a patent application for an intranasal oxytocin
administration delivery device (application No. US
14/946,389). No other disclosures are reported.
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