Journal of Affective Disorders 350 (2024) 698–705

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review Article

A comparison between psilocybin and esketamine in treatment-resistant

depression using number needed to treat (NNT): A systematic review
Sabrina Wong a, e, Angela T.H. Kwan a, b, c, Kayla M. Teopiz a, Gia Han Le a, c, f, Shakila Meshkat c,
Roger Ho g, h, Giacomo d’Andrea i, Bing Cao j, Joshua D. Di Vincenzo a, c,
Joshua D. Rosenblat c, d, e, Roger S. McIntyre a, c, d, e, *
a
Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
b
Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
c
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada
d
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
e
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
f
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
g
Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
h
Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore
i
Department of Neuroscience, Imaging and Clinical Sciences, University “G. d’Annunzio”, Chieti, Italy
j
Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing 400715, PR China

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Inadequate outcomes with monoamine-based treatments in depressive disorders are common and
Esketamine provide the impetus for mechanistically-novel treatments. Esketamine is a proven treatment recently approved
Psilocybin for adults with Treatment-Resistant Depression (TRD) while psilocybin is an investigational treatment. Trans­
Treatment-resistant depression
lation of the clinical meaningfulness for these foregoing agents in adults with TRD is required. Herein we
Number needed to treat
evaluate the Number Needed to Treat (NNT) and Harm (NNH) of esketamine and psilocybin in adults with TRD.
Methods: We conducted a systematic review of randomized controlled trials, comparing the clinical efficacy of
oral psilocybin to the co-commencement of intranasal esketamine with an oral antidepressant in adults with
TRD.
Results: 25 mg psilocybin had a significant reduction in depressive symptoms at 21-days post-dose, the NNT was 5
[95 % CI = 3.1, 18.5]. Psilocybin-induced nausea had a significant NNH = 5. Fixed-dosed esketamine at 56 mg
and 84 mg had a significant effect at 28-days post-dose, (NNT of 7 [95 % CI56mg = 3.5, 46.7], [95 % CI84mg = 3.6,
142.2]). Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs <10.
Limitations: The preliminary results may only reflect a small portion of the patient population. These results
require replication and longer term studies investigating maintenance therapy.
Conclusion: Relatively few pharmacologic agents are proven safe and effective in adults with TRD. NNT estimates
for investigational psilocybin and esketamine in TRD indicate clinical meaningfulness. The NNH profile for both
aforementioned agents is clinically acceptable. Our results underscore the clinical relevance of these treatment
options in adults with TRD.

1. Introduction a depressive episode consists of at least five of the manual’s list of

Major Depressive Disorder (MDD) is a mood disorder that affects
approximately 3.8 % of the world’s population (World Health Organi­
zation, 2023). According to the Diagnostic and Statistical Manual for
Mental Disorders, 5th edition (DSM-5) criteria, MDD is diagnosed when
symptoms (e.g. depressed mood, unintentional weight change,
decreased concentration, fatigue, etc) lasting for at least 2 consecutive
weeks, without the occurrence of a manic episode (Substance Abuse and
Mental Health Services Administration, 2016; McIntyre et al., 2023).
Concomitantly, MDD can affect an individual psychologically,

* Corresponding author at: Brain and Cognition Discovery Foundation, 77 Bloor Street West, Suite 617, Toronto, ON M5S 1M2, Canada.
E-mail address: roger.mcintyre@bcdf.org (R.S. McIntyre).

https://doi.org/10.1016/j.jad.2024.01.142
Received 5 September 2023; Received in revised form 12 January 2024; Accepted 14 January 2024
Available online 18 January 2024
0165-0327/© 2024 Elsevier B.V. All rights reserved.

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S. Wong et al.
cognitively, and physically, resulting in significant functional impair­
ment and disability (Akil et al., 2018). While treatment options may
include psychotherapy, medication, or neurostimulation (Kverno and
Mangano, 2021), currently the most effective treatment scheme to
achieve remission follows the guidelines from the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D) trial (Rush et al., 2004,
2006). Inadequate response to traditional monoamine-based antide­
pressants is common (Rush et al., 2006), resulting in rates of treatment
resistant depression (TRD) ranging from 30 to 60 % (McIntyre et al.,
2021b). The US Food and Drug Administration (FDA) and the European
Medicines Agency (EMA) define TRD as a failure to respond to at least
two antidepressant treatments in a single depressive episode, despite
adequate dose, duration, and adherence (McIntyre et al., 2023). The
high rate of TRD and its associated disability and health-related costs
invite the need for safe and innovative therapeutics.
As opposed to traditional antidepressants, psychedelics are proposed
as TRD treatments by acting through different mechanisms of action
(McIntyre et al., 2021b). Esketamine, the first glutamate-based antide­
pressant approved for adults living with TRD (Food and Drug Admin­
istration, 2020), is a non-competitive antagonist of the N-Methyl-D-
Aspartate (NMDA) glutamate receptors (d’Andrea et al., 2023). In
addition to acute and maintenance efficacy of intranasal esketamine for
adults with TRD (McIntyre et al., 2021a), intravenous ketamine is re­
ported to be efficacious in both single and multiple infusion studies
(Nikolin et al., 2023). Psilocybin, a substituted tryptamine, is currently
an investigational agent for TRD (Food and Drug Administration, 2023),
which acts as an agonist of the 5-HT2A serotonergic receptors and
secondarily on the 5-HT2B and 5-HT2C receptors (Moliner et al., 2023).
Recent evidence suggests that the antidepressant efficacy of esketamine
and psilocybin converge on rapid activation of synaptogenesis, cellular
excitability, and second messenger pathways responses (i.e., Brain-
derived neurotrophic factor (BDNF)/mammalian target of rapamycin
(mTOR) pathways and tyrosine kinase þ (TRKþ) activation), pointing to
a common mechanism of action underlying the rapid antidepressant
effect (Moliner et al., 2023). A meta-analysis that pooled three clinical
trials investigating esketamine in TRD reported a mean change in
Montgomery-Asberg Depression Rating Scale (MADRS) scores of − 4.09
[95 % CI = − 5.73, − 2.45, p = 0.00001] after 4-weeks of treatment
(Floriano et al., 2023). Furthermore, evidence from a feasibility trial
investigating oral psilocybin in TRD indicate an onset of action occurred
one hour post-dose, and a reduced mean Quick Inventory of Depressive
Symptomatology (QIDS) score of − 11.8 [95 % CI = − 9.15, − 14.35, p =
0.002] after one week (Carhart-Harris et al., 2016). Together, initial
clinical trials show promising, rapid reductions in depressive symptoms
in individuals with TRD following esketamine or psilocybin treatment.
While there are numerous clinical trials investigating psilocybin and
esketamine for individuals living with TRD, their relative efficacies have
not been established. In the absence of a head-to-head comparison, de­
terminations of relative efficacy can be arrived at by disparate indirect
comparisons (Donegan et al., 2010). There are multiple methods
wherein the magnitude of an effect and/or difference in effect can be
conveyed. For example, statistical significance denotes whether an
outcome of interest is attributable to chance, where a probability <5 %
is considered significant. Statistical significance however does not
equate with clinical significance. Clinical significance is often expressed
as an effect size such as a Cohen’s d or Hedges G. Number Needed to
Treat (NNT) refers to the number of participants needed to identify an
additional therapeutic benefit when compared to placebo - the smaller
the NNT, the more effective the treatment is than placebo (Andrade,
2015). NNT is not necessarily an effect size per se, but it attempts to take
outcome measures and translate it into a clinically relevant and appli­
cable metric. The assumption of NNT, reflected in its calculation, is that
a proportion of the outcome of interest that is desirable (i.e., NNT) is
placebo expectancy and similarly, a proportion of the outcome that is
undesirable (i.e., NNH) is nocebo effect. By using the risk difference, it
can be reasonably assumed that the practicing clinician would be able to
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Journal of Affective Disorders 350 (2024) 698–705
detect one additional event of interest by treating the calculated NNT.
The foregoing statistics are highly practical to clinicians and have been
identified as an important method to indirectly compare the relative
efficacy and tolerability of treatment (Nguyen et al., 2021).
Herein, we sought to compare the relative efficacies of esketamine
and psilocybin in adults with TRD. We delimit our scrutiny to the
foregoing two agents as both have received “breakthrough” status by the
FDA and are highly mechanistically dissimilar interventions to each
other and to existing monoaminergic treatments in MDD. Although
esketamine is currently FDA approved for adults living with TRD and
psilocybin is investigational, the extraordinary resources required for
implementation of esketamine and psilocybin (if approved) invites the
need for careful comparisons for these agents to inform clinical practice
guidelines and policies with respect to implementation. To determine
the clinical efficacy of esketamine compared to psilocybin in treating
TRD, we aim to compare the effects of psilocybin and esketamine on
depressive symptoms in persons with TRD through the evaluation of
published clinical trials. Secondarily, we evaluated the relative safety
and tolerability of the foregoing treatments in adults with TRD.
2. Methods
2.1. Study selection
Relevant clinical trials were searched for on PubMed and BIOSIS
using the Boolean search terms: (Psilocybin OR Esketamine) AND
(Treatment-Resistant Depression) AND (“Randomized Controlled Trial”
[Publication Type]). There were no restrictions on publication language
or date from inception to present - last searched on July 25th, 2023. Key
eligibility criteria included randomized controlled trials that primarily
investigated participant response to psilocybin or esketamine. Inclusion
criteria for the enrolled participants included diagnosis with TRD
without psychotic features. To have a standardized method of measuring
the effect of the drug on depression symptoms, the studies must utilize
the standardized Montgomery–Åsberg Depression Rating Scale
(MADRS). Key exclusion criteria included persons with general health
comorbidities, types of depression other than TRD, or other psychiatric
disorders; papers that were abstract-only reports or did not have full-text
availability; case studies, case reports, letter to editors, preclinical
studies, and systematic reviews. To have a standardized method of
measuring the NNT of the drug on depressive symptoms, we sought to
evaluate studies based on changes in the standardized Montgomer­
y–Åsberg Depression Rating Scale (MADRS), a priori; notably, the search
did not identify any studies that utilized other depressive symptom
assessment scales in replacement of the MADRS.
2.2. Data selection and extraction
The data used to calculate the NNTs were manually extracted from
each study. Relevant data included the proportion of participants from
each treatment group that had a significant reduction in MADRS score,
the time-point at which a MADRS score was collected, treatment groups,
mean participant age, dosage, the number of participants in each
treatment group at a given time, and the rate of adverse events in each
treatment arm.
2.3. Quantitative analyses
Clinical relevance of each treatment was determined by calculating
the NNT value from the results of each study, where a clinically relevant
drug was defined as having a NNT value <10 (Andrade, 2015). The NNT
was calculated as the inverse of the absolute risk reduction (ARR), the
difference between the proportion of placebo responders and the treat­
ment responders, i.e. NNT = 1/(response rate in treatment arm) -
(response rate in placebo arm). Similarly, a NNH value <10 was also
considered to be a clinically relevant adverse event (Citrome et al.,
S. Wong et al. Journal of Affective Disorders 350 (2024) 698–705

2020). The NNH was calculated using the inverse of the difference in the (2023).
rate of treatment-emergent adverse events (TEAEs) between treatment
arms. As adapted from Citrome et al. (2020) the NNH was calculated for 3.2. Risk of bias assessment
TEAEs that were reported in ≥5 % of the investigational agent group and
had an incidence rate greater than the placebo group. Each treatment To assess for potential risk of bias in the included studies, the Revised
group was compared to the control group. The results of each study were Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2) was utilized
handled separately because each study investigated different treatment (Sterne et al., 2019). All included studies were assessed by one reviewer
doses or defined a clinical response using different criteria. The calcu­ (S.W.) (Supplementary Table 1). As all of the studies obtained from the
lated NNT/NNHs were accompanied by 95 % intervals which were search were deemed to have a low risk of bias, all of the studies were
derived using the Wald Interval formula for the ARR. The confidence included in this review.
intervals (CIs) for the NNT/NNHs were calculated using the inverse of
the ARR CIs. Confidence intervals that included infinity were deemed to
3.3. Study participants and design
be not statistically significant (ns) in replacement of two non-continuous
CIs to ease interpretability (Citrome et al., 2020; Bender, 2001). The
From the 5 obtained studies, a total of 1065 participants with TRD
forest plot was constructed using RStudio version 2023.06.1 + 524
were included in this review. The study design characteristics of the
“Mountain Hydrangea” Release.
individual studies are detailed in Table 1. Goodwin et al. (2022) enrolled
233 participants who were randomly assigned 1:1:1 to receive 1 mg
3. Results
psilocybin control, 10 mg psilocybin, or 25 mg psilocybin orally once
with psychological support. MADRS tests were administered the day
3.1. Study samples
before treatment, at day 2, and weeks 1, 3, 6, 9, 12. The primary
endpoint was to measure changes in MADRS scores from baseline to
The initial search resulted in a total of 791 articles. Study titles and
week 3 where clinical response was defined as a decrease in MADRS
abstracts were screened by two independent reviewers (S.W. and A.T.H.
score by at least 50 %. Participants were followed-up until week 12 to
K). After screening, 65 articles were then assessed for eligibility in
determine if remission was reached.
accordance with the outlined eligibility criteria. Full details on the study
Popova et al. (2019) enrolled 227 participants from 39 outpatient
exclusion process are outlined in Fig. 1. Out of the published articles, 5
centers. The participants were randomly assigned to receive combina­
of the studies met eligibility criteria and were included in the analysis
tion therapy consisting of intranasal esketamine and an oral antide­
(Fig. 1). The studies included were Goodwin et al. (2022), Popova et al.
pressant or a placebo and an oral antidepressant. Esketamine was
(2019), Ochs-Ross et al. (2020), Fedgchin et al. (2019), and Chen et al.
flexibly-dosed (56 mg or 84 mg twice weekly) according to the

Fig. 1. PRISMA flowchart of the study selection process. Initial search results using the terms “Psilocybin”, “Esketamine”, and “Treatment-Resistant Depression”
totaled 791 articles. For this systematic review, only randomized controlled clinical trials were included. Other studies were excluded based on enrolled participants
having general health comorbidities or other psychiatric disorders, including types of depression other than treatment-resistant depression or other psychotic fea­
tures. 5 published studies met these criteria and were available for analysis.

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S. Wong et al. Journal of Affective Disorders 350 (2024) 698–705

Table 1 56 mg or 84 mg of esketamine, depending on tolerability. The respective

Design and participant randomization of selected studies. treatments were given for 28 days and were followed by a 8-week
Study Number of Sample age, Treatments Primary follow-up period. The primary efficacy endpoint measured changes in
Participants mean (sd) endpoint MADRS score from baseline to day 28. Notably, the authors defined a
enrolled at clinical response as a decrease in MADRS score equal to or >30 %.
baseline

Chen et al. 126 Esketamine: Flexibly-dosed 28 days

3.4. Goodwin et al. – the efficacy of psilocybin in TRD
(2023) 36.9 (12.04) esketamine (56 mg
Placebo: 37.8 or 84 mg, based on
(12.36) tolerability) and This study primarily investigated increasing doses of oral psilocybin
oral antidepressant to 1 mg of active control. The study administered MADRS tests at 3
vs placebo and oral weeks post-dose and 12 weeks post-dose to measure the severity of the
antidepressant
Fedgchin 342 Esketamine, 56 mg esketamine 28 days
participants’ depression symptoms (Fig. 2). The 10 mg and 25 mg psi­
et al. 56 mg: 46.4 vs 84 mg locybin treatment groups were compared relative to an active control
(2019) (11.18) esketamine vs consisting of 1 mg psilocybin. At 3-weeks post-dose, the 1 mg control
Esketamine, placebo group had 18 % of the participants respond while the 10 mg and 25 mg
84 mg: 45.7
treatment groups had response rates of 19 % and 37 %, respectively.
(11.10)
Placebo: 46.8 Therefore, the NNTs for 10 mg psilocybin was 100 [95 % CI = − 7.5, 8.9]
(11.36) and for the 25 mg psilocybin was 5.3 [95 % CI = 3.1, 18.5]. At 12-weeks
Goodwin 233 Psilocybin, 1 1 mg psilocybin vs 21 days post-dose, the 1 mg group had 10 % of the participants respond, the 10
et al. mg: 38.7 10 mg psilocybin vs mg group had 5 % of participants respond, and the 25 mg group had 20
(2022) (11.7) 25 mg psilocybin
% of the participants respond. At this time point, the NNTs were − 20
Psilocybin,
10 mg: 40.6 [95 % CI10 mg = − 7.5, 30.5] and 10 [95 % CI25 mg = − 4.8, 97.6] for the
(12.8) 10 mg and 25 mg treatments, respectively.
Psilocybin,
25 mg: 40.2
(12.2) 3.5. Popova et al. – the efficacy of flexibly-dosed esketamine and an
Ochs-Ross 137 Esketamine: Flexibly-dosed 28 days adjunctive antidepressant in TRD
et al. 70.6 (4.79) esketamine (28 mg,
(2020) Placebo: 69.4 56 mg, or 84 mg,
The study investigated flexibly-dosed intranasal esketamine com­
(4.15) based on
tolerability) and
bined with a standard oral antidepressant and compared it to a control
oral antidepressant group which was given a placebo plus a standard oral antidepressant.
vs placebo and oral Each treatment was given once every 2 weeks. This study aimed to
antidepressant investigate the efficacy of esketamine treatment by comparing changes
Popova 227 Esketamine: Flexibly-dosed 28 days
in MADRS score primarily 28 days after baseline measurements, but also
et al. 44.9 (12.58) esketamine (56 mg
(2019) Placebo: 46.4 or 84 mg, based on measured 2-days post-dose (Fig. 2). At the 28-day point, the placebo
(11.14) tolerability) and group had a response rate of 10.8 % and the esketamine group had a
oral antidepressant response rate of 16.5 %, the NNT was 30.3 [95 % CI = − 10.0, 29.6]. At
vs placebo and oral
the 2-day point, 4.6 % of the placebo group responded while the
antidepressant
esketamine group had a response rate of 7.6 %, making the NNT 17.5
[95 % CI = − 6.6, 26.7].
participant’s tolerability. Treatment was given for 4 weeks. The primary
endpoint was to determine the change in participant MADRS scores from 3.6. Ochs-Ross et al. - the efficacy of flexibly-dose esketamine and an
baseline to day 2 with clinical response defined as a decrease in MADRS adjunctive antidepressant in elderly TRD patients
score by at 50 %. Secondarily, the authors investigated whether a clin­
ical response could be maintained until day 28. Participants were The study investigated the efficacy of intranasal esketamine in per­
followed-up for 24 weeks. sons with TRD, ages 65 and over. To investigate this, the participants
Ochs-Ross et al. (2020) enrolled 137 participants who were were randomized into either an esketamine and antidepressant treat­
randomly assigned to receive intranasal esketamine and an oral anti­ ment group or a placebo plus antidepressant control group. Participants
depressant or a placebo and an oral antidepressant. All the participants in the esketamine group were given 28, 56, or 84 mg of esketamine with
were aged 65 and over. Each treatment was flexibly-dosed (28 mg, 56 an oral antidepressant depending on their tolerability. Each treatment
mg, or 84 mg twice weekly) for 4 weeks and had a 2 week follow-up was given twice per week. At the 28-day point, the placebo group had a
period. The primary efficacy endpoint was to measure the change in response rate of 13.3 % while the esketamine group had a 27 % response
MADRS scores from baseline to 28 days after the initial dose. The au­ rate. The calculated NNT was 7 [95 % CI = − 3.6, 436.7] (Fig. 2).
thors defined clinical response as a decrease in MADRS score by at least
50 % from baseline to primary endpoint.
3.7. Fedgchin et al. - the efficacy of fixed-dose esketamine and an
The study conducted by Fedgchin et al. (2019) enrolled 342 partic­
adjunctive antidepressant in TRD
ipants who were randomly assigned to receive fixed-dose 56 mg esket­
amine, 84 mg esketamine, or a placebo. Each treatment was given
The authors wanted to compare the efficacies of 56 mg and 84 mg
intranasally twice per week for 28 days. The changes in MADRS scores
intranasal esketamine to a placebo group, which were randomized 1:1:1.
were measured from baseline to day 28. Responders were considered as
Each treatment group also received an oral antidepressant. The treat­
individuals with a decrease in MADRS score by at least 50 % from
ments were given twice per week for 28 days. This study did not have a
baseline to day 28.
follow-up period. After 28 days, the placebo group had a response rate of
Chen et al. (2023) investigated flexibly-dosed intranasal esketamine
38.9 %, the 56 mg esketamine group had a response rate of 54.1 %, and
and an oral antidepressant combination therapy compared to a placebo
the 84 mg esketamine group had a response rate of 53.1 %. The NNTs for
and antidepressant group. A total of 126 participants were randomly
both esketamine doses was 7 [95 % CI for 56 mg esketamine = 3.5,
assigned to each group. The esketamine treatment group received either
46.7], [95 % CI for 84 mg esketamine = 3.6, 142.2] (Fig. 2).

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S. Wong et al.
Fig. 2. Forest plot of the calculated number needed to treat (NNT) for each treatment. The NNT was calculated for each investigated treatment at multiple time
points. Clinically significant NNTs are <10. The corresponding 95 % confidence intervals were based on the Wald Interval, which were calculated by deriving the
standard error for each absolute risk reduction (ARR). The inverse of the ARR 95 % CI was then used to determine the lower and upper limits for each NNT 95 % CI.
The reported time-points are relative to the initial dose.
3.8. Chen et al. - the efficacy of flexibly-dosed esketamine and an
adjunctive antidepressant in TRD
The study was conducted in China and investigated flexibly-dosed
intranasal esketamine with an oral antidepressant compared to a pla­
cebo and antidepressant treatment group. The esketamine group
received either 56 mg or 84 mg depending on the participant’s tolera­
bility. Each treatment was given twice per week for 4 weeks. The study
also had a 8-week follow-up period. The primary endpoint of this study
was 28-days after the initial dose. At the 28-day point, the authors re­
ported a 34 % response rate in the placebo group and a 35.5 % response
rate in the esketamine group, the calculated NNT was 67 [95 % CI =
− 7.0, 8.9] (Fig. 2).
3.9. Number needed to harm (NNH) of commonly reported treatment-
emergent adverse events in psilocybin versus esketamine treatment
The TEAEs for the psilocybin treatment were variable (Table 2)
(Goodwin et al., 2022). As Goodwin et al. (2022) investigated single-
dose psilocybin, reported TEAEs were separated by time. When
considering the commonly-reported psilocybin-associated TEAEs after
day 1, only nausea obtained a clinically relevant NNH for 25 mg psilo­
cybin (NNH = 5.0, 95 % CI = [3.4, 9.2]). In terms of the TEAEs that were
reported from day 2 up to week 3, none of the commonly reported TEAEs
obtained clinically relevant NNHs. While TEAEs were recorded for the
entirety of the study period, incidence rates decreased and remained
below 5 % beyond the primary endpoint (Goodwin et al., 2022).
Therefore, this indicates that single-dosed psilocybin may be a safe and
tolerable acute treatment for depressive symptoms in persons with TRD.
For the esketamine treatments, the most commonly-reported TEAEs
that were clinically relevant included headache, nausea, dizziness, and
dissociation (Table 2) (Chen et al., 2023; Fedgchin et al., 2019; Ochs-
Ross et al., 2020; Popova et al., 2019). Notably, between studies, the
incidence rates and the NNHs of each TEAE were variable. Similarly,
while each of the studies reported a large quantity of other TEAEs, the
incidence rates varied between studies and the NNHs were not clinically
relevant. Notably, the most commonly-reported TEAEs were transient
and did not meet criteria for a serious adverse event (Chen et al., 2023;
Fedgchin et al., 2019; Ochs-Ross et al., 2020; Popova et al., 2019). In
general, the TEAEs with single-digit NNHs did not result in treatment
discontinuation, which indicates that esketamine may be a safe and
tolerable treatment option for TRD.
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Journal of Affective Disorders 350 (2024) 698–705
4. Discussion
In this study, we aimed to compare the clinical efficacies of esket­
amine and psilocybin in adults with TRD, via the NNT metric, with a
value <10 accepted as clinically meaningful/efficacious (Andrade,
2015). Single dose 25 mg psilocybin produced a clinically significant
reduction in MADRS score to the primary endpoint of 3-weeks post-dose.
This further supports Goodwin et al. (2022) who reported a statistically
significant effect for only the 25 mg psilocybin group. While only one of
the included studies investigated psilocybin treatment in TRD, this
preliminary evaluation suggests that 25 mg psilocybin may cause sig­
nificant acute reductions in depressive symptom severity. Additionally,
only nausea obtained a clinically relevant NNH (NNH = 5.0, [95 % CI =
3.4, 9.2]), where the incidence rate decreased to below 5 % after day 1,
which suggests transient effects. This suggests that TEAEs were variable
and not likely to be clinically relevant. Notably, the original paper by
Goodwin et al. (2022) reported insignificant changes in MADRS scores
for both 10 mg and 25 mg psilocybin at the 12-week point, which aligns
with our results. Therefore, limited conclusions can be made regarding
the sustained clinical efficacy of single-dose 10 and 25 mg psilocybin.
Overall, this preliminary result suggests that the acute benefits of psi­
locybin treatment may outweigh any risks. Subsequently, the clinical
efficacy and tolerability of psilocybin requires further investigation.
For fixed-dose intranasal esketamine, both 56 mg and 84 mg had
clinically significant NNTs of 7.0 after 28-days, which suggests that both
dosages may be clinically effective in significantly reducing depressive
symptom severity (Fedgchin et al., 2019). Notably, while the results of
the Fedgchin et al. (2019) study reports clinically meaningful NNTs, the
accompanying CIs are relatively wide, which suggests that the NNTs
may lack precision. Conversely, in terms of flexibly-dosed esketamine
and antidepressant combination therapy, none of the studies reported
clinical significance. Specifically with Ochs-Ross et al. (2020), while this
study had a NNT below 10, the corresponding 95 % CI indicates insig­
nificance. Similarly, the other studies that investigated flexibly-dosed
esketamine treatment had NNT values above 10 with insignificant CIs
(Chen et al., 2023; Popova et al., 2019). Despite headache, nausea,
dizziness, and dissociation being consistently reported as common
TEAEs in the esketamine studies and obtaining clinically relevant NNHs
in the analysis, they did not meet criteria for a serious adverse event and
did not result in discontinuation of treatment. Especially when consid­
ering the urgency to establish a treatment for TRD and the associated
consequences, the benefit of esketamine treatment may also outweigh
S. Wong et al. Journal of Affective Disorders 350 (2024) 698–705

Table 2 Table 2 (continued )

Calculated NNH of TEAEs for included studies. Study Adverse event in ≥5 % of the treatment NNH (95 % CI)
Study Adverse event in ≥5 % of the treatment NNH (95 % CI) group
group
Nausea 6.0 (3.4, 9.4)
Chen et al. (2023) Dizziness 2.0 (1.5, 2.1) Vertigo 5.0 (3.1, 6.7)
Dissociation 2.0 (1.6, 2.3) Dysgeusia 8.0 (4.4, 37.6)
Nausea 4.0 (2.6, 5.5) Dizziness 7.0 (4.0, 12.5)
Increased blood pressure 6.0 (3.4, 9.8) Headache 37 (ns)
Hypoesthesia 6.0 (3.8, 8.4) Somnolence 15 (ns)
Vomiting 7.0 (4.2, 10.4) Blurred vision 11 (6.1, 36.2)
Blurred vision 6.0 (4.1, 9.5) Paresthesia 10 (6.0, 22.8)
Somnolence 14 (ns) Anxiety 17 (ns)
Headache 64 (ns) Increased blood pressure 11 (6.6, 23.6)
Dysgeusia 16 (ns) Insomnia 20 (ns)
Fedgchin et al. Adverse events for pooled doses: Vomiting 13 (7.3, 54.4)
(2019) Nausea 6.0 (3.7, 9.4) Diarrhea 249 (ns)
Dissociation 5.0 (3.3, 6.0) Dry mouth 20 (ns)
Dizziness 7.0 (4.2, 11.6) Feeling drunk 15 (8.2, 58.4)
Vertigo 6.0 (4.0, 7.6) Oral hypoesthesia 15 (8.2, 58.4)
Headache 29 (ns) Oral paresthesia 15 (8.2, 58.4)
Somnolence 13 (6.3, 539.4) Throat irritation 31 (ns)
Dysgeusia 103 (ns) Postural dizziness 17 (9.0, 92.5)
Hypoesthesia 9.0 (6.2, 16.0) Hypoesthesia 17 (9.0, 92.5)
Paresthesia 10 (6.4, 19.7) Nasal discomfort 93 (ns)
Hypoesthesia oral 10 (6.6, 18.2)
Abbreviations: CI = confidence interval, ns = not significant, TEAE = treatment-
Vomiting 14 (8.5, 34.6)
Fatigue 24 (ns) emergent adverse event.
Anxiety 70 (ns)
Increased blood pressure 30 (ns) the side effects. Notwithstanding, the results indicate that fixed-dosed
Insomnia 52 (ns)
intranasal esketamine and oral antidepressant combination therapy for
Blurred vision 14 (9.3, 25.0)
Dizziness postural 17 (10.9, 33.5) TRD may be a safe and efficacious treatment for depressive symptoms.
Sedation 20 (11.5, 60.7) Future studies should further investigate the safety and tolerability of
Throat Irritation 46 (ns) long-term administration of flexibly-dosed intranasal esketamine treat­
Diarrhea 34 (ns) ment in persons with TRD.
Lethargy 24 (13.1,
103.4)
While this study compares the efficacy of psilocybin to esketamine in
Goodwin et al. Day 1: TRD, there are several factors that need to be considered for future
(2022) - Psilocybin, 10 mg: research and prior to their widespread application. Naturally, due to the
- Nausea 19 (ns) usage of psychedelics for TRD being a novel topic, a limitation of this
- Euphoric mood 35 (ns)
report is that we are only evaluating the results of 5 preliminary studies
- Anxiety 13 (7.1, 53.8)
- Paresthesia 19 (9.6, 403.2) and there is substantial heterogeneity in the sample composition within
- Abnormal thinking 19 (9.6, 403.2) and between the esketamine and psilocybin studies. Specifically, only
- Psilocybin, 25 mg: one study investigated psilocybin in TRD. Subsequently, a pooled
- Headache 14 (ns) analysis cannot be conducted and the clinical efficacy of psilocybin
- Nausea 5.0 (3.4, 9.2)
- Euphoric mood 79 (ns)
treatment for depressive symptoms requires further investigation.
- Fatigue 80 (ns) Additionally when considering the 4 studies that investigated esket­
- Mood altered 20 (10.1, amine, each of the esketamine studies investigated different dosages;
437.4) therefore, a pooled analysis could not be conducted. An additional
- Dizziness 16 (8.5, 104.2)
limitation of our analysis is that we have only evaluated studies based on
From day 2 to week 3
- Psilocybin, 10 mg: the MADRS as an outcome measure. The rationale for doing so was to
- Anxiety 24 (ns) have a consistent measure across studies, especially in light of the sub­
- Suicidal ideation 36 (ns) stantial heterogeneity of the sample composition and the mechanistic
- Psilocybin, 25 mg: dissimilarity of the drugs being compared, we thought it would be (in
- Anxiety 79 (ns)
- Fatigue 27 (ns)
the interest of translatability) a convergent outcome measure.
- Suicidal ideation 27 (ns) Concomitantly, future studies should aim to re-evaluate this topic as it
- Mood altered 29 (ns) develops and more articles are published. Within this study, the evi­
Ochs-Ross et al. Dizziness 8.0 (4.1, 57.4) dence surrounding the efficacy of esketamine in TRD is variable. First,
(2020) Nausea 8.0 (4.2, 31.3)
we need to consider the sample size of each study. As depression is
Increased blood pressure 13 (ns)
Fatigue 21 (ns) known to have large heterogeneity, a larger participant sample would be
Headache 11 (5.5, 141.6) required to detect a significant effect (McIntyre et al., 2021b).
Dissociation 10 (5.2, 36.3) Furthermore, due to significant participant drop-out over time for each
Vertigo 13 (ns) trial, this can limit our ability to detect clinically meaningful changes in
Urinary tract infection 15 (ns)
Hypoesthesia oral 15 (7.8, 93.2)
depressive symptoms. Future studies should aim to replicate these
Vomiting 19 (ns) studies with a larger sample size to further establish the efficacy of each
Dysgeusia 107 (ns) treatment regimen.
Dysphoria 18 (9.2, 377.9) Wald intervals are the standard method of calculating 95 % CIs for
Hypoesthesia 25 (ns)
NNTs; however, the estimations are found to be inaccurate for sample
Insomnia 107 (ns)
Paresthesia 41 (ns) sizes <100, especially when the NNT becomes larger than 10. Sugges­
Popova et al. (2019) Dissociation 5.0 (3.2, 7.2) tions to gain more accurate estimations are the utilization of Wilson
intervals for smaller samples (Bender, 2001). Furthermore, proper

703

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S. Wong et al.
interpretation of CIs that do not contain the NNT have also raised con­
cerns. ARR CIs that contain zero indicate no significant difference. As
NNT 95 % CIs are derived from the inverse of the ARR 95 % CI, instances
of non-significant ARRs can result in the NNT 95 % CI approaching in­
finity and may not include the point estimate. Therefore, to avoid
misinterpretation, some have suggested for non-significant NNTs to
report two separate intervals to include the point estimate and that Wald
intervals are only appropriate for significant ARRs (Schechtman, 2002;
Altman, 1998).
Esketamine is noted to have an onset of action of approximately 40
min after administration in persons with MDD and suicidal ideation
(Muttoni et al., 2019); however, the magnitude of improvement that is
clinically meaningful may be variable, especially when extrapolating
towards the TRD population (Psiuk et al., 2022). This, again, may be due
in part to heterogeneity in the patient population. When considering
psilocybin alone, other studies have suggested that psilocybin has peak
therapeutic effects at 5- to 6-week post-dose (Psiuk et al., 2022). As the
study conducted by Goodwin et al. did not administer the MADRS test
during this period, the calculated NNTs may not fully capture the effi­
cacy of psilocybin. Similarly, this can also be applied to esketamine. In
general, when considering NNTs, the observed effects vary with time. As
we cannot assume that changes in depression symptoms occur linearly
over time (McAlister, 2008), this requires further trials investigating the
time course of the effects of each treatment on depression symptoms.
Taken together, the NNT of esketamine in TRD is clinically mean­
ingful as evidenced by single digit estimates. It should be pointed out
that symptom improvement that is clinically meaningful in adults with
TRD may not be identical to persons with non-TRD (McIntyre et al.,
2021a). Currently available NNT estimates opined to be clinically rele­
vant largely apply to non-TRD populations. Preliminary results for psi­
locybin suggest improvements that are highly meaningful do require
replication. Multiple phase III clinical trials with psilocybin in TRD are
currently underway. Cost effectiveness analysis is informed by a full
scope of treatment involvement including NNT, infrastructure and
personnel. There is a need for longer term studies to estimate NNT with
maintenance treatment of which currently only esketamine has multi-
year efficacy data in adults with TRD and FDA approval for treating
TRD.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jad.2024.01.142.
CRediT authorship contribution statement
Sabrina Wong: Writing – review & editing, Writing – original draft,
Visualization, Methodology, Investigation, Formal analysis, Conceptu­
alization. Angela T.H. Kwan: Writing – review & editing, Investigation,
Formal analysis. Kayla M. Teopiz: Writing – review & editing. Gia Han
Le: Writing – review & editing. Shakila Meshkat: Writing – review &
editing. Roger Ho: Writing – review & editing. Giacomo d’Andrea:
Writing – review & editing. Bing Cao: Writing – review & editing.
Joshua D. Di Vincenzo: Writing – review & editing. Joshua D. Rose­
nblat: Writing – review & editing. Roger S. McIntyre: Writing – review
& editing, Project administration, Conceptualization.
Declaration of competing interest
Dr. Roger McIntyre has received research grant support from CIHR/
GACD/National Natural Science Foundation of China (NSFC) and the
Milken Institute; speaker/consultation fees from Lundbeck, Janssen,
Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen,
Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Suno­
vion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-
Cellular, NewBridge Pharmaceuticals,Viatris, Abbvie, Atai Life Sci­
ences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp.
Dr. Roger Ho has received funding from the National University of
Singapore iHeathtech Other Operating Expenses (A-0001415-09-00).
704
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Journal of Affective Disorders 350 (2024) 698–705
Kayla M. Teopiz has received fees from Braxia Scientific Corp.
Acknowledgements
None.
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