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Psychological Medicine
cambridge.org/psm
Original Article
Cite this article: Ellenbogen MA, Cardoso C,
Serravalle L, Vadaga K, Joober R (2024). The
effects of intranasal oxytocin on the efficacy of
psychotherapy for major depressive disorder:
a pilot randomized controlled trial.
Psychological Medicine 1–11. https://doi.org/
10.1017/S0033291724000217
Received: 23 September 2021
Revised: 14 August 2023
Accepted: 22 January 2024
Keywords:
intranasal oxytocin; major depressive disorder;
psychotherapy; therapeutic alliance
Corresponding author:
Mark A. Ellenbogen;
Email: mark.ellenbogen@concordia.ca
© The Author(s), 2024. Published by
Cambridge University Press. This is an Open
Access article, distributed under the terms of
the Creative Commons Attribution licence
(http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted re-use, distribution
and reproduction, provided the original article
is properly cited.
The effects of intranasal oxytocin on the
efficacy of psychotherapy for major depressive
disorder: a pilot randomized controlled trial
Mark A. Ellenbogen1, Christopher Cardoso1, Lisa Serravalle1, Kiran Vadaga1
and Ridha Joober2
1
Centre for Research in Human Development, Department of Psychology, Concordia University, Montréal, Canada
and
2
The Douglas Research Centre, Department of Psychiatry, McGill University, Montréal, Canada
Abstract
Background. Although both pharmacotherapy and psychological treatments are considered
to be efficacious in the treatment of major depressive disorder (MDD), one third of patients
do not respond to treatment and many experience residual symptoms post-treatment. In this
double-blind placebo-controlled randomized control trial (RCT), we assessed whether intra-
nasal oxytocin (OT) augments the therapeutic efficacy of psychotherapy for MDD and
improves the therapeutic alliance.
Methods. Twenty-three volunteers (12 female) with MDD underwent 16 sessions of interper-
sonal therapy. Prior to each session, volunteers self-administered 24 International Units of
intranasal OT (n= 12; Syntocinon) or placebo (n= 11). Depressive symptoms were assessed
with the Inventory of Depressive Symptomatology at pre- and post-treatment, and at a six
month follow-up.
Results. Multilevel modeling found a significant effect of OT on the negative slope of depres-
sive symptoms over time ( p< 0.05), with medium-large effect sizes at post-treatment (Cohen’s
d= 0.75) and follow-up (Cohen’sd= 0.82). Drug intervention also predicted the intercept
when examining the weekly ratings of the therapeutic alliance ( p< 0.05), such that volunteers
receiving OT, relative to placebo, reported improved therapeutic alliance at session 1. The
agreement of goals between therapists and participants, a facet of the therapeutic alliance,
mediated the relationship between drug intervention and clinical outcome.
Conclusion. In this pilot study, the administration of intranasal OT, relative to placebo,
improved the therapeutic alliance at the beginning of therapy and therapeutic efficacy of psy-
chotherapy in persons with MDD. Future RCTs should attempt to replicate these findings in
larger samples with different therapeutic modalities (ClinicalTrials.gov: NCT02405715).
Although a range of therapies are considered to be efficacious in the short-term treatment of
major depressive disorder (Hollon & Ponniah, 2010; Kennedy et al., 2016; MDD), approxi-
mately 40–50% of patients either drop out of treatment prematurely or do not achieve full clin-
ical remission following acute phase treatment with pharmacotherapy (Gitlin, 2014; Rush
et al., 2004) or psychological treatments (DeRubeis et al., 2005; Hollon et al., 2005). Many
patients with MDD do not maintain their treatment gains following successful treatment,
with approximately 30 and 55% of remitted MDD patients evidencing recurrence by one
and two years following treatment, respectively (Solomon, 2000; Vittengl, Clark, Dunn, &
Jarrett, 2007). Moreover, residual symptoms and poor psychosocial functioning often persist
following successful treatment of depressive symptoms, and these are robust predictors of
recurrence of MDD (Harkness, Theriault, Stewart, & Bagby, 2014; ten Doesschate,
Bockting, Koeter, Schene, & Group, 2010). Given the modest efficacy rates, high recurrence,
and persistent residual symptoms among those with MDD, there is an acute need for more
efficacious treatment strategies. Various augmentation strategies to improve treatment efficacy,
such as adding an additional drug (i.e. antipsychotic, lithium, etc.) or psychological interven-
tion (i.e. mindfulness meditation) have been studied (Dupuy, Ostacher, Huffman, Perlis, &
Nierenberg, 2011; Kleeblatt, Betzler, Kilarski, Bschor, & Kohler, 2017; Segal, Williams, &
Teasdale, 2002). To date, there has been mixed success with augmentation strategies for the
treatment of MDD, and a need for further research (Kleeblatt et al., 2017). In the present
study, we propose that exogenous oxytocin (OT) might be useful as a potential augmentation
agent in the treatment of MDD.
It is well known that OT is involved in promoting mother–offspring attachment and pair
bonding across a variety of animal species through its actions in the central nervous system
(Bosch & Young, 2018; Carter, 1998). Human studies of the oxytocinergic system, using the
exogenous intranasal administration of OT, indicate a more complex relationship with social
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
behavior. While some studies have found that the administration
of intranasal OT, relative to placebo, elicits increases in trust,
cooperation, attachment and positive communication (Bernaerts
et al., 2017; Ditzen et al., 2009; Kosfeld, Heinrichs, Zak,
Fischbacher, & Fehr, 2005; Yang, Wang, Wang, & Wang, 2021),
other studies have failed to replicate these findings (Declerck,
Boone, Pauwels, Vogt, & Fehr, 2020; Lane et al., 2015) or report
opposite effects including increased aggression and gloating in
response to competitive games (De Dreu, Greer, Van Kleef,
Shalvi, & Handgraaf, 2011;Ne’eman, Perach-Barzilay,
Fischer-Shofty, Atias, & Shamay-Tsoory, 2016; Shamay-Tsoory
et al., 2009; Zhang, Gross, De Dreu, & Ma, 2019). Contextual fac-
tors may explain the heterogeneity observed in the human litera-
ture on OT. Based on the theory that OT increases the salience of
emotional and social cues, rather than indiscriminately promoting
prosocial behavior (Shamay-Tsoory & Abu-Akel, 2016), OT’s
effects on social behavior might be context-dependent (Bartz,
Zaki, Bolger, & Ochsner, 2011; Wong, Cardoso, Orlando,
Brown, & Ellenbogen, 2021). In a within-subject placebo-
controlled study comparing the effects of OT on perceived emo-
tional support during autobiographical memory recall elicited by
a computer (non-social context) or a research assistant (social
context), OT increased perceived support by the research assistant
in the social context among women motivated to affiliate, but
decreased perceived emotional support in men and women in
the non-social context (Cardoso, Valkanas, Serravalle, &
Ellenbogen, 2016). Thus, while OT may promote prosocial behav-
ior in contexts where social relationships are available, it may
decrease the motivation to affiliate when such relationships are
untrustworthy or unavailable. These findings highlight the need
to consider context when using of OT therapeutically, particularly
in populations with deficient interpersonal functioning such as
those with MDD (Joiner & Timmons, 2009).
The use of intranasal OT as a therapeutic agent has been
mixed. While studies have reported positive effects in reducing
post-traumatic stress disorder symptoms (among those with
high acute symptoms at baseline; van Zuiden et al., 2017) and
negative symptoms in schizophrenia (Gibson et al., 2014), a num-
ber of studies have found that intranasal OT, relative to placebo,
failed to decrease symptoms of anxiety (Guastella, Howard,
Dadds, Mitchell, & Carson, 2009), autism spectrum disorder
(Guastella et al., 2015), and psychotic and negative symptoms
in schizophrenia (Buchanan et al., 2021; Cacciotti-Saija et al.,
2015; Lee et al., 2013). Little is known about the therapeutic use
of OT in persons with MDD (see De Cagna et al., 2019 for
review). Although OT had beneficial effects in a case study and
one open trial of a small sample of patients with resistant MDD
on antidepressant medication (Scantamburlo, Ansseau, Geenen,
& Legros, 2011; Scantamburlo, Hansenne, Geenen, Legros, &
Ansseau, 2015), neither of the studies included a placebo com-
parison. A study of 16 patient with postnatal depression (five
on OT) found no therapeutic effects of daily OT administration
in combination with psychodynamic therapy (Clarici et al.,
2015). In this study, OT was administered in the morning and
may have been given hours prior to the psychotherapy sessions.
Similarly, another study found that a single OT administration,
relative to placebo, prior to a 20 min psychotherapy session had
no antidepressant effects but increased anxiety in patients with
MDD (MacDonald et al., 2013). These results might have
occurred because the therapy was too brief and the therapists
were instructed to be neutral and unsupportive, both of which
might have created a negative context that is atypical of
psychotherapy in general (Cardoso & Ellenbogen, 2013). Given
the scarcity of data from multi-session randomized controlled
trials, it is not known whether the use of adjunct intranasal OT
in the treatment of MDD is beneficial. However, there is evidence
that individuals with MDD might benefit from the use of OT in
the context of psychotherapy. First, the administration of intrana-
sal OT alters social cognition more strongly in persons reporting
high sub-clinical depressive symptoms than persons with low
depressive symptoms (Boyle, Johnson, & Ellenbogen, 2022;
Ellenbogen, Linnen, Cardoso, & Joober, 2013; Ellenbogen,
Linnen, Grumet, Cardoso, & Joober, 2012). Thus, depressed indi-
viduals may have an increased sensitivity to the administration of
intranasal OT. Second, given the context effects described previ-
ously (Wong et al., 2021), the positive and supportive nature of
a psychotherapy session might be an excellent venue to elicit
OT’s putative prosocial effects. Moreover, the patient-therapist
relationship in psychotherapy, known as the therapeutic alliance,
might be a key target of OT’s therapeutic potential, given OT’s
positive effects on interpersonal behaviour among dyads (Ditzen
et al., 2009). Indeed, it is well known that the therapeutic alliance
is a robust predictor of the efficacy of psychotherapy across a wide
range of mental disorders and therapy orientations (Ardito &
Rabellino, 2011).
As its primary aim, the present study assessed whether the
adjunct administration of OT with psychotherapy, relative to
placebo, would improve treatment efficacy in persons diagnosed
with MDD. A secondary aim of the study is to assess whether
OT improves the participant–therapist relationship, known as
the therapeutic alliance, and whether these changes might
represent a putative mechanism for the therapeutic effects of
OT. Three hypotheses were put forth. First, it was predicted
that adjunct intranasal OT, relative to placebo, would lead to
lower depression scores at post-treatment and a six-month
follow-up. Second, it was predicted that intranasal OT, relative
to placebo, would lead to improved participant ratings of the
therapeutic alliance during the intervention. Third, it was
hypothesized that OT-induced changes in the therapeutic alli-
ance would mediate the relationship between drug administra-
tion and treatment efficacy.
Method
Participants
Seventy-one English-speaking participants between the ages of
18 and 50 years of age were recruited through advertisements
placed online and in print via a free newspaper distributed to
subway commuters in Montréal, Canada. Exclusion criteria
included (1) major medical illness, in particular, subjects with
evidence or history of malignancy or any significant hemato-
logical, endocrine, cardiovascular (including any rhythm dis-
order), respiratory, renal, hepatic, or gastrointestinal disease,
(2) current (in the past month) use of any endocrine-relevant
or psychotropic medication other than antidepressants, (3)
current substance dependence or abuse, (4) use of illicit drugs
(stimulants, narcotics, psychedelics/hallucinogens, cannabis, non-
prescription medication) in the previous 8 weeks, (5) lifetime
history of a psychosis (except if part of MDD) or pervasive devel-
opmental disorder, (6) past or current comorbid axis-1 disorder,
except dysthymia, adjustment disorder, generalized anxiety dis-
order, social phobia, and specific phobia, and (7), for females,
being pregnant or breastfeeding, or planning to become pregnant.
2 Mark A. Ellenbogen et al.
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
As described in the Consort Flow Diagram (Fig. 1), 25 partici-
pants with MDD were randomized into one of two study arms,
and 23 participants (12 OT, 11 placebo) completed the interven-
tion and assessments (baseline, post-treatment, and six-month
follow-up). Demographic data and comorbid mental disorders
are presented in Table 1.
Materials and measures
Structured Clinical Interview for DSM-IV-TR (SCID; First, Spitzer,
Gibbon, and Williams, 2002)
The SCID was used to determine participant eligibility into the
study. It has strong diagnostic specificity and test–retest reliability
(Lobbestael, Leurgans, & Arntz, 2011; Osório et al., 2019).
Interviewers rated the Global Assessment of Functioning scale
(0–100).
Inventory of Depressive Symptomatology –Clinician Rated
(IDS-C; Rush et al., 1986)
The IDS-C is a 30 item structured interview for assessing the
severity of DSM-IV symptoms of MDD, with high internal con-
sistency (Cronbach’s alpha, α= 0.94), strong criterion validity,
and excellent sensitivity to treatment effects (Rush et al., 1986;
Rush, Gullion, Basco, Jarrett, & Trivedi, 1996; Trivedi et al.,
2004). Participants also underwent a second structured interview,
the Hamilton Depression Rating Scale (HAM-D), and completed
the Beck Depression Inventory (Beck, Steer, & Brown, 1996) and
Beck Anxiety Inventory (Beck & Steer, 1993).
Figure 1. The consort flow diagram describing study recruitment and exclusion into the randomized controlled trial comparing adjunct oxytocin and psychother-
apy and placebo and psychotherapy.
Psychological Medicine 3
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Working alliance inventory –short form, patient, and therapist
version (WAI-S; Horvath and Greenberg, 1989)
The WAI-S assesses three key aspects of the therapeutic alliance:
agreement of goals (outcomes) of therapy (4-items), agreement on
tasks of therapy (4-items), and the development of a bond
between the patient and therapist (4-items). The WAI-S demon-
strates strong internal consistency (patient: α= 0.93; therapist: α
= 0.87) and criterion validity (Horvath & Greenberg, 1989).
Internal consistency in the present sample for the patient version
were 0.89, 0.82, 0.80, and 0.75 for the total score, goals, tasks, and
bond subscales of the WAI-S.
Other measures
To assess group differences at baseline, study participants com-
pleted the UCLA Life Stress Interview (Hammen, Shih, Altman,
& Brennan, 2003), Suicidal Behavior Questionnaire- Revised
(Osman et al., 2001), Beck Anxiety Inventory (Beck & Steer,
Table 1. Baseline and study outcome measures
Placebo Oxytocin
N11 12
Sex (male/female) 5M/6F 6M/6F
Mean age (S.D.; range) in years 29.4 (7.5; 21–46) 27.2 (5.4; 20–37)
Mean (S.D.) education (scale of 1–8
a
) 5.4 (2.2) 4.9 (1.7)
# (%) Caucasian 9 (81.8) 7 (58.3)
# (%) on antidepressant medication
b
1 (9.1) 2 (16.7)
# (%) with any comorbid diagnosis 5 (45%) 5 (42%)
# (%) comorbid social phobia 4 (36%) 4 (33%)
# (%) comorbid generalized anxiety disorder 1(9%) 1(8%)
# (%) agoraphobia 0 1 (8%)
# (%) recurrent episode of depression 10 (91) 8 (67)
Mean (S.D.; range) number of therapy sessions 14.9 (1.6; 11–16) 14.7 (2.1; 9–16)
Mean (S.D.; range) BDI depression time 1 28.8 (10.9; 8–46) 31.2 (9.9; 14–45)
Mean (S.D.; range) suicidal behaviour time 1 8.8 (3.7; 4–15) 9.1 (2.8; 3–15)
Mean (S.D.; range) BAI anxiety time 1 18.7 (8.3; 6–34) 19.3 (13.4; 4–50)
Mean (S.D.; range) interpersonal stress time 1 10.5 (2.1; 7–14.5) 9.0 (2.8; 4.5–13.5)
Mean (S.D.; range) non-interpersonal stress time 1 9.4 (2.4; 6.5–13.5) 10.1 (2.5; 6–13)
Mean (S.D.; range) GAF time 1 59.9 (9.3; 45–80) 57.4 (11.8; 35–75)
Mean (S.D.; range) social support time 1 4.3 (1.2; 2.6–6.2) 4.1 (1.1; 2.4–5.8)
Mean (S.D.; range) IDS-C depression time 1 29.4 (6.8; 15–39) 32.8 (11.5; 15–57)
Mean (S.D.) IDS-C depression time 2 12.2 (8.3) 7.2 (6.6)
Mean (S.D.) IDS-C depression time 3 10.2 (8.5) 4.7 (4.6)
Mean (S.D.) ISD-C time 2 minus time 1 −17.2 (9.7) −25.7 (12.7)
Mean (S.D.) ISD-C time 3 minus time 1 −19.2 (10.0) −28.2 (11.8)
# (%) ⩾50% decrease in IDSC scores at time 2 6 (54) 11 (92)
# (%) ⩾50% decrease in IDSC scores at time 3 9 (82) 11 (92)
Mean (S.D.) WAI-S Patient-Report Alliance Total Session 1 28.4 (7.9) 37.3 (10.7)
Mean (S.D.) WAI-S Patient-Report Alliance Total Session 8 48.1 (7.6) 50.5 (10.6)
Mean (S.D.) WAI-S Patient-Report Alliance Total Session 16 (or final session) 51.1 (9.5) 54.6 (6.3)
Mean (S.D.) WAI-S Goals Subscale Session 1 7.4 (2.5) 10.7 (5.1)
Mean (S.D.) WAI-S Goals Subscale Session 8 15.9 (2.7) 16.7 (3.6)
Mean (S.D.) WAI-S Goals Subscale Session 16 (or final session) 16.9 (3.1) 18.3 (2.0)
S.D., standard deviation; BDI, Beck Depression Inventory; suicidal behaviour from the Suicidal Behavior Questionnaire-Revised; BAI, Beck Anxiety Inventory; interpersonal and
non-interpersonal chronic stress are from UCLA Life Stress Interview; GAF, Global Assessment of Functioning; social support from the Multiple Scale of Perceived Social Support; IDS-C,
Inventory of Depressive Symptomatology –Clinician Rated; WAIS-S, Working Alliance Inventory-Short Form (patient ratings).
a
1 = Grade 6 or less, 2 = grade 7 to 12 (without graduating high school), 3 = graduated high school or high school equivalent, 4 = part college, 5 = graduated 2 year college, 6 = graduated 4 year
college, 7 = part graduate/professional school, 8 = completed graduate/professional school.
b
Although not included, one participant in the oxytocin group was taking St. John’s wort (300 mg).
Note. No significant group differences were found at time 1.
4 Mark A. Ellenbogen et al.
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
1993), and the Multiple Scale of Perceived Social Support
(Canty-Mitchell & Zimet, 2000).
Procedure
Following a telephone screening, eligible participants were invited
for a laboratory visit, where they provided written informed con-
sent, completed a battery of questionnaires and underwent a diag-
nostic assessment using the SCID, as well as an assessment of
clinician-rated depressive symptoms using the IDS-C and the
Hamilton Depression Rating Scale. Senior graduate students in
clinical psychology, who received extensive training in administer-
ing the SCID and IDS-C, conducted the interviews. If participants
were eligible for the study, a visit to a private health clinic for a
routine physical examination and blood work, and a serum preg-
nancy test for women, were scheduled. Next, participants were
randomized into one of two treatment arms: Interpersonal
Psychotherapy (IPT) with adjunct intranasal OT or IPT with
adjunct placebo. Treatment allocation was based on a computer-
generated randomization sequence using block-randomization
with a ratio of 1:1 and block sizes of four. Allocation concealment
with respect to drug condition was achieved by using pre-
determined envelope-concealed assignment, administered by a
laboratory coordinator not involved in the assessment of potential
participants. Importantly, therapists and participants were blind
to treatment allocation, as the nasal sprays were identical with
respect to appearance, taste, smell, and administration procedure.
Participants underwent up to 16 50-minute sessions of IPT
conducted by four (2 male; 2 female) senior graduate students
in clinical psychology, trained in IPT through accredited work-
shops. The principal investigator (Dr Ellenbogen), also trained
in IPT, supervised the therapy sessions through weekly meetings
with therapists. IPT is a time-limited empirically supported psy-
chological treatment of MDD that focuses on ameliorating inter-
personal difficulties most closely related to the depressive episode
(Weissman, Markowitz, & Klerman, 2000). Thirty minutes prior
to each session, participants self-administered 24 I.U. of intrana-
sal OT (Syntocinon, Novartis) or a placebo with matched inactive
ingredients, under the supervision of the therapist. Drug admin-
istration was conducted in accordance with published guidelines
on intranasal OT administration (Guastella et al., 2013).
Following each session, participants and therapists completed rat-
ings of the therapeutic alliance (WAIS-S). Participants underwent
assessments of their depressive symptoms, chronic stress (not
reported, except at time 1), personality (not reported), and social
functioning (not reported, except at time 1) at baseline, at the end
of the therapy, and at a six-month follow-up. Measures collected
in the study but not reported in the present manuscript are
reported in online Supplemental Table S1. Senior graduate stu-
dents in clinical psychology who were blind to the treatment allo-
cation conducted the assessments. Participants were remunerated
$120 CAD for their participation at each assessment phase. The
project was approved by the Human Research Ethics
Committee at Concordia University (Montreal, Canada) and
was registered at ClinicalTrials.gov (registration number:
NCT02405715).
Statistical analyses
Growth-curve multilevel modelling using Hierarchical Linear
Modeling (version 8.0; Raudenbush, Bryk, Cheong, Congdon, &
du Toit, 2019) was used to assess these data. Multilevel modeling
has distinct advantages with data such as these because it can
accommodate for violations of the statistical assumption of inde-
pendence in sampling. A person’s depression scores at a given
time point is inherently dependent on the previous depression
score and will subsequently influence later time points. At level
1 (within-subject), we estimated the variance in depression scores
across the three phases of testing as a function of the uncentered
scores of time and a residual term. The coefficient of primary
interest was the estimation of the slope (time), which examined
changes in depression across time. Since we did not expect differ-
ences at baseline because the study design was a randomized con-
trolled trial, we constrained the intercept to be fixed for the level 2
model. This would allow for all of the potential between-subject
variability to be associated with differences in the changes over
time, which is the central aim of the study. At level 2 (between-
subject), intervention group and control measures (sex of the par-
ticipant and education as a proxy of socioeconomic status) were
used to account for variability observed in the level-1 slope. The
interaction between group and sex of the participant was assessed
but was subsequently dropped from the analyses because it did
not add anything to the model. All level 2 predictor variables
were standardized prior to conducting the analyses. The analyses
of therapeutic alliance were conducted in the same fashion, except
that both slope and intercept were modelled at level 2. Intercept
for therapeutic alliance was of interest because it denotes thera-
peutic alliance at the end of the first session. Only linear effects
for changes in depression and therapeutic alliance scores across
time are presented. Modeling with quadratic trends over time
did not add anything new to the model.
The reported effects are based on models using restricted max-
imum likelihood estimation and robust standard errors.
Chi-square and logistic regression were used to examine whether
the drug intervention improved response rates, defined as a 50%
decline in IDSC scores from baseline. Exploratory analyses using
ordinary least squares regression with 95% confidence interval
bias-corrected bootstrapping (Hayes, 2018) were conducted to
assess whether changes in the therapeutic alliance mediated the
relationship between the intervention group and change in
IDS-C depression scores.
Results
Means, standard deviations, and frequencies of baseline and out-
come variables, as well as the number of sessions completed, are
presented in Table 1. No baseline group differences were
observed.
The effect of adjunct intranasal OT on depression scores across
time
Multilevel modelling analyses, presented in Table 2 (top), were
conducted to estimate the effect of intervention group (adjunct
OT v. placebo) on IDS-C scores across the three time points
(pre-, post-intervention, follow-up; Table 1). The level 1 model
for IDS-C scores at baseline (intercept) and change over time
(slope) found significant effects for the intercept and slope, indi-
cating that participants’IDS-C scores at baseline ( p< 0.001) and
across time ( p< 0.001) were significantly different from zero.
Next, the effect of intervention group was added to the level 2
model, along with sex and education as covariates. Group was a
significant predictor of slope ( p< 0.05), such that patients receiv-
ing OT exhibited a steeper slope in IDS-C scores over time (Fig. 2,
Psychological Medicine 5
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
panel A). Relative to the level 1 model with only time entered, the
addition of the intervention group led to a 33% decrease in
between-subject variability in slope. A likelihood ratio test indi-
cated that the level 2 random effects model with predictors pro-
vided a better fit of the data than the null or unconditional
fixed effect model, χ
2
(2) = 52.4, p< 0.001.
Effect sizes (Cohen’sd) were computed by comparing IDS-C
change scores (T2 minus T1 and T3 minus T1; see Table 1)
between groups. Effects sizes for the intervention were 0.75,
95% CI (−0.10 to 1.59), and 0.82, 95% CI (−0.033 to 1.67), at
post-intervention and follow-up, respectively, which are consid-
ered to be in the medium to large range (Cohen, 1988). The inter-
vention had a significant effect on the number of participants who
achieved a 50% decline in symptoms at Time 2 (response rate)
from their baseline IDS-C score (χ
2
[1, N= 23] = 4.1, p= 0.043),
but not at Time 3 (χ
2
[1, N= 23] = 0.49, p= 0.48; see Table 1).
The absence of an intervention effect on the response rate at
Time 3 was due to a ceiling effect at Time 2, as 11/12 patients
receiving adjunct OT had already achieved clinical response at
Time 2.
The same analyses were conducted on HAM-D scores. In the
multilevel analyses, intervention group also predicted steeper
slope in HAM-D scores over time, but this effect fell short of con-
ventional levels of statistical significance ( p= 0.062; online
Supplemental Tables S2 and S3). Effects sizes for the intervention
were 0.49, 95% CI (−0.34 to 1.32), and 0.76, 95% CI (−0.09 to
1.61), at post-intervention and follow-up, respectively, which are
considered to be in the medium to large range (Cohen, 1988).
Similar results were found for the Beck Depression Inventory
(online Supplemental Tables S2 and S3), with medium effect
sizes of 0.54, 95% CI (−0.32 to 1.35), and 0.40, 95% CI (−0.43
to 1.22), at post-intervention and follow-up respectively. There
were no effects of group on Beck Anxiety Inventory scores across
time (online supplemental Tables S2 and S3).
The effect of adjunct intranasal OT on the therapist–patient
relationship across time
Multilevel modelling analyses, presented in Table 2 (bottom), esti-
mated the effect of intervention group on patient-reported thera-
peutic alliance scores across 16 sessions. The Level 1 model for
therapeutic alliance scores at baseline (intercept) and change
over time (slope) found significant effects for the intercept and
slope, indicating that participants’ratings of therapeutic alliance
at baseline ( p< 0.001) and across time ( p< 0.001) were signifi-
cantly different from zero. Next, the effect of intervention group
was added to the level 2 model, along with sex and education
as covariates. Intervention group was a significant predictor of
the intercept ( p< 0.05), such that patients receiving OT, relative
to placebo, reported higher therapeutic alliance scores at the
beginning of therapy, after session 1 (Fig. 2, panel B). Relative
to the level 1 model with only time entered, the addition of the
intervention group led to an 11.6% decrease in between-subject
variability in intercept. Intervention group was also a significant
predictor of slope ( p< 0.01). However, for this effect, participants
receiving placebo showed a steeper slope than patients receiving
OT across the 16 sessions, indicating that patients in the placebo
group improved their therapeutic alliance over time to catch up to
Table 2. Effects of intervention group (oxytocin versus placebo) on clinician ratings of depressive symptoms (top) across time (baseline; post-intervention; six-month
follow-up) and patient-report therapeutic alliance (bottom) across 16 sessions
IDSC depression
Intercept (baseline/time 1) Slope (time)
Coefficient (S.E.) Tratio Coefficient (S.E.) Tratio
Level 1 (b
0
;b
1
)
a
26.5 (1.5) 17.2** −2.2 (0.2) −9.9**
Level 2: Main effects
Intercept 26.5 (1.5) 17.5** −2.2 (0.2) −10.7**
Sex −0.30 (1.5) −0.2 0.01 (0.20) 0.06
Education 0.49 (1.3) 0.4 −0.06 (0.15) −0.42
Intervention group 0.75 (1.5) 0.5 −0.43 (0.21) −2.12*
WAI-S therapeutic alliance
Intercept (baseline/session 1) Slope (time)
Coefficient (S.E.) TRatio Coefficient (S.E.) Tratio
Level 1 (b
0
;b
1
)
a
37.7 (1.9) 22 4*** 1.2 (0.1) 11.7***
Level 2: Main effects
Intercept 37.6 (1.7) 22.4*** 1.18 (0.08) −14.8***
Sex 0.43 (1.9) 0.23 0.02 (0.08) 0.26
Education 2.24 (2.2) 1.02 −0.17 (0.08) −2.05
Intervention group 3.87 (1.8) 2.19* −0.25 (0.08) −3.13**
Notes. IDSC, Inventory of Depressive Symptomatology, Clinician Rating; S.E., standard error; WAI-S, Working Alliance Inventory-Short Form (patient report).
aThe first parameter estimated (b
0
) estimated the intercept, which represents participants depressive symptoms at time 1 and therapeutic alliance at session 1, and the second parameter
(b
1
) estimates the slope, which represents the within-person change over time in depressive symptoms and across session for the therapeutic alliance.
*p< 0.05; **p< 0.01; ***p< 0.001.
6 Mark A. Ellenbogen et al.
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
the gains of the OT group early in therapy (Fig. 2, panel B).
Relative to the level 1 model with only time entered, the addition
of the intervention group led to a 30.2% decrease in between-
subject variability in slope. A likelihood ratio test indicated that
the level 2 random effects model with predictors provided a better
fit of the data than the null or unconditional fixed effect model, χ
2
(2) = 270.7, p< 0.001.
Effect sizes (Cohen’s d) were computed by comparing thera-
peutic alliance scores at session one and across the first four ses-
sions between groups. Effects sizes were 0.89, 95% CI (0.06–1.73),
and 0.86, 95% CI (0.22–1.69) respectively, which are considered to
be large effect sizes (Cohen, 1988). No effect of intervention group
was found for the therapist-rated therapeutic alliance (see online
Supplemental Tables S2 and S3).
Do changes in the therapist–patient relationship early in
therapy mediate the relationship between the intervention and
depression scores post-intervention?
Mediation analyses tested whether the drug intervention indir-
ectly reduced Time 2 IDS-C depression (T2 minus T1) through
therapeutic alliance scores at session 1, based on the robust
intercept (session 1) finding from the previous section. The bias-
corrected bootstrap 95% confidence interval for the indirect effect
based on 10 000 bootstrap samples found no evidence of medi-
ation (Confidence intervals [CI] were not entirely above or
below zero, which is the measure of statistical significance in
this analysis), ab (indirect effect) = −3.35, S.E. = 3.24; CI −11.9
to 0.53. The indirect effect, ab =−3.90, S.E. = 2.95, CI −11.2 to
0.07, for the mediation at time 3 (T3 minus T1) also failed to
show evidence of significant mediation, although here it fell just
short of statistical significance.
We then conducted a parallel mediation assessing whether any
of the three sub-scales of the WAI-S (bonding, agreement of tasks,
and agreement of goals) mediated the relationship between drug
intervention and time 3 IDS-C depression. For the agreement of
goals sub-scale (see Fig. 3), the bias-corrected bootstrap 95% con-
fidence interval for the indirect effect, ab =−5.75, S.E. = 4.05,
based on 10 000 bootstrap samples was entirely below zero
(−15.6 to −0.03), indicating significant mediation. Mediations
with the bonding and tasks sub-scales were not statistically signifi-
cant at time 3, and no mediations for the three scales were signifi-
cant at time 2 (data not shown). In sum, improved therapeutic
alliance goal agreement mediated the relationship between
adjunct OT administration and improvements in IDS-C depres-
sion scores at time 3.
Discussion
Consistent with the primary hypothesis, persons with MDD who
underwent up to 16 sessions of psychotherapy with adjunct intra-
nasal OT showed a greater reduction of depressive symptoms at
post-treatment and a six-month follow-up than those receiving
psychotherapy with adjunct placebo administration. Consistent
in part with our second hypothesis that intranasal OT would
improve the therapeutic alliance during psychotherapy, we
found that OT improved the patient-reported therapeutic alliance
at the beginning of therapy relative to placebo, an effect that dis-
appeared over time. Finally, as the third hypothesis, we predicted
that OT-induced changes in the therapeutic alliance would medi-
ate the relationship between drug administration and treatment
efficacy. Although the hypothesis was not supported with the
full score of the therapeutic alliance measure, OT-induced
changes in the subscale assessing the agreement of therapeutic
goals between therapists and patients mediated the relationship
between drug administration and therapeutic efficacy at the six-
month follow-up.
OT improved the treatment of MDD when administered in the
context of an empirically supported psychotherapy with trained
therapists. Although previous studies have found limited support
of the efficacy of OT as a therapeutic agent for MDD (De Cagna
et al., 2019), the literature is scarce and the few studies examining
the effects of OT on MDD symptoms have been methodologically
weak (Clarici et al., 2015; MacDonald et al., 2013). Intranasal OT
reduced symptoms of depression and post-traumatic stress dis-
order (PTSD), and improved the therapeutic alliance, during
exposure therapy in 17 patients with PTSD, but none of these
effects were statistically significant (Flanagan, Sippel, Wahlquist,
Moran-Santa Maria, & Back, 2018). The use of OT in individual
psychotherapy has advantages over other types of treatment in
that it can control for proximal contextual factors that might hin-
der OT effects when, for example, the drug is self-administered by
patients at home in the context of their poor relationships and
other negative environmental factors (Guastella et al., 2015).
Figure 2. a. The administration of intranasal oxytocin, relative to placebo, increased
the rate of improvement (slope) on the Inventory of Depressive
Symptomatology-Clinician Rated (IDS-C) at post-treatment and at a six-month
follow-up in persons with major depressive disorder undergoing interpersonal
psychotherapy. b. The administration of intranasal oxytocin, relative to placebo,
improved participants’ratings of the therapeutic alliance on the Working Alliance
Inventory-Short Form at session 1 (intercept) in persons with major depressive dis-
order. The rate of improvement (slope) of the placebo group across 16 sessions of
interpersonal therapy was greater than that of the oxytocin group.
Psychological Medicine 7
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
There is growing evidence that OT’s effects on human behavior
are context-dependent, in that OT administered in non-optimal
conditions (during competition, alone with no social contact,
etc.) can elicit negative effects (Alcorn, Green, Schmitz, & Lane,
2015; Shamay-Tsoory & Abu-Akel, 2016; Wong et al., 2021).
Group therapy, compared to individual psychotherapy, might
not be as effective in harnessing OT’s therapeutic effects and
has yielded mixed results. Among males with methamphetamine
use disorder, intranasal OT administered prior to six motivational
interviewing group therapy sessions elicited higher attendance to
sessions than those who received placebo (Stauffer et al., 2020),
but did not alter outcome measures of their addiction. Studies
of schizophrenia using OT combined with group social cognition
and/or social skills training found no effects of OT, relative to pla-
cebo, on clinical outcome measures (Cacciotti-Saija et al., 2015;
Davis et al., 2014; Strauss et al., 2019). Thus, it may be the intim-
acy and closeness of a dyadic therapeutic relationship in multi-
session psychotherapy, as shown by OT’s improvements in the
early therapeutic alliance in the present study, which are critical
for OT’s therapeutic benefits.
The pattern of findings in the present study suggests that OT is
eliciting its therapeutic benefits by enhancing participants’per-
ception of aspects of the therapeutic alliance in the beginning
of therapy. This effect was strongest, and statistically significant,
only for the agreement of therapeutic goals between therapists
and participants. This aspect of the therapeutic alliance is a crit-
ical step in the early stages of therapy and has been shown to pre-
dict positive therapeutic outcomes more strongly than ratings of
the therapeutic bond (Khalifian, Beard, Björgvinsson, & Webb,
2019; Webb et al., 2011). OT’s effects on the therapeutic alliance
in the present study are consistent with research showing that OT
in saliva and plasma are positively associated with positive thera-
peutic outcomes in MDD (Jobst et al., 2018; Zilcha-Mano,
Goldstein, Dolev-Amit, & Shamay-Tsoory, 2021), possibly being
driven by changes in the therapeutic alliance (Zilcha-Mano,
Shamay-Tsoory, Dolev-Amit, Zagoory-Sharon, & Feldman,
2020). Thus, studies of naturalistic OT levels during psychother-
apy for MDD provide converging evidence that changes in the
therapeutic alliance might be central in OT’s effects on improving
psychotherapy outcomes in persons with MDD.
The results of the present study, particularly those related to
the therapeutic alliance, are consistent with the general view
that intranasal OT administration facilitates trust and cooperative
behavior when administered in a social context that provides
appropriate outlets for such behavior (Ditzen et al., 2009;
Kosfeld et al., 2005; Van IJzendoorn & Bakermans-Kranenburg,
2012; Yang et al., 2021), although there is still controversy over
the replicability of these findings (Declerck et al., 2020; Walum,
Waldman, & Young, 2016). One limitation of this literature is
the lack of studies examining the effects of repeated OT adminis-
trations over time. In a study of two weeks of daily OT or placebo
administrations in 40 men, OT reduced attachment avoidance and
increased attachment toward peers compared to placebo, with the
strongest effects being in those persons reporting high insecure
attachment to peers at baseline (Bernaerts et al., 2017). These
findings are congruent with the results of the present study,
where participants received up to 16 weekly intranasal OT admin-
istrations. Similarly, persons with MDD might be more sensitive
to OT and its contextual effects than populations with no history
of MDD (Boyle et al., 2022; Ellenbogen et al., 2013). Participants
with high depressive symptoms, for example, were more sensitive
to a manipulation of context than those with low depressive
Figure 3. Parallel mediation model testing the
agreement of goals, agreement of tasks, and
bond between patients and therapist scales of
the Working Alliance Inventory- Short Form
(patient report) at session 1 as a mediator of
the relationship between intervention group (oxy-
tocin, OT, v. placebo, PLB) and time 3 (T3) change
from baseline (T1) on the Inventory of Depressive
Symptomatology, Clinician Rating (IDSC). A. Path
cis the total effect of intervention group on
change in depression scores (sum of direct and
indirect effects; c=c΄+ab). B. Path c΄is the direct
effect of intervention group on change in depres-
sion, path ais the direct effect of intervention
group on therapeutic alliance, and path bis the
direct effect of therapeutic alliance on change
in depression. The indirect effect (ab) of interven-
tion group predicting change in depression
through the mediators found that the goal agree-
ment scale was significant (confidence intervals:
−15.6 to −0.03). Coefficients are unstandardized
regression coefficients.
#
:p< 0.065 + ; *p< 0.05.
8 Mark A. Ellenbogen et al.
https://doi.org/10.1017/S0033291724000217 Published online by Cambridge University Press
symptoms, in that across two studies depressed participants
reported more negative autobiographical memories following
OT relative to placebo when the task was administered by com-
puter (no social contact) than when administered by an attentive
research assistant (Wong et al., 2021). Possibly, this might explain
the stronger findings observed here in persons with MDD than in
other clinical populations (Guastella et al., 2009; Stauffer et al.,
2020). Unfortunately, there are still few OT studies of persons
with MDD and fewer of individual psychotherapy to draw strong
conclusions.
There are several study limitations. First, the sample size was
small and certain analyses (mediation) were underpowered.
However, the present study benefitted from the repeated measures
design (data from three assessments and up to 16 sessions).
Moreover, the sample size in the present study was larger than
others in the literature assessing OT in persons with MDD
(Clarici et al., 2015; Jobst et al., 2018; MacDonald et al., 2013)
and similar to other studies assessing novel therapeutics such
psilocybin-assisted therapy (n= 24; Davis et al., 2021). Second,
the present findings are limited to a community sample of per-
sons with mild to moderate MDD, which may not generalize to
inpatient samples and persons with severe MDD. Third, the pre-
sent findings are limited to the use of interpersonal therapy in the
treatment of MDD. It is not known whether they can be extended
to more common psychological treatments of MDD such as
cognitive-behavioral therapy. Fourth, important non-psychiatric
outcomes such as quality of life were not directly assessed in
the study. In sum, the present study demonstrated that repeated
intranasal administrations of OT prior to psychotherapy sessions,
compared to placebo, improved therapeutic outcomes at post-
treatment and a six-month follow-up in persons with MDD.
The therapeutic effects of OT appear to be driven by the early
improvement of the therapeutic alliance at the beginning of ther-
apy, particularly on the agreement of goals between therapists and
participants. Future research in this area will need to replicate
these findings in larger samples and using different empirically
supported psychological interventions.
Supplementary material. The supplementary material for this article can
be found at https://doi.org/10.1017/S0033291724000217
Acknowledgments. In addition to our gratitude to the participants who
volunteered to participate in the study, we thank the dedicated clinicians,
Christina Gentile and Lisa A Pascale (as well as two co-authors, Christopher
Cardoso and Kiran Vadaga) who conducted the psychotherapy intervention
in the study.
Funding statement. This work was supported by a grant from Canadian
Institutes of Health Research (#136875) awarded to Mark A. Ellenbogen (prin-
cipal investigator).
Competing interests. The authors report no biomedical financial interests
or potential conflicts of interest.
Ethical standards. The authors assert that all procedures contributing to
this work comply with the ethical standards of the relevant national and insti-
tutional committees on human experimentation and with the Helsinki
Declaration of 1975, as revised in 2008.
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