Although a range of therapies are considered to be efficacious in the short-term treatment of major depressive disorder (Hollon & Ponniah, Reference Hollon and Ponniah2010; Kennedy et al., Reference Kennedy, Lam, McIntyre, Tourjman, Bhat and Blier2016; MDD), approximately 40–50% of patients either drop out of treatment prematurely or do not achieve full clinical remission following acute phase treatment with pharmacotherapy (Gitlin, Reference Gitlin, Gotlib and Hammen2014; Rush et al., Reference Rush, Trivedi, Carmody, Biggs, Shores-Wilson, Ibrahim and Crismon2004) or psychological treatments (DeRubeis et al., Reference DeRubeis, Hollon, Amsterdam, Shelton, Young, Salomon and Gallop2005; Hollon et al., Reference Hollon, DeRubeis, Shelton, Amsterdam, Salomon, O'Reardon and Gallop2005). 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, Reference Solomon2000; Vittengl, Clark, Dunn, & Jarrett, Reference Vittengl, Clark, Dunn and Jarrett2007). 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, Reference Harkness, Theriault, Stewart and Bagby2014; ten Doesschate, Bockting, Koeter, Schene, & Group, Reference ten Doesschate, Bockting, Koeter, Schene and Group2010). 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 intervention (i.e. mindfulness meditation) have been studied (Dupuy, Ostacher, Huffman, Perlis, & Nierenberg, Reference Dupuy, Ostacher, Huffman, Perlis and Nierenberg2011; Kleeblatt, Betzler, Kilarski, Bschor, & Kohler, Reference Kleeblatt, Betzler, Kilarski, Bschor and Kohler2017; Segal, Williams, & Teasdale, Reference Segal, Williams and Teasdale2002). To date, there has been mixed success with augmentation strategies for the treatment of MDD, and a need for further research (Kleeblatt et al., Reference Kleeblatt, Betzler, Kilarski, Bschor and Kohler2017). 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, Reference Bosch, Young, Hurlemann and Grinevich2018; Carter, Reference Carter1998). Human studies of the oxytocinergic system, using the exogenous intranasal administration of OT, indicate a more complex relationship with social 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., Reference Bernaerts, Prinsen, Berra, Bosmans, Steyaert and Alaerts2017; Ditzen et al., Reference Ditzen, Schaer, Gabriel, Bodenmann, Ehlert and Heinrichs2009; Kosfeld, Heinrichs, Zak, Fischbacher, & Fehr, Reference Kosfeld, Heinrichs, Zak, Fischbacher and Fehr2005; Yang, Wang, Wang, & Wang, Reference Yang, Wang, Wang and Wang2021), other studies have failed to replicate these findings (Declerck, Boone, Pauwels, Vogt, & Fehr, Reference Declerck, Boone, Pauwels, Vogt and Fehr2020; Lane et al., Reference Lane, Mikolajczak, Treinen, Samson, Corneille, de Timary and Luminet2015) or report opposite effects including increased aggression and gloating in response to competitive games (De Dreu, Greer, Van Kleef, Shalvi, & Handgraaf, Reference De Dreu, Greer, Van Kleef, Shalvi and Handgraaf2011; Ne'eman, Perach-Barzilay, Fischer-Shofty, Atias, & Shamay-Tsoory, Reference Ne'eman, Perach-Barzilay, Fischer-Shofty, Atias and Shamay-Tsoory2016; Shamay-Tsoory et al., Reference Shamay-Tsoory, Fischer, Dvash, Harari, Perach-Bloom and Levkovitz2009; Zhang, Gross, De Dreu, & Ma, Reference Zhang, Gross, De Dreu and Ma2019). Contextual factors may explain the heterogeneity observed in the human literature 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, Reference Shamay-Tsoory and Abu-Akel2016), OT's effects on social behavior might be context-dependent (Bartz, Zaki, Bolger, & Ochsner, Reference Bartz, Zaki, Bolger and Ochsner2011; Wong, Cardoso, Orlando, Brown, & Ellenbogen, Reference Wong, Cardoso, Orlando, Brown and Ellenbogen2021). In a within-subject placebo-controlled study comparing the effects of OT on perceived emotional 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, Reference Cardoso, Valkanas, Serravalle and Ellenbogen2016). Thus, while OT may promote prosocial behavior 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, Reference Joiner, Timmons, Gotlib and Hammen2009).
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., Reference van Zuiden, Frijling, Nawijn, Koch, Goslings, Luitse and Olff2017) and negative symptoms in schizophrenia (Gibson et al., Reference Gibson, Penn, Smedley, Leserman, Elliott and Pedersen2014), a number of studies have found that intranasal OT, relative to placebo, failed to decrease symptoms of anxiety (Guastella, Howard, Dadds, Mitchell, & Carson, Reference Guastella, Howard, Dadds, Mitchell and Carson2009), autism spectrum disorder (Guastella et al., Reference Guastella, Gray, Rinehart, Alvares, Tonge, Hickie and Einfeld2015), and psychotic and negative symptoms in schizophrenia (Buchanan et al., Reference Buchanan, Kelly, Strauss, Gold, Weiner, Zaranski and Granholm2021; Cacciotti-Saija et al., Reference Cacciotti-Saija, Langdon, Ward, Hickie, Scott, Naismith and Guastella2015; Lee et al., Reference Lee, Wehring, McMahon, Linthicum, Cascella, Liu and Kelly2013). Little is known about the therapeutic use of OT in persons with MDD (see De Cagna et al., Reference De Cagna, Fusar-Poli, Damiani, Rocchetti, Giovanna, Mori and Brondino2019 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, Reference Scantamburlo, Ansseau, Geenen and Legros2011; Scantamburlo, Hansenne, Geenen, Legros, & Ansseau, Reference Scantamburlo, Hansenne, Geenen, Legros and Ansseau2015), neither of the studies included a placebo comparison. 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., Reference Clarici, Pellizzoni, Guaschino, Alberico, Bembich, Giuliani and Panksepp2015). 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., Reference MacDonald, MacDonald, Brüne, Lamb, Wilson, Golshan and Feifel2013). 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, Reference Cardoso and Ellenbogen2013). 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 intranasal OT alters social cognition more strongly in persons reporting high sub-clinical depressive symptoms than persons with low depressive symptoms (Boyle, Johnson, & Ellenbogen, Reference Boyle, Johnson and Ellenbogen2022; Ellenbogen, Linnen, Cardoso, & Joober, Reference Ellenbogen, Linnen, Cardoso and Joober2013; Ellenbogen, Linnen, Grumet, Cardoso, & Joober, Reference Ellenbogen, Linnen, Grumet, Cardoso and Joober2012). Thus, depressed individuals may have an increased sensitivity to the administration of intranasal OT. Second, given the context effects described previously (Wong et al., Reference Wong, Cardoso, Orlando, Brown and Ellenbogen2021), 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., Reference Ditzen, Schaer, Gabriel, Bodenmann, Ehlert and Heinrichs2009). 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, Reference Ardito and Rabellino2011).
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 alliance would mediate the relationship between drug administration 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 hematological, endocrine, cardiovascular (including any rhythm disorder), 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 developmental disorder, (6) past or current comorbid axis-1 disorder, except dysthymia, adjustment disorder, generalized anxiety disorder, social phobia, and specific phobia, and (7), for females, being pregnant or breastfeeding, or planning to become pregnant. As described in the Consort Flow Diagram (Fig. 1), 25 participants with MDD were randomized into one of two study arms, and 23 participants (12 OT, 11 placebo) completed the intervention and assessments (baseline, post-treatment, and six-month follow-up). Demographic data and comorbid mental disorders are presented in Table 1.
The consort flow diagram describing study recruitment and exclusion into the randomized controlled trial comparing adjunct oxytocin and psychotherapy and placebo and psychotherapy.
Baseline and study outcome measures
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.
Materials and measures
Structured Clinical Interview for DSM-IV-TR (SCID; First, Spitzer, Gibbon, and Williams, Reference First, Spitzer, Gibbon and Williams2002)
The SCID was used to determine participant eligibility into the study. It has strong diagnostic specificity and test–retest reliability (Lobbestael, Leurgans, & Arntz, Reference Lobbestael, Leurgans and Arntz2011; Osório et al., Reference Osório, Loureiro, Hallak, Machado-De-Sousa, Ushirohira, Baes and Crippa2019). Interviewers rated the Global Assessment of Functioning scale (0–100).
Inventory of Depressive Symptomatology – Clinician Rated (IDS-C; Rush et al., Reference Rush, Giles, Schlesser, Fulton, Weissenburger and Burns1986)
The IDS-C is a 30 item structured interview for assessing the severity of DSM-IV symptoms of MDD, with high internal consistency (Cronbach's alpha, α = 0.94), strong criterion validity, and excellent sensitivity to treatment effects (Rush et al., Reference Rush, Giles, Schlesser, Fulton, Weissenburger and Burns1986; Rush, Gullion, Basco, Jarrett, & Trivedi, Reference Rush, Gullion, Basco, Jarrett and Trivedi1996; Trivedi et al., Reference Trivedi, Rush, Ibrahim, Carmody, Biggs, Suppes and Kashner2004). Participants also underwent a second structured interview, the Hamilton Depression Rating Scale (HAM-D), and completed the Beck Depression Inventory (Beck, Steer, & Brown, Reference Beck, Steer and Brown1996) and Beck Anxiety Inventory (Beck & Steer, Reference Beck and Steer1993).
Working alliance inventory – short form, patient, and therapist version (WAI-S; Horvath and Greenberg, Reference Horvath and Greenberg1989)
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 demonstrates strong internal consistency (patient: α = 0.93; therapist: α = 0.87) and criterion validity (Horvath & Greenberg, Reference Horvath and Greenberg1989). 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 completed the UCLA Life Stress Interview (Hammen, Shih, Altman, & Brennan, Reference Hammen, Shih, Altman and Brennan2003), Suicidal Behavior Questionnaire- Revised (Osman et al., Reference Osman, Bagge, Gutierrez, Konick, Kopper and Barrios2001), Beck Anxiety Inventory (Beck & Steer, Reference Beck and Steer1993), and the Multiple Scale of Perceived Social Support (Canty-Mitchell & Zimet, Reference Canty-Mitchell and Zimet2000).
Procedure
Following a telephone screening, eligible participants were invited for a laboratory visit, where they provided written informed consent, completed a battery of questionnaires and underwent a diagnostic 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 administering 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 pregnancy 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 workshops. 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 psychological treatment of MDD that focuses on ameliorating interpersonal difficulties most closely related to the depressive episode (Weissman, Markowitz, & Klerman, Reference Weissman, Markowitz and Klerman2000). Thirty minutes prior to each session, participants self-administered 24 I.U. of intranasal OT (Syntocinon, Novartis) or a placebo with matched inactive ingredients, under the supervision of the therapist. Drug administration was conducted in accordance with published guidelines on intranasal OT administration (Guastella et al., Reference Guastella, Hickie, McGuinness, Otis, Woods, Disinger and Banati2013). Following each session, participants and therapists completed ratings 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 students in clinical psychology who were blind to the treatment allocation 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, Reference Raudenbush, Bryk, Cheong, Congdon and du Toit2019) 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 independence 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 differences at baseline because the study design was a randomized controlled 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 participant 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 therapeutic 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 maximum 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, Reference Hayes2018) 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 outcome 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, indicating 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 receiving OT exhibited a steeper slope in IDS-C scores over time (Fig. 2, 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 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, χ2 (2) = 52.4, p < 0.001.
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
Notes. IDSC, Inventory of Depressive Symptomatology, Clinician Rating; s.e., standard error; WAI-S, Working Alliance Inventory-Short Form (patient report).
a The 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.
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 disorder. The rate of improvement (slope) of the placebo group across 16 sessions of interpersonal therapy was greater than that of the oxytocin group.
Effect sizes (Cohen's d) 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 considered to be in the medium to large range (Cohen, Reference Cohen1988). The intervention 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 (χ2[1, N = 23] = 4.1, p = 0.043), but not at Time 3 (χ2 [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 conventional 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, Reference Cohen1988). 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), estimated the effect of intervention group on patient-reported therapeutic 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 significantly 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 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, χ2 (2) = 270.7, p < 0.001.
Effect sizes (Cohen's d) were computed by comparing therapeutic alliance scores at session one and across the first four sessions 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, Reference Cohen1988). 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 indirectly 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 mediation (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% confidence 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 significant at time 3, and no mediations for the three scales were significant 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 depression scores at time 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 (oxytocin, OT, v. placebo, PLB) and time 3 (T3) change from baseline (T1) on the Inventory of Depressive Symptomatology, Clinician Rating (IDSC). A. Path c is 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 depression, path a is the direct effect of intervention group on therapeutic alliance, and path b is the direct effect of therapeutic alliance on change in depression. The indirect effect (ab) of intervention group predicting change in depression through the mediators found that the goal agreement scale was significant (confidence intervals: −15.6 to −0.03). Coefficients are unstandardized regression coefficients. #: p < 0.065 + ; *p < 0.05.
Discussion
Consistent with the primary hypothesis, persons with MDD who underwent up to 16 sessions of psychotherapy with adjunct intranasal 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 disappeared over time. Finally, as the third hypothesis, we predicted that OT-induced changes in the therapeutic alliance would mediate 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., Reference De Cagna, Fusar-Poli, Damiani, Rocchetti, Giovanna, Mori and Brondino2019), the literature is scarce and the few studies examining the effects of OT on MDD symptoms have been methodologically weak (Clarici et al., Reference Clarici, Pellizzoni, Guaschino, Alberico, Bembich, Giuliani and Panksepp2015; MacDonald et al., Reference MacDonald, MacDonald, Brüne, Lamb, Wilson, Golshan and Feifel2013). Intranasal OT reduced symptoms of depression and post-traumatic stress disorder (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, Reference Flanagan, Sippel, Wahlquist, Moran-Santa Maria and Back2018). 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 hinder 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., Reference Guastella, Gray, Rinehart, Alvares, Tonge, Hickie and Einfeld2015). 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, Reference Alcorn, Green, Schmitz and Lane2015; Shamay-Tsoory & Abu-Akel, Reference Shamay-Tsoory and Abu-Akel2016; Wong et al., Reference Wong, Cardoso, Orlando, Brown and Ellenbogen2021). 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., Reference Stauffer, Moschetto, McKernan, Meinzer, Chiang, Rapier and Woolley2020), 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 placebo, on clinical outcome measures (Cacciotti-Saija et al., Reference Cacciotti-Saija, Langdon, Ward, Hickie, Scott, Naismith and Guastella2015; Davis et al., Reference Davis, Green, Lee, Horan, Senturk, Clarke and Marder2014; Strauss et al., Reference Strauss, Granholm, Holden, Ruiz, Gold, Kelly and Buchanan2019). Thus, it may be the intimacy 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' perception 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 critical step in the early stages of therapy and has been shown to predict positive therapeutic outcomes more strongly than ratings of the therapeutic bond (Khalifian, Beard, Björgvinsson, & Webb, Reference Khalifian, Beard, Björgvinsson and Webb2019; Webb et al., Reference Webb, DeRubeis, Amsterdam, Shelton, Hollon and Dimidjian2011). 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 therapeutic outcomes in MDD (Jobst et al., Reference Jobst, Sabaß, Hall, Brücklmeier, Buchheim, Hall and Padberg2018; Zilcha-Mano, Goldstein, Dolev-Amit, & Shamay-Tsoory, Reference Zilcha-Mano, Goldstein, Dolev-Amit and Shamay-Tsoory2021), possibly being driven by changes in the therapeutic alliance (Zilcha-Mano, Shamay-Tsoory, Dolev-Amit, Zagoory-Sharon, & Feldman, Reference Zilcha-Mano, Shamay-Tsoory, Dolev-Amit, Zagoory-Sharon and Feldman2020). Thus, studies of naturalistic OT levels during psychotherapy 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., Reference Ditzen, Schaer, Gabriel, Bodenmann, Ehlert and Heinrichs2009; Kosfeld et al., Reference Kosfeld, Heinrichs, Zak, Fischbacher and Fehr2005; Van IJzendoorn & Bakermans-Kranenburg, Reference Van IJzendoorn and Bakermans-Kranenburg2012; Yang et al., Reference Yang, Wang, Wang and Wang2021), although there is still controversy over the replicability of these findings (Declerck et al., Reference Declerck, Boone, Pauwels, Vogt and Fehr2020; Walum, Waldman, & Young, Reference Walum, Waldman and Young2016). One limitation of this literature is the lack of studies examining the effects of repeated OT administrations 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., Reference Bernaerts, Prinsen, Berra, Bosmans, Steyaert and Alaerts2017). These findings are congruent with the results of the present study, where participants received up to 16 weekly intranasal OT administrations. Similarly, persons with MDD might be more sensitive to OT and its contextual effects than populations with no history of MDD (Boyle et al., Reference Boyle, Johnson and Ellenbogen2022; Ellenbogen et al., Reference Ellenbogen, Linnen, Cardoso and Joober2013). Participants with high depressive symptoms, for example, were more sensitive to a manipulation of context than those with low depressive symptoms, in that across two studies depressed participants reported more negative autobiographical memories following OT relative to placebo when the task was administered by computer (no social contact) than when administered by an attentive research assistant (Wong et al., Reference Wong, Cardoso, Orlando, Brown and Ellenbogen2021). Possibly, this might explain the stronger findings observed here in persons with MDD than in other clinical populations (Guastella et al., Reference Guastella, Howard, Dadds, Mitchell and Carson2009; Stauffer et al., Reference Stauffer, Moschetto, McKernan, Meinzer, Chiang, Rapier and Woolley2020). 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., Reference Clarici, Pellizzoni, Guaschino, Alberico, Bembich, Giuliani and Panksepp2015; Jobst et al., Reference Jobst, Sabaß, Hall, Brücklmeier, Buchheim, Hall and Padberg2018; MacDonald et al., Reference MacDonald, MacDonald, Brüne, Lamb, Wilson, Golshan and Feifel2013) and similar to other studies assessing novel therapeutics such psilocybin-assisted therapy (n = 24; Davis et al., Reference Davis, Barrett, May, Cosimano, Sepeda, Johnson and Griffiths2021). Second, the present findings are limited to a community sample of persons with mild to moderate MDD, which may not generalize to inpatient samples and persons with severe MDD. Third, the present 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 therapy, 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 (principal 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 institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
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