Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03566069 |
| Other study ID # |
0023-17-SHA |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2018 |
| Est. completion date |
December 2021 |
Study information
| Verified date |
March 2021 |
| Source |
Shalvata Mental Health Center |
| Contact |
Ariella Grossman Giron, Mrs. |
| Phone |
+972-50-4816471 |
| Email |
ariellakg[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Intranasal administration of Oxytocin (OT) has been found to improve social communication
skills and encoding of social cues. Studies indicate that the provision of OT enhances the
ability to develop trust 1, to improve the benefits of social support during social stress
induction tasks 2 and to increase positive communication during couples' conflict discussions
3. These studies, and many others, point to the potential beneficial effects of OT as a
facilitator of relationship-focused processes such as psychotherapy. Studies assessing the
effect of OT as a possible outcome enhancer in psychotherapy for clinical populations are
scarce, and their findings are largely inconsistent 4. Reasons for this state of affairs
include the complexity of recruitment in this population; the provision of single-dose OT,
which tends to cause a lower and insufficient effect 5; and methodological constraints, such
as the lack of a control group 6 or insufficient probing of interpersonal factors 7.
In this study we intend to overcome these constraints by evaluating the impact of intranasal
administration of OT in patients suffering from acute stages of anxiety and depression
disorders and undergoing intensive, relationship-focused psychotherapy during psychiatric
hospitalization. One-hundred-and-twenty admitted patients with anxiety and depression
disorders will be randomized and double-blindly allocated to two groups: (a) psychotherapy +
OT (n=60), and (b) psychotherapy + placebo (n=60). Patients will be followed for three weeks,
beginning at the start of their hospitalization, and will be assessed for the severity of
their anxiety and depression symptoms; their working alliance with their therapist; and their
treatment outcome after each session. Psychotherapy will be delivered twice a week.
Intranasal OT will be administered twice a day.
This study can provide insights regarding the potential involvement of OT in the trajectories
leading to the production of detectable changes in brain activity following psychotherapy.
Additionally, it can support the development of an integrating model combining recent
findings in psychotherapy research pertaining to the significant role of therapeutic alliance
in psychotherapy outcome, and findings from neuroimaging studies. Finally, provision of OT as
a psychotherapy enhancer can facilitate a rapid therapeutic response and subsequently replace
aggressive psychiatric medication usage, needed to create a rapid decrease of distress during
psychiatric admissions.
Description:
1. Introduction 1.1 Oxytocin (OT) OT is a nine-amino acid neuropeptide synthesized in the
magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei (SON) of the
hypothalamus, and released by the pituitary gland (Meyer-Lindenberg, Domes, Kirsch, &
Heinrichs, 2011). OT has both peripheral and central effects, and serves as a
neurotransmitter, a neuromodulator and a hormone (see reviews in de Bono, 2003; Skuse &
Gallagher, 2009). Peripherally, it is released from the posterior pituitary into the
bloodstream where it functions as a hormone and influences bodily functions, such as
regulating uterine contractions during labor and lactation (Keverne & Kendrick, 1992).
Centrally, through direct axonal release from the PVN, OT acts as a neurotransmitter
projecting to various critical brain structures rich with OT receptors such as the
hippocampus, amygdala, striatum, and nucleus accumbens (Landgraf & Neumann, 2004;Macdonald &
Macdonald, 2010; Ross & Young, 2009). As a neuromodulator, OT creates general volume
diffusion, as it is released from all parts of the neuronal membrane into the extracellular
space, affecting many regions of the brain (Landgraf & Neumann, 2004; Leng, Meddle, &
Douglas, 2008; Ludwig & Leng, 2006).
1.2. Oxytocin and Social Behavior Perhaps one of the most well-known associations of OT is
with social behavior. Often referred to as the "social bonding" hormone, OT has been
consistently found to be involved in the formation and management of social bonds and in the
promotion of affiliative prosocial behavior (Theodoridou, Rowe, Penton-Voak, & Rogers, 2009).
Several studies have shown that OT administration increases cooperation, generosity and trust
in others. For example, Mikolajczak et al. (2010) investigated the role of OT in
interpersonal trust, by evaluating participants' willingness to take social risks compared to
nonsocial risks. They found that participants who received IN-OT showed higher levels of
trust, and expressed willingness to take risks during social (but not general) interactions,
as compared to the placebo group. Similarly, Zak et al. (2007) infused participants with
IN-OT or placebo before engaging in a blinded money gifting generosity game, in which there
had to make a one-shot decision on how to split a sum of money with a stranger. Their
findings indicated that participants in the IN-OT group were 80% more generous than those
given a placebo (Zak et al., 2007). In an attempt to assess the neural correlatives of the
OT-trust association, Baumgartner, Heinrichs, Vonlanthen, Fischbacher, & Fehr, (2008)
assessed participants willingness to trust others even in light of a possible betrayal. They
found that participants who had received IN-OT continued to show trusting behavior, even
though their trust had been betrayed, as opposed to participants in the placebo group. During
this task, they found reduced neural activation in the amygdala and caudate nucleus among
participants receiving IN-OT, brain areas which are known to be involved in fear processing
(amygdala) and behavioral adaptation (caudate nucleus) in situations with unknown outcome
contingencies (Baumgartner, Heinrichs, Vonlanthen, Fischbacher, & Fehr, 2008).
Several studies have put forth the hypothesis that OT is responsible primarily to pro-social
behavior. For example, Guastella, et al., (2008) presented participants with happy, angry, or
neutral human faces after receiving IN-OT\placebo, and then tested their memory of these
faces. They found that participants administered with OT were more likely to remember
previously seen happy faces compared with angry and neutral human faces. These findings have
indicated that OT has specific influence aimed encoding and recalling positive social
information (Guastella, et al., 2008). In another double-blind, placebo-controlled study,
Domes et al., (2007) evaluated male volunteers' ability to infer the affective mental state
of others using the Reading the Mind in the Eyes Test (RMET) after IN-OT\placebo. They found
that IN-OT significantly improved performance on the RMET compared with placebo, suggesting
that OT facilitate the interpretation of subtle social cues from eye regions (Domes,
Heinrichs, Michel, Berger, & Herpertz, 2007). These, as well the previous studies on the
effect of OT on trust and generosity, have set grounds for the hypothesis suggesting OT is
responsible for pro-social behavior.
Although many studies have demonstrated an association between OT and pro-social behavior,
other studies have found some contradicting findings which called the pro-social hypothesis
into question. These studies have seemed to demonstrate that OT, under specific contexts,
might actually induce a negative effect on social behavior. For example, Shamay-Tsoory et
al., (2009) found that OT administration increased feelings of envy in a simulated money game
when the other player gained more money, and feelings of gloating during the experience of
success. Eckstein et al., (2014) exposed participants to social stress following
IN-OT\placebo administration, and found that participants in the OT group reported increased
perceived social stress, as well as increased activity in the precuneus and cingulate cortex,
areas which are known to be sensitive to signals of social stress. Striepens et al., (2012)
found that IN-OT enhanced the impact of negative social stimuli on the induction of startle
response, and induced the subsequent memory toward negative rather than neutral items. Using
fMRI analysis, the authors also demonstrated that despite reducing amygdala activity, IN-OT
have increased the impact of aversive social information by increasing neural responses in
the insular cortex - which play a role in emotional modulation of memory.
A proposed theoretical framework that has been suggested to reconcile these seemingly
conflicting studies is "The social salience hypothesis" (Shamay-Tsoory & Abu-Akel, 2016).
According to this hypothesis, OT may increase the salience of safety signals, attenuate
stress and promote social approach in positive supportive contexts, yet increase the salience
of threat signals, diminish social approach and increase anxiety in unpredictable threatening
situations. In other words, this hypothesis suggests that OT affects human behavior in an
adaptive and context-dependent manner (Andari, Hurlemann, & Young, 2017). It has been
suggested that the underlying mechanism which associates OT with modulation of salience
throughout different contexts is through the role of OT in attentional processes. OT
receptors are found in visual associative areas in humans (Freeman and Young 2016) and in
regions involved in attention such as the diagonal band of Broca (Freeman et al. 2014).
Moreover, IN-OT has been found to increases visual fixation towards communicative areas of
the face such as the eye regions (Guastella et al. 2008), and has also been found to improve
the capacity to read subtle non-verbal cues from eye regions, through which individuals
understand the intentions and behaviors of social partners (Domes, Heinrichs, Michel, Berger,
& Herpertz, 2007). These findings have put forth the idea that OT operates through the
induction of attentional shifts towards important social information, and thereby increase
the salience of socially relevant cues.
A possible neurobiological trajectory to explain the effect of OT on social salience is
through its regulatory functions in the dopaminergic system (Grace, 1991), a system which was
previously offered to be involved in alerting level of salience to potentially important
sensory cues (Bromberg-Martin et al., 2010). In this trajectory, alerting signals are sent to
salience-coding dopamine neurons in the VTA, and from the VTA to mesolimbic structures (e.g.
the nucleus accumbens). These structures are equally responsive to aversive and rewarding
stimuli, and are responsible for the assessment of their value and valence (Bromberg-Martin
et al., 2010). It has been suggested that these dopaminergic-mediated effects are modulated
by the oxytocinergic system, as OT has also been found to increase activity in the VTA in
response to social cues (Groppe et al., 2013), irrespective of their valence. The dopamine-OT
interactive effect on salience and attention-reorienting has been suggested to also take
place in the amygdala, given its established role in attention reorienting and the assignment
of salience to social and positive and negative emotional stimuli (Rosenfeld, Lieberman, &
Jarskog, 2011). Accordingly, fMRI studies found that IN-OT administration enhances
connectivity between amygdala and rostral medial frontal areas, regions that are crucial for
social information processing and emotion regulation (Sripada et al., 2013).
In addition to contextual variables, the "social salience hypothesis" also stresses
inter-individual factors such as gender, and personality traits. Studies have shown that the
salience of the social environment, are also influenced by differential interpretations due
to inter-individual factors. For example, Kubzansky et al., (2012) examined whether OT
enhances responses to social stress, comparing effects across men and women. They found
gender differences in response to IN-OT, where men reported less negative affect after the
social stress task, while women reported more anger but better math performance. Similarly,
Fischer-Shofty et al's (2013) found that OT improved the accuracy of perception of kinship in
women, but not in men, while men's performance was improved only for competition recognition.
Another inter-imdividual factor which was previously suggested to moderate the effect of OT
on social salience is baseline social capabilities. Bartz, et al. (2010) examined whether the
normal variance in social proficiency moderates the effects of OT on social-cognitive
performance. After receiving IN-OT\placebo participants performed an empathic accuracy task
that naturalistically measures social-cognitive abilities (Zaki, Bolger, & Ochsner, 2008).
They found that OT improved empathic accuracy only for less socially proficient individuals
(e.g., Shamay-Tsoory & Abu-Akel, 2016). Similarly, Feeser et al., (2015) examined whether OT
improves metalizing abilities in individuals with impaired empathy. They found that OT (but
not placebo) enhanced metalizing accuracy in participants with lower empathy scores. This
supports the hypothesis that OT effects are strongly depends on inter-individual factors,
such as social-cognitive skills like empathy. Other inter-individual differences in OT's
effect on social behavior, such as attachment styles, will be discussed later in this paper.
1.3 Oxytocin and Psychotherapy Wampold (2001) defines psychotherapy as a "primarily
interpersonal treatment that is based on psychological principles and involves a trained
therapist and a client who has a mental disorder, problem or complaint". Several theorists
have emphasized the importance of interpersonal connectedness in a therapeutic process. For
example, Sigmund Freud, the founder of psychoanalysis, stated that a positive attachment
between patient and therapist is crucial for the patient to stay committed to psychotherapy
(Freud, 1912, 1913) (see Horvath and Luborsky, 1993). He felt that the positive,
reality-based component of the relationship provided the basis for a therapeutic partnership,
against the common foe, the client's neurosis (Freud, 1958). Carl Rogers, the founder of
client-centered therapy, believed that the effectiveness of every form of psychotherapy is
ultimately due to the therapist's capacity to form an authentic, accepting, and empathic
relationship with the patient (Rogers, 1957). Accordingly, several studies have shown that
successful psychotherapy relies on communication and understanding between the patient and
therapist, and on the patient's perception of different aspects of the therapist's character,
for example his\her trustworthiness (Ackermann & Hilsenroth 2003). Given the weight of
interpersonal aspects to psychotherapy, it is not surprising that OT, which has a
well-established role in social bonding, has been suggested to play a part in different
aspects of psychotherapy.
Several studies indicate that OT affects a number of interpersonal processes which are
central to a successful therapy. Kéri & Kiss (2011) explored OT's role in trust, by measuring
OT levels after a task requiring intimate trust, sharing personal secrets with a stranger, in
60 healthy participants. They found that OT was elevated in the trust-related condition,
(i.e. after sharing secrets), relative to a neutral baseline, (i.e. sharing neutral
information), and also relative to a trust-unrelated condition (i.e. a mental arithmetic
task), using repeated measures. They also found that stronger habituation of autonomic
arousal (using skin conductance response) was associated with higher trust-related OT levels
(Kéri & Kiss, 2011). In another study, Lane et al (2013) examined OT's effect on people's
willingness to share their emotions. After receiving IN-OT\placebo, 60 healthy men were then
instructed to retrieve a painful memory. Next, participants' willingness to disclose to
another person event-related facts vs. event-related emotions was evaluated. Interestingly,
while the two groups were equally willing to disclose event-related facts, OT was found to
specifically increase the willingness to share event-related emotions, which is known to have
both calming and bonding effects (Lane et al., 2013). In another double-blind randomized
placebo controlled study, OT's effect on Compassion Focused Imagery (CFI) was explored, that
is, imagining another "mind" being deeply compassionate to oneself, while also evaluating the
interaction of these effects with self-criticism and feeling socially safe with others. After
completion of self-report measures (of self-criticism, attachment style, and social
safeness), and receiving OT\placebo, participants attended two imagery sessions. Positive
affect was measured before and after each session. They found that OT increased the ease of
imagining compassionate qualities, however they found important individual differences in how
CFI was experienced, indicating that the effects of oxytocin on affiliation may depend on
attachment and self-evaluative styles (as participants higher in self-criticism, lower in
self-reassurance, social safeness, and attachment security had less positive experiences of
CFI under OT than placebo).
The idea that OT may be instrumental as a facilitator of relationship-focused processes such
as psychotherapy has been suggested before (Olff, Langeland, Witteveen & Denys, 2010), yet it
has not been sufficiently studied. For example, in a study conducted among patients with
schizophrenia, IN-OT given daily over 6 weeks, improved empathic accuracy when paired with
social cognitive training (Davis et al. 2014). In another study related to the therapeutic
alliance, IN-OT, but not placebo, improved the level of hypnotic responding in low
hypnotizable individuals. It was suggested that this augmentation was made possible through
neural networks related to the connection\rapport between the patient and the therapist
(Bryant et al., 2012). In Guastella et al.'s (2009) study, 24 IU of IN-OT was given adjacent
to exposure therapy for social anxiety disorder (in a period of 5 weeks). The findings showed
improved mental representations of self\positive evaluations of appearance and speech
performance as exposure treatment sessions progressed, as opposed to placebo, but overall
treatment outcome from exposure therapy was not improved (Guastella et al., 2009).
A relatively methodologically sound research design that assessed the impact of IN-OT on
facilitation of psychotherapy, can be found In MacDonald et al.'s (2013) study. In this
study, 18 men\psychiatric outpatients, diagnosed with major depressive disorder, were given
40IU IN-OT or placebo, prior to a videotaped 20-muinute single session with a therapist.
Contrary to their initial hypothesis, they found an increase of anxiety over the course of
the therapy session under the influence of IN-OT relative to a placebo. Although these
findings seemingly contradict the notion of IN-OT as facilitator of psychotherapy, the
authors noted that several restrictions, aimed at improving the internal validity, might have
hampered the results. For example, patients were instructed to prepare "3 personal event
prompts…. personal incidents that would evoke distress between 4 and 6 on 10 point subjective
units of distress scale" and were told that "one of these event prompts would be randomly
chosen immediately before a session in which they would discuss this event with a therapist".
This clearly does not resemble a first session of psychotherapy. Secondly, the therapists
were instructed to "consult a script they held in their lap that contained a limited set of
relatively neutral verbal interventions (i.e. "can you tell me more about that"); the script
also reminded them to minimize verbal interaction, expressed warmth and overt support", which
also do not resemble most kinds of psychotherapy. In line with the salience theory, it can be
speculated that the IN-OT increased the salience of anxiety-provoking cues in this situation,
as the participants later reported experiencing a lack of warmth from their therapist. As
Cardoso (2013) expressed in his letter to the editor reviewing Macdonald's study, the results
of this study "remind us that the effects of intranasal oxytocin on behavior vary across
context and between persons". Thus, the question of the effect of IN-OT on outcome in
standard, interpersonally-focused, psychotherapy, remains to be answered.
One of the suggested mechanisms which might underlie the association between OT and increased
outcomes of psychotherapy is through the therapeutic alliance. A trans-theoretical definition
of the therapeutic alliance has been defined by Bordin (1979), as consisting of (1) agreement
of goals; (2) assignment of tasks; and (3) the development of a bond between patient and
therapist. According to this, the optimal therapeutic alliance is achieved when patient and
therapist share beliefs with regard to the goals of the treatment and view the methods used
to achieve these as efficacious and relevant. Yet, these two components of the alliance can
only develop if there is a personal relationship of confidence and regard, since any
agreement on goals and tasks requires the patient to believe in the therapist's ability to
help them, and the therapist in turn must be confident in the patient's resources.
Substantial empirical literature has identified the therapeutic alliance as the most
consistent predictor of psychotherapy outcome. Some theorists have referred to the alliance
as the "quintessential integrative variable" (Wolfe & Goldfried, 1988, p. 449) across
treatment modalities (Horvath & Symonds 1991; Martin, Garske & Davis, 2000). A Recent
meta-analysis that examined the impact of the therapeutic alliance found that the alliance
was a robust, albeit moderate (r = 0.275) predictor of therapeutic outcome, accounting for
about eight percent of variability in outcomes (Horvath et al., 2011). Therefore, one
possible trajectory to associate OT to psychotherapy outcome is as an agent which facilitates
the enactment of the therapeutic alliance. Accordingly, it has been proposed, that if given
adjacent to psychotherapy, IN-OT may strengthen the engagement in the relational component,
and act as "reinforcement\augmentation agent" of the therapeutic alliance (Olff et al 2010).
Two recent studies provide some support to the hypothesis that IN-OT is related to changes in
the working alliance, which might in turn facilitate psychotherapy outcome. Zilcha-Mano,
Porat, Dolev and Shamay-Tsoory (2017) recently conducted a correlational study aimed at
assessing OT levels during psychotherapy sessions. 22 patients with major depressive disorder
were randomized to one of two 16-session manualized short-term psychodynamic treatments,
supportive-expressive or supportive, as part of an on-going randomized control trial. A total
of 172 saliva samples were collected, before and after treatment sessions 4, 8, 12, and 16.
Findings showed that the levels of OT increased significantly as sessions progressed, and
were associated with more instances of conflict and rupture in the alliance, as assessed by
(a) drops in the strength of the patient-rated alliance and (b) external behavioral coding of
alliance ruptures, as were also seen by stronger efforts by therapists to resolve these
rupture. In another recent study, Jobst et al (2018) evaluated whether OT plasma levels
predict the clinical outcome of chronic depressive patients after Cognitive Behavioral
Analysis System of Psychotherapy (CBASP). In their study, 16 patients with chronic
depression, participated in this 10-week inpatient program. OT levels were measured before
and after participants played a virtual ball-tossing game that mimics social exclusion.
Clinical outcome after CBASP was evaluated with the Beck Depression Inventory-II (BDI-II) and
the Hamilton Depression Rating Scale (HAMD-24). Using a repeated measures design, they found
that lower OT levels at baseline predicted worse therapeutic outcome, as seen by smaller
changes in self-rated depression scores, while higher levels of OT predicted superior
outcome. This correlation was not found regarding the observer-rated scores.
To sum, it seems that studies assessing the effect of OT as a possible outcome enhancer in
psychotherapy for clinical populations are scarce, and their findings are largely
inconsistent. Moreover, these studies have listed many limitations, stemming from the
complexity of recruitment in clinical\hospitalized populations; the provision of single-dose
OT, which tends to cause a lower and insufficient effect (Goldman, Gomes, Carter, & Lee,
2011); and short-term studies which do not allow to understand the long term effects OT has
on interpersonal processes in therapy. Methodological constraints from past studies include
no control group (Scantamburlo, Hansenne, Geenen, Legros, & Ansseau, 2015), or insufficient
manipulation of interpersonal aspects (MacDonald et al., 2013). Therefore, although some have
suggested that administration of OT before psychotherapy may strengthen engagement in the
therapeutic alliance (Macdonald & Macdonald 2010), the question regarding this neuropeptide's
ability to promote therapeutic processes remains unanswered.
2. The current study In this study we intend to overcome past constraints by evaluating the
impact of intranasal administration of OT in patients suffering from acute stages of anxiety
and depression disorders and undergoing intensive, relationship-focused psychotherapy during
psychiatric hospitalization.
3. Research hypotheses
1. Patients receiving IN-OT will show a larger decreases in anxiety and depression symptoms
as compared to a placebo controlled group.
2. Patients receiving IN-OT will exhibit faster increases in WA during psychotherapy as
compared to a placebo controlled group.
3. This slope will be differential across patients with different attachment pattern
(exploratory).
4. Findings will sustain after controlling for demographic, clinical and personality
characteristics.
4. Methods and Procedure One-hundred-and-twenty admitted patients with anxiety and depression
disorders will be randomized and double-blindly allocated to two groups: (a) psychotherapy +
OT (n=60), and (b) psychotherapy + placebo (n=60). Patients will be followed for four weeks
beginning at the start of their hospitalization, after signing a consent form. After
completing baseline self-report measurements, they will be assessed for the severity of their
anxiety and depression symptoms; their working alliance with their therapist; and their
treatment outcome after each session. Psychotherapy will be delivered twice a week.
Intranasal OT will be administered twice a day (at 08:00 a.m. and at 17:00 p.m.). The
experimental group will receive - 32IU (16IU*2) of OT, Sorbitol, Benzyl, alcohol glycerol,
distilled water. The control group will receive - 32IU (16IU*2) of Sorbitol, Benzyl, alcohol
glycerol, meaning all ingredients except for the OT.
The substance for both study groups will be prepared in the hospital pharmacy, and will then
be delivered to the wards according to names (in identical bottles), after randomization that
will be conducted by the pharmacist. OT\PLACEBO will be inhaled in two sprays, one in each
nostril. The dosage and form of delivery were determined according to standard guidelines in
IN-OT studies. The nursing staff will administer the IN-OT\PLACEBO after proper training by
the chief hospital pharmacist and principle investigator. As mentioned, the staff and
researchers will be blind to the substance administered to each patient (OT\PLC). A month
post intervention, patients will complete self-report measurements as part of a follow-up
evaluation.
4.1 Measurements " Socio-demographic questionnaire " The Scale for Suicidal Ideation (SSI)
(Beck Steer & Ranieri, 1988) " The self-report measurement of Adult Attachment (Brennan,
Clark, & Shaver, 1998).
" State-Trait Anxiety Inventory (STAI) (Spielberger, 2010). " Hamilton Rating Scale for
Depression (HAM-D) (Hamilton, 1980). " The Big Five Inventory - 5a (John, Donzhue & Kentle,
1991). " OQ-45 Outcome Questionnaire (Lambert et al., 2012). " Side-effects questionnaire
(Maoz, 2018) " Suicidal evaluation will be performed by a senior staff psychiatrist " Hopkins
symptoms checklist -short form (HSCL-11) (Lutz, Tholen, Schurch, & Berking, 2006) " The 6
item Working Alliance Inventory (WAI-6) (Falkenström, Hatcher, Skjulsvik, Larsson, &
Holmqvist, 2014)
5. Safety Past studies have shown that the IN-OT side-effects potential is very low. In a
meta-analysis examining IN-OT safety, it was found that the side effect profile of IN-OT is
identical to that of Placebo (MacDonald et al., 2011). Minor side effects which were reported
by 5-6% of the patients include an increase in calmness\euphoric sensation, light headedness,
and headache. Moreover, 3% of the patients reported a sense of stimulation in the nostrils as
a result of the spray and dryness in mouth. Previous studies have found that a combination of
IN-OT and standard anti-depressant medication does not harm their effectiveness and these
pharmaceutical drugs and has even been found as beneficial (Scantamburlo, et al., 2015).
Nowithstanding these results, and in order to insure optimal safety, side-effects profile
will be evaluated by a one of the study psychiatrists in the entire intervention period, and
if needed participation cessation of the patient will be cosidered.
6. Research Participation Cessation All participants will be notified in the informed consent
form as well as verbally that they may cease their participation in the study at any time,
without any consequences to their overall treatment in the ward, and without effecting their
psychotherapy sessions, which they receive as part of their hospitalization. Moreover, if
patients will report abnormal side-effects or increased suicidality (SSI>12) - their
participation in the study will be terminated. In cases in which the patient will be
discharged from hospitalization during the intervention period, for safety reasons, their
participation in the study will be terminated.
7. Information safety The study questionnaires will be stored in a locked storage closet in
the research lab in Shalvata for 7 years, and then will be shredded. Information collected
for statistical analysis will not include participant names or any identifying information,
just the participants study serial number, which will be listed in the study LOG and locked
as well in the lab unit closet.
8. Statistical analyses
To assess the effect of OT on overall levels of anxiety and depression:
" A One way ANCOVA of t5 levels will be conducted of anxiety and depression, controlling for
age, gender, t1 level of anxiety and depression, attachment and personality.
To assess the effect of OT administration on the psychotherapy process (WAI-6):
" Repeated measures ANCOVA will be conducted with demographic, personality and attachment
entered as covariates and assessed for their interaction with WAI slope.
" A significant interaction will signify differential slopes of the working alliance across
the OT and placebo groups, attachment pattern or personality variables.
" To assess the mediating role of the working alliance on OT-therapy outcome, a mediation
analysis (Preacher & Hayes, 2004) will be performed.
9. Limitations " No control for psychotherapy characteristics. " No control for therapists
characteristics. " Produces noise but will not affect the validity of significant findings. "
Clinical diagnoses is not confirmed using standardized empirical measures " Mostly
self-report measures " The context is not measured
