Oxytocin as Adjunctive Treatment of Schizophrenia
|First Received Date ICMJE||March 28, 2012|
|Last Updated Date||March 19, 2013|
|Start Date ICMJE||March 2013|
|Estimated Primary Completion Date||January 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||eye tracking [ Time Frame: within two hours after administration of oxytocin vs. placebo ] [ Designated as safety issue: No ]
In order to assess the processing of social stimuli, subjects will be presented with a series of human faces of mixed sex and race showing neutral emotions and instructed to visually scan each face. Six regions of interest (ROIs) will be defined for each face stimulus: eyes, nose mouth, forehead, cheeks, and outside the contours of the face. The data will be processed off line for each face stimulus as the total time of fixation inside each of the ROIs. The initial analysis will compare time spent by subjects after oxytocin vs. placebo looking at the ROIs within vs. outside the facial contours.
|Original Primary Outcome Measures ICMJE
||Positive and Negative Symptom Scale (PANSS) [ Time Frame: Change from baseline at 21 days ] [ Designated as safety issue: No ]
Intranasal OT added to antipsychotic will improve positive symptoms of schizophrenia.
|Change History||Complete list of historical versions of study NCT01568528 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Social reward ball-tossing task [ Time Frame: within two hours after administration of oxytocin vs. placebo ] [ Designated as safety issue: No ]
Subjects will perform a computerized Social Reward Ball-Tossing Task in which they decide to return the ball to one of three fictional partners. The photos of the partners and their reciprocity in returning the ball to the subject will be manipulated. These trials will be interleaved with non-social trials where subjects will play with random geometric shapes or landscape scenes associated with positive and negative non-social rewards. The number of balls sent to each of the partners will be quantified to assess socially reinforced learning. These measures will be compared between the oxytocin and placebo group.
|Original Secondary Outcome Measures ICMJE
||MATRICS [ Time Frame: change from baseline at 21 days ] [ Designated as safety issue: No ]
The MATRICS score will be used as a measure of cognition.
|Current Other Outcome Measures ICMJE
||Facial Emotion Identification Task [ Time Frame: within two hours after administration of oxytocin vs. placebo ] [ Designated as safety issue: No ]
The stimuli are 19 standard black and white pictures of faces showing one of six different emotions (happy, sad, angry, surprise, disgusted, ashamed) that were developed by Ekman and Friesen (1976). The pictures are shown for 15 sec, with 10 sec between each face. After the presentation of each face the subject is asked to choose which of the six emotions was displayed. The score on the test is the sum of correct responses. Subjects in the two groups (oxytocin vs. placebo) will be compared.
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Oxytocin as Adjunctive Treatment of Schizophrenia|
|Official Title ICMJE||Oxytocin as Adjunctive Treatment of Schizophrenia|
The focus of the current project is to advance our understanding of the effects of oxytocin (OT) on components of social cognition in schizophrenia (SCZ). Despite the rapid increase in our understanding of the role of OT in rodent models of social behavior and an explosion of interest in the prosocial effects of OT in healthy controls, little work has been done to dissect the potential effects of OT on SCZ subjects with social deficits. Social deficits are a crucial aspect of the functional impairments that limit the rehabilitation of patients with SCZ. In particular, SCZ patients with enduring negative symptoms (deficit syndrome, Kirkpatrick et al. 1989) have prominent social deficits as a core feature of this subtype of the illness. Our currently available medications do very little to improve these social deficits. Hence it is of utmost public health importance to address the knowledge gap regarding the potential of OT to improve social function in this illness. Intact social function depends on the competent functioning of several cognitive domains that subserve perception of social cues and the generation of motivated social behavior. We propose to conduct a pharmacological challenge study of OT vs. placebo administration to study the effects of OT on specific components of social cognition in male deficit syndrome SCZ subjects.
Primary Hypothesis: Intranasal OT will improve social cognition in subjects with deficit syndrome SCZ.
Specific Aim 1: Administer OT intranasally vs. placebo in a parallel group double-blind design to 40 deficit syndrome SCZ subjects. Following OT or placebo (PBO) dosing, components of social cognition will be assessed as follows.
Impaired social functioning is an important symptom in SCZ SCZ is a chronic severe psychotic illness that affects two to three million Americans, over 100,000 of whom are veterans (Owen et al. 2004). There are several key symptom domains that characterize the illness. Positive symptoms (such as hallucinations and delusions) are at least somewhat responsive to antipsychotic medication in a majority of patients. Negative symptoms such as poor motivation, anhedonia, poor social function, and poor occupational function are poorly responsive to medication or other currently available treatments. The deficit syndrome has been defined as a complex of these negative symptoms that endure throughout the course of a schizophrenia patient's disease (Kirkpatrick et al. 1989). The social impairments seen in these patients are core deficits that have been linked to poor functional outcomes (Couture et al. 2006; Fett et al. 2011). Furthermore, deficits in social cognition have been proposed to underlie and contribute significantly to impaired social functioning (Kern et al. 2008; Green et al. 2008). An underlying hypothesis of this work is that if social cognition could be effectively treated, these patients would improve their social and functional outcomes, potentially enabling them to achieve occupational competence, sustain stable independent living, and lead more fulfilling independent lives. Thus our understanding and treatment of the social impairments of SCZ is very important from a public health perspective.
OT effects on social cognition and behavior Studies in rodents demonstrate a critical role for the neuropeptide OT in social bonding (Young et al. 2005). A large and rapidly growing translational literature indicates that this neuropeptide may also play a prosocial role in human behavior. The prosocial effects of OT administration have already been extensively reviewed in the literature (Striepens N et al., 2011). In the area of trust and altruism, studies utilizing a variety of economic and cooperation paradigms indicate that OT enhances trusting and social cooperation (Baumgartner T et al., 2008; De Dreu CK et al., 2010; Declerck CH et al., 2010; Kosfeld M et al., 2005; Mikolajczak M et al., 2010; Zak PJ et al., 2007). Feelings of empathy to others were enhanced with OT in three studies (Domes et al. 2007; Bartz et al. 2010; Hurlemann et al. 2010). Several studies indicate that OT increases the ability of healthy controls to identify emotion in faces (Di Simplicio et al. 2009; Fischer-Shofty et al. 2010, Marsh et al. 2010). There are reports using memory paradigms, in which OT administration induced enhanced recall of faces after OT (Savaskan et al. 2008; Rimmele et al. 2009), although an earlier study found no improvement (Ferrier et al. 1980). OT administration also increased recall of social words (Unkelbach et al. 2008). There is some indication that OT effects on recall are specific to emotional stimuli since several studies in healthy controls found that OT did not improve memory for nonsocial stimuli (Bruins J et al., 1992; Fehm-Wolfsdorf G et al., 1984; Geenen V et al., 1988; Kennett DJ et al., 1982).
OT as potential treatment in SCZ Several lines of reasoning suggest that OT could be helpful as adjunct treatment of SCZ.
Dissecting components of social impairment in SCZ Intact social competence depends on adequate function in several cognitive domains that subserve perception of social cues and motivated social behavior. We propose to interrogate these composite domains after administration of OT vs. placebo in this project.
i. Eye tracking. Relevant social cues must be of sufficient salience to command attention. This aspect of social cognition has been investigated by means of visual scan path paradigms that quantify the amount of time a subjects spends looking at the eyes and mouth regions of pictures of faces presented while the position of the eyes is tracked. The amount of eye gaze is predictive of a subject's ability to correctly identify emotions and meaning in others (Haxby et al. 2002). A single dose of OT significantly increases the amount of eye gaze in healthy controls (Guastella et al. 2008a) and in high functioning subjects with autism spectrum disorders (Andari et al. 2010). SCZ subjects have abnormalities in visual scan paths while viewing pictures of faces (Phillips and David 1997; Loughland et al. 2002a). Thus we hypothesize that OT will increase gaze at the eyes in subjects with deficit syndrome SCZ (Specific Aim 2a).
ii. Social Reward Ball-Tossing Task. Social stimuli must be sufficiently rewarding to motivate decision-making and behavior. This aspect of social function has been investigated with a computerized social interaction game that assays the effects of social reinforcement on decision-making. In a task developed by Andari et al. (2010) that was derived from an earlier task by Williams et al. (2000), subjects engage in a computerized version of a ball-toss game in which three fictional partners vary the proportion of times they throw the ball back to the subject. The outcome measure of interest was the choices made by the subject regarding to which fictional player they would throw the ball. In a study of high functioning autism spectrum subjects, OT administration selectively enhanced return of the ball to the most socially cooperative fictional partner (Andari et al. 2010). This result was interpreted as evidence that OT enhances appropriate behavioral responses to the social reward of reciprocity. We hypothesize that OT administration will enhance socially reinforced behavior in subjects with deficit syndrome SCZ (Specific Aim 2b).
iii. Facial Emotion Identification Task (FEIT). The socially competent person must be able to correctly identify the emotions in others in order to respond appropriately during social communication. The correct identification of emotions in others is a key aspect of social cognition that has been linked to functional outcomes in SCZ (Couture et al. 2006). This aspect of social cognition has been investigated in paradigms that query the subjects on identifying emotions displayed in pictures. Most studies in the literature report that patients with SCZ are deficient in the correct identification of emotions displayed in pictures of faces (Addington et al. 2006; Bigelow et al. 2006; van't Wout et al. 2007; Averbeck et al. 2012 and see review in Couture et al. 2006), although not all studies have found such impairments (de Achaval et al. 2010). The classic series of pictures of faces introduced by Eckman and Friesen (1976) have been used in many studies of affect recognition, but other series of pictures have also been utilized (Erwin et al. 1992; Kerr and Neale 1993). OT administration has been shown in two studies to increase the correct identification of emotions in faces in subjects with SCZ (Goldman et al. 2011; Averbeck et al. 2012). We hypothesize that deficit syndrome SCZ subjects will exhibit improvement in facial emotion recognition after administration of OT (Specific Aim 2c).
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Study Arm (s)||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||40|
|Estimated Completion Date||March 2014|
|Estimated Primary Completion Date||January 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Subjects for the study will be forty male VA patients with a diagnosis of schizophrenia. Diagnosis will be determined using the Structured Clinical Interview for DSM-IV Axis I Disorders/SCID-P (Spitzer et al. 1992). Subjects must be categorized as having a primary deficit syndrome on the Kirkpatrick Schedule for the Deficit Syndrome (Kirkpatrick et al. 1989).
Additional inclusion criteria:
|Ages||18 Years to 55 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT01568528|
|Other Study ID Numbers ICMJE||IND 111935|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Erica Duncan, MD, Emory University|
|Study Sponsor ICMJE||Emory University|
|Collaborators ICMJE||Atlanta VA Medical Center|
|Information Provided By||Emory University|
|Verification Date||March 2013|
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