Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT01028677 |
| Other study ID # |
07-0879 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
December 4, 2009 |
| Last updated |
September 7, 2012 |
| Start date |
November 2009 |
| Est. completion date |
November 2012 |
Study information
| Verified date |
September 2012 |
| Source |
University of North Carolina, Chapel Hill |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
Purpose: Test whether intranasal administration of the neuropeptide, oxytocin, improves
social cognition, social functioning and decreases paranoia and other psychotic symptoms in
schizophrenia.
Participants: 80 adults with schizophrenia for at least one year and with a high rating for
paranoia.
Procedures (methods): Oxytocin or placebo will be administered twice daily in an intranasal
spray (6 insufflations/dose or 24 IU) for 6 weeks. Before, during and at the end of the
trial, each subject will undergo psychiatric symptom ratings and tests of mental abilities
used in social functioning and social competence and subjects and an informant will complete
ratings of social functioning.
Description:
Inclusion criteria: meeting DSM-IV criteria for paranoid or undifferentiated schizophrenia
for at least 1 year; scoring > 4 on the suspiciousness/persecution (hereafter referred to as
paranoia) subscale of the Positive and Negative Symptoms Scale (PANSS) or 3 on the paranoia
subscale and > 3 on the hostility, active social avoidance, passive/apathetic social
withdrawal or uncooperativeness subscale and > 60 on the full PANSS: stability of symptom
severity and on the same medication(s) and dose(s) for at least 1 month; low to moderate
depressive symptoms.
Exclusion criteria: low literacy as indicated by an inability to read and understand the
consent form; dependence on substances other than tobacco or caffeine; positive urine drug
screen for illegal substances or drugs that have not been prescribed; debilitating medical
conditions (including AIDS; HIV infection alone will not be grounds for exclusion); major
surgery or trauma in the past year will be grounds for exclusion although subjects
determined to be recovered and stable may be included at the discretion of the PI;
pregnancy, breast-feeding; having given birth in the past 6 months or breast-feeding in the
past 3 months. Individuals judged unable to learn self-administration of intranasal
treatments and/or not sufficiently reliable to do so will be excluded. Abnormalities found
during medical evaluation will be grounds for exclusion (see details below) although
subjects with laboratory measures somewhat out of the normal range may be included at the
discretion of Drs. Pedersen, Gilmore, Rau and/or Salimi.
Study Design: We will use a randomized, double-blind, placebo-controlled design. 80 subjects
will complete the protocol; 40 subjects will be treated with oxytocin and 40 with normal
saline placebo. Prior to the treatment trial, baseline measures of social cognition, social
competence, paranoia, other psychotic and psychiatric symptoms will be obtained. Social
cognition and psychiatric symptoms will be measured on days 7, 14, 28 and 42 of the 6 week
treatment trial. Social competence measures will be obtained on day 14 and 42 of the
treatment trial.
Procedures: Subjects will be recruited from the UNC Department of Psychiatry Schizophrenia
Treatment and Evaluation Program outpatient clinics, the UNC Hospitals Psychotic Disorders
inpatient unit, the inpatient units of Central Regional Hospital (at Dorothea Dix Hospital
in Raleigh or Butner, NC) and from the community. After giving informed consent, they will
be evaluated using the Positive and Negative Symptoms Scale (PANSS). If their total PANSS
score is > or equal to 60, their PANSS sub-score for suspiciousness/persecution (paranoia)
is > or equal to 4 (maximum sub-score is 7), their medical history will be reviewed
including medications and dosages over the past month. If they do not have exclusionary
medical or medication history, their psychiatric history will be reviewed. If necessary to
confirm their diagnosis, they will undergo the Structured Clinical Interview for DSM-IV
(SCID) patient version. If they have met criteria for schizophrenia, paranoid or
undifferentiated type, for at least one year, they will undergo a physical exam and blood
will be drawn and urine collected for laboratory measures including CBC, electrolytes, BUN,
creatinine, liver function tests, glucose, TSH, urinanalysis, urine drug screen and
pregnancy test. This initial evaluation may require up to 3-4 hours. Prospective subjects
will be encouraged to rest for 20-30 minutes between the initial interviews (PANSS, SCID)
and the history, physical exam and blood/urine collections. Psychiatric, medical and
medication history will be confirmed by reviewing medical records and contacting clinicians
in charge of the prospective subject's psychiatric care. The initial evaluation will be
conducted in the CTRC outpatient clinic or at the UNC Psychiatry Clinical Research Unit
(CRU) at Central Regional Hospital (Raleigh or Butner).
SCID, PANSS, other psychological results and medical labs and history will be reviewed
during conferences with Dr. Pedersen accompanied by Drs. Gilmore, Salimi and/or Rau. Drs.
Pedersen and Gilmore are Board-certified Psychiatrists and Full Professors in the UNC
Department of Psychiatry. Drs. Salimi and Rau are Board-certified Assistant Professors in
the UNC Department of Psychiatry and co-Directors of the Department of Psychiatry CRU at
Central Regional Hospital (currently at Dorothea Dix Hospital but soon to be moved to
Butner, NC). Consensus decisions will be made during these conferences about whether
subjects meet the diagnostic and other criteria for inclusion in the study.
If prospective subjects meet inclusion but not exclusion criteria, they will be eligible to
continue in the study. In the week prior to initiating the daily treatment trial, baseline
measurements of social cognition, social competence, social functioning, paranoia, other
psychotic and psychiatric symptoms will be obtained (see descriptions below). This will
require approximately 3 hours. Social cognition and competence testing will be conducted by
Psychology graduate or advanced undergraduate students or postdoctoral fellow who have been
trained and are supervised by Dr. Penn, Professor of Clinical Psychology and an expert in
social cognition measurement and a prominent investigator of social cognition deficits in
psychotic disorders and autism. Psychiatric ratings will be made by one of the Co-PIs,
Psychology graduate students, an experienced research RN or a Psychology or Psychiatry
postdoctoral fellow. Research staff conducting social cognition testing and psychiatric
ratings will be blind to treatment group. Baseline measurements will be conducted in the
CTRC outpatient clinic or at the UNC Psychiatry Clinical Research Unit (CRU) at Central
Regional Hospital (Raleigh or Butner).
During the treatment trial, twice daily test treatments will be self-administered by
subjects in the morning shortly after breakfast and late in the afternoon/early evening
prior to dinner. Each treatment will consist of 6 insufflations (3/nostril alternating
between nostrils) of Syntocinon Spray (Novartis), which contains approximately 24
international units (IU) of oxytocin, or placebo. There will be a 30-60 second pause between
each insufflation. The placebo solution will be a solution that has all ingredients in
Syntocinon Spray except for oxytocin in 2 oz vials containing 30 ml of solution designed to
deliver 0.1 ml metered volume per insufflation prepared by Triangle Compounding Pharmacy.
Treatment assignments will be random within each gender. Vials containing oxytocin and
placebo spray will be relabeled by the Dorothea Dix Hospital Pharmacy or UNC Investigational
Drug Service so that subjects and raters are blind to treatment.
Social cognition and competence testing will begin 50 min after the morning treatment on
days 14, 28 and 42 of the treatment trial and will be followed by ratings of psychotic, mood
and anxiety symptoms (requiring 1-3 hr depending on how much social cognition testing is
done). The FEIT, Reading the Mind in the Eyes test (Eyes Test) and Trustworthiness Tasks
(see below) as well as psychiatric ratings will be conducted at all time points and the
Brüne, AIHQ, and social competence tasks (see below) will be conducted on treatment days 14
and 42. On these treatment days, subjects will take 20-30 min breaks after the FEIT, Eyes
Test, Trustworthiness and Brüne tasks and after the ensuing AIHQ and social competence tasks
which will be followed by psychiatric ratings. At the end of the treatment protocol
(treatment day 42), subjects and research staff who have conducted social cognition testing
or made psychiatric ratings will be asked to guess which treatment the subjects received.
Subjects may take part in this study as outpatients or inpatients or may start as inpatients
and complete the protocol in the outpatient setting. Subjects will be trained by research
nurses during their first dosing with test substance in intranasal self-administration
shortly after baseline measurements are completed. During preliminary studies at the
Dorothea Dix CRU, all 10 subjects that were enrolled quickly and easily mastered this
procedure. After learning intranasal self-administration, subjects who wish to participate
in the study as outpatients will be given written instructions about the timing of each
day's test treatments and other procedures to follow at home. They will then be given one 2
ounce vial containing 30 ml of test substance and other supplies to last until their first
outpatient clinic testing appointment and instructed when to begin the twice daily
intranasal treatments. Subjects who wish to be studied in the hospital who are not already
inpatients on the CRU will be admitted shortly after completing baseline measurements.
Outpatient subjects will visit an outpatient study site (CTRC or CRU) on the mornings of
treatment days 14, 28 and 42 (where they will be provided with a snack or breakfast and
lunch depending on the length of the visit). They will self administer test substance at the
site so staff can confirm they are using proper technique. In addition to social
cognition/competence testing and psychiatric ratings, blood samples as well as vital signs
will be obtained during these visits. At 40 min after the last intranasal insufflation,
blood (15 ml) will be drawn to measure plasma oxytocin concentrations and other lab values
(Na, K, glucose [treatment days 14, 28 and 42], CBC, BUN, creatinine, GGT [treatment days
14, 42]). An ECG will also be obtained on the morning of treatment days 14 and 42
approximately 3-4 hr after intranasal treatment (when social cognition/competence testing
and psychiatric ratings are completed). Urine will also be collected from female subjects on
the day of baseline measurements and on treatment days 28 and 42 for pregnancy testing.
These same procedures will conducted on the morning of treatment days 14, 28, 42 in subjects
studied as inpatients.
After procedures at the study site on the morning of treatment days 14 and 28, outpatient
subjects will be given a new vial containing 30 ml test substance so they can self
administer doses twice daily until their next visit to the study site. Subjects will be
instructed to store vials at room temperature and to clean the tip of the spray nozzle with
an alcohol wipe after each dose is administered. Vials will be weighted before dispensing
and upon return to the clinic 2 wks later to determine how much solution was actually
ejected from the vial.
Measurements: A battery of well-validated instruments to quantify psychiatric symptoms,
social cognition and social competence will be used in this study. The domains to be
measured and the instruments that will be used are summarized below. Psychiatric symptoms
will be rated by research staff among which good inter-rater reliability will be
established.
Psychiatric Measures Psychotic symptoms: The Positive and Negative Symptoms Scale (PANSS,
White et al., 1997) is a 30-item scale on which an interviewer rates the subject for
severity of positive and negative psychotic symptoms and mood and behavioral symptoms after
asking a standard series of questions. Items are rated on a scale of 1 (absent) to 7
(severe), and yield five scaled scores: positive symptoms (this includes several subscales
including paranoia), negative symptoms, dysphoric mood, activation, and autistic
preoccupation.
Depressive symptoms: The Montgomery-Åsberg Depression Rating Scale (Montgomery & Åsberg
1979) is administered by an interviewer who rates the severity of the subject's depressive
symptoms between 0 and 6 in 10 symptom domains.
Anxiety (general and social) and other psychiatric symptoms: The Brief Symptom Inventory
(BSI, Derogatis 1993) consists of 53 questions covering nine symptom dimensions:
Obsession-Compulsion, Interpersonal Sensitivity, Depression, Anxiety, Hostility, Phobic
anxiety, Paranoid ideation and Psychoticism (each rated on a 0-4 scale). Only the subset of
questions used to measure anxiety will be used (items 1, 12, 19, 38, 45, 49). Subjects will
rate themselves on these questions which should require no more than 2-3 min. The Liebowitz
Social Anxiety Scale (Liebowitz 1987) is a self-rating instrument that lists 24 social
situations on which the subject rates (0-3) how much fear/anxiety he/she would experience
and how much he/she would avoid each situation (0-3). The instrument requires approximately
5 min to complete.
Paranoia: The Paranoia Scale (Fenigstein & Vanable, 1992) is a questionnaire filled out by
the subject on which he/she rates on a 1-5 scale whether each of 20 statements applies to
him/her.
Social Cognition Measures Emotion recognition: The Face Emotion Identification Task (Kerr &
Neale 1993) is comprised of 19 images of faces expressing one of six basic emotions (happy,
sad, angry, afraid, surprised, and ashamed) that are presented sequentially on a computer
screen. The participant's task is to identify the emotion that is being expressed by each
face. The scoring sheet accompanies this application although the facial expression pictures
are not.
The Reading the Mind in the Eyes Test- Revised Version: The Eyes Test (Baron-Cohen et al
2001) consists of 36 photographs and participants are asked to guess the mental state (i.e.
what the person is thinking or feeling) from among 4 choice words. Participants are given a
practice item to ensure that they understand the task. Each eye region is presented on a
note card or is displayed on a computer screen with the four choice mental states shown in
the four corners of the card or computer screen (one target word and three foil words).
There is no time constraint in choosing the mental state. A glossary of the mental states is
made available, if the participants are unsure of the meaning of a word. Performance is
measured by the number of faces correctly discriminated.
Trustworthiness task: This task (Adolphs et al., 1998) is comprised of 42 faces of
unfamiliar people. Participants will be shown each picture individually (on a computer
monitor) and will be asked to rate how much they would trust that person (with their money
or their life) on a 7-point scale, ranging from -3 (very untrustworthy) to +3 (very
trustworthy).
Theory of mind: In the Theory of Mind Picture Stories Task (Brüne, 2003), the subject is
shown a series of 6 sets of 4 cartoon pictures that illustrate interactions between two or
more individuals. The subject is asked to rearrange the pictures, initially presented in an
illogical sequence, in an order that conveys a logical story. The period of time the subject
takes to complete the task and the accuracy of the sequencing is recorded. Then, after the
subject or (if the subject fails to do so) the examiner correctly organizes the pictures,
the subject is asked questions about characters in the cartoons own beliefs and beliefs of
other characters in the cartoons. The subject's interpretations of the characters' beliefs
are scored as correct or incorrect.
Attributional style: The Ambiguous Intentions Hostility Questionnaire (AIHQ, Combs et al
2007) is comprised of 15 short vignettes that reflect negative events that vary in
intentionality (i.e., obvious, accidental, and ambiguous intentions). Participants are asked
to read each vignette, to imagine the scenario happening to her/him (e.g., "You walk past a
bunch of teenagers at a mall and you hear them start to laugh"), and to write down the
reason why the other person (or persons) acted that way toward her/him. Two independent
raters subsequently code this written response for the purpose of computing a "hostility
bias". The participant then rates, on Likert scales, whether the other person (or persons)
performed the action on purpose (anchored by [1], definitely no, and [6], definitely yes),
how angry it would make her/him feel (anchored by [1], not at all angry, and [5], very
angry), and how much they would blame the other person (or persons) (anchored by [1], not at
all, and [5], very much). Finally, the participant is asked to write down how she/he would
respond to the situation, which is later coded by two independent raters to compute an
"aggression index.".
Neurocognition Measures: The Brief Assessment of Cognition in Schizophrenia (BACS) will be
administered to assess non-social cognition.
Social Skill Measures Social competence: This task is comprised of two brief, 3-min role
plays (which are videotaped). The first role-play is an unstructured conversation whereby
the research confederate tells the participant that she/he is a new patient admitted to an
inpatient ward and they should get to know one another. We have used similar role plays like
this one in the past (Pinkham & Penn, 2006). In the second role play, we instruct the
participant that their task is to comfort another patient who is in distress (because they
aren't being discharged from the hospital that day).
Social Functioning: The Specific Levels of Functioning (SLOF) questionnaire will be filled
out by the subject and a reliable informant who has known the subject well for over a year
at baseline and at the end of the treatment trial.
