Adjunctive Intranasal Oxytocin Reduces Symptoms in
Schizophrenia PatientsDavid Feifel, Kai Macdonald, Angel Nguyen, Patrice Cobb, Heather Warlan, Barbara Galangue,
Arpi Minassian, Olga Becker, Jason Cooper, William Perry, Mischelle Lefebvre, James Gonzales, andAllison Hadley
Background: Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial
to directly test this notion.
Methods: Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic wereenrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) andplacebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout betweentreatments.
Results: Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive
and Negative Symptom Scale (p ⬍ .001) and Clinical Global Impression-Improvement Scale (p ⬍ .001) compared with placebo at the 3-weekend point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patientreports or laboratory analysis.
Conclusions: The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer
duration of treatment may produce larger benefits and should be evaluated in future studies.
Key Words: Oxytocin, schizophreniaO

xytocin and its receptors exist in areas of the brain
implicated in the symptoms of schizophrenia such as thenucleus accumbens and the hippocampus (1). Previously, our laboratory demonstrated that peripherally administered oxytocin produces reversal of prepulse inhibition deficits
induced in rats by amphetamine and the N-methyl-D-aspartate
receptor antagonist, MK-801 (2), a finding consistent with theeffects of atypical antipsychotics. Subsequently, other investigators have also reported preclinical findings supporting an antipsychotic role for oxytocin (3,4).
Human studies have provided further indirect support for thecontention that oxytocin may have antipsychotic properties.
Schizophrenia patients have been found to have altered oxytocinergic functions ([5–10] but see [11]). Recent studies found that
intranasal oxytocin administered to normal human subjects increased perceived trustworthiness (12,13), suggesting paranoia
may be ameliorated in schizophrenia patients. We conducted a
proof-of-concept, pilot study of intranasal oxytocin in schizophrenia patients to test the hypothesis that oxytocin can reduce
symptoms of this disease.

Methods and Materials
Participants
Subjects with a DSM-IV diagnosis of schizophrenia, confirmedby Structured Clinical Interview for DSM-IV interview, wereenrolled in this double-blind, placebo-controlled, crossoverstudy. Other main inclusion criteria were minimum 18 years ofFrom the Department of Psychiatry (DF, KM, AN, PC, HW, BG, AM, OB, JC, WP,AH), and Investigational Drug Service, Pharmacy Department (ML, JG),
University of California, San Diego Medical Center, San Diego, California.
Address correspondence to David Feifel, M.D., Ph.D., University of California,
San Diego Medical Center, Department of Psychiatry, 200 West Arbor
Drive, San Diego, CA 92103-8218; E-mail: dfeifel@ucsd.edu.
Received Mar 9, 2010; revised Apr 29, 2010; accepted Apr 30, 2010.

0006-3223/$36.00
doi:10.1016/j.biopsych.2010.04.039

age, treatment with one or two approved antipsychotic medications with no dose changes in the previous 4 weeks, Positive andNegative Syndrome Scale (PANSS) score of at least 55, and a
Clinical Global Impressions-Severity (CGI-S) scale score of atleast 4 (moderately ill) at randomization. Because it was hypothesized that oxytocin may improve paranoia due to its protrust
effect, subjects were also required to have a score of at least 4(moderate) on item 6 (suspiciousness/persecution) of thePANSS. This study was approved by the University of California,
San Diego Institutional Review Board and written informed
consent was obtained from all subjects.
Study Drugs
Subjects were maintained on their prestudy antipsychotic
medication regimen and doses were not changed during thestudy. Subjects received 3 weeks of daily intranasal oxytocin(Syntocinon, Novartis, Basel, Switzerland) and 3 weeks of daily
intranasal placebo. Oxytocin was dosed at 20 IU (5 sprays) twice
a day for the first week and 40 IU (10 sprays) twice a day
thereafter. Order of treatment (placebo-oxytocin or oxytocinplacebo) was randomly assigned using a computer-generatedrandom sequence.
Efficacy and Safety Assessments
Subjects, raters, and study staff enrolling patients wereblinded to treatment condition. The total study duration for eachindividual subject was 7 weeks. Subjects were evaluated seventimes. Visits 1 and 5 were baseline assessments and visits 2, 3,and 4 and 6, 7, and 8 were the weekly visits for the two treatment
periods, respectively. Washout occurred in the week betweenvisits 4 and 5. At each visit, raters assessed subjects using thePANSS (14), CGI-S, and Clinical Global Impressions-Improvement (CGI-I) (15). The PANSS total at the final visit of eachtreatment period was chosen a priori as the primary efficacy end
point.
Safety was assessed at each visit by a medical examination
and assessment of reported adverse events. In addition, urine
was collected for osmolality testing and blood was drawn at each
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D. Feifel et al.
visit and analyzed at University of California, San Diego laboratories for basic chemistry analysis.
Statistical Methods
Data from all subjects who received at least one dose and one
assessment in both treatment periods (intent-to-treat population)
were subjected to analysis using SPSS version 11.0 (SPSS Inc.,Chicago, Illinois). Baseline scores for both drug treatments werecompared for similarity using paired t test. The change inbaseline scores from period 1 to period 2 was compared among
the placebo-oxytocin versus oxytocin-placebo groups using atwo-sample t test to assess for period carryover effects (16). The
PANNS and Clinical Global Impressions data were subjected torepeated measures analysis of variance with drug and treatment
week as repeated measures factors. Treatment sequence wasincluded as a between-subjects factor to evaluate possible period
and carryover effects. Paired t tests, corrected for multiple
comparisons using Bonferoni method, were used to compare
placebo and oxytocin scores at end point and each of the otherassessment visits. Cohen’s d statistic was calculated for eachmeasure at end point (17).

Results
Fifteen of 19 randomized subjects completed all study visits.
Four randomized subjects were discontinued before completingthe study, one due to nasal discomfort from the intranasal sprays
and three due to insufficient compliance. None of the discontinued subjects reached the second treatment period; therefore,
intent-to-treat population was identical to completer population.
Eighty percent of completers were male, 53% black and 27%
white, and average age and duration of disease were 48 (8.9) and26 (14.6), respectively (Table S1 in Supplement 1). They were ona wide range of antipsychotics on entering the study (Table S2 inSupplement 1).
Table 1 lists efficacy results. Baseline scores at the start of eachplacebo and oxytocin treatment arm were highly similar for
PANSS total (82.1 ⫾ 11.06 and 81.4 ⫾ 12.43) and CGI-S (4.60 ⫾.74 and 4.67 ⫾ .74). Change in scores between first period andsecond period baselines did not significantly differ between
groups, suggesting there was not significant carryover.
There was a significantly greater improvement in PANSS total
scores across visits with oxytocin compared with placebo, asrevealed by a significant drug by treatment week interaction[F (2,26) ⫽ 6.493, p ⫽ .005]. None of the other main or interaction
effects were significant. Scores were significantly lower withoxytocin versus placebo at the end point (week 3) visit (difference ⫽ 5.46, p ⬍ .001, Cohen’s d effect size ⫽ .43), whereas there
was no significant difference at baseline (difference ⫽ .60), week
1 (difference ⫽ .60), or week 2 (difference ⫽ 1.20).
The CGI-I scores revealed a drug by treatment week interaction that approached significance (p ⫽ .065, Cohen’s d ⫽ .74). No
other main or interaction effect was significant. The CGI-I wassignificantly lower for oxytocin versus placebo at week 3 (p ⬍.001) but not at baseline, week 1, or week 2.
Analysis of PANSS negative subscale scores did not reveal any
significant main factor or interaction effects but were significantly
lower for oxytocin versus placebo at week 3 only (p ⫽ .023,Cohen’s d ⫽ .50).
A greater decrease in PANSS positive subscale scores underoxytocin was reflected in a nonsignificant trend toward a drug bytreatment week interaction (p ⫽ .089). There was also a significant drug by treatment sequence effect [F (1.13) ⫽ 11.57, p ⫽.005] reflected in the fact that PANSS positive scores weresignificantly lower with oxytocin treatment (p ⫽ .01) when it was
the first treatment but not when it was the second treatment.
There were no other significant main or interaction effects.
Oxytocin scores were significantly lower than placebo scores atweek 3 (p ⫽ .006, Cohen’s d ⫽ .4) but not at baseline, week 1,or week 2.
A greater decrease in PANSS general psychopathology subscale scores under oxytocin was reflected in a nonsignificant
trend toward a drug by visit interaction (p ⫽ .069, Cohen’s d ⫽.24). Oxytocin scores were not significantly different from placebo at any time point.
Overall, differences in the first period by itself (betweensubjects analysis) did not reach statistical significance.
There were no serious adverse events reported during theTable 1. Efficacy Scores (⫾ Standard Deviation)PANSS Total
Placebo
OxytocinPANSS Positive
Placebo
OxytocinPANSS Negative
Placebo
OxytocinPANSS General Psychopathology
Placebo
OxytocinPANSS CGI-I
Placebo
Oxytocin

Baseline

Week 1

Week 2

Week 3 [Cohen’s d]a82.1 (11.1)
81.5 (12.4)

76.9 (10.6)
76.3 (11.3)

75.7 (12.7)
76.9 (13.2)

79.1 (12.9)
73.6 (13.6)b [.43]22.8 (5.2)
21.7 (4.1)

21.2 (5.0)
20.6 (4.5)

20.0 (4.6)
20.5 (4.6)

21.9 (4.8)
19.9 (5.2)b [.40]

21.8 (4.7)
20.2 (4.7)

20.5 (4.4)
20.1 (4.8)

20.2 (4.6)
19.7 (4.3)

20.7 (4.3)
18.5 (4.5)c [.50]

37.5 (6.6)
38.8 (7.6)

35.2 (6.2)
36.4 (8.1)

35.4 (7.3)
36.3 (8.2)

36.4 (7.3)
34.8 (6.9) [.24]

4.60 (.74)d4.67 (.61)d3.53 (.92)
3.33 (.62)

3.53 (.92)
3.33 (1.20)

3.73 (1.03)
3.07 (.70)b [.74]

CGI-I, Clinical Global Impressions-Improvement; PANSS, Positive and Negative Syndrome Scale.
a.2 small, .5 medium, .8 large (17).
bSignificantly different versus placebo p ⬍ .05.
c
Significantly different versus placebo p ⬍ .01.
dClinical Global Impressions-Severity and not Clinical Global Impressions-Improvement noted for baseline.

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D. Feifel et al.

Table 2. Reported Adverse Events

HeadacheDyspepsia or Nausea
Sleep Impairment
Dizzy or Lightheaded
Nasal Irritation
Lethargy

Oxytocin (n)Placebo (n)26.7% (4)26.7% (4)33.3% (5)26.7% (4)26.7% (4).0% (0)20.0% (3)40.0% (6)26.7% (4)20.0% (3)
13.3% (2)
13.3% (2)study and no significant differences in rates of reported adverse
effects with oxytocin compared with placebo (Table 2). There
were no significant differences between oxytocin and placebo in
any of the measured blood chemistry or urine osmolality tests(Table S3 in Supplement 1).

Discussion
We found that 3 weeks of intranasal oxytocin, given adjunctive to standard antipsychotic medications, caused significantly
greater reductions in schizophrenia symptoms at the study end
point compared with placebo. This result supports our hypothesis that oxytocin exhibits antipsychotic properties and validates
preclinical studies, case reports, and less well-controlled clinicalstudies suggesting oxytocin’s ability to ameliorate symptoms ofschizophrenia (18,19).
Oxytocin’s effect appeared to manifest broadly across symptom clusters including positive and negative symptoms, although
the improvement in positive symptoms appeared statisticallymore robust. Though the numerical effect of oxytocin is modest(7.9 point reduction on the PANSS total compared with 3.0 points
for placebo), three points regarding its observed magnitude ofbenefit warrant consideration. First, subjects were already on
stable therapeutic doses of at least one antipsychotic and oxytocin represented adjunctive treatment. Compared with a medication-free cohort, improvements in this already treated cohort are
generally harder to come by. Notwithstanding this fact, the effectsize of the improvements we observed were medium [(.43)
PANSS scores] to large [(.74) CGI-I] (17). Second, this study had
dosing and duration limitations that may have prevented theoptimal magnitude of benefit from being observed: only one
oxytocin dose was studied, and subjects were treated for only 3weeks. Either higher doses or longer treatment duration may
have yielded greater symptom improvements. Supporting thislatter point, oxytocin’s benefits emerged only at the week 3
assessment, a finding that suggests a delayed onset of action that
may have grown with a longer treatment duration. Finally, while
it is possible that a certain subpopulation of schizophrenia
patients is particularly responsive to the benefits of oxytocin(based on oxytocin receptor variations or diagnostic subtype),
our sample size was too small for a subanalysis along these lines.
To fully characterize oxytocin’s antipsychotic potential, futurestudies are warranted with larger sample sizes, different doses,
and longer treatment durations, as well as pharmacogenetic andbehavioral investigations.
Despite its therapeutic potential, there have been very few
trials of oxytocin for psychiatric conditions. As such, our findingthat oxytocin— given twice daily for 3 weeks—was well tolerated
and did not appear to produce any subjective or objective
adverse events is noteworthy.
This study was supported by a grant to DF from Stanley
Medical Research Institute.
www.sobp.org/journal

DF has received funding for research, consulting, or speaking
from Abbott Laboratories, Addrenex, Alexza, AstraZeneca, Danipon-Sumitomo, Eli Lilly, Forest, Janssen, Merck, Otsuka, Pfizer,Shire, and Wyeth. KM has received funding for research, consulting, or speaking from Wyeth, Pfizer, Eli Lilly, Janssen, andCephalon. All other authors reported no biomedical financial
interests or potential conflicts of interest.
ClinicalTrials.gov: Oxytocin Treatment of Schizophrenia; http://clinicaltrials.gov/ct2/show/NCT00506909?termoxytocin&rank7;
NCT00506909.
Supplementary material cited in this article is available
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