Schizophrenia Research 124 (2010) 13–21

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Schizophrenia Researchj o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s

Peripheral oxytocin is associated with reduced symptom severityin schizophrenia
Leah H. Rubin a,⁎, C. Sue Carter b, Lauren Drogos a, Hossein Pournajaﬁ-Nazarloo b,
John A. Sweeney a, Pauline M. Maki aab

Departments of Psychiatry, Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, IL, USA
Department of Psychiatry, Brain Body Center, University of Illinois at Chicago, Chicago, IL, USAa r t i c l e

i n f oArticle history:
Received 14 July 2010
Received in revised form 11 September 2010
Accepted 20 September 2010
Available online 13 October 2010
Keywords:
Oxytocin
Estrogen
Progesterone
Schizophrenia
Menstrual cyclea b s t r a c t
Background: Emerging evidence from clinical trials suggests that oral estrogen and intranasal
oxytocin might reduce symptom severity in schizophrenia. Whether increases in endogenous
hormones are similarly associated with improved symptoms is unknown. We investigated theeffects of menstrual cycle phase and related fluctuations in peripheral hormone levels on
clinical symptoms in women with chronic schizophrenia.
Method: Twenty-three women with schizophrenia were administered the Positive and
Negative Syndrome Scale (PANSS), a measure of clinical symptom severity, at two menstrual
cycle phases: 1) early follicular (Days 2–4; low estrogen/progesterone) and 2) midluteal (Days
20–22; high estrogen/progesterone). Twenty-seven males with schizophrenia and 58 controls(31 female) completed testing at comparable intervals. Men were included to examine
whether the relationships between clinical symptoms and hormone levels in women generalize to men. Plasma hormone assays of estrogen, oxytocin, progesterone, and testosterone
were obtained.
Results: Female patients showed less severe symptoms during the midluteal versus earlyfollicular phase (p's b 0.01). Oxytocin did not ﬂuctuate across phases, but in female patients(p's b 0.01) higher oxytocin levels were associated with less severe positive symptoms andoverall psychopathology. In both sexes, higher oxytocin levels were associated with moreprosocial behaviors (p b 0.05).
Conclusion: Consistent with previous findings in acutely ill patients, our results suggest thatclinical symptoms vary across the menstrual cycle in patients with chronic schizophrenia.
Similar to recent findings regarding benefits of intranasal oxytocin, these new findings indicatethat high levels of endogenous oxytocin might improve positive symptom severity and general
psychopathology in women and social behaviors in both sexes.
© 2010 Elsevier B.V. All rights reserved.

1. Introduction
Sex modulates the clinical presentation and course of
schizophrenia. The course of the disease is more benign in⁎ Corresponding author. University of Illinois at Chicago, Department of
Psychiatry, 912 S. Wood St. (MC 913), Chicago, Illinois 60612, USA. Tel.: + 1
312 355 5017; fax: + 1 312 413 7856.
E-mail address: lrubin@psych.uic.edu (L.H. Rubin).
0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2010.09.014

women than in men; females generally have a later age of
onset, shorter and less frequent acute episodes of psychosis,
less severe negative symptoms, better premorbid functioning,
and a better treatment response to antipsychotic medicationcompared to males (Riecher-Rossler and Hafner, 2000;
Halbreich and Kahn, 2003; Rao and Kolsch, 2003). These sex
differences suggest involvement of hormonal factors. In thisstudy, we use a menstrual cycle paradigm to explore changes
in clinical symptoms in relation to ﬂuctuating peripheral
hormone levels.

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L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

Patients with schizophrenia show reduced levels of estrogen and other sex hormones such as progesterone andtestosterone (Oades and Schepker, 1994; Goyal et al., 2004;
Huber et al., 2004; Bergemann et al., 2005a; Huber et al.,2005; Howes et al., 2007; Ko et al., 2007), and alterations
in neurohormones such as oxytocin (Linkowski et al., 1984;
Beckmann et al., 1985; Legros et al., 1992; Mai et al., 1993, cf.,
Glovinsky et al., 1994; Goldman et al., 2008; Keri et al., 2009).
Impressively, four (Kulkarni et al., 2002; Akhondzadeh et al.,
2003; Louza et al., 2004; Ko et al., 2006; Kulkarni et al., 2008) ofﬁve (Bergemann et al., 2005b) randomized, placebo-controlled
clinical trials (RCT) demonstrate beneﬁcial effects of short-term
adjunctive estrogen treatment on clinical symptoms including
overall, positive, negative, and/or general psychopathology inpremenopausal women with chronic schizophrenia. The one
neutral trial differed from the other four positive trials in its
use of high-dose oral estrogen (Bergemann et al., 2005b).
Following promising ﬁndings from open label studies(Bujanow, 1972; Bakharev et al., 1984), intranasal oxytocin is
now being examined in RCTs as a therapy for schizophrenia. A
randomized clinical trial of short-term adjuvant intranasal
oxytocin (versus placebo) demonstrated therapeutic effects
on clinical symptoms in a small sample of predominantly maleschizophrenia patients with residual symptoms (Feifel et al.,2010). Oxytocin has widespread effects beyond its characteristic roles in pregnancy and lactation, including effects on
behaviors that are impaired in schizophrenia such as emotional
processing, stress management, afﬁliative behavior, and certain
aspects of cognition (Carter et al., 2008; Heinrichs et al., 2009).
Whether natural changes in endogenous estrogen or oxytocin
inﬂuence clinical symptoms in women with schizophrenia is
unknown.
Menstrual cycle paradigms provide insights into how
clinical symptoms might change in relation to physiologicalchanges in estrogen and progesterone (which reliably change
across cycle phases) and oxytocin (which changes in somestudies) (Salonia et al., 2005; Liedman et al., 2008). These
paradigms allow for assessment of symptoms in relation tosigniﬁcant change in hormone levels across speciﬁc menstrual phases as well as average hormone levels across different phases. Four (Hallonquist et al., 1993; Riecher-Rossler
et al., 1994; Choi et al., 2001; Bergemann et al., 2007) of six(Harris, 1997; Thompson et al., 2000) studies in premenopausal women with schizophrenia demonstrate improved
clinical symptoms in relation to natural ﬂuctuations acrossthe menstrual cycle; speciﬁcally, symptom improvement wasevident in the midluteal (high estrogen/progesterone) versus
the early follicular (low estrogen/progesterone) phase. In
two of these studies, higher estradiol levels were associatedwith improved clinical symptoms and in particular positive
symptoms (Riecher-Rossler et al., 1994; Bergemann et al.,2007). Of the two studies ﬁnding no cycle-related changes,
one did not validate menstrual cycle phase with hormone
assays (Harris, 1997) and the other did not tightly control
menstrual cycle phase (Thompson et al., 2000), allowing
for a wide range of estradiol and progesterone levels.
Animal studies suggest that estrogen can upregulate thesynthesis of oxytocin (Young et al., 1998; Patisaul et al.,2003), but the relationship between oxytocin and clinicalsymptoms has not been investigated in a menstrual cycle
study, and no previous study has examined endogenous

oxytocin levels over time in relation to clinical symptom
severity.
The purpose of this study was to investigate the effects ofmenstrual phase and hormone levels on clinical symptom
severity in women with chronic schizophrenia. We hypothesized that like acutely ill women with schizophrenia, womenwith chronic schizophrenia would show improvements inclinical symptoms during the midluteal versus early follicularphase, and that these improvements would relate to increases
in estradiol. We also extended previous studies by including
measures of oxytocin. We predicted that oxytocin levels
would be inversely related to clinical symptom severity inpatients with schizophrenia. We examined progesterone andtestosterone because metabolites of both hormones as well as
testosterone can inﬂuence clinical symptom expression inschizophrenia (Ko et al., 2008; Marx et al., 2009; Ritsner et al.,2010). We also evaluated relationships between clinicalsymptoms and hormone levels in men with schizophrenia
and included male controls. Male patients were included to
examine whether the relationships between hormone levels
and clinical symptoms in female patients generalize to men.
2. Methods
2.1. Participants
The sample included 108 participants, including 50 patients(23 women, 27 men) and 58 controls (31 women, 27 men).
Inclusion criteria for all participants were: (1) age 18–40;(2) English as ﬁrst language; (3) for patients, Structured ClinicalInterview for DSM (SCID; First et al., 1995) diagnosis of
schizophrenia or schizoaffective disorder depressed type;(4) for patients, reported medication compliance and consistency in treatment medication for 2 months prior to the study;and (5) for women, regular menstrual cycles (28 ± 5 days).
Additional inclusion criteria for women helped to validate
menstrual phase based on the normal range for the estradiol assay (Diagnostic Products, Los Angeles, CA), including(6) early follicular levels ≤90 pg/ml and (7) midluteal levels
between 27–246 pg/ml. Exclusion criteria for all participants
were: (1) history of moderate/severe head trauma or otherneurological disorder; (2) history of substance abuse/dependence, excluding cigarettes; (3) high intake of phytoestrogens(3 ≥ servings of soy/day or supplements); (4) conditions
resulting in abnormal gonadal hormone secretion; (5) significant medical illness; (6) use of hormone treatments; and(7) for women, pregnancy/lactation within the last year. Controls were also excluded if they (8) currently used medications
known to inﬂuence the central nervous system or (9) had an
Axis I psychiatric disorder (based on SCID interview).
Controls were recruited from the community, and patientsfrom outpatient clinics and residential facilities in the Chicago
metropolitan area. Patients were diagnosed with schizophrenia (68%) or schizoaffective disorder—depressed type (32%),
were clinically stable, and self-reported stable medication
regimens for the prior 2 months. Most patients (84%) wereprescribed second generation antipsychotics. Antipsychotic
medication dosages ranged from 40–1133 mg chlorpromazine equivalents (Woods, 2003; Lehman et al., 2004) per day(median dosage, 400 mg/day). Forty-six percent of patientswere taking antidepressants, 4% were taking mood stabilizers,

L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

and 38% met criteria for hyperprolactinemia (N20 ng/mL).
Written informed consent was obtained from all participants.
Study procedures were approved by the UIC Institutional
Review Board.
Table 1 shows demographic and clinical information for
the 108 participants. The sample had high body mass index
scores (BMI; 42% obese; 21% overweight according tostandard criteria (1998)). Compared to controls, patientswere older by 3–4 years and had higher BMIs (p's b 0.05).
Controlling for age and BMI did not affect the signiﬁcance ofthe results. Male and female patients were similar acrossmost clinical variables, but male patients received higher
doses of antipsychotic medication (p b 0.05).
2.2. Measures
2.2.1. Clinical symptoms
The Positive and Negative Symptom Scale (PANSS; Kayet al., 1987) was administered to patients at each study visit
to generate measures of positive symptoms, negative symptoms, general psychopathology, and a total score. A PANSS
prosocial factor derived from an exploratory factor analysis
in a sample of outpatients with SCID diagnoses within theschizophrenia spectrum was also examined (Purnine et al.,2000). Items in this subscale were active social avoidance,emotional withdrawal, passive social withdrawal, stereotyped thinking, hallucinatory behavior, and suspiciousness/paranoia.

15

day during both sessions. Samples were stored in plain tubes,
centrifuged (2400 ×g for 15 min at 4 °C), placed into −80 °C
freezers, and assayed in duplicate. Batched samples (placed in
dry ice; shipped overnight) were sent to the University of
Alabama at Birmingham's General Clinical Research Center
for analysis (Gower and Nyman, 2000). Serum concentrations
were analyzed using commercial kits: estradiol by doubleantibody radioimmunoassay (RIA; Diagnostic Products, Los
Angeles, CA) (sensitivity 1.61 pg/ml, intra-assay CV = 4.01%),
progesterone by “Coat-a-Count” coated tube RIA (Diagnostic
Products, Los Angeles, CA) (sensitivity 0.05 ng/ml, intra-assay
CV = 2.33%), prolactin (for determination of possible hyperprolactinemia, N20 ng/mL) by a two-site immunoenzymometric assay (TOSOH Bioscience, CA) (sensitivity = 1 ng/mL,
intra-assay CV = 1.5%), and sex hormone binding globulin
by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) (sensitivity = 3 nmol/L; intra-assay CV =1.37%). Free testosterone was calculated using the methodof Stephen J. Winters (University of Louisville; Louisville, KY)(sensitivity 0.82 ng/dl; intra-assay CV = 2%). Oxytocin wasquantiﬁed at UIC with an EIA kit (Assay Designs, Ann Arbor,MI) (sensitivity 16 pg/mL, intra-assay CV b 11%) that is highly
speciﬁc for oxytocin versus other peptides, as determinedby HPLC (Carter et al., 2007). Samples were initially run
undiluted. Twenty of 203 samples showed values greaterthan 600 pg/ml. Dilution (1:2 ratio) was subsequently used to
conﬁrm the accuracy of those samples.
2.3. Procedures

2.2.2. Serum hormone assays
To account for circadian rhythm effects (Brambilla et al.,2009), blood samples were drawn once at the same time of

Women were evaluated once during the early follicularphase (Day 2–4; low estradiol/progesterone) and once during

Table 1
Demographics and other descriptive information.
Women
Patients (n = 23)

Men
Healthy controls (n = 31)

Patients (n = 27)

Healthy controls (n = 27)

Variables

M (SD)

M (SD)

M (SD)

M (SD)

AgeG
Parental SES
Race
CaucasianAfrican–American
Asian
Hispanic or Latino
Other/unknown
ParousPast oral contraceptive use
Body mass indexG
Test sessions in afternoon (after 12 pm)
SCID diagnosis
Schizophrenia
Schizoaffective (depressed type)
Duration of illness in years†
Antipsychotics (on second generation)
Risperidone‖
Chlorpromazine mg equivalentsS
Antipsychotic + antidepressantAntipsychotic + mood stabilizer
Hyperprolactinemia, N 20 ng/ml (%)

30.65 (5.73)
3.00 (0.95)

27.55 (6.67)
3.13 (1.34)

31.19 (6.60)
3.14 (1.08)

27.93 (5.99)
3.33 (1.30)

31%
48%
4%
17%
–
30%
57%
33.28 (8.52)
70%

29%
45%
16%
10%
–
19%
39%
28.17 (9.18)
55%

15%
59%
4%
15%
7%
–
–
32.24 (7.55)
63%

44%
30%
15%
4%
7%
–
–
27.20 (7.03)
52%

57%
43%
12.96 (5.50)
87%
26%
320 (255)
56%
4%
38%

78%
22%
11.39 (7.89)82%
33%
484 (288)
37%
4%
33%

Note. Parental SES higher scores reﬂect higher SES; SCID = Structured Clinical Interview for DSM. † In years since initial treatment for psychosis. ‖ Higher
propensity to elevate prolactin levels compared to other second generation antipsychotics. G Main effect of group was signiﬁcant at p b 0.05. S Main effect of sex was
signiﬁcant at p b 0.05.

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L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

the midluteal phase (Day 20–22; high estradiol/progesterone). Phase at ﬁrst session was counterbalanced acrossparticipants. Sessions were held during two separate cycles
about 42 days apart. Menstrual phase was initially estimatedby counting back to Day 1 of the last menstrual cycle, andwas later validated with estradiol and progesterone levels.
Examiners were blinded to menstrual cycle status. Men were
tested in separate sessions approximately 42 days apart.
Given that half of the women were randomly assigned tofollicular phase ﬁrst and half to luteal phase ﬁrst, half of themen were randomly assigned to have their second session
data reversed with that of the ﬁrst session. This counterbalancing reduces confounds related to carry over effects(e.g., change in symptom ratings due to increased comfort
with the examiner).
2.4. Statistical analyses
Our hypotheses were tested using multilevel random
coefﬁcient models in which the two measurement time
points (i.e., follicular and midluteal) were nested within
individuals. The ﬁrst analyses examined changes in hormone
levels across the menstrual cycle (follicular and midluteal),
with menstrual phase as a within-subjects variable (Level 1 inmodel) and group (patients, controls) as a between-subjects
variable (Level 2 in model). The second analyses (benchmark
model) examined the effect of menstrual phase (Level 1 inmodel) on clinical symptoms (primary outcome) in female
patients. Next, we examined the degree to which individual
variations in hormone levels that ﬂuctuate across themenstrual cycle (i.e., estradiol, progesterone) were associatedwith clinical symptoms that change across the menstrual
cycle in female patients. To accomplish this, we added
estradiol and progesterone levels as time-varying covariates(Level 1 in model) to our benchmark model. These models
provide an estimate of how individual variation in a speciﬁc
hormone (e.g., estradiol) is associated with changes in clinicalsymptoms while controlling for variations in other hormones(e.g., progesterone). Finally, we examined the degree towhich hormone levels that did not change across themenstrual cycle (e.g., testosterone) predicted average symptom presentation in female patients. This was accomplishedby adding these hormones as time-invariant covariates to themodel (Level 2 in model). Parallel analyses were conducted inmale patients to examine changes in hormones and clinicalsymptoms across sessions spaced at equivalent time inter-vals. Analyses in patients examined the following covariates:
BMI, primary SCID diagnosis (schizophrenia versus schizoaffective), type of antipsychotic medication (ﬁrst versus second
generation) and dosage, use of SSRI or mood stabilizer, andhyperprolactinemia (N20 ng/ml). Non-signiﬁcant covariates
were eliminated from the models. Regression coefﬁcients arepresented as unstandardized beta weights (standard errors).
Only p values b 0.10 are reported (so that trend-level effects
are noted). Multilevel models were analyzed with SAS (v.9.02
for Windows; SAS, Cary, NC).
3. Results
3.1. Hormone levels in women and men
Table 2 shows average hormone levels for female participants. As expected for females overall, estradiol and progesterone levels were signiﬁcantly higher during the midluteal
versus early follicular phase, (p's b 0.001). Testosterone andoxytocin levels did not change signiﬁcantly across the cycle.
Progesterone levels were lower in patients compared tocontrols (p b 0.01), but levels of estradiol, free testosterone,
and oxytocin did not differ between female groups. Bothgroups showed similar progesterone levels during the earlyfollicular phase, but patients showed lower progesterone
levels compared to controls during the midluteal phase(p b 0.001). Patients and controls showed a similar magnitude of change in estrogen, testosterone, and oxytocin acrossphase.
Table 3 presents hormone levels for men. Free testosterone levels were lower in male patients compared to controls(p b 0.05), but estradiol and oxytocin levels did not differ
between the two groups. As expected, no hormone levels
differed as a function of test session, and there were no Groupby Session interactions.
3.2. Changes in clinical symptoms in women with schizophrenia
across the menstrual cycle
Table 4 shows PANSS ratings for female patients at eachcycle phase as well as the change score. Scores on the positive(Cohen's d = 0.15) and general psychopathology (Cohen'sd = 0.50) subscales and the total symptom score (Cohen'sd = 0.34) were lower during the midluteal versus earlyfollicular phase (p's b 0.01), whereas scores on the negative
symptom subscale and prosocial factor did not change.

Table 2
Endogenous serum hormone levels (M and SD) in a function of menstrual cycle phase (early follicular, midluteal) in female patients and healthy controls.
Group
Patients (n = 23)Phase

17-β-Estradiol (pg/ml)P
Progesterone (ng/ml)P,G,I,†
Free testosterone (pm/L)
Oxytocin (pg/ml)

Early follicular

Controls (n = 31)
Midluteal

Average

Early follicular

Midluteal

Average

M (SD)

M (SD)

M (SD)

M (SD)

M (SD)

M (SD)

42.47 (21.95)
0.78 (0.48)
17.02 (17.19)
284.35 (187.50)

120.82 (57.04)
5.69 (4.77)
16.91 (13.86)
321.88 (229.45)

81.64 (7.15)
3.23 (2.45)
16.77 (13.46)
299.45 (192.04)

42.48 (21.64)
0.77 (0.40)
15.68 (19.74)
327.75 (231.76)

121.67 (48.63)
11.19 (7.21)
13.59 (8.60)
316.16 (174.70)

82.08 (27.39)
5.99 (3.66)
14.25 (10.50)
322.93 (187.05)

Note. P Menstrual phase signiﬁcant at p b 0.05. G Signiﬁcant group differences p b 0.05. I Subject group x menstrual phase interaction signiﬁcant at p b 0.05. † Patients
had lower values than controls during the midluteal phase.

L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

17

Table 3
Endogenous serum hormone levels (M and SD) in male patients and controls over two study sessions (A, B).
Group
Patients (n = 27)17-β-estradiol (pg/ml)
Free testosterone (pm/L)

G

Oxytocin (pg/ml)

Controls (n = 27)

Session A

Session B

Average

Session A

Session B

Average

M (SD)

M (SD)

M (SD)

M (SD)

M (SD)

M (SD)

46.14(20.91)314.06(121.90)277.56(243.14)42.75(20.61)326.74(115.56)265.82(225.24)44.45(18.81)320.40(99.55)273.52(228.85)40.31(14.85)383.16(153.02)293.19(210.46)

38.63(12.50)385.26(134.84)
310.87(241.89)

39.47(11.95)384.21(133.08)302.03(219.10)Note. G Signiﬁcant group differences p b 0.05.

Clinical symptoms in male patients did not differ signiﬁcantly
from Session A and B.
3.3. Relationships between clinical symptoms and hormone
levels in women and men with schizophrenia
Individual variation in estradiol and progesterone levels
did not signiﬁcantly account for changes in clinical symptomscores. Average levels of oxytocin, which was very consistentover time (test-retest reliability r = 0.81, p b 0.001), wereassociated with average symptom presentation in female
patients (Table 5). Speciﬁcally, higher levels of oxytocin wereassociated with lower scores on the total symptom, andpositive, general psychopathology, and prosocial measures(p's b 0.01; see Fig. 1). There was a trend for higher oxytocinlevels to be related to lower negative symptom scores inwomen (p = 0.06). In men, higher oxytocin levels were associated with better prosocial scores (p b 0.05). Testosterone did
not relate to symptoms in either sex.
Exploratory analyses on individual PANSS items indicatedthat in female patients, higher levels of oxytocin were significantly associated with better clinical symptoms on delusions,hallucinatory behavior, suspiciousness/paranoia, passive social withdrawal, and tension (p's b 0.05). Trends were also
noted on blunted affect, emotional withdrawal, and depression (p b 0.10). In male patients, trends were noted on active
social avoidance and hostility (p b 0.10).
4. Discussion
The primary goal of this study was to examine the effectsof menstrual cycle phase and peripheral hormone levels on

clinical symptom severity in women with schizophrenia. In
women, menstrual cycle-related changes on the PANSS wereobserved, with lower positive symptoms, total symptoms,
and general psychopathology in the midluteal compared toearly follicular phase. Individual variations in hormone levels
across the cycle were not related to these cycle-relatedchanges in symptoms. Although oxytocin did not varysigniﬁcantly across the menstrual cycle, higher average levelsof oxytocin predicted less severe positive, general, andprosocial symptoms in women. In men, higher levels ofoxytocin predicted better prosocial symptom scores. Theseﬁndings in chronic patients extend previous work in acutely
ill patients showing that symptoms ﬂuctuate across themenstrual cycle. Additionally, our ﬁndings support continued
investigation of hormones in relation to symptom severity inschizophrenia, and continued investigation of exogenous
oxytocin as an adjunctive treatment in schizophrenia.
4.1. Clinical symptoms, menstrual cycle, and hormones inwomen with schizophrenia
Our ﬁnding that clinical symptoms improve during the
midluteal versus follicular phase is consistent with previous
studies (Hallonquist et al., 1993; Riecher-Rossler et al., 1994;
Bergemann et al., 2007). We observed small to medium improvements (i.e., according to Cohen's d effect sizes) in positive, general, and total symptoms in the midluteal versus
follicular phase. This ﬁnding is similar to that of Bergemannet al. (2007) who studied changes in symptoms across themenstrual cycle in 125 premenopausal women with schizophrenia. The negative symptom subscale was only marginallyaffected by menstrual cycle in the Bergemann et al. (2007)

Table 4The effects of menstrual cycle phase in female patients and test session in male patients on the Positive and Negative Syndrome Scale ratings (PANSS).
Female patients (n = 23)

Male patients (n = 27)

Early follicular

Midluteal

Outcomes

M (SD)

M (SD)

M (SD)

M (SD)

M (SD)

M (SD)

Total score
Positive scale
Negative scale
General psychopathology
Prosocial factor

63.00 (9.31)
15.35 (4.34)
14.91 (3.87)
32.74 (4.13)
15.30 (4.11)

60.02 (8.06)
14.70 (4.06)
14.57 (3.27)
30.76 (3.84)
14.65 (3.65)−2.98 (4.16)⁎⁎−0.65 (0.92)⁎⁎−0.35 (1.70)−1.98 (2.85)⁎⁎

65.67 (13.67)
14.89 (2.91)
18.67 (6.37)
32.11 (6.90)
16.00 (4.54)

64.93 (11.04)
15.26 (3.63)
17.48 (4.38)
32.19 (5.52)
15.59 (3.75)−0.74 (10.10)
0.37 (2.27)−1.19 (4.36)
0.07 (5.47)−0.41 (4.23)

Note. ⁎⁎p b 0.01.

Change−0.65 (2.54)

Session A

Session B

Change18

L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

Table 5The effects of menstrual cycle change, ﬂuctuating and non-ﬂuctuating hormones in female patients on the Positive and Negative Syndrome Scale ratings (PANSS).
ScalesTotal score

Positive

Negative

GeneralProsocial factorβ̂ (SE)β̂ (SE)β̂ (SE)β̂ (SE)β̂ (SE)−5.67 (2.09)⁎
6.02 (2.75)⁎−7.28 (2.11)⁎⁎−3.27 (0.92)⁎⁎−3.02 (0.84)⁎⁎
3.78 (1.14)⁎⁎−2.76 (0.86)⁎⁎−0.64 (0.20)⁎⁎–––−0.45 (0.39)−2.78 (1.23)–−3.61 (1.26)⁎−2.17 (0.62)⁎⁎––−2.92 (1.09)−1.00 (0.53)

Fluctuating hormones (hormone change predicts symptom change)
Estradiol− 0.0002 (0.02)
Progesterone− 0.06 (0.20)− 0.002 (0.004)− 0.04 (0.05)––

0.004 (0.01)− 0.10 (0.13)––

Non-ﬂuctuating hormones (average levels predicts average symptoms)
Oxytocin− 0.03 (0.005)⁎⁎⁎
Free testosterone− 0.15 (0.08)− 0.01 (0.002)⁎⁎− 0.05 (0.03)− 0.01 (0.004)T− 0.03 (0.05)− 0.01 (0.003)⁎⁎− 0.05 (0.05)− 0.01 (0.003)⁎− 0.04 (0.04)

Predictors
Covariatesa
SSRI
Second generation antipsychotic
SCID diagnosis of schizophrenia
Change (Δ) from follicular to midluteal

Note. ⁎⁎⁎p b 0.001, ⁎⁎p b 0.01, ⁎p b 0.05, Tp N 0.05 and p b 0.10. aOnly signiﬁcant covariates (p b 0.05) were included in the models. For symptom Δ, a negative sign
preceding a coefﬁcient refers to symptom improvement. For hormone levels, a negative sign preceding a coefﬁcient refers to higher levels of a hormone relating tobetter symptom presentation.

study and was not signiﬁcantly related to menstrual cycle inour study, possibly because our study was underpowered todetect a subtle change. Our study did not replicate previous
reports that estrogen levels related to clinical symptoms(Riecher-Rossler et al., 1994; Bergemann et al., 2007). Thisdifference may reﬂect different characteristics of our patient
populations; in earlier studies, patients showed reduced estrogen levels across the entire menstrual cycle and were
either acutely ill or tested following recent hospitalization.
In contrast, our study involved an outpatient female sample
with similar estradiol compared to controls, regular menstrual cycles, stable drug therapy, and comparatively low
and stable psychopathology scores. Thus, our study provides
evidence that menstrual cycle ﬂuctuations in symptoms
are evident not only in acutely ill women with high levelsof symptoms, but also in chronically ill stable women withlower levels of symptoms.
In this study, we also related clinical symptoms to endogenous levels of oxytocin, progesterone, and testosterone.

Progesterone levels in female patients were not signiﬁcantly
associated with changes in clinical symptoms. However, wefound reduced midluteal progesterone levels, as in otherstudies (Bergemann et al., 2005a; Bergemann et al., 2007) andreduced overall progesterone levels in women with schizophrenia, similar to some (Riecher-Rossler et al., 1994; Howeset al., 2007) but not all studies (Huber et al., 2004). Reduced
levels of progesterone may indicate anovulatory cycles andinsufﬁcient follicular maturation (Bergemann et al., 2007) or
could be due to stress or nutritional deﬁciencies (Huber et al.,2004).
Consistent with previous studies, we found indications of
reduced free testosterone levels in men with schizophrenia(Goyal et al., 2004; Huber et al., 2005; Akhondzadeh et al.,2006; Ko et al., 2007; Konarzewska et al., 2009). There are
a number of factors reported to affect testosterone level inboth men with and without schizophrenia including obesity(Zumoff et al., 1990; Jensen et al., 2004) and over half of themale patients in our sample were overweight (56% with BMI

Fig. 1. Fitted subscale scores on the Positive and Negative Syndrome Scale (PANSS) using multilevel random coefﬁcient models as a functions of plasma oxytocinlevels in female patients for three scales: positive subscale (p b 0.001), general psychopathology subscale (p b 0.01), and the prosocial factor (p b 0.05).

L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

scores N 30). Further work is needed to examine the impactof idiopathic or drug-induced obesity factors in hormonepsychopathology relationships in schizophrenia patients.
4.2. Oxytocin and clinical symptoms in men and women withschizophrenia

19

was taken out of the model, a signiﬁcant relationship between
oxytocin levels and positive and overall symptoms was evident in men (p b 0.05). This pattern suggests that the relationship between oxytocin and symptoms in men may beinﬂuenced by estradiol levels.
4.3. Limitations

High oxytocin levels were associated with reduced prosocial
symptoms in both sexes. The relationship between oxytocin
and prosocial behaviors may reﬂect the well-established roleof oxytocin in afﬁliative behaviors (Carter et al., 2008). There
are several neurobiological mechanisms by which oxytocin
might inﬂuence prosocial behaviors in schizophrenia. Oxytocin/glutamate interactions have been documented in two
preclinical studies involving prepulse inhibition (PPI), a widelyused measure of sensorimotor gating. PPI is impaired in schizophrenia and is used to test the efﬁcacy and action of antipsychotic drugs in preclinical models. In one study, oxytocin
treatment in male rats reversed deﬁcits in PPI induced by
dizocilpine, a non-competitive NMDA antagonist. Oxytocin had
smaller beneﬁts following PPI induced by amphetamine, andwas ineffective in reversing apomorphine-induced deﬁcits
in PPI (Feifel and Reza, 1999). In the second study, oxytocin
knock-out mice show disrupted PPI following treatment
with phencyclidine, a non-competitive NMDA antagonist, but
not following treatment with amphetamine or apormorphine(Caldwell et al., 2009). Oxytocin also reversed social deﬁcits inmale rats caused by chronic phencyclidine (Lee et al., 2005).
Oxytocin was also associated with positive, general, andoverall symptoms in female but not male patients. The novelof ﬁnding of oxytocin relating to positive symptoms was inpart due to decreasing suspiciousness/paranoia, hallucinations, and delusions, as indicated by the exploratory item
analysis. Intranasal oxytocin given to healthy individuals
increases trust (Kosfeld et al., 2005; Theodoridou et al., 2009),
and peripheral oxytocin levels are associated with increased
trustworthiness (Zak et al., 2005). The relationship between
oxytocin and lower levels of general symptoms in women wasin part due to decreasing depression and tension. Oxytocin
may have a more global effect on general psychopathology
due to its role in emotional processing, stress management,
afﬁliative behavior, and depression (Scantamburlo et al.,2007; Carter et al., 2008; Heinrichs et al., 2009; Parker et al.,2010).
The relationship between oxytocin and positive symptoms
in particular might be inﬂuenced by dopamine/neuropeptide
interactions (Shahrokh et al.; Rosenfeld et al., 2010). Mesolimbic dopamine projections are thought to be hyperactive,
especially in the acute phase of schizophrenia (Abi-Dargham
and Moore, 2003). Peripheral administration of oxytocin has
been shown to inhibit dopamine transmission in mesolimbic
pathways (Sarnyai and Kovacs, 1994). Animal and clinicalstudies demonstrate that antipsychotic medication increases
both central (Beckmann et al., 1985) and peripheral (UvnasMoberg et al., 1992) oxytocin levels, suggesting that enhancing endogenous oxytocin may play a role in the therapeutic
effects of antipsychotic drugs.
In men, oxytocin levels were not related to most symptom
domains. Our analytic model examined the relationship between oxytocin and symptoms while controlling for theeffects of other hormones, including estrogen. When estrogen

One limitation to our study is that statistical controls for
medication effects (antipsychotic type, SSRIs, mood stabilizers) only partially adjust for the diverse neurochemical
effects of different antipsychotic drugs. Studies suggest that
antipsychotic medications may impact oxytocin (Beckmann
et al., 1985; Uvnas-Moberg et al., 1992), particularly clozapine and olanzapine (20% on these medications in current
study) and less by risperidone and haloperidol (36% on these
medications in current study) (Kiss et al. 2009); (Beckmann
et al., 1985; Uvnas-Moberg et al., 1992). Future studies should
examine untreated acutely ill ﬁrst episode patients where
biology/symptom associations can be examined early in thecourse of illness without confounding inﬂuence of psychiatric
medications. Second, the EIA measurement of oxytocin was
done in unextracted samples, which is associated with higher
levels of this peptide. However, earlier work separating
samples with HPLC prior to assay revealed that this assay
is highly speciﬁc for oxytocin (Carter et al., 2007). Also, inthe present study oxytocin samples showed comparable
values when rerun after dilution; within and between assay
coefﬁcients of variation were less than 11%. Third, we measured oxytocin once at each of two menstrual phases. Although, test–retest reliabilities were high (r = 0.81), oxytocin
secretion may be pulsatile and measurement at multiple time
points during each cycle phase might yield a more ﬁnegrained understanding of oxytocin secretion. However, wewere only able to measure oxytocin at one point at each phaseof the menstrual cycle due to funding limitations. Fourth,neuropeptides do not readily cross the blood–brain barrier.
However, most endogenous oxytocin is synthesized within
the brain, and there is some evidence in animals that central and peripheral oxytocin are correlated (Landgraf and
Neumann, 2004). Peripheral administration of oxytocin as
well as peripheral levels may inﬂuence behavior by bypassing
the brain through circumventricular organs. Furthermore,
peptide effects on mood and behavior may result from effects on peripheral receptors, which are abundant in visceralorgans, including organs innervated by the vagus. Finally,
while the prosocial factor has been used in two additional
studies (Loebel et al., 2004; Docherty et al., 2010) it has notbeen revalidated.
4.4. Conclusions
In summary, the present study examined the effect of
menstrual cycle phase and hormones on clinical symptoms inwomen with schizophrenia. Earlier studies involving acutely
ill patients demonstrated that clinical symptoms ﬂuctuate
across the menstrual cycle (Riecher-Rossler et al., 1994;
Bergemann et al., 2007). Here we show the same pattern ofﬁndings in chronically ill, clinically stable female patients.
Peripheral hormone levels did not account for these cyclerelated changes but peripheral measures are an imperfect20

L.H. Rubin et al. / Schizophrenia Research 124 (2010) 13–21

index of CNS levels, and secondary effects of hormones orother cycle-related factors were not measured. Endogenous
oxytocin levels, which had not been examined in previous
menstrual cycle studies, were signiﬁcantly associated withimprovements in positive symptoms in female patients andprosocial symptoms in male and female patients. This work
supports the general hypothesis that endogenous hormones
can modulate symptoms in chronically-treated men andwomen with schizophrenia. It may be important to consider
sex when evaluating oxytocin in the management ofschizophrenia.
Role of funding source
The funding agencies had no role in the design and conduct of the study
collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Contributors
Drs. Rubin and Maki conceived the idea and methodology for the study.
Dr. Carter developed the methodology to explore oxytocin and served as anadvisor and resource on this project for understanding oxytocin. Dr. Sweeney
served as an advisor on this project and provided his expertise inschizophrenia. Dr. Pournajaﬁ-Nazarloo and Ms. Drogos ran the oxytocin
assays. Dr. Rubin, Dr. Maki's lab, and the Center for Cognitive Medicine wereinvolved in recruitment and clinical assessments. Dr. Rubin conducted thestatistical analyses and wrote the ﬁrst draft. Drs. Rubin, Maki, Carter, andSweeney exchanged multiple versions of the manuscript. All authors
contributed to the writing of the manuscript and approval of the ﬁnal
version.
Conﬂict of interest
Dr. Sweeney is a consultant to Pﬁzer and has a research grant from
Janssen. Dr. Maki received honoraria from the American Nutraceutical
Association and research support from the Soy Health Research Program.
All other authors declare that, except for income received from their primary
employer, no ﬁnancial support or compensation has been received fromany individual or corporate entity over the past 3 years for research or
professional service, and there are no personal ﬁnancial holdings that could
be perceived as constituting a potential conﬂict of interest.
Acknowledgements
This work was supported by Award Number F31MH082480 from the
National Institute of Mental Health. The content is solely the responsibility of
the authors and does not necessarily represent the ofﬁcial views of the
National Center for Research Resources or the National Institutes of Health.
Other support for this work was by a Psi Chi Graduate Research Grant, by the
Alice J. Dan Dissertation Award from the UIC Center for Research on Womenand Gender (CRWG), and by the University of Illinois at Chicago (UIC) Centerfor Clinical and Translational Science (CCTS), Award Number UL1RR029879
from the National Center for Research Resources, and by the Core Lab of
the GCRC/CNRU at the University of Alabama, which is supported by NIH
grants M01-RR-00032, P30-DK56336). Validation of the oxytocin assay was
supported by MH 072935 (CSC). Dr. Sweeney is supported by a Humboldt
Research Award for Senior Research Scientists. We would also like to thankErin Eatough, Antonia Savarese, Jill Breit, Pamela Perschler, Stephanie
Klenotich, Jessica Jandak, and Melissa Arcabos for their assistance with thisstudy. Special thanks goes to Ellen Herbener, Jim Pellegrino, Julie Dumas,
Cherise Rosen, Sheila Dowd, Sandra Wilkniss and the Thresholds PsychiatricRehabilitation Center, and the Center for Cognitive Medicine at the University
of Illinois at Chicago.

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