sex-specific self-reported mood changes by patients with bipolar disorder

7
Sex-specific self-reported mood changes by patients with bipolar disorder q Natalie Rasgon a,b, * , Michael Bauer b,c , Paul Grof d , Laszlo Gyulai e , Shana Elman b , Tasha Glenn f , Peter C. Whybrow b a Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 2360, Palo Alto, CA 94305-5723, USA b Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and Hospital, University of California Los Angeles (UCLA), Los Angeles, CA, USA c Department of Psychiatry and Psychotherapy, Humboldt-University at Berlin, Charit e University Hospital, Berlin, Germany d Department of Psychiatry, University of Ottawa, Royal Ottawa Hospital, Ottawa, Canada e Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA f ChronoRecord Association Inc., Fullerton, CA, USA Received 4 August 2003; received in revised form 13 May 2004; accepted 17 May 2004 Abstract Introduction: While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes. Methods: Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications, sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80 patients: 3483 days from 35 men and 5179 days from 45 women. Results: The distribution of the time spent in mood categories differed between men and women (p <:001). Men were depressed 17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic 64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged women (55%) reported significant mood changes across the menstrual cycle. Conclusions: The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations in mood more frequently than men. Women also experienced mood changes across the menstrual cycle. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Bipolar disorder; Sex; Menstrual cycle; Mood changes; ChronoRecord software 1. Introduction Some studies suggest that the course of bipolar dis- order may vary by sex. Women may have a higher in- cidence of bipolar II disorder (Tondo and Baldessarini, 1998; Baldassano et al., 2002) and may be more likely to develop a rapid cycling course (Coryell et al., 1992). Compared to men with bipolar disorder, women may suffer more depressed (Angst, 1978; Perugi et al., 1990) and mixed episodes (Taylor and Abrams, 1981; McEl- roy et al., 1995). While depressed, women more often experience atypical features (Benazzi, 1999). Several lines of evidence suggest an endocrine basis for the observed differences in the clinical course of bi- polar disorder between the sexes including (a) the re- peated fluctuations of reproductive hormones during the menstrual cycle, (b) the receipt of oral contraceptives (OC) and hormone replacement therapy which may modulate the menstrual cycle and influence affective q Presented at the American Psychiatric Association Annual Meet- ing, Philadelphia, PA, May 18–23, 2002. * Corresponding author. Tel.: +1-650-724-6689; fax: +1-650-724- 3144. E-mail address: [email protected] (N. Rasgon). 0022-3956/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2004.05.006 Journal of Psychiatric Research 39 (2005) 77–83 J OURNAL OF P SYCHIATRIC RESEARCH www.elsevier.com/locate/jpsychires

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JOURNALOF

PSYCHIATRIC

Journal of Psychiatric Research 39 (2005) 77–83RESEARCH

www.elsevier.com/locate/jpsychires

Sex-specific self-reported mood changes by patients withbipolar disorderq

Natalie Rasgona,b,*, Michael Bauerb,c, Paul Grofd, Laszlo Gyulaie, Shana Elmanb,Tasha Glennf, Peter C. Whybrowb

a Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 2360,

Palo Alto, CA 94305-5723, USAb Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and Hospital, University of California Los Angeles (UCLA),

Los Angeles, CA, USAc Department of Psychiatry and Psychotherapy, Humboldt-University at Berlin, Charit�e University Hospital, Berlin, Germany

d Department of Psychiatry, University of Ottawa, Royal Ottawa Hospital, Ottawa, Canadae Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

f ChronoRecord Association Inc., Fullerton, CA, USA

Received 4 August 2003; received in revised form 13 May 2004; accepted 17 May 2004

Abstract

Introduction: While the prevalence of bipolar disorder I is similar between men and women, the clinical course may differ. This

study investigated if there are differences in the clinical presentation of bipolar disorder between the sexes.

Methods:Mood patterns were documented using ChronoRecord software for self-reporting. Patients entered mood, medications,

sleep, life events and menstrual data daily acquired over the period of three months. 8662 Days of data were received from 80

patients: 3483 days from 35 men and 5179 days from 45 women.

Results: The distribution of the time spent in mood categories differed between men and women (p < :001). Men were depressed

17.0% of the time, euthymic 74.0% of the time and manic 5.6% of the time. Women were depressed 28.3% of the time, euthymic

64.2% of the time and manic 7.5% of the time. Over 80% of all reported symptoms for both sexes were mild. Women exhibited large

mood fluctuations (greater than 10 in either direction on a 100-unit scale) more frequently than men. Most of the reproductive aged

women (55%) reported significant mood changes across the menstrual cycle.

Conclusions: The clinical course of bipolar disorder differed between the sexes. Women reported depression and large fluctuations

in mood more frequently than men. Women also experienced mood changes across the menstrual cycle.

� 2004 Elsevier Ltd. All rights reserved.

Keywords: Bipolar disorder; Sex; Menstrual cycle; Mood changes; ChronoRecord software

1. Introduction

Some studies suggest that the course of bipolar dis-

order may vary by sex. Women may have a higher in-

cidence of bipolar II disorder (Tondo and Baldessarini,

1998; Baldassano et al., 2002) and may be more likely to

develop a rapid cycling course (Coryell et al., 1992).

qPresented at the American Psychiatric Association Annual Meet-

ing, Philadelphia, PA, May 18–23, 2002.* Corresponding author. Tel.: +1-650-724-6689; fax: +1-650-724-

3144.

E-mail address: [email protected] (N. Rasgon).

0022-3956/$ - see front matter � 2004 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jpsychires.2004.05.006

Compared to men with bipolar disorder, women may

suffer more depressed (Angst, 1978; Perugi et al., 1990)and mixed episodes (Taylor and Abrams, 1981; McEl-

roy et al., 1995). While depressed, women more often

experience atypical features (Benazzi, 1999).

Several lines of evidence suggest an endocrine basis

for the observed differences in the clinical course of bi-

polar disorder between the sexes including (a) the re-

peated fluctuations of reproductive hormones during the

menstrual cycle, (b) the receipt of oral contraceptives(OC) and hormone replacement therapy which may

modulate the menstrual cycle and influence affective

78 N. Rasgon et al. / Journal of Psychiatric Research 39 (2005) 77–83

symptoms (Oinonen and Mazmanian, 2002; Zweifel and

O’Brien, 1997) and (c) a lifetime prevalence of thyroid

disease (excluding thyroid cancer) that is 4–10 times

higher in women (Whybrow, 1995). Furthermore, re-

productive endocrine abnormalities may be related tothe development of affective symptoms in women. A

high prevalence of menstrual abnormalities has been

reported, in many cases preceding the diagnosis of bi-

polar disorder (Rasgon et al., 2000, 2003). In addition,

anticonvulsant drugs that are routinely used to treat

bipolar disorder may influence serum levels of repro-

ductive hormones in women with epilepsy (Isojarvi

et al., 1993; Rattya et al., 2001), and to some extent inwomen with bipolar disorder (O’Donovan et al., 2002;

Akdeniz et al., 2003).

Increased understanding of sex specific issues in the

course of bipolar disorder may help to optimize treat-

ment throughout the patient’s lifetime. This study in-

vestigates the relationship between sex and mood

patterns, and the impact of the menstrual cycle on mood

using a prospective, longitudinal, naturalistic design tofollow a sample of individuals with bipolar disorder

receiving standard outpatient care. Daily self-reported

mood ratings were obtained for a 3-month period from

80 patients. The data were grouped by sex and com-

pared for differences in the frequency in mood categories

(depressed, euthymic and hypomanic/manic) and the

frequency of mood changes. Additionally, in women,

changes in mood across the menstrual cycle wereinvestigated.

2. Methods

Data for this study were collected in a multi-center

validation study of the ChronoRecord software re-

ported elsewhere (Bauer et al., 2004). Eighty patientswere consecutively recruited from the mood disorders

clinics at UCLA, the University of Ottawa, and the

University of Pennsylvania. After a complete explana-

tion of the study, all patients signed the written consent

form approved by the Institutional Review Board at

their respective institution.

All patients met the DSM-IV criteria for bipolar

disorder, diagnosed by clinical interview and confirmedwith the MINI International Neuropsychiatric Inter-

view (Sheehan et al., 1998). Other inclusion criteria

were: age 18 years or older, daily access to a personal

computer and the skills to use it, and fluency in English.

Patients with antisocial personality disorder or dementia

were excluded from the study. No other inclusion or

exclusion criteria were used to avoid creating a bias in

the patient sample. After one-half hour of training, thepatients were given ChronoRecord software to install on

their home computers. For a 3-month period, the pa-

tients entered mood, sleep, menstrual data, psychiatric

medications and life events daily, and weight weekly.

Self-reported ChronoRecord scores were compared with

clinician-rated Hamilton Depression Rating Scale

(HAMD) (Hamilton, 1960), and Young Mania Rating

Scale (YMRS) (Young et al., 1978), and paper-basedself-ratings on the Beck Depression Inventory (BDI)

(Beck, 1996) from four visits over the 3-month study

period (Bauer et al., 2004).

2.1. ChronoRecord

ChronoRecord is a computerized version of the

ChronoSheet, an established paper based form for self-reporting (Bauer et al., 1991, 2004). The ChronoRecord

data collection software presents the patient with large,

colorful icons for mood, medication and sleep to facili-

tate data entry. ChronoRecord uses a 100-unit visual

analogue scale between the extremes of mania and de-

pression on which the patient marks mood proportion-

ately. During the patient’s training, personal anchor

points were set by the patient to describe the most de-pressed and most manic moods they ever experienced

during their most extreme episodes. By personalizing the

calibration of the anchor point for mania, the patient’s

most manic mood may be either dysphoric or euphoric.

A mood entry less than 40 was considered depression,

40–60 euthymia, and greater than 60 hypomania/mania.

Within depression, an entry of 20–39 represented mild

symptoms and an entry of 0–19 moderate to severesymptoms. An entry of 61–80 represented mild symp-

toms and 81–100 moderate to severe symptoms of

mania.

2.2. Statistical analysis

Demographic data were used to evaluate sample

bias. Distributions were compared between men andwomen using the Pearson 2-sided asymptotic v2-test.Mean values were compared between the groups using

the independent sample 2-sided t-test. Mean values

were also compared using general linear model (GLM)

fixed factor parameter estimates with and without the

patient specified as a random factor. No covariates

were used in the GLM analyses. The Kolmogorov–

Smirnov (KS) test was used to evaluate if large moodchanges (P10) were normally distributed. To evaluate

whether the menstrual cycle has an impact on mood,

data were analyzed for each woman, for each cycle

using a GLM with individual patient as a random

factor. K-Means cluster analysis using Euclidian dis-

tance was used to evaluate categorical mood groupings.

Mood changes across the menstrual cycle compared the

first seven days and the last seven days of same cycle.The start of the menstrual cycle was defined as day one

of bleeding in all cases. All analyses were evaluated at a

0.05 probability of incorrectly rejecting the hypothesis

N. Rasgon et al. / Journal of Psychiatric Research 39 (2005) 77–83 79

that there is no difference between men and women

(type I error). SPSS Version 11.5 was used to perform

the statistical computations.

3. Results

Overall, 8662 days of data were received from the 80

patients, and grouped by sex into 3483 days of data

from 35 men (40.2% of all data) and 5179 days of data

from 45 women (59.8% of all data). The patient demo-

graphic characteristics are listed in Table 1 and there

were no significant differences in the patient samplebetween men and women. Of the 80 patients, 79 were

receiving medication for bipolar disorder; one patient

received no medication. There was no significant sex

difference in the distribution of any of 17 comorbid

DSM-IV diagnoses found in the 80 patients (p ¼ 0:349).Four of the men (3 BP I; 1 BP II) had an ultra-rapid

cycling form of bipolar disorder. One of these four men

had a cycle periodicity of 24 h that was inconsistent withall other patients in the dataset. This patient was ex-

cluded because his data did not contribute to the anal-

ysis of mood patterns between men and women. There

were no ultra-rapid cyclers who were female although

there were two females with rapid cycling (both BP II).

All further analysis reported uses data from 79 patients.

A comparison of the 79 patients for clinical character-

istics upon entry to the study and compliance with theautomated data collection tool also showed no obvious

bias between the sexes (Table 2). Of the 79 patients, 26

had a change in psychotropic medications during the

study but the sex distribution of these patients by di-

Table 1

Demographic and medication characteristics of all men and women returnin

Women (N ¼ 45)

Agea 37.4� 10.2

BP I:BP IIb 31:14

Number of hospitalizationsa 0.8� 2.6

Receiving government disability N (%)b 13 (28.9%)

Number of medicationsa 4.09� 1.7

Lithium N (%)b 15 (33.3%)

Antipsychotics N (%)b 17 (37.8%)

Divalproexsodium N (%)b 17 (37.8%)

Gabapentin N (%)b 8 (17.8%)

Lamotrigine N (%)b 14 (31.1%)

Carbamazepine N (%)b 4 (8.9%)

Topiramate N (%)b 6 (13.3%)

Benzodiazepines N (%)b 22 (48.9%)

Triiodothyronine (T3) N (%)b 2 (2.5%)

LL-thyroxine N (%)b 10 (22.2%)a t-test with unequal variance assumed.b v2 Analysis.

agnosis was not significantly different (BP I p ¼ 0:059;BP II p ¼ 0:149).

3.1. Cluster analysis

The K-Means cluster analysis of the daily Chrono-

Record mood values using 3 and 5 clusters validated the

ChronoRecord mood category boundaries. The 3 clus-

ters were estimated with centers at 25 (1600 observa-

tions), 48 (5631 observations), and 65 (1220

observations). The 5 clusters were estimated with centers

at 15 (566 observations), 32 (1276 observations), 48

(4973 observations), 59 (1272 observations) and 76 (364observations). The ChronoRecord mood categories

(depressed, euthymic, manic) approximate the mid-

points between each of the clusters in the 3-cluster

analysis. The 5-cluster analysis generated approximately

the same 3 clusters but additionally had a cluster that

was more manic and a cluster more depressed, similar to

analysis of severe symptoms. The cluster analysis shows

a reasonable distribution of ChronoRecord mood rat-ings across all values.

3.2. Frequency in mood categories between sexes

A GLM was used to analyze the individual percent of

days in the mood categories using sex as a fixed factor.

The percent of time depressed was 17.0% for men and

28.3% for women with a coefficient ()10.9) significantlydifferent from zero (p ¼ 0:046). The percent of time

euthymic was 74.0% for men and 64.2% for women with

a coefficient (12.8) significantly different from zero

(p ¼ 0:029). The percent of time manic was 5.6% for

g data (N ¼ 80)

Men (N ¼ 35) P

40.3� 11.5 0.243

26:9 0.706

3.2� 4.6 0.107

10 (28.6%) 0.975

3.34� 1.8 0.072

8 (22.9%) 0.304

14 (40.0%) 0.840

11 (31.4%) 0.555

7 (20%) 0.801

10 (28.6%) 0.806

6 (17.1%) 0.268

2 (5.7%) 0.260

12 (34.3%) 0.190

2 (5.7%) 0.104

5 (14.3%) 0.367

Table 2

Comparison of men and women at start of study (N ¼ 79)

Women (N ¼ 45) Men (N ¼ 34) P

Entry rating on HAMDa 9.51� 7.6 7.38� 6.5 0.186

Entry rating on YMRSa 4.34� 5.9 2.76� 3.5 0.168

Entry mood category if BP I N (%)b 0.471

Depressed 8 (25.8%) 7 (28.0%)

Euthymic 21 (67.7%) 14 (56.0%)

Manic 2 (6.5%) 4 (16.0%)

Entry mood category if BP II N (%)b 0.520

Depressed 7 (50.0%) 3 (33.3%)

Euthymic 6 (42.9%) 4 (44.4%)

Manic 1 (7.1%) 2 (22.2%)

Days of returned dataa 115 99 0.343

Percent days missing mood dataa 4.5 8.2 0.107a t-test with unequal variance assumed.b v2 Analysis.

80 N. Rasgon et al. / Journal of Psychiatric Research 39 (2005) 77–83

men and 7.5% for women with a coefficient ()1.9) thatwas not significantly different from zero (p ¼ 0:379).Both sexes reported predominantly mild symptoms

while depressed (men 83.1%, women 82.9%) or manic

(men 86.7%, women 81.3%).

3.3. Frequency of mood changes between sexes

Change in mood was calculated across all days for a

difference of 1, 2, or 3 days and stratified into nine tiers

from the largest negative to largest positive daily

change. For both men and women, with a lag of 1, 2, or

3 days, the majority of mood changes were small. For a

lag of 1 day, 66.9% of all of mood changes for men were

between )5 and 5, and 86.4% were between )10 and 10.

For women, 66.1% of all changes were between )5 and5, and 83.5% between )10 and 10. These distributions of

mood change for a lag of 1, 2 or 3 days were significantly

different between men and women using the v2 statistic

(lag 1 day, p ¼ 0:005; lag 2 days, p < 0:001; lag 3 days

p < 0:001) (Table 3).

Table 3

Distribution of all mood changes in men (N ¼ 34) and women

(N ¼ 45) for a lag of 1 day (p ¼ 0:005)

Size of mood

change

Number of mood

changes (men) (%)

Number of mood

changes (women) (%)

<)20 67 (2.2%) 145 (2.9%)

P)20 & <)10 147 (4.7%) 266 (5.3%)

P)10 & <)5 242 (7.8%) 423 (8.5%)

P)5 & <0 514 (16.6%) 850 (17%)

¼ 0 1074 (34.7%) 1538 (30.8%)

>0 & 6 5 566 (18.3%) 909 (18.2%)

>5 & 6 10 277 (8.9%) 444 (8.9%)

>10 & 6 20 150 (4.8%) 285 (5.7%)

>20 58 (1.9%) 127 (2.5%)

For each patient, the percent of mood switches with

an absolute value P 10 with a lag of 1, 2 and 3 days

were normally distributed using the KS test (p ¼ 0:487,p ¼ 562, p ¼ 0:454, respectively). A GLM was estimated

using sex as a fixed factor for the proportion of large

mood switches P 10 for a lag of 1–3 days. All estimates

for the parameters were significantly different from zero

by t-test (lag 1: men 16.9%, women 23.4%, p ¼ 0:049; lag2: men 20.1%, women 28.9%, p ¼ 0:023; lag 3: men

22.1%, women 30.2%, p ¼ 0:035).

3.4. Mood changes across the menstrual cycle

Of the 45 women, seven were menopausal and seven

did not report a complete cycle; the remaining 31 women

reported 101 menstrual cycles. The mean length of themenstrual cycle was increased in 12 of 31 women (39%):

nine women had long cycles (29–35 days) and three

women had oligomenorrhea (>35 days). A GLM was

estimated to compare the mean mood in the first seven

days of the menstrual cycle with the mean mood in the

last seven days of the same cycle for each cycle of each

woman. The patient was specified as a random factor.

The majority of the women (17 of 31; 55%) had a sig-nificant mood change during at least one menstrual cy-

cle. Of these 16 women, 8 (50%) reported significant

mood changes in more than one cycle. However, the

significant changes in mean mood did not have a dis-

cernable pattern or consistent direction (Table 4).

Nine of the 31 premenopausal women received OC.

By t-test, the mean mood during the first seven days of

the menstrual cycle of women receiving OC was49.1� 13.2 as compared to 40.9� 13.8 for women not

receiving OC (p < 0:001), and during the last seven days

was 46.9� 13.8 for women receiving OC and 42.2� 13.4

for those not receiving OC (p < 0:001). For these 31

Table 4

Details on the 31 menstrual cycles from 17 women in which a significant mood change occurred

Subject # Age BP type Taking OC Mean cycle length (days) Mean mood days 1–7 Mean mood last 7 days pa

7 33 I N 32.5� 3.8 34.5� 9.5 45� 2.3 0.020

9b 40 I N 28.3� 3.9 23.5� 4.9 33.5� 4.6 0.033

31.0� 3.9 20.1� 2.6 0.020

20.7� 4.3 34.5� 7.2 0.009

13 37 I N 26.2� 1.5 36.14� 12.6 45.6� 5.5 0.035

16b 43 I Y 21.33� 7.5 47.1� 6.9 34.1� 8.8 0.004

44.3� 13.7 35.1� 8.3 0.041

18b 43 I N 39� 19 20.5� 6.2 48.5� 23.6 <0.001

66.0� 18.0 43.6� 11.8 0.001

49.6� 9.5 33.5� 5.5 <0.001

19 34 II Y 27.3� 2.1 40.3� 17.3 53.3� 8.7 0.004

22 45 I N 30.75� 5.3 45.0� 4.9 31.5� 7.1 0.003

23 29 II N 31.5� 0.7 7.0� 6.0 21.6� 20.2 <0.001

26b 39 I N 38.5� 17.6 37.4� 8.7 56.1� 10.7 0.033

61.1� 1.2 52.6� 11.4 0.006

32b 19 I Y 29.6� 6.0 64.3� 4.5 53.6� 18.7 <0.001

56.0� 15.3 63.4� 13.3 0.001

35b 34 II N 27.6� 0.5 18.9� 9.3 40.6� 16.6 <0.001

34.0� 10.6 18.0� 2.0 0.009

35.3� 6.0 59.0� 12.7 <0.001

40b 38 II N 27� 1.4 40.6� 0.5 28.8� 3.5 0.009

30.1� 0.6 60.1� 10.1 <0.001

41 31 I Y 19� 0 35.4� 10.6 48.3� 4.4 0.006

44 44 I N 28.6� 1.2 27.2� 5.5 49.2� 3.2 <0.001

56 42 I N 26.0� 0.7 14.7� 9.1 34.4� 16.4 <0.001

60 35 I N 40.4� 15.9 22. 1� 5.9 37.8� 10.9 <0.001

O67b 38 I Y 29.0� 1.4 48.9� 15.4 31.8� 28.2 <0.001

52.5� 12.2 31.8� 14.3 <0.001a t-test of estimated parameter.b Subjects with significant mood change across more than one cycle.

N. Rasgon et al. / Journal of Psychiatric Research 39 (2005) 77–83 81

women, the distribution of time depressed was 16.7% for

women receiving OC and 27% for women not receiving

OC, which is statistically different using the v2 statistic

(p < 0:001).

4. Discussion

The main results of this study are: (1) women re-

ported depression more frequently than men; (2) women

reported large mood fluctuations more frequently than

men; (3) mood fluctuations in females may be due in

part to the effects of the menstrual cycle. As this was a

naturalistic study of consecutively recruited patients at

mood clinics, all mood states and subtypes of the bi-

polar disorder were included. In this sample of outpa-tients compliant with treatment for bipolar disorder,

both sexes reported being euthymic for the majority of

observation, about 74% of the time for men and about

64% of the time for women. However, despite treatment,

women reported depression more frequently than men

(28.3% vs. 17.0%), consistent with prior findings that

women have more depressive episodes (Perugi et al.,

1990). Patient reports of mild inter-episode symptomsare also consistent with findings from other longitudinal

studies of bipolar disorder (Judd et al., 2002; Benazzi,

2001; Keitner et al., 1996). Large mood changes were

infrequent. For both men and women, about 85% of all

mood changes calculated with a 1, 2, or 3-day lag were

between )10 and 10 on a 100-point scale. However, the

distribution of mood changes was significantly different

between the sexes with women having large mood

changes in both directions more often than men.As in our previous report (Rasgon et al., 2003), the

majority of pre-menopausal females were found to have

significant mood changes across at least one menstrual

cycle. As with our and others prior findings, there was

no pattern or consistent direction to these mood changes

(Leibenluft et al., 1999; Rasgon et al., 2003). Such lack

of pattern may be due to the phenotypic heterogeneity

of bipolar disorder, small sample size, and the poten-tially obscuring effects of medications. A longer con-

trolled study with a larger sample may be required to

detect a pattern. Similarly, as in our previous report, the

women receiving OC reported depression less frequently

than those not on OC. This is consistent with some re-

ports that OC have mood-stabilizing effects in women

with treatment-resistant bipolar disorder (Rasgon et al.,

2003; Chouinard et al., 1987; Hatotani et al., 1983; Priceand Giannini, 1985). Menstrual cycle length was long in

82 N. Rasgon et al. / Journal of Psychiatric Research 39 (2005) 77–83

39% of the women, with 10% displaying oligomenor-

rhea, another finding consistent with previous reports of

menstrual abnormalities in women with bipolar disorder

receiving mood stabilizers (Rasgon et al., 2000, 2003).

Taken together, the high frequency of menstrual ab-normalities in women with bipolar disorder further

supports both the concepts of a trait-related liability for

reproductive dysfunction in women with bipolar disor-

der and of reproductive dysfunction associated with the

medications used to treat bipolar disorder.

This study uses self-reported mood ratings. While the

use of self-reported mood ratings to evaluate bipolar

disorder is widely accepted for depressive mood states(Denicoff et al., 2000), recent studies have shown that

the central feature of mania is increased activation ra-

ther than elevated mood (Cassidy et al., 1998, Akiskal

et al., 2001). Also, scores on both clinician and self-

rating instruments are highly correlated with activation-

related features and not mood (Bauer et al., 1991).

Within this framework, the patient’s anchor point for

mania in ChronoRecord and subsequent self-ratings ofmania reflect activation levels for either euphoric or

dysphoric mood (Bauer et al., 2004).

The limitations of this naturalistic study include the

variation in the patient’s symptoms, severity, phase of

the disorder, medications received, and the lack of

comparison with healthy controls. Also, the analyses in

this study were constrained by the data elements col-

lected with ChronoRecord. A longer data collectionperiod from each patient would be preferable and would

permit episode-based analysis. Sex differences in the re-

sponse to medications taken for bipolar disorder could

be the cause of some the observed mood changes. The

limitations in relation to menstrual cycle analysis also

include the lack of hormonal analysis, and the relatively

few number of cycles per woman included in the anal-

ysis. Further study is required to determine if the sta-tistically significant differences found are clinically

significant.

This study took advantage of the dramatic increase in

computer usage by the general public in the United

States, as compliance with the automated self-reporting

tool was excellent. As of September 2001, two-thirds of

137,000 individuals surveyed used a computer at work

or school while 56% of households had at least onecomputer at home (US Department of Commerce,

2002).

In summary, using ChronoRecord monitoring of

mood among patients treated for bipolar disorder, we

found that women reported depression and large fluc-

tuations in mood more frequently than men. Most

mood changes reported by both men and women were

small. In addition, mood in bipolar women was influ-enced by the menstrual cycle. Since the observed mood

fluctuations occurred despite treatment, these findings

are important both clinically and for further investiga-

tion of the neurobiology of sex-specific differences in

bipolar disorder. Some of the findings noted may be a

direct result of the medications received. Small sample

size, clinical heterogeneity, and short duration of ob-

servation prevent us from making clear recommenda-tions, yet present observations support variable

approaches to management of bipolar disorder between

sexes. Larger, longitudinal controlled studies are neces-

sary to discern the patterns of such differences.

References

Akdeniz F, Taneli F, Novan A, Yuncu Z, Vahip S. Valproate-

associated reproductive and metabolic abnormalities: are epileptic

women at greater risk than bipolar women? Progress in Neuro-

psychopharmacology and Biological Psychiatry 2003;27:115–21.

Akiskal HS, Hantouche EG, Bourgeois ML, Azorin JM, Sechter D,

Allilaire JF, et al. Toward a refined phenomenology of mania:

combining clinician-assessment and self-report in the French

EPIMAN study. Journal of Affective Disorders 2001;67:89–96.

Angst J. The course of affective disorders, II. Topology of bipolar

manic-depressive illness. Archiv fur Psychiatrie und Nervenkran-

kheiten 1978;226:65–7.

Baldassano CF, Kim DR, Joffe H, Marangall LB, Sagduyu K,

Wisniewski, SR, et al. Gender differences in bipolar disorder:

Systematic Treatment Enhancement Program first 500 (STEP-BD).

Program and abstracts of the American Psychiatric Association

155th Annual Meeting, May 18–23, Philadelphia, PA. Symposium

No. NR232; 2002.

Bauer M, Grof P, Gyulai L, Rasgon N, Glenn T, Whybrow PC. Using

technology to improve longitudinal studies: self-reporting in

bipolar disorder. Bipolar Disorders 2004;6:67–74.

Bauer MS, Crits-Christoph P, Ball WA, Dewees E, McAllister T, Alahi

P, et al. Independent assessment of manic and depressive symptoms

by self-rating. Scale characteristics and implications for the study

of mania. Archives of General Psychiatry 1991;48:807–12.

Beck AT. Beck depression inventory. San Antonio: Harcourt Brace &

Company; 1996.

Benazzi F. Prevalence and clinical correlates of residual depressive

symptoms in bipolar II disorder. Psychotherapy and Psychoso-

matics 2001;70:232–8.

Benazzi F. Gender differences in bipolar II and unipolar depressed

outpatients: a 557-case study. Annals of Clinical Psychiatry

1999;11:55–9.

Cassidy F, Murry E, Forest K, Carroll BJ. Signs and symptoms of

mania in pure and mixed episodes. Journal of Affective Disorders

1998;50:187–201.

Chouinard G, Steinberg S, Steiner W. Estrogen-progesterone combi-

nation: another mood stabilizer? (letter). American Journal of

Psychiatry 1987;144:826.

Coryell W, Endicott J, Keller M. Rapidly cycling affective disorder.

Demographics, diagnosis, family history, and course. Archives of

General Psychiatry 1992;49:126–31.

Denicoff KD, Leverich GS, Nolen WA, Rush AJ, McElroy SL, Keck

PE, et al. Validation of the prospective NIMH-Life-Chart Method

(NIMH-LCM-p) for longitudinal assessment of bipolar illness.

Psychological Medicine 2000;30:1391–7.

Hamilton M. A rating scale for depression. Journal of Neurology

Neurosurgery Psychiatry 1960;23:56–62.

Hatotani N, Kitayama I, Inoue K, Nomure J. Psychoendocrine studies

of recurrent psychoses. In: Hatotani N, Nomura J, editors.

Neurobiology of periodic psychoses. Tokyo: Igaku-Shoin; 1983.

p. 77–92.

N. Rasgon et al. / Journal of Psychiatric Research 39 (2005) 77–83 83

Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KTS, Myllyla W.

Polycystic ovaries and hyperandrogenism in women taking dival-

proex sodium for epilepsy. New England Journal of Medicine

1993;329(19):1383–8.

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA,

et al. The long-term natural history of the weekly symptomatic

status of bipolar I disorder. Archives of General Psychiatry

2002;59:530–7.

Keitner GI, Solomon DA, Ryan CE, Miller IW, Mallinger A, Kupfre

DJ, et al. Prodromal and residual symptoms in bipolar I disorder.

Comprehensive Psychiatry 1996;37:267–362.

Leibenluft E, Ashman SB, Feldman-Naim S, Yonkers KA. Lack of

relationship between menstrual cycle phase and mood in a sample

of women with rapid cycling bipolar disorder. Biological Psychiatry

1999;46:577–80.

McElroy SL, Strakowski SM, Keck Jr PE, Trugul KL, West SA,

Lonczak HS. Differences and similarities in mixed and pure mania.

Comprehensive Psychiatry 1995;36:187–94.

O’Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual

abnormalities and polycystic ovary syndrome in women taking

valproate for bipolar mood disorder. Journal of Clinical Psychiatry

2002;63:322–30.

Oinonen KA, Mazmanian D. To what extent do oral contraceptives

influence mood and affect? Journal of Affective Disorders

2002;70:229–40.

Perugi G, Musetti L, Simonini E, Piagentini F, Cassano GB, Akiskal

HS. Gender-mediated clinical features of depressive illness. The

importance of tempermental differences. British Journal of Psychi-

atry 1990;157:835–41.

Price WA, Giannini AJ. Antidepressant effects of estrogen. Journal of

Clinical Psychiatry 1985;46:506.

Rasgon NL, Altshuler LL, Gudeman D, Burt VK, Tanavoli S,

Hendrick V, et al. Medication status and polycystic ovary

syndrome in women with bipolar disorder: a preliminary report.

Journal of Clinical Psychiatry 2000;61:173–8.

Rasgon NL, Bauer M, Glenn T, Elman S, Whybrow PC. Menstrual

cycle related mood changes in women with bipolar disorder.

Bipolar Disorders 2003;5:48–52.

Rattya J, Pakarinen AJ, Knip M, Repo-Outakoski M, Myllyla VV,

Isojarvi JI. Early hormonal changes during valproate or

carbamazepine treatment: a 3-month study. Neurology 2001;57:

440–1.

Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller

E, et al. The Mini-International Neuropsychiatric Interview

(MINI): the development and validation of a structured diagnostic

psychiatric interview for DSM-IV and ICD-10. Journal of Clinical

Psychiatry 1998;59(Suppl. 20):22–33.

Taylor MA, Abrams R. Gender differences in bipolar

affective disorder. Journal of Affective Disorders 1981;3:

261–71.

Tondo R, Baldessarini RJ. Rapid cycling in women and men with

bipolar manic-depressive disorders. American Journal of Psychia-

try 1998;155:1434–6.

US Department of Commerce, Economics and Statistics Administra-

tion and National Telecommunications and Information Admin-

istration. A nation online: how Americans are expanding their use

of the Internet; February 2002.

Whybrow PC. Sex differences in thyroid axis function: relevance

to affective disorder and its treatment. Depression 1995;3:

33–42.

Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania:

reliability, validity and sensitivity. British Journal of Psychiatry

1978;133:429–35.

Zweifel JE, O’Brien WH. A meta-analysis of the effect of hormone

replacement therapy upon depressed mood. Psychoneuroendocri-

nology 1997;22:189–212.