Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue1.2001:
Hormone Replacement Therapy in Postmenopausal
Women with Schizophrenia: Positive Effect on
Negative Symptoms?
Laurie A. Lindamer, Dawn C. Buse, James B. Lohr, and Dilip V. Jeste
Background: Some studies of premenopausal women
suggest that the severity of psychopathology associated
with schizophrenia may be related to levels of estrogen.
Methods: We examined psychopathology in communitydwelling postmenopausal women with schizophrenia who
had received (n 5 24) versus had never received (n 5 28)
hormone replacement therapy.
Results: Users of hormone replacement therapy and
nonusers did not differ significantly with respect to age,
ethnicity, education, age of onset, duration of schizophrenia, global cognitive functioning, or neuroleptic-induced
movement disorders. The hormone replacement therapy
users received lower average daily doses of antipsychotic
medication; they had similar levels of positive symptoms
but significantly less severe negative symptoms compared
with hormone replacement therapy nonusers, independent
of differences in antipsychotic dosage.
Conclusions: Our results suggest that the use of hormone
replacement therapy in conjunction with antipsychotic
medication in postmenopausal women with schizophrenia
may help reduce negative, but not positive, symptoms.
Biol Psychiatry 2001;49:47–51 © 2001 Society of Biological Psychiatry
Key Words: Psychosis, aging, estrogen, positive and
negative symptoms, antipsychotics
Introduction
S
everal studies of gender differences in psychopathology associated with schizophrenia suggest that women
with schizophrenia tend to have more severe positive
symptoms and less severe negative symptoms than men
(Andia et al 1995; Goldstein and Link 1988; Gur et al
1996; Lindamer et al 1999; Shtasel et al 1992). The data
From the Department of Psychiatry, University of California, San Diego (LAL,
JBL, DVJ), Psychiatry and Psychology Services, VA San Diego Healthcare
System (LAL, JBL, DVJ), and Veterans Medical Research Foundation (LAL,
DCB, JBL, DVJ), San Diego, California.
Address reprint requests to Laurie A. Lindamer, Ph.D., San Diego VAMC 116A,
3350 La Jolla Village Drive, San Diego CA 92161.
Received May 3, 2000; revised July 17, 2000; accepted July 19, 2000.
© 2001 Society of Biological Psychiatry
on gender differences in depressive symptoms are inconsistent (Addington et al 1996; Goldstein and Link 1988).
Several explanations for the gender differences in psychopathology have been proposed, including psychosocial
factors (Seeman 1997), cerebral lateralization (Seeman
1981), and levels of estrogen (Hafner et al 1993; Lindamer
et al 1997; Seeman 1997).
Some of the evidence supporting a role of estrogen
comes from studies of changes in psychopathology during
different phases of the menstrual cycle in premenopausal
women with schizophrenia (Seeman 1996). Researchers
have generally found lower scores on measures of psychosis and general psychopathology (Hallonquist et al 1993;
Riecher-Rossler et al 1994) or better treatment response
(Gattaz et al 1994) during phases of the menstrual cycle
when estrogen levels are higher. No relationship of estradiol levels to measures of depression has been observed in
women with schizophrenia. The relationship with negative
symptoms of schizophrenia has received little attention,
however, except for a report of an inverse association
between estradiol levels and anergia (Riecher-Rossler et al
1994).
An open-label treatment study of 18 premenopausal
women (Kulkarni et al 1995) found a more rapid response
in general psychopathology and positive symptom scores
in women receiving estrogen supplementation of their
antipsychotic medication relative to a group that received
only antipsychotic medication. At the end of the 45 days,
however, no significant differences between the groups on
measures of psychopathology were present. Although
there have been studies of estrogen effects on depression
(Morrison and Tweedy 2000) and tardive dyskinesia
(Glazer and Nasrallah 1988), to our knowledge there have
been no published studies examining the association between use of hormone replacement therapy (HRT) and
psychopathology in postmenopausal women with
schizophrenia.
We investigated the relationship between the use of
HRT and psychopathology in community-dwelling postmenopausal women with schizophrenia in a cross-sectional study. It was hypothesized that compared to non0006-3223/01/$20.00
PII S0006-3223(00)00995-1
48
L.A. Lindamer et al
BIOL PSYCHIATRY
2001;49:47–51
Table 1. Comparisons (Means and SDs) on Demographic and Clinical Variables in
Postmenopausal Women with Schizophrenia Ever Treated versus Never Treated with Hormone
Replacement Therapy
Age (years)
Education (years)
Ethnicity
(% white)
Age of onset of
illness (years)
Duration of illness
(years)
Schizoaffective
disorder (%)
Daily dose of
antipsychotic
(mg CPZE)a
Modified
Simpson–Angus
total scoreb
AIMS total
scoreb
MMSE total
scorec
HRT Exposure
(n 5 24)
No Exposure
(n 5 28)
t value or x2
value
df
p value
60.0 (10.4)
13.0 (2.0)
83.3
56.2 (6.6)
12.0 (2.2)
67.9
21.609
21.603
1.651
50
50
50,1
.114
.115
.199
32.3 (15.3)
29.4 (13.3)
2.691
49
.493
27.8 (13.9)
25.4 (11.8)
2.674
48
.503
31.8
25.0
.948
50,1
.330
114.5
244.8
2.019
42
.050
17.5 (5.0)
17.9 (4.3)
.309
37
.759
4.1 (3.8)
3.7 (2.6)
2.127
41
.899
26.7 (2.7)
26.9 (3.4)
2.913
49
.366
CPZE, chlorpromazine equivalent; AIMS, Abnormal Involuntary Movement Scale; MMSE, Mini-Mental State Examination.
Median, analysis performed on log-transformed values of means.
Square root transformed.
c
Reflected log transformed.
a
b
HRT users, women with schizophrenia who had used HRT
would have lower scores on measures of general psychopathology and positive and negative symptoms but that
both groups would have similar levels of depression.
Methods and Materials
Fifty-seven outpatient women over the age of 45 with the
DSM-IV (American Psychiatric Association 1994) diagnosis of
schizophrenia or schizoaffective disorder were included in our
study. Details of clinical evaluation in our research center have
been described elsewhere (Jeste et al 1995). Briefly, exclusion
criteria were a history of moderate to severe head trauma or other
neurologic disorder, current alcohol or other substance abuse or
dependence meeting DSM-IV criteria (American Psychiatric
Association 1994), and any systemic medical disease that was
judged likely to affect central nervous system functioning. Our
study was approved by the University of California at San Diego
Human Subjects Committee, and all the patients signed a
voluntary written informed consent for research participation.
They were interviewed about their gynecological and reproductive history, which included information regarding menopausal
status and the use of HRT. Five women who were not yet
postmenopausal, as defined by the absence of a menstrual cycle
for at least 6 months, were excluded. Of the remaining 52
women, 28 had never received HRT, and 24 had received HRT
for at least 1 year.
The following rating scales were used: Brief Psychiatric
Rating Scale (BPRS; Overall and Gorham 1988) (including the
total score and depression, hostility, disorganization and negative
symptom subscales), Scales for the Assessment of Positive and
Negative Symptoms (SAPS and SANS, respectively; Andreasen
1981, 1984), Positive and Negative Syndrome Scale (PANSS;
Kay et al 1987) (including the positive, negative, and general
symptoms subscales), Hamilton Depression Rating Scale
(HAM-D; Hamilton 1967), modified Simpson–Angus Scale
(Simpson and Angus 1970), Abnormal Involuntary Movement
Scale (AIMS; National Institute of Mental Health1976), and the
Mini-Mental State Examination (MMSE; Folstein et al 1975).
All clinical assessments were performed by raters who were
blind to the hormonal status of the subjects.
Continuous variables were transformed, when necessary, to
meet the assumptions of normality. Independent t tests were
performed to compare the patient groups on continuous variables, and x2 tests were used to compare the groups on categorical variables. Statistical analysis was performed using SPSS
(Norusis 1993), and all the statistical tests were two-tailed.
Results
Patients who had ever received versus never received HRT
were similar with respect to age, ethnicity, diagnosis,
education, age of onset, duration of illness, severity of
extrapyramidal symptoms and dyskinesia, and global cognitive function (Table 1). Similar proportions (approxi-
HRT in Schizophrenia
BIOL PSYCHIATRY
2001;49:47–51
49
mately 90%) of subjects in each group were on antipsychotics (including atypical agents in about a third of the
patients) and anticholingeric medications (approximately
20%). More women who had received HRT had a history
of hysterectomy (67% vs. 19%, x2 5 9.617, p 5 .002). In
addition, the women who had received HRT were on
lower mean daily doses of antipsychotic medication.
There were no significant differences between the
groups on general measures of psychopathology (BPRS
total score or the PANSS general score), measures of
depression (BPRS depression subscale or HAM-D), or
positive symptoms (BRPS disorganization and hostility
subscales, SAPS total, or PANSS positive subscale; Figure
1). The HRT users had lower scores on measures of
negative symptoms that were significantly different for the
BPRS negative subscale [t(1,49) 5 2.800, p 5 .007] and
PANSS negative syndrome scale [t(1,45) 5 2.104, p 5
.041] and at a trend level for the SANS total [t(1,45) 5
1.886, p 5 .066].
Because the HRT users and nonusers differed on the
mean current daily dose of antipsychotic medication, the
analysis was rerun using an analysis of covariance, with
daily neuroleptic dose (mg chlorpromazine equivalent or
CPZE; Jeste and Wyatt 1982) as a covariate, on the BPRS
negative subscale, the SANS total, and the PANSS negative syndrome scores. The association with the BRPS
negative subscale remained significant (F 5 6.409, p 5
.015), whereas the results on the PANSS (F 5 3.329, p 5
.075) and the SANS (F 5 2.968, p 5 .092) became
nonsignificant trends.
Discussion
No significant differences between women with schizophrenia who had received or had never received HRT were
found on measures of overall psychopathology, positive or
depressive symptoms, extrapyramidal symptoms, or dyskinesia. Use of HRT appeared to be related to the severity
of negative symptoms, however. Women who had never
received HRT had higher scores on negative symptoms
even when controlling for the amount of antipsychotic
medication. The less severe negative symptoms seen in the
HRT users could not be explained by group differences in
the use of atypical antipsychotic medication because
comparable proportions of both groups were taking atypical antipsychotics. Women using HRT required lower
doses of antipsychotic medications. Although data are
sparse, hormonal status may affect pharmacokinetics of
antipsychotic metabolism (Yonkers and Hamilton 1996);
however, covarying for the antipsychotic dose did not
neutralize the significant difference in BPRS negative
symptoms subscale, which has been shown to have valid-
Figure 1. Comparison of scores on psychopathology scales in
postmenopausal women with schizophrenia who had hormone
replacement therapy (HRT) exposure (lighter bars) versus no
exposure (darker bars). p values are derived from two-tailed t
tests. BPRS, Brief Psychiatric Rating Scale; PANSS, Positive
and Negative Syndrome Scale; HAM-D, Hamilton Depression
Rating Scale; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms.
50
L.A. Lindamer et al
BIOL PSYCHIATRY
2001;49:47–51
ity in older outpatients with schizophrenia (McAdams et al
1996).
The finding of less severe negative symptoms in postmenopausal women with schizophrenia who received
HRT is consistent with the results reported by RiecherRossler et al (1994). Estrogen may reduce negative symptoms by several mechanisms, including modulating dopaminergic or other neurotransmitter systems involved in
pathophysiology schizophrenia or providing neuroprotective effects (Seeman 1996, 1997). The association between
postmenopausal HRT use and less severe negative symptoms in women with schizophrenia may have important
clinical implications. The addition of HRT to antipsychotic medication in stable outpatients may have the effect
of improving negative symptoms.
Contrary to our hypotheses, our study found no significant difference between postmenopausal HRT users and
nonusers on positive symptoms. The lack of differences
may be due to the fact that this sample consisted of older
outpatients who were stable on antipsychotic medication
and who had only mild positive symptoms, thereby restricting variability and the ability to detect differences.
Positive symptoms have been shown to decrease with age
possibly because of age-related decreases in dopaminergic
activity, whereas negative symptoms persist (Eyler-Zorrilla et al 2000; Harvey et al 1997; Schultz et al 1997).
This study has several limitations. First, the differences
on the SANS and PANSS negative subscale were significant at the trend level only when neuroleptic dose was
taken into account. The consistency of the finding of lower
scores on the three different negative symptom measures
in HRT users was striking, however. The lack of a
relationship between HRT and global cognition could
reflect our use of a crude measure (i.e., MMSE) that might
lack sensitivity to detect such differences. A recent randomized controlled trial of estrogen replacement therapy
found no effect on cognition in patients with mild to
moderate Alzheimer’s disease (Mulnard et al 2000). The
cross-sectional design is another limitation of this study.
Although we found less severe negative symptoms in HRT
users, it is not possible to conclude that this result is due
to the use of HRT directly. It is possible that the severity
of negative symptoms may affect the interest in or ability
to seek medical care, resulting in women with higher
negative symptoms not receiving HRT. Finally, this was a
sample of convenience, and available information on the
type, dosage, or duration of HRT was limited. Consequently, the sample may be biased.
Double-blind, placebo-controlled studies of estrogen
supplementation in postmenopausal women with schizophrenia are needed for more definitive conclusions to be
drawn about the effects of estrogen on the psychopathology and functioning in these patients.
This work was supported, in part, by National Institute of Mental Health
Grants Nos. MH43693, MH51459, MH45131, MH49671, and
MH01580; by the National Alliance for Research on Schizophrenia and
Depression; and by the Department of Veterans Affairs.
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(1995): Clinical and neuropsychological characteristics of
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Women with Schizophrenia: Positive Effect on
Negative Symptoms?
Laurie A. Lindamer, Dawn C. Buse, James B. Lohr, and Dilip V. Jeste
Background: Some studies of premenopausal women
suggest that the severity of psychopathology associated
with schizophrenia may be related to levels of estrogen.
Methods: We examined psychopathology in communitydwelling postmenopausal women with schizophrenia who
had received (n 5 24) versus had never received (n 5 28)
hormone replacement therapy.
Results: Users of hormone replacement therapy and
nonusers did not differ significantly with respect to age,
ethnicity, education, age of onset, duration of schizophrenia, global cognitive functioning, or neuroleptic-induced
movement disorders. The hormone replacement therapy
users received lower average daily doses of antipsychotic
medication; they had similar levels of positive symptoms
but significantly less severe negative symptoms compared
with hormone replacement therapy nonusers, independent
of differences in antipsychotic dosage.
Conclusions: Our results suggest that the use of hormone
replacement therapy in conjunction with antipsychotic
medication in postmenopausal women with schizophrenia
may help reduce negative, but not positive, symptoms.
Biol Psychiatry 2001;49:47–51 © 2001 Society of Biological Psychiatry
Key Words: Psychosis, aging, estrogen, positive and
negative symptoms, antipsychotics
Introduction
S
everal studies of gender differences in psychopathology associated with schizophrenia suggest that women
with schizophrenia tend to have more severe positive
symptoms and less severe negative symptoms than men
(Andia et al 1995; Goldstein and Link 1988; Gur et al
1996; Lindamer et al 1999; Shtasel et al 1992). The data
From the Department of Psychiatry, University of California, San Diego (LAL,
JBL, DVJ), Psychiatry and Psychology Services, VA San Diego Healthcare
System (LAL, JBL, DVJ), and Veterans Medical Research Foundation (LAL,
DCB, JBL, DVJ), San Diego, California.
Address reprint requests to Laurie A. Lindamer, Ph.D., San Diego VAMC 116A,
3350 La Jolla Village Drive, San Diego CA 92161.
Received May 3, 2000; revised July 17, 2000; accepted July 19, 2000.
© 2001 Society of Biological Psychiatry
on gender differences in depressive symptoms are inconsistent (Addington et al 1996; Goldstein and Link 1988).
Several explanations for the gender differences in psychopathology have been proposed, including psychosocial
factors (Seeman 1997), cerebral lateralization (Seeman
1981), and levels of estrogen (Hafner et al 1993; Lindamer
et al 1997; Seeman 1997).
Some of the evidence supporting a role of estrogen
comes from studies of changes in psychopathology during
different phases of the menstrual cycle in premenopausal
women with schizophrenia (Seeman 1996). Researchers
have generally found lower scores on measures of psychosis and general psychopathology (Hallonquist et al 1993;
Riecher-Rossler et al 1994) or better treatment response
(Gattaz et al 1994) during phases of the menstrual cycle
when estrogen levels are higher. No relationship of estradiol levels to measures of depression has been observed in
women with schizophrenia. The relationship with negative
symptoms of schizophrenia has received little attention,
however, except for a report of an inverse association
between estradiol levels and anergia (Riecher-Rossler et al
1994).
An open-label treatment study of 18 premenopausal
women (Kulkarni et al 1995) found a more rapid response
in general psychopathology and positive symptom scores
in women receiving estrogen supplementation of their
antipsychotic medication relative to a group that received
only antipsychotic medication. At the end of the 45 days,
however, no significant differences between the groups on
measures of psychopathology were present. Although
there have been studies of estrogen effects on depression
(Morrison and Tweedy 2000) and tardive dyskinesia
(Glazer and Nasrallah 1988), to our knowledge there have
been no published studies examining the association between use of hormone replacement therapy (HRT) and
psychopathology in postmenopausal women with
schizophrenia.
We investigated the relationship between the use of
HRT and psychopathology in community-dwelling postmenopausal women with schizophrenia in a cross-sectional study. It was hypothesized that compared to non0006-3223/01/$20.00
PII S0006-3223(00)00995-1
48
L.A. Lindamer et al
BIOL PSYCHIATRY
2001;49:47–51
Table 1. Comparisons (Means and SDs) on Demographic and Clinical Variables in
Postmenopausal Women with Schizophrenia Ever Treated versus Never Treated with Hormone
Replacement Therapy
Age (years)
Education (years)
Ethnicity
(% white)
Age of onset of
illness (years)
Duration of illness
(years)
Schizoaffective
disorder (%)
Daily dose of
antipsychotic
(mg CPZE)a
Modified
Simpson–Angus
total scoreb
AIMS total
scoreb
MMSE total
scorec
HRT Exposure
(n 5 24)
No Exposure
(n 5 28)
t value or x2
value
df
p value
60.0 (10.4)
13.0 (2.0)
83.3
56.2 (6.6)
12.0 (2.2)
67.9
21.609
21.603
1.651
50
50
50,1
.114
.115
.199
32.3 (15.3)
29.4 (13.3)
2.691
49
.493
27.8 (13.9)
25.4 (11.8)
2.674
48
.503
31.8
25.0
.948
50,1
.330
114.5
244.8
2.019
42
.050
17.5 (5.0)
17.9 (4.3)
.309
37
.759
4.1 (3.8)
3.7 (2.6)
2.127
41
.899
26.7 (2.7)
26.9 (3.4)
2.913
49
.366
CPZE, chlorpromazine equivalent; AIMS, Abnormal Involuntary Movement Scale; MMSE, Mini-Mental State Examination.
Median, analysis performed on log-transformed values of means.
Square root transformed.
c
Reflected log transformed.
a
b
HRT users, women with schizophrenia who had used HRT
would have lower scores on measures of general psychopathology and positive and negative symptoms but that
both groups would have similar levels of depression.
Methods and Materials
Fifty-seven outpatient women over the age of 45 with the
DSM-IV (American Psychiatric Association 1994) diagnosis of
schizophrenia or schizoaffective disorder were included in our
study. Details of clinical evaluation in our research center have
been described elsewhere (Jeste et al 1995). Briefly, exclusion
criteria were a history of moderate to severe head trauma or other
neurologic disorder, current alcohol or other substance abuse or
dependence meeting DSM-IV criteria (American Psychiatric
Association 1994), and any systemic medical disease that was
judged likely to affect central nervous system functioning. Our
study was approved by the University of California at San Diego
Human Subjects Committee, and all the patients signed a
voluntary written informed consent for research participation.
They were interviewed about their gynecological and reproductive history, which included information regarding menopausal
status and the use of HRT. Five women who were not yet
postmenopausal, as defined by the absence of a menstrual cycle
for at least 6 months, were excluded. Of the remaining 52
women, 28 had never received HRT, and 24 had received HRT
for at least 1 year.
The following rating scales were used: Brief Psychiatric
Rating Scale (BPRS; Overall and Gorham 1988) (including the
total score and depression, hostility, disorganization and negative
symptom subscales), Scales for the Assessment of Positive and
Negative Symptoms (SAPS and SANS, respectively; Andreasen
1981, 1984), Positive and Negative Syndrome Scale (PANSS;
Kay et al 1987) (including the positive, negative, and general
symptoms subscales), Hamilton Depression Rating Scale
(HAM-D; Hamilton 1967), modified Simpson–Angus Scale
(Simpson and Angus 1970), Abnormal Involuntary Movement
Scale (AIMS; National Institute of Mental Health1976), and the
Mini-Mental State Examination (MMSE; Folstein et al 1975).
All clinical assessments were performed by raters who were
blind to the hormonal status of the subjects.
Continuous variables were transformed, when necessary, to
meet the assumptions of normality. Independent t tests were
performed to compare the patient groups on continuous variables, and x2 tests were used to compare the groups on categorical variables. Statistical analysis was performed using SPSS
(Norusis 1993), and all the statistical tests were two-tailed.
Results
Patients who had ever received versus never received HRT
were similar with respect to age, ethnicity, diagnosis,
education, age of onset, duration of illness, severity of
extrapyramidal symptoms and dyskinesia, and global cognitive function (Table 1). Similar proportions (approxi-
HRT in Schizophrenia
BIOL PSYCHIATRY
2001;49:47–51
49
mately 90%) of subjects in each group were on antipsychotics (including atypical agents in about a third of the
patients) and anticholingeric medications (approximately
20%). More women who had received HRT had a history
of hysterectomy (67% vs. 19%, x2 5 9.617, p 5 .002). In
addition, the women who had received HRT were on
lower mean daily doses of antipsychotic medication.
There were no significant differences between the
groups on general measures of psychopathology (BPRS
total score or the PANSS general score), measures of
depression (BPRS depression subscale or HAM-D), or
positive symptoms (BRPS disorganization and hostility
subscales, SAPS total, or PANSS positive subscale; Figure
1). The HRT users had lower scores on measures of
negative symptoms that were significantly different for the
BPRS negative subscale [t(1,49) 5 2.800, p 5 .007] and
PANSS negative syndrome scale [t(1,45) 5 2.104, p 5
.041] and at a trend level for the SANS total [t(1,45) 5
1.886, p 5 .066].
Because the HRT users and nonusers differed on the
mean current daily dose of antipsychotic medication, the
analysis was rerun using an analysis of covariance, with
daily neuroleptic dose (mg chlorpromazine equivalent or
CPZE; Jeste and Wyatt 1982) as a covariate, on the BPRS
negative subscale, the SANS total, and the PANSS negative syndrome scores. The association with the BRPS
negative subscale remained significant (F 5 6.409, p 5
.015), whereas the results on the PANSS (F 5 3.329, p 5
.075) and the SANS (F 5 2.968, p 5 .092) became
nonsignificant trends.
Discussion
No significant differences between women with schizophrenia who had received or had never received HRT were
found on measures of overall psychopathology, positive or
depressive symptoms, extrapyramidal symptoms, or dyskinesia. Use of HRT appeared to be related to the severity
of negative symptoms, however. Women who had never
received HRT had higher scores on negative symptoms
even when controlling for the amount of antipsychotic
medication. The less severe negative symptoms seen in the
HRT users could not be explained by group differences in
the use of atypical antipsychotic medication because
comparable proportions of both groups were taking atypical antipsychotics. Women using HRT required lower
doses of antipsychotic medications. Although data are
sparse, hormonal status may affect pharmacokinetics of
antipsychotic metabolism (Yonkers and Hamilton 1996);
however, covarying for the antipsychotic dose did not
neutralize the significant difference in BPRS negative
symptoms subscale, which has been shown to have valid-
Figure 1. Comparison of scores on psychopathology scales in
postmenopausal women with schizophrenia who had hormone
replacement therapy (HRT) exposure (lighter bars) versus no
exposure (darker bars). p values are derived from two-tailed t
tests. BPRS, Brief Psychiatric Rating Scale; PANSS, Positive
and Negative Syndrome Scale; HAM-D, Hamilton Depression
Rating Scale; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms.
50
L.A. Lindamer et al
BIOL PSYCHIATRY
2001;49:47–51
ity in older outpatients with schizophrenia (McAdams et al
1996).
The finding of less severe negative symptoms in postmenopausal women with schizophrenia who received
HRT is consistent with the results reported by RiecherRossler et al (1994). Estrogen may reduce negative symptoms by several mechanisms, including modulating dopaminergic or other neurotransmitter systems involved in
pathophysiology schizophrenia or providing neuroprotective effects (Seeman 1996, 1997). The association between
postmenopausal HRT use and less severe negative symptoms in women with schizophrenia may have important
clinical implications. The addition of HRT to antipsychotic medication in stable outpatients may have the effect
of improving negative symptoms.
Contrary to our hypotheses, our study found no significant difference between postmenopausal HRT users and
nonusers on positive symptoms. The lack of differences
may be due to the fact that this sample consisted of older
outpatients who were stable on antipsychotic medication
and who had only mild positive symptoms, thereby restricting variability and the ability to detect differences.
Positive symptoms have been shown to decrease with age
possibly because of age-related decreases in dopaminergic
activity, whereas negative symptoms persist (Eyler-Zorrilla et al 2000; Harvey et al 1997; Schultz et al 1997).
This study has several limitations. First, the differences
on the SANS and PANSS negative subscale were significant at the trend level only when neuroleptic dose was
taken into account. The consistency of the finding of lower
scores on the three different negative symptom measures
in HRT users was striking, however. The lack of a
relationship between HRT and global cognition could
reflect our use of a crude measure (i.e., MMSE) that might
lack sensitivity to detect such differences. A recent randomized controlled trial of estrogen replacement therapy
found no effect on cognition in patients with mild to
moderate Alzheimer’s disease (Mulnard et al 2000). The
cross-sectional design is another limitation of this study.
Although we found less severe negative symptoms in HRT
users, it is not possible to conclude that this result is due
to the use of HRT directly. It is possible that the severity
of negative symptoms may affect the interest in or ability
to seek medical care, resulting in women with higher
negative symptoms not receiving HRT. Finally, this was a
sample of convenience, and available information on the
type, dosage, or duration of HRT was limited. Consequently, the sample may be biased.
Double-blind, placebo-controlled studies of estrogen
supplementation in postmenopausal women with schizophrenia are needed for more definitive conclusions to be
drawn about the effects of estrogen on the psychopathology and functioning in these patients.
This work was supported, in part, by National Institute of Mental Health
Grants Nos. MH43693, MH51459, MH45131, MH49671, and
MH01580; by the National Alliance for Research on Schizophrenia and
Depression; and by the Department of Veterans Affairs.
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