International Journal of Psychiatry in Clinical Practice, 2006; 10(2): 97 104
ORIGINAL ARTICLE
Effect of hormone replacement therapy on cognitive function in women with chronic schizophrenia
YOUNG-HOON KO1, SOOK-HAENG JOE1, WOONG CHO2, JEONG-HYUN PARK2, JUNG-JAE LEE2, IN-KWA JUNG1, LEEN KIM1 & SEUNG-HYUN KIM1 1
Department of Psychiatry, Korea University College of Medicine, Seoul, South Korea, and 2Department of Psychiatry, Bugok National Hospital, Gyeongsangnam-do, South Korea
Abstract Objective. The purpose of this investigation was to assess the cognitive effects of adjuvant hormone replacement therapy (HRT) when used to treat premenopausal women with chronic schizophrenia using an 8-week, double-blind, placebocontrolled, randomized trial. Method. Women of childbearing age with chronic schizophrenia were recruited and randomized into placebo and HRT groups, the latter of which was administered 0.625 mg of conjugated oestrogen with 2.5 mg of medroxyprogesterone acetate daily. Each group contained 14 subjects. The principal outcome measure was a cognitive function assessment comprised of the following; the Immediate Visual Recognition Scale, List Recall Scale, Oral Fluency Test, Trail-Making Tests A and B, and Digit Symbol Test. Psychopathology was measured using the Scale for the Assessment of Negative Symptoms (SANS) and the Calgary Depression Scale for Schizophrenia. Extrapyramidal symptoms were evaluated using the Drug-Induced Extra-Pyramidal Symptoms Scale. Results. Improvements in SANS and in cognitive function as assessed using the List Recall Scale, Oral Fluency Test, and Trail-Making Test A, were significantly greater in the HRT group than in the placebo group. Conclusion. The results of this study suggest that short-term HRT is an effective adjuvant modality for improving cognitive function in women of childbearing age with chronic schizophrenia.
Key Words: Schizophrenia, oestrogen, cognitive function, negative symptoms, women
Introduction Several lines of evidence indicate that oestrogen has multiple effects on brain function, especially cognition. Normal postmenopausal women receiving oestrogen were found to exhibit better verbal memory, proper-name recall, problem solving skills, and psychomotor speed than those who did not [1 3]. In a study involving women with a surgically induced menopause, oestrogen appeared to have a selective effect on verbal declarative memory [4]. Moreover, females with Alzheimer’s disease who were treated by oestrogen replacement showed improvements in general cognitive ability and confrontation naming [5,6]. Oestrogen may exert a neuroprotective effect in schizophrenia, which would partly explain the observed sex differences [7,8]. Gender differences in schizophrenia have been reported for age of onset, premorbid adjustment, illness course, and symptom expression. Female patients exhibit an older age of onset [9,10], better premorbid functioning [9,11],
better treatment response [11,12], and more affective and paranoid symptoms and fewer negative symptoms [13,14]. In addition, female patients were found to experience postmenopausal symptom aggravation and to require higher antipsychotic doses during postmenopause [15,16]. Data supporting the influence of oestrogen in schizophrenia were obtained during clinical studies undertaken to investigate the relationship between oestrogen and cognitive function. Thompson et al. demonstrated that oestrogen has an activational effect on cognition that varies over the menstrual cycle in women with psychosis [17], and a study performed to determine how oestrogen levels are related to neuropsychological function in female schizophrenics showed that higher oestrogen levels are associated with an improved cognitive ability [18]. These studies may have implications for the treatment of cognitive dysfunction using adjuvant oestrogen in female schizophrenics. However, in terms of cognitive function, relatively few trials have investigated the combined use of oestrogen
Correspondence: Dr Sook-Haeng Joe, Department of Psychiatry, Korea University College of Medicine, Guro Hospital, #80 Guro-gu, Guro-dong, Seoul 152703, South Korea. Tel: +82 28186739. Fax: +82 28521937. E-mail:
[email protected];
[email protected]
(Received 22 March 2005; accepted 7 December 2005) ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500500526235
98
Young-Hoon Ko et al.
and antipsychotics for the treatment of schizophrenic patients. In the present study, we investigated whether oestrogen supplementation has a therapeutic effect on cognitive dysfunction and the negative symptoms associated with cognitive function in female schizophrenics. For this purpose, we performed a placebo-controlled, double-blind trial in 35 schizophrenic women on conjugated oestrogen/medroxyprogesterone, added to a fixed dosage of antipsychotics over period of 8 weeks. Methods Thirty-five chronic inpatient women of childbearing age with regular menstrual period (28 35 days), who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [19] criteria for schizophrenia or schizoaffective disorder were recruited at Bugok National Hospital. Psychiatric symptoms had remained stable for at least 2 months prior to study commencement, and only minor positive symptoms were observed. Women were excluded if they had any known endocrine abnormalities, were pregnant or lactating, were taking synthetic steroids (including the oral contraceptive pill), or were using illicit drugs. All patients were randomized to either a HRT group, members of which received active conjugated oestrogen (0.625 mg/day) with medroxyprogesterone acetate (2.5 mg/day), or an identical placebo group. The dosages of antipsychotics (risperidone, clozapine, quetiapine, and aripiprazole) and concomitant psychotropic drugs were constant throughout the 8week trial period. The Bugok National Hospital Ethics Committee approved the study, and all patients gave written informed consent. Each subject was enrolled in the trial for 8 weeks (approximately two menstrual cycles) and received baseline psychopathology and cognitive function tests followed by assessments at 2, 4, 6, and 8 weeks. Times between each of these sessions were tightly controlled, at 12 16 days. At each assessment, psychopathology was measured using the Scale for the Assessment of Negative Symptoms (SANS) [20]. Extrapyramidal symptoms and depressive mood, which may affect cognitive function, were measured using the Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) [21] and the Calgary Depression Scale for Schizophrenia (CDSS) [22], respectively. At baseline, and at 4 and 8 weeks hormone assays were performed for serum oestradiol, progesterone, prolactin, luteinizing hormone, and follicle-stimulating hormone. The follicular phase in menstrual cycles was defined as baseline. Menstrual phase was verified by hormone assay results according to reference ranges supplied by the laboratory, and by subjective self-reporting of the date of commencement of the previous menses. The follicular phase referred to days 114 of the
menstrual cycle and was designated when hormone values were as follows: prolactin, 2.8 29.2 ng/ml; luteinizing hormone, 1.9 12.5 mIU/ml; folliclestimulating hormone, 2.5 10.2 mIU/ml; oestradiol, 18.9 246.7 pg/ml; and progesterone, 0.15 1.40 ng/ ml. Separate chemiluminescence immunoassays (Bayer, USA) were performed on each individual sample for all hormonal assays. The following battery of cognitive tests was performed in the late morning (between 10:00 and 12:00 h): the Memory Assessment Scale subtest, the Immediate Visual Recognition Scale [23] for visual memory; the Memory Assessment Scale subtest, the List Recall Scale with List Acquisition Scale [23] for verbal memory; Oral Fluency Test [24] for verbal fluency and executive function; the Trail-Making Test A [25] for psychomotor speed/visual scanning; the Trail-Making Test B [25] for visuomotor speed and executive function; the Wechsler Adult Intelligence Scale Revised subtest, the Digit Symbol Test [26] for executive function. These tests were selected based on cognitive domains in previous studies on the effects of oestradiol on cognitive function. All statistical analyses were performed using SPSS 10 (SPSS, Chicago). The Student’s t -test was used to compare baseline demographic variables between the HRT and placebo groups. Results of the cognitive performance tests were analysed using general linear model analyses of covariance with repeated measures at all measurement points up to 8 weeks. Design effects were medication group and time (and their interaction), with baseline score and investigator as covariates. Additionally, univariate repeatedmeasures analyses of variance (ANOVAs) were performed for each measure if a group difference was found. Post hoc analysis using Bonferroni t -tests were performed on each measure (at each week) if the time effect was significant. The two groups were compared with respect to changes in serum hormonal levels and in DIEPSS and CDSS scores from baseline each week using the Student’s t -test. Exploratory Pearson’s correlations were used to investigate relationships during the 8-week trial between the cognitive test scores and the SANS total score. Significance was set at P B/0.05. Results Of the 35 patients recruited, 28 completed the 8week trial. Two patients left the medical centre against medical advice, the dosage of antipsychotic could not be fixed in another two patients due to aggravation of psychotic symptoms, and a further three patients complaining of difficulties concerning the cognitive tests and withdrew from the study. The remaining 28 patients constituted the study group, 14 patients were randomly assigned to the placebo group and 14 to the HRT group. The following parameters did not differ significantly between the
Effect of HRT on cognitive function
99
Table I. Baseline characteristics of schizophrenic patients randomly assigned to 8 weeks of double-blind treatment with either placebo or estrogen. Variable Age (years) Education duration (years) Number of admissions Length of illness (months) Menstrual period (days) Daily dose of antipsychotic (mg, chlorpromazine equivalent) Length of maintenance treatment with current antipsychotics (months)
Placebo (N /14)
Estrogen (N /14)
Pa
35.99/7.6 12.09/3.0 6.09/3.2 143.19/58.1 29.39/1.8 280.09/101.2 2.89/1.6
33.49/5.0 12.09/2.4 7.59/4.4 132.19/62.2 30.79/2.7 496.19/635.9 2.89/1.0
0.326 0.951 0.315 0.650 0.166 0.302 0.949
Values represent mean9/SD, aanalyzed using Student’s t -test
with the placebo group (df /1, F /5.79, P B/0.001). Additionally, a one-way repeated-measures ANOVA showed that HRT significantly affected the Oral Fluency Test score ( df /4, F /27.02, P B/0.001), and post hoc analyses revealed that difference from baseline reached significance in the HRT group from week 6. Mean Trail-Making Test A scores differed significantly in the two groups (df /1, F /5.23, P / 0.033). Additionally, one-way repeated-measures ANOVA showed that oestrogen treatment significantly affected the Trail-Making Test A score (f /4, F /7.36, P /0.006), and post hoc analyses revealed that difference from baseline reached significance in the HRT group from week 2. No significant differences were observed between the two groups with respect to the other cognitive function tests (Immediate Visual Recognition Scale, Trail-Making Test B, and Digit Symbol Test). Exploratory correlation analyses failed to identify a significant correlation between the mean 8-week change in the SANS total score and the individual cognitive function test scores (data not shown).
two groups: basic demographic data, including age and education and mean length of illness and menstrual period, dosage of current antipsychotics, and the length of maintenance treatment with current antipsychotics (Table I). The changes in DIEPSS and CDSS scores from baseline in the two groups are listed in Table II, and these did not differ significantly between the two groups at any time point. Changes in serum hormone levels from baseline for the two groups are listed in Table III. Only serum oestradiol and prolactin levels changed significantly from baseline in the HRT group (at 8 weeks). Figure 1 shows mean SANS total scores over the 8-week trial period. The mean SANS total score in the HRT group decreased significantly over time versus the placebo group (df /1, F /6.19, P / 0.022). Additionally, one-way repeated-measures ANOVA showed that HRT significantly affected the SANS total score (df /4, F /5.51, P /0.016). Post hoc analyses revealed that difference versus baseline achieved significance in the HRT group from week 4. Figure 1 also shows mean cognitive function test scores. The mean List Recall Scale score in the HRT group increased significantly over time versus the placebo group (df /1, F /5.79, P B/ 0.001). Additionally, one-way repeated-measures ANOVA showed that oestrogen treatment significantly affected the List Recall Scale score (df /4, F /26.61, P B/0.001). Post hoc analyses revealed that List Recall Scale score difference from baseline reached significance in the HRT group from week 4. The mean Oral Fluency Test score of the HRT group increased significantly over time compared
Discussion The present study shows that conjugated oestrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) provided a better outcome in several cognitive function tests (List Recall Scale, Oral Fluency Test, and the Trail-Making Test A) than placebo treatment. Recent clinical trials have demonstrated that oestrogen supplementation enhances verbal cognition and psychomotor ability [16]. Thus, our findings that short-term HRT
Table II. Changes in Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) and Calgary Depression Scale for Schizophrenia (CDSS) scores from baseline (week 0). DIEPSS Week 2 4 6 8
CDSS a
Placebo (N /14)
Estrogen (N /14)
P
0.49/2.4 0.09/2.9 0.89/4.2 0.39/3.6
0.89/1.9 1.09/2.4 1.39/4.4 1.19/5.1
0.629 0.381 0.787 0.660
Values represent mean9/SD, aanalyzed using Student’s t -test.
Placebo (N /14)
Estrogen (N /14)
Pa
1.09/2.2 /0.29/2.9 /0.79/3.3 /1.49/3.2
0.09/1.9 /0.49/3.0 /1.09/2.5 /1.29/2.8
0.232 0.839 0.808 0.896
100
Young-Hoon Ko et al.
Table III. Changes in serum reproductive hormone levels from baseline (week 0). Week 4 Hormone
Placebo (N /14)
Prolactin (ng/ml) LH (mIU/ml) FSH (mIU/ml) Estradiol (pg/ml) Progesterone (ng/ml)
6.119/27.31 /1.149/2.51 /0.549/2.66 /5.409/29.67 0.219/0.68
Estrogen (N /14) 17.029/24.54 /1.459/1.55 /2.939/3.43 12.389/33.61 0.629/1.90
Week 8 Pa
Placebo (N /14)
Estrogen (N /14)
Pa
0.326 0.717 0.083 0.200 0.523
12.809/23.01 0.759/5.83 0.169/0.43 6.929/29.44 5.099/13.26
51.149/52.28 0.519/3.92 /2.179/4.51 93.069/125.99 1.359/5.54
0.043 0.905 0.223 0.047 0.367
Values represent mean9/SD. a Analyzed using Student’s t -test. LH, luteinizing hormone; FSH, follicle-stimulating hormone.
enhances cognitive functions such as verbal memory, language ability, and concentration/speed are consistent with previous reports. Our results suggest that short-term HRT is an effective adjuvant modality in terms of enhancing the cognitive performance of women of childbearing age with chronic schizophrenia. Recent studies have shown that the negative symptoms of schizophrenia are associated with performance at various cognitive function tests [27 29]. Additionally, the subjects in the present study were chronic schizophrenia with minimal positive symptoms. Thus, we additionally evaluated the SANS scale for negative symptoms in subjects over the 8-week trial period. An observational study showed that oestrogen treatment can improve negative symptoms in female schizophrenics [30], and a clinical trial similarly found that low-dosage oestrogen may also have a positive effect on these symptoms in this patient group [31]. However, such findings have not always been confirmed. In acutely psychotic female patients, oestrogen treatment failed to achieve an improvement in negative symptoms [32,33]. However, in the present study on chronic schizophrenics, a significant improvement in negative symptoms was observed for those on shortterm HRT. Further studies are required to determine the influences of other factors such as, oestrogen dosage, disease phase, and chronicity on the efficacy of oestrogen replacement for the treatment of the negative symptoms in schizophrenia. As mentioned above, relations between cognitive function and negative symptomatology have been previously reported. However, in the present study, exploratory analyses revealed no relationship between an improvement in negative symptoms and cognitive function despite the fact that both improved during the 8-week trial. Furthermore, the times at which these improvements occurred were temporally inconsistent. These results suggest that improved cognitive performance does not occur secondary to an improvement in negative symptoms, and that HRT would be an effective adjuvant treatment for both negative symptoms and cognitive deficiency in female schizophrenics.
A previous clinical trial on female schizophrenics suggested that high-dosage oestradiol supplementation for antipsychotic treatment leads to recovery from positive symptoms more so than negative symptoms, due to a direct effect on dopamine and serotonin systems or via an indirect prolactinmediated effect [31]. Interestingly, in the present study, negative symptoms and cognitive performance improved in parallel with prolactin and oestradiol increases. These results may have several explanations. Firstly, oestrogen may potentiate the effects of atypical antipsychotics by enhancing their uptake by increasing liver microsomal drug metabolism systems or by affecting drug absorption, which may increase blood prolactin levels [34]. Secondly, oestrogen directly modulates dopaminergic and serotonergic systems via estrogen receptors, which have been found in the cerebral cortex, hypothalamus, pituitary, and limbic system [35]. Moreover, oestrogen attenuates the sensitivity of D2 receptors [36], and reduces the total amount of dopamine D2 receptor cDNA by influencing the splicing of dopamine D2 receptor RNA [37,38]. In the serotonergic system, oestrogen treatment has been reported to increase the density of 5-HT2A receptor in the brain area associated with mood, mental state, cognition, and motor function [35,39]. In addition, the expression and binding of the 5-HT1A receptor were found to be reduced after treatment with 17b-oestradiol [12,40]. Further laboratory studies are needed to elucidate the mechanisms underlying the complex interactions between the oestradiol, dopamine, and serotonin neurotransmitter systems. Stip and Mancini-Marie observed that depression affected cognitive performance in schizophrenia [41], and another study showed that memory performance in schizophrenia may be affected by a lack of motivation, psychomotor retardation, and depression [42]. Additionally, there is evidence that oestrogen is a useful treatment for depression during menopause and at other times [4346]. Therefore, in the present study, CDSS was used to evaluate depression, but we found no significant difference between the two groups in terms of CDSS scores from baseline at any time, even though cognitive performance improved in the HRT group. Seeman
Effect of HRT on cognitive function
101
Figure 1. Scores for each measure in schizophrenic patients randomly assigned to 8 weeks of double-blind treatment with either placebo or estrogen. /A group difference was shown by repeated measures ANCOVA, *P B/0.05, **P B/0.01, post-hoc t -test, compared with baseline.
and Lang hypothesized that high levels of oestrogen during the menstrual cycle may increase the severity of extrapyramidal side effects in women taking antipsychotic medication, due to the additive effects of oestrogen and neuroleptic medication on dopamine transmission [47]. However, a recent study by Thompson et al. found that high levels of oestrogen and progesterone during the luteal phase may attenuate tremor and akathisia in women taking antipsychotics [48]. However, we found no significant difference between the HRT and placebo groups in terms of DIEPSS score changes from
baseline for extrapyramidal side effects, though oestradiol and prolactin levels were significantly elevated at 8 weeks in the HRT group. Most experimental studies on cognitive dysfunction in women have investigated only oestrogen. However, in the general female population, hormone replacement therapy usually includes progesterone as its use prevents endometrial disease [49,50], and it is biologically plausible that progesterone could reverse or oppose the positive effect of oestrogen on cognitive performance [51 53]. In contrast, several other studies have found adding progesterone had no
102
Young-Hoon Ko et al.
detrimental effect on cognitive function in healthy postmenopausal women [2,54,55]. In the present study, it is difficult to quantify how progesterone might influence cognitive processing and psychopathology in female schizophrenics, because a combined HRT regimen was used. Interactions between these two major sex hormones in female schizophrenia will need to be addressed in future studies. The limitations of this study include the small number of patients and the short trial duration. The menstrual phase of each patient was not considered on the subsequent course of the evaluation, which prevents us excluding the possibility of biases resulting from menstrual-cycle phase. Additionally, due to the focus placed on cognitive functions and negative symptomatology, changes in positive symptoms were overlooked during HRT. This study shows that HRT in female schizophrenics produces results that are similar to those observed in peri- and postmenopausal healthy women. However, inconsistent findings have been obtained in this respect for hormone replacement therapy. Data from the Women’s Health Initiative Memory Study (WHIMS) revealed an increased risk of cognitive decline and dementia in women treated with conjugated equine estrogens and medroxyprogesterone acetate [16,56], and recently this was also reported for hysterectomized women treated with conjugated equine estrogens alone [57,58]. However, these findings are not in accord with previous epidemiological studies [59,60]. Moreover, longterm large-scale oestrogen and combined oestrogen progesterone treatment present other health risk issues, such as, the elevated risks of breast cancer, cardiovascular disease, and stroke [10,61,62]. Thus, controlled long-term clinical studies are needed to confirm our findings, which indicate that HRT should be considered a therapeutic option for the treatment of women with chronic schizophrenia.
References [1] Robinson D, Friedman L, Marcus R, Tinklenberg J, Yesavage J. Estrogen replacement therapy and memory in older women. J Am Geriatr Soc 1994;42:919 22. [2] Kampen DL, Sherwin BB. Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 1994;83: 979 83. [3] Schmidt R, Fazekas F, Reinhart B, Kapeller P, Fazekas G, Offenbacher H, et al. Estrogen replacement therapy in older women: A neuropsychological and brain MRI study. J Am Geriatr Soc 1996;44:1307 13. [4] Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992;17:485 95. [5] Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG. Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 1994;51: 896 900. [6] Henderson VW, Watt L, Buckwalter JG. Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology 1996;21:421 30. [7] Riecher-Rossler A, Seeman MV. Oestrogens and schizophrenia Introduction. Arch Women Ment Health 2002;5:91 2. [8] Kolsch H, Rao ML. Neuroprotective effects of estradiol17beta: Implications for psychiatric disorders. Arch Women Ment Health 2002;5:105 10. [9] Goldstein JM, Tsuang MT, Faraone SV. Gender and schizophrenia: implications for understanding the heterogeneity of the illness. Psychiatry Res 1989;28:243 53. [10] Grimes DA, Lobo RA. Perspectives on the Women’s Health Initiative trial of hormone replacement therapy. Obstet Gynecol 2002;100:1344 53. [11] Goldstein JM. Gender differences in the course of schizophrenia. Am J Psychiatry 1988;145:684 9. [12] Pecins-Thompson M, Bethea CL. Ovarian steroid regulation of serotonin-1A autoreceptor messenger RNA expression in the dorsal raphe of rhesus macaques. Neuroscience 1999;89: 267 77. [13] Lindamer LA, Lohr JB, Harris MJ, McAdams LA, Jeste DV. Gender-related clinical differences in older patients with schizophrenia. J Clin Psychiatry 1999;60:61 7. [14] Hafner H, Hambrecht M, Loffler W, Munk-Jorgensen P, Riecher-Rossler A. Is schizophrenia a disorder of all ages? A comparison of first episodes and early course across the lifecycle. Psychol Med 1998;28:351 65. [15] Seeman MV. Current outcome in schizophrenia: women vs men. Acta Psychiatr Scand 1986;73:609 17. [16] Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, et al. Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women’s Health Initiative Memory Study: A randomized controlled trial. J Am Med Assoc 2003;289: 2663 72. [17] Thompson K, Sergejew A, Kulkarni J. Estrogen affects cognition in women with psychosis. Psychiatry Res 2000; 94:201 9. [18] Hoff AL, Kremen WS, Wieneke MH, Lauriello J, Blankfeld HM, Faustman WO, et al. Association of estrogen levels with neuropsychological performance in women with schizophrenia. Am J Psychiatry 2001;158:1134 9. [19] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. [20] Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen Psychiatry 1982;39: 784 8. /
/
/
/
The authors have no conflict of interest with any commercial or other associations in connection with the submitted article.
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
Statement of interest
/
/
/
. Conjugated oestrogen and medroxyprogesterone acetate provided a better outcome in several cognitive tests, namely, the List Recall Scale, the Oral Fluency Test, and Trail-Making Test A versus placebo . Short-term oestrogen supplementation is an effective adjuvant treatment for both cognitive deficiency and negative symptoms in women of childbearing age with chronic schizophrenia.
/
/
/
/
/
/
/
Key points
/
/
/
/
103
Effect of HRT on cognitive function [21] Inada T. Evaluation and diagnosis of drug-induced extrapyramidal symptoms: Commentary on DIEPSS and guide to its usage. Tokyo: Seiwa Shoten Publishers; 1996. [22] Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr Res 1990;3:247 51. [23] Williams JM. Memory Assessment Scale. Professional manual. Odessa, FL: Psychological Assessment Resources; 1991. [24] Benton AL. Differential behavioral effects in frontal lobe disease. Neuropsychologia 1968;6:53 60. [25] Reitan RM, Wolfson D. The Halstead-Reitan neuropsychological test battery. Tucson, AZ: Neuropsychology Press; 1985. [26] Kaplan E, Fein D, Morris R. WAIR-R NI Manual. San Antonio, TX: Psychological Corporation; 1991. [27] Bozikas VP, Kosmidis MH, Kioperlidou K, Karavatos A. Relationship between psychopathology and cognitive functioning in schizophrenia. Compr Psychiatry 2004;45:392 400. [28] Voruganti LN, Heslegrave RJ, Awad AG. Neurocognitive correlates of positive and negative syndromes in schizophrenia. Can J Psychiatry 1997;42:1066 71. [29] Schuepbach D, Keshavan MS, Kmiec JA, Sweeney JA. Negative symptom resolution and improvements in specific cognitive deficits after acute treatment in first-episode schizophrenia. Schizophr Res 2002;53:249 61. [30] Lindamer LA, Buse DC, Lohr JB, Jeste DV. Hormone replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms? Biol Psychiatry 2001;49:47 51. [31] Kulkarni J, Riedel A, de Castella AR, Fitzgerald PB, Rolfe TJ, Taffe J, et al. Estrogen A potential treatment for schizophrenia. Schizophr Res 2001;48:137 44. [32] Akhondzadeh S, Nejatisafa AA, Amini H, Mohammadi MR, Larijani B, Kashani L, et al. Adjunctive estrogen treatment in women with chronic schizophrenia: a double-blind, randomized, and placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:1007 12. [33] Kulkarni J, de Castella A, Smith D, Taffe J, Keks N, Copolov D. A clinical trial of the effects of estrogen in acutely psychotic women. Schizophr Res 1996;20:247 52. [34] Yonkers KA, Kando JC, Cole JO, Blumenthal S. Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication. Am J Psychiatry 1992;149:587 95. [35] Fink G, Sumner BE, McQueen JK, Wilson H, Rosie R. Sex steroid control of mood, mental state and memory. Clin Exp Pharmacol Physiol 1998;25:764 75. [36] Hafner H, Behrens S, De Vry J, Gattaz WF. An animal model for the effects of estradiol on dopamine-mediated behavior: Implications for sex differences in schizophrenia. Psychiatry Res 1991;38:125 34. [37] Guivarc’h D, Vincent JD, Vernier P. Alternative splicing of the D2 dopamine receptor messenger ribonucleic acid is modulated by activated sex steroid receptors in the MMQ prolactin cell line. Endocrinology 1998;139:4213 21. [38] Kukstas LA, Domec C, Bascles L, Bonnet J, Verrier D, Israel JM, et al. Different expression of the two dopaminergic D2 receptors, D2415 and D2444, in two types of lactotroph each characterized by their response to dopamine, and modification of expression by sex steroids. Endocrinology 1991;129:1101 3. [39] Sumner BEH, Fink G. Estradiol-17-beta in its positive feedback mode significantly increases 5-Ht2A receptor density in the frontal, cingulate and piriform cortex of the female rat. J Physiol 1995;483P:52. [40] Raap DK, DonCarlos L, Garcia F, Muma NA, Wolf WA, Battaglia G, et al. Estrogen desensitizes 5-HT(1A) receptors and reduces levels of G(z), G(i1) and G(i3) proteins in the hypothalamus. Neuropharmacology 2000;39:1823 32. /
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
[41] Stip E, Mancini-Marie A. Cognitive function and depression in symptom resolution in schizophrenia patients treated with an atypical antipsychotic. Brain Cogn 2004;55:463 5. [42] Brebion G, Amador X, Smith M, Malaspina D, Sharif Z, Gorman JM. Depression, psychomotor retardation, negative symptoms, and memory in schizophrenia. Neuropsychiatry Neuropsychol Behav Neurol 2000;13:177 83. [43] Epperson CN, Wisner KL, Yamamoto B. Gonadal steroids in the treatment of mood disorders. Psychosom Med 1999; 61:676 97. [44] Klaiber EL, Kobayashi Y, Broverman DM, Hall F. Plasma monoamine oxidase activity in regularly menstruating women and in amenorrheic women receiving cyclic treatment with estrogens and a progestin. J Clin Endocrinol Metab 1971;33:630 8. [45] Sichel DA, Cohen LS, Robertson LM, Ruttenberg A, Rosenbaum JF. Prophylactic estrogen in recurrent postpartum affective disorder. Biol Psychiatry 1995;38:814 8. [46] Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. Transdermal oestrogen for treatment of severe postnatal depression. Lancet 1996;347:930 3. [47] Seeman MV, Lang M. The role of estrogens in schizophrenia gender differences. Schizophr Bull 1990;16:185 94. [48] Thompson KN, Kulkarni J, Sergejew AA. Extrapyramidal symptoms and oestrogen. Acta Psychiatr Scand 2000;101: 130 4. [49] Judd HL. Oestrogen replacement therapy: Physiological considerations and new applications. Baillieres Clin Endocrinol Metab 1987;1:177 206. [50] Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaecol 1977;4:31 47. [51] Paganini-Hill A, Henderson VW. The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women. J Am Geriatr Soc 1996;44:818 22. [52] McEwen BS, Woolley CS. Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol 1994;29: 431 6. [53] McEwen BS, Alves SE, Bulloch K, Weiland NG. Ovarian steroids and the brain: implications for cognition and aging. Neurology 1997;48:S8 15. [54] Drake EB, Henderson VW, Stanczyk FZ, McCleary CA, Brown WS, Smith CA, et al. Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology 2000;54:599 603. [55] Grodstein F, Chen J, Pollen DA, Albert MS, Wilson RS, Folstein MF, et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc 2000;48:746 52. [56] Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women’s Health Initiative Memory Study: A randomized controlled trial. J Am Med Assoc 2003;289:2651 62. [57] Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, et al. Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. J Am Med Assoc 2004;291:2959 68. [58] Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. J Am Med Assoc 2004;291:2947 58. [59] Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: A meta-analysis. Neuroscience 2000;101:485 512. /
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
104
Young-Hoon Ko et al.
[60] LeBlanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and meta-analysis. J Am Med Assoc 2001;285:1489 99. [61] Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419 27. /
/
/
/
[62] Kuller LH. Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women’s Health Initiative. Arterioscler Thromb Vasc Biol 2003;23:11 6. /
/
