Journal of Womens Health & Gender-based Medicine, 2001
Treatment of major depression in menopausal women is controversial. Estrogen replacement therapy ... more Treatment of major depression in menopausal women is controversial. Estrogen replacement therapy (ERT) treats mild depression but may not treat more severe depression in this population. Antidepressants are recommended as treatment for major depression in menopausal women, but the specific efficacy of antidepressants has not been examined in menopause-associated depression. Twenty-two perimenopausal and postmenopausal women aged 40-61 taking stable doses of ERT who met Structured Clinical Interview for DSM-IV (SCID-IV) criteria for major depression were accessioned into an open-label clinical trial of mirtazapine. Subjects were treated with 30-45 mg/day mirtazapine for 8 weeks and were assessed every 2 weeks with the Hamilton Depression Rating Scale-17 (HDRS-17), Beck Depression Inventory (BDI), and Clinical Global Impression (CGI) Scale. Remission of depression was defined as an HDRS-17 score < or =7 at the week 8 study visit. Sixteen (73%) of the enrolled subjects completed the 8-week study. The median HDRS-17 score declined from 20.5 (range 12-37) at baseline to 2 (range 0-9) at week 8 (Wilcoxon signed-rank test, p < 0.001). Remission of depression was achieved by 14 of 16 (87.5%) study completers. Subjects responded well to mirtazapine regardless of whether their depression preceded ERT use or developed after ERT was initiated. Therapeutic response also appeared independent of menopausal status (perimenopausal vs. postmenopausal), ERT preparation, and concomitant use of medroxyprogesterone. Mirtazapine is an effective treatment for major depression in perimenopausal and postmenopausal women whose depression precedes ERT use and does not respond to ERT or whose depression develops after ERT is initiated.
Periods of intense hormonal fluctuations have been associated with heightened prevalence and exac... more Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.
Menopause-the Journal of The North American Menopause Society, 2002
To compare the relationship between vasomotor symptoms (hot flushes and night sweats) and depress... more To compare the relationship between vasomotor symptoms (hot flushes and night sweats) and depression in perimenopausal women with that in postmenopausal and older premenopausal women. Questionnaire data assessing current depressive symptoms (Center for Epidemiologic Studies Depression Scale), hot flushes, night sweats, menopausal status, depression history, hormonal therapy use, and demographic characteristics were collected from women aged 40 to 60 years seeking primary care. Multivariable logistic regression models were used to examine the relationship between vasomotor symptoms and depression. Depression (defined by a Center for Epidemiologic Studies Depression Scale score >/= 25) was observed in 14.9% of 141 perimenopausal women, 13.9% of 151 postmenopausal women, and 7.6% of 184 older premenopausal women. Recent vasomotor symptoms were reported by 53.9% of perimenopausal women, 43.7% of postmenopausal women, and 20.7% of older premenopausal women. Perimenopausal women with vasomotor symptoms were 4.39 times more likely to be depressed than those without vasomotor symptoms (95% CI, 1.40-13.83), an association that did not change after controlling for depression history. In contrast with perimenopausal women, postmenopausal and older premenopausal women with vasomotor symptoms did not have a significantly greater risk for depression than women of the same menopausal status without vasomotor symptoms (adjusted odds ratios, 1.28 and 1.77; 95% CI, 0.47-3.46 and 0.53-5.89, respectively). Hot flushes and night sweats are associated with depression in perimenopausal women. Further investigation is warranted to elucidate the mechanism by which hot flushes may be associated with depression in perimenopausal women and not in postmenopausal or older premenopausal women.
Few studies have determined the impact of a lifetime history of major depression on an early tran... more Few studies have determined the impact of a lifetime history of major depression on an early transition to menopause. Reproductive and psychiatric interviews and early follicular-phase blood specimens were obtained at study enrollment and every 6 months during 36 months of follow-up from 332 women with and 644 women without a history of major depression, 36 to 45 years of age. We used menstrual cycle markers to determine inception of perimenopause, defined as time from study enrollment to a follow-up interview with: (1) 7-day or more change in menstrual cycle length; (2) a change in menstrual flow amount or duration; or (3) amenorrhea lasting at least 3 months. Women with a history of depression had 1.2 times the rate of perimenopause of women with no such history (95% confidence interval, 0.9-1.6). Compared with nondepressed women, depressed women with more pronounced depressive symptoms at study enrollment (Hamilton Rating Scale for Depression scores >8) had twice the risk of an earlier perimenopausal transition. Among the women with greater depressive symptoms (Hamilton scores >8), those who also reported use of antidepressants had nearly 3 times the risk of an earlier perimenopausal transition (hazard ratio, 2.7; 95% confidence interval, 1.5-4.8) of nondepressed women. Women with a lifetime history of depression also had higher follicle-stimulating hormone and luteinizing hormone levels and lower estradiol levels at study enrollment and during the follow-up period after adjustment for covariates. A lifetime history of major depression may be associated with an early decline in ovarian function.
Transition to menopause has long been considered a period of increased risk for depressive sympto... more Transition to menopause has long been considered a period of increased risk for depressive symptoms. However, it is unclear whether this period is one of increased risk for major depressive disorder, particularly for women who have not had a previous episode of depression. To examine the association between the menopausal transition and onset of first lifetime episode of depression among women with no history of mood disturbance. Longitudinal, prospective cohort study. A population-based cross-sectional sample. Premenopausal women, 36 to 45 years of age, with no lifetime diagnosis of major depression (N = 460), residing in 7 Boston, Mass, metropolitan area communities. Main Outcome Measure Incidence of new onset of depression based on structured clinical interviews, Center for Epidemiologic Studies Depression Scale scores, and an operational construct for depression. Premenopausal women with no lifetime history of major depression who entered the perimenopause were twice as likely to develop significant depressive symptoms as women who remained premenopausal, after adjustment for age at study enrollment and history of negative life events. The increased risk for depression was somewhat greater in women with self-reported vasomotor symptoms. The current study suggests that within a similarly aged population of women with no lifetime history of depression, those who enter the menopausal transition earlier have a significant risk for first onset of depression. Further studies are needed to determine more definitively whether other factors, such as the presence of vasomotor symptoms, use of hormone therapy, and the occurrence of adverse life events, independently modify this risk. Physical symptoms associated with the menopausal transition and mood changes seen during this period may affect many women as they age and may lead to a significant burden of illness.
Women frequently report depressive and vasomotor symptoms during the menopausal transition. Hormo... more Women frequently report depressive and vasomotor symptoms during the menopausal transition. Hormone therapy has been shown to improve some of these symptoms, although its safety as a long-term treatment has been questioned. It is still unclear whether the use of antidepressants alone may alleviate menopause-related mood and vasomotor symptoms or enhance the response observed with short-term use of estrogen therapy. Perimenopausal and postmenopausal women with depressive disorders (DSM-IV criteria) and menopause-related symptoms received treatment with 20 to 60 mg/day of citalopram alone (N = 22) or adjunctive to estrogen therapy (N = 13). Adjunctive treatment was offered to subjects who had failed to show remission of depression after 4 weeks with estrogen therapy (estradiol [E(2)]) alone. Depressive symptoms, menopause-related symptoms, and global clinical improvement were assessed at baseline and at endpoint of adjunctive treatment (8 weeks) or citalopram monotherapy (12 weeks). Remission of depression was defined as a score of < 10 on the Montgomery-Asberg Depression Rating Scale and a score of < or = 2 on the Clinical Global Impressions scale at endpoint. Data were collected from November 2000 to February 2002. Twelve women (92.3%) concluded the 8-week adjunctive treatment; 11 subjects (91.6%) achieved full remission of depression. Symptoms that had persisted after an initial 4-week treatment with E(2) alone (e.g., tension, anxiousness, tiredness, and difficulty in concentrating) improved significantly (p <.05). Fifteen subjects concluded the treatment with citalopram monotherapy; 13 subjects (86.6%) showed full remission of depression. Anxiety and other somatic complaints had significant improvement (p <.05), while there was a trend toward improvement in vasomotor symptoms in those receiving monotherapy (p =.06). Citalopram alone is an efficacious treatment for perimenopausal and postmenopausal women with depression. Citalopram also appears to be efficacious as an adjunctive treatment for depressed subjects who remain symptomatic after treatment with E(2) (i.e., E(2) nonremitters). The role of citalopram monotherapy for the management of vasomotor symptoms warrants further investigation.
Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms e... more Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women. Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 microgram) or placebo in a 12-week, double-blind, placebo-controlled study. A 4-week washout period followed the 12-week treatment phase. Outcome measures were the Montgomery-Asberg Depression Rating Scale and Blatt-Kupperman Menopausal Index scores. Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder. Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P =.001). Subjects responded similarly to estradiol treatment, regardless of DSM-IV diagnosis. Patients treated with estradiol sustained antidepressant benefit of treatment after the 4-week washout period, although somatic complaints increased in frequency and intensity. Treatment was well tolerated and adverse events were rare in both groups. Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women.
Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and... more Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-l-thyronine.
The primary and three-dimensional structures of a [NiFe] hydrogenase isolated from D. desulfitric... more The primary and three-dimensional structures of a [NiFe] hydrogenase isolated from D. desulfitricans ATCC 27774 were determined, by nucleotide analysis and single-crystal X-ray crystallography. The three-dimensional structural model was refined to R=0.167 and Rfree=0.223 using data to 1.8 A resolution. Two unique structural features are observed: the [4Fe-4S] cluster nearest the [NiFe] centre has been modified [4Fe-3S-3O] by loss of one sulfur atom and inclusion of three oxygen atoms; a three-fold disorder was observed for Cys536 which binds to the nickel atom in the [NiFe] centre. Also, the bridging sulfur atom that caps the active site was found to have partial occupancy, thus corresponding to a partly activated enzyme. These structural features may have biological relevance. In particular, the two less-populated rotamers of Cys536 may be involved in the activation process of the enzyme, as well as in the catalytic cycle. Molecular modelling studies were carried out on the interaction between this [NiFe] hydrogenase and its physiological partner, the tetrahaem cytochrome c3 from the same organism. The lowest energy docking solutions were found to correspond to an interaction between the haem IV region in tetrahaem cytochrome c3 with the distal [4Fe-4S] cluster in [NiFe] hydrogenase. This interaction should correspond to efficient electron transfer and be physiologically relevant, given the proximity of the two redox centres and the fact that electron transfer decay coupling calculations show high coupling values and a short electron transfer pathway. On the other hand, other docking solutions have been found that, despite showing low electron transfer efficiency, may give clues on possible proton transfer mechanisms between the two molecules.
Journal of Womens Health & Gender-based Medicine, 2001
Treatment of major depression in menopausal women is controversial. Estrogen replacement therapy ... more Treatment of major depression in menopausal women is controversial. Estrogen replacement therapy (ERT) treats mild depression but may not treat more severe depression in this population. Antidepressants are recommended as treatment for major depression in menopausal women, but the specific efficacy of antidepressants has not been examined in menopause-associated depression. Twenty-two perimenopausal and postmenopausal women aged 40-61 taking stable doses of ERT who met Structured Clinical Interview for DSM-IV (SCID-IV) criteria for major depression were accessioned into an open-label clinical trial of mirtazapine. Subjects were treated with 30-45 mg/day mirtazapine for 8 weeks and were assessed every 2 weeks with the Hamilton Depression Rating Scale-17 (HDRS-17), Beck Depression Inventory (BDI), and Clinical Global Impression (CGI) Scale. Remission of depression was defined as an HDRS-17 score < or =7 at the week 8 study visit. Sixteen (73%) of the enrolled subjects completed the 8-week study. The median HDRS-17 score declined from 20.5 (range 12-37) at baseline to 2 (range 0-9) at week 8 (Wilcoxon signed-rank test, p < 0.001). Remission of depression was achieved by 14 of 16 (87.5%) study completers. Subjects responded well to mirtazapine regardless of whether their depression preceded ERT use or developed after ERT was initiated. Therapeutic response also appeared independent of menopausal status (perimenopausal vs. postmenopausal), ERT preparation, and concomitant use of medroxyprogesterone. Mirtazapine is an effective treatment for major depression in perimenopausal and postmenopausal women whose depression precedes ERT use and does not respond to ERT or whose depression develops after ERT is initiated.
Periods of intense hormonal fluctuations have been associated with heightened prevalence and exac... more Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.
Menopause-the Journal of The North American Menopause Society, 2002
To compare the relationship between vasomotor symptoms (hot flushes and night sweats) and depress... more To compare the relationship between vasomotor symptoms (hot flushes and night sweats) and depression in perimenopausal women with that in postmenopausal and older premenopausal women. Questionnaire data assessing current depressive symptoms (Center for Epidemiologic Studies Depression Scale), hot flushes, night sweats, menopausal status, depression history, hormonal therapy use, and demographic characteristics were collected from women aged 40 to 60 years seeking primary care. Multivariable logistic regression models were used to examine the relationship between vasomotor symptoms and depression. Depression (defined by a Center for Epidemiologic Studies Depression Scale score >/= 25) was observed in 14.9% of 141 perimenopausal women, 13.9% of 151 postmenopausal women, and 7.6% of 184 older premenopausal women. Recent vasomotor symptoms were reported by 53.9% of perimenopausal women, 43.7% of postmenopausal women, and 20.7% of older premenopausal women. Perimenopausal women with vasomotor symptoms were 4.39 times more likely to be depressed than those without vasomotor symptoms (95% CI, 1.40-13.83), an association that did not change after controlling for depression history. In contrast with perimenopausal women, postmenopausal and older premenopausal women with vasomotor symptoms did not have a significantly greater risk for depression than women of the same menopausal status without vasomotor symptoms (adjusted odds ratios, 1.28 and 1.77; 95% CI, 0.47-3.46 and 0.53-5.89, respectively). Hot flushes and night sweats are associated with depression in perimenopausal women. Further investigation is warranted to elucidate the mechanism by which hot flushes may be associated with depression in perimenopausal women and not in postmenopausal or older premenopausal women.
Few studies have determined the impact of a lifetime history of major depression on an early tran... more Few studies have determined the impact of a lifetime history of major depression on an early transition to menopause. Reproductive and psychiatric interviews and early follicular-phase blood specimens were obtained at study enrollment and every 6 months during 36 months of follow-up from 332 women with and 644 women without a history of major depression, 36 to 45 years of age. We used menstrual cycle markers to determine inception of perimenopause, defined as time from study enrollment to a follow-up interview with: (1) 7-day or more change in menstrual cycle length; (2) a change in menstrual flow amount or duration; or (3) amenorrhea lasting at least 3 months. Women with a history of depression had 1.2 times the rate of perimenopause of women with no such history (95% confidence interval, 0.9-1.6). Compared with nondepressed women, depressed women with more pronounced depressive symptoms at study enrollment (Hamilton Rating Scale for Depression scores >8) had twice the risk of an earlier perimenopausal transition. Among the women with greater depressive symptoms (Hamilton scores >8), those who also reported use of antidepressants had nearly 3 times the risk of an earlier perimenopausal transition (hazard ratio, 2.7; 95% confidence interval, 1.5-4.8) of nondepressed women. Women with a lifetime history of depression also had higher follicle-stimulating hormone and luteinizing hormone levels and lower estradiol levels at study enrollment and during the follow-up period after adjustment for covariates. A lifetime history of major depression may be associated with an early decline in ovarian function.
Transition to menopause has long been considered a period of increased risk for depressive sympto... more Transition to menopause has long been considered a period of increased risk for depressive symptoms. However, it is unclear whether this period is one of increased risk for major depressive disorder, particularly for women who have not had a previous episode of depression. To examine the association between the menopausal transition and onset of first lifetime episode of depression among women with no history of mood disturbance. Longitudinal, prospective cohort study. A population-based cross-sectional sample. Premenopausal women, 36 to 45 years of age, with no lifetime diagnosis of major depression (N = 460), residing in 7 Boston, Mass, metropolitan area communities. Main Outcome Measure Incidence of new onset of depression based on structured clinical interviews, Center for Epidemiologic Studies Depression Scale scores, and an operational construct for depression. Premenopausal women with no lifetime history of major depression who entered the perimenopause were twice as likely to develop significant depressive symptoms as women who remained premenopausal, after adjustment for age at study enrollment and history of negative life events. The increased risk for depression was somewhat greater in women with self-reported vasomotor symptoms. The current study suggests that within a similarly aged population of women with no lifetime history of depression, those who enter the menopausal transition earlier have a significant risk for first onset of depression. Further studies are needed to determine more definitively whether other factors, such as the presence of vasomotor symptoms, use of hormone therapy, and the occurrence of adverse life events, independently modify this risk. Physical symptoms associated with the menopausal transition and mood changes seen during this period may affect many women as they age and may lead to a significant burden of illness.
Women frequently report depressive and vasomotor symptoms during the menopausal transition. Hormo... more Women frequently report depressive and vasomotor symptoms during the menopausal transition. Hormone therapy has been shown to improve some of these symptoms, although its safety as a long-term treatment has been questioned. It is still unclear whether the use of antidepressants alone may alleviate menopause-related mood and vasomotor symptoms or enhance the response observed with short-term use of estrogen therapy. Perimenopausal and postmenopausal women with depressive disorders (DSM-IV criteria) and menopause-related symptoms received treatment with 20 to 60 mg/day of citalopram alone (N = 22) or adjunctive to estrogen therapy (N = 13). Adjunctive treatment was offered to subjects who had failed to show remission of depression after 4 weeks with estrogen therapy (estradiol [E(2)]) alone. Depressive symptoms, menopause-related symptoms, and global clinical improvement were assessed at baseline and at endpoint of adjunctive treatment (8 weeks) or citalopram monotherapy (12 weeks). Remission of depression was defined as a score of < 10 on the Montgomery-Asberg Depression Rating Scale and a score of < or = 2 on the Clinical Global Impressions scale at endpoint. Data were collected from November 2000 to February 2002. Twelve women (92.3%) concluded the 8-week adjunctive treatment; 11 subjects (91.6%) achieved full remission of depression. Symptoms that had persisted after an initial 4-week treatment with E(2) alone (e.g., tension, anxiousness, tiredness, and difficulty in concentrating) improved significantly (p <.05). Fifteen subjects concluded the treatment with citalopram monotherapy; 13 subjects (86.6%) showed full remission of depression. Anxiety and other somatic complaints had significant improvement (p <.05), while there was a trend toward improvement in vasomotor symptoms in those receiving monotherapy (p =.06). Citalopram alone is an efficacious treatment for perimenopausal and postmenopausal women with depression. Citalopram also appears to be efficacious as an adjunctive treatment for depressed subjects who remain symptomatic after treatment with E(2) (i.e., E(2) nonremitters). The role of citalopram monotherapy for the management of vasomotor symptoms warrants further investigation.
Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms e... more Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women. Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 microgram) or placebo in a 12-week, double-blind, placebo-controlled study. A 4-week washout period followed the 12-week treatment phase. Outcome measures were the Montgomery-Asberg Depression Rating Scale and Blatt-Kupperman Menopausal Index scores. Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder. Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P =.001). Subjects responded similarly to estradiol treatment, regardless of DSM-IV diagnosis. Patients treated with estradiol sustained antidepressant benefit of treatment after the 4-week washout period, although somatic complaints increased in frequency and intensity. Treatment was well tolerated and adverse events were rare in both groups. Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women.
Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and... more Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-l-thyronine.
The primary and three-dimensional structures of a [NiFe] hydrogenase isolated from D. desulfitric... more The primary and three-dimensional structures of a [NiFe] hydrogenase isolated from D. desulfitricans ATCC 27774 were determined, by nucleotide analysis and single-crystal X-ray crystallography. The three-dimensional structural model was refined to R=0.167 and Rfree=0.223 using data to 1.8 A resolution. Two unique structural features are observed: the [4Fe-4S] cluster nearest the [NiFe] centre has been modified [4Fe-3S-3O] by loss of one sulfur atom and inclusion of three oxygen atoms; a three-fold disorder was observed for Cys536 which binds to the nickel atom in the [NiFe] centre. Also, the bridging sulfur atom that caps the active site was found to have partial occupancy, thus corresponding to a partly activated enzyme. These structural features may have biological relevance. In particular, the two less-populated rotamers of Cys536 may be involved in the activation process of the enzyme, as well as in the catalytic cycle. Molecular modelling studies were carried out on the interaction between this [NiFe] hydrogenase and its physiological partner, the tetrahaem cytochrome c3 from the same organism. The lowest energy docking solutions were found to correspond to an interaction between the haem IV region in tetrahaem cytochrome c3 with the distal [4Fe-4S] cluster in [NiFe] hydrogenase. This interaction should correspond to efficient electron transfer and be physiologically relevant, given the proximity of the two redox centres and the fact that electron transfer decay coupling calculations show high coupling values and a short electron transfer pathway. On the other hand, other docking solutions have been found that, despite showing low electron transfer efficiency, may give clues on possible proton transfer mechanisms between the two molecules.
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Papers by Claudio Soares