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Gonadal steroids and serotonin: Development and treatment of mood disorders
6S
BIOL PSYCHIATRY 1997;42:15-2975
side effects were greatly reduced. This study confirmed the results of several smaller RCTs and open label studies. Only one RCT of f1uvoxamine has been reported In the literature. Women with premenstrual complaints were randomised to receive either placebo or f1uvoxamine (50-150 ~day) for two consecutive cycles. A beneficial effect was reported in both groups, but the effect of f1uvoxamlne was not statistically different from placebo. A more recent open-label study of fiuvoxamlne In women with PMDD showed significant improvement from baseline, with a starting dose 01 50 ~d Increased to 100 mgld. In an open study, paroxetlne was effective in women diagnosed with PMDD who received placebo for one cycle followed by paroxetine 10 to 30 mgld for 3 cycles. Following this study, paroxeline was compared with maprotiline In e double-blind, RCT. At the end of the trial, symptoms were reduced significantly In women treated with paroxetine compared with placebo. Additionally, paroxetine was significantly superior to maprotiline with respect to certain symptoms. Preliminary results from a multl-centre RCT of sertraline have demonstrated that sertrallne was significantly more effective than placebo In the treatment of women with a confinmed diagnosis of PMDD. An open study of sertraline versus desipramine for 2 cycles has also identified Improvement in the sertraline group. Citalopram, the most selective of the SSRls has recently been shown to be effective in LLPDD, both In continuous and intenmittent dosing. There were no differences In the type of side effects between SSRls, and the most frequently reported side effects attributed to SSRls were: disturt>ed sleep, nausea, headache, fatigue, sexual disturbance, sweating, dry mouth, and sedation. Reported side effects were most often mild and transient, and severe adverse events were nonexistent. The etiology of PMDD is still unclear, however, changes along the central serotanergic cascade continue to be identified as relevant to mood and behavioral disturbances prior to menstruation. Recent RCTs have shown that most of the SSRls, as well as clomipramine, are efficacious In helping women with premenstrual dysphoria. Further studies are required to address the Issues of SSRI non-responders, as well as continuous versus intenmittent treatment and Iong-tenm maintenance. References [1 l Rublnow DR, Schmidt PJ (1995); The Ireatment of premenslrual syndrome-Forward Into IIMI pasl N Eng! J M6I1332: 1574-1575. [21 Steiner t.4, Steinberg S. Stewart D. Carter D. Berger C, Reid R, Grover D, Slrelner o (1995); FIuoxatine In IIMI treatment 01 premenstrual dyIphoria. N EngJ J Med332: 1529-1534. [31 Yonkers KA, Brown WA (1996): Pharmacologic: treatments lor premenaltUa/ dyspho• ric disorder. Psychiatric Annals 26: 586-689.
14-21 treatment Gonadal steroids and serotonin: Development and of mood disorders D.R. Rubinow, P.J. Schmidt, L Zhang, C.A. Roca, T-P. Su, B. Greenberg, D.L. Murphy. Behavioral Endocrinology Branch, Nationallnstitufe of Mental Health, Bethesda MD, USA The sex steroids function as major neuroregulators and presumably undertie many of the gender-related differences (sexual dimorphisms) in brain struc• ture and function. In animals, gonadal steroids modulate neurotransmitter (particularly serotonin) receptor ontogeny, distribution, and actiVity as well as create capacnies for certain behaviors In adunhood. Serotonin (5-HT) agonists, In tum, regulate gonadal steroid modulated behaviors (e.g. sexual activity, aggression). These reciprocallnteraetions Implicate central nervous system (CNS) serotonin systems as potentially Involved in reproductive endocrine-nelated mood disorders. Studies described below identify devel· opmental stage dependent regulatory effects of gonadal steroids on sero• tonin receptor expressJon In animals, differential effects 01 gonadal steroids on mood regulation in women, and the role of serotonin in a reproductive endocrine-related mood disorder, premenstrual syndrome (PMS). Method: 1. 5-HTl. and 5-HT2• receptor message and binding were examined with In situ hybridization and receptor autoradiography In male and female rats (4 weeks old) and following castration (males only). 2. The gonadotropin agonist Lupron was administered to women with PMS (20) and controls (15) for six months, during the last three of which SUbjects also received estrogen and progesterone for four weeks each. 3. Ten women with PMS received the serotonin agonist m-CPP (0.5 mglkg) during both the follicular and luteal phases. and eight women who demonstrated a therapeutic response to the serotonin reuptake Inhibnor f1uoxetine took part in a double blind, placebo controlled administration of the serotonin receptor antagonist metergoline (8 mg, p.o.). Results: 1. Sexual dimorphisms In 5-HTla receptor m-RNA were promi• nent in rat hippocampus and hypothalamus; dimorphisms in 5-HT2. binding
Mood disorders, ovarian steroids and serotonin neuronal function
wene seen in the hippocampus. Castration In male rats Increased 5-HT,. m-RNA In cortex, hippocampus, hypothalamus, and thelamus. with all in• creases blocked by testosterone administration. No effects on serotonin receptors were seen eartler In development (prenatally) when animals were exposed to androgen receptor blockade. 2. Lupron eliminated symptoms of PMS, which recurred following addition of enher estrogen or progesterone. No perturbation of mood was seen In controls undergoing the same Pro• tocol. 3. Both m-CPP and f1uoxetine significantly decreased symptoms of PMS during the luteal phase, while the efficacy of f1uoxetine appears to be reversed 24 hours after acute administration of metergoline. These data suggest that gonadal steroids cneate a context that shapes development and, in tum, produce activational effects that ane context dependent (e.g. present in women with a history of PMS but not In those lacking that history). The data further suggest that CNS serotonin systems (particularly 5-HT2c and 2a receptor SUbsystems) may detenmlne the context that confers vulnerability to the potential mood perturbing effects of gonadal steroids.
14-31 The effect of estrogen and progesterone on gene
expression In serotonin neurons of rhesus macaques
M. Pecins-Thompson, C.L Bethea. Division of Reproductive Sciences and DIvision 01 NeuroscIence Oregon Regional Primate Research Center, Beaverton, Oregon, USA Twice as many women suffer from depression as men. Much has been made of the potential social and psychological etiology of this discrepancy. but there are biological differences between the genders which warrent consideration. Women have a menstrual cycle, bear children, lactate and then undergo menopause at a relatively early age. Each of these reproductive events has an associated emotional vulnerability which is related to the withdraWal of the steroid hormones, estrogen (E) and progesterone (P). Thus, it is Widely hypothesized that E and P act on neural systems involved In the regUlation of mood. One of the most important neural systems for the regulation of mood is the serotonin system. E and P act through nuclear receptors which are transcription factors and we previously demonstrated that serotonin neurons contain nuclear progestin receptors (Bethea, 1994). Therefore, we questioned whether E or P regulate the expression of genes which are pivotal for serotonin neurotransmission. Approach: The levels of mRNA for tryptophan hydroxylase (TPH). lor the serotonin neuptake transporter (SERT) and for the 5HTt a autorecePtor were detenmlned with in situ hybridization (ISH) In the dorsal raphe of steroid treated rhesus macaques. Method: Rhesus monkeys were ovariectomized and hysterectomiZed (Spayed) for ~ months and treated with E and P In a manner that mimics the menstrual cycle. Steroid honmone treatment was achieved by subcu• taneous Implantation of silastic capSUles containing crystalline hormone. Three treatment groups were established (n .. 5 animals/group). The COntrol group received an empty capsule. The E-treated group received an E-filled capsule for 28 days. The E+P-treated group received an E-filled capsule for 28 days and then in addition, a P-filled capsule was Implanted for the last 14 days of the 28 day treatment pertod. The serum level of E obtained Is In the range of 200 pglml and the level of P obtained is between 4 and 8 nglml. After steroid treatment, the animals were eu1hanlzed and the cranium was heavily perfused with 4% parafonmaldehyde. A pontine midbrain block Was dissected, postfixed, Infiltrated with sucrose and sectioned at 10 ILm on a erytostat. The sections for ISH were vacuum dryed ovemight and stored at -70"C until processed. Adjacent sections wene stained for serotonin Using Immunocytochemistry. ISH for TPH, SERT and 5HT1 a receptor mRNAs Was performed with monkey or human cRNA probes. Sections were hybridiZed ovemlght with 3SS-antisense probe. After a final wash In O.lX SSC at SOOc (TPH) or 6O"C (SERT) or 70"C (5HT1a), the sections were exposed to film for 3-14 days. Sections wene matched anatomically and densnometric analysis was performed employing graylevel thresholding for positive piXels and mean optical density (OD-arbitrary units). Results: The signal for TPH mRNA, represented by the number of POsitive pixels, was significantly Increased with E and E+P treatment over spaYed controls (p < 0.05) but there was no difference between E- and E+P-treated groups. The signal for SERT mRNA, also represented by the number 01 positive pixels, was significantly decreased with E and E+P treatment compared to spayed controls (p < 0.05) but thare was no difference between E- and E+P-treated groups. Similar results were obtained with pixel analysis of 5HT1a mRNA. However, the mean CD for 5HT1a mRNA was Slgnificantty decreesed by E treatment and then further decreased with addition of P treatment (p < 0.05). Thus, the 5HTta mRNA level In the E+P-treated Orou was significantly less than In the E-treated group and the 5HT1 a mRNA lev~
BIOL PSYCHIATRY 1997;42:15-2975
side effects were greatly reduced. This study confirmed the results of several smaller RCTs and open label studies. Only one RCT of f1uvoxamine has been reported In the literature. Women with premenstrual complaints were randomised to receive either placebo or f1uvoxamine (50-150 ~day) for two consecutive cycles. A beneficial effect was reported in both groups, but the effect of f1uvoxamlne was not statistically different from placebo. A more recent open-label study of fiuvoxamlne In women with PMDD showed significant improvement from baseline, with a starting dose 01 50 ~d Increased to 100 mgld. In an open study, paroxetlne was effective in women diagnosed with PMDD who received placebo for one cycle followed by paroxetine 10 to 30 mgld for 3 cycles. Following this study, paroxeline was compared with maprotiline In e double-blind, RCT. At the end of the trial, symptoms were reduced significantly In women treated with paroxetine compared with placebo. Additionally, paroxetine was significantly superior to maprotiline with respect to certain symptoms. Preliminary results from a multl-centre RCT of sertraline have demonstrated that sertrallne was significantly more effective than placebo In the treatment of women with a confinmed diagnosis of PMDD. An open study of sertraline versus desipramine for 2 cycles has also identified Improvement in the sertraline group. Citalopram, the most selective of the SSRls has recently been shown to be effective in LLPDD, both In continuous and intenmittent dosing. There were no differences In the type of side effects between SSRls, and the most frequently reported side effects attributed to SSRls were: disturt>ed sleep, nausea, headache, fatigue, sexual disturbance, sweating, dry mouth, and sedation. Reported side effects were most often mild and transient, and severe adverse events were nonexistent. The etiology of PMDD is still unclear, however, changes along the central serotanergic cascade continue to be identified as relevant to mood and behavioral disturbances prior to menstruation. Recent RCTs have shown that most of the SSRls, as well as clomipramine, are efficacious In helping women with premenstrual dysphoria. Further studies are required to address the Issues of SSRI non-responders, as well as continuous versus intenmittent treatment and Iong-tenm maintenance. References [1 l Rublnow DR, Schmidt PJ (1995); The Ireatment of premenslrual syndrome-Forward Into IIMI pasl N Eng! J M6I1332: 1574-1575. [21 Steiner t.4, Steinberg S. Stewart D. Carter D. Berger C, Reid R, Grover D, Slrelner o (1995); FIuoxatine In IIMI treatment 01 premenstrual dyIphoria. N EngJ J Med332: 1529-1534. [31 Yonkers KA, Brown WA (1996): Pharmacologic: treatments lor premenaltUa/ dyspho• ric disorder. Psychiatric Annals 26: 586-689.
14-21 treatment Gonadal steroids and serotonin: Development and of mood disorders D.R. Rubinow, P.J. Schmidt, L Zhang, C.A. Roca, T-P. Su, B. Greenberg, D.L. Murphy. Behavioral Endocrinology Branch, Nationallnstitufe of Mental Health, Bethesda MD, USA The sex steroids function as major neuroregulators and presumably undertie many of the gender-related differences (sexual dimorphisms) in brain struc• ture and function. In animals, gonadal steroids modulate neurotransmitter (particularly serotonin) receptor ontogeny, distribution, and actiVity as well as create capacnies for certain behaviors In adunhood. Serotonin (5-HT) agonists, In tum, regulate gonadal steroid modulated behaviors (e.g. sexual activity, aggression). These reciprocallnteraetions Implicate central nervous system (CNS) serotonin systems as potentially Involved in reproductive endocrine-nelated mood disorders. Studies described below identify devel· opmental stage dependent regulatory effects of gonadal steroids on sero• tonin receptor expressJon In animals, differential effects 01 gonadal steroids on mood regulation in women, and the role of serotonin in a reproductive endocrine-related mood disorder, premenstrual syndrome (PMS). Method: 1. 5-HTl. and 5-HT2• receptor message and binding were examined with In situ hybridization and receptor autoradiography In male and female rats (4 weeks old) and following castration (males only). 2. The gonadotropin agonist Lupron was administered to women with PMS (20) and controls (15) for six months, during the last three of which SUbjects also received estrogen and progesterone for four weeks each. 3. Ten women with PMS received the serotonin agonist m-CPP (0.5 mglkg) during both the follicular and luteal phases. and eight women who demonstrated a therapeutic response to the serotonin reuptake Inhibnor f1uoxetine took part in a double blind, placebo controlled administration of the serotonin receptor antagonist metergoline (8 mg, p.o.). Results: 1. Sexual dimorphisms In 5-HTla receptor m-RNA were promi• nent in rat hippocampus and hypothalamus; dimorphisms in 5-HT2. binding
Mood disorders, ovarian steroids and serotonin neuronal function
wene seen in the hippocampus. Castration In male rats Increased 5-HT,. m-RNA In cortex, hippocampus, hypothalamus, and thelamus. with all in• creases blocked by testosterone administration. No effects on serotonin receptors were seen eartler In development (prenatally) when animals were exposed to androgen receptor blockade. 2. Lupron eliminated symptoms of PMS, which recurred following addition of enher estrogen or progesterone. No perturbation of mood was seen In controls undergoing the same Pro• tocol. 3. Both m-CPP and f1uoxetine significantly decreased symptoms of PMS during the luteal phase, while the efficacy of f1uoxetine appears to be reversed 24 hours after acute administration of metergoline. These data suggest that gonadal steroids cneate a context that shapes development and, in tum, produce activational effects that ane context dependent (e.g. present in women with a history of PMS but not In those lacking that history). The data further suggest that CNS serotonin systems (particularly 5-HT2c and 2a receptor SUbsystems) may detenmlne the context that confers vulnerability to the potential mood perturbing effects of gonadal steroids.
14-31 The effect of estrogen and progesterone on gene
expression In serotonin neurons of rhesus macaques
M. Pecins-Thompson, C.L Bethea. Division of Reproductive Sciences and DIvision 01 NeuroscIence Oregon Regional Primate Research Center, Beaverton, Oregon, USA Twice as many women suffer from depression as men. Much has been made of the potential social and psychological etiology of this discrepancy. but there are biological differences between the genders which warrent consideration. Women have a menstrual cycle, bear children, lactate and then undergo menopause at a relatively early age. Each of these reproductive events has an associated emotional vulnerability which is related to the withdraWal of the steroid hormones, estrogen (E) and progesterone (P). Thus, it is Widely hypothesized that E and P act on neural systems involved In the regUlation of mood. One of the most important neural systems for the regulation of mood is the serotonin system. E and P act through nuclear receptors which are transcription factors and we previously demonstrated that serotonin neurons contain nuclear progestin receptors (Bethea, 1994). Therefore, we questioned whether E or P regulate the expression of genes which are pivotal for serotonin neurotransmission. Approach: The levels of mRNA for tryptophan hydroxylase (TPH). lor the serotonin neuptake transporter (SERT) and for the 5HTt a autorecePtor were detenmlned with in situ hybridization (ISH) In the dorsal raphe of steroid treated rhesus macaques. Method: Rhesus monkeys were ovariectomized and hysterectomiZed (Spayed) for ~ months and treated with E and P In a manner that mimics the menstrual cycle. Steroid honmone treatment was achieved by subcu• taneous Implantation of silastic capSUles containing crystalline hormone. Three treatment groups were established (n .. 5 animals/group). The COntrol group received an empty capsule. The E-treated group received an E-filled capsule for 28 days. The E+P-treated group received an E-filled capsule for 28 days and then in addition, a P-filled capsule was Implanted for the last 14 days of the 28 day treatment pertod. The serum level of E obtained Is In the range of 200 pglml and the level of P obtained is between 4 and 8 nglml. After steroid treatment, the animals were eu1hanlzed and the cranium was heavily perfused with 4% parafonmaldehyde. A pontine midbrain block Was dissected, postfixed, Infiltrated with sucrose and sectioned at 10 ILm on a erytostat. The sections for ISH were vacuum dryed ovemight and stored at -70"C until processed. Adjacent sections wene stained for serotonin Using Immunocytochemistry. ISH for TPH, SERT and 5HT1 a receptor mRNAs Was performed with monkey or human cRNA probes. Sections were hybridiZed ovemlght with 3SS-antisense probe. After a final wash In O.lX SSC at SOOc (TPH) or 6O"C (SERT) or 70"C (5HT1a), the sections were exposed to film for 3-14 days. Sections wene matched anatomically and densnometric analysis was performed employing graylevel thresholding for positive piXels and mean optical density (OD-arbitrary units). Results: The signal for TPH mRNA, represented by the number of POsitive pixels, was significantly Increased with E and E+P treatment over spaYed controls (p < 0.05) but there was no difference between E- and E+P-treated groups. The signal for SERT mRNA, also represented by the number 01 positive pixels, was significantly decreased with E and E+P treatment compared to spayed controls (p < 0.05) but thare was no difference between E- and E+P-treated groups. Similar results were obtained with pixel analysis of 5HT1a mRNA. However, the mean CD for 5HT1a mRNA was Slgnificantty decreesed by E treatment and then further decreased with addition of P treatment (p < 0.05). Thus, the 5HTta mRNA level In the E+P-treated Orou was significantly less than In the E-treated group and the 5HT1 a mRNA lev~