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A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria
Abstract
Antidepressant drugs, including specific serotonin reuptake inhibitors, have been shown to be beneficial in the treatment of premenstrual dysphoric disorders. The present study tests the efficacy of L-tryptophan, which acts specifically on serotonergic neurons, in this disorder.
In a randomized controlled clinical trial, 37 patients with premenstrual dysphoric disorder were treated with L-tryptophan 6 g per day, and 34 were given placebo. The treatments were administered under double-blind conditions for 17 days, from the time of ovulation to the third day of menstruation, during three consecutive menstrual cycles.
The Visual Analogue Scales (VAS) revealed a significant (p = .004) therapeutic effect of L-tryptophan relative to placebo for the cluster of mood symptoms comprising the items of dysphoria, mood swings, tension, and irritability. The magnitude of the reduction from baseline in maximum luteal phase VAS-mood scores was 34.5% with L-tryptophan compared to 10.4% with placebo.
These results suggest that increasing serotonin synthesis during the late luteal phase of the menstrual cycle has a beneficial effect in patients with premenstrual dysphoric disorder.
... These diagnostic criteria were developed as prospective criteria to be met, which demonstrate an unambiguous and clinically relevant worsening of symptoms during late-LP compared to FP, with the VAS scores serving to illustrate prospective day-to-day objective differences in the DSM-IV diagnostic symptoms. The criteria are modeled after, but are more stringent than those used by Steinberg et al. [22] and Steiner et al. [21], which were a 50% worsening in three core symptoms or a 100% worsening of one core symptom. All potential PMDD participants met with a psychiatrist (P.L.) twice, at FP and late-LP, to confirm the diagnosis. ...
... Mean scores were calculated across days 6-10 after menstruation (FP) and across the last 5 days of the menstrual cycle (late-LP) for each of the four core PMDD symptoms individually (depressed mood, tension, affective lability, and irritability). The four core measures were averaged together to yield a mean score representing overall mood symptoms called the VAS-core [21,22]. ...
... Decreases were observed for whole blood serotonin levels [40] and platelet serotonin uptake [41] in PMS compared to controls during the symptomatic phase. Furthermore, the efficacy of selective serotonin reuptake inhibitors (SSRIs) [42], fenfluramine [43], and Ltryptophan [22] in the treatment of PMDD symptoms also supports a central role of serotonin in PMDD. ...
Women with premenstrual dysphoric disorder (PMDD) experience mood deterioration and altered circadian rhythms during the luteal phase (LP) of their menstrual cycles. Disturbed circadian rhythms may be involved in the development of clinical mood states, though this relationship is not fully characterized in PMDD. We therefore conducted an extensive chronobiological characterization of the melatonin rhythm in a small group of PMDD women and female controls. In this pilot study, participants included five women with PMDD and five age-matched controls with no evidence of menstrual-related mood disorders. Participants underwent two 24-hour laboratory visits, during the follicular phase (FP) and LP of the menstrual cycle, consisting of intensive physiological monitoring under "unmasked", time-isolation conditions. Measures included visual analogue scale for mood, ovarian hormones, and 24-hour plasma melatonin. Mood significantly (P≤.03) worsened during LP in PMDD compared to FP and controls. Progesterone was significantly (P = .025) increased during LP compared to FP, with no between-group differences. Compared to controls, PMDD women had significantly (P<.05) decreased melatonin at circadian phases spanning the biological night during both menstrual phases and reduced amplitude of its circadian rhythm during LP. PMDD women also had reduced area under the curve of melatonin during LP compared to FP. PMDD women showed affected circadian melatonin rhythms, with reduced nocturnal secretion and amplitude during the symptomatic phase compared to controls. Despite our small sample size, these pilot findings support a role for disturbed circadian rhythms in affective disorders. Possible associations with disrupted serotonergic transmission are proposed.
... On this basis, we speculated that the decrease in wholeblood serotonin may potentially reflect a decrease in serotonin concentration in the brain and may thereby lead to a decrease in central serotonergic activity, which may account for some of the symptoms of PMS. Subsequently other investigators have demonstrated decreased platelet uptake of serotonin in women with PMS (2) and there are numerous reports that administration of SSRIs and other serotonergic agonists leads to improvement in the symptoms of PMS/PMDD (3,4,22,23). More recently, a relationship between the administration of SSRIs and the concentration of the neurosteroid allopregnanolone in human plasma and cerebrospinal fluid (CSF), and in rat brain sections (13, 24±26) have been reported. ...
... Therefore any mechanism by which central serotonergic activity is increased, as with the administration of L-TP in our study, or after administration of SSRIs ± especially if the baseline central serotonergic activity is low ± is likely to increase allopregnanolone concentrations to a greater degree than when the central serotonergic activity is high. This may potentially explain and, at least in part, account for some of the benefit observed in women with PMS treated with serotonergic agonists such as SSRIs, L-TP, fenfluramine and serotonergic tricyclic antidepressants (3,4,22,23,37,39). ...
To evaluate the circulating concentrations of the neuroactive steroids in response to an i.v. L-tryptophan (L-TP) challenge across the menstrual cycle in women with premenstrual syndrome (PMS) and in controls.
An i.v. L-TP challenge was administered eight times during 1 month to five women with prospectively documented PMS and five age- and body mass-matched controls. Progesterone, allopregnanolone pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone were assessed 15 and 0 min before, and at 30, 60 and 90 min after the challenge, across the menstrual cycle.
In response to L-TP challenge, only allopregnanolone concentrations were significantly increased across the cycle and this increase was of a greater magnitude in women with PMS. Pregnenolone and 3alpha-5alpha-tetrahydrocorticosterone concentrations were not affected in women with PMS or controls after L-TP challenge.
The data provide evidence for possible interaction between the serotonergic system and the neuroactive steroid, allopregnanolone. Women with PMS demonstrated a more significant increase in allopregnanolone concentrations in response to L-TP challenge, which could be due to an initial low basal serotonergic tone in the luteal phase in the PMS group.
... In fact, SSRIs are the current first-line treatment approach for PMS/PMDD, with approximately 60% treatment response (94). Similar observations of a reduction in premenstrual symptoms following modifications to serotonergic functioning after administering compounds that increase the amount of available or released serotonin are observed with metachlorophenylpiperazine (mCPP) (95), d-fenfluramine (96), and the serotonin precursor tryptophan (97). Whereas drugs that counteract or decrease serotonin activity are found to worsen premenstrual symptoms, as reported with dietary tryptophan depletion studies (98) and administration of the serotonin receptor antagonist metergoline in women who achieved remission via SSRI (99). ...
... Two RCTs reported improvements in premenstrual symptoms following the ingestion of a carbohydrate-rich beverage compared to an isocaloric placebo drink (156,157). A different study administered L-tryptophan amino acid to women with PMDD found a significant effect on alleviating premenstrual mood symptoms compared to placebo (97). ...
Premenstrual syndrome (PMS) or the more severe and debilitating form premenstrual dysphoric disorder (PMDD) affects a large proportion of menstruating women. PMS and PMDD are associated with a cyclical recurrence of mood and behavioural and physical symptoms in the late luteal menstrual phase, which significantly interferes with a woman’s physical and psychological well-being. The aetiology of these disorders is unclear, but research suggests involvement of altered neurotransmitter systems and increased sensitivity to gonadal hormone fluctuations. Due to the complexity of the disorder, there is no single treatment that is successful for all women; however, various treatments aimed at regulating neurotransmitter systems and suppressing gonadal steroids have been efficacious. This chapter will provide an updated review on diagnosis, prevalence, morbidity, risk factors, and evidence-based treatments that have been effective in treating the symptoms of PMDD.
... Depressive symptomer er også en del af PMD. AEndret serotonerg transmission er observeret ved PMD [3,17], og både SSRI og tryptofan (et forstadie til serotonin) reducerer symptomerne [4,19], men er ikke effektivt hos alle. Ved depression indtraeder virkningen af SSRI efter uger, hvorimod virkningen ved PMD indtraeder inden for dage [4], hvilket støtter en teori om midlertidig serotonerg dysfunktion [2,15]. ...
... Tvillingestudier har vist en heritabilitet på 35-56% [19]. Ud over den manglende association til serotonintransporteren har studier af polymorfier i østrogenreceptorer vist modstridende resultater, hvorfor det er uklart, om de bidrager til patogenesen [20]. ...
Premenstrual dysphoric disorder (PMDD) is a cluster of severe affective symptoms recurring during the luteal phase of the menstrual cycle, and it affects up to 8% of menstruating women. In Denmark, this disorder is often overlooked. Unlike in the treatment of anxiety and depression, selective serotonin reuptake inhibitors need not be given continuously but can be effective when used only in the luteal phase. This review provides an overview of the current knowledge on the diagnosis and treatment of PMDD in Denmark.
Review in Danish for the Journal of the Danish Medical Association "Ugeskrift for Læger"
... There are a substantial number of studies that have addressed the efficacy of Trp given alone as an antidepressant (Bowers, 1970;Chouinard et al., 1979Chouinard et al., , 1983Mendels et al., 1975;Murphy et al., 1974;Steinberg et al., 1999;Thomson et al., 1982), and there are many reviews available on the topic (Baldessarini, 1984;Carroll, 1971;Cole et al., 1980). However, there is little consensus in terms of Trp's efficacy in treating depression as studies vary considerably in terms of sample size, study populations, dosages, study designs, and control conditions. ...
... In contrast, Trp has been reported to be an effective antidepressant in mild to moderately depressed outpatients (Thomson et al., 1982). While in patients with premenstrual dysphoric disorder, Steinberg et al. (1999) found that 6 g L-Trp (given as 2 g three times a day for 17 days) was more effective than placebo in controlling extreme mood swings, dysphoria, irritability, and tension. ...
Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that mirror those of ATD. The current review examines the evidence for such effects, notably those on cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs, and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on the initial state of the serotonergic system of the subject. Memory improvements following Trp loading have generally been shown in clinical and sub-clinical populations where initial serotonergic disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is likely to be attributed to its mild sedative effects.
... Mean scores per menstrual phase were calculated for each symptom. The four core symptoms were averaged together to yield a mean score called the VAS-Mood [26,27]. Symptoms were also tracked using the PRISM calendar. ...
We previously found normal polysomnographic (PSG) sleep efficiency, increased slow wave sleep (SWS) and a blunted melatonin secretion in women with premenstrual dysphoric disorder (PMDD) compared to controls. Here, we investigated the effects of exogenous melatonin in five patients previously studied. They took 2 mg of slow-release melatonin 1 hour before bedtime during their luteal phase (LP) for three menstrual cycles. At baseline, patients spent every third night throughout one menstrual cycle sleeping in the laboratory. Measures included morning urinary 6-sulfatoxymelatonin (aMt6), PSG sleep, nocturnal core body temperature (CBT), visual analogue scale for mood (VAS-Mood), Prospective Record of the Impact and Severity of Menstrual Symptoms (PRISM), and ovarian hormones. Participants also underwent two 24-hour intensive physiological monitoring (during the follicular phase and LP) in time-isolation/constant conditions to determine 24-hour plasma melatonin and CBT rhythms. The same measures were repeated during their third menstrual cycle of melatonin administration. In the intervention condition compared to baseline, we found increased urinary aMt6 (p<0.001), reduced objective SOL (p=0.01), reduced SWS (p<0.001) and increased Stage 2 sleep (p<0.001). Increased urinary aMt6 was associated with reduced SWS (r=-0.51, p<0.001). Circadian parameters derived from 24-hour plasma melatonin and CBT did not differ between conditions, except for an increased melatonin mesor in the intervention condition (p=0.01). Ovarian hormones were comparable between the conditions (p≥0.28). Symptoms improved in the intervention condition, as measured by the VAS-Mood (p=0.02) and the PRISM (p<0.001). These findings support a role for disturbed melatonergic system in PMDD that can be partially corrected by exogenous melatonin.
... Second, the SSRIs reduce premenstrual irritability with a larger effect size and response rate than they display in any other SSRI indication, and this effect correlates better in time with the influence of these compounds on serotonergic levels in the synapse than do the antidepressant and anti-anxiety effects (i.e., the effect is more rapid in onset) . Third, also other compounds facilitating serotonergic neurotransmission, such as the serotonin precursor tryptophan (Steinberg et al., 1999), the serotonin-releasing agents mCPP (Su et al., 1997) and fenfluramine (Brzezinski et al., 1990), and the 5HT1A agonist buspirone , reduce premenstrual irritability. Fourth, PMD symptoms are aggravated by ATD (Menkes et al., 1994). ...
... 29 Steinberg and colleagues conducted a randomized, double-blind, placebo-controlled trial to assess the effi cacy of tryptophan (6 g/day) for treating Premenstrual Dysphoric Disorder symptoms. 194 Those patients receiving tryptophan reported signifi cant reductions in dysphoria, mood swings, and irritability compared with those receiving placebo. These effects were thought to be the result of increased kynurenine synthesis during the late-luteal phase of the menstrual cycle. ...
An essential component of the human diet, L-tryptophan is critical in a number of metabolic functions and has been widely used in numerous research and clinical trials. This review provides a brief overview of the role of L-tryptophan in protein synthesis and a number of other metabolic functions. With emphasis on L-tryptophan's role in synthesis of brain serotonin, details are provided on the research uses of L-tryptophan, particularly L-tryptophan depletion, and on clinical trials that have been conducted using L-tryptophan supplementation. The ability to change the rates of serotonin synthesis in the brain by manipulating concentrations of serum tryptophan is the foundation of much research. As the sole precursor of serotonin, experimental research has shown that L-tryptophan's role in brain serotonin synthesis is an important factor involved in mood, behavior, and cognition. Furthermore, clinical trials have provided some initial evidence of L-tryptophan's efficacy for treatment of psychiatric disorders, particularly when used in combination with other therapeutic agents.
... Le magnésium a été proposé par certains comme un traitement efficace des syndromes prémenstruels, mais des résultats négatifs ont par la suite été publiés, de même qu'en ce qui concerne la vitamine B6. L'apport de L-tryptophane (6 mg j -1 ), précurseur de la sérotonine, serait efficace d'après une étude récente [28]. D'autres traitements sont cités dans la littérature : lithium, ß-bloquants, bromocriptine, thyroxine, diurétiques, spironolactone, naltrexone, phytothérapie (kami-shoyo-san), vitamine E ou encore doxycycline, mais sans résultats démontrés. ...
... 9 In a placebocontrolled study on premenstrual dysphoric disorder (PMDD), tryptophan caused a significant decline in irritability, the mental state associated with agonistic interactions. 10 The effect of tryptophan, relative to placebo, was compared in 2 crossover studies on healthy participants, using ecological momentary assessment to investigate their social behaviour in everyday life. Participants repeatedly checked off, on a list, behaviours they displayed during social interactions lasting more than 5 minutes throughout many days. ...
Increasing serotonin decreases quarrelsome behaviours and enhances agreeable behaviours in humans. Antidepressants, even those whose primary action is not on serotonin, seem to increase serotonin function. We suggest that antidepressants act in part by effects on social behaviour, which leads to a gradual improvement in mood. We review the evidence supporting the idea that antidepressants may be moving behaviour from quarrelsome to agreeable. The more positive social responses of interaction partners would initiate a cycle of more positive social behaviour, and this iterative process would result in a clinically significant improvement in mood.
... Le magnésium a été proposé par certains comme un traitement efficace des syndromes prémenstruels, mais des résultats négatifs ont par la suite été publiés, de même qu'en ce qui concerne la vitamine B6. L'apport de L-tryptophane (6 mg j -1 ), précurseur de la sérotonine, serait efficace d'après une étude récente [28]. D'autres traitements sont cités dans la littérature : lithium, ß-bloquants, bromocriptine, thyroxine, diurétiques, spironolactone, naltrexone, phytothérapie (kami-shoyo-san), vitamine E ou encore doxycycline, mais sans résultats démontrés. ...
Premenstrual dysphoric disorder is a form of mood disorder causing a significant reduction in the quality of life and in the daily function for about 3 % to 5 % of women of fertile age. Premenstrual dysphoric disorder (PMDD) includes various symptoms regularly present during the luteal phase of menstrual cycles, with principally depressive mood, anxiety, emotional lability and decrease of interest. The serotoninergic system is in close reciprocal relation with the gonadal hormones and has been identified as the most plausible target for interventions. The selective serotonin reuptake inhibitors are increasingly used as first-line therapy for severe PMDD. The response rate reported are better than responses to treatment of depression, obsessive-compulsive disorder or panic disorder. The doses used are variable, between 20 and 60 mg/day for fluoxétine, 50 and 150 mg/day for sertraline and 10–30 mg/day for paroxetine. The administration may be continuous every day in the menstrual cycle or intermittent (premenstrual only) or semi-intermittent (low doses during follicular phase and higher doses during luteal phase). Several studies indicate that intermittent treatment is more efficient in these women and thus, may offer an attractive treatment option because with reduced side-effects.
... In further steps, serotonin is then converted into melatonin probable to arise when higher doses are used (i.e., 70-200 mg/kg; for a review see Fernstrom 2012). The amount and diversity of described side-effects increments when higher doses are supplemented over longer periods (e.g., 6 g daily for 3 months; Steinberg et al. 1999). This is not surprising if we consider that TPH enzyme saturates already at a dose up to 3 g ( Young and Gauthier 1981), pointing out that doses higher than this will not lead to any further enhancement of 5-HT function. ...
Tryptophan (TRP), the chemical forerunner of serotonin (5-HT), is one of the most investigated amino acids. The administration of TRP can augment 5-HT levels in the brain and because of that several studies have examined whether the supplementation of TRP can enhance prosocial behavior that depends on serotonergic function. In this chapter, we review the available studies in healthy humans. It seems that TRP supplementation promotes social behavior. Even though more research is needed to better comprehend the relations between individual differences, TRP effectivity, 5-HT functioning, and social interactions, we suggest that TRP can be a promising tool for promoting prosocial behavior in healthy humans.
... Hastalara serotonin prekürsörü olan L-triptofanın 17 gün boyunca günde 6 g verildiği bir çalışmada, L-triptofanın gerginlik ve sinirlilik, depresif ruh durumu gibi belirtiler üzerinde iyileştirici etkisi olduğu görülmüştür. 38 Triptofanın, sağlıklı bireylerde duygu durumu üzerine etkisi tam bilinmese de depresyon hastalarında, premenstrüel disforik bozukluk şikâyeti olan bireylerde, serotonin türevi ilaçlarla birlikte faydalı etkisi olabileceği düşünülmektedir. ...
Triptofan; metabolizmasının karmaşıklığı, metabolit-lerinin çeşitliliği ve önemi, ayrıca saflaştırılmış hâlde farmakolojik ajan olarak kullanılması bakımından farklı bir amino asittir. Esansiyel aromatik amino asit olan ve yapısında indol halkası taşıyan triptofan, önemli bileşiklerin sentezinde rol alır. Bu nedenle se-rotonin, melatonin, triptamin, kuinolinik asit ve kinü-renik asit gibi pek çok biyolojik aktif bileşiğin ön mad-desidir. Bununla birlikte triptofanın karaciğerdeki yıkım yolunda niasin (B 3 vitamini) oluşur. 1,2 Triptofanın dönüşümü sonucu oluşan seroto-nin (5-dihidroksitriptamin) beslenme, vücut ağırlığı düzenlenmesi, toplumsal hiyerarşiler, saldırganlık ve intihar, obsesif-kompulsif bozukluklar, alkolizm, ÖZET Triptofan; serotonin, melatonin, triptamin, nikotinik asit gibi önemli bileşiklerin sentezinde rol alan esansiyel aromatik bir amino asittir. Bu nedenle iştah, ağırlık kazanımı, uyku, ruh durumu, ağrı gibi pek çok fizyolojik durum ile ilişkilidir. Günlük triptofan gereksinimi, vücut ağırlığının kg'ı başına 5 mg'dır. Triptofanın beyine alınması ve aktif metabolitlere dönüşümü, alım miktarıyla ilişkili olduğu kadar or-tamdaki diğer amino asitlerin özellikle büyük nötral amino asitlerin (valin, lösin, izolösin, fenilalanin, tirozin) varlığına da bağlıdır. Akut triptofan eksikliğinin, hafif şişman bireylerde şekerli besinlerden gelen enerji alımını artırdığı, düzelmiş depresyon hastalarında depresif yanıtı uyardığı, uyku süresi ve kalitesinde azalmaya, uzun süreli bellek işlev-lerinde bozukluğa, migren hastalarında ışık kaynaklı ağrının ve migren ataklarının artmasına yol açtığı saptanmıştır. Triptofanın uyku üzerine olumlu etkisi dışında besin olarak alımının, vücutta ilaç benzeri hasta-lıklara karşı aktif bir işlevine rastlanmamıştır. Bununla birlikte tripto-fan destekleri, özellikle depresyon, bazı kognitif bozukluklar, kronik ağrı ve uyku bozukluklarında uzun süredir kullanılmaktadır. Ayrıca bu desteklerin, hafif şişman bireylerde tek başına enerji alımını azalttığı ve ağırlık kaybını sağladığı görülmüştür. Ancak triptofan desteklerinin, 1989 yılında eozinofili miyalji hastalığına yol açması ve bu durumdan pek çok kişinin zarar görmesi sebebiyle Amerikan Gıda ve İlaç Dairesi tarafından kullanımı bir süre yasaklanmış olup, 2005 yılında bu yasak kalkmıştır. Bununla birlikte 2005 yılından itibaren triptofan desteği kul-lanım sonucu, 2 adet eozinofilia miyalji ve 2 adet miyalji tanısı almış toplam 4 olgu bulunmaktadır. Anah tar Ke li me ler: Triptofan; obezite; uyku; ağrı ABS TRACT Tryptophan is an essential aromatic aminoacid. It plays role for the important substances synthesis such as serotonine, melato-nine, tryptamine, nicotinic acid. Therefore, it affects some physiological conditions such as weight gain, sleep activity, mood, pain. Daily triptophan requirement is 5 mg per kg body weight. Brain tryptophan uptake and conversion to active metabolites there, related with its amount of intake and presence of other aminoacids especially large neutral amino acids (valine, leucine, isoleucine, phenylalanine, tyrosine) in blood. Acute tryptophan depletion increases energy intake from foods high in sugar in overweight adults, stimulates depressive responses in patients with depression, decreases sleep duration and efficiancy, causes impaired long-term memory functioning and increases migraine symptoms and photophobia in patients who suffer from migraine. Except for sleep problems, there is no drug-like, active effects of tryptop-han taken in food for diseases. Neverthless, tryptophan supplement has been used for a long time especially for depression, some cognitive problems, chronic pain and sleep problems. Besides, it is reported that tryptophan supplement decreases energy intake and provides weight loss alone in overweight adults. However, in 1989 since it caused eosi-nophilia myalgia syndrome and most of people harmed, it was banned by Food and Drug Administration for a while and in 2005, this ban was lifted. Because of using tryptophan two cases having eosinophilia myal-gia sendrome and 2 cases having myalgias have been reported since 2005.
... Of the many herbal supplements that have been tried for PMS, few were tested in properly controlled trials, and none of them have been tested in a population of women with strictly defined PMDD. 37 Cognitive Behavioural Therapy Women with severe PMS or PMDD may opt for seeking psychological treatments in light of some concerns regarding the tolerability and side effect profile of hormonal and pharmacological options. CBT is the most extensively studied alternative in this case. ...
Most ovulatory women experience premenstrual symptoms (premenstrual syndrome, molimina) which indicate impending menstruation and are of little clinical relevance because they do not affect quality of life. A few women, however, experience significant physical and/or psychological symptoms before menstruation that, if left untreated, would result in deterioration in functioning and relationships. The precise etiology remains elusive, although new theories are gaining support in pre-clinical and early clinical trials. Refined diagnostic criteria allow better discrimination of this condition from other psychiatric diagnoses and the selection of symptom appropriate therapies that afford relief for most women. Pharmacotherapies (particularly selective serotonin reuptake inhibitors and SNRIs) represent the first-line treatment for premenstrual dysphoric disorder and severe, mood-related premenstrual syndrome. Continuous combined oral contraceptives have limited evidence for usefulness in premenstrual dysphoric disorder, whereas medical ovarian suppression is often recommended for patients who fail to respond or cannot tolerate first-line treatments (e.g., selective serotonin reuptake inhibitors). The use of cognitive behavioural therapies is promising, but it remains limited by sparse data and restricted access to trained professionals. A proper diagnosis (particularly the distinction from other underlying psychiatric conditions) is crucial for the implementation of effective therapy and alleviation of this impairing condition.
... However, it is unclear whether this is due to the vegetarian diet, lower protein intakes, B-vitamin supplements and/or the low-fat diet. Lastly, Steinberg et al. conducted a clinical trial assessing supplementation of tryptophan (6 g) in women with premenstrual dysphoric disorder for 17 d, where supplementation with tryptophan (n 37) was more effective than placebo (n 34) in reducing mood symptom severity among women with premenstrual dysphoric disorder (21) . Our study found no association with tryptophan and risk of developing PMS; however, our mean intake of tryptophan was less than 1 g (mean = 0·98 (SD 0·17) g/d). ...
Objective
To examine the relationship between protein intake and the risk of incident premenstrual syndrome (PMS).
Design
Nested case–control study. FFQ were completed every 4 years during follow-up. Our main analysis assessed protein intake 2–4 years before PMS diagnosis (for cases) or reference year (for controls). Baseline (1991) protein intake was also assessed.
Setting
Nurses’ Health Study II (NHS2), a large prospective cohort study of registered female nurses in the USA.
Participants
Participants were premenopausal women between the ages of 27 and 44 years (mean: 34 years), without diagnosis of PMS at baseline, without a history of cancer, endometriosis, infertility, irregular menstrual cycles or hysterectomy. Incident cases of PMS ( n 1234) were identified by self-reported diagnosis during 14 years of follow-up and validated by questionnaire. Controls ( n 2426) were women who did not report a diagnosis of PMS during follow-up and confirmed experiencing minimal premenstrual symptoms.
Results
In logistic regression models adjusting for smoking, BMI, B-vitamins and other factors, total protein intake was not associated with PMS development. For example, the OR for women with the highest intake of total protein 2–4 years before their reference year (median: 103·6 g/d) v . those with the lowest (median: 66·6 g/d) was 0·94 (95 % CI 0·70, 1·27). Additionally, intakes of specific protein sources and amino acids were not associated with PMS. Furthermore, results substituting carbohydrates and fats for protein were also null.
Conclusions
Overall, protein consumption was not associated with risk of developing PMS.
... carlomagno@gmail.com PMDD (Su et al., 1997, Steinberg et al., 1999, Eriksson et al., 2006, with symptomatic women having lower density of serotonin transporter receptors than controls (Melke et al., 2003). ...
Premenstrual dysphoric disorder (PMDD) is a mood disorder disrupting social and/or occupational life of affected women. Premenstrual dysphoric disorder etiology is unknown, although a pivotal role is played by the serotoninergic system. Indeed, one of the most effective treatments is selective serotonin reuptake inhibitors. Several studies have proposed a selective serotonin reuptake inhibitor-like role for myo-inositol, likely due to the fact that myo-inositol is the second messenger of serotonin. In the present study, we aimed to investigate the effect of myo-inositol in the treatment of PMDD.
We used a two-phase clinical trial approach (phase I: placebo washout; phase II: comparisons between treatment and placebo) and treated PMMD patients with two different myo-inositol formulations: powder or soft gel capsules. We decided to test these two formulations because according to the manufacturer, 0.6 g of myo-inositol in soft gel capsule has a pharmacokinetic equivalent to 2 g of myo-inositol in powder.
Our results showed a significant improvement of three different scales: a reduction in the Daily Symptoms Records scale and an improvement of the Hamilton Depression Rating and Clinical Global Impression-Severity of Illness scales. Results were similar for both formulations.
In the present study, by using a new pharmaceutical formulation, we were able to clearly prove the efficacy of myo-inositol in PMDD.
... Hastalara serotonin prekürsörü olan L-triptofanın 17 gün boyunca günde 6 g verildiği bir çalışmada, L-triptofanın gerginlik ve sinirlilik, depresif ruh durumu gibi belirtiler üzerinde iyileştirici etkisi olduğu görülmüştür. 38 Triptofanın, sağlıklı bireylerde duygu durumu üzerine etkisi tam bilinmese de depresyon hastalarında, premenstrüel disforik bozukluk şikâyeti olan bireylerde, serotonin türevi ilaçlarla birlikte faydalı etkisi olabileceği düşünülmektedir. ...
Triptofan; metabolizmasının karmaşıklığı, metabolitlerinin çeşitliliği ve önemi, ayrıca saflaştırılmış hâlde farmakolojik ajan olarak kullanılması bakımından farklı bir amino asittir. Esansiyel aromatik amino asit olan ve yapısında indol halkası taşıyan triptofan, önemli bileşiklerin sentezinde rol alır. Bu nedenle serotonin, melatonin, triptamin, kuinolinik asit ve kinürenik asit gibi pek çok biyolojik aktif bileşiğin ön mad-desidir. Bununla birlikte triptofanın karaciğerdeki yıkım yolunda niasin (B 3 vitamini) oluşur. 1,2 Triptofanın dönüşümü sonucu oluşan seroto-nin (5-dihidroksitriptamin) beslenme, vücut ağırlığı düzenlenmesi, toplumsal hiyerarşiler, saldırganlık ve intihar, obsesif-kompulsif bozukluklar, alkolizm, ÖZET Triptofan; serotonin, melatonin, triptamin, nikotinik asit gibi önemli bileşiklerin sentezinde rol alan esansiyel aromatik bir amino asittir. Bu nedenle iştah, ağırlık kazanımı, uyku, ruh durumu, ağrı gibi pek çok fizyolojik durum ile ilişkilidir. Günlük triptofan gereksinimi, vücut ağırlığının kg'ı başına 5 mg'dır. Triptofanın beyine alınması ve aktif metabolitlere dönüşümü, alım miktarıyla ilişkili olduğu kadar ortamdaki diğer amino asitlerin özellikle büyük nötral amino asitlerin (valin, lösin, izolösin, fenilalanin, tirozin) varlığına da bağlıdır. Akut triptofan eksikliğinin, hafif şişman bireylerde şekerli besinlerden gelen enerji alımını artırdığı, düzelmiş depresyon hastalarında depresif yanıtı uyardığı, uyku süresi ve kalitesinde azalmaya, uzun süreli bellek işlevlerinde bozukluğa, migren hastalarında ışık kaynaklı ağrının ve migren ataklarının artmasına yol açtığı saptanmıştır. Triptofanın uyku üzerine olumlu etkisi dışında besin olarak alımının, vücutta ilaç benzeri hastalıklara karşı aktif bir işlevine rastlanmamıştır. Bununla birlikte triptofan destekleri, özellikle depresyon, bazı kognitif bozukluklar, kronik ağrı ve uyku bozukluklarında uzun süredir kullanılmaktadır. Ayrıca bu desteklerin, hafif şişman bireylerde tek başına enerji alımını azalttığı ve ağırlık kaybını sağladığı görülmüştür. Ancak triptofan desteklerinin, 1989 yılında eozinofili miyalji hastalığına yol açması ve bu durumdan pek çok kişinin zarar görmesi sebebiyle Amerikan Gıda ve İlaç Dairesi tarafından kullanımı bir süre yasaklanmış olup, 2005 yılında bu yasak kalkmıştır. Bununla birlikte 2005 yılından itibaren triptofan desteği kullanım sonucu, 2 adet eozinofilia miyalji ve 2 adet miyalji tanısı almış toplam 4 olgu bulunmaktadır. Anahtar Kelimeler: Triptofan; obezite; uyku; ağrı ABSTRACT Tryptophan is an essential aromatic aminoacid. It plays role for the important substances synthesis such as serotonine, melatonine, tryptamine, nicotinic acid. Therefore, it affects some physiological conditions such as weight gain, sleep activity, mood, pain. Daily triptophan requirement is 5 mg per kg body weight. Brain tryptophan uptake and conversion to active metabolites there, related with its amount of intake and presence of other aminoacids especially large neutral amino acids (valine, leucine, isoleucine, phenylalanine, tyrosine) in blood. Acute tryptophan depletion increases energy intake from foods high in sugar in overweight adults, stimulates depressive responses in patients with depression, decreases sleep duration and efficiancy, causes impaired long-term memory functioning and increases migraine symptoms and photophobia in patients who suffer from migraine. Except for sleep problems, there is no drug-like, active effects of tryptophan taken in food for diseases. Neverthless, tryptophan supplement has been used for a long time especially for depression, some cognitive problems, chronic pain and sleep problems. Besides, it is reported that tryptophan supplement decreases energy intake and provides weight loss alone in overweight adults. However, in 1989 since it caused eosinophilia myalgia syndrome and most of people harmed, it was banned by Food and Drug Administration for a while and in 2005, this ban was lifted. Because of using tryptophan two cases having eosinophilia myalgia sendrome and 2 cases having myalgias have been reported since 2005.
... 122,123 Given the role of serotonin in mood and aggression, as well the likely role of serotonin in sex steroid-driven behavior, this transmitter promises to be an important factor in PMS/PMDD pathophysiology. Premenstrual symptoms are diminished both by serotonin reuptake inhibitors (SRIs) and by other treatments that increase serotonin, such as releasing agents, 124,125 a precursor, 126 and a receptor agonist. 127 In contrast, tryptophan-free diets 128 and serotonin receptor antagonists 129 can evoke PMS symptoms. ...
Many women in their reproductive years experience some mood, behavioral. or physical symptoms in the week prior to menses. Variability exists in the level of symptom burden in that some women experience mild symptoms, whereas a small minority experience severe and debilitating symptoms. For an estimated 5%-8% of premenopausal women, work or social functioning are affected by severe premenstrual syndrome. Many women in this group meet diagnostic criteria for premenstrual dysphoric disorder (PMDD). Among women who suffer from PMDD, mood and behavioral symptoms such as irritability, depressed mood, tension, and labile mood dominate. Somatic complaints, including breast tenderness and bloating, also can prove disruptive to women's overall functioning and quality of life. Recent evidence suggests that individual sensitivity to cyclical variations in levels of gonadal hormones may predispose certain women to experience these mood, behavioral, and somatic symptoms. Treatments include: antidepressants of the serotonin reuptake inhibitor class, taken intermittently or throughout the menstrual cycle; medications that suppress ovarian cyclicity; and newer oral contraceptives with novel progestins.
Background:
5 Hydroxytryptophan (5-HTP) and tryptophan are so-called natural alternatives to traditional antidepressants, used to treat unipolar depression and dysthymia.
Objectives:
To determine whether 5-HTP and tryptophan are more effective than placebo, and whether they are safe to use to treat depressive disorders in adults.
Search strategy:
Trials were searched in computerized general (Medline, Psychlit, and Embase) and specialized databases (Cochrane Controlled Clinical Trials Register, Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trial Register); by checking reference lists of relevant articles; by handsearching relevant specialist journals; and by contacting relevant authors where appropriate. Publications in all languages were sought.
Selection criteria:
Trials were included if they were randomized, included patients with unipolar depression or dysthymia, compared preparations of 5-HTP or tryptophan with placebo, and included clinical outcomes assessed by scales assessing depressive symptoms.
Data collection and analysis:
Data was extracted independently by the three reviewers, onto data collection forms. Inclusion criteria were applied to all potential studies independently and a coefficient of agreement (Kappa) was calculated for them. Disagreement was resolved by reaching consensus. Trial quality was scored according to risk of bias. Analysis for 5-HTP and tryptophan were combined due to the small number of included trials.
Main results:
108 trials were located using the specified search strategy. Of these, only two trials, involving a total of 64 patients, were of sufficient quality to meet inclusion criteria. The available evidence suggests these substances were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78). However, the evidence was of insufficient quality to be conclusive.
Reviewer's conclusions:
A large number of studies appear to address the research questions, but few are of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluate the efficacy and safety of 5-HTP and tryptophan before their widespread use can be recommended. The possible association between these substances and the potentially fatal Eosinophilia-Myalgia Syndrome has not been elucidated. Because alternative antidepressants exist which have been proven to be effective and safe the clinical usefulness of 5-HTP and tryptophan is limited at present.
The inclusion of research diagnostic criteria for premenstrual dysphoric disorder (PMDD) in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, recognizes the fact that some women have extremely distressing emotional and behavioural symptoms premenstrually. PMDD can be differentiated from premenstrual syndrome (PMS), which presents with milder physical symptoms, headache, and more minor mood changes. In addition, PMDD can be differentiated from premenstrual magnification of physical or psychological symptoms of a concurrent psychiatric or medical disorder. As many as 75% of women with regular menstrual cycles experience some symptoms of PMS, according to epidemiologic surveys. PMDD is much less common; it affects only 3% to 8% of women in this group. The etiology of PMDD is largely unknown, but the current consensus is that normal ovarian function (rather than hormone imbalance) is the cyclical trigger for PMDD-related biochemical events within the central nervous system and other target organs. The serotonergic system is in a close reciprocal relation with the gonadal hormones and has been identified as the most plausible target for interventions. Thus, beyond conservative treatment options such as lifestyle and stress management, other non-antidepressant treatments, or the more extreme intervneitons that eliminate ovulation altogether, selective serotonin reuptake inhibitors (SSRIs) are emerging as the most effective treatment option. Results from several randomized, placebo-controlled trials in women with PMDD have clearly demonstrated that SSRIs have excellent efficacy and minimal side effects. More recently, several preliminary studies indicate that intermittent (premenstrual only) treatment with selective SSRIs is equally effective in these women and, thus, may offer an attractive treatment option for a disorder that is itself intermittent.
Among women with breast cancer, hot flashes are frequent, severe, and bothersome symptoms that can negatively impact quality of life and compromise compliance with life-saving medications (eg, tamoxifen and aromatase inhibitors). Clinicians' abilities to treat hot flashes are limited due to inadequate understanding of physiological mechanisms involved in hot flashes. Using an acute tryptophan depletion paradigm, we tested whether alterations in central serotonin levels were involved in the induction of hot flashes in women with breast cancer.
This was a within-participant, double-blind, controlled, balanced, crossover study. Twenty-seven women completed two 9-hour test days. On one test day, women ingested a concentrated amino acid drink and encapsulated amino acids (no tryptophan) according to published procedures that have been shown to have specific effects on serotonin within 4.5 to 7 hours. On the other test day, women ingested a control drink. Serial venous blood sampling and objective hot flash monitoring were used to evaluate response to each condition.
Response to acute tryptophan depletion was variable and unexplained by use of selective serotonin reuptake inhibitors, antiestrogens, breast cancer disease and treatment variables, or genetic polymorphisms in serotonin receptor and transporter genes. Contrary to our hypothesis, hot flashes were not worsened with acute tryptophan depletion.
Physiologically documented and self-reported hot flashes were not exacerbated by tryptophan depletion. Additional mechanistic research is needed to better understand the etiology of hot flashes.
Although selective serotonin reuptake inhibitors are considered the first-line treatment option for premenstrual syndrome, several other such options are also available. Multiple studies have indicated that medications that suppress ovulation alleviate premenstrual emotional and physical symptoms. However. the use of such medications, such as the gonadotropin-releasing hormone agonists, leads to prolonged low estrogen levels and cardiac and osteoporotic health risks. A recent double-blind, placebo-controlled study of 466 women with premenstrual syndrome reported that calcium was effective in reducing emotional, behavioral, and physical premenstrual symptoms. Recent preliminary trials have suggested efficacy for cognitive therapy, light therapy, and tryptophan. Future studies of diet recommendations, exercise, relaxation, magnesium, nonsteroidal anti-inflammatory drugs, diuretics, opiate antagonists, and alternative therapies are needed.
Study of monomer-template interactions in molecularly imprinted polymer (MIP) is inevitable to comprehend best selectivity at the molecular level in pre-polymer solution. In the present work, binding energies of tryptophan, an amino acid template, complexed with different monomers were computed using second order Moller Plesset theory (MP2) at 6-311++g** level in gas phase. This helped in recommending a generic MIP, suitable for the selective and sensitive diagnosis of tryptophan, in clinical setting as disease biomarker, at primitive level. The tryptophan is an important biomarker owing to its highly regulated physiological process in the treatment of premenstrual dysphoric disorder and pellagra like diseases. Frequency calculations were performed using Density Functional Theory (DFT) at B3LYP employing 6-31+g (2d, 2p) level including thermal and entropy corrections. The monomer, p-nitrophenyl acrylate (2 mol), was adjudged having giving best binding score for the complexation at ground state with tryptophan (1 mol) for MIP development.
Since the introduction of antidepressants in the 1950s, it was assumed for the next several decades that there were no special reasons to look at the application of these medications to women. In the past half-century, particularly in the past decade, since the advent of the selective serotonin re-uptake inhibitors (SSRI), a series of specific foci have developed. Firstly, there appear to be differences in the degree of response to particular antidepressants between the genders. Secondly, there is data concerning hormonal effects of particular relevance to women, i.e. prolactin, which separates out among the antidepressants. Also of concern to women are the potential teratogenic effects of these medications, which impact on their use during pregnancy. Finally, there are certain diagnostic syndromes that are particularly relevant to women: premenstrual dysphoric disorder (PMDD); postpartum depression (PPD) and perimenopausal depression (PMD). It appears that the SSRIs may be more effective, relative to the older tricyclic antidepressants (TCA), in women than in men. The SSRIs have shown to be effective in treating these disorders, with the possibility of intermittent luteal phase treatment of PMDD. Non-antidepressant (AD) approaches have generally been found to be less effective. In the first trimester of pregnancy, there is data available supporting the safe use of SSRIs, particularly those first released, i.e. fluoxetine and sertraline. Finally, all SSRIs, with the exception of sertraline, can increase the risk of hyperprolactinaemia. This can lead to a variety of complications including amenorrhea and osteoporosis. This effect of sertraline, due to its unique profile in blocking re-uptake of dopamine, extends itself into additional relative benefits for sleep and memory. The issues associated for women with bipolar disorder are dealt with in terms of both increased risk of relapse during pregnancy and postpartum periods, as well as the relative risk of use of lithium and mood stabilizers in pregnancy and lactation.
Three outpatients who fulfilled full DSM-IV diagnostic criteria for premenstrual dysphoric disorder (PDD) were successfully treated with intermittent (luteal phase) nefazodone. They received the medication at low doses of up to 100 mg/day (50 mg b.i.d.), for 2 weeks through the luteal phase of the menstrual cycle only. All the patients reported a marked symptomatic improvement, including full remission of their emotional symptoms, and two achieved in addition full remission of their somatic symptoms. Side-effects reported during the treatment were mild. The use of luteal phase nefazodone seems to be a promising treatment strategy for the management of PDD. It offers advantages over daily dosing throughout the menstrual cycle, such as reduced incidence and severity of side-effects, and avoids the stigma that may accompany the continuous use of psychopharmacological treatment, with the advantage that compliance may be improved.
Premenstrual dysphoric disorder (PMDD), as defined in DSM-IV, is a mood disorder. One of the leading theories for the pathogenesis of mood disorders is dysfunction of the serotonergic system. An increasing database suggests that serotonergic dysfunction also characterises PMDD. Evidence that treatments which enhance serotonergic function are beneficial in reducing the symptoms of PMDD support this hypothesis. Indeed, most of the evidence from baseline studies suggests predominantly a serotonergic rather than a noradrenergic or dopaminergic dysfunction. Challenge studies further support this hypothesis. These findings of neurotransmitter dysfunction are more consistent than those of other neuroendocrine abnormalities for example. Based on treatment studies, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, fluoxetine, has been approved for use in PMDD by the US Food and Drug Administration.
Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. TPH belongs to the family of the aromatic amino acid hydroxylases, including phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict requirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases. Although structural information about TPH is not yet available, the high sequence homology between the three mammalian hydroxylases, notably at the catalytic domains, and the similarity of the reactions that they catalyze, indicate that they share a similar 3D-structure and a common catalytic mechanism. Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH. This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines. The interactions of these ligands with the enzyme are discussed focusing on the physiological and pharmacological regulation of serotonin biosynthesis, notably by tryptophan supplementation therapy and substitution therapy with tetrahydrobiopterin analogues (positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinson's disease patients (enzyme inhibition).
About 5% of women of reproductive age experience affective or physical premenstrual symptoms that markedly influence work, social activities, or relationships. Prospective charting of symptoms for at least two menstrual cycles is required to facilitate an accurate diagnosis of premenstrual syndrome or premenstrual dysphoric disorder. The optimal treatment plan begins with lifestyle modifications, followed by pharmacotherapy. Evidence from numerous controlled trials has clearly demonstrated that low-dose serotonin reuptake inhibitors, using intermittent or continuous administration, have excellent efficacy with minimal side effects. Modification of the menstrual cycle should be considered only after all other treatment options have failed.
here are many popular beliefs about the effects of diet on mood and behav- iour. No one doubts that food ingestion can influence mood and behav- iour, but the mechanisms by which this happens are not fully understood. For example, who has not heard the statement "I'm feeling hypoglycemic"? What this statement probably means is that the person saying it feels somewhat tired and irritable and knows that she or he will feel better after eating. In fact, these "hypo- glycemic" states are not usually accompanied by hypoglycemia 1 and the cause of the initial state is unknown, as is the way in which food ingestion alleviates it. The acute behavioural effects of food can be striking. Perhaps the most dramatic effect is in the neonate. The transformation of an infant from crying and irritability (a state also not accompanied by hypoglycemia) to postprandial contentment and re- sponsiveness that delights its parents can be dramatic. 2
Several forms of depression are unique to women because of their apparent association with changes in gonadal hormones, which in turn modulate neuroregulatory systems associated with mood and behavior. This review examines the evaluation and treatment of depression that occurs premenstrually, postpartum, or in the perimenopause on the basis of current literature. The serotonergic antidepressants consistently show efficacy for severe premenstrual syndromes (PMSs) and premenstrual dysphoric disorder (PMDD), and are the first-line treatment for these disorders. The use of antidepressants for postpartum depression is compromised by concerns for effects in the infants of breast-feeding mothers, but increasing evidence suggests the relative safety of the antidepressant medications, and the risk calculation should be made on an individual basis. Estradiol may be effective for postpartum depression and for moderate-to-severe major depression in the perimenopause. In spite of its frequent use, progesterone is not effective for the mood and behavioral symptoms of PMS/PMDD, postpartum depression, or perimenopausal depressive symptoms.
Hot flashes are a frequent, severe and bothersome symptom for women with breast cancer. Unfortunately, this symptom; is difficult to treat due to limitations in understanding hot flash physiology. Although serotonin may be involved in hot flashes, it has not been directly manipulated to study effect on hot flashes. Our study purpose was to improve our understanding of the role of serotonin in hot flashes by altering central serotonin concentrations using a well-established acute tryptophan depletion paradigm. The main hypothesis was that alterations in central serotonin levels are involved in the induction of hot flashes in women with breast cancer and that variability in response to serotonin manipulation could be partly explained by genetic variations in the serotonin receptors and transporters. The study opened to enrollment in September, 2005 as planned with 75 women completing being our target goal. As reported in previous reports, a revised power analysis in year 2 indicated 26 participants would provide sufficient power. Overall, 28 women completed week 1 and 27 completed weeks 1 and 2. Our hypothesis was not supported. Despite achieving adequate tryptophan depletion with the active drink, we did not see any difference in objective or subjective hot flashes between the study arms. In addition, individual variation in response to depletion did not appear to be explained by genetic polymorphisms.
Women with premenstrual dysphoric disorder (PMDD) experience disturbed mood, altered melatonin circadian rhythms, and frequent reports of insomnia during the luteal phase (LP) of their menstrual cycle. In this study we aimed to investigate nocturnal polysomnographic (PSG) sleep across the menstrual cycle in PMDD women and controls.
Seven PMDD women who indicated insomnia during LP, and five controls, spent every third night throughout a complete menstrual cycle sleeping in the laboratory.
In PMDD and controls progesterone and core body temperature (BT(core)) were elevated during LP compared to the follicular phase (FP). Stage 2 sleep showed a significant main effect of menstrual phase and was significantly increased during mid-LP compared to early-FP in both groups. Rapid eye movement (REM) sleep for both groups was decreased during early-LP compared to early-FP. Slow wave sleep (SWS) was significantly increased, and melatonin significantly decreased, in PMDD women compared to controls.
PMDD women who experience insomnia during LP had decreased melatonin secretion and increased SWS compared to controls. The sleep and melatonin findings in PMDD women may be functionally linked. Results also suggest an altered homeostatic regulation of the sleep-wake cycle in PMDD, perhaps implicating melatonin in the homeostatic process of sleep-wake regulation.
PMDD, a severe form of PMS, is characterized by affective and somatic symptoms in luteal phase of menstrual cycle, and cause social impairment. ICD-10 diagnostic criteria of PMS are less precise and less strict than DSM-IV. In diagnostic process very important is taking carefully a history. Helpful may be also special scales estimating symptoms during at least two menstrual cycles. Etiology and pathogenesis are unknown but evidence suggests that serotonergic activity and gonadal steroids influence on PMDD. At the beginning, non-pharmacological therapy, like lifestyle and diet changes, is advisable. SSRI are the first-line drugs for PMDD for example: fluoxetine, sertraline, paroxetine (recommended by FDA). The efficacy of venlafaxine has been also reported. Intermitted treatment, e.g. only in luteal phase, is as effective as continuous therapy and minimizes exposure to drugs, costs of therapy, long-term adverse effects like sexual dysfunctions and weight gain. The second-line therapy included: spironolactone, bromocriptine, alprazolam, GnRH agonist, danazol, oral contraceptives. Promising seems to be drospirenone, which have not only antimineralocorticoid but also antiandrogenic activity.
GPR139 is a G-protein coupled receptor expressed in circumventricular regions of the habenula and septum. Amino acids L-tryptophan and L-phenylalanine have been shown to activate GPR139 at physiologically relevant concentrations. The aim of the present study was to investigate the role of GPR139 on sleep modulation using pharmacological and genetic (GPR139 knockout mice, KO) rodent models. To evaluate the effects of GPR139 pharmacological activation on sleep, rats were orally dosed with the selective GPR139 agonist JNJ-63533054 (3–30 mg/kg). When acutely administered at the beginning of the light phase, the GPR139 agonist dose-dependently reduced non-rapid eye movement (NREM) latency and increased NREM sleep duration without altering rapid eye movement (REM) sleep. This effect progressively dissipated upon 7-day repeated dosing, suggesting functional desensitization. Under baseline conditions, GPR139 KO mice spent less time in REM sleep compared to their wild type littermates during the dark phase, whereas NREM sleep was not altered. Under conditions of pharmacologically enhanced monoamine endogenous tone, GPR139 KO mice showed a blunted response to citalopram or fluoxetine induced REM sleep suppression and an attenuated response to the wake promoting effect of amphetamine. These findings indicate an emerging role of GPR139 in the modulation of sleep states.
The major criticisms made to the conceptualization of PMDD as a clinical syndrome focus on pathologizing of women’s biology and its consequent medicalization which perpetuated misconceptions related to menses. This is a reality in History of Medicine. The excessive medicalization of the menstrual experience that interferes in life is very important in Western countries. Premenstrual syndrome (PMS) is a health problem that affects millions of women of reproductive age and, in some cases, may be severe enough to be considered as a premenstrual dysphoric disorder (PMDD). Both, PMS and PMDD, are composed by affective, behavioural, and physical symptoms. Risk factors identified, which predispose to PMS/PMDD, are the age between 25 and 35 years, to have a psychiatric history, family history of PMDD, unhealthy living habits, and the apparition of stressful life events. In addition to that, it has been established a comorbidity of PMDD with various psychiatric disorders as major depression and anxiety disorders. The first-line treatment for PMDD is pharmacological with SSRIs. From the medical point of view, there is some evidence of the efficacy of non-pharmacological treatments such as relaxation and aerobic and cognitive behavioural therapy that are used mostly in mild cases. Some authors remind us the historical and negative conceptions about the female body plus a reproductivist vision, as the cause of many women’s behaviour, have had a determinate influence in the consideration about women’s experience as diseases. In our opinion, we consider it is important to rethink about it and talk about premenstrual experience instead of syndrome. It could be used to reinforce and maintain the patriarchal model. If women are treated medically because of their own biology, they would respond again to the female stereotype of women as mild, placid, and undemanding. At the same time, for some women could represent an attractive explanation to justify their oppression and their relative lack of success compared to men. This means that women can attribute their subordination and oppression to something identifiable and potentially curable, rather than attributing to gender power relations. Finally, the concept clearly benefits to the pharmaceutical industry, as the medicalization of premenstrual experiences increased their market.
This study was designed to identify how the incidence and severity of premenstrual. syndrome (PMS) correlate with the nutrient intakes and exercise habit of women. The subjects of this study were 299 women residing in Busan metropolitan city. Each subject was asked to complete a menstrual discomfort questionnaire (MDQ) for PMS and nutrient intakes. PMS symptom scores of women in their twenties ranked in order of severity were: behavioral change (2.45), followed by pain (2.36) and water retention (2.28), negative effects (2.20), autonomic reaction (1.91), arousal (1.87), decreased concentration (1.76) and decreased control (1.74). For Women in their thirties, the symptom of pain was the most dominant (2.93) followed by autonomic reaction (2.69) and behavioral change (2.54), and for those in their forties, negative effect (3.06) was highest, followed by pain (2.97) and autonomic reaction (2.86). The overall symptoms of PMS significantly increased with age (20`: 2.07 points, 30`: 2.34 points, 40`: 2.47 points). There was no correlation of the BMI of the subjects with the symptoms of PMS, but there was a significant negative correlation between the symptoms of PMS and exercise frequency for women in their thirties and forties. Subjects in their twenties exhibited a significant negative correlation for PMS symptoms with the intake of carbohydrate (p
Objectives:
Premenstrual dysphoric disorder (PMDD) is a disabling condition affecting approximately 2% to 8% of women during reproductive age. It has been recently included in the mood disorder section of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, but its treatment as a primary psychiatric illness is still debated, because of the high prevalence of other mental disturbances in PMDD patients. On the other hand, clear clinical guidelines for PMDD patients not suffering from comorbid mental conditions are not yet available. The aim of the present study was therefore to systematically review the original articles pertaining to the treatment of PMDD in adult women free of any current or previous psychiatric comorbidity.
Methods:
We searched PubMed to identify published studies on PMDD, including randomized controlled trials, open-label trials, and case series or case reports involving adult women with no history of comorbid mental conditions. The search was conducted in April 2015.
Results:
We found 55 studies fulfilling our inclusion criteria, 49 of them focused on pharmacological/chemical agents and the remaining 6 on nonpharmacological interventions.
Conclusions:
Based on the results of our qualitative synthesis, the best therapeutic option in the treatment of adult PMDD patients free of other mental disorders are selective serotonin reuptake inhibitor antidepressants (especially paroxetine and fluoxetine) and low doses of oral estroprogestins. Other interventions, such as light therapy, cognitive behavioral therapy, food supplements, and herbal medicines, showed promising effects, but other investigations are needed to confirm their efficacy.
Premenstrual syndrome (PMS) is a combination of emotional, behavioral, and physical symptoms that occur in the premenstrual or luteal phase of the menstrual cycle. Approximately 5% of women with the severest form of PMS usually have symptoms that meet the diagnostic criteria for Premenstrual Dysphoric Disorder (PMDD). Women with severe PMS and PMDD have reported disruption in their social relationships, parenting roles, and work productivity as well as increased healthcare utilization. Premenstrual symptoms have been reported in women from menarche through perimenopause. PMS has been reported to be more common in women who assign negative attributions to premenstrual symptoms, have poor coping strategies and problem-solving abilities, and feel their symptoms are not in their control. One of the unique aspects of treating women with severe PMS and PMDD is that symptoms, though cyclical, may be present for 40 years of a woman's life.
Tryptophan (TRP), the precursor of serotonin (5-HT), is one of the most investigated amino-acids. TRP supplementation can increase 5-HT levels in the brain and for this reason numerous studies have investigated whether administration of TRP can positively influence social behavior that relies on serotonergic function. Here we review the available studies on TRP, to clarify if and under what circumstances TRP supplementation might modulate social behavior. TRP supplementation seems to improve control over social behavior in patients and individuals suffering from disorders or behaviors associated with dysfunctions in serotonergic functioning. In contrast, in healthy humans TRP supplementation seems to promote social behavior. Although more research is needed to disentangle and understand the relations between individual differences, TRP effectivity, 5-HT functioning, social interactions, and context, we conclude TRP can be a promising tool for modulating social behavior.
Clinically significant premenstrual symptoms occur in 25-50% of menstruating women, and 5% of menstruating women have severe premenstrual symptoms and impairment of functioning, defined as premenstrual dysphoric disorder. It is important that women chart their symptoms prospectively for two menstrual cycles to rule out other diagnoses. The etiology of severe premenstrual syndrome and premenstrual dysphoric disorder is multifactorial and involves neurotransmitters, neurosteroids, neuroendocrine factors, and circadian rhythms. Several effective treatment options exist, including antidepressants, hormones that suppress ovulation, anxiolytics, cognitive therapy, chasteberry, and calcium.
Determination of cysteamine and tryptophan is described by electrochemical methods using p-aminophenol-multiwall carbon nanotubes paste electrode. Cysteamine and tryptophan in mixture can each be measured independently from each other with a potential difference of 600 mV. The results showed that the electrocatalytic currents increased linearly with cysteamine and tryptophan concentrations over the ranges 0.5–300 µmol L−1 and 10.0–650 µmol L−1, respectively. The detection limits for cysteamine and tryptophan are found to be 0.14 and 5.9 µmol L−1, respectively. The proposed method is successfully employed for the determination of cysteamine in both capsule and urine samples.
Premenstrual dysphoria (PMD) is a severe form of premenstrual syndrome, causing a marked reduction in the quality of life for about 5% of all women of fertile age. The cardinal symptoms are irritability and anger, which surface regularly between ovulation and menstruation and disappear completely within a few days after the onset of menstruation. Other frequent symptoms are depressed mood, affect lability, tension, and carbohydrate craving. In placebo-controlled trials, the serotonin reuptake inhibitors (SRIs) clomipramine, fluoxetine, sertraline, paroxetine, and citalopram have proven very effective for PMD, with a response rate of 60% or higher; in contrast, nonserotonergic antidepressants are not effective. The onset of action of SRIs is rapid, allowing for intermittent administration during luteal phases only. The impressive effect of SRIs for PMD is probably not equivalent to the anti-depressant effect of these drugs, but is more likely to be a manifestation of the well-established influence of serotonin on aggression and irritability. It strongly reinforces the assumption that a major function of serotonergic neurons in the brain is to modulate sex-steroid - driven behavior.
Premenstrual syndrome (PMS) is considered as a health problem that affects millions of women of reproductive age and, in some cases, may be severe enough to be considered a premenstrual dysphoric disorder (PMDD). Both PMS and PMDD are composed of affective, behavioral, and physical symptoms. Risk factors identified that predispose to PMS/PMDD are age between 25 and 35 years, a psychiatric history, a family history of PMDD, unhealthy living habits, and stressful life events. In addition, a comorbidity of PMDD with various psychiatric disorders such as major depression and anxiety disorders has been established. Although the etiology is unknown, it is considered that PMDD is of a multifactorial nature and is likely to develop because of the interactions among genes, biological variables (the neurotransmitters and gonadal hormones), and environmental influences. The first-line treatment for PMDD is pharmacological with selective serotonin reuptake inhibitors. From a medical point of view there is some evidence of the efficacy of nonpharmacological treatments such as relaxation, aerobic, and cognitive behavioral therapy, which are used mostly in mild cases. The major criticisms made to the conceptualization of PMDD as a clinical syndrome focus on pathologizing women’s biology and its consequent medicalization, which perpetuated misconceptions related to menses. Medicine would be opened up to other fields such as anthropology, sociology, and gender studies with qualitative studies to look for context and meaning to women’s suffering. It has been suggested that it might be more appropriate to introduce the concept of premenstrual or perimenstrual experience instead of PMDD.
This study was designed to compare the incidence and severity of premenstrual syndrome (PMS) between normal (N = 85) and overweight or obese (N = 28) college female students and investigated correlation between PMS, nutrient intake, hematological index and psychological index (depression, anxiety, stress). Each subject was asked a Menstrual Discomfort Questionnaire (MDQ) for PMS by 5 Likert scale. The PMS scores of women in the normal weight subjects ranked in order of severity were water retention (2.71), followed by behavioral change (2.58), negative affect (2.46), pain (2.31), autonomic reaction (2.27), decreased concentration (2.16). The symptoms of 'pain' and 'behavioral change' of overweight or obese subject were significantly higher than those of normal subject (p < 0.05). And total cholesterol concentration of overweight or obese subjects was significantly higher than in normal subject (p < 0.05). There was a significant positive correlation (p < 0.05) between the symptoms of 'negative effect' and BMI. And the triglyceride concentration was positively related with 'water retention (p < 0.01)'. The symptoms of 'decreased concentration' were negatively correlated with calcium (p < 0.01) and vitamin B6 intake (p < 0.05). The depression score were positively related with symptoms of 'behavioral change (p < 0.05)', 'negative affect' (p < 0.01), and the anxiety score was positively correlated with 'behavioral change (p < 0.05)' and 'decreased concentration (p < 0.05)'. The stress score was positively correlated with 'decreased concentration (p < 0.01)', 'behavioral change (p < 0.05)' and 'negative affect (p < 0.05)'. This suggests that PMS represents the clinical manifestation of a calcium, vitamin B6 deficiency and psychological disorder. Therefore we concluded that nutrient supplementation, depression and stress management may help to relieve PMS symptoms.
N-(3,4-Dihydroxyphenethyl)-3,5-dinitrobenzamide modified-multiwall carbon nanotubes paste electrode was fabricated
and used as an electrocatalyst for the oxidation of ascorbic acid (AA), acetaminophen (AC), and tryptophan
(TP) at pH 7.0. In a mixture containing AA, AC, and TP, the separation potentials were large enough to determine
those compounds individually and simultaneously. The peak currents obtained were found to be linearly dependent
on AA, AC, and TP concentrations in the ranges of 0.03–70, 0.6–452, and 0.7–270 mmolL�1, respectively. The sensor
was used for the determination of AC, AC, and TP in different real samples with satisfactory results.
The recent inclusion of research diagnostic criteria for premenstrual dysphoric disorder (PMDD) in the DSM-IV recognises the fact that some women in their reproductive years have extremely distressing emotional and behavioural symptoms premenstrually. Through the use of these criteria, PMDD can be differentiated from premenstrual syndrome (PMS) which has milder physical symptoms, i.e. breast tenderness, bloating, headache and minor mood changes. PMDD can also be differentiated from premenstrual exacerbation of a current psychiatric disorder or medical condition, although some women may meet criteria for a dual diagnosis.
Epidemiological surveys have estimated that as many as 75% of women with regular menstrual cycles experience some symptoms of PMS. PMDD, on the other hand, is much less common. It affects only 3 to 8% of women in this group, but it is more severe and exerts a much greater psychological toll. These women report premenstrual symptoms that seriously interfere with their lifestyle and relationships. The aetiology of PMDD is largely unknown but the current consensus seems to be that normal ovarian function (rather than hormone imbalance) is the cyclical trigger for PMDD-related biochemical events within the CNS and other target organs.
The serotonergic system is in close reciprocal relationship with the gonadal hormones and has been identified as the most plausible target for interventions. Thus, beyond the conservative treatment options such as lifestyle and stress management, and the more extreme interventions that eliminate ovulation altogether, the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are emerging as the most effective treatment options for this population.
Results from several randomised placebo-controlled trials in women with PMDD, with predominantly psychological symptoms of irritability, tension, dysphoria and lability of mood, have clearly demonstrated that the SSRIs have excellent efficacy and minimal adverse effects. More recently, several preliminary studies indicate that intermittent (premenstrually only) treatment with SSRIs is equally effective in these women and, thus, may offer an attractive treatment option for a disorder that is itself intermittent.
N-(3,4-dihydroxyphenethyl)-3,5-dinitrobenzamide modified multiwall carbon nanotubes paste electrode was used as a voltammetric sensor for oxidation of penicillamine (PA), uric acid (UA) and tryptophan (TP). In a mixture of PA, UA and TP, those voltammograms were well separated from each other with potential differences of 300, 610, and 310 mV, respectively. The peak currents were linearly dependent on PA, UA and TP concentrations in the range of 0.05–300, 5–420, and 1.0–400 µmol L−1, with detection limits of 0.021, 2.0, and 0.82 µmol L−1, respectively. The modified electrode was used for the determination of those compounds in real samples.
Seasonal affective disorder (SAD) and premenstrual dysphoric disorder (PMDD) share many clinical features, and have been associated with brain serotonin dysfunction. Females with SAD frequently fulfil the diagnostic criteria for PMDD. A polymorphism in the serotonin transporter promoter gene (5-HTTLPR) has been associated with SAD. We investigated the role of family history and 5-HTTLPR in female SAD patients with and without PMDD. Forty-four SAD females with, and 43 SAD females without PMDD, were genotyped for 5-HTTLPR. Family history of affective disorders in first degree relatives was assessed. An association between the presence of PMDD and family history (P=0.0029) and 5-HTTLPR long/short allele-heterozygosity (P=0.033) was found in females with SAD. PMDD and SAD may share genetic vulnerability factors, one candidate gene being 5-HTTLPR. The elevated rate of affective disorders in relatives of patients with SAD and PMDD suggests higher genetic vulnerability in this subgroup when compared to patients with SAD alone.
The cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the dopamine metabolite homovanillic acid (HVA) were measured in a group of drug-free non-depressed women with premenstrual syndrome (PMS) (late luteal phase dysphoric disorder) (n = 13) and in controls with no premenstrual complaints (n = 13). In six patients and eight controls, CSF samples from both the luteal and the follicular phase were obtained, whereas in the remainder of the subjects, samples from either the follicular phase (patients: 4, controls: 2) or the luteal phase (patients: 3, controls: 3) were taken. The following observations were made: (1) Neither in the follicular phase nor in the luteal phase did the mean concentrations of CSF monoamine metabolites in the PMS group differ from the corresponding values in the control group. (2) Neither in the PMS group nor in the control group did the mean concentrations of monoamine metabolites in CSF samples obtained in the luteal phase differ from the corresponding values obtained in the follicular phase. (3) The intraindividual, intersample variations of CSF HVA and 5-HIAA concentrations were significantly smaller in the PMS group than in the control group. (4) CSF HVA correlated strongly to CSF 5-HIAA in the luteal phase of both patients and controls whereas in the follicular phase, particularly in controls, this correlation was much weaker. (5) In the luteal phase, the CSF HVA/5-HIAA ratio correlated negatively to serum levels of estradiol, progesterone, and testosterone. (6) The CSF HVA/5-HIAA ratio was significantly lower in PMS patients than in controls. (7) A positive correlation between CSF MHPG and serum luteinizing hormone was observed in the follicular phase. (8) A positive correlation between CSF HVA and serum prolactin was observed in the luteal phase. Because the study was comprised of a small number of subjects, the reported findings until replicated should be interpreted with caution.
Although its etiology is unknown, it has been hypothesized that premenstrual syndrome (PMS) is linked to a deficiency of central serotoninergic activity. In the present study, we evaluated the effect of fluoxetine, a specific serotonin uptake inhibitor, on PMS symptoms.
Following extensive screening, including several psychological inventories, eight women with severe persistent PMS participated in a 6-month double-blind, placebo-controlled, crossover study which included three months each of daily fluoxetine 20 mg or placebo, administered in a randomized order. Symptoms were evaluated using the Calendar of Premenstrual Experiences and other psychometric measures.
Compared with placebo, treatment with fluoxetine was associated with an improvement in PMS symptoms as judged by highly significant decreases in behavioral (P less than .005), physical (P less than .05), and total (P less than .005) Calendar of Premenstrual Experiences scores; Beck Depression Inventory scores (P less than .005); Profile of Mood States subscales scores including depression (P less than .005), tension (P less than .005), and anger (P less than .01); and State-Trait Anxiety Inventory scores. The use of fluoxetine was associated with a greater mean reduction in behavioral (75%) than in physical scores (40%), with a mean decrease in total Calendar of Premenstrual Experiences scores of 62%, which rendered these scores similar to follicular phase values. Thus, the luteal phase symptomatology of PMS was effectively abolished. At this dose, no significant side effects or complications were noted during treatment.
Fluoxetine appears to be a highly effective, well-tolerated treatment for the psychological and physical symptoms accompanying severe PMS.
A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness.
Plasma tryptophan was reduced by 89% 5 hours after the administration of the tryptophan-deficient amino acid mixture. Six of 20 subjects with a family history of affective illness and none of 19 subjects without a family history of psychiatric illness showed a lowering of mood of 10 or more points on the Profile of Mood States depression scale (P = .012, Fisher's Exact Test) 5 hours after tryptophan depletion. No significant mood changes were observed following the control treatment (balanced amino acid mixture) in either group.
Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.
Thirteen patients diagnosed during two menstrual cycles as suffering from late luteal phase dysphoric disorder were then followed in an open pilot study for a further three cycles. During one complete cycle, baseline levels of symptoms were obtained. During the next three cycles, the patients were treated with L-tryptophan, six grams per day. L-tryptophan treatment was associated with a significant amelioration of symptoms with only mild side effects. These data suggest that L-tryptophan should be tested at a dose of six grams of L-tryptophan per day in a placebo-controlled study in patients with late luteal phase dysphoric disorder who suffer from symptoms such as depression, irritability, insomnia and carbohydrate craving, which may respond to potentiation of serotonin function.
Recent studies indicate that antidepressant drugs with potent serotonin reuptake inhibiting properties are effective in reducing the symptoms of premenstrual syndrome (PMS). In order to elucidate whether all antidepressant drugs are equally effective in the treatment of PMS or whether potent serotonin reuptake inhibition is a prerequisite for reducing premenstrual complaints, women suffering from severe PMS were treated daily for three menstrual cycles with a selective serotonin reuptake inhibitor, paroxetine (n = 22), or with a selective noradrenaline reuptake inhibitor, maprotiline (n = 21); in addition, a placebo group was included (n = 22). Six symptoms (irritability, depressed mood, tension/anxiety, increased appetite/craving for carbohydrates, bloating, and breast tenderness) were rated by the participants daily throughout the study. With respect to all outcome measurements, the symptom reduction obtained with paroxetine was significantly superior to that obtained with placebo; with respect to irritability, increased appetite/carbohydrate craving, bloating, and breast tenderness, as well as global self-rating, paroxetine was significantly superior also to maprotiline. The clear-cut superiority of paroxetine over maprotiline indicates that not all antidepressant drugs are equally effective in the treatment of PMS; rather, like panic disorder and obsessive compulsive disorder, but in contrast to depression, PMS apparently responds better to serotonin reuptake inhibitors than to antidepressants with a noradrenergic profile.
The importance of serotonin in the pathogenesis of bipolar affective disorder continues to be documented through investigation of the serotonin precursor tryptophan. Evidence suggests that serotonergic neurotransmission is augmented by lithium. In the four cases of maintenance therapy reported here, clinical response to lithium carbonate is enhanced by giving tryptophan to bipolar patients who are resistant to lithium monotherapy. Abrupt discontinuation of tryptophan will produce the recurrence of symptoms. Furthermore, when tryptophan is reintroduced, the benefits to mood stability originally achieved with a lithium-tryptophan combination may not always be duplicated to the same degree. This suggests that readjustments to or discontinuation of tryptophan should always be gradual.
Background
Premenstrual dysphoria shares certain features with depression and anxiety states, which have been linked to serotonergic dysregulation. We evaluated the efficacy and safety of fluoxetine (which selectively inhibits the reuptake of serotonin) in the treatment of premenstrual dysphoria.
Methods
The trial consisted of a single-blind, placebo washout period lasting two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial of fluoxetine at a dose of either 20 mg or 60 mg per day or placebo for six menstrual cycles. Healthy women meeting criteria for what was then called late-luteal-phase dysphoric disorder were recruited at seven university-affiliated women's health clinics in Canada. The primary outcome measure consisted of visual-analogue scales for tension, irritability, and dysphoria during the late luteal phase of each cycle.
Results
Of 405 women enrolled in the placebo washout period, 313 subsequently entered the randomized phase of the study, which lasted six menstrual cycles, and 180 completed it. Fluoxetine at a dose of 20 or 60 mg per day was significantly superior to placebo in reducing symptoms of tension, irritability, and dysphoria, as measured by the visual-analogue scales (P<0.001). The women who received 60 mg of fluoxetine per day reported significantly more side effects than those who received 20 mg per day or placebo (P<0.001).
Conclusions
Fluoxetine is useful in the treatment of premenstrual dysphoria. Treatment with fluoxetine at a dose of 20 mg per day reduces the potential for side effects while maximizing therapeutic efficacy.
The dyadic adjustment scale is critically evaluated by reconsidering the factor structure of the scale and its subscales using a maximum likelihood, confirmatory factor-analysis procedure. A new sample is studied three years later from the same geographical area. High reliability was confirmed for the overall scale. The four subscale factors appear robust and account for 94% of the covariance among the items, although subscale affiliations were not perfectly replicated in the confirmatory factor solution. The findings of the re-evaluation are encouraging, suggesting that confidence in the scale is warranted for subsequent users.
Methods:
A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness.Results:
Plasma tryptophan was reduced by 89% 5 hours after the administration of the tryptophan-deficient amino acid mixture. Six of 20 subjects with a family history of affective illness and none of 19 subjects without a family history of psychiatric illness showed a lowering of mood of 10 or more points on the Profile of Mood States depression scale (P=.012, Fisher's Exact Test) 5 hours after tryptophan depletion. No significant mood changes were observed following the control treatment (balanced amino acid mixture) in either group.Conclusions:
Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.
This study reports on the development of the Dyadic Adjustment Scale, a new measure for assessing the quality of marriage and other similar dyads. The 32 item scale is designed for use with either married or unmarried cohabiting couples. Despite widespread criticisms of the concept of adjustment, the study proceeds from the pragmatic position that a new measure, which is theoretically grounded, relevant, valid, and highly reliable, is necessary since marital and dyadic adjustment continue to be researched. This factor analytic study tests a conceptual definition set forth in earlier work and suggests the existence of four empirically verified components of dyadic adjustment which can be used as subscales [dyadic satisfaction, dyadic cohesion, dyadic consensus and affectional expression]. Evidence is presented suggesting content, criterion related, and construct validity. High scale reliability is reported. The possibility of item weighting is considered and endorsed as a potential measurement technique, but it is not adopted for the present Dyadic Adjustment Scale. It is concluded that the Dyadic Adjustment Scale represents a significant improvement over other measures of marital adjustment, but a number of troublesome methodological issues remain for future research.
Context.
—Premenstrual dysphoric disorder is an important cause of symptoms and functional impairment in menstruating women.
The Pleasant Events Schedule is a behavioral self-report inventory of potentially reinforcing events. The test–retest method, involving 181 Ss of various ages and social classes, demonstrated good to excellent stability for the 8 most used scales of the schedule across periods of 1, 2, and 3 mo. Concurrent validity was assessed by comparison with peer and observer ratings. Predictive validity of the test's frequency ratings was studied in relation to subsequent self-monitoring data, while predictive validity of test enjoyability ratings was determined by comparison with subsequent choice behavior. Construct validity was inferred from the results of other research. Adequate validity of all types was found. Scale intercorrelations are also reported, and the question of response bias is addressed. (29 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Thirty-eight subjects who met criteria for the DSM-III-R diagnosis late luteal phase dysphoric disorder (LLPDD) were compared with 18 controls in 5-HT uptake kinetics of the platelets in the premenstrual (day 26) as well as in the postmenstrual phase (day 4) of the cycle. Furthermore, 5-hydroxytryptophan (5-HTP) was administered to LLPDD patients and controls in both phases of the cycle, to investigate pituitary sensitivity for serotonin. Plasma samples for the measurement of cortisol and beta-endorphin were taken before and after oral administration of 200 mg 5-HTP, and considered as an index of pituitary-adrenal function. LLPDD was not associated with a lower platelet 5-HT uptake and content in the premenstrual phase of the cycle, compared with the postmenstrual phase. Patients appeared not to be different from controls in 5-HT uptake kinetics of platelets in the premenstrual phase of the cycle. No main differences were observed between LLPDD patients and controls in their ability to respond with secretion of cortisol and beta-endorphin to 5-HTP stimulation, either in the premenstrual, or in the postmenstrual phase. This observation could not be attributed to differences in 5-HTP metabolism. The findings of the present study do not support a specific role for 5-HT in the pathophysiology LLPDD.
An abnormality of the serotonin system may play a role in the genesis of the symptoms of premenstrual syndrome, especially those related to mood and appetite. Whole blood and platelet uptake of serotonin are decreased during the luteal phase in women with premenstrual syndrome. The ratio of L-tryptophan (the amino acid precursor of serotonin) to the sum of the other neutral amino acids that compete for the same protein carrier cerebral uptake mechanism has been suggested to reflect central L-tryptophan levels and resultant serotonin levels in the brain. We evaluated the ratio of plasma L-tryptophan to the sum of five competing neutral amino acids in women with premenstrual syndrome and in controls. There were no significant differences between groups or across time, suggesting that it is unlikely that the aberrations of the serotonergic system in women with premenstrual syndrome are due to saturation of the tryptophan-carrying protein.
SYNOPSIS
The neuroendocrine response to L-tryptophan infusion was measured at two stages of the menstrual cycle, premenstrually and postmenstrually, in 13 women with and 13 women without premenstrual depression (the MC and NMC groups respectively). Previous studies have shown that in non-depressed women, this challenge test results in an increase in circulating prolactin and growth hormone. In depressed women both responses are blunted. In this study the growth hormone and cortisol responses were smaller in the MC group than the NMC group on both occasions. The prolactin response was blunted premenstrually compared with postmenstrually in both groups. These findings suggest that women who experience premenstrual depression may have neuroendocrine abnormalities throughout the cycle. The neurotransmitter abnormalities reflected in these altered endocrine responses appear to interact with neuroendocrine changes that normally occur premenstrually resulting in a vulnerability to depression at that phase of the cycle.
This double-blind, placebo-controlled study tested the effectiveness of tryptophan (TRP) in the treatment of aggressive psychiatric inpatients. After a baseline observation period of 1 month, patients were randomly assigned to treatment either with TRP (up to 6 g/day) or with placebo. There were 10 subjects in each treatment group. These treatments were administered for 25-35 days, after which the patients were observed for 1 month. Throughout this study, patients were receiving other medications. Injections of antipsychotics and sedatives were administered as needed to control agitated or violent behavior. Blood levels of TRP and other large neutral amino acids were obtained repeatedly, and ratios between TRP and other amino acids were computed. These analyses confirmed significant increases of TRP ratios in TRP-treated patients. TRP treatment had no effect on the number of violent incidents, but it significantly reduced the need for injections of antipsychotics and sedatives. The study thus provided indirect support for beneficial effects of TRP in aggressive psychiatric inpatients.
Despite many associations between late luteal phase dysphoric disorder (LLPDD) and major depression, there have been no placebo-controlled trials of an antidepressant in this disorder.
The authors conducted a double-blind, randomized, placebo-controlled trial of fluoxetine in the treatment of LLPDD. The diagnosis of LLPDD was based on daily, prospective self-rating forms that subjects completed over two menstrual cycles. Subjects with other psychiatric disorders, determined by the Schedule for Affective Disorders and Schizophrenia interview, were excluded from the study. Women who continued to meet criteria for LLPDD after a single-blind trial of placebo were randomly assigned to treatment for two menstrual cycles with either fluoxetine 20 mg/day (N = 10) or placebo (N = 10).
Nine of the 10 subjects receiving fluoxetine responded to treatment, whereas only 2 of the 10 receiving placebo did (p less than .0003). Symptoms decreased significantly in all 10 LLPDD diagnostic categories in the fluoxetine-treated group. All subjects taking fluoxetine elected to continue with this treatment after completion of the study.
These results suggest that fluoxetine is an effective and well-tolerated treatment for LLPDD.
Twenty women with premenstrual complaints were treated in a double-blind placebo controlled trial during two consecutive menstrual cycles with fluvoxamine, a selective serotonin uptake blocker. A beneficial effect was found on somatic and affective symptoms in both treatment groups, the effect of fluvoxamine being not different from placebo. The results of this study do not support a role for serotonin in menstrually related affective symptoms.
The authors examined the reporting of daily life events by women with prospectively confirmed menstrual-related mood disorder (N = 40) and asymptomatic control subjects (N = 20). During the follicular and late luteal phases of the menstrual cycle, subjects completed a schedule of life events that monitors an individual's perception of 1) the frequency of occurrence of life events and 2) the degree of associated distress or pleasure. The patient group reported significantly more negative life events than the control group. Further, the patients with menstrual-related mood disorder showed significantly more distress associated with the same event when it occurred in the premenstrual phase than when it occurred in the post-menstrual phase.
The ability of d-fenfluramine, a drug that releases brain serotonin and blocks its reuptake, to relieve premenstrual depression and excessive calorie and carbohydrate intakes was examined in 17 women with premenstrual syndrome. Subjects received d-fenfluramine (15 mg twice daily) or placebo, in random order, during the luteal phases of six menstrual cycles; ie, for three control and three treatment cycles each. Behavior was assessed with the Hamilton Rating Scale for Depression and its Addendum, and intakes of calories and nutrients were measured by allowing subjects unlimited access to isocaloric meal and snack foods rich in carbohydrates or protein. Pre-treatment follicular scores using the Hamilton Rating Scale for Depression and its Addendum were 2.0 +/- 0.5 and 0.5 +/- 0.5 (mean +/- SEM), respectively; corresponding luteal scores were 21.2 +/- 0.8 and 10.2 +/- 0.6 (P less than .0001). Luteal phase intakes of kilocalories, carbohydrates, and fats were also increased above follicular levels (P less than .01). d-Fenfluramine decreased premenstrual Hamilton Rating Scale for Depression and Addendum scores by 62% (P less than .001) and 60% (P less than .001), respectively; placebo reduced them by only 28% (P less than .02) and 30% (P less than .02). d-Fenfluramine also fully suppressed the premenstrual rise in kilocalorie, carbohydrate, and fat intakes (P less than .01).
There are no reports on treatment of premenstrual syndrome with antidepressants, although depression is a common symptom of the syndrome. Eleven women who met DSM-III-R criteria for late luteal phase dysphoric disorder were treated with nortriptyline in an open pilot study after they failed to respond to placebo or another medication. Eight of 11 patients had a good therapeutic response. The efficacy of antidepressants in the treatment of premenstrual depression needs confirmation with double-blind studies.
Synopsis
Visual Analogue Scales (VAS) provide a simple technique for measuring subjective experience. They have been established as valid and reliable in a range of clinical and research applications, although there is also evidence of increased error and decreased sensitivity when used some subject groups. Decisions concerned with the choice of scoring interval, experimental design, and statistical analysis for VAS have in some instances been based on convention, assumption and convenience, highlighting the need for more comprehensive assessment of individual scales if this versatile and sensitive measurement technique is to be used to full advantage.
We examined the use of a six-item linear analog scoring system comprised of three somatic and three mood-related items for the documentation of premenstrual syndrome. One hundred forty women with suspected premenstrual syndrome completed the linear analog scale, as well as the validated 36-item Self-Rating Scale for Premenstrual Tension Syndrome and the 35-item Prospective Record of the Impact and Severity of Menstrual Symptomatology calendar. Ninety patients and 20 normal control subjects completed two cycles of records. With use of clinical criteria and self-rating scale scores as the "gold standard," 73 patients were diagnosed as having premenstrual syndrome. Linear analog scale scores were highly correlated with both self-rating scale scores (r = 0.72, day 9; r = .66, day 27; p = 0.001) and prospective record scores (r = 0.74, day 9; r = 0.60, day 27; p = 0.001). Our results suggest that the linear analog scale may be a useful clinical tool in the study of premenstrual syndrome. Because of its simplicity, the linear analog scale may increase patient compliance. Because of its sensitivity to detect changes in symptom severity throughout the menstrual cycle, it may prove useful in evaluating the effects of therapy for premenstrual syndrome.
The presence of a premenstrual tension syndrome (PMTS) should be considered during the clinical assessment of any women of childbearing age with intermittent or fluctuating psychological symptoms. Appropriate identification of this disorder depends on knowledge of its specific diagnostic features, most particularly its time-limited course. The clinician must also be aware that the syndrome can coexist with, exacerbate, or be exacerbated by other psychological distress or illness. Through the presentation of four case histories, the authors discuss the diagnostic complexities of PMTS and the treatment implications of a diagnosis of PMTS.
This paper reports reliability and validity data on the Unpleasant Events Schedule (UES), a 320-item scale that assesses stressful life events. The UES assesses both the frequency and aversiveness of events within a 1-month time frame. Rational, empirical, and factorial scales were derived from the UES. Of these, nine scales were retained that were mutually independent, demonstrated good internal reliability, and tapped various dimensions of clinical interest. A short 53-item form of the UES also was developed. The UES correlated moderately (r = .37) with depression. A discriminant analysis revealed that the UES contributed significantly above and beyond scores on the PES (MacPhillamy & Lewinsohn, 1982) to the proportion of variance in discriminating depressed from nondepressed subjects.
The behavioral effects of altering serotonin neurotransmission by chronic drug treatments in socially living vervet monkeys (Cercopithecus aethiops sabaeus) were examined. Animals received tryptophan (TRP, 20 mg/kg/day), parachlorophenylalanine (PCPA, 80 mg/kg/day), 5-hydroxytryptophan (5-HTP, 40 mg/kg/day), chlorgyline (10 mg/kg/day), or PCPA followed by concurrent PCPA and 5-HTP. Grooming, approaching, resting, and eating were increased by TRP and decreased by PCPA; TRP decreased and PCPA increased locomoting, avoiding, being solitary, and being vigilant. Grooming, being vigilant, and receiving aggression were increased by 5-HTP, and PCPA increased initiating aggression and decreased huddling. Concurrent administration of 5-HTP and PCPA reversed the effects of PCPA on approaching, grooming, and resting; augmented the PCPA effects on avoiding, being solitary, and aggression; and did not alter the PCPA effects on eating, locomoting, and huddling. Chlorgyline increased grooming, approaching, and being vigilant and decreased being solitary. No treatment significantly affected sexual behavior. These data suggest that serotonergic systems contribute relatively substantially to the mediation of grooming and approaching, participate less strongly in resting and locomoting, are implicated still more weakly in being solitary, avoiding, and being vigilant, and have little if any involvement in huddling, aggression, and sexual behavior.
For prospective longitudinal confirmation of menstrually related mood changes, the authors selected a 100-mm visual analogue scale for twice-daily self-rating of mood. The advantages of this method are simplicity; increased compliance; ease of graphic presentation, allowing evaluation of severity and relationship to menstruation; and greater uniformity among studies of menstrually related syndromes. In a preliminary application of this measure to 20 women with self-diagnosed premenstrual syndrome, eight (40%) had a mean depression rating during the week before menstruation that was 30% higher than during the week after cessation of menstruation.
Techniques that describe the use of covariance when heterogeneity of slopes exists are severely limited. Although a few procedures for model selection have been recommended, none, except the hierarchical approach, is straightforward and usable with present computer programs. The hierarchical subset selection procedure presented in this paper is based on the proposition that heterogeneity may be present only for certain terms in the model. After hierarchical selection, those terms which do not involve heterogeneity are interpreted as in the usual analysis for covariance. The interpretations of those terms which do involve heterogeneity are modified with respect to significance tests performed at various values of the covariate. The hierarchical subset selection method allows one to investigate heterogeneity of slopes in covariance models as functions of the classification variables present in the design.
For some patients psychopathology, although not aggression, seemed to be exacerbated by the tryptophan. This was a surprising conclusion as previous studies have found little or no effect of tryptophan (given in the absence of a monoamine oxidase inhibitor) in chronic schizophrenia. However, tryptophan may be useful in treating aggressive symptoms in patients with poor impulse control who were characterized in this study as having high Buss-Durkee scores, high lifetime aggression frequency, and normal GSRs. Although aggressive behavior has been linked to many neurotransmitters the present study indicates that 5HT can be manipulated in a simple way through administration of the nontoxic dietary 5HT precursor, tryptophan, to modulate aggressive symptomatology.
The premenstrual syndrome (PMS) is a major clinical entity afflicting a large segment of the female population. Available information are descriptive in nature and the etiology of this syndrome remains unclear. In this review, both biochemical and psychosocial elements of the syndrome have been explored in an effort to redefine the pathophysiology of this seemingly multifactorial psychoneuroendocrine dysfunction. We propose that luteal phase sensitivity to and subsequent withdrawal from the central effects of the neuropeptides beta-endorphin and alpha-melanocyte-stimulating hormone result in a cascade of neuroendocrine changes within the brain-hypothalamus-pituitary complex. Modulation of neurotransmitter function by these peptides may produce alterations in mood and behavior as well as enhance pituitary release of prolactin and vasopressin. Variable gonadal steroid modulation of these responses from subject to subject likely accounts for the heterogeneous clinical manifestations of the PMS.
A 63-year-old woman with bipolar II illness failed to respond to imipramine and lithium but responded well to a trial of L-tryptophan alone for 11 months. Although doses and mechanisms have not yet been determined, L-tryptophan may be a treatment alternative when lithium is ineffective.
Synopsis
One hundred and fifteen patients from 5 general practices participated in a 12-week, double-blind study comparing L-tryptophan, amitriptyline, L-tryptophan–amitriptyline combination and placebo in the treatment of depression. Analysis of total score on the Hamilton Depression Scale and a global rating of depression showed that all 3 active treatments were more effective than placebo. Significantly more patients were withdrawn as treatment failures in the placebo group compared with the active treatment groups. Side-effects necessitated withdrawal of more patients from the amitriptyline group than from the other active tratment groups, but this difference was not significant. Plasma amitriptyline and nortriptyline levels were similar in the difference was not significant. Plasma amitriptyline and nortriptyline and biochemical profiles did not alter significantly in any group, but mean heart rate was significantly increased in patients receiving amitriptyline. There was no change in free or total plasma tryptophan concentration with treatment or on remission of symptoms.
Research diagnostic criteria for premenstrual tension syndrome (PMTS) are developed using data collected from a study of 42 women who were suffering from severe PMTS but were well at other times. Two specific scales are also devised for rating the severity of PMTS, a 36-item self-report questionnaire and a 10-item scale for use by therapist/researcher. It is proposed that after further evaluation and validation, these instruments may permit more useful comparisons of data on the etiology and treatment of this disorder.
The cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the dopamine metabolite homovanillic acid (HVA) were measured in a group of drug-free non-depressed women with premenstrual syndrome (PMS) (late luteal phase dysphoric disorder) (n = 13) and in controls with no premenstrual complaints (n = 13). In six patients and eight controls, CSF samples from both the luteal and the follicular phase were obtained, whereas in the remainder of the subjects, samples from either the follicular phase (patients: 4, controls: 2) or the luteal phase (patients: 3, controls: 3) were taken. The following observations were made: (1) Neither in the follicular phase nor in the luteal phase did the mean concentrations of CSF monoamine metabolites in the PMS group differ from the corresponding values in the control group. (2) Neither in the PMS group nor in the control group did the mean concentrations of monoamine metabolites in CSF samples obtained in the luteal phase differ from the corresponding values obtained in the follicular phase. (3) The intraindividual, intersample variations of CSF HVA and 5-HIAA concentrations were significantly smaller in the PMS group than in the control group. (4) CSF HVA correlated strongly to CSF 5-HIAA in the luteal phase of both patients and controls whereas in the follicular phase, particularly in controls, this correlation was much weaker. (5) In the luteal phase, the CSF HVA/5-HIAA ratio correlated negatively to serum levels of estradiol, progesterone, and testosterone. (6) The CSF HVA/5-HIAA ratio was significantly lower in PMS patients than in controls. (7) A positive correlation between CSF MHPG and serum luteinizing hormone was observed in the follicular phase. (8) A positive correlation between CSF HVA and serum prolactin was observed in the luteal phase. Because the study was comprised of a small number of subjects, the reported findings until replicated should be interpreted with caution.
Premenstrual dysphoria shares certain features with depression and anxiety states, which have been linked to serotonergic dysregulation. We evaluated the efficacy and safety of fluoxetine (which selectively inhibits the reuptake of serotonin) in the treatment of premenstrual dysphoria.
The trial consisted of a single-blind, placebo washout period lasting two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial of fluoxetine at a dose of either 20 mg or 60 mg per day or placebo for six menstrual cycles. Healthy women meeting criteria for what was then called late-luteal-phase dysphoric disorder were recruited at seven university-affiliated women's health clinics in Canada. The primary outcome measure consisted of visual-analogue scales for tension, irritability, and dysphoria during the late luteal phase of each cycle.
Of 405 women enrolled in the placebo washout period, 313 subsequently entered the randomized phase of the study, which lasted six menstrual cycles, and 180 completed it. Fluoxetine at a dose of 20 or 60 mg per day was significantly superior to placebo in reducing symptoms of tension, irritability, and dysphoria, as measured by the visual-analogue scales (P < 0.001). The women who received 60 mg of fluoxetine per day reported significantly more side effects than those who received 20 mg per day or placebo (P < 0.001).
Fluoxetine is useful in the treatment of premenstrual dysphoria. Treatment with fluoxetine at a dose of 20 mg per day reduces the potential for side effects while maximizing therapeutic efficacy.
Recent studies indicate that antidepressant drugs with potent serotonin reuptake inhibiting properties are effective in reducing the symptoms of premenstrual syndrome (PMS). In order to elucidate whether all antidepressant drugs are equally effective in the treatment of PMS or whether potent serotonin reuptake inhibition is a prerequisite for reducing premenstrual complaints, women suffering from severe PMS were treated daily for three menstrual cycles with a selective serotonin reuptake inhibitor, paroxetine (n = 22), or with a selective noradrenaline reuptake inhibitor, maprotiline (n = 21); in addition, a placebo group was included (n = 22). Six symptoms (irritability, depressed mood, tension/anxiety, increased appetite/craving for carbohydrates, bloating, and breast tenderness) were rated by the participants daily throughout the study. With respect to all outcome measurements, the symptom reduction obtained with paroxetine was significantly superior to that obtained with placebo; with respect to irritability, increased appetite/carbohydrate craving, bloating, and breast tenderness, as well as global self-rating, paroxetine was significantly superior also to maprotiline. The clear-cut superiority of paroxetine over maprotiline indicates that not all antidepressant drugs are equally effective in the treatment of PMS; rather, like panic disorder and obsessive compulsive disorder, but in contrast to depression, PMS apparently responds better to serotonin reuptake inhibitors than to antidepressants with a noradrenergic profile.
