Alprazolam in the treatment of premenstrual syndrome. A double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of alprazolam in the treatment of premenstrual syndrome. DESIGN: A randomized, double-blind, placebo-controlled, crossover trial of alprazolam during eight menstrual cycles. SETTING: Outpatient clinic at the National Institute of Mental Health, Bethesda, Md. PARTICIPANTS: Twenty-two women with prospectively confirmed premenstrual syndrome entered this study. All subjects were either self-referred or were referred by their physicians. All reported having regular menstrual cycle lengths, were taking no medication, and were free of current or recent medical or psychiatric illness. Two subjects did not complete the trial. INTERVENTION: Participants were assigned to receive alprazolam or placebo as follows: cycle 1, 0.25 mg of alprazolam or placebo three times daily beginning on menstrual cycle day 16; cycle 2, 0.50 mg of alprazolam or placebo three times daily according to the regimen during the first cycle; cycles 3 and 4, 0.75 mg of alprazolam or placebo three times daily from menstrual cycle day 16 and continued throughout the fourth menstrual cycle to evaluate the efficacy of relatively long-term (approximately 6 weeks) treatment with alprazolam. MAIN OUTCOME MEASURES: Daily self-report symptoms ratings were completed during the entire study period. RESULTS: We observed no significant differences in the severity of premenstrual symptom ratings during alprazolam administration compared with placebo on any scale except the Beck Depression Inventory Scale. The Beck Depression Inventory ratings demonstrated a statistically (F1,19 = 7.1, P < .05), but not clinically, significant improvement in depressive symptoms during alprazolam administration compared with placebo. CONCLUSION: Our findings do not support alprazolam as a uniformly effective treatment for the symptoms of premenstrual syndrome.

Thyroid function in women with premenstrual syndrome.

UNLABELLED: We have examined the relationship between thyroid function and the presence of symptoms in women with prospectively confirmed premenstrual syndrome (PMS) in the following ways: 1) basal thyroid function tests (n = 124); 2) thyroid auto-antibody levels (n = 63); 3) TRH stimulation tests performed during the follicular phase (n = 39) or during both the follicular and luteal phase (n = 21); and 4) the efficacy of L-T4 in the treatment of PMS (n = 30). RESULTS: Thirteen women (10.5%) had basal evidence of either grade I or II hypothyroidism or hyperthyroidism. Elevated thyroid auto-antibody titers were observed in eight women (13%). Eighteen women (30%) (all with normal basal TSH levels) had abnormal responses to TRH, either blunted (n = 6) or exaggerated (n = 12). L-T4 was not superior to placebo in the treatment of PMS in a double blind placebo controlled cross-over trial. Although it is clear that PMS is not simply masked hypothyroidism, abnormalities of stimulated thyroid function appear with greater than expected frequency in women with PMS and may define a subgroup of women with this disorder. L-T4 supplementation appears to have no place in the routine management of PMS.

A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine-treated patients with obsessive-compulsive disorder.

In this study, 16 patients with obsessive-compulsive disorder (OCD) who had partially improved during at least 6 months of treatment with clomipramine were sequentially treated with triiodothyronine and lithium carbonate in an 8-week double-blind cross-over study. Both triiodothyronine and lithium carbonate have been reported to be efficacious in open trials as adjunctive agents when combined with tricyclics in the treatment of OCD and depressed patients. However, in our controlled study, OCD and depressive symptoms, as assessed by standardized rating scales in the patient group as a whole, did not significantly change after either adjuvant treatment. Further analysis on an individual patient basis revealed that neither adjuvant medication was associated with a clinically meaningful change (greater than 25%) in OCD symptoms. However, lithium, but not triiodothyronine, adjuvant therapy was associated with a 25% or greater reduction in depression scores in 44% of the patients. This controlled study lends further support to the contention that OCD may represent a disorder with characteristics distinct from affective disorders.

Lack of effect of induced menses on symptoms in women with premenstrual syndrome.

BACKGROUND: No physiologic abnormality of the luteal phase has been consistently demonstrated in women with premenstrual syndrome (PMS). Using the progesterone antagonist mifepristone, we truncated the late luteal phase of the menstrual cycle in a blinded fashion to evaluate the relation of the events of the late luteal phase to the symptoms of PMS. METHODS: Fourteen women with PMS were given mifepristone (12.5 or 25 mg per kilogram of body weight) by mouth on the seventh day after the surge of luteinizing hormone. On the sixth through the eighth days after the surge, they also received injections of either placebo or human chorionic gonadotropin (2000 IU). Seven women with PMS received placebo instead of both mifepristone and human chorionic gonadotropin. All the women completed daily questionnaires measuring a variety of mood-related and somatic symptoms. RESULTS: Mifepristone consistently induced menses. The women receiving only mifepristone had plasma progesterone levels like those of the follicular phase (less than 3 nmol per liter) within four days, whereas all the other women had plasma progesterone levels characteristic of the luteal phase (greater than 8 nmol per liter) for at least seven days after treatment. In all three groups, the severity of symptoms was significantly higher after treatment than before, according to an analysis of variance with repeated measures. The level and pattern of the ratings of symptom severity were similar in all treatment groups. CONCLUSIONS: Neither the timing nor the severity of PMS symptoms was altered by mifepristone-induced menses or luteolysis. The temporal association of typical PMS symptoms with an artificially induced follicular phase suggests that endocrine events during the late luteal phase do not directly generate the symptoms of PMS.

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder.

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP), administered orally to patients with obsessive-compulsive disorder (OCD) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPP's behavioral effects in humans remains controversial. To further study m-CPP's actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus m-CPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes. m-CPP's ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergoline's ability to block m-CPP's effects on behavior and plasma prolactin lends further support to a serotonergic mediation of m-CPP's effects, including its elicitation of OCD symptoms.

Controlled comparison of buspirone and clomipramine in obsessive-compulsive disorder.

Eighteen outpatients with obsessive-compulsive disorder were treated with either buspirone, a partial serotonin agonist, or clomipramine, a serotonin uptake inhibitor, in a double-blind, random-assignment study. Both drugs led to statistically significant and similar improvements in scores on the Yale-Brown Obsessive-Compulsive Rating Scale and other obsessive-compulsive and depression scales. This preliminary result warrants further exploration with a larger sample and other serotonergic agents.

Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Behavioral and biological results.

Treatment with fluoxetine hydrochloride was compared with treatment with clomipramine hydrochloride in two groups of patients with obsessive-compulsive disorder using two different experimental designs. In the first group of 11 patients with obsessive-compulsive disorder studied using a randomized, double-blind, crossover design, treatment with fluoxetine for 10 weeks was found to produce therapeutic effects similar to treatment with clomipramine for 10 weeks. There were significantly fewer total side effects reported during fluoxetine than clomipramine treatment. Drug tapering and placebo substitution in the 4-week crossover interval phase led to substantial relapses in obsessive-compulsive disorder symptoms and depression. Furthermore, responses to the second drug took as long to occur as responses to the first drug, although both drugs are thought to act by a common mechanism, serotonin uptake inhibition. A second group of 21 patients with obsessive-compulsive disorder that had been previously stabilized on clomipramine treatment with at least partial benefit were crossed over to fluoxetine treatment in a double-blind fashion. After 10 weeks of fluoxetine administration, most patients manifested behavioral rating scores of obsessive-compulsive disorder and depressive symptoms that were comparable with precrossover ratings completed during clomipramine treatment. A significant exacerbation in obsessive-compulsive disorder and depression ratings as well as a similar lag in therapeutic efficacy were also noted in this second cohort of patients with obsessive-compulsive disorder. Platelet 5-HT concentrations were reduced 95% during both clomipramine and fluoxetine treatment periods. These results suggest that fluoxetine may represent a viable alternative to clomipramine in the treatment of obsessive-compulsive disorder, although further studies with larger sample sizes are needed.

A case of autoimmune thyroiditis presenting as menstrual related mood disorder.

A case of autoimmune thyroiditis presenting as menstrual related mood disorder (MRMD) is described. The symptoms of the patient's prospectively confirmed MRMD remitted following thyroid hormone supplementation. Although most patients with prospectively confirmed MRMD are not clinically hypothyroid or hyperthyroid, the importance of routine thyroid function tests in the initial evaluation of MRMD is underscored by the successful treatment of this patient with thyroid hormone replacement.

Glucose tolerance testing in women with premenstrual syndrome.

Glucose tolerance tests (GTTs) were administered to 11 women with premenstrual syndrome (PMS) to ascertain whether the patients had abnormalities of glucose tolerance, to determine whether such abnormalities were related to menstrual cycle phase, and to compare the symptoms during the GTT with the PMS symptoms experienced in the luteal phase. Two GTTs were performed for each patient, one during the late follicular phase and one during the late luteal phase. Although many patients experienced symptoms of hypoglycemia during the GTT, the hypoglycemia symptoms were not specific to the luteal phase and did not resemble the patients' PMS symptoms.

State-dependent alterations in the perception of life events in menstrual-related mood disorders.

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.

Menstrual cycle phase-related changes in appetite in patients with premenstrual syndrome and in control subjects.

Menstrual cycle phase-dependent changes in appetite in women with premenstrual syndrome has not thus far been systematically demonstrated. In this study of 21 patients with premenstrual syndrome and 13 control subjects, there were significant increases in appetite in both groups, with a greater effect of menstrual cycle phase on appetite in the patients. Further, the premenstrual increase in appetite was highly correlated with self-ratings of mood (particularly depression) in the patients only. The authors discuss these findings with respect to endocrine influences on appetite regulation and potential implications for investigation of atypical depression.

Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects.

A variety of hypotheses have been proposed to explain the premenstrual syndromes. These hypotheses serve as rationales for an equally diverse range of proposed treatments. To investigate these hypotheses, we obtained multiple blood samples across the menstrual cycle in women with well-characterized menstrually related mood disorder and in control subjects. No diagnosis-related differences were observed in the levels or patterns of secretion of progesterone, estradiol, follicle-stimulating hormone, luteinizing hormone, testosterone-estradiol-binding globulin, dehydroepiandrosterone sulfate, dihydrotestosterone, prolactin, or cortisol. Our data suggest that premenstrual syndrome does not represent a simple hormonal deficiency and that the cited rationales for several of the proposed treatments are of questionable merit.

TSH and prolactin responses to TRH in patients with premenstrual syndrome.

The thyroid-stimulating hormone (TSH) and prolactin responses to thyrotropin-releasing hormone (TRH), administered during the follicular and luteal phases of the menstrual cycle, were examined in 14 women with prospectively confirmed premenstrual syndrome and in nine control subjects. There were no differences in basal or maximum increase in TSH or prolactin values between menstrual cycle phases in patients or in control subjects or between patients and control subjects in either phase. However, there was significantly greater variability in TSH response to TRH among symptomatic patients (seven of 10 patients: three with blunted and four with augmented response) than among control subjects (none of nine patients).

Premenstrual mood changes. Characteristic patterns in women with and without premenstrual syndrome.

Methodologic errors have compromised previous attempts to establish the relationship between mood and menstruation in women with the premenstrual syndromes. These syndromes cannot be diagnosed by history and require confirmation with longitudinal, prospective ratings. In this paper we present the characteristic pattern of mood changes in women with and without menstrually-related mood syndrome. The theoretical and diagnostic implications of the pattern differences are discussed.

Cortisol response to dexamethasone in women with premenstrual syndrome.

There were no significant differences in post-dexamethasone cortisol between the follicular and luteal phase of the menstrual cycle in both women with premenstrual syndrome (PMS) and control subjects tested on these two occasions. Within each menstrual cycle phase, there were also no differences in post-dexamethasone cortisol between the two groups. In a second group of control subjects tested on a single occasion, post-dexamethasone cortisol values were higher when subjects were tested in the middle 2 weeks of the menstrual cycle compared with the first and last weeks of the cycle. This phenomenon, possibly due to estrogen effects, suggests that post-dexamethasone cortisol should be assessed weekly in women with PMS to determine whether they also manifest this normally observed menstrual cycle phase-related pattern, or whether it is absent, reflecting a reproductive endocrine abnormality in this patient group.

Premenstrual syndromes: past and future research strategies.

Premenstrual Syndrome remains a poorly understood controversial disorder largely because of the errors in design found in research into this subject. The first task is to clearly define the entity to be studied. It is necessary to look at the nature, intensity and time of occurrence of symptoms in relation to menstruation. One must further differentiate the appearance of symptoms premenstrually from the premenstrual exacerbation of symptoms present throughout the menstrual cycle. Research has clearly shown the superiority of prospective versus retrospective data in establishing a linkage between symptoms and menstruation. Premenstrual Syndrome research offers a unique opportunity to study classical psychiatric disorders. A relationship appears to exist between this syndrome and major affective disorders. Studies of the appearance or exacerbation of mood disturbances in relation to the menstrual cycle may inform us about the development, course and vicissitudes of psychiatric illness.

Premenstrual mood disorder and psychiatric illness.

The results of several studies suggest that a special relationship exists between premenstrual syndromes and major psychiatric disorders, particularly affective illness. These studies in general have not employed prospective criteria to diagnose premenstrual syndrome. In this paper the authors report a significant difference in the lifetime history of psychiatric illness between women with prospectively confirmed menstrually related mood disorder and those without it.