Uriel Halbreich

The prevalence, impairment, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD)

Currently it is estimated that 3-8% of women of reproductive age meet strict criteria for premenstrual dysphoric disorder (PMDD). Assessment of published reports demonstrate that the prevalence of clinically relevant dysphoric premenstrual disorder is probably higher. 13-18% of women of reproductive age may have premenstrual dysphoric symptoms severe enough to induce impairment and distress, though the number of symptoms may not meet the arbitrary count of 5 symptoms on the PMDD list. The impairment and lowered quality of life for PMDD is similar to that of dysthymic disorder and is not much lower than major depressive disorder. Nevertheless, PMS/PMDD is still under-recognized in large published epidemiological studies, as well as assessments of burden of disease. It is demonstrated here that the burden of PMS/PMDD as well as the disability adjusted life years (DALY) lost due to this repeated-cyclic disorder is in the same magnitude as major recognized disorders. Appropriate recognition of the disorder and its impact should lead to treatment of more women with PMS/PMDD. Efficacious treatments are available. They should reduce individual suffering and impact on family, society, and economy.

The diversity of premenstrual changes as reflected in the Premenstrual Assessment Form

The Premenstrual Assessment Form (PAF) is a new self report procedure designed to measure changes in mood, behavior, and physical condition during the premenstrual period. It reflects the great variability of premenstrual syndromes as opposed to the common practice of viewing these changes as a single entity. In comparison to commonly used procedures, the PAF 1) contains a broader variety and more specific descriptions of positive as well as negative changes; 2) provides Unipolar Summary Scales and Bipolar Continua which are sensitive measures for indexing levels of severity on various types of change; and 3) provides specific criteria for Typological Categories descriptive of different syndromes of change, especially those of mood and behavior. The paper describes the development of the PAF and the three scoring Systems and illustrates the sensitivity of the individual items and scoring Systems in reflecting the great diversity of change manifested during the premenstrual period.

The etiology, biology, and evolving pathology of premenstrual syndromes

Menstrually related symptoms and disorders are multidimensional and affect diverse physiologic systems. Elucidation of the pathophysiologic mechanisms of these disorders should allow for a more precise diagnosis, and provide direction for targeted therapeutic interventions. Several biologic mechanisms that underlie menstrually related symptoms have been proposed. They focus mostly on gonadal hormones, their metabolites and interactions with neurotransmitters and neurohormonal systems, such as serotonin, GABA, cholecystokinin, and the renin-angiotensin-aldosterone system. Altered responses of these systems to gonadal hormones fluctuations during the menstrual cycle, as well as an increased sensitivity to changes in gonadal hormones may contribute to menstrually related symptoms in vulnerable women. Disrupted homeostasis and deficient adaptation may be core underlying mechanisms. Future directions for clinically-relevant progress include identification of specific subgroups of menstrually-related syndromes, assessment of the genetic vulnerability and changes in vulnerability along the life cycle, the diversified mechanisms by which vulnerability is translated into pathophysiology and symptoms, the normalization process as well as syndromes-based and etiology-based clinical trials.

Role of estrogen in the aetiology and treatment of mood disorders.

Worldwide, the prevalence of depression in women is significantly greater than in men. Available data suggest that estrogen, or its absence, is strongly implicated in the regulation of mood and behaviour, as well as in the pathobiology of mood disorders.The multiple effects of estrogens and their complex interactions with the CNS and endocrine system have been well documented, although the specific, multifaceted role of estrogen in each dysphoric state has yet to be elucidated. Several facts suggest that estrogen plays a vital role in the precipitation and course of mood disorders in women. Gender differences in the prevalence of depression first appear after menarche, continue through reproductive age, and dissipate after perimenopause. Periods of hormonal fluctuations or estrogen instability (i.e. premenstrually, postpartum, perimenopausally) have been associated with increased vulnerability to depression among susceptible women. It is plausible that the phenotype of these depressions is distinguishable from those that are not associated with reproductive events or that occur in men.Based on current knowledge, estrogen treatment for affective disorders may be efficacious in two situations: (i) to stabilise and restore disrupted homeostasis — as occurs in premenstrual, postpartum or perimenopausal conditions; and (ii) to act as a psychomodulator during periods of decreased estrogen levels and increased vulnerability to dysphoric mood, as occurs in postmenopausal women. There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women. It is still unclear whether estrogen is efficacious as an adjunct to selective serotonin reuptake inhibitors or as one of the paradigms to manage treatment-resistance depression in menopausal women, but such efficacy is plausible.

Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone

OBJECTIVE The prevalence of hyperprolactinemia during treatment with conventional antipsychotic drugs or risperidone is under-recognized and requires further investigation. This open-label study was designed to determine the extent of this potential problem in a routine clinical setting. METHODS Four hundred and two adult inpatients or outpatients with a diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder were studied in a 1-day, point prevalence trial. Neither clinicians nor patients had any prior knowledge of serum prolactin levels or any potential associated adverse events, and patients were required to have been treated with a conventional antipsychotic drug or risperidone for a minimum of 3 months prior to study entry. Patients taking concomitant medications known to elevate prolactin were excluded. Rigorous assessment of serum prolactin was performed to estimate the prevalence rate of hyperprolactinemia, defined as a level above the upper limit of normal (>18.77 ng/ml for males, and >24.20 ng/ml for females). Patients were stratified within antipsychotic treatment by gender and, for females, by menopausal status. RESULTS Serum prolactin was obtained from 147 females (age range: 21-69 years; mean age=44.51 years) and 255 males (age range: 18-66 years; mean age=40.76 years). The prevalence of hyperprolactinemia among women of reproductive age (n=90) was 65.6% (mean serum prolactin=69.0 ng/ml), and among postmenopausal women (n=51), it was 45.1% (mean serum PRL=49.0 ng/ml). The prevalence of hyperprolactinemia across all males (n=255) was 42.4% (mean serum PRL= 32.4 ng/ml). The prevalence of hyperprolactinemia among females taking risperidone (N=42) was 88% versus 47.6% of those taking conventional antipsychotic drugs (N=105), with 48% of those females of reproductive age on risperidone experiencing abnormal menstrual cycles (secondary amenorrhea, oligomenorrhea, or polymenorrhea). Of all premenopausal females with hyperprolactinemia, 31.6% had estradiol levels <or=19.8 pg/ml (which is the mean estradiol level in postmenopausal female patients with normal prolactin). Across both genders, there were trends of low key reproductive hormone levels associated with prolactin elevations. Additionally, there was a trend correlation (p=0.064) between prolactin concentration and the risk of menstrual abnormality among females of reproductive age. CONCLUSIONS Hyperprolactinemia is very prevalent among women and men treated with conventional antipsychotic medications or risperidone. Due to the adverse effects associated with hyperprolactinemia, this likelihood should be seriously considered when choosing an antipsychotic suitable for the patient.

DECREASED BONE MINERAL DENSITY IN MEDICATED PSYCHIATRIC PATIENTS

Osteoporosis is a common problem in postmenopausal women.It has been linked to estrogen deficiency, other neuroendocrine processes such as hypercortisolemia and male hypogonadism, nutritional deficiencies, and other mechanisms. Some of these changes have been also reported in male and female patients with mental disorders, especially those receiving psychotropic medications. Therefore, bone mineral density was measured by dual-photon absorptiometry in the lumbar spine and in the femoral neck of 33 female and 35 male consenting psychiatric inpatients admitted consecutively. Patients were diagnosed as having major depressive disorder (N = 21), schizophrenia (N = 33), schizoaffective disorder (N = 7), mania (N = 2), and adjustment disorder (N = 5). Plasma levels of prolactin, estrogen, cortisol, and testosterone were also measured in a subgroup of these patients. It is reported that female patients, but especially male patients, had a highly significant decrease in bone mineral density when compared with age- and sex-matched normal data. It is suggested that psychiatric patients treated with antidepressants or neuroleptics might have decreased bone mineral density than is normal for their age and sex, and may be at an increased risk for fractures. These results may be related to low levels of gonadal hormones, especially in male subjects. Data should be confirmed with a larger number of patients with and without medications to distinguish between diagnosis-related and treatment-related effects.

Relationship of dysphoric premenstrual changes to depressive disorders

ABSTRACT An association between premenstrual dysphoric changes and depressive disorders is demonstrated in 170 women. Each woman underwent an evaluation for current and life‐time diagnosis using the Research Diagnostic Criteria (RDC). Premenstrual dysphoric changes were evaluated with the Premenstrual Assessment Form (PAF). Criteria for PAF Full Depressive Syndrome were met by 57 % of women with a life‐time diagnosis of Major Depressive Disorder. Only 14 % of the Never Mentally 111 women met these PAF criteria. Eighty‐four percent of those who had PAF Full Depressive Syndrome also had RDC Major Depressive Disorder while only 9 % were Never Mentally Ill.

Role of estrogen in postmenopausal depression

Article abstract-Estrogen has been reported to improve the cognitive functioning of postmenopausal women. It is suggested that estrogen replacement therapy (ERT) might be beneficial for improvement of mood and cognition in menopausal women. We have shown that this improvement is selective and is probably more apparent in complex integrative functions. We have also shown that estrogen can augment serotonergic activity as well as some norepinephrine-related processes in postmenopausal women. Because of its effects on mood-related neurotransmitter processes, ERT might decrease vulnerability to depression and be effective as an adjunct therapy to prevent treatment nonresponse to conventional antidepressants. NEUROLOGY 1997;48(Suppl 7): S16-S20

Premenstrual changes and affective disorders.

&NA; The differential relationship between specific subtypes of premenstrual changes and specific subtypes of mental disorder was studied. Premenstrual changes were evaluated with the Premenstrual Assessment Form, which provides specific criteria for the classification of the various subtypes of premenstrual change. The Research Diagnostic Criteria were used to make lifetime diagnoses of mental disorder. Differential relationships were found between subtypes of premenstrual change and subtypes of mental disorder. The results suggest that premenstrual changes characterized by a depressive syndrome may represent a mild or subclinical manifestation of affective disorder.

Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials

BACKGROUND Atypical antipsychotic drugs for the treatment of schizophrenia provide effective treatment of psychotic symptoms with a safety profile superior to conventional antipsychotic medications. Neuroendocrine abnormalities in patients with schizophrenia, such as chronic hyperprolactinemia, may now potentially be minimized by the use of newer prolactin-sparing antipsychotic drugs. A discrimination of prolactin-sparing versus prolactin-elevating antipsychotic drugs may provide the clinician with treatment choices in order to avoid or mitigate hyperprolactinemia-associated morbidity. METHODS Results from five clinical trials were used to characterize factors that may influence antipsychotic drug effects on levels of serum prolactin. Factors investigated included drug treatment, gender, time course, potential for reduction or reversibility, and age. RESULTS Factors that influenced the risk of hyperprolactinemia included gender, with females appearing to be more sensitive than males, and drug treatment, with risperidone and conventional antipsychotic agents increasing prolactin more than olanzapine. Patients of all ages demonstrated sensitivity to increased prolactin. Furthermore, patients with hyperprolactinemia sustained the effect over time. Hyperprolactinemia reversed when patients were switched to a prolactin-sparing antipsychotic medication. CONCLUSION Effects of antipsychotic medications on serum prolactin are multi-factorial. Evidence for sexual, reproductive, and general medical consequences of antipsychotic-induced hyperprolactinemia is developing, and identifying antipsychotic drugs with a favorable prolactin profile would be important in mitigating these consequences. Most notably for women, atypical or novel antipsychotic drugs with a prolactin-sparing profile may offer effective clinical treatment with preservation of physiological hormonal function.