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.

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

Enhancing the technology of clinical trials and the trials model to evaluate newly developed, targeted antidepressants.

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on "improving the technology of clinical trials." The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on "whole" disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) , Unites States and Food and Drug Administration (FDA), Unites States participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.