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      Serum Prolactin and Macroprolactin Levels among Outpatients with Major Depressive Disorder Following the Administration of Selective Serotonin-Reuptake Inhibitors: A Cross-Sectional Pilot Study

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          Abstract

          Clinical trials evaluating the rate of short-term selective serotonin-reuptake inhibitor (SSRI)-induced hyperprolactinemia have produced conflicting results. Thus, the aim of this study was to clarify whether SSRI therapy can induce hyperprolactinemia and macroprolactinemia. Fifty-five patients with major depressive disorder (MDD) were enrolled in this study. Serum prolactin and macroprolactin levels were measured at a single time point (i.e., in a cross-sectional design). All patients had received SSRI monotherapy (escitalopram, paroxetine, or sertraline) for a mean of 14.75 months. Their mean prolactin level was 15.26 ng/ml. The prevalence of patients with hyperprolactinemia was 10.9% for 6/55, while that of patients with macroprolactinemia was 3.6% for 2/55. The mean prolactin levels were 51.36 and 10.84 ng/ml among those with hyperprolactinemia and a normal prolactin level, respectively. The prolactin level and prevalence of hyperprolactinemia did not differ significantly within each SSRI group. Correlation analysis revealed that there was no correlation between the dosage of each SSRI and prolactin level. These findings suggest that SSRI therapy can induce hyperprolactinemia in patients with MDD. Clinicians should measure and monitor serum prolactin levels, even when both SSRIs and antipsychotics are administered.

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          Most cited references30

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          Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats.

          Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for depression. Recent reports in the literature describe differences in antidepressant effects among SSRIs. Although each SSRI apparently has different pharmacological actions aside from serotonin reuptake inhibition, the relations between antidepressant effects and unique pharmacological properties in respective SSRIs remain unclear. This study was designed to compare abilities of three systemically administered SSRIs to increase the extracellular levels of serotonin, dopamine, and noradrenaline acutely in three brain regions of male Sprague-Dawley rats. We examined effects of sertraline, fluvoxamine, and paroxetine on extracellular serotonin, dopamine, and noradrenaline levels in the medial prefrontal cortex, nucleus accumbens and striatum of rats using in vivo microdialysis. Dialysate samples were collected in sample vials every 20 min for 460 min. Extracellular serotonin, dopamine, and noradrenaline levels were determined using high-performance liquid chromatography with electrochemical detection. All SSRI administrations increased extracellular serotonin levels in all regions. Only sertraline administration increased extracellular dopamine concentrations in the nucleus accumbens and striatum. All SSRI administrations increased extracellular noradrenaline levels in the nucleus accumbens, although fluvoxamine was less effective. These results suggest that neurochemical differences account for the differences in clinical antidepressant effects among SSRIs. Copyright © 2010 Elsevier B.V. All rights reserved.
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            Drugs and prolactin.

            Medications commonly cause hyperprolactinemia and their use must be differentiated from pathologic causes. The most common medications to cause hyperprolactinemia are the antipsychotic agents, although some of the newer atypical antipsychotics do not do so. Other medications causing hyperprolactinemia include antidepressants, antihypertensive agents, and drugs which increase bowel motility. Often, the medication-induced hyperprolactinemia is symptomatic, causing galactorrhea, menstrual disturbance, and erectile dysfunction. In the individual patient, it is important differentiate hyperprolactinemia due to a medication from a structural lesion in the hypothalamic-pituitary area. This can be done by stopping the medication temporarily to determine if the prolactin (PRL) levels return to normal, switching to another medication in the same class which does not cause hyperprolactinemia (in consultation with the patient's physician and/or psychiatrist), or by performing an MRI or CT scan. If the hyperprolactinemia is symptomatic, management strategies include switching to an alternative medication which does not cause hyperprolactinemia, using estrogen/testosterone replacement, or cautiously adding a dopamine agonist.
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              The impact on clinical practice of routine screening for macroprolactin.

              Macroprolactin has reduced bioactivity in vivo and accumulates in the sera of some subjects, resulting in pseudo-hyperprolactinemia and consequent misdiagnosis. We have audited our experience of routine screening for macroprolactin using polyethylene glycol (PEG) precipitation over a 5-yr period in a single center. Application of a reference range for monomeric prolactin (the residual prolactin present in macroprolactin-depleted serum) for normal individuals revealed that 453 of 2089 hyperprolactinemic samples (22%) identified by Delfia immunoassay were explained entirely by macroprolactin. The percentage of hyperprolactinemic samples explained by macroprolactinemia was similar across all levels of total prolactin (18, 21, 19, and 17% of samples from 700-1000, 1000-2000, 2000-3000, and greater than 3000 mU/liter, respectively). Application of an absolute prolactin threshold after polyethylene glycol treatment of sera, rather than the traditional method, i.e. less than 40% recovery, minimizes the opportunity for misclassification of patients in whom macroprolactin accounted for more than 60% of prolactin and the residual bioactive prolactin was present in excess. Macroprolactinemic patients could not be differentiated from true hyperprolactinemic patients on the basis of clinical features alone. Although oligomenorrhea/amenorrhea and galactorrhea were more common in patients with true hyperprolactinemia (P < 0.05), they were also frequently present in macroprolactinemic patients. Plasma levels of estradiol and LH and the LH/FSH ratio were significantly greater in macroprolactinemic compared with true hyperprolactinemic subjects (P < 0.05). Reduced use of imaging and dopamine agonist treatment resulted in a net cost savings, offsetting the additional cost associated with the introduction of screening. Routine screening of all hyperprolactinemic sera for macroprolactin is recommended.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                2 December 2013
                : 8
                : 12
                : e82749
                Affiliations
                [1 ]Department of Laboratory Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
                [2 ]Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
                University of Naples Federico II, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SK YMP. Performed the experiments: SK YMP. Analyzed the data: YMP. Contributed reagents/materials/analysis tools: SK. Wrote the manuscript: SK YMP.

                Article
                PONE-D-13-21361
                10.1371/journal.pone.0082749
                3846723
                24312671
                073e4c03-3b3d-4ed2-9741-bc7cc4f29a22
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 May 2013
                : 28 October 2013
                Funding
                This work was supported by the 2012 Inje University research grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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