Treatment of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).

Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.

Impulse control disorders in patients with dopamine agonist-treated pituitary adenomas: a cross-sectional multicenter study.

BACKGROUND: Impulse control disorders (ICDs) have been described as underrecognized side effects of dopamine agonists (DAs) in neurological disorders but are not sufficiently understood in endocrine conditions. OBJECTIVE: To identify the prevalence of DAs induced ICDs and determine potential risk factors related to these disorders in patients with prolactinoma and non-function pituitary adenomas (NFPAs). METHODS: This is a cross-sectional multicenter study involving 200 patients with prolactinoma and NFPAs, who received follow-ups in tertiary referral centers. DA-induced ICDs were assessed using ICD questionnaires modified from prior studies. RESULT: At least one ICD was reported by 52% of participants, among whom 28.5% mentioned compulsive shopping, 24.5% punding, and 24.5% hypersexuality. Furthermore, 33% of the patients reported the presence of one type of ICD behavior, while 12% specified two and 7% had three types of such behavior. The multivariable logistic regression showed that the significant risk factors of ICD were younger age (adjusted odds ratio [AOR]: 0.92, 95% confidence interval [CI]: 0.88-0.97, p 0.001), being single (AOR: 0.15, 95%CI: 0.03-0.84, p 0.03), and a positive history of psychiatric illness (AOR: 7.67, 95% CI: 1.37-42.97, p 0.021). CONCLUSION: ICDs with a broad range of psychiatric symptoms are common in individuals with DA-treated prolactinoma and NFPAs. Endocrinologists should be aware of this potential side effect, particularly in patients with a personal history of psychiatric disorder.

Suicide attempt in a dopamine agonist withdrawal syndrome in Parkinson's disease.

Dopamine agonist withdrawal syndrome (DAWS) results from the reduction or suspension of dopamine agonist medications; it encompasses mainly psychiatric symptoms, including suicidal behaviors. In patients with Parkinson's disease (PD), the impact of DAWS can be significant in terms of distress and disability; however, we must take this syndrome into account as a threatening condition because suicidal behaviors could be developing in the context of DAWS. Here we present a brief case of DAWS affecting a young man with PD, whom abruptly discontinued DA treatment and developed psychiatric symptoms within two weeks which led to a suicidal attempt.

[Overcoming therapy resistance in prolactinomas: from perspectives to real clinical practice].

The main treatment option of prolactin-secreting pituitary adenomas is dopamine agonist therapy, which demonstrates prolactin level normalizing and reducing the size of an adenoma in the majority of cases. However, significant amount of patients - about 20% - poorly responds even to high doses of dopamine agonists that is explained by the resistance to therapy. The occurrence of pharmacodynamic characteristics is one of the causes responsible for the development of resistance to typical therapy. Clinical manifestations of persistent hyperprolactinemia are due to following pathological factors: hormonal hypersecretion and the mass-effect of pituitary adenoma. Prevention of irreversible changes is possible only with timely detection of resistance and determination of the optimal personalized treatment algorithm.We report a clinical case of dopamine-agonist resistant microprolactinoma. Patient's health stabilisation, normal level of prolactin and reduction in size of adenoma were achieved due to administration of combined treatment with tamoxifen and dopamine agonists. Hyperprolactinaemia occurring because of prolactin-secreting pituitary adenoma and associated adverse effects are significant problem, decreasing quality of life and demographics in general. This underlines the importance of figuring out causes and identifying predictors of the therapy resistance.The results of the study, illustrated by a clinical example, are presented in the present paper.

Chronic dizziness in restless legs syndrome (RLS) patients responsive to levodopa or dopamine agonists.

Apart from the legs, restless legs syndrome (RLS) also affects the arms, head, neck, face, oral cavity, genital area, abdomen, intestines and bladder. RLS is also linked to several comorbid diseases, including headache disorders. Its association with dizziness has never been explored. We are reporting on two patients with RLS who also had a history of chronic dizziness. The treatment with levodopa or dopamine agonists completely alleviated both RLS and dizziness. We propose that RLS-like symptoms in the head may be experienced as dizziness and that dizziness may be part of the symptom complex of RLS. A large number of patients with chronic dizziness remain undiagnosed in clinical practice. We suggest exploring the history of RLS in patients presenting with chronic dizziness. Such patients may respond to levodopa or dopamine agonists. Because the response was seen in only two patients, a prospective placebo-controlled trial is needed to confirm these findings.

Dopamine agonist serum concentrations and impulse control disorders in Parkinson's disease.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) are common among Parkinson's disease patients using dopamine agonists. We wanted to determine whether ICD patients have higher dopamine agonist serum concentrations than those without any sign of ICD. METHODS: Patients who used either pramipexole or ropinirole depot once daily were screened for ICDs using the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale. Those who scored above the cut-off for one or more of the four defined ICDs (gambling, compulsive sexual behavior, compulsive shopping, and binge-eating) were compared in a case-control study to patients who scored zero points (no evidence of ICD) on the same items. They were examined clinically and evaluated using relevant scales. Three blood samples were taken on the same day: before daily dose, and then 6 and 12 h later. RESULTS: Forty-six patients were included: 19 ICD-positive and 27 controls. Ropinirole serum concentrations 6 h after daily intake (Cmax ) were higher in the case group compared to the control group, as was the daily ropinirole dosage. No differences were observed in serum concentrations, dosage or total drug exposure for pramipexole. Disease duration and length of dopamine agonist treatment was significantly longer among ICD patients for ropinirole, but not for pramipexole. CONCLUSIONS: The use of pramipexole may in itself confer high ICD risk, whereas ICDs among ropinirole users depend more on serum concentration and drug exposure. The pharmacokinetic properties of ropinirole make it challenging to predict its effects on patients, which supports the need for therapeutic drug monitoring to reduce risk of ICD.

Daytime impulsiveness, attention, and learning in the restless legs syndrome.

INTRODUCTION: Restless legs syndrome (RLS) is a sensorimotor condition characterized by disturbing sensations and the desire to move, often localized in the legs. Cognitive changes and impulsivity can be present in RLS, although the potential effect of commonly co-occurring attention-deficit/hyperactivity disorders (ADHD) or dopamine agonist (DA) use on these are unclear. METHOD: Twenty-three RLS patients and 22 healthy controls were included. Rey Auditory Verbal Learning Test (RAVLT), Continuous Performance Test (CPT), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), State and Trait Anxiety Inventory (STAI), and Adult Attention Deficit Self-Evaluation Scale (ASRS) were administered. Performance was compared between RLS patients and controls accounting for the presence of attention-deficit/hyperactivity disorder (ADHD) and DA use. RESULTS: Age, education, BDI, ESS, STAI, and ASRS scores were similar for control and RLS groups. Control and RLS groups performed similarly on auditory verbal learning and general attention tests. In the CPT, commission error was significantly higher and response time was significantly shorter in the RLS group compared to controls (p = .014 and p = .010, respectively). These significant differences persisted after adjusting for ADHD and DA usage. CONCLUSION: In this study, RLS patients were more impulsive than the healthy individuals independent of ADHD and DA use. However, learning and attention performances of the patients are not affected.

Impulse control disorders in Parkinson's disease: a retrospective analysis of 1824 patients in a 12-year period.

OBJECTIVE: This study aims to clinically evaluate the impulse control disorders (ICDs) encountered in treating Parkinson's disease. METHOD: This is a retrospective analysis between 2010 and 2022. We retrieved the medical records of all patients diagnosed with idiopathic Parkinson's disease. The demographic and clinical findings were recorded. ICDs constituted a specific item in the examination, and each one (compulsive shopping, compulsive eating, pathological gambling, hypersexuality, punding, dopamine dysregulation syndrome, and hobbyism) was noted separately. RESULTS: In the study period, we identified 1824 patients (56.2% men, n = 1025). The mean age was 70.5 ± 11.9 years. In the cohort, 128 (7%) patients with Parkinson's disease had one or more ICDs. The ICDs were compulsive shopping, punding/hobbyism, compulsive eating, hypersexuality, pathological gambling, and dopamine dysregulation syndrome. When we compared patients with and without ICDs, patients with ICDs were younger (p ≤ 0.001), and the men/women ratio was higher in this group with ICDs. Although the mean daily pramipexole dose was higher in patients with ICDs, mean daily long-acting pramipexole dose was only 1.4 ± 0.92 mg/day. CONCLUSION: The significant findings in this study were (i) the lower frequency of ICDs (7%); (ii) the common occurrence of compulsive shopping, punding/hobbyism, and compulsive eating; and (iii) the development of ICDs under relatively lower doses of pramipexole. We suggest that ICDs in Parkinson's disease should be associated with a personal trait with dopamine agonists, and potential electrophysiological or genetic markers of this trait warrant further analysis to avoid treatment in these patients.

Ropinirole for the Treatment of Hyperprolactinemia: A Dose-Escalation Study of Efficacy and Tolerability.

CONTEXT: Treatment of hyperprolactinemia with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. OBJECTIVE: This study examines the efficacy and tolerability of the nonergot DA ropinirole for the long-term treatment of hyperprolactinemia. METHODS: Twelve hyperprolactinemic women were treated with ropinirole in a 6-month, open-label, dose-escalation trial; 7 of the 12 continued treatment in an extension study for up to 17 months. Ropinirole doses were uptitrated to achieve normal prolactin (PRL) levels, restore menses, and eliminate galactorrhea. RESULTS: Two of the 12 participants were DA naive; 6 of 12 were ergot DA intolerant; and 1 of 12 had known ergot DA resistance. Baseline PRL levels were 126.2 ± 41.4 ng/mL (SEM). Ropinirole was uptitrated from 0.125 to 0.25 mg/h to a median total daily dose (TDD) of 2 mg/d (1-4 mg/d [interquartile range]). PRL normalization was achieved in 50% of the participants (5 with microadenomas and 1 with idiopathic hyperprolactinemia) at a median effective TDD of 1 mg/d. Of the patients achieving PRL normalization, 83% were ergot DA intolerant. A persistent partial biochemical response (PRL reduction >50% from baseline) was achieved in 17% of the participants. During treatment, menses resumed in 67% of amenorrheic patients; galactorrhea resolved in 67%. Mild adverse effects were reported in 92% of participants; however, ropinirole was not discontinued because of intolerance even among the 50% of individuals with a prior history of ergot DA intolerance and resultant medication discontinuation. CONCLUSION: These data demonstrate the efficacy and tolerability of ropinirole for the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia and suggest ropinirole may represent a novel therapeutic alternative for treating hyperprolactinemic disorders in patients with ergot DA intolerance.

Transdermal Rotigotine at End-of-Life for Parkinson's Disease: Association With Measures of Distress.

BACKGROUND: End-of-life (EOL) care for Parkinson's disease (PD) can be challenging when oral medications are no longer tolerated. MEASURES: To assess EOL prescribing for people with PD (PWP), focusing on rotigotine dosing and proxy measures of distress: benzodiazepine and opioid use. INTERVENTION: A retrospective audit of patient records from PWP who died between January 2019 and May 2022 at the Royal Hobart Hospital (RHH), Australia, was conducted. Data was systematically collated on demographics, symptoms, levodopa equivalent daily dose (LEDD) and rotigotine, oral morphine equivalent (OME) and benzodiazepine doses in the last 72 hours of life . OUTCOMES: Pain (72%), respiratory secretions (66%) and agitation (66%) were the most documented EOL symptoms. 83% (n = 52) of PWP were eligible for rotigotine and, of those, 13% (n = 7) received the correct dose, 38% (n = 20) a lower dose, 12% (n = 6) a higher dose and 37% (n = 19) did not receive any. Rotigotine dose was positively associated with total (P = 0.016) and PRN (P = 0.037) benzodiazepine dose. LEDD was positively associated with total benzodiazepine (P = 0.018) and total OME dose (P = 0.046). Contraindicated dopamine antagonists were prescribed for 43% of PWP and administered in 31% of those cases. CONCLUSIONS: Rotigotine dose and admission LEDD were both associated with proxy measures of distress in the last 72 hours of life. This suggests cautious use of rotigotine at EOL. LEDD may help identify patients at risk of distress. Rates of inappropriate prescribing and symptom prevalence were high, indicating a need for further staff education to optimize the care of PWP.

Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial.

BACKGROUND: There is a large population of restless legs syndrome (RLS) patients who are refractory to medication. Whereas experts recommend off-label opioids as an effective long-term treatment for refractory RLS, reducing opioid dose could substantially reduce side effects and risks. Tonic motor activation (TOMAC) is a nonpharmacological therapeutic device indicated for refractory RLS. Here, we investigated if TOMAC could enable opioid dose reduction for refractory RLS. METHODS: This prospective, open-label, single-arm clinical trial [NCT04698343] enrolled 20 adults taking ≤ 60 morphine milligram equivalents (MMEs) per day for refractory RLS. Participants self-administered 30-min TOMAC sessions bilaterally over the peroneal nerve when RLS symptoms presented. During TOMAC treatment, opioid dose was reduced iteratively every 2-3 weeks until Clinician Global Impression of Improvement (CGI-I) score relative to baseline exceeded 5. Primary endpoint was percent of participants who successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Secondary endpoints included mean successful percent opioid dose reduction with CGI-I ≤ 5. RESULTS: On average, participants were refractory to 3.2 medications (SD 1.6) and were taking a stable dose of opioids for 5.3 years (SD 3.9). Seventy percent of participants (70%, 14 of 20) successfully reduced opioid dose ≥ 20% with CGI-I ≤ 5. Mean percent opioid dose reduction with CGI-I ≤ 5 was 29.9% (SD 23.7%, n = 20) from 39.0 to 26.8 MME per day. Mean CGI-I score at the reduced dose was 4.0 (SD 1.4), indicating no change to RLS severity. CONCLUSIONS: For refractory RLS, TOMAC enabled substantial opioid dose reduction without increased RLS symptoms. These results suggest that TOMAC has the potential to reduce the risk profile associated with opioid therapy for refractory RLS. TRIAL REGISTRATION: ClinicalTrials.gov trial number NCT04698343 registered on January 6, 2021.

Impulse Control Disorders in Patients with Pituitary Tumors Treated with Dopamine Agonists: A Systematic Review.

BACKGROUND: The increased prevalence of Impulse Control Disorders (ICDs) in dopamine agonist (DA) treated patients with Parkinson's disease is well described. Despite the frequent use of DAs in the management of pituitary tumors, the relationship between DAs and prevalence of ICDs in patients with pituitary tumours is unclear. AIMS: To establish the prevalence of ICDs in patients with prolactinoma or acromegaly and determine whether prevalence differs in those on DAs to those treated without. METHODS: Systematic review of the literature (registered a priori) reporting prevalence of ICDs in patients with prolactinoma or acromegaly (conducted June 2023). A narrative synthesis describing prevalence of ICDs according to assessment method was performed. Prevalence comparisons between patients with prolactinoma or acromegaly treated with DAs, to patients treated without, were summarised. RESULTS: Studies were largely retrospective, observational and heterogenous, with few patients with prolactinoma and acromegaly treated without DA. Prevalence of ICDs varied between 0-60% in patients with prolactinoma, and from 5-23% in studies with at least five patients with acromegaly. In most studies comparing DA exposed to non-DA exposed cases, DA use was not associated with ICDs. CONCLUSIONS: Reported prevalence of ICDs in patients with prolactinoma and acromegaly varies considerably. Given ICDs were reported to be highly prevalent in some studies, clinicians should be mindful of these potentially serious disorders. ICD screening tools validated for use in patients with pituitary tumors combined with prospective studies including appropriate controls, are necessary to accurately establish prevalence of ICDs and true impact of DAs in their development.

Incident mental health episodes after initiation of gabapentinoids vs. dopamine agonists for early-onset idiopathic restless legs syndrome.

Limited long-term safety information exists for gabapentinoid treatment of idiopathic restless legs syndrome (RLS). We estimated incident mental health-related emergency department visits and hospitalizations with a primary mental health diagnosis (primary outcome) among early-onset idiopathic RLS patients following first-line treatment initiation and examined outcome risk with gabapentinoids compared with dopamine agonists (DAs). A retrospective cohort study was conducted using administrative claims data from 2012 to 2019. Adults with early-onset (18-44 years) idiopathic RLS initiating either gabapentinoids or DAs within 60 days of new diagnosis were followed up to two years. Incidence rates were calculated and a log-binomial regression model with propensity score weighting estimated relative risk of the outcome and of substance use disorders (SUDs) as a secondary analysis with gabapentinoids. Among a cohort of 6,672 patients, 4,986 (74.7%) initiated DAs and 1,686 (25.3%) gabapentinoids. Incidence of the primary outcome (49.8 [95% CI 40.8-69.3] per 1,000 person-years) and SUDs (49.5 [95% CI 40.6-59.9] per 1,000 person-years) were higher in the gabapentinoid group compared with the DA group. A statistically significant risk of mental health diagnoses with gabapentinoids was not detected, but SUD risk was significant after covariate adjustment. High-risk mental health comorbidities (i.e., SUDs) should be considered when initiating RLS treatments.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

An update on the pharmacogenetic considerations when prescribing dopamine receptor agonists for Parkinson's disease.

INTRODUCTION: Parkinson's disease is a chronic neurodegenerative multisystemic disorder that affects approximately 2% of the population over 65 years old. This disorder is characterized by motor symptoms which are frequently accompanied by non-motor symptoms such as cognitive disorders. Current drug therapies aim to reduce the symptoms and increase the patient's life expectancy. Nevertheless, there is heterogeneity in therapy response in terms of efficacy and adverse effects. This wide range in response may be linked to genetic variability. Thus, it has been suggested that pharmacogenomics may help to tailor and personalize drug therapy for Parkinson's disease. AREAS COVERED: This review describes and updates the clinical impact of genetic factors associated with the efficacy and adverse drug reactions related to common medications used to treat Parkinson's disease. Additionally, we highlight current informative recommendations for the drug treatment of Parkinson's disease. EXPERT OPINION: The pharmacokinetic, pharmacodynamic, and safety profiles of Parkinson's disease drugs do not favor the development of pharmacogenetic tests with a high probability of success. The chances of obtaining ground-breaking pharmacogenetics biomarkers for Parkinson's disease therapy are limited. Nevertheless, additional information on the metabolism of certain drugs, and an analysis of the potential of pharmacogenetics in novel drugs could be of interest.

Can brexpiprazole be switched safely in patients with schizophrenia and dopamine supersensitivity psychosis? A retrospective analysis in a real-world clinical practice.

BACKGROUND: Several studies have reported that a switch to the dopamine partial agonist (DPA) aripiprazole (ARP), especially when the switch is abrupt, is likely to fail and sometimes worsen psychosis in schizophrenia patients already under high-dose antipsychotic treatment. Such a switching failure is speculated to be related to be the dopamine supersensitivity state. The risks of switching to the DPA brexpiprazole (BREX) have not been reported. AIMS AND METHODS: We retrospectively analyzed the cases of 106 patients with schizophrenia to identify any factors related to the success or failure of switching to BREX. RESULTS: The comparison between the patients with dopamine supersensitivity psychosis (n = 44) and those without (n = 62) revealed no significant difference in the switching failure judged at the sixth week. A comparison of the patients with successful switching (n = 80) and those who failed (n = 26) revealed that patients with treatment-resistant schizophrenia (TRS) were significantly more likely to fail. A logistic regression analysis also revealed that patients with past failure of switching to ARP are likely to succeed in switching to BREX. The 2-year follow-up of the patients with successful switching to BREX suggested that the patients who were treated with BREX, even temporarily, experienced some improvement in their Global Assessment of Functioning and Clinical Global Impression-Severity scores. CONCLUSIONS: Overall, the results indicate that patients with schizophrenia can be switched more safely to BREX compared to ARP. However, the failure of switching to BREX could be higher in patients with TRS, and thus, starting BREX treatment in refractory patients warrants careful monitoring.

Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial.

STUDY OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety/tolerability of bilateral high-frequency tonic motor activation (TOMAC) in patients with medication-refractory restless legs syndrome (RLS). METHODS: RESTFUL was a multicenter, randomized, double-blind, sham-controlled trial in adults with medication-refractory moderate-to-severe primary RLS. Participants were randomized 1:1 to active or sham TOMAC for a double-blind, 4-week stage 1 and all received active TOMAC during open-label, 4-week stage 2. The primary endpoint was the Clinical Global Impressions-Improvement (CGI-I) responder rate at the end of stage 1. Key secondary endpoints included change to International RLS Study Group (IRLS) total score from study entry to the end of stage 1. RESULTS: A total of 133 participants were enrolled. CGI-I responder rate at the end of stage 1 was significantly greater for the active versus sham group (45% vs. 16%; Difference = 28%; 95% CI 14% to 43%; p = .00011). At the end of stage 2, CGI-I responder rate further increased to 61% for the active group. IRLS change at the end of stage 1 improved for the active versus sham group (-7.2 vs. -3.8; difference = -3.4; 95% CI -1.4 to -5.4; p = .00093). There were no severe or serious device-related adverse events (AEs). The most common AEs were mild discomfort and mild administration site irritation which resolved rapidly and reduced in prevalence over time. CONCLUSIONS: TOMAC was safe, well tolerated, and reduced symptoms of RLS in medication-refractory patients. TOMAC is a promising new treatment for this population. CLINICAL TRIAL: Noninvasive Peripheral Nerve Stimulation for Medication-Refractory Primary RLS (The RESTFUL Study); clinicaltrials.gov/ct2/show/NCT04874155; Registered at ClinicalTrials.gov with the identifier number NCT04874155.