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Best Practice & Research. Clinical... Dec 2022While the prevalence of hyperprolactinemia under antidepressants is very low, its prevalence under antipsychotics, particularly of the first generation, is high.... (Review)
Review
While the prevalence of hyperprolactinemia under antidepressants is very low, its prevalence under antipsychotics, particularly of the first generation, is high. Antipsychotics act by blocking dopamine activity at the level of the dopamine type 2 receptor (D2R). When prolactin levels exceed 80-100 ng/ml, a pituitary adenoma must be ruled out by MRI. Treatment of hyperprolactinemia is necessary only in cases with clinical symptoms of hypogonadism. Three treatment options are possible: switch to a less hyperprolactinemic antipsychotic, sex steroid supplementation or dopamine agonist (which normalizes prolactin levels in only half of cases). Fortunately, psychotic exacerbation due to the opposing effects of antipsychotics and dopamine agonists on the D2R seems very rare. When a patient presents with a macroprolactinoma, particularly with optic chiasm compression, surgery or dopamine agonists may be proposed. The agonists are effective in reducing tumor mass and improving visual defects in the majority of patients but rarely normalize prolactin levels.
Topics: Humans; Dopamine Agonists; Prolactin; Dopamine; Hyperprolactinemia; Pituitary Neoplasms; Antipsychotic Agents; Mental Disorders
PubMed: 36280567
DOI: 10.1016/j.beem.2022.101711 -
Dopamine agonist for the rapid improvement of visual field defects in giant and macro-prolactinomas.Journal Francais D'ophtalmologie May 2022To evaluate effect of first-line dopamine agonist (DA) therapy as an alternative to surgery for visual field defect (VFD) recovery in giant and macro-prolactinoma.
PURPOSE
To evaluate effect of first-line dopamine agonist (DA) therapy as an alternative to surgery for visual field defect (VFD) recovery in giant and macro-prolactinoma.
METHODS
In this retrospective study, 125 patients with giant and macro-prolactinoma, except those with a history of previous surgery or radiotherapy, were evaluated. Those who underwent visual field examinations using the Humphrey Visual Field analyser upon initial assessment and after treatment were included for analysis. Twelve patients with VFD were included. The effects of DA therapy on both VFD and tumor size were evaluated within the first three months.
RESULTS
There were twelve patients analysed: three females and nine males, five giant and seven macroprolactinomas; eight patients received cabergoline (CAB) and four patients received bromocriptine (BRC). The mean adenoma diameter was 35±13mm (range 15-60), and the mean PRL level was 3,523ng/dL (range 312-11,703). Eight patients (67%) complained of blurred vision, while four patients (33%) reported no visual symptoms. After a median duration of three weeks, the VFD completely resolved in ten patients (83%) but only partially improved in two (17%). The mean initial doses of CAB and BRC that provided VFD improvement were 0.5±0.2mg/week and 6.3±1.4mg/day, respectively. After a mean duration of 2.2±0.9months, the mean decrease in adenoma size was 43.6±24.5% (range 10-95%).
CONCLUSION
The use of DA as a first-line treatment for at least one month before deciding on surgery is recommended in giant and macro-prolactinomas with VFD. Surgery should be considered only in cases with DA resistance or persistent visual impairment despite medical therapy.
Topics: Bromocriptine; Cabergoline; Dopamine Agonists; Female; Humans; Male; Pituitary Neoplasms; Prolactin; Prolactinoma; Retrospective Studies; Vision Disorders; Visual Fields
PubMed: 35272874
DOI: 10.1016/j.jfo.2022.01.002 -
Endocrinology and Metabolism Clinics of... Sep 2020Dopamine agonist therapy is the primary therapy for prolactin-secreting adenomas and usually results in normoprolactinemia, eugonadism, and tumor reduction. Cabergoline... (Review)
Review
Dopamine agonist therapy is the primary therapy for prolactin-secreting adenomas and usually results in normoprolactinemia, eugonadism, and tumor reduction. Cabergoline is superior to bromocriptine with regard to efficacy and tolerance. Withdrawal of cabergoline can be attempted in patients with normal prolactin levels on low doses of medication and evidence of radiographic tumor involution. Dopamine agonists have been used off label in patients with acromegaly, Cushing disease, and nonfunctioning adenomas. A trial of cabergoline monotherapy can be effective in patients with biochemically mild acromegaly. Cabergoline combination with somatostatin receptor ligands or pegvisomant improves insulin-like growth factor level 1 in majority of patients.
Topics: Acromegaly; Adenoma; Cabergoline; Dopamine Agonists; Human Growth Hormone; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Prolactinoma; Treatment Outcome
PubMed: 32741482
DOI: 10.1016/j.ecl.2020.05.006 -
Hormone and Metabolic Research =... Jul 2021Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments... (Review)
Review
Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFβ and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors' proliferative index (Ki67) increased from 5-6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.
Topics: Combined Modality Therapy; Dopamine Agonists; Drug Resistance, Neoplasm; Humans; Prognosis; Prolactinoma
PubMed: 34282593
DOI: 10.1055/a-1525-2131 -
Annales D'endocrinologie Jun 2021The surveillance strategy for patients taking low dose cabergoline for hyperprolactinaemia is controversial. As more evidence has emerged that the risks of cardiac... (Review)
Review
The surveillance strategy for patients taking low dose cabergoline for hyperprolactinaemia is controversial. As more evidence has emerged that the risks of cardiac valvulopathy in this population of patients are low, fewer and fewer endocrinologists adhere strictly to the original medicines and healthcare products agency MHRA guidance of "at least" annual echocardiography. Strict adherence to this guidance would be costly in monetary terms (£5.76 million/year in the UK) and also in resource use (90,000 extra echocardiograms/year). This article reviews the proposed pathophysiological mechanism underlying the phenomenon of dopamine agonist valvulopathy, the characteristic echocardiographic changes seen, summarises the published literature on the incidence of valvulopathy with low dose cabergoline and examines the previous and current evidence-based screening guidelines.
Topics: Cost-Benefit Analysis; Dopamine Agonists; Drug Monitoring; Echocardiography; Heart Valve Diseases; Humans; Hyperprolactinemia; Incidence; Monitoring, Physiologic; United Kingdom
PubMed: 32178837
DOI: 10.1016/j.ando.2020.02.007 -
Expert Review of Endocrinology &... Nov 2022Treatment of prolactinomas with dopamine agonists has been the established first-line treatment option for many years, with surgery reserved for refractory cases or...
INTRODUCTION
Treatment of prolactinomas with dopamine agonists has been the established first-line treatment option for many years, with surgery reserved for refractory cases or medication intolerance. This approach may not be the best option in many cases.
AREAS COVERED
Review of the epidemiology, biology, and treatment options available for prolactinomas, including best available data on outcomes, costs, and morbidities for each therapy. These data are then used to propose a 'surgery-first' treatment approach for a subset of prolactinomas as an alternative to primary medical management.
EXPERT OPINION
Based on the available data, there is a strong rationale that transsphenoidal surgery should be considered a first-line treatment option for both micro- and macro-prolactinomas that do not demonstrate high grade cavernous sinus invasion on MRI imaging, with dopamine agonists administered as a secondary therapy for tumors not in remission following surgery, and for giant tumors. This 'surgery-first' approach assumes the availability of skilled and experienced pituitary surgeons to ensure optimal outcomes. This approach should result in high cure rates and reduced DA requirements for patients not cured from initial surgery. Further, it will reduce medical costs over a patient's lifetime and the chronic morbidities associated with protracted dopamine agonist usage.
Topics: Humans; Prolactinoma; Dopamine Agonists; Bromocriptine; Pituitary Neoplasms; Magnetic Resonance Imaging
PubMed: 36200144
DOI: 10.1080/17446651.2022.2131531 -
Psychiatry and Clinical Neurosciences Mar 2023Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on...
INTRODUCTION
Impulse control disorders (e.g. pathological gambling, hypersexuality) may develop as adverse reactions to drugs. Pathogenetic hypotheses have mainly focused on D3-receptor agonism, and switching to alternatives with different pharmacologic mechanisms represents a common management strategy. Nonetheless, treatment failure is common and gaining pathophysiological insights is needed.
AIM
We aimed to identify targets potentially contributing to pathologic impulsivity.
METHOD
We performed a pharmacovigilance-pharmacodynamic study on dopamine agonists and antipsychotics using the Food and Drug Administration Adverse Event Reporting System (January 2004-December 2021). We estimated disproportionate reporting using the Bayesian information component. Using online public databases (IUPHAR, ChEMBL, PDSP, DrugBank), we calculated drug occupancies. To identify the targets potentially contributing to impulsivity, we fitted univariate regression models interpolating information components and occupancies within dopamine agonists and antipsychotics. Sensitivity analyses were performed to check for the robustness of the results.
RESULTS
Among 19 887 reports of impulsivity, 5898 recorded an antipsychotic, and 3100 a dopamine agonist. The more robust signals concerned aripiprazole (N = 3091; median information component [95% confidence interval] = 4.51[4.45-4.55]) and brexpiprazole (229; 4.00[3.78-4.16]) for antipsychotics, pergolide (105; 5.82[5.50-6.06]) and pramipexole (2009; 5.43[5.36-5.48]) for dopamine agonists. Robust, significant positive associations between drug occupancy and impulsivity reporting were found for D3 within dopamine agonists (beta = 1.52; P-value = 0.047) and 5-HT1a within antipsychotics (1.92, 0.029).
CONCLUSION
Our results supported the role of D3-receptor agonism in inducing impulsivity in dopamine receptor agonists and identified a potential role of 5-HT1a receptor agonism in antipsychotics. Investigating these receptors may drive towards a better management of drug-induced impulsivity.
Topics: Humans; Dopamine Agonists; Antipsychotic Agents; Pharmacovigilance; Bayes Theorem; Disruptive, Impulse Control, and Conduct Disorders
PubMed: 36436204
DOI: 10.1111/pcn.13511 -
Neuropharmacology Feb 2022Motor complications, characterized by "off" periods - when anti-parkinsonian medications are ineffective - and dyskinesia, are the hallmark of advanced Parkinson's... (Review)
Review
BACKGROUND
Motor complications, characterized by "off" periods - when anti-parkinsonian medications are ineffective - and dyskinesia, are the hallmark of advanced Parkinson's disease (PD). While levodopa is the gold standard PD medication in terms of efficacy, its short duration of effect coupled with progressive loss of dopaminergic neurons leads to motor complications and fails to treat off periods.
PURPOSE OF REVIEW
This review focuses on novel dopaminergic therapies that were recently made clinically available or are currently in development for the treatment of motor complications. First, it will discuss rescue therapies for the treatment of off episodes, including novel apomorphine and levodopa formulations. Second, it will highlight adjunctive dopaminergic medications approved to reduce total daily off time. Third, it will discuss longer-acting levodopa formulations in development and introduce a novel selective dopamine agonist under study. Finally, it will cover novel dopaminergic delivery mechanisms, with specific focus on continuous subcutaneous infusions in development.
SUMMARY
The breadth of dopaminergic therapies recently approved or in development for motor complications, and specifically off time reduction, evokes cautious optimism. Gains in reducing off time with rescue therapies, adjunctive medications or longer-acting levodopa formulations are modest, and underscore the need for more continuous dopaminergic delivery to address the underlying pathophysiology and translate to clinically meaningful improvement in motor complications.
Topics: Alanine; Antiparkinson Agents; Apomorphine; Benzylamines; Delayed-Action Preparations; Disease Progression; Dopamine Agents; Dopamine Agonists; Drug Compounding; Drug Delivery Systems; Dyskinesias; Humans; Levodopa; Oxadiazoles; Parkinson Disease
PubMed: 34742740
DOI: 10.1016/j.neuropharm.2021.108869 -
CNS Drugs May 2020Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In... (Comparative Study)
Comparative Study Review
Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.
Topics: Animals; Antipsychotic Agents; Aripiprazole; Dopamine Agonists; Humans; Piperazines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thiophenes
PubMed: 32246399
DOI: 10.1007/s40263-020-00718-4 -
Biomolecules Nov 2023L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel...
L-DOPA is the mainstay of treatment for Parkinson's disease (PD). However, over time this drug can produce dyskinesia. A useful acute PD model for screening novel compounds for anti-parkinsonian and L-DOPA-induced dyskinesia (LID) are dopamine-depleted dopamine-transporter KO (DDD) mice. Treatment with α-methyl--tyrosine rapidly depletes their brain stores of DA and renders them akinetic. During sensitization in the open field (OF), their locomotion declines as vertical activities increase and upon encountering a wall they stand on one leg or tail and engage in climbing behavior termed "three-paw dyskinesia". We have hypothesized that L-DOPA induces a stereotypic activation of locomotion in DDD mice, where they are unable to alter the course of their locomotion, and upon encountering walls engage in "three-paw dyskinesia" as reflected in vertical counts or beam-breaks. The purpose of our studies was to identify a valid index of LID in DDD mice that met three criteria: (a) sensitization with repeated L-DOPA administration, (b) insensitivity to a change in the test context, and (c) stimulatory or inhibitory responses to dopamine D1 receptor agonists (5 mg/kg SKF81297; 5 and 10 mg/kg MLM55-38, a novel compound) and amantadine (45 mg/kg), respectively. Responses were compared between the OF and a circular maze (CM) that did not hinder locomotion. We found vertical counts and climbing were specific for testing in the OF, while oral stereotypies were sensitized to L-DOPA in both the OF and CM and responded to D1R agonists and amantadine. Hence, in DDD mice oral stereotypies should be used as an index of LID in screening compounds for PD.
Topics: Mice; Animals; Levodopa; Dopamine Agonists; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dyskinesia, Drug-Induced; Mice, Knockout; Parkinson Disease; Amantadine
PubMed: 38002340
DOI: 10.3390/biom13111658