Predictors of neuropsychiatric side effects of dopamine-agonist therapy in patients with prolactinomas

Background: Prolactinomas are the most frequent pituitary adenomas. The treatment with cabergoline, the most common dopamine agonist used, is associated with side effects such as nausea, vomiting, dizziness, headaches, movement disorders and fatigue. There is some additional evidence from case reports and small studies that some patients report neuropsychiatric side effects such as depression, gambling, hypersexuality and impulsive control disorders. Objective: In this cross-sectional study we sought to investigate the baseline clinical, demographic and disease characteristics of our patient group as well as life-time comorbidities. Additionally, side effects under treatment with cabergoline (prevalence and enhancement) and whether genetic variants of the ABCB1 gene (coding MDR1 or P-gp) could account for difference in the central neuropsychiatric side effects were investigated. Methods: Questionnaires evaluating medical history, therapy side effects and further demographic characteristics were sent to all prolactinoma patients currently treated at the Max Planck Institute of Psychiatry in Munich. Additionally, DNA extracted either from blood or saliva samples was genotyped for each patient. Results: The clinical study included a total of 92 patients (23 male and 69 female, macro-to-microadenoma-ratio 1:1). The mean age of our group at the time of the study was 49,2 ± 13,8 years. Of the 79 patients treated with cabergoline, the following side effects associated with treatment were more prominent: fatigue (n=35), headaches (n=26), depressed mood (n=26), sleep disorders (n=26), dizziness (n=22), aggressiveness (n=17), anxiety (n=19) and weight loss (n=16). 18 patients reported of decreased and 16 of increased libido. Significant effects were observed for the C-carriers and heterozygous CT-individuals of rs1045642 that presented less frequent fatigue and sleep disorders under cabergoline. In the analysis of SNP rs2032582, G-carriers seemed to be protected from enhancement of dizziness under cabergoline. SNPs rs2235015 and rs2032583 were found to have no association with the examined symptoms. Conclusion: In our group we described an increased prevalence of symptoms such as fatigue and weight loss under cabergoline, as well as neuropsychiatric side effects such as depressed mood, aggressiveness and anxiety in comparison to the available data of the literature. We demonstrated that polymorphisms of SNPs rs1045642 and rs2032582 of the ABCB1 gene predispose for fatigue, sleep disorders and dizziness under cabergoline. This is the first study demonstrating that individual ABCB1 gene polymorphisms could account for a different occurrence or enhancement of central side effects of this systematically administered medication

Predictors of neuropsychiatric side effects of dopamine-agonist therapy in patients with prolactinomas

Background: Prolactinomas are the most frequent pituitary adenomas. The treatment with cabergoline, the most common dopamine agonist used, is associated with side effects such as nausea, vomiting, dizziness, headaches, movement disorders and fatigue. There is some additional evidence from case reports and small studies that some patients report neuropsychiatric side effects such as depression, gambling, hypersexuality and impulsive control disorders. Objective: In this cross-sectional study we sought to investigate the baseline clinical, demographic and disease characteristics of our patient group as well as life-time comorbidities. Additionally, side effects under treatment with cabergoline (prevalence and enhancement) and whether genetic variants of the ABCB1 gene (coding MDR1 or P-gp) could account for difference in the central neuropsychiatric side effects were investigated. Methods: Questionnaires evaluating medical history, therapy side effects and further demographic characteristics were sent to all prolactinoma patients currently treated at the Max Planck Institute of Psychiatry in Munich. Additionally, DNA extracted either from blood or saliva samples was genotyped for each patient. Results: The clinical study included a total of 92 patients (23 male and 69 female, macro-to-microadenoma-ratio 1:1). The mean age of our group at the time of the study was 49,2 ± 13,8 years. Of the 79 patients treated with cabergoline, the following side effects associated with treatment were more prominent: fatigue (n=35), headaches (n=26), depressed mood (n=26), sleep disorders (n=26), dizziness (n=22), aggressiveness (n=17), anxiety (n=19) and weight loss (n=16). 18 patients reported of decreased and 16 of increased libido. Significant effects were observed for the C-carriers and heterozygous CT-individuals of rs1045642 that presented less frequent fatigue and sleep disorders under cabergoline. In the analysis of SNP rs2032582, G-carriers seemed to be protected from enhancement of dizziness under cabergoline. SNPs rs2235015 and rs2032583 were found to have no association with the examined symptoms. Conclusion: In our group we described an increased prevalence of symptoms such as fatigue and weight loss under cabergoline, as well as neuropsychiatric side effects such as depressed mood, aggressiveness and anxiety in comparison to the available data of the literature. We demonstrated that polymorphisms of SNPs rs1045642 and rs2032582 of the ABCB1 gene predispose for fatigue, sleep disorders and dizziness under cabergoline. This is the first study demonstrating that individual ABCB1 gene polymorphisms could account for a different occurrence or enhancement of central side effects of this systematically administered medication

Sleep patterns in patients treated for non-secreting intra- and parasellar tumors

PURPOSE: In this study we evaluate sleep patterns of patients treated for non-secreting intra- and parasellar tumors and age- and sex-matched healthy controls. METHODS: We conducted a self-report cross-sectional case-control study with 104 patients treated for non-secreting intra- and parasellar tumors and 1800 healthy controls in an 1:8 matching. All subjects answered the Munich ChronoType Questionnaire, whereas patients were provided the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Short-Form 36 Health survey, the Beck Depression Inventory and the State-Trait Anxiety Inventory additionally. RESULTS: Patients treated for non-secreting intra- and parasellar tumors go to bed earlier, fall asleep earlier, need less time to prepare to sleep but also to get up. Additionally, they lie and sleep longer. The subgroup analysis showed that patients with secondary adrenal insufficiency compared to controls experienced shorter daily light exposure and longer sleep latency. Higher hydrocortisone dose (>20mg) was associated with worse score in global, physical and mental health, shorter time to prepare to sleep, earlier sleep onset and longer sleep duration. CONCLUSION: Our study shows that patients treated for non-secreting intra- and parasellar tumors, even if successfully treated, experience altered sleep patterns compared to controls. We suggest that managing clinicians should enlighten these possible sleep alterations to their patients and use specific questionnaires to document sleep disturbances. Additionally, when treating patients surgically, especially by transcranial approach, damaging the suprachiasmatic nucleus should be avoided. Furthermore, circadian hydrocortisone replacement therapy ideally with dual-release hydrocortisone - if possible, in a dose not more than 20mg daily - that resembles physiological cortisol levels more closely may be beneficial and could improve sleep patterns and sleep-related quality of life

Kinetics of human myeloid-derived suppressor cells after blood draw

Background: Human myeloid-derived suppressor cells (MDSC) have been described as a group of immature myeloid cells which exert immunosuppressive action by inhibiting function of T lymphocytes. While there is a huge scientific interest to study these cells in multiple human diseases, the methodological approach varies substantially between published studies. This is problematic as human MDSC seem to be a sensible cell type concerning not only cryopreservation but also time point after blood draw. To date data on delayed blood processing influencing cell numbers and phenotype is missing. We therefore evaluated the kinetics of granulocytic MDSC (gMDSC) and monocytic MDSC (mMDSC) frequencies after blood draw in order to determine the best time point for analysis of this recently defined cell type. Methods: In this study, we isolated peripheral blood mononuclear cells (PBMC) of patients with HIV infection or solid tumors directly after blood draw. We then analyzed the frequencies of gMDSC and mMDSC 2, 4 and 6 h after blood draw and after an overnight rest by FACS analysis using the standard phenotypic markers. In addition, part of the cells was frozen directly after PBMC preparation and was measured after thawing. Results: gMDSC levels showed no significant difference using fresh PBMC over time with a limitation for the overnight sample. However they were massively diminished after freezing (p = 0.0001 for all subjects). In contrast, frequencies of fresh mMDSC varied over time with no difference between time point 2 and 4 h but a significantly reduction after 6 h and overnight rest (p = 0.0005 and p = 0.005 respectively). Freezing of PBMC decreased the yield of mMDSC reaching statistical significance (p = 0.04). For both MDSC subgroups, FACS analysis became more difficult over time due to less sharp divisions between populations. Conclusions: According to our data human MDSC need to be studied on fresh PBMC. gMDSC can be studied with delay, mMDSC however should be studied no later than 4 h after blood draw. These results are crucial as an increasing number of clinical trials aim at analyzing MDSC nowadays and the logistics of blood processing implies delayed sample processing in some cases

Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality?

Objective: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing's disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing's disease). Design/methods: Here, we examine telomere length from blood in patients (n=115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case-control (n= 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length. Results: We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n=52) was a significant predictor for shorter telomere length (beta=0.377;P=0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres. Conclusion: These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates

Mapping Health Literacy Research in the European Union: A Bibliometric Analysis

Background: To examine and compare the research productivity on selected fields related to health literacy of the curren

A meta-analysis of the relationship between brain dopamine receptors and obesity: a matter of changes in behavior rather than food addiction?

Addiction to a wide range of substances of abuse has been suggested to reflect a ‘Reward Deficiency Syndrome'. That is, drugs are said to stimulate the reward mechanisms so intensely that, to compensate, the population of dopamine D(2) receptors (DD2R) declines. The result is that an increased intake is necessary to experience the same degree of reward. Without an additional intake, cravings and withdrawal symptoms result. A suggestion is that food addiction, in a similar manner to drugs of abuse, decrease DD2R. The role of DD2R in obesity was therefore examined by examining the association between body mass index (BMI) and the Taq1A polymorphism, as the A1 allele is associated with a 30–40% lower number of DD2R, and is a risk factor for drug addiction. If a lower density of DD2R is indicative of physical addiction, it was argued that if food addiction occurs, those with the A1 allele should have a higher BMI. A systematic review found 33 studies that compared the BMI of those who did and did not have the A1 allele. A meta-analysis of the studies compared those with (A1/A1 and A1/A2) or without (A2/A2) the A1 allele; no difference in BMI was found (standardized mean difference 0.004 (s.e. 0.021), variance 0.000, Z=0.196, P<0.845). It was concluded that there was no support for a reward deficiency theory of food addiction. In contrast, there are several reports that those with the A1 allele are less able to benefit from an intervention that aimed to reduce weight, possibly a reflection of increased impulsivity

Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications

The ability to deliver drug molecules effectively across the blood–brain barrier into the brain is important in the development of central nervous system (CNS) therapies. Cerebral microdialysis is the only existing technique for sampling molecules from the brain extracellular fluid (ECF; also termed interstitial fluid), the compartment to which the astrocytes and neurones are directly exposed. Plasma levels of drugs are often poor predictors of CNS activity. While cerebrospinal fluid (CSF) levels of drugs are often used as evidence of delivery of drug to brain, the CSF is a different compartment to the ECF. The continuous nature of microdialysis sampling of the ECF is ideal for pharmacokinetic (PK) studies, and can give valuable PK information of variations with time in drug concentrations of brain ECF versus plasma. The microdialysis technique needs careful calibration for relative recovery (extraction efficiency) of the drug if absolute quantification is required. Besides the drug, other molecules can be analysed in the microdialysates for information on downstream targets and/or energy metabolism in the brain. Cerebral microdialysis is an invasive technique, so is only useable in patients requiring neurocritical care, neurosurgery or brain biopsy. Application of results to wider patient populations, and to those with different pathologies or degrees of pathology, obviously demands caution. Nevertheless, microdialysis data can provide valuable guidelines for designing CNS therapies, and play an important role in small phase II clinical trials. In this review, we focus on the role of cerebral microdialysis in recent clinical studies of antimicrobial agents, drugs for tumour therapy, neuroprotective agents and anticonvulsants