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Journal of Psychopharmacology (Oxford,... Jun 2024A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but... (Review)
Review
A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments.
Topics: Humans; Antipsychotic Agents; Receptors, Dopamine D2; Schizophrenia; Animals; Receptors, G-Protein-Coupled
PubMed: 38654553
DOI: 10.1177/02698811241249415 -
Pediatric Neurology Jun 2024In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous...
BACKGROUND
In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa.
METHODS
Levodopa/carbidopa (4:1) was started at age 11 to 13 months, aiming at escalating to 5 to 6 mg/kg levodopa per day. Follow-up focused on dystonia severity and whether self-injury occurred. In addition, the literature was reviewed to delineate the age at onset of self-injury for all reported cases to date.
RESULTS
During long-term follow-up, self-injury appears to have been prevented in two patients (now aged 14 and 15.5 years), as their HPRT1 gene mutations had been invariably associated with self-injury before. Future self-injury is unlikely, as only 1.1% of 264 published cases had self-injury onset later in life than these patients' current ages. The third patient started self-injury at age 1.5 years, while on a substantially lower levodopa dose. A clear effect of levodopa on dystonia could not be determined.
CONCLUSIONS
Our observations suggest that levodopa, given early enough and sufficiently dosed, might be able to prevent self-injury in LND. Therefore, levodopa could be considered in patients with LND as early as possible, at least before the self-injury appears. Further research is needed to establish very early levodopa as an effective treatment strategy in LND, and to optimize timing and dosing.
Topics: Humans; Levodopa; Lesch-Nyhan Syndrome; Self-Injurious Behavior; Adolescent; Male; Female; Infant; Carbidopa; Dopamine Agents; Drug Combinations
PubMed: 38653184
DOI: 10.1016/j.pediatrneurol.2024.03.020 -
Addiction & Health Feb 2024The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal... (Review)
Review
The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.
PubMed: 38651025
DOI: 10.34172/ahj.2024.1478 -
Reproductive Biology and Endocrinology... Apr 2024Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is...
CONTEXT
Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child.
OBJECTIVE
To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly.
DESIGN & METHODS
Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry.
RESULTS
87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications.
CONCLUSION
Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.
Topics: Humans; Female; Pregnancy; Acromegaly; Retrospective Studies; Registries; Adult; Germany; Pregnancy Outcome; Pregnancy Complications; Diabetes, Gestational; Infant, Newborn; Somatostatin
PubMed: 38650041
DOI: 10.1186/s12958-024-01207-9 -
Frontiers in Neurology 2024Apomorphine, a potent dopamine agonist, is a therapeutic option for patients with Parkinson's disease and motor fluctuations. However, the adoption of and adherence to...
INTRODUCTION
Apomorphine, a potent dopamine agonist, is a therapeutic option for patients with Parkinson's disease and motor fluctuations. However, the adoption of and adherence to this therapy have been limited by the need for complex delivery devices and specialized care as well as resource consumption, posing challenges for new physicians. Thailand is a unique example of a developing nation that has successfully implemented and continued the use of this therapy by employing cooperative technology that has dramatically enhanced apomorphine delivery services.
METHODS
Establishing apomorphine delivery services requires significant resources and step-by-step solutions. We began our services by implementing various strategies in three chronological stages: the initial stage (2013-2015), intermediate stage (2016-2019), and current stage (2020-present), each presenting unique challenges. Together, we also implemented a proposed set of five mottos to strengthen our apomorphine delivery service. Using additive technology, we developed a patient registry platform that combined electronic data acquisition, video and remote monitoring using wearable sensors, and in-house mobile applications to support our service.
RESULTS
At the initial stage, we assembled a team to enhance the efficacy and confirm the safety of apomorphine treatment in our hospital. At the intermediate stage, we expanded our apomorphine delivery services beyond just the patients at our hospital. We supported other hospitals in Thailand in setting up their own apomorphine services by educating both physicians and nurses regarding apomorphine therapy. With this educational undertaking, increased apomorphine-related knowledge among medical professionals, and a greater number of hospitals providing apomorphine services, an increasing number of patients were administered apomorphine in subsequent years. Currently, we are providing effective apomorphine delivery to improve patient outcomes and are seamlessly integrating technology into clinical practice. Incorporating integrative technologies in our apomorphine delivery program yielded positive results in data collection and support throughout patient care, in tracking patients' statuses, in the long-term use of this treatment, and in increasing medication adherence rates.
CONCLUSION
This perspective paper describes how technology can help provide supportive healthcare services in resource-constrained environments, such as in Thailand, offering a step-by-step approach to overcoming several limitations. The valuable insights from our 10-year journey in successfully integrating technology into apomorphine delivery services can benefit new physicians seeking to replicate our success.
PubMed: 38645746
DOI: 10.3389/fneur.2024.1379459 -
Frontiers in Endocrinology 2024Prolactinomas (PRLs) are prevalent pituitary adenomas associated with metabolic changes and increased cardiovascular morbidity. This study examined clinical, endocrine,...
Metabolic and inflammatory parameters in relation to baseline characterization and treatment outcome in patients with prolactinoma: insights from a retrospective cohort study at a single tertiary center.
BACKGROUND
Prolactinomas (PRLs) are prevalent pituitary adenomas associated with metabolic changes and increased cardiovascular morbidity. This study examined clinical, endocrine, metabolic, and inflammatory profiles in PRL patients, aiming to identify potential prognostic markers.
METHODS
The study comprised data from 59 PRL patients gathered in a registry at the University Hospital of Zurich. Diagnostic criteria included MRI findings and elevated serum prolactin levels. We assessed baseline and follow-up clinical demographics, metabolic markers, serum inflammation-based scores, and endocrine parameters. Treatment outcomes were evaluated based on prolactin normalization, tumor shrinkage, and cabergoline dosage.
RESULTS
The PRL cohort exhibited a higher prevalence of overweight/obesity, prediabetes/diabetes mellitus, and dyslipidemia compared to the general population. Significant correlations were found between PRL characteristics and BMI, HbA1c, and fT4 levels. Follow-up data indicated decreases in tumor size, tumor volume, prolactin levels, and LDL-cholesterol, alongside increases in fT4 and sex hormones levels. No significant associations were observed between baseline parameters and tumor shrinkage at follow-up. A positive association was noted between PRL size/volume and the time to achieve prolactin normalization, and a negative association with baseline fT4 levels.
CONCLUSION
This study underscores the metabolic significance of PRL, with notable correlations between PRL parameters and metabolic indices. However, inflammatory markers were not significantly correlated with patient stratification or outcome prediction. These findings highlight the necessity for standardized follow-up protocols and further research into the metabolic pathogenesis in PRL patients.
Topics: Humans; Prolactinoma; Female; Male; Adult; Retrospective Studies; Middle Aged; Pituitary Neoplasms; Treatment Outcome; Inflammation; Tertiary Care Centers; Cabergoline; Prolactin; Prognosis; Follow-Up Studies; Cohort Studies; Young Adult
PubMed: 38645431
DOI: 10.3389/fendo.2024.1363939 -
Molecular Pharmaceutics May 2024The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The...
The main purpose of our studies is to demonstrate that commercially available mesoporous silica (MS) can be used to control the physical state of aripiprazole (ARP). The investigations performed utilizing differential scanning calorimetry and broadband dielectric spectroscopy reveal that silica can play different roles depending on its concentration in the system with amorphous ARP. At low MS content, it activates recrystallization of the active pharmaceutical ingredient and supports forming the III polymorphic form of ARP. At intermediate MS content (between ca. 27 and 65 wt %), MS works as a recrystallization inhibitor of ARP. At these concentrations, the formation of III polymorphic form is no longer favorable; therefore, it is possible to use this additive to obtain ARP in either IV or X polymorphic form. At the same time, employing MS in concentrations >65 wt % amorphous form of ARP with high physical stability can be obtained. Finally, regardless of the polymorphic form it crystallizes into, each composite is characterized by the same temperature dependence of relaxation times in the supercooled and glassy states.
Topics: Aripiprazole; Silicon Dioxide; Calorimetry, Differential Scanning; Porosity; Crystallization; Dielectric Spectroscopy; X-Ray Diffraction
PubMed: 38644570
DOI: 10.1021/acs.molpharmaceut.3c01095 -
Progress in Neurobiology May 2024The gut-brain peptide ghrelin and its receptor are established as a regulator of hunger and reward-processing. However, the recently recognized ghrelin receptor inverse...
The gut-brain peptide ghrelin and its receptor are established as a regulator of hunger and reward-processing. However, the recently recognized ghrelin receptor inverse agonist, liver-expressed antimicrobial peptide 2 (LEAP2), is less characterized. The present study aimed to elucidate LEAP2s central effect on reward-related behaviors through feeding and its mechanism. LEAP2 was administrated centrally in mice and effectively reduced feeding and intake of palatable foods. Strikingly, LEAP2s effect on feeding was correlated to the preference of the palatable food. Further, LEAP2 reduced the rewarding memory of high preference foods, and attenuated the accumbal dopamine release associated with palatable food exposure and eating. Interestingly, LEAP2 was widely expressed in the brain, and particularly in reward-related brain areas such as the laterodorsal tegmental area (LDTg). This expression was markedly altered when allowed free access to palatable foods. Accordingly, infusion of LEAP2 into LDTg was sufficient to transiently reduce acute palatable food intake. Taken together, the present results show that central LEAP2 has a profound effect on dopaminergic reward signaling associated with food and affects several aspects of feeding. The present study highlights LEAP2s effect on reward, which may have applications for obesity and other reward-related psychiatric and neurological disorders.
Topics: Animals; Male; Mice; Antimicrobial Cationic Peptides; Blood Proteins; Dopamine; Eating; Feeding Behavior; Nucleus Accumbens; Reward
PubMed: 38641041
DOI: 10.1016/j.pneurobio.2024.102615 -
Wellcome Open Research 2023There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism....
BACKGROUND
There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis.
METHODS
Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis.
PROTOCOL REGISTRATION
PROSPERO-ID: CRD42023451628.
PubMed: 38634067
DOI: 10.12688/wellcomeopenres.19866.1 -
Journal of Medical Case Reports Apr 2024Significant elevation of creatine kinase levels (above three digits) and leucocytosis in the absence of muscle rigidity, tremors, or autonomic dysfunction can pose a...
BACKGROUND
Significant elevation of creatine kinase levels (above three digits) and leucocytosis in the absence of muscle rigidity, tremors, or autonomic dysfunction can pose a real challenge in the context of antipsychotic treatment as an early herald of neuroleptic malignant syndrome.
CASE PRESENTATION
We present here two cases of adult male patients of Black British heritage, ages 51 years and 28 years, respectively. Both received a diagnosis of schizoaffective disorder and presented with massive increase of creatine kinase blood level after aripiprazole depot administration, one with pernicious increase associated with silent neuroleptic malignant syndrome, and the second with asymptomatic benign enzyme elevation.
CONCLUSION
Though aripiprazole use is less likely to cause neuroleptic malignant syndrome, on rare occasions it can produce massive symptomatic or asymptomatic increase in serum creatine kinase enzyme levels, raising the need for close monitoring, especially at the initial doses of the drug.
Topics: Adult; Humans; Male; Aripiprazole; Neuroleptic Malignant Syndrome; Antipsychotic Agents; Psychotic Disorders; Creatine Kinase
PubMed: 38632633
DOI: 10.1186/s13256-024-04508-0