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Drug Development Research Nov 2016Preclinical Research After the identification of the schizophrenia as an illness over a century ago, treatment of affected individuals included unspecific, mostly very... (Review)
Review
Preclinical Research After the identification of the schizophrenia as an illness over a century ago, treatment of affected individuals included unspecific, mostly very robust methods including deep insulin coma and lobectomy/leucotomy. The first relatively specific treatment of schizophrenia started about 60 years ago with the antipsychotic chlorpromazine. All currently approved antipsychotic drugs block dopamine receptors, indicating that manipulation of dopaminergic function is fundamental to a therapeutic response in psychosis. Despite refinements in their mechanism of action, the therapeutic effects of subsequent generations of antipsychotics are insufficient in claiming superiority over the first generation, with the possible exception of clozapine. Dopamine receptor blockade is necessary but not always sufficient for antipsychotic response and improvements have been reported with molecules acting on other receptors (glutamate, glycine, cannabidiol, estrogen), intracellular signaling proteins, or products of identified risk genes. Here, we review the current status of drugs under investigation. In addition, we emphasize that the development of the novel compounds to target the underlying cognitive dysfunction and negative symptom dimension of full blown schizophrenia, or attenuated psychosis syndrome and specific endophenotypes related to the increased risk of psychosis in the general population, alongside efforts to deconstruct the concept of schizophrenia(s), represent the best way to meet patient needs for better therapies and more favorable outcomes. Drug Dev Res 77 : 357-367, 2016. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Antipsychotic Agents; Chlorpromazine; Clozapine; Cognitive Dysfunction; Dopamine Antagonists; Drug Design; Humans; Schizophrenia
PubMed: 27633376
DOI: 10.1002/ddr.21337 -
The Journal of Emergency Medicine Oct 2017Chlorpromazine is the only drug approved by the US Food and Drug Administration for the treatment of hiccups; however, many other pharmacologic treatments have been... (Review)
Review
BACKGROUND
Chlorpromazine is the only drug approved by the US Food and Drug Administration for the treatment of hiccups; however, many other pharmacologic treatments have been proposed for intractable and persistent hiccups. Currently, there is little evidence to support the use of one agent over another.
OBJECTIVE
This review aims to identify literature concerning the use of pharmacologic treatments for intractable and persistent hiccups with the goal of evaluating therapies in terms of their level of evidence, mechanism of action, efficacy, dosing, onset of action, and adverse effects.
METHODS
A systematic literature search of PubMed, Embase, the Cochrane Library, and the New York Academy of Medicine was performed to find articles where a pharmacologic agent was used to treat intractable or persistent hiccups between the years 1966 and 2016. The GRADE method was used to assess the level of evidence for the studies included in this review.
RESULTS
This review identified 26 articles involving 10 pharmacologic treatment options that met our inclusion criteria. Amitriptyline, baclofen, gabapentin, haloperidol, metoclopramide, midazolam, nifedipine, nimodipine, orphenadrine, and valproic acid were found in the literature to be successful in treating hiccups.
CONCLUSION
Baclofen, gabapentin, and metoclopramide were the only agents that were studied in a prospective manner, while only baclofen and metoclopramide were studied in randomized controlled trials. No specific recommendations can be made for treating intractable and persistent hiccups with the evidence currently available in the literature. Therapy selection should be specific to individual patients, their underlying comorbidities, etiology of hiccups, and take into account the individual properties of the drugs.
Topics: Adrenergic Uptake Inhibitors; Chlorpromazine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Emergency Service, Hospital; GABA-B Receptor Agonists; Hiccup; Humans
PubMed: 29079070
DOI: 10.1016/j.jemermed.2017.05.033 -
Journal of the Neurological Sciences Jun 2018Tardive syndromes are a group of hyperkinetic and hypokinetic movement disorders that occur after some delay following exposure to dopamine receptor blocking agents such... (Review)
Review
Tardive syndromes are a group of hyperkinetic and hypokinetic movement disorders that occur after some delay following exposure to dopamine receptor blocking agents such as antipsychotic and anti-emetic drugs. The severity of these disorders ranges from mild to disabling or even life-threatening. There is a wide range of recognized tardive phenomenologies that may occur in isolation or in combination with each other. These phenomenologies include stereotypy, dystonia, chorea, akathisia, myoclonus, tremor, tics, gait disorders, parkinsonism, ocular deviations, respiratory dyskinesia, and a variety of sensory symptoms. Recognition of the various tardive phenomenologies may not only lead to early diagnosis but also to appropriate therapeutic intervention. This review focuses on the diagnosis and clinical course of tardive syndromes and how to distinguish between the various phenomenologies as well as how to differentiate them from other, similar but etiologically different, movement disorders.
Topics: Akathisia, Drug-Induced; Dopamine Antagonists; Humans; Tardive Dyskinesia
PubMed: 29506749
DOI: 10.1016/j.jns.2018.02.005 -
CNS Spectrums Apr 2020In community settings, negative symptoms and cognitive deficits are the primary barriers to independent living, stable relationships, and employment for individuals... (Review)
Review
In community settings, negative symptoms and cognitive deficits are the primary barriers to independent living, stable relationships, and employment for individuals suffering from schizophrenia-spectrum disorders. In contrast, however, positive psychotic symptoms (e.g., command hallucinations and persecutory delusions) often drive behavior which serves as the gateway to arrest and criminalization. Historically, the keystone of treatment for positive psychotic symptoms has been antagonism of dopamine D2 receptors in the mesolimbic tract. In this article, we review and explore the principles underlying dopamine antagonism for the treatment of psychosis; optimization of dopamine antagonists in treating positive psychotic symptoms; the advantages of depot dopamine antagonist antipsychotics in forensic settings; the concepts of pharmacokinetic and pharmacodynamic treatment failures; and the role of medication plasma concentrations in optimizing and managing treatment.
Topics: Antipsychotic Agents; Dopamine Antagonists; Forensic Psychiatry; Humans; Medication Adherence; Schizophrenia; Schizophrenic Psychology
PubMed: 31060635
DOI: 10.1017/S1092852919000841 -
ACS Chemical Neuroscience Jan 2019The discovery of chlorpromazine in the early 1950s revolutionized the clinical treatment of schizophrenia, galvanized the development of psychopharmacology, and... (Review)
Review
The discovery of chlorpromazine in the early 1950s revolutionized the clinical treatment of schizophrenia, galvanized the development of psychopharmacology, and standardized protocols used for testing the clinical efficacy of antipsychotics. Furthermore, chlorpromazine expanded our understanding of the role of chemical messaging in neurotransmission and reduced the stigma associated with mental illness, facilitating deinstitutionalization in the 1960s and 1970s. In this review, we will discuss the synthesis, manufacturing, metabolism and pharmacokinetics, pharmacology, structure-activity relationship, and adverse effects of chlorpromazine. In conclusion, we summarize the history and significant contributions of chlorpromazine that have resulted in this potent first-generation antipsychotic maintaining its clinical relevance for nearly 70 years.
Topics: Animals; Antipsychotic Agents; Chlorpromazine; Dopamine Antagonists; Humans; Schizophrenia; Structure-Activity Relationship; Treatment Outcome
PubMed: 29929365
DOI: 10.1021/acschemneuro.8b00258 -
Life Sciences Nov 2022Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall... (Review)
Review
Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall behavior. Thus, dopamine receptor antagonist antipsychotic drugs are commonly used to treat multiple psychiatric disorders. Although less discussed, these receptors are also expressed in other peripheral organ systems, such as the kidneys, eyes, gastrointestinal tract, and cardiac tissue. Consequently, therapies for certain psychiatric disorders which target dopamine receptors could have unidentified consequences on certain functions of these peripheral tissues. The existence of an intrinsic dopaminergic system in the human heart remains controversial and debated within the literature. Therefore, this review focuses on literature related to dopamine receptors within cardiac tissue, specifically dopamine receptor 3 (D3R), and summarizes the current state of knowledge while highlighting areas of research which may be lacking. Additionally, recent findings regarding crosstalk between D3R and dopamine receptor 1 (D1R) are examined. This review discusses the novel concept of understanding the role of the loss of function of D3R may play in collagen accumulation and cardiac fibrosis, eventually leading to heart failure.
Topics: Animals; Antipsychotic Agents; Dopamine; Dopamine Agonists; Dopamine Antagonists; Fibrosis; Humans; Mammals; Receptors, Dopamine D1; Receptors, Dopamine D3
PubMed: 36041503
DOI: 10.1016/j.lfs.2022.120918 -
Neurogastroenterology and Motility May 2021Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve...
BACKGROUND
Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve terminals surrounding autonomic neurons of the defecation center, whereas ghrelin is not present in the spinal cord. Dopamine at D2 receptors generally inhibits neurons, but at the defecation center, its effect is excitatory.
METHODS
In vivo recording of defecation and colorectal propulsion was used to investigate interaction between DRD2 and GHSR1a. Localization studies were used to determine sites of receptor expression in rat and human spinal cord.
KEY RESULTS
Dopamine, and the DRD2 agonist, quinpirole, directly applied to the lumbosacral cord, caused defecation. The effect of intrathecal dopamine was inhibited by the GHSR1a antagonist, YIL781, given systemically, but YIL781 was not an antagonist at DRD2. The DRD2 agonist, pramipexole, administered systemically caused colorectal propulsion that was prevented when the pelvic nerves were cut. Drd2 and Ghsr were expressed together in autonomic preganglionic neurons at the level of the defecation centers in rat and human. Behaviorally induced defecation (caused by water avoidance stress) was reduced by the DRD2 antagonist, sulpiride. We had previously shown it is reduced by YIL781.
CONCLUSIONS AND INFERENCES
Our observations imply that dopamine is a transmitter of the defecation pathways whose actions are exerted through interacting dopamine (D2) and ghrelin receptors on lumbosacral autonomic neurons that project to the colorectum. The results explain the excitation by dopamine agonists and the conservation of GHSR1a in the absence of ghrelin.
Topics: Animals; Defecation; Dopamine; Dopamine Agonists; Dopamine Antagonists; Gastrointestinal Motility; Ghrelin; Humans; Piperidines; Pramipexole; Quinazolinones; Quinpirole; Rats; Receptors, Dopamine D2; Receptors, Ghrelin; Spinal Cord; Spinal Cord Lateral Horn; Sulpiride
PubMed: 33264473
DOI: 10.1111/nmo.14051 -
Current Neurology and Neuroscience... May 2020Pediatric migraine is common, and appropriate abortive treatment is important to limit impact on school performance and mental health. This review will describe the... (Review)
Review
PURPOSE OF REVIEW
Pediatric migraine is common, and appropriate abortive treatment is important to limit impact on school performance and mental health. This review will describe the latest evidence for abortive treatment in the emergency department and inpatient settings.
RECENT FINDINGS
It is recognized that a protocol for emergency department treatment can increase efficacy and prevent admissions. These protocols commonly include a non-opioid analgesic and dopamine receptor antagonist. A novel approach to treatment with valproic acid is use of a continuous infusion. Administration of ketamine or propofol and peripheral nerve blocks could add more expedited treatment options to the armamentarium for pediatric migraine. There is increasing variety in the abortive treatment of pediatric migraine, but continued research is necessary for validation of these approaches.
Topics: Adolescent; Child; Dopamine Antagonists; Emergency Service, Hospital; Headache; Humans; Inpatients; Migraine Disorders
PubMed: 32410204
DOI: 10.1007/s11910-020-01035-5 -
Expert Opinion on Investigational Drugs Jun 2017Schizophrenia is a debilitating illness with a chronic impact on social function and daily living. Although various antipsychotics are available, there are still many... (Review)
Review
Schizophrenia is a debilitating illness with a chronic impact on social function and daily living. Although various antipsychotics are available, there are still many challenges and unmet needs. Thus, many compounds with diverse mechanisms have been investigated, but all approved antipsychotics still require interactions with dopamine D receptors. Areas covered: We searched for investigational drugs using the key words 'dopamine' and 'schizophrenia' in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Embase, Medline, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Web of Science and the Cochrane Central Register of Controlled Trials Library. Expert opinion: The prospect of developing a dopamine antagonist is hopeful. Brexpiprazole and cariprazine, which were agents listed as 'investigational dopamine antagonists,' just received FDA approval. Novel agents such as BL 1020, ITI-007, and JNJ-37822681 have solid published data available, and agents such as L-THP, Lu AF35700, S33138, and SB-773812 are under vigorous investigation. However, the expected benefits of the newly developed antagonists may not be great because they offer little enhanced efficacy for negative symptoms, cognition and functional outcomes.
Topics: Animals; Antipsychotic Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Design; Drugs, Investigational; Humans; Receptors, Dopamine D2; Schizophrenia
PubMed: 28443355
DOI: 10.1080/13543784.2017.1323870 -
Naunyn-Schmiedeberg's Archives of... Jan 2020Repeated administration of stimulants induces conditioned place preference (CPP). Dopamine receptor supersensitivity is developed in stimulant-induced CPP animals;...
Repeated administration of stimulants induces conditioned place preference (CPP). Dopamine receptor supersensitivity is developed in stimulant-induced CPP animals; however, dopamine receptor subtypes associated with the development of supersensitivity in CPP animals are largely unknown. The present preclinical study aimed to examine whether dopamine D1 or D2 receptor antagonists exert inhibitory effects on stimulant-induced psychological behaviors. Additionally, the authors aimed to elucidate the role of dopamine receptor supersensitivity on the development of reward-related behavior. Sprague Dawley rats subjected to methamphetamine- and cocaine-induced CPP tests were treated with dopamine D1 (SCH23390) or D2 (sulpiride) receptor antagonists. Following the CPP experiment, rats were challenged with apomorphine (dopamine receptor agonist), and locomotor activity was measured. Methamphetamine- and cocaine-induced CPP was reduced with the administration of SCH23390, but not sulpiride. In addition, the apomorphine challenge evoked an increase in locomotor activity in stimulant-pre-treated rats, reflecting dopamine receptor supersensitivity. SCH23390 pre-treatment inhibited the development of dopamine receptor supersensitivity, while sulpiride demonstrated no inhibitory effects. These results suggest that the dopamine D1 receptor antagonist SCH23390 inhibits the development of dopamine receptor supersensitivity which is associated with the development of CPP.
Topics: Animals; Benzazepines; Central Nervous System Stimulants; Cocaine; Conditioning, Psychological; Dopamine Antagonists; Locomotion; Male; Methamphetamine; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulpiride
PubMed: 31372696
DOI: 10.1007/s00210-019-01694-3