Blocking Dopamine D2 Receptors Research Articles

Development of Glycerosomal pH Triggered In Situ Gelling System to Ameliorate the Nasal Delivery of Sulpiride for Pediatric Psychosis.

Sulpiride (Sul) is a medication that blocks dopamine D2 receptors. It is used to treat gastrointestinal disturbances and has antipsychotic effects depending on the dose given. Sulpiride is subject to P-glycoprotein efflux, resulting in limited bioavailability and erratic absorption. Hence, the aim of this study was to generate a glycerosomal in situ gel of sulpiride for intranasal administration, specifically targeting children with schizophrenia who may have difficulty swallowing traditional solid medications, for enhancing its bioavailability. This study aimed to demonstrate the efficacy of intranasal administration of glycerin-encapsulated lipid-nanovesicles (glycerosomes) mixed with in situ gels for prolonged release of anti-psychotic medication. A Box-Behnken design was utilized to create sulpiride-loaded glycerosomes (Sul-GMs), with the lipid amount (A), glycerin concentration (B), and sonication time (C) acting as independent variables. Their impact on the entrapment efficiency, EE% (Y1), and in vitro drug release (Y2) were evaluated. The sulpiride EE% showed an increase when the glycerin concentration was raised to 25% v/v. Nevertheless, when the glycerin concentration was raised to 40% v/v, there was a notable decrease in the EE%. The optimized glycerosome was added to pH triggered carbopol 974P in situ gel formulations including HPMC K15M with different concentrations. The in situ gel formulation (G3) comprising 0.6% carbopol 974P and 0.6% hydroxypropyl methyl cellulose-K15M (HPMC K15M) demonstrated suitable pH, viscosity, desired gel strength, spreadability, and mucoadhesive strength. Consequently, it was selected for in vitro study, ex vivo permeation investigation, and in vivo evaluations. The glycerosomal in situ gel exhibited favorable ex vivo permeability of SU when applied to the nasal mucosa. The pharmacokinetic investigation revealed that the optimized Sul-loaded glycerosomal in situ gel exhibited a significant fourfold and twofold enhancement in systemic bioavailability compared to both the control gel and the commercially available formulation. Finally, the intranasal administration of Sul-loaded glycerosomal in situ gel is a promising alternative to oral treatment for pediatric patients with psychosis.

Fentanyl dose-sparing in polyarthritic rats requires full agonism at 5-HT1A receptors: Comparison between NLX-112, (±)8-OH-DPAT, and buspirone.

NLX-112 (a.k.a. F13640, befiradol) is a highly selective and fully efficacious agonist at 5-hydroxytryptamine (5-HT1A) receptors. It has been shown to be robustly and potently active in nociceptive, neuropathic and traumatic pain models in rats and mice. In particular, NLX-112 decreases oral fentanyl self-administration (FSA) in polyarthritic rats, ie, it has opioid dose-sparing effects. To examine if the dose-sparing effects of NLX-112 in polyarthritic rats are shared by other 5-HT1A ligands: the prototypical 5-HT1A receptor agonist 8-HYDROXY-2-(DI-n-PROPYLAMINO)TETRALIN ((±)8-OH-DPAT), and the 5-HT1A receptor partial agonist and weak dopamine D2 receptor blocker, -buspirone. Polyarthritis was induced by inoculating rats with heat-killed Mycobacterium butyricum. They then had access to either a fentanyl (0.008 mg/mL) or a sweetened solution in their home cage. NLX-112, (±)8-OH-DPAT, or buspirone was administered via an osmotic minipump (5 µL/h) during a 2-week infusion period from day 14 to day 28 post-inoculation with Mycobacterium butyricum. Control infusions consisted of sterile 0.9 percent NaCl. NLX-112 (0.63 mg/day) significantly decreased FSA by 47 percent and increased total fluid consumption (TFC) by 7 percent (vehicle-loaded minipumps as controls). Both (±)8-OH-DPAT and buspirone (0.63 and 2.5 mg/day, respectively) failed to reduce FSA; (±)8-OH-DPAT did not modify TFC, while buspirone significantly decreased it by 17 percent. These results suggest that oral FSA dose-sparing effect, in this rat polyarthritis pain model, requires high efficacy activation of 5-HT1A receptors, such as that afforded by NLX-112. By contrast, the agonist efficacy of (±)8-OH-DPAT and buspirone seems insufficient for FSA dose-sparing.

New Therapeutic Targets and Drugs for Schizophrenia Beyond Dopamine D2 Receptor Antagonists.

Schizophrenia is a disease with a complex pathological mechanism that is influenced by multiple genes. The study of its pathogenesis is dominated by the dopamine hypothesis, as well as other hypotheses such as the 5-hydroxytryptamine hypothesis, glutamate hypothesis, immune-inflammatory hypothesis, gene expression abnormality hypothesis, and neurodevelopmental abnormality hypothesis. The first generation of antipsychotics was developed based on dopaminergic receptor antagonism, which blocks dopamine D2 receptors in the brain to exert antipsychotic effects. The second generation of antipsychotics acts by dual blockade of 5-hydroxytryptamine and dopamine receptors. From the third generation of antipsychotics onwards, the therapeutic targets for antipsychotic schizophrenia expanded beyond D2 receptor blockade to explore D2 receptor partial agonism and the antipsychotic effects of new targets such as D3, 5-HT1A, 5-HT7, and mGlu2/3 receptors. The main advantages of the second and third generation antipsychotics over first-generation antipsychotics are the reduction of side effects and the improvement of negative symptoms, and even though third-generation antipsychotics do not directly block D2 receptors, the modulation of the dopamine transmitter system is still an important part of their antipsychotic process. According to recent research, several receptors, including 5-hydroxytryptamine, glutamate, γ-aminobutyric acid, acetylcholine receptors and norepinephrine, play a role in the development of schizophrenia. Therefore, the focus of developing new antipsychotic drugs has shifted towards agonism or inhibition of these receptors. Specifically, the development of NMDARs stimulants, GABA receptor agonists, mGlu receptor modulators, cholinergic receptor modulators, 5-HT2C receptor agonists and alpha-2 receptor modulators has become the main direction. Animal experiments have confirmed the antipsychotic effects of these drugs, but their pharmacokinetics and clinical applicability still require further exploration. Research on alternative targets for antipsychotic drugs, beyond the dopamine D2 receptor, has expanded the potential treatment options for schizophrenia and gives an important way to address the challenge of refractory schizophrenia. This article aims to provide a comprehensive overview of the research on therapeutic targets and medications for schizophrenia, offering valuable insights for both treatment and further research in this field.

OR2806 Levosulpiride-Induced Hyperprolactinemia For The Treatment Of Diabetic Macular Edema: A Phase 2 Pilot Clinical Trial

Abstract Disclosure: C. Clapp: None. C.D. Núñez-Amaro: None. M. López: None. E. Adán-Castro: None. M. Robles Osorio: None. R. García-Franco: None. M. García-Roa: None. Y. Villalpando: None. P. Ramírez-Neria: None. N. Pineiro: None. J.F. Rubio-Mijangos: None. J. Sánchez: None. G. Ramirez-Hernandez: None. L. Siqueiros-Márquez: None. N. Díaz-Lezama: None. E. López-Star: None. T. Bertsch: None. G. Martínez de la Escalera: None. J. Triebel: None. Vasoinhibin is a fragment of prolactin that inhibits the permeability and growth of blood vessels. The prokinetic dopamine D2 receptor blocker, levosulpiride, elevates the circulating levels of prolactin and the accumulation of vasoinhibin in the vitreous of patients with proliferative diabetic retinopathy (PDR) (1) suggesting clinical benefits due to the vascular properties of vasoinhibin. Here, we describe the 2-month results of a phase 2 clinical trial (2) investigating the biological activity of levosulpiride in center-involving diabetic macular edema (DME). This prospective, randomized, double-masked, dual-center, placebo-controlled, pilot study was carried out in individuals (aged 40 to 69 years) with DME involving the center of the macula and best-corrected visual acuity (BCVA) between 58 and 16 ETDRS letters at 4 m (20/16 to 20/100 Snellen equivalent) or with PDR undergoing elective pars plana vitrectomy. Oral treatment (TID) with levosulpiride or placebo was for 8 weeks in DME patients or for the 1 week before vitrectomy in PDR patients. Primary outcome measures included changes from baseline in BCVA, central foveal thickness (CFT), and mean macular volume (MMV) every 2 weeks for 8 weeks in placebo- (17 patients, 18 eyes) and levosulpiride- (17 patients, 22 eyes) treated DME groups; whereas vitreous levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were primary outcomes in PDR patients after placebo (18 patients) or levosulpiride (18 patients). Starting at 4 weeks, levosulpiride improved changes from baseline in BCVA (P < 0.037), CFT (P < 0.013), and MMV (P < 0.002) compared to placebo. At 8 weeks, the proportion of eyes gaining >5 letters (41% vs. 28%), loosing > 21 μm in CFT (55% vs. 28%), and dropping > 0.06 mm3 in MMV (65% vs. 29%) were higher in levosulpiride vs placebo. The overall grading of visual (BCVA) and structural parameters (CFT, MMV, OCT macula image, fundoscopy, and fluorescein angiography) showed improvement with levosulpiride (P = 0.029). Levosulpiride reduced VEGF (P = 0.025) and PlGF (P= 0.008) levels in the vitreous of PDR patients. There were no apparent adverse side-effects. In conclusion, oral levosulpiride administration for 8 weeks improved visual and structural outcomes in patients with center involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted. Reference: (1) Núñez-Amaro et al., Transl Vis Sci Technol. 2020 Aug 17;9(9):27. (2) www.clinicaltrials.gov, ID: NCT03161652; Supported by UNAM grant 405PC. Presentation: Sunday, June 18, 2023

New Developments in the Treatment of Schizophrenia: An Expert Roundtable.

Schizophrenia is a disabling disorder that profoundly affects functioning and quality of life. While available antipsychotics have improved outcomes for patients with schizophrenia, they are relatively ineffective for negative and cognitive symptoms and are associated with a range of troublesome side effects. A significant unmet medical need for more effective and better-tolerated therapies remains. A roundtable consisting of 4 experts in the treatment of patients with schizophrenia convened to discuss the current treatment landscape, unmet needs from patient and societal perspectives, and the potential of emerging therapies with novel mechanisms of action (MOAs). Key areas of unmet need include optimal implementation of available treatments, effective treatment of negative and cognitive symptoms, improvements in medication adherence, novel MOAs, avoidance of postsynaptic dopamine blockade-related adverse effects, and individualized approaches to treatment. With the possible exception of clozapine, all currently available antipsychotics primarily act by blocking dopamine D2 receptors. Agents with novel MOAs are urgently needed to effectively target the full range of symptoms in schizophrenia and facilitate an individualized treatment approach. Discussion focused on promising novel MOAs that have demonstrated potential in phase 2 and 3 trials include muscarinic receptor agonism, trace amine-associated receptor 1 agonism, serotonin receptor antagonism/inverse agonism, and glutamatergic modulation. Results from early clinical trials of agents with novel MOAs are encouraging, particularly for muscarinic and trace amine-associated receptor 1 agonists. These agents offer renewed hope for meaningful improvement in the management of patients with schizophrenia.

Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal

Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics.

Executive functions neither associated with agentic extraversion nor sensitive to the dopamine D2 blocker sulpiride in a preregistered study

Initial studies suggest that extraversion and executive functions (EFs) are associated because of shared dopaminergic mechanisms. Aiming to conceptually replicate these findings we conducted a preregistered study to investigate (1) associations between extraversion and performance in three tasks (3-back, switching, AX-CPT) and (2) whether these associations are sensitive to administration of the dopamine D2 receptor blocker sulpiride in a placebo-controlled between-subjects design (N = 200). Against expectations, neither (agentic) extraversion, nor its interaction with substance condition explained performance in any of the EF tasks. As the current results are limited by an unexpectedly low reliability of the measures derived from the switching task and the AX-CPT, further preregistered studies using psychometrically superior measures are needed.

Pimavanserin and Parkinson's Disease Psychosis: A Narrative Review.

Pimavanserin (PMV) is the first approved drug for treating hallucinations and delusions in Parkinson’s disease (PD) psychosis. Psychosis is one of the leading causes of nursing home placement in people with PD. Furthermore, hallucinations are a more frequent cause of institutionalization than motor disability or dementia related to PD. The management of PD psychosis involves antipsychotic medications. Most of the drugs in this class directly block dopamine D2 receptors, leading to significantly worsening motor symptoms in patients with PD. The most commonly used medications for managing PD psychosis are quetiapine, clozapine, and PMV. This literature review aims to study pimavanserin’s history, mechanism, clinical trials, and post-marketing experience. PMV is a potent 5-HT2A receptor antagonist/inverse agonist. Moreover, this drug can interact with 5-HT2C receptors. We calculated some physicochemical descriptors and pharmacokinetic properties of PMV. Eight clinical trials of PMV and PD psychosis are registered on ClinicalTrials.gov. Only four of them have complete results already published. Meta-analytic results showed that PMV efficacy is inferior to clozapine. However, PMV has a significantly lower number of side-effects for managing psychosis in PD. Medicare database assessment revealed 35% lower mortality with PMV compared to other atypical antipsychotics. Moreover, sensitive statistical analysis demonstrated that PMV is a protective factor for the risk of falls in individuals with PD.

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

TAAR1 agonists are an emerging drug class in the treatment of schizophrenia as they may offer a novel mechanism of action for symptom management without blocking dopamine D2 receptors, unlike currently available antipsychotic medications that act primarily via D2 binding. Two TAAR1 agonists are currently in clinical development for schizophrenia. The first is ulotaront, a TAAR1 full agonist with 5-hydroxytryptamine 1A agonist activity that is administered orally once daily, and the other is ralmitaront, a TAAR1 partial agonist that is also administered orally once daily. The published clinical trial evidence on TAAR1 agonists currently only pertains to ulotaront, which includes a 4-week, phase II, placebo-controlled randomized trial on patients with acute exacerbation of schizophrenia and a 26-week, open-label extension study of this same trial. These studies demonstrated improvements across disease-specific and global impression scales following treatment with ulotaront, with statistically significant differences compared to placebo, and no increased risk of the side effects (extrapyramidal symptoms and metabolic changes) associated with traditional D2-binding antipsychotic therapies. There is currently no cost information available for TAAR1 agonists. Ulotaront is currently undergoing phase III trials and, though it is not currently approved in any country and the date of Health Canada licensing and marketing in Canada is not yet known, it is expected to be the first TAAR1 agonist for schizophrenia in the Canadian market. Ulotaront received Breakthrough Therapy designation from the FDA in 2019 to expedite its development and the drug’s manufacturer is planning to file a New Drug Application with the FDA in 2023. Ralmitaront is currently in phase II trials, which are expected to be completed in 2023.

Analgesic Effects of Oxycodone in Combination With Risperidone or Ziprasidone: Results From a Pilot Randomized Controlled Trial in Healthy Volunteers.

Background and ObjectivesPatients taking opioids are at risk of developing dependence and possibly abuse. Given the role of the mesolimbic dopamine system in opioid reward, blocking dopamine D2 receptors should limit the abuse liability of opioid analgesics. This pilot study evaluates the analgesic efficacy of oxycodone combined with an atypical antipsychotic (dopamine D2 receptor antagonist).MethodsA randomized, double-blind, within-subjects, controlled trial in healthy volunteers was conducted at UT Health SA Pain Clinic. Fifteen volunteers with previous medical exposure to opioids were enrolled. Risperidone (2 mg) or ziprasidone (80 mg) in combination with oxycodone (5, 10, 15 mg) was administered. Pain intensity using the cold pressor test, Current Opioid Misuse Measure (COMM), Addiction Research Center Inventory (ARCI, opioid subscale), Drug likability with drug effects questionnaire (DEQ) were assessed.ResultsOxycodone produced dose dependent increases in thermal analgesia on the cold pressor test that was significant at 10 and 15 mg (t = 3.087, P = 0.017). The combination did not significantly alter thermal analgesia. There was no significant effect of the combination on the ARCI or the POMS.Discussion and ConclusionThe combination of an atypical antipsychotic with oxycodone does not alter analgesic response or increase the incidence of adverse effects when compared to oxycodone alone. Such information is critical for the development of drug combinations for the treatment of pain and provide the foundation for future studies of abuse potential in drug users.Scientific SignificanceThis intervention in chronic pain patients is unique because it utilizes FDA approved drugs in combination to reduce abuse liability. The first step, and aim of this study, is to confirm the drug combination does not interfere with analgesic efficacy. The next step is to examine the combination in recreational drug users to assess the potential to block the euphoric effects of oxycodone. Ultimately, if this combination is effective, this approach could be beneficial in management of chronic pain.

Impairment of the cardiac ejection fraction by blocking dopamine D2 receptors induced by long-acting injectable antipsychotic treatment.

Introduction: Atypical antipsychotics have numerous benefits compared to conventional ones in respect to the possible adverse effects. However, like the other ones, they may induce direct cardiovascular alterations, probably through the apoptotic effect of dopamine receptor D2 (DRD2) blockade. The main objective of the study was to assess the cardiac ejection fraction (EF) using transthoracic speckle tracking echocardiography (TSTE) in patients treated with long-acting injectable (LAI) atypical antipsychotics. Patients, Materials and Methods: This cross-sectional study was conducted on 123 patients with schizophrenia or schizoaffective disorder divided in four samples according to their treatment: Aripiprazole, Olanzapine, Paliperidone and Risperidone. We analyzed socio-demographic data, the intensity of psychiatric symptoms, the duration of psychosis and of LAI treatment, and the cardiac EF measured with TSTE. Results: We found no statistically significant differences between the four antipsychotics regarding the values of the EF. Nevertheless, we observed a trend indicating that patients treated with an antipsychotic associated with a lower affinity for the DRD2, such as Olanzapine, have higher EF values than patients treated with antipsychotics with a stronger binding to the DRD2, such as Paliperidone and Risperidone. Patients receiving Aripiprazole, which has the strongest affinity for the DRD2 from all four antipsychotics but is also a partial DRD2 agonist, display higher EF values than those on Paliperidone and Risperidone. Conclusions: Antipsychotics with a lower affinity for the DRD2 or a partial agonism for it may be associated with higher EF. Cardiac monitoring should be performed periodically in patients on LAI antipsychotic therapy.

Risk of Breast Cancer With Prolactin Elevating Antipsychotic Drugs: An Observational Study of US Women (Ages 18-64 Years).

Antipsychotic drugs are well established to alter circulating prolactin levels by blocking dopamine D2 receptors in the pituitary. Prolactin activates many genes important in the development of breast cancer. Prior studies have found an association with antipsychotic use and risk of breast cancer. The IBM MarketScan Commercial and Medicaid Databases were used to establish a large, observational cohort of women taking antipsychotics drugs compared with anticonvulsants or lithium. A new user design was used that required 12 months of insurance enrollment before the first antipsychotic or anticonvulsant/lithium prescription. Invasive breast cancer was identified using diagnostic codes. Multivariable Cox proportional hazards models were used to evaluate the risk of breast cancer with antipsychotic drug exposure controlling for age and other risk factors. A total of 914 cases (0.16%) of invasive breast cancer were identified among 540,737 women. Exposure to all antipsychotics was independently associated with a 35% increased risk of breast cancer (aHR [adjusted hazard ratio], 1.35; 95% confidence interval, 1.14-1.61). Category 1 drugs (high prolactin) were associated with a 62% increased risk (aHR, 1.62; 95% CI, 1.30-2.03), category 2 drugs a 54% increased risk (aHR, 1.54; 95% CI, 1.19-1.99), and category 3 drugs were not associated with breast cancer risk. In the largest study of antipsychotics taken by US women, a higher risk between antipsychotic drug use and increased risk for breast cancer was observed, with a differential higher association with antipsychotic categories that elevate prolactin. Our study confirms other recent observational studies of increased breast cancer risk with antipsychotics that elevate prolactin.

The Selective Dopamine D2 Blocker Sulpiride Modulates the Relationship Between Agentic Extraversion and Executive Functions

Initial studies suggest that agentic extraversion and executive functions (EF) are associated, because they share influences of individual differences in the dopamine (DA) system. However, it is unclear whether previously reported associations are specific to certain EFs (e.g., to updating or shifting) or due to shared variance among EF tasks. We investigated the DA-related relationship between agentic extraversion and two EF tasks in a placebo-controlled between-group design with the DA D2 receptor blocker sulpiride (200 mg) in 92 female volunteers. Our goals were to investigate whether (1) there is an association between agentic extraversion and EFs measured with two different tasks (3-back and switching), (2) this association is sensitive to a pharmacological manipulation of DA, and (3) the effects can be ascribed to shared or specific task variance. We observed the expected interaction between drug condition and agentic extraversion for both tasks in a multivariate multiple linear regression model, which supports the DA theory of extraversion. Subsequent univariate analyses revealed a highly similar interaction effect between drug condition and agentic extraversion on two of three performance measures and this effect was somewhat attenuated when we controlled for shared task variance. This pattern matches the interpretation that the association between agentic extraversion and both tasks is partly due to DA-based processes shared among the tasks. Our results, although limited by the low reliability of the switching task, suggest that variance components and measurement difficulties of EF tasks should be considered when investigating personality-related individual differences in EFs.

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia.

Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathology in vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.

Pathophysiology and management of Akathisia 70 years after the introduction of the chlorpromazine, the first antipsychotic.

Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients, and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors, Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs. This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles. Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage-gated calcium channel blockers (gabapentin, pregabalin) and opioids may be effective. Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzodiazepines or gabapentinoids for symptomatic relief is the basis of management.

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia.

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.

Profil Penggunaan Obat Kombinasi Risperidone-Clozapine dan Risperidone dengan Antipsikotik Lain pada Pasien Gangguan Mental Psikotik di Rumah Sakit Jiwa Grhasia Yogyakarta

Approximately 7% of Indonesia's population experience mental disorders psychosis. Yogyakarta Special Region is the second-highest incidence of psychotic mental disorders with a rate of 10 per 1000 population and 80% of those treated in mental hospitals with schizophrenia. Pharmacotherapy management in patients with psychotic mental disorders with the use of antipsychotics, both single and combination. Antipsychotics are classified as atypical antipsychotics and typical antipsychotics. Both groups of antipsychotics have the same pharmacological activity, namely blocking dopamine D2 receptors. The study design is prospective. Inclusion criteria for adult patients (18-65 years), who are inpatient, get risperidone-clozapine antipsychotic therapy and risperidone with other antipsychotics and have complete data. Data obtained from medical records and analyzed with univariate tests to describe the distribution of patients. Bivariate testing to compare the two treatment groups. The number of samples at the end of the study were 32 patients who were divided into 2 groups of antipsychotic antipsychotics, risperidone-clozapine, and risperidone with other antipsychotics. The results of this study show that the therapeutic group that is often used is the combination of risperidone-clozapine compared to risperidone with other antipsychotics in patients with psychotic mental disorders at Yogyakarta Grhasia Mental Hospital.

Haloperidol-Induced Preclinical Tardive Dyskinesia Model in Rats.

Haloperidol is a first-generation antipsychotic used in the treatment of psychoses, especially schizophrenia. This drug acts by blocking dopamine D2 receptors, reducing psychotic symptoms. Notwithstanding its benefits, haloperidol also produces undesirable impacts, in particular extrapyramidal effects such as tardive dyskinesia (TD), which limit the use of this and related drugs. TD is characterized by repetitive involuntary movements occurring after chronic exposure therapy with haloperidol. Symptoms most commonly manifest in the orofacial area and include involuntary movements, tongue protrusion, pouting lips, chewing in the absence of any object to chew, and facial grimacing. The most serious aspect of TD is that it may persist for months or years after drug withdrawal and is irreversible in some patients. This unit, aimed at facilitating the study of TD, describes methods to induce TD in rats using haloperidol, as well as procedures for evaluating the animals's TD-related symptoms. © 2019 by John Wiley & Sons, Inc.

Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol

GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/− mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/− mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/− mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.

The relation between dopamine D2 receptor blockade and the brain reward system: a longitudinal study of first-episode schizophrenia patients

Psychotic symptoms have been linked to salience abnormalities in the brain reward system, perhaps caused by a dysfunction of the dopamine neurotransmission in striatal regions. Blocking dopamine D2 receptors dampens psychotic symptoms and normalises reward disturbances, but a direct relationship between D2 receptor blockade, normalisation of reward processing and symptom improvement has not yet been demonstrated. The current study examined the association between blockade of D2 receptors in the caudate nucleus, alterations in reward processing and the psychopathology in a longitudinal study of antipsychotic-naïve first-episode schizophrenia patients. Twenty-two antipsychotic-naïve first-episode schizophrenia patients (10 males, mean age 23.3) and 23 healthy controls (12 males, mean age 23.5) were examined with single-photon emission computed tomography using 123I-labelled iodobenzamide. Reward disturbances were measured with functional magnetic resonance imaging (fMRI) using a modified version of the monetary-incentive-delay task. Patients were assessed before and after 6 weeks of treatment with amisulpride. In line with previous results, patients had a lower fMRI response at baseline (0.2 ± 0.5 v. 0.7 ± 0.6; p = 0.008), but not at follow-up (0.5 ± 0.6 v. 0.6 ± 0.7), and a change in the fMRI signal correlated with improvement in Positive and Negative Syndrome Scale positive symptoms (ρ = -0.435, p = 0.049). In patients responding to treatment, a correlation between improvement in the fMRI signal and receptor occupancy was found (ρ = 0.588; p = 0.035). The results indicate that salience abnormalities play a role in the reward system in schizophrenia. In patients responding to a treatment-induced blockade of dopamine D2 receptors, the psychotic symptoms may be ameliorated by normalising salience abnormalities in the reward system.