ArticleLiterature Review

The Role of Serotonin in Antipsychotic Drug Action

September 1999
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 21(2 Suppl):106S-115S

September 1999
21(2 Suppl):106S-115S

DOI:10.1016/S0893-133X(99)00046-9

Source
PubMed

Authors:

Herbert Meltzer

Northwestern University

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptor which these drugs directly, the 5-HT1a and 5-HT2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT6 and 5-HT7 receptors may also be of some importance. Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes.

MDMA for the Treatment of Negative Symptoms in Schizophrenia

Article

Full-text available

Jun 2022

The profound economic burden of schizophrenia is due, in part, to the negative symptoms of the disease, which can severely limit daily functioning. There is much debate in the field regarding their measurement and classification and there are no FDA-approved treatments for negative symptoms despite an abundance of research. 3,4-Methylenedioxy methamphetamine (MDMA) is a schedule I substance that has emerged as a novel therapeutic given its ability to enhance social interactions, generate empathy, and induce a state of metaplasticity in the brain. This review provides a rationale for the use of MDMA in the treatment of negative symptoms by reviewing the literature on negative symptoms, their treatment, MDMA, and MDMA-assisted therapy. It reviews recent evidence that supports the safe and potentially effective use of MDMA to treat negative symptoms and concludes with considerations regarding safety and possible mechanisms of action.

Exploring the kinetic selectivity of antipsychotics for dopamine D 2 and 5-HT 2A receptors: implications for the prevalence of EPS and receptor occupancy

Preprint

Full-text available

Nov 2021

Certain atypical antipsychotic drugs (APDs) used in the treatment of schizophrenia have been hypothesized to show reduced extrapyramidal side effects (EPS), due to their ability to promote nigrostriatal dopamine release through 5-HT 2A receptor (5-HT 2A R) blockade. The strength of this hypothesis is currently limited to a consideration of the relative receptor affinities of APDs for the 5-HT 2A R and dopamine D 2 receptor (D 2 R). Here we measure the 5-HT 2A R kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay and correlate these properties with their observed EPS at therapeutic doses. For compounds with negligible affinity for 5-HT 2A R, EPS is robustly predicted by a D 2 R specific rebinding model that integrates D 2 R association and dissociation rates to calculate the net rate of reversal of receptor blockade ( k r ). However, we show that for compounds with significant affinity for the 5-HT 2A R, such as sertindole, higher relative 5-HT 2A occupancy over time is an indicator for a reduced propensity to cause EPS. This study suggests that there is room for the development of novel kinetically optimised antipsychotic agents that modulate both serotonergic and dopamine function in a manner beneficial in the treatment of this chronic and debilitating disease.

Безопасность и эффективность тиаприда (тиапридала) в геронтологической практике и обзор новейших данных // Safety and efficacy of tiapridal (tiapride) in geriatric practice, with a review of latest scientific data on tiapride in general

Article

Full-text available

Nov 2020

Как известно, психотические расстройства представляют большую клиническую проблему при ведении пациентов позднего возраста, и они весьма распространены в этой возрастной группе. Среди психотических расстройств, наблюдаемых у пациентов позднего возраста, встречаются как эндогенные психозы (обычно имевшие манифестацию и развитие в более ранние периоды жизни, как, например, шизофрения, биполярное аффективное расстройство, и продолжающие проявляться и в более позднем возрасте), так и психозы экзогенно-органического или соматогенного характера (например, сосудистые, климактерические, связанные с деменцией Альцгеймера, болезнью Паркинсона и т. п., с наличием злокачественных опухолей, с уремией и т. д.), и реактивные психозы (например, вследствие утраты супруга/супруги или другого близкого человека). Ведение психозов в позднем возрасте осложняется плохой переносимостью пациентами этой возрастной группы как типичных антипсихотиков (ТАП), так и многих атипичных антипсихотиков (ААП). Пациенты этой возрастной группы склонны испытывать выраженные побочные эффекты (ПЭ) при применении этих препаратов, в частности, выраженный экстрапирамидный синдром (ЭПС), акатизию, ортостатическую гипотензию (ОГ), антихолинергические ПЭ, чрезмерную сонливость и седацию, кардиометаболические осложнения (неблагоприятные изменения в липидном и гликемическом профилях крови и т. д.). Самым неприятным свойством как ТАП, так и большинства ААП при их применении у пациентов позднего возраста является их способность статистически достоверно уменьшать продолжительность жизни этих пациентов, повышать их общую смертность и смертность от сердечно-сосудистых причин, пролежней и пневмонии (последнее связано с гипокинезией и беспомощностью). В данной статье мы показываем, что препарат Тиапридал (тиаприд) выгодно отличается и от ТАП, и от большинства ААП очень хорошим общим и сердечно-сосудистым профилем безопасности в геронтологической группе, и высокоэффективен для пациентов этой возрастной группы с психозами и с нарушениями поведения. Поэтому он заслуживает более широкого применения у таких пациентов. Кроме того, мы также представляем читателю новые данные, касающиеся клинического применения тиаприда (не только в геронтологии), появившиеся в научной литературе после 2015 года. Ключевые слова: тиаприд, Тиапридал, психотические расстройства, нарушения поведения, деменция, поздний возраст, безопасность терапии. Для цитирования: П.В. Морозов, Ю.В. Быков, Р.А. Беккер. Безопасность и эффективность тиаприда (Тиапридала) в геронтологической практике и обзор новейших данных. Психиатрия и психофармакотерапия. 2020; 5: 15–26. It is well known that various psychotic disorders represent a major clinical problem in the management of elderly patients. Such disorders are very common in this frailty age group. Among the various psychotic disorders that can be encountered in elderly patients by any clinician, there could be both endogenous psychoses (usually manifesting and developing in earlier periods of life, such as schizophrenia, bipolar affective disorder, and continuing to manifest themselves at a later age), and psychoses of organic or somatogenic nature (for example, vascular and climacteric psychoses, psychoses associated with Alzheimer’s dementia, with Parkinson’s disease, etc., psychoses associated with the presence of malignant tumors, with uremia, etc.), and also reactive psychoses (for example, due to the loss of a spouse or another valuable person). The management of psychosis in later life is complicated by the poor tolerance of patients in this age group to both typical antipsychotics and many atypical antipsychotics. Patients in this age group tend to experience severe side effects when using these drugs, in particular, severe extrapyramidal syndrome, akathisia, orthostatic hypotension, anticholinergic side effects, excessive sleepiness and sedation, cardio-metabolic complications (adverse changes in the lipid and glycemic profiles of blood, etc.). The most disturbing problem of using either typical or most of the atypical antipsychotics in elderly patients is that they all have the ability to statistically significantly reduce the life expectancy of these patients, to increase their overall mortality and their mortality from cardiovascular causes, from pressure ulcers and pneumonia (the latter is associated with hypokinesia and helplessness). In this article, we show that the drug Tiapridal (tiapride) compares favorably with both typical and most of the atypical antipsychotics by its very good general and cardiovascular safety profile in the advanced age patient group, while being highly effective for patients of this age group, which suffer from psychoses and/or behavioral disturbances. Therefore, Tiapridal (tiapride) deserves much wider use in patients of this age group. In addition, we also present to the reader new data on the clinical use of tiapride (not only in advanced age patients) that have appeared in the scientific literature since 2015. Keywords: tiapride, Tiapridal, psychotic disorders, behavioral disturbances, dementia, advanced age, safety of therapy. For citation: P.V. Morozov, Yu.V. Bykov, R.A. Bekker. Safety and efficacy of Tiapridal (tiapride) in geriatric practice, with a review of latest scientific data on tiapride in general. Psychiatry and psychopharmacotherapy. 2020; 5: 15–26.

XOB: A novel phenylalkylamine antagonist of 5-HT2A receptors and voltage-gated sodium channels

Article

May 2024
MOL PHARMACOL

Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia

Article

Full-text available

Jul 2023
CNS DRUGS

Patients with schizophrenia experience a broad range of detrimental health outcomes resulting from illness severity, heterogeneity of disease, lifestyle behaviors, and adverse effects of antipsychotics. Because of these various factors, patients with schizophrenia have a much higher risk of cardiometabolic abnormalities than people without psychiatric illness. Although exposure to many antipsychotics increases cardiometabolic risk factors, mortality is higher in patients who are not treated versus those who are treated with antipsychotics. This indicates both direct and indirect benefits of adequately treated illness, as well as the need for beneficial medications that result in fewer cardiometabolic risk factors and comorbidities. The aim of the current narrative review was to outline the association between cardiometabolic dysfunction and schizophrenia, as well as discuss the confluence of factors that increase cardiometabolic risk in this patient population. An increased understanding of the pathophysiology of schizophrenia has guided discovery of novel treatments that do not directly target dopamine and that not only do not add, but may potentially minimize relevant cardiometabolic burden for these patients. Key discoveries that have advanced the understanding of the neural circuitry and pathophysiology of schizophrenia now provide possible pathways toward the development of new and effective treatments that may mitigate the risk of metabolic dysfunction in these patients. Novel targets and preclinical and clinical data on emerging treatments, such as glycine transport inhibitors, nicotinic and muscarinic receptor agonists, and trace amine-associated receptor-1 agonists, offer promise toward relevant therapeutic advancements. Numerous areas of investigation currently exist with the potential to considerably progress our knowledge and treatment of schizophrenia.

Synthesis and evaluation of 99mTc-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5HT7 receptors

Article

Mar 2023
BIOORG CHEM

Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HT7Rs); hence, this study aims to develop 5-HT7R targeted radiotracers. Aryl piperazine derivatives can act as ligands for 5-HT7R. Therefore, compounds 6 and 7 as 1-(3- nitropyridin-2-yl)piperazine derivatives were synthesized and radiolabeled with 99mTcN2+ core. Radiolabeled 6 and 7 (99mTcN-[6] and 99mTcN-[7]) were prepared with high radiochemical purity (RCP > 96%). They displayed high affinity toward U-87 MG cell line 5-HT7R. The calculated Ki for 99mTcN-[7] was lower than that of 99mTcN- [6] (14.85 ± 0.32 vs 22.57 ± 0.73 nM) which indicates the higher affinity of 99mTcN-[7] toward 5-HT7R. A molecular docking study also confirmed the binding of these radiotracers to 5-HT7R. The biodistribution study in normal mice revealed that 99mTcN-[7] has the highest brain accumulation at 30 min post-injection (0.54 ± 0.12 %ID/g) while the uptake of 99mTcN-[6] is much lower (0.14 ± 0.02 %ID/g). The biodistribution study in the xenograft model confirms that the radiotracers recognize the tumor site. 99mTcN-[6], and 99mTcN-[7] showed the highest tumor uptake at 1-hour post-injection (5.44 ± 0.58 vs 4.94 ± 1.65 %ID/g) and tumor-to-muscle ratios were (4.61 vs. 5.61). The injection of pimozide blocks the receptors and significantly reduces the tumor-tomuscle ratios at 1-hour post-injection to 0.81 and 0.31, respectively. In correlation with in vitro study, 99mTcN-[6] and 99mTcN-[7] visualize the tumor site in U-87 MG glioma xenografted nude mice and display the tumor-to-muscle ratios of 7.05 and 6.03.

Neuropsychological functioning in schizophrenia patients. Psychiatry, theory, applications, and treatments

Chapter

Full-text available

Feb 2023

Behrooz Afshari

Impact of specific serotonin receptor modulation on restricted repetitive behaviors

Article

Full-text available

Dec 2022

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs.

Apo2ph4 : A Versatile Workflow for the Generation of Receptor-based Pharmacophore Models for Virtual Screening

Article

Full-text available

Dec 2022

Pharmacophore models are widely used as efficient virtual screening (VS) filters for the target-directed enrichment of large compound libraries. However, the generation of pharmacophore models that have the power to discriminate between active and inactive molecules traditionally requires structural information about ligand-target complexes or at the very least knowledge of one active ligand. The fact that the discovery of the first known active ligand of a newly investigated target represents a major hurdle at the beginning of every drug discovery project underscores the need for methods that are able to derive high-quality pharmacophore models even without the prior knowledge of any active ligand structures. In this work, we introduce a novel workflow, called apo2ph4, that enables the rapid derivation of pharmacophore models solely from the three-dimensional structure of the target receptor. The utility of this workflow is demonstrated retrospectively for the generation of a pharmacophore model for the M2 muscarinic acetylcholine receptor. Furthermore, in order to show the general applicability of apo2ph4, the workflow was employed for all 15 targets of the recently published LIT-PCBA dataset. Pharmacophore-based VS runs using the apo2ph4-derived models achieved a significant enrichment of actives for 13 targets. In the last presented example, a pharmacophore model derived from the etomidate site of the α1β2γ2 GABAA receptor was used in VS campaigns. Subsequent in vitro testing of selected hits revealed that 19 out of 20 (95%) tested compounds were able to significantly enhance GABA currents, which impressively demonstrates the applicability of apo2ph4 for real-world drug design projects.

Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Ligands Containing a 5-Norbornene-2- Carboxamide Nucleus

Article

Full-text available

Oct 2022
MOLECULES

A new series of 5-norbornene-2-carboxamide derivatives was prepared and their affinities to the 5-HT1A, 5-HT2A, and 5-HT2C receptors were evaluated and compared to a previously synthesized series of derivatives characterized by exo-N-hydroxy-5-norbornene-2,3-dicarboximidenu-cleus, in order to identify selective ligands for the above-mentioned subtype receptors. Arylpipera-zines represents one of the most important classes of 5-HT1AR ligands, and recent research concerning new derivatives has been focused on the modification of one or more portions of such pharma-cophore. The combination of structural elements (heterocyclic nucleus, propyl chain and 4-substituted piperazine), known to be critical to the affinity to 5-HT1A receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that Norbo-4 and Norbo-18 were the most active and promising derivatives for the serotonin receptor considered in this study. Keywords: 5-norbornene-2-carboxilic acid; serotonin; arylpiperazine derivatives; 5-HT1A; 5-HT2A and 5-HT2C receptor ligands Citation: Sparaco, R.; Kędzierska, E.; Kaczor, A.A.; Bielenica, A.; Magli, E.; Severino, B.; Corvino, A.; Gibuła-Tarłowska, E.; Kotlińska, J.H.; Andreozzi, G.; et al. Synthesis, Docking Studies and Pharmacological Evaluation of Serotoninergic Lig-ands Containing a 5-Norbornene-2-Carboxamide Nucleus. Molecules 2022, 27, 6492.

Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity

Article

Full-text available

Sep 2022
NATURE

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1–4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines—a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C–H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5–7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.

New Strategies to Improve Cognitive Symptom Domain in the Treatment of Schizophrenia

Chapter

Sep 2022

Cognitive impairment, in past decades, has been consistently reported in patients with schizophrenia [1]. Neurocognitive disability appears early in the course of the disease, even in prodromal phases, and these deficits are widely present in different stages of the illness whether in patients or in their first-degree family members [2]. In 2004, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project has identified seven distinct cognitive domains that are impaired in patients with schizophrenia: speed of processing, attention/vigilance, working memory, verbal and visual learning, reasoning and problem solving, and social cognition [3–5]. Moreover, in the third meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) project, it was cleared that six areas of cognitive domains are damaged in patients with schizophrenia: perception, working memory, attention, executive functions, long-term memory, and social cognition [6]. Regarding social cognitive deficits, they include impairments in facial affect recognition, in perceiving and interpreting social cues, in theory of mind (ToM), and in the ability to make appropriate causal attributions for events [7]. Several studies have shown that both neurocognitive and social cognitive deficits are among the major causes of severe functional disabilities in patients with schizophrenia and they are also related to a worse outcome of the disorder [8–10]. In a comprehensive literature review, Green et al. [10] underlined that different cognitive deficits might have an impact on specific areas of psychosocial functioning. As a matter of fact, cognitive deficits seem to explain 20–60% of the variance of everyday functioning [3, 4, 11]. The influence of cognition on functional outcomes may happen through its influence on functional capacity, the ability to perform critical everyday living skills [12]. Thus, functional capacity may actually be considered as a proxy measure between neurocognition and everyday functioning and it has been found to be quite strongly associated with cognitive performance [13]. Recent studies have shown how cognitive impairment predicts functional outcomes even more than positive and negative symptoms and how it is associated with disability in phases of clinical remission too [2, 14]. From the greater and detailed knowledge of the role and meaning of cognitive impairment in schizophrenia, its improvement became an essential target in the treatment and in the clinical management of the illness [15]. In order to restore cognitive deficits in schizophrenic patients, there are different pharmacological and non-pharmacological approaches developed. Whereas pharmacological interventions include approved treatments (e.g., antipsychotics and antidepressants) and under-study treatments, non-pharmacological interventions include cognitive remediation, noninvasive brain stimulation techniques, and physical activity techniques [16–20].

Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract

Article

Jul 2022

The neuromodulatory arousal system imbues the nervous system with the flexibility and robustness required to facilitate adaptive behaviour. While there are well understood mechanisms linking dopamine, noradrenaline and acetylcholine to distinct behavioural states, similar conclusions have not been as readily available for serotonin. Fascinatingly, despite clear links between serotonergic function and cognitive capacities as diverse as reward processing, exploration, and the psychedelic experience, over 95% of the serotonin in the body is released in the gastrointestinal tract, where it controls digestive muscle contractions (peristalsis). Here, we argue that framing neural serotonin as a rostral extension of the gastrointestinal serotonergic system dissolves much of the mystery associated with the central serotonergic system. Specifically, we outline that central serotonin activity mimics the effects of a digestion/satiety circuit mediated by hypothalamic control over descending serotonergic nuclei in the brainstem. We review commonalities and differences between these two circuits, with a focus on the heterogeneous expression of different classes of serotonin receptors in the brain. Much in the way that serotonin-induced peristalsis facilitates the work of digestion, serotonergic influences over cognition can be reframed as performing the work of cognition. Extending this analogy, we argue that the central serotonergic system allows the brain to arbitrate between different cognitive modes as a function of serotonergic tone: low activity facilitates cognitive automaticity, whereas higher activity helps to identify flexible solutions to problems, particularly if and when the initial responses fail. This perspective sheds light on otherwise disparate capacities mediated by serotonin, and also helps to understand why there are such pervasive links between serotonergic pathology and the symptoms of psychiatric disorders.

Scaffolding group II metabotropic glutamate receptors

Thesis

Jan 2004

B. Pilkington

p>This study identified 5 candidate interacting proteins for the group II mGluRs; microtubule-associated serine threonine kinase (MAST), syntrophin associated serine/threonine kinase (SAST), rhophilin-1, protein kinase C interacting cousin of thioredoxin (PICOT) and calmodulin. MAST, SAST and rhophilin-1 all contain a PDZ (Post Synaptic Density-95, Discs large, ZO-1) domain, a common protein:protein interaction domain found in many receptor scaffolding proteins. Mutation analysis of the C-tail of mGluR2 and mGluR3 suggests that they interact with MAST, SAST and rhophilin-1 through the PDZ domain although the interaction is atypical, requiring more of the receptor C-tail than initially thought to constitute the interaction domain. The interactions of MAST, SAST and rhophilin-1 with mGluR2 and mGluR3 were recapitulated biochemically utilising glutathione S-transferase pulldown experiments. The interaction of calmodulin with group II mGluRs as shown by the yeast two-hybrid screen could not be reproduced biochemically in agreement with published data, highlighting the importance of biochemically confirming candidate interactions identified in yeast two-hybrid screens. When co-expressed heterologously SAST or rhophilin-1 co-localised with group II mGluRs suggesting the interactions occur in a cellular context. SAST is expressed in areas of the brain in which group II mGluRs are present, MAST and rhophilin-1 are present in brain but little known about the distribution, so there is potential for the interactions to have in vivo functions. These studies provide a platform for further investigation of the role of MAST, SAST and rhophilin-1 in the regulation of mGluR function.</p

Association between the loudness dependence of auditory evoked potentials and age in patients with schizophrenia and depression

Article

Full-text available

Jul 2022
J INT MED RES

Objective: Although serotonergic dysfunction is significantly associated with major depressive disorder (MDD) and schizophrenia (SCZ), comparison of serotonergic dysfunction in both diseases has received little attention. Serotonin hypotheses have suggested diminished and elevated serotonin activity in MDD and SCZ, respectively. However, the foundations underlying these hypotheses are unclear regarding changes in serotonin neurotransmission in the aging brain. The loudness dependence of auditory evoked potentials (LDAEP) reflects serotonin neurotransmission. The present study compared the LDAEP between patients with SCZ or MDD and healthy controls (HCs). We further examined whether age was correlated with the LDAEP and clinical symptoms. Methods: This prospective clinical study included 105 patients with SCZ (n = 54) or MDD (n = 51). Additionally, 35 HCs were recruited for this study. The LDAEP was measured on the midline channels via 62 electroencephalography channels. Results: Patients with SCZ or MDD showed a significantly smaller mean LDAEP than those in HCs. The LDAEP was positively correlated with age in patients with SCZ or MDD. Conclusions: Changes in central serotonergic activity could be indicated by evaluating the LDAEP in patients with SCZ or MDD. Age-related reductions in serotonergic activity may be screened using the LDAEP in patients with SCZ or MDD.

Clozapine’s multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia

Article

Jun 2022
PHARMACOL THERAPEUT

Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine’s multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HT2R, D1R, α2c, and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine’s exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS.

Alternative Therapy of Psychosis: Potential Phytochemicals and Drug Targets in the Management of Schizophrenia

Article

Full-text available

May 2022

Schizophrenia is a chronic mental and behavioral disorder characterized by clusters of symptoms including hallucinations, delusions, disorganized thoughts and social withdrawal. It is mainly contributed by defects in dopamine, glutamate, cholinergic and serotonergic pathways, genetic and environmental factors, prenatal infections, oxidative stress, immune system activation and inflammation. Management of schizophrenia is usually carried out with typical and atypical antipsychotics, but it yields modest benefits with a diversity of side effects. Therefore, the current study was designed to determine the phytochemicals as new drug candidates for treatment and management of schizophrenia. These phytochemicals alter and affect neurotransmission, cell signaling pathways, endocannabinoid receptors, neuro-inflammation, activation of immune system and status of oxidative stress. Phytochemicals exhibiting anti-schizophrenic activity are mostly flavonoids, polyphenols, alkaloids, terpenoids, terpenes, polypropanoids, lactones and glycosides. However, well-designed clinical trials are consequently required to investigate potential protective effect and therapeutic benefits of these phytochemicals against schizophrenia.

Selective 5HT3 antagonists and sensory processing: A systematic review

Article

Full-text available

Jan 2022

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson’s disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

KANPHOS: A Database of Kinase-Associated Neural Protein Phosphorylation in the Brain

Article

Full-text available

Dec 2021

Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The “KANPHOS” (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways.

A new class of 5‐HT2A/5‐HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2‐aminotetralins

Article

Full-text available

Mar 2022
BRIT J PHARMACOL

Background and Purpose The 5‐HT receptor subtypes 5‐HT2A and 5‐HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5‐HT2B and H1 receptors is challenging. Here, we delineated molecular determinants of selective binding to 5‐HT2A and 5‐HT2C receptors for novel 4‐phenyl‐2‐dimethylaminotetralins (4‐PATs). Experimental Approach We synthesized 42 novel 4‐PATs with halogen or aryl moieties at the C(4)‐phenyl meta‐position. Affinity, function, molecular modeling and 5‐HT2A receptor mutagenesis studies were performed to understand structure–activity relationships at 5‐HT2‐type and H1 receptors. Lead 4‐PAT‐type 5‐HT2A/5‐HT2C receptor inverse agonists were compared with pimavanserin, a selective 5‐HT2A/5‐HT2C receptor inverse agonist approved to treat Parkinson's disease‐related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development. Key Results Most 4‐PAT diastereomers in the (2S,4R)‐configuration bound non‐selectively to 5‐HT2A, 5‐HT2C and H1 receptors, with >100‐fold selectivity over 5‐HT2B receptors, whereas diastereomers in the (2R,4R)‐configuration bound preferentially to 5‐HT2A over 5‐HT2C receptors and had >100‐fold selectivity over 5‐HT2B and H1 receptors. Results suggest that G2385.42 and V2355.39 in 5‐HT2A receptors (conserved in 5‐HT2C receptors) are important for high affinity binding, whereas interactions with T1945.42 and W1584.56 determine H1 receptor affinity. The 4‐PAT analog (2S,4R)‐4‐(4'‐(dimethylamino)‐[1,1'‐biphenyl]‐3‐yl)‐N,N‐dimethyl‐1,2,3,4‐tetrahydronaphthalen‐2‐amine, (2S,4R)‐2k, a potent and selective 5‐HT2A/5‐HT2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity. Conclusions and Implications The novel 4‐PAT chemotype can yield selective 5‐HT2A/5‐HT2C receptor inverse agonists for antipsychotic drug development by optimizing ligand–receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H1 receptors, which may circumvent sedative effects.

Tardive Dyskinesia in Older Persons Taking Antipsychotics

Article

Full-text available

Oct 2021

Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use of dopamine receptor-blocking agents (DRBAs), a category of medications that includes first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people of all ages, older age is associated with increased risk of TD and also with the emergence of TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is characterized by involuntary movements that include the face, limbs, and trunk, and is associated with increased comorbidities, social stigmatization, and impaired physical and mental health. Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with the use of US Food and Drug Administration (FDA)-approved medications for TD, symptoms may persist. Because the leading hypothesis for the pathophysiology of TD has been dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and management of TD, with a focus on older people.

Nicht dopaminerge Antipsychotika: Hintergründe und neue Substanzen

Article

Apr 2021

Bridging the gap between single receptor type activity and whole‐brain dynamics

Article

Full-text available

Apr 2021
FEBS J

What is the effect of activating a single modulatory neuronal receptor type on entire brain network dynamics? Can such effect be isolated at all? These are important questions because characterizing elementary neuronal processes that influence network activity across the given anatomical backbone is fundamental to guide theories of brain function. Here, we introduce the concept of the cortical ‘receptome’ taking into account the distribution and densities of expression of different modulatory receptor types across the brain's anatomical connectivity matrix. By modelling whole‐brain dynamics in silico, we suggest a bidirectional coupling between modulatory neurotransmission and neuronal connectivity hardware exemplified by the impact of single serotonergic (5‐HT) receptor types on cortical dynamics. As experimental support of this concept, we show how optogenetic tools enable specific activation of a single 5‐HT receptor type across the cortex as well as in vivo measurement of its distinct effects on cortical processing. Altogether, we demonstrate how the structural neuronal connectivity backbone and its modulation by a single neurotransmitter system allow access to a rich repertoire of different brain states that are fundamental for flexible behaviour. We further propose that irregular receptor expression patterns—genetically predisposed or acquired during a lifetime—may predispose for neuropsychiatric disorders like addiction, depression and anxiety along with distinct changes in brain state. Our long‐term vision is that such diseases could be treated through rationally targeted therapeutic interventions of high specificity to eventually recover natural transitions of brain states.

Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

Article

Full-text available

Mar 2021
eLife

Serotonin (5-HT) is one of the major neuromodulators present in the mammalian brain and has been shown to play a role in multiple physiological processes. The mechanisms by which 5-HT modulates cortical network activity, however, are not yet fully understood. We investigated the effects of 5-HT on slow oscillations (SOs), a synchronized cortical network activity universally present across species. SOs are observed during anesthesia and are considered to be the default cortical activity pattern. We discovered that (±)3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine, two potent 5-HT releasers, inhibit SOs within the entorhinal cortex (EC) in anesthetized mice. Combining opto- and pharmacogenetic manipulations with in vitro electrophysiological recordings, we uncovered that somatostatin-expressing (Sst) interneurons activated by the 5-HT 2A receptor (5-HT 2A R) play an important role in the suppression of SOs. Since 5-HT 2A R signaling is involved in the etiology of different psychiatric disorders and mediates the psychological effects of many psychoactive serotonergic drugs, we propose that the newly discovered link between Sst interneurons and 5-HT will contribute to our understanding of these complex topics.

Hippocampal neuroanatomy in first episode psychosis: A putative role for glutamate and serotonin receptors

Article

Mar 2021

Disrupted serotonergic and glutamatergic signaling interact and contribute to the pathophysiology of schizophrenia, which is particularly relevant for the hippocampus where diverse expression of serotonin receptors is noted. Hippocampal atrophy is a well-established feature of schizophrenia, with select subfields hypothesized as particularly vulnerable due to variation in glutamate receptor densities. We investigated hippocampal anomalies in first-episode psychosis (FEP) in relation to receptor distributions by leveraging 4 sources of data: (1) ultra high-field (7-Tesla) structural neuroimaging, and (2) proton magnetic resonance spectroscopy (1H-MRS) of glutamate from 27 healthy and 41 FEP subjects, (3) gene expression data from the Allen Human Brain Atlas and (4) atlases of the serotonin receptor system. Automated methods delineated the hippocampus to map receptor density across subfields. We used gene expression data to correlate serotonin and glutamate receptor genes across the hippocampus. Measures of individual hippocampal shape-receptor alignment were derived through normative modelling and correlations to receptor distributions, termed Receptor-Specific Morphometric Signatures (RSMS). We found reduced hippocampal volumes in FEP, while CA4-dentate gyrus showed greatest reductions. Gene expression indicated 5-HT1A and 5-HT4 to correlate with AMPA and NMDA expression, respectively. Magnitudes of subfield volumetric reduction in FEP correlated most with 5-HT1A (R = 0.64, p = 4.09E-03) and 5-HT4 (R = 0.54, p = 0.02) densities as expected, and replicated using previously published data from two FEP studies. Right-sided 5-HT4-RSMS was correlated with MRS glutamate (R = 0.357, p = 0.048). We demonstrate a putative glutamate-driven hippocampal variability in FEP through a serotonin receptor-density gated mechanism, thus outlining a mechanistic interplay between serotonin and glutamate in determining the hippocampal morphology in schizophrenia.

Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property

Article

Full-text available

Feb 2021

Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as “micro” doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3–3 mg/kg [10–73 ng/ml]) and psilocybin/psilocin (0.05–0.1 mg/kg [7–12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1–3 mg/kg IP) and psilocybin (0.05–0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as “low performing”. Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.

The impact of psychotropic drugs on brain functionality and connectivity in bipolar disorder

Chapter

Jan 2021

Bipolar disorder (BD) is a common, severe, and chronic psychiatric condition characterized by affective instability and disability. Functional neuroimaging techniques provide measures of brain activity and connectivity that have helped to elucidate neurobiological basis of this disorder. Indeed, functional magnetic resonance imaging (fMRI) has proven extremely useful for exploring the abnormalities in brain regions during the performance of specific tasks or in resting-state conditions. However, deeper consideration of pharmacological treatment effects on neural function may be required when considering fMRI results. In this context the aim of this chapter is to provide an overview of the evidence reported by fMRI and resting-state fMRI studies evaluating the effects of pharmacological treatment in patients with BD. Overall the available evidence supports normalizing effects of medications on brain activity/connectivity, ultimately suggesting that medications have a positive impact on neural circuitries. Specifically the majority of these studies found a normalization in prefrontal regions and interconnected areas involved in emotion regulation and processing, regardless of the task employed. Additionally, distinct classes of medications showed different results in terms of regional specificity, maybe due to their different pharmacological properties. In conclusion, these findings provide key insight on the neurobiology of BD by the identification of specific biomarkers of treatment outcome.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

Article

Full-text available

Jan 2021

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. Significance Statement Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.

Salience Network and Olanzapine in Schizophrenia: Implications for Treatment in Anorexia Nervosa

Article

Full-text available

Mar 2015

The salience network (SN), a set of brain regions composed of the anterior fronto-insular cortex (aFI) and the anterior cingulate cortex (ACC), is usually involved in interoception, self-regulating, and action selection. Accumulating evidence indicates that dysfunctions in this network are associated with various pathophysiological deficits in both schizophrenia and eating disorders, stemming mainly from dysfunctional information processing of internal or external stimuli. In addition, the metabolic side effects of some antipsychotics (APs), as well as their pharmacological mechanisms of action, also suggest a link between the functional and neurophysiological changes in the brain in both schizophrenia and in eating disorders. Nevertheless, there is still a knowledge gap in explicitly and directly linking the metabolic side effects associated with AP treatment with the dysfunction in SN associated with processing of food-related information in schizophrenia. Here we provide neuroimaging evidence for such a link, by presenting data on a group of schizophrenia patients who followed 16 weeks of olanzapine treatment and undertook a passive viewing task while their brain activity was recorded. In response to food-related dynamic stimuli (video clips), we observed a decreased activity in SN (aFI and ACC) after the treatment, which also correlated with ghrelin plasma concentration and a measure of dietary restraint. Taken together with past findings regarding the role of SN in both schizophrenia and eating disorders, our results suggest that enhancing the reactivity in the SN has the potential to be a treatment strategy in people with anorexia nervosa. Clinical Trial Registration Number: NCT 00290121 W W W Réseau de salience et olanzapine dans la schizophrénie : implications pour le traitement de l'anorexie mentale Le réseau de la salience (RS), un ensemble de régions cérébrales formé du cortex fronto-insulaire antérieur (FIa) et du cortex cingulaire antérieur (CCA), est habituellement impliqué dans l'intéroception, l'autorégulation, et la sélection d'actions. Les données probantes qui s'accumulent indiquent que les dysfonctions de ce réseau sont associées avec divers déficits pathophysiologiques dans la schizophrénie et les troubles alimentaires, émanant principalement du traitement dysfonctionnel de l'information des stimuli internes et externes. En outre, les effets secondaires métaboliques de certains antipsychotiques (AP), ainsi que leurs mécanismes d'action pharmacologiques suggèrent aussi un lien entre les changements fonctionnels et neurophysiologiques du cerveau dans la schizophrénie et les troubles alimentaires. Néanmoins, les connaissances ne suffisent pas encore à lier explicitement et directement les effets secondaires métaboliques associés au traitement par AP avec la dysfonction du RS associée au traitement de l'information liée aux aliments dans la schizophrénie. Nous offrons ici des preuves en neuroimagerie de ce lien, en présentent des données d'un groupe de patients souffrant de schizophrénie qui ont suivi un traitement de 16 semaines par olanzapine et qui ont effectué une tâche de visualisation passive pendant que leur activité cérébrale était enregistrée. En réponse aux stimuli dynamiques liés aux aliments (vidéoclips), nous avons observé une activité réduite du RS (FIa et CCA) après le traitement, qui corrélait aussi avec la concentration plasmatique de ghréline et une mesure des restrictions alimentaires. Pris conjointement avec les constatations passées sur le rôle du RS dans la schizophrénie et les troubles alimentaires, nos résultats suggèrent qu'accroître la réactivité du RS pourrait être une stratégie de traitement chez les personnes souffrant d'anorexie mentale. Numéro d'enregistrement d'essai clinique : NCT 00290121 open access

Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment

Article

Full-text available

Jan 2012

There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.

Ligand bias and inverse agonism on 5-HT2A receptor-mediated modulation of G protein activity in post-mortem human brain

Article

Apr 2024
BRIT J PHARMACOL

Background and Purpose Whereas biased agonism on the 5‐HT 2A receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5‐HT 2A receptor constitutive activity has been suggested, highlighting the therapeutic relevance of inverse agonism. This study characterized the modulation of G protein activity promoted by different drugs, commonly considered as 5‐HT 2A receptor antagonists, in post‐mortem human brain cortex. Experimental Approach Modulation of [ ³⁵ S]GTPγS binding to different subtypes of Gα proteins exerted by different 5‐HT 2A receptor drugs was determined by scintillation proximity assays in brain from human, WT and 5‐HT 2A receptor KO mice. Key Results MDL‐11,939 was the only drug having no effect on the basal activity of 5‐HT 2A receptor. Altanserin and pimavanserin decreased basal activation of G i1 , but not G q/11 proteins. This effect was blocked by MDL‐11,939 and absent in 5‐HT 2A receptor KO mice. Volinanserin showed 5‐HT 2A receptor‐mediated inverse agonism both on G i1 and G q/11 proteins. Ketanserin exhibited 5‐HT 2A receptor partial agonism exclusively on G q/11 proteins. On the other hand, eplivanserin and nelotanserin displayed inverse agonism on G q/11 and/or G i1 proteins, which was insensitive to MDL‐11,939 and was present in KO mice suggesting a role for another receptor. Conclusion and Implications The results reveal the existence of constitutively active 5‐HT 2A receptors in human pre‐frontal cortex and demonstrate different pharmacological profiles of various 5‐HT 2A receptor drugs previously considered antagonists. These findings indicate that altanserin and pimavanserin possess biased inverse agonist profile towards 5‐HT 2A receptor activation of G i1 proteins.

Safety and effectiveness of lurasidone in the treatment of Chinese schizophrenia patients: An interim analysis of post-marketing surveillance

Article

Full-text available

Nov 2023

99mTc(CO)3-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5-HT7 receptors

Article

Nov 2023
ANN NUCL MED

The 5-hydroxytryptamine receptor (5-HTR) family includes seven classes of receptors. The 5-HT7R is the newest member of this family and contributes to different physiological and pathological processes. As a pathology, glioblastoma multiform (GBM) overexpresses 5-HT7R; hence, this study aims to develop radiolabeled aryl piperazine derivatives as 5-HT7R imaging agents. Compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were radiolabeled with fac-[99mTc(CO)3(H2O)3]+ and 99mTc(CO)3-[6] and 99mTc(CO)3-[7] were obtained with high radiochemical purity (RCP > 94%). The stability of the radiotracers was evaluated in both saline and mouse serum. Specific binding on different cell lines including U-87 MG, MCF-7, SKBR3, and HT-29 was performed. The biodistribution of these radiotracers was evaluated in normal and U-87 MG Xenografted models. Finally, 99mTc(CO)3-[6] and 99mTc(CO)3-[7] were applied for in vivo imaging in U-87 MG Xenografted models. Specific binding study indicates that 99mTc(CO)3-[6] and 99mTc(CO)3-[7] can recognize 5-HT7R of U87-MG cell line. The biodistribution study in normal mice indicates that the brain uptake of 99mTc(CO)3-[6] and 99mTc(CO)3-[7] is the highest at 30 min post-injection (0.8 ± 0.25 and 0.64 ± 0.18%ID/g, respectively). The data of the biodistribution study in the U87-MG xenograft model revealed that these radiotracers could accumulate in the tumor site, and the highest tumor uptake was observed at 60 min post-injection (3.38 ± 0.65 and 3.27 ± 0.5%ID/g, respectively). The injection of pimozide can block the tumor’s radiotracer uptake, indicating the binding of these radiotracers to the 5-HT7R. The imaging study in the xenograft model also confirms the biodistribution data. The acquired images clearly show the tumor site, and the tumor-to-muscle ratio for 99mTc(CO)3-[6] and 99mTc(CO)3-[7] at 60 min was 3.33 and 3.88, respectively. 99mTc(CO)3-[6] and 99mTc(CO)3-[7] can visualize tumor in the U87-MG xenograft model due to their affinity toward 5-HT7R.

Antipsychotic Use: Cross-Sectional Opinion Survey of Psychiatrists in India and United Kingdom

Article

Full-text available

Oct 2023

The aim of this survey of psychiatrists from the UK and India was to compare their opinions on antipsychotic medication choice and their experiences of such medications’ effectiveness and tolerability in patients who were newly diagnosed with acute schizophrenia. Following ethical approval, a cross-sectional online survey of psychiatrists from the UK and India was conducted. Ninety-five responses were received from each country. The most selected first-line APDs in both countries were olanzapine (47.5%), risperidone (42.8%) and aripiprazole (25.3%). A total of 60% of psychiatrists from India (60%) and 48% from the UK (48%) selected ‘medication efficacy’ as the main factor in their choice. Reassessment and consideration to switch most often took place within 4–6 weeks (53.7%) and 3–6 months (11.6%). The major reasons for switching antipsychotic medications were poor clinical efficacy (69%) and lack of tolerability (45%). Nonadherence was the most common reason for relapse (90% of UK psychiatrists and 70% of Indian psychiatrists), followed by illicit drug use (27.6%). The most commonly reported side effects that led to nonadherence were weight gain (10.8%), drowsiness (10.4%), erectile dysfunction and movement disorders (equally 8.7%). It was concluded that olanzapine, risperidone and aripiprazole are the most commonly selected as the initial treatment choice by psychiatrists from India and the UK. They are perceived as widely effective and well tolerated.

Psychopharmacology

Chapter

Apr 2014

Federal support and independent testing by the pharmaceutical industry have resulted in a number of trials leading to considerable advances in the pharmacological treatment of adults and children with ASD over the past decade. Four categories of pharmaceuticals in particular are discussed in this chapter: (1) atypical antipsychotics, (2) serotonin reuptake inhibitors, (3) stimulants, and (4) nonstimulant medications for hyperactivity in patients with ASDs. There is a pressing need for additional reliable and valid outcome measures that are sensitive to change. Effects of pharmacological treatments on aggression, anxiety, adaptive functioning, cognition, and subdomains of social behavior are reviewed throughout this chapter.

Schizophrenia

Chapter

Nov 2009

Role of Oxidative Stress in Pathophysiological Progression of Schizophrenia

Article

Aug 2022

Background Oxidative stress (OS) is a chief contributing factor in the pathological advancement of Schizophrenia (SCZ). In recent years, OS has emerged as an important aspect in the SCZ research and provides abundant opportunities and expectation for a better understanding of its pathophysiology, which may lead to novel treatment strategies. Introduction The increased OS and formation of reactive oxygen species (ROS) leads to damage of cellular macromolecules. The excessive OS is associated with several physiological processes such as dysfunction of mitochondria and neuroglia, inflammation, underactive N-methyl-D-aspartate (NMDA) receptors and the abnormalities of fast-spiking gamma-aminobutyric acid (GABA) interneurons. Methods The method adopted for the study are mainly based on the secondary search through a systemic literature review. The role of various anti-oxidants including vitamins are discussed in the reduction of SCZ. Results Various preclinical and clinical evidence are also suggesting the involvement of OS and ROS in the progression of the disease. Recent human trials have shown that treatment with antioxidants to be effective in ameliorating symptoms and delaying the progression of SCZ pathology. The studies demonstrated that Innate and dietary antioxidants have shown beneficial effects by reducing the severity of positive symptoms (PS) and/or negative symptoms (NS) of SCZ. Conclusion The present review critically evaluates the effect of antioxidants and highlights the role of OS in SCZ.

Risperidone Induced Hyperprolactinemia: From Basic to Clinical Studies

Article

Full-text available

May 2022

Risperidone is one of the most commonly used antipsychotics (AP), due to its safety and efficacy in reducing psychotic symptoms. Despite the favorable side effect profile, the therapy is accompanied by side effects due to the non-selectivity of this medicine. This review will briefly highlight the most important basic and clinical findings in this area, consider the clinical effects of AP-induced hyperprolactinemia (HPL), and suggest different approaches to the treatment.The route of application of this drug primarily affects the daily variation and the total concentration of drug levels in the blood, which consequently affects the appearance of side effects, either worsening or even reducing them. Our attention has been drawn to HPL, a frequent but neglected adverse effect observed in cases treated with Risperidone and its secondary manifestations. An increase in prolactin levels above the reference values result in impairment of other somatic functions (lactation, irregular menses, fertility) as well as a significant reduction in quality of life. It has been frequently shown that the side effects of the Risperidone are the most common cause of non-compliance with therapy, resulting in worsening of psychiatric symptoms and hospitalization. However, the mechanism of Risperidone-induced HPL is complicated and still far from fully understood. Most of the preclinical and clinical studies described in this study show that hyperprolactinemia is one of the most common if not the leading side effect of Risperidone therefore to improve the quality of life of these patients, clinicians must recognize and treat HPL associated with the use of these drugs.

Clozapine's Multiple Cellular Mechanisms: What Do We Know after More than Fifty Years? a Systematic Review and Critical Assessment of Translational Mechanisms Relevant for Innovative Strategies in Treatment-Resistant Schizophrenia

Preprint

Jan 2022

Mirtazapine in schizophrenia – an undeservedly overlooked option?

Article

Mar 2022
INT CLIN PSYCHOPHARM

Mirtazapine has often been prescribed as add-on treatment for schizophrenia in patients with suboptimal response to conventional treatments. In this review, we evaluate the existing evidence for efficacy and effectiveness of add-on mirtazapine in schizophrenia and reappraise the practical and theoretical aspects of mirtazapine-antipsychotic combinations. In randomized controlled trials (RCTs), mirtazapine demonstrated favourable effects on negative and cognitive (although plausibly not depressive) symptoms, with no risk of psychotic exacerbation. Mirtazapine also may have a desirable effect on antipsychotic-induced sexual dysfunction, but seems not to alleviate extrapyramidal symptoms, at least if combined with second-generation antipsychotics. It is noteworthy that all published RCTs have been underpowered and relatively short in duration. In the only large pragmatic effectiveness study that provided analyses by add-on antidepressant, only mirtazapine was associated with both decreased rate of hospital admissions and number of in-patient days. Mirtazapine hardly affects the pharmacokinetics of antipsychotics. However, possible pharmacodynamic interactions (sedation and metabolic offence) should be borne in mind. The observed desired clinical effects of mirtazapine may be due to its specific receptor-blocking properties. Alternative theoretical explanations include its possible neuroprotective effect. Further well-designed RCTs and real-world effectiveness studies are needed to determine whether add-on mirtazapine should be recommended for difficult-to-treat schizophrenia.

Efficacy of VMAT2 inhibition and synergy with antipsychotics in animal models of schizophrenia

Article

Feb 2022
J PHARMACOL EXP THER

Antipsychotic medications function by blocking postsynaptic dopaminergic signaling in the central nervous system. Dopamine transmission can also be modulated presynaptically by inhibitors of vesicular monoamine transporter 2 (VMAT2), which inhibit loading of dopamine into presynaptic vesicles. Here we investigated the combination of these mechanisms in animal models of schizophrenia and weight gain (a primary side effect of antipsychotics). When dosed alone, the highly selective VMAT2 inhibitor RRR-dihydrotetrabenazine (RRR-DHTBZ, also known as [+]-α-HTBZ) elicited efficacy comparable to conventional antipsychotics in pre-pulse inhibition and conditioned avoidance models without eliciting weight gain. In combination experiments, synergy was observed: subthreshold doses of RRR-DHTBZ and risperidone or olanzapine produced robust efficacy, and in dose response experiments, RRR-DHTBZ increased the antipsychotic potency in the efficacy models but did not affect weight gain. The combinations did not affect plasma compound concentrations. The synergy is consistent with VMAT2 inhibition blocking the counterproductive presynaptic stimulation of dopamine by antipsychotics. These results suggest a therapeutic strategy of adding a VMAT2 inhibitor to lower the antipsychotic dose and reduce the side-effect burden of the antipsychotic while maintaining and potentially enhancing its therapeutic effects. Significance Statement Antipsychotics effectively reduce psychotic symptoms and are often necessary and life-changing medications; however, these benefits are at the expense of a high side effect burden. This study shows that combining these postsynaptic dopaminergic modulators with a presynaptic dopamine modulator (VMAT2 inhibitor) potentiates efficacy synergistically in animal models of schizophrenia without potentiating weight gain. Our data suggest that adding a VMAT2 inhibitor may be a viable therapeutic strategy for reducing antipsychotic side effects by lowering antipsychotic dose while maintaining therapeutic efficacy.

Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3

Article

Full-text available

Mar 2022

Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6–8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (−/−) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.

DDQ as a versatile and easily recyclable oxidant: a systematic review

Article

Full-text available

Sep 2021

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is the most widely used quinone with a high reduction potential, and it commonly mediates hydride transfer reactions and shows three accessible oxidation states: quinone (oxidized), semiquinone (one-electron-reduced), and hydroquinone (two-electron-reduced). DDQ has found broad utility as a stoichiometric oxidant in the functionalization of activated C-H bonds and the dehydrogenation of saturated C-C, C-O, and C-N bonds. The cost and toxicity of DDQ triggered recent efforts to develop methods that employ catalytic quantities of DDQ in combination with alternative stoichiometric oxidants. The aerobic catalytic approach was established for the selective oxidation of non-sterically hindered electron-rich benzyl methyl ethers and benzylic alcohols, and effectively extended to the oxidative deprotection of p-methoxybenzyl ethers to generate the alcohols in high selectivity. A combination of DDQ and protic acid is known to oxidize several aromatic donors to the corresponding cation radicals. The excited-state DDQ converts benzyls, heteroarenes, fluoroarenes, benzene, and olefins into their radical cation forms as well as chloride and other anions into their respective radicals. These reactive intermediates have been employed for the generation of C-C and C-X (N, O, or Cl) bonds in the synthesis of valuable natural products and organic compounds. To the best of our knowledge, however, there is still no review article exclusively describing the applications of DDQ in organic synthesis. Therefore, in the present review, we provide an overview of DDQ-induced organic transformations with their scope, limitations and the proposed reaction mechanisms.

Synthesis and Biological Evaluation of 99m Tc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

Article

May 2021

Radiosynthesis and Biological Evaluation of [ 18 F]R91150, a Selective 5-HT 2A Receptor Antagonist for PET-Imaging

Article

Apr 2021

Serotonergic 5-HT2A receptors in cortical and forebrain regions are an important substrate for the neuromodulatory actions of serotonin in the brain. They have been implicated in the etiology of many neuropsychiatric disorders and serve as a target for antipsychotic, antidepressant, and anxiolytic drugs. Positron emission tomography imaging using suitable radioligands can be applied for in vivo quantification of receptor densities and receptor occupancy for therapy evaluation. Recently, the radiosynthesis of the selective 5-HT2AR antagonist [18F]R91150 was reported. However, the six-step radiosynthesis is cumbersome and time-consuming with low radiochemical yields (RCYs) of <5%. In this work, [18F]R91150 was prepared using late-stage Cu-mediated radiofluorination to simplify its synthesis. The detailed protocol enabled us to obtain RCYs of 14 ± 1%, and the total synthesis time was reduced to 60 min. In addition, autoradiographic studies with [18F]R91150 in rat brain slices revealed the typical uptake pattern of 5-HT2A receptor ligands.

Synthesis, docking studies, and pharmacological evaluation of 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands

Article

Feb 2021
ARCH PHARM

A new series of norbornene and exo-N-hydroxy-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide derivatives was prepared, and their affinities to the 5-HT1A , 5-HT2A , and 5-HT2C receptors were evaluated and compared with a previously synthesized series of derivatives characterized by the same nuclei, to identify selective ligands for the subtype receptors. Arylpiperazines represent one of the most important classes of 5-HT1A R ligands, and the research of new derivatives has been focused on the modification of one or more portions of this pharmacophore. The combination of structural elements (heterocyclic nucleus, hydroxyalkyl chain, and 4-substituted piperazine), known to be critical for the affinity to 5-HT1A receptors, and the proper selection of substituents resulted in compounds with high specificity and affinity toward serotoninergic receptors. The most active compounds were selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies were performed. The results of the pharmacological studies showed that 3e, 4j, and 4n were the most active and promising derivatives for the serotonin receptor considered in this study.

Management Strategies for Antipsychotic-Related Sexual Dysfunction: A Clinical Approach

Article

Full-text available

Jan 2021

Antipsychotic medication can be often associated with sexual dysfunction (SD). Given its intimate nature, treatment emergent sexual dysfunction (TESD) remains underestimated in clinical practice. However, psychotic patients consider sexual issues as important as first rank psychotic symptoms, and their disenchantment with TESD can lead to important patient distress and treatment drop-out. In this paper, we detail some management strategies for TESD from a clinical perspective, ranging from prevention (carefully choosing an antipsychotic with a low rate of TESD) to possible pharmacological interventions aimed at improving patients’ tolerability when TESD is present. The suggested recommendations include the following: prescribing either aripiprazole or another dopaminergic agonist as a first option antipsychotic or switching to it whenever possible. Whenever this is not possible, adjunctive treatment with aripiprazole seems to also be beneficial for reducing TESD. Some antipsychotics, like olanzapine, quetiapine, or ziprasidone, have less impact on sexual function than others, so they are an optimal second choice. Finally, a variety of useful strategies (such as the addition of sildenafil) are also described where the previous ones cannot be applied, although they may not yield as optimal results.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function

Article

Full-text available

Jan 2021

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

Antipsychotic and anticholinergic drugs

Chapter

Feb 2012

The discovery by Delay and Denicker in 1953 that chlorpromazine was highly effective in alleviating delusions, hallucinations, and disorganized thinking, was the seminal breakthrough in the treatment of schizophrenia, the first agent to produce sufficient relief of core psychotic symptoms to permit life outside of institutions for many patients with schizophrenia, and even a return to a semblance of function within normal limits. Chlorpromazine and the other related typical antipsychotic drugs which were introduced over the next 30 years have proven to be of immense benefit to vast numbers of people who experience psychotic symptoms as a component of a diverse group of neuropsychiatric and medical disorders, as well as drug-induced psychoses. These drugs have been invaluable in providing clues to the aetiology of schizophrenia and other forms of mental illness with psychotic features and as tools in understanding fundamental neural processes, especially those involving dopamine, a key neurotransmitter involved in psychosis. This class of drugs has now been supplanted by the so-called atypical antipsychotic drugs, of which clozapine is the prototype. This chapter will describe the various classes of antipsychotic agents, with emphasis on the atypical antipsychotic drugs, their benefits and adverse effects, recommendations for use in clinical practice, and mechanism of action. The drugs used to treat the extrapyramidal side-effects (EPS) produced mainly by the typical antipsychotic drugs are also considered.

CHAPTER 19. Multi-target Drug Discovery for Psychiatric Disorders

Chapter

Nov 2012

The discovery and development of effective medicines for the treatment of psychiatric disorders such as schizophrenia and depression has been heralded as one of the great medical achievements of the past century. Indeed, the profound impact of these medicines on our understanding of the pathophysiology underlying these diseases, the treatment of psychiatric patients and even our social perception of mental illnesses cannot be underestimated. However, there is still an urgent medical need for even more effective, safe and well-tolerated treatments. For example, currently available treatments for schizophrenia address mainly the positive symptoms and largely neglect the negative symptoms and cognitive disfunction which greatly impact overall morbidity. Similarly, whilst the current first line antidepressants show significantly improved side effect profiles compared to the first generation therapies, there still up to 40% of patients who are treatment resistant, and even in the patient population which responds well, the onset of action is slow at typically 2-3 weeks. The aim of this book is to provide the first point of call for those involved or just interested in this rapidly expanding and increasingly fragmented field of research and drug discovery. The editors will combine their wide ranging experience and extensive network of contacts with leading scientists and opinion leaders in this field to provide an authoritative reference text covering the evolution, major advances, challenges and future directions in drug discovery and medicinal chemistry for major psychiatric disorders.

Relapse following clozapine withdrawal: Effect of neuroleptic drugs and cyproheptadine

Article

Full-text available

Apr 1996

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Risperidone compared with new and reference antipsychotic drugs: In vitro and in vivo receptor binding

Article

Full-text available

Apr 1996

Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra

The role of serotonin in schizophrenia and the mechanism of action on anti-psy-chotic drugs

Article

Jan 1996

Do novel antipsychotics have similar pharmacological characteristics?

Article

Jan 1998

in Psychopharmacology: The Fourth Generation of Progress, Ed by M

Article

Jan 1994

Risperidone Dose-Dependently Increases Extracellular Concentrations of Serotonin in the Rat Frontal Cortex: Role of α2 –Adrenoceptor Antagonism

Article

Jul 1997

We have previously shown that risperidone, an antipsychotic drug with high affinity for 5-hydroxytryptamine (5-HT)2A and dopamine (DA)2 receptors, as well as for α1- and α2-adrenoceptors, enhances 5-HT metabolism selectively in the rat frontal cortex (FC). To further study the influence of risperidone on central 5-HT systems, we compared its effects on dialysate 5-HT in the FC, as assessed by microdialysis, with those obtained with other antipsychotic drugs, i.e., clozapine, haloperidol, and amperozide, as well as with the selective α2- or 5-HT2A receptor antagonists idazoxan or MDL 100,907, respectively. The underlying mechanism for risperidone’s effect on 5-HT output in the FC was also investigated using single-cell recording in the dorsal raphe nucleus (DRN). Administration of risperidone (0.2, 0.6, and 2.0 mg/kg, SC) dose-dependently increased 5-HT levels in the FC. This stimulatory action was mimicked by amperozide (10 mg/kg, SC) and, to some extent, by idazoxan (0.25 mg/kg, SC). In contrast, clozapine (10 mg/kg, SC), haloperidol (2.0 mg/kg, SC), and MDL 100,907 (1.0 mg/kg, SC) exerted only minor effects on 5-HT output in brain. Local administration of risperidone or idazoxan (1.0–1000 μmol/L) in the FC dose-dependently increased dialysate levels of 5-HT in this region. On the other hand, risperidone 25-800 μg/kg, IV) dose-dependently decreased the firing rate of 5-HT cells in the DRN, an effect that was largely antagonized by pretreatment with the selective -HT1A receptor antagonist WAY 100,635 (5.0 μg/kg, IV). These results indicate that the risperidone-increased 5-HT output in the FC may be related to its α2-adrenoceptor antagonistic action, a property shared with both amperozide and idazoxan, and that this action probably is executed at the nerve terminal level. The inhibition of 5-HT cell firing by risperidone is probably secondary to increased 5-HT availability, e.g., in the DRN, since it could be antagonized by a -HT1A receptor antagonist. The enhanced 5-HT output in the FC by risperidone may be of particular relevance for the treatment of schizophrenia when associated with depression and in schizoaffective disorder.

The apparent antipsychotic action of the 5-HT2a receptor antagonist M100907 in a mouse model of schizophrenia is counteracted by ritanserin

Article

Apr 1997

Summary The apparent antipsychotic action of the selective 5-HT2a receptor antagonist M100907 in MK-801-treated NMRI mice was shown to be markedly counteracted by the 5-HT2a/2c receptor antagonist ritanserin. The mechanism of action and potential implications are discussed.

Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo

Article

Aug 1997
BIOL PSYCHIAT

Five fixed doses of the atypical antipsychotic "Seroquel" (quetiapine) were evaluated to delineate a dose–response relationship and to compare efficacy and tolerability opposite placebo and haloperidol. This was measured by changes from baseline responses in the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Modified Scale for the Assessment of Negative Symptoms (SANS) summary scores. 361 18–64 yr olds hospitalized with schizophrenia completed a single-blind, placebo washout phase and were randomized to double-blind treatment with quetiapine (75, 150, 300, 600, or 750 mg daily), haloperidol, or placebo and evaluated weekly for 6 wks. Differences in adjusted mean changes from baseline were identified between the 4 highest doses of quetiapine and placebo for BPRS total, BPRS positive-symptom cluster, and CGI Severity of Illness item scores and between quetiapine 300 mg and placebo for SANS summary score. Dose-response modeling showssignificant linear and quadratic functions of quetiapine dose for all primary efficacy variables. Quetiapine is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and in reducing negative symptoms at a dose of 300 mg/day. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

Clozapine for the treatment-resistant schizophrenic: results of a US multicenter trial

Article

Mar 1989

A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients - A re-evaluation of the North American risperidone study

Article

Mar 1995

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2=0.50–0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens

Article

Jul 1998
EUR J PHARMACOL

Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)2A receptor antagonists than dopamine D2-like receptor antagonists. Haloperidol and S(−)-sulpiride are potent or selective dopamine D2-like receptor antagonists and lack 5-HT2A receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(−)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT2A receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT2A receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT2A receptors, e.g., reuptake inhibition (amperozide) and blockade of α2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.

DOI, a 5-HT2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum

Article

Dec 1995
BRAIN RES

The effects of (±)-DOI (1-(2,5-dimethoxy-4-iodophenyl)-aminopropane) hydrochloride, a mixed 5-HT2A/2C receptor agonist, on the release of dopamine (DA) following d-amphetamine sulfate (AMP) or a DA D2 autoreceptor selective dose of (−)-apomorphine hydrochloride (APO), were investigated in rat striatum (STR) and nucleus accumbens (NAC), using in vivo microdialysis. AMP (1.0 mg/kg, s.c.) produced marked increases in extracellular DA levels in both the STR and the NAC whereas DOI (2.5 mg/kg, i.p.) alone had no significant effect on extracellular DA levels in either region. Pretreatment with DOI 30 min prior to AMP, further enhanced the AMP-induced increase in striatal extracellular DA levels. On the other hand, DOI pretreatment attenuated the APO (50 μg/kg, s.c.)-induced decrease in extracellular DA levels in the STR. Pretreatment with DOI did not affect the ability of either AMP or APO to modulate extracellular DA levels in the NAC. These results provide further evidence that 5-HT2A/2C receptors modulate the release mechanisms of DA in the STR. Possible mechanisms are discussed.

Serotonin Subtype 2 Receptor Genes and Clinical Response to Clozapine in Schizophrenia Patients

Article

Sep 1998

Using a pharmacogenetic approach in 185 schizophrenics who have been prospectively assessed for clozapine response, we have examined the hypothesis that polymorphisms in the 5-HT2A (HTR2A), and 5-HT2C (HTR2C) genes are involved in its variable response. A -1438 A→ G polymorphism in the putative promoter and a silent T→ C 102 substitution in HTR2A were in almost complete linkage disequilibrium, and neither was associated with response (T→ C 102 allele: χ2 = 0.02; 1 df, p = .90; genotype: χ2 = 0.02, 2 df, p = .99). A his452tyr HTR2A polymorphism was found to be associated with clozapine response (his452tyr allele: χ2 = 6.43, 1 df, p = .01 [p = .04, Bonferroni corrected]; genotype: χ2 = 6.54, 2 df, p = .04 [p = .16, Bonferroni corrected]). No HTR2A haplotype was associated with response. Interethnic differences were observed in the frequencies of the cys23ser HTR2C polymorphism. This polymorphism was not significantly associated with response in either of the ethnic groups (Caucasian and African American genotype: χ2 = 3.46, 2 df, p = .18; χ2 = .31, 2 df, p = .86, respectively). Although replication is required, the overall results suggest that the his452tyr HTR2A polymorphism may be involved in clozapine response.

A pharmacological analysis of serotonergic receptors: Effects of their activation of blockade in learning

Article

Mar 1997
PROG NEURO-PSYCHOPH

1.1. The authors have tested several 5-HT selective agonists and antagonists (5-HT1A/1B, 5-HT1A/2B/2C, 5-HT3 or 5-HT4), an uptake inhibitor and 5-HT depletors in the autoshaping learning task.2.2. The present work deals with the receptors whose stimulation increases or decreases learning.3.3. Impaired consolidation of learning was observed after the presynaptic activation of 5-HT1B, 5-HT3 or 5-HT4 or the blockade of postsynaptic 5-HT2C/2B receptors.4.4. In contrast, an improvement occurred after the presynaptic activation of 5-HT1A, 5-HT2C, and the blockade of presynaptic 5-HT2A, 5-HT2C and 5-HT3 receptors.5.5. The blockade of postsynaptic 5-HT1A,5-HT1B,5-HT3 or 5-HT4 receptors and 5-HT inhibition of synthesis and its depletion did no alter learning by themselves.6.6. The present data suggest that multiple pre- and postsynaptic serotonergic receptors are involved in the consolidation of learning7.7. Stimulation of most 5-HT receptors increases learning, however, some of 5-HT subtypes seem to limit the data storage.8.8. Furthermore, the role of 5-HT receptors in learning seem to require an interaction with glutamatergic, GABAergic and cholinergic neurotransmission systems.

R (+)-8-OH-DPAT, a 5-HT1A receptor agonist, inhibits amphetamine-induced dopamine release in rat striatum and nucleus accumbens

Article

Jan 1996
EUR J PHARMACOL

Systemic administration of R(+)-8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), a selective serotonin (5-hydroxytryptamine, 5-HT)1A receptor agonist (25, 50, and 100 μg/kg s.c.), administered 30 min prior to d-amphetamine, significantly inhibited the d-amphetamine sulfate (1.0 mg/kg s.c.)-induced increase in extracellular dopamine levels in the striatum and nucleus accumbens of freely moving rats, as determined by in vivo microdialysis. The ability of R(+)-8-OH-DPAT (50 μg/kg s.c.) to inhibit d-amphetamine sulfate (1.0 mg/kg s.c.)-induced increase in extracellular dopamine levels was abolished by WAY 100,635 (n-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-n-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), a selective 5-HT1A receptor antagonist (100 μg/kg s.c.), administered 5 min prior to R(+)-8-OH-DPAT in both regions. These results indicate that the 5-HT1A receptor may exert an inhibitory effect on amphetamine-induced dopamine release.

Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory

Article

May 1995
J PSYCHOPHARMACOL

We investigated the effects of serotonergic drugs on working memory (WM) in a delayed conditional discrimination task. The 5-HT(1A) receptor full agonist flesinoxan (0.3-3.0 mg/kg) dose- and delay-dependently impaired performance, indicating a specific effect on WM. The 5-HT(1A) receptor partial agonist ipsapirone, the 5-HT( 1B/1D/2C) agonist TFMPP, the 5-HT(1A) antagonist NAN190 and the serotonin re-uptake inhibitor fluvoxamine dose-dependently impaired performance, in a delay-independent manner, indicating no specific effect on WM. The 5-HT( 2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron did not affect performance. It is suggested that the role of central serotonin receptors in WM may be restricted to 5-HT(1A) receptors.

Roth BL, Ciaranello RD, Meltzer HY. Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther 260: 1361-1365

Article

Apr 1992

We determined the affinities of clozapine and 21 other typical and atypical antipsychotic agents for the cloned 5-hydroxytryptamine-1C (5-HT1C) receptor. For these studies, 5-HT1C receptors were transiently expressed in COS-7 cells using the vector pSVK3-5HT1C. We discovered that clozapine and several other putative typical and atypical antipsychotic agents (loxapine greater than tiosperone greater than SCH23390 greater than fluperlapine greater than rilapine greater than chlorpromazine) had relatively high affinities (7-30 nM) for the cloned 5-HT1C receptor. Other antipsychotic agents (risperidone greater than tenilapine greater than mesoridazine greater than thioridazine greater than cis-fluphenthixol) had intermediate affinities (30-100 nM), whereas many other antipsychotics (fluphenazine greater than spiperone greater than amperozide greater than melperone greater than thiothixene greater than haloperidol, metoclopramide, pimozide, domperidone, sulpiride) had low affinities (greater than 500 nM) for the cloned 5-HT1C receptor. The results indicate that although several putative atypical antipsychotic agents have high affinities for the cloned rat 5-HT1C receptor, the spectrum of drug binding does not correlate with the atypical nature of these compounds.

Treatment of the Neuroleptic-Nonresponsive Schizophrenic Patient

Article

Feb 1992
SCHIZOPHRENIA BULL

Herbert Meltzer

The treatment and management of neuroleptic-resistant schizophrenic patients, who comprise 5 to 25 percent of all patients with that diagnosis, are major problems for psychiatry. In addition, another large group of schizophrenic patients, perhaps 5 to 20 percent, are intolerant of therapeutic dosages of neuroleptic drugs because of extrapyramidal symptoms, including akathisia, parkinsonism, and tardive dyskinesia. Because about 60 percent of neuroleptic-resistant schizophrenic patients respond to clozapine and a large percentage of neuroleptic-intolerant patients are able to tolerate clozapine, it should be considered the treatment of choice for such patients until other therapies are proven to be superior. A trial of clozapine alone should usually be continued for up to 6 months before it is terminated or supplemental agents are tried. Plasma levels of clozapine may be useful to guide dosage. The major side effects of clozapine are granulocytopenia or agranulocytosis (1%-2%) and a dose-related increase in the incidence of generalized seizures. Psychosocial treatments such as education of the patient and the family about the nature of the illness, rehabilitation programs, social skills training, and assistance in housing are generally needed to obtain optimal benefit from clozapine, as with other somatic therapies. If clozapine is unavailable, unacceptable, or not tolerated, a variety of approaches may be employed to supplement typical antipsychotic drugs for patients who do not respond adequately to these agents alone. These include lithium; electroconvulsive therapy; carbamazepine or valproic acid; benzodiazepines; antidepressant drugs; reserpine; L-dopa and amphetamine; opioid drugs; calcium channel blockers; and miscellaneous other pharmacologic approaches. The evidence for the efficacy of these ancillary somatic therapies in treatment-resistant patients is relatively weak. Polypharmacy should be tried only for discrete periods and with clear goals. If these are not achieved, supplemental medications should be discontinued. Psychosurgery is not a recommended alternative at this time.

Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy induced by SCH 23390 in the rat

Article

Feb 1992

Marie-Louise G Wadenberg

In the present experiments, it was shown that the catalepsy induced by the dopamine D1 antagonist SCH 23390 (0.2 mg kg-1 sc), was completely antagonised by the administration of 8-OH-DPAT (0.1 mg kg-1 sc) for the duration of the effect of SCH 23390 (approx. 120 min). Neither the catalepsy induced by raclopride (16 mg kg-1 sc) nor that induced by SCH 23390 (0.2 mg kg-1 sc) could be antagonised by treatment with the 5-HT2 receptor antagonist ritanserin (0.13-2.0 mg kg-1 sc). Administration of SCH 23390 (0.0125-0.2 mg kg-1 sc) produced a significant suppression of avoidance behavior at all doses, and also produced a significant decrease in the number of intertrial crosses. At the higher doses, 0.05 and 0.2 mg kg-1 sc, there were also escape failures. In contrast to the finding in our previous report that raclopride and 8-OH-DPAT in a synergistic manner produce a suppression of conditioned avoidance behavior, no such interaction was found between 8-OH-DPAT (0.1 mg kg-1 sc) and SCH 23390 (6 micrograms kg-1 sc) in the present study.

Biochemical and pharmacological properties of SR 46349B, a new potent and selective 5-hydroxytryptamine2 receptor antagonist

Article

Sep 1992

A new potent, selective and p.o. active serotonergic [5-hydroxytryptamine (5-HT2)] receptor antagonist, SR 46349B [trans, 4-([3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-flurophenyl++ +)propen-1-yl]phenol hemifumarate) has been characterized by a series of "in vitro" and "in vivo" methods. Based upon binding studies with 5-HT2 receptors in rat brain cortical membranes and blockade of 5-HT-induced contractions in isolated tissues (rabbit thoracic aorta, rat jugular vein, rat caudal artery, rat uterus and guinea pig trachea), SR 46349B showed high affinity for 5-HT2 receptors. Furthermore, SR 46349B displayed moderate affinity for the 5-HT1C receptor and had no affinity for the other 5-HT1 subclass (5-HT1A, 5-HT1B or 5-HT1D), dopamine (D1 or D2), "alpha" adrenergic (alpha-1 or alpha-2), sodium and calcium channel and histamine (H1) receptors. It did not interact with histamine (H1), alpha-1 adrenergic and 5-HT3 receptors in smooth muscle preparations. No inhibition of the uptake of norepinephrine, dopamine or 5-HT was seen. Based upon blockade of pressor responses to 5-HT in pithed rats and in vivo binding studies in mice, SR 46349B was found to be a potent and p.o. active 5-HT2 receptor antagonist with a relatively long duration of action. Behavioral experiments, including mescaline- and 5-hydroxytryptophan-induced head twitches and learned helplessness, as well as sleep-waking cycle and EEG spectral parameter studies, indicated that SR 46349B has a classical 5-HT2 psychopharmacological antagonist profile.

Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy

Article

Feb 1991

The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg-1 sc-20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg-1 sc. The number of intertrial crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg-1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg-1 sc, or by 8-OH-DPAT, 0.1 mg kg-1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in "immobility" (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg-1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg-1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg-1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg-1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects.

Extrapyramidal syndromes in nonhuman primates: Typical and atypical neuroleptics

Article

Feb 1991
Psychopharmacol Bull

D E Casey

The traditional (typical) neuroleptic drugs produce acute extrapyramidal symptoms (EPS) in the majority of patients, whereas the atypical neuroleptics produce only minimal motor system side effects. Studies of acute dystonia in nonhuman primates with typical (haloperidol, fluphenazine), atypical (clozapine), and putative novel antipsychotic compounds with low EPS (remoxipride, melperone) were conducted across a wide dose range in double-blind, placebo-controlled trials. Haloperidol and fluphenazine caused dystonia, and clozapine did not. Remoxipride and melperone also produced dystonia, but remoxipride only did so at doses that were higher than needed for antipsychotic efficacy. Melperone produced dystonia in doses that are in the antipsychotic dose range. The clinical relevance of the findings is discussed.

VII. Effects of antipsychotic drugs on serotonin receptors

Article

Jan 1992

Do functional relationships exist between 5-HT1A and 5-HT2A receptors?

Article

Sep 1990
PHARMACOL BIOCHEM BE

To investigate the possible functional relationship between 5-HT1 and 5-HT2 receptors, we studied the effects of a nonselective 5-HT agonist (5-MeO DMT), a 5-HT1A-selective (8-OH-DPAT) and a 5-HT1B/5-HT1C-selective (TFMPP) agonist on the head-twitch behavior induced by the putative 5-HT2-selective receptor agonist (+/-)-DOI. In the mouse (+/-)-DOI produced the head-twitch response in a dose-dependent manner and (-)-DOI was twice as potent as the (+) isomer. Selective 5-HT2 antagonists, ketanserin and spiperone, dose-dependently inhibited the (+/-)-DOI-induced head-twitch response. The nonselective and the 5-HT1A-selective agonists also dose-dependently reduced the behavior, whereas 5-HT1B/5-HT1C-selective agonist (TFMPP) failed to affect the (+/-)-DOI-induced response. Taken together with previously published literature data, we propose a 5-HT1A inhibitory action on the 5-HT2 receptor-mediated response when induced by its selective agonist (+/-)-DOI.

Antipsychotic-like properties of the 5-HT(1A) agonist 8-OH-DPAT in the rat

Article

Feb 1989

Sven Ahlenius

Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pK1 values

Article

Nov 1989

The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptor binding sites and cortical serotonin (5-HT2) receptor binding sites were determined. The atypical antipsychotics had significantly lower pKi values for the D-2 but not 5-HT2 binding sites. There was a trend for a lower pKi value for the D-1 binding site for the atypical APD. The 5-HT2 and D-1 pKi values were correlated for the typical APD whereas the 5-HT2 and D-2 pKi values were correlated for the atypical APD. A stepwise discriminant function analysis to determine the independent contribution of each pKi value for a given binding site to the classification as a typical or atypical APD entered the D-2 pKi value first, followed by the 5-HT2 pKi value. The D-1 pKi value was not entered. A discriminant function analysis correctly classified 19 of 20 of these compounds plus 14 of 17 additional test compounds as typical or atypical APD for an overall correct classification rate of 89.2%. The major contributors to the discriminant function were the D-2 and 5-HT2 pKi values. A cluster analysis based only on the 5-HT2/D2 ratio grouped 15 of 17 atypical + one typical APD in one cluster and 19 of 20 typical + two atypical APDs in a second cluster, for an overall correct classification rate of 91.9%. When the stepwise discriminant function was repeated for all 37 compounds, only the D-2 and 5-HT2 pKi values were entered into the discriminant function.(ABSTRACT TRUNCATED AT 250 WORDS)

Typical and atypical antipsychotic occupancy of D2 and S2 receptors: An autoradiographic analysis in rat brain

Article

May 1986
BRAIN RES BULL

In thin sections of rat brain, [3H]spiperone binds to D2 sites in the basal ganglia (caudate-putamen, nucleus accumbens, olfactory tubercle) and S2 sites in the claustrum and motor cortex. The in vitro displacement of [3H]spiperone from these regions was quantified autoradiographically with the "atypical" neuroleptics clozapine and thioridazine, which ameliorate psychosis, a "typical" neuroleptic, haloperidol, which also induces extrapyramidal side effects, or with metoclopramide, which induces extrapyramidal side effects but is an ineffective antipsychotic. Whereas metoclopramide was equipotent at D2 sites, haloperidol was less potent and clozapine and thioridazine more potent by 2- to 3-fold at competing for D2 sites in the nucleus accumbens or olfactory tubercle than in the caudate-putamen. As measured autoradiographically or with tissue homogenates, clozapine, thioridazine, and five other atypical neuroleptics were 4- to 800-times more potent at competing for S2 sites in the frontal cortex than for D2 sites in the basal ganglia. A preference of atypical antipsychotics for D2 receptors in the nucleus accumbens and olfactory tubercle and for the S2 receptor may explain the relative lack of extrapyramidal side effects produced by these compounds.

Potency of antipsychotics in reversing the effects of hallucinogenic drug on locus coeruleus neurons correlates with 5-HT2 binding affinity

Article

Jun 1988

Systemic administration of the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) has previously been shown to decrease spontaneous activity but increase the response to peripheral nerve stimulation of locus coeruleus (LC) neurons in anesthetized rats. Five antipsychotic drugs (spiperone, chlorpromazine, clozapine, haloperidol, and sulpiride) were tested for their ability to antagonize these effects of DOM in the LC. Spiperone, chlorpromazine, clozapine, and haloperidol were able to completely reverse the effects of a standard dose of DOM, while sulpiride was ineffective. The ED100s for reversing the effects of DOM showed a significant correlation only with the previously shown binding affinity for 5-HT2 receptors. These results suggest that certain types of antipsychotic drugs have activity as 5-HT2 antagonists in vivo.

Evidence for a possible functional interaction between serotonergic and cholinergic mechanisms in memory retrieval

Article

Aug 1987
Behav Neural Biol

A total of three experiments were conducted. In Experiment 1, the dose-dependent effects of the pretest administration of the serotonergic agonist alaproclate and the selective muscarinic cholinergic agonist oxotremorine, alone and in combination, were assessed in a one-trial inhibitory avoidance task. A clear dose-dependent enhancement of performance was demonstrated as a result of all three treatment conditions, which could not be explained in terms of nonspecific effects of the drugs on behavior in general. In addition, the facilitation of retrieval performance produced by the combined treatment of alaproclate and oxotremorine was observed at dose levels well below those observed following administration of either compound alone. In Experiment 2 attempts were made to block the enhancements of retention resulting from the different treatment conditions (alaproclate, oxotremorine, or the combination of alaproclate and oxotremorine) by pretreating the mice with either scopolamine (a muscarinic cholinergic antagonist) or quipazine (a serotonergic agonist). The results of these experiments indicate that (a) quipazine completely blocked the enhancement of retrieval resulting from alaproclate but not that following oxotremorine or oxotremorine in combination with alaproclate, while (b) scopolamine blocked the enhancement of retrieval resulting from oxotremorine alone as well as that resulting from alaproclate plus oxotremorine but failed to block the memory enhancement resulting from alaproclate. The present results lend further support to the view that both serotonin and acetylcholine play important roles in memory retrieval. More importantly, the results of the present series of experiments provide additional support for a functional interaction between the serotonergic and cholinergic nervous systems in the mediation of behavior.

Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 151: 825-835

Article

Jul 1994

The purpose of this study was to investigate the safety and efficacy of risperidone in the treatment of schizophrenic patients and determine its optimal dose. This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States. Patients were randomly assigned to 8 weeks' treatment with placebo, one of four doses of risperidone (2, 6, 10, or 16 mg), or 20 mg of haloperidol daily. Clinical improvement (20% reduction in total scores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% of the patients receiving 2 mg of risperidone, 57% receiving 6 mg, 40% receiving 10 mg, and 51% receiving 16 mg; and by 30% receiving haloperidol and 22% receiving placebo. Statistically significant differences in clinical improvement were found between 6 and 16 mg of risperidone versus placebo and versus haloperidol. Positive symptom scores were significantly lower after 6, 10, and 16 mg of risperidone and 20 mg of haloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 16 mg of risperidone. The incidence of extra-pyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 16 mg of risperidone or 20 mg of haloperidol than placebo. The results indicate that the optimal daily dose of risperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 16 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo. Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia.

Stimulation of median, but not dorsal, raphe 5-HT1A autoreceptors by the local application of 8-OH-DPAT reverses raclopride-induced catalepsy in the rat

Article

Jun 1995
NEUROPHARMACOLOGY

The local application of 8-OH-DPAT (0.5 or 2.5 micrograms/rat, 10 min) into the median, but not the dorsal, raphe nucleus resulted in a reversal of the catalepsy induced by the DA D2 receptor blocking agent raclopride (16 mg kg-1 s.c., 60 min). The local application of 8-OH-DPAT into serotonergic projection areas of the forebrain (dorso-lateral neostriatum, accumbens core; 0.5 or 2.0 micrograms/side) did not affect raclopride-induced catalepsy. Thus, the 5-HT1A autoreceptor in the median raphe nucleus is an important site of action for the reversal of DA D2 receptor antagonist-induced catalepsy by systemic administration of 5-HT1A receptor agonists, in the rat.

Receptor mechanisms mediating clozapine-induced C-Fos expression in the forebrain

Article

May 1995
NEUROSCIENCE

The atypical antipsychotic clozapine produces distinctly different regional patterns ofc-fos expression in rat forebrain than does the prototypical neuroleptic haloperidol. While haloperidol-inducedc-fos expression appears to be mediated by its D2 dopamine receptor antagonist properties, the mechanisms by which clozapine increasesc-fos expression remain uncertain. Using a combination of brain lesion, pharmacological and immunohistochemical techniques, the present study sought to determine the receptor mechanisms by which clozapine increases the number of Fos-like immunoreactive neurons in various regions of the forebrain.

Clozapine decreases serotonin extracellular levels in the nucleus accumbens by a dopamine receptor-independent mechanism

Article

Mar 1995
NEUROSCI LETT

By using brain microdialysis, clear differences in the effects of the systemic administration of clozapine and haloperidol on the extracellular concentration of dopamine (DA) and serotonin (5-HT) were found in the nucleus accumbens of freely moving rats. Haloperidol (0.5 mg/kg s.c.) significantly increased DA (ca. 40%) but did not modify 5-HT extracellular concentration, while clozapine (5 mg/kg s.c.) significantly decreased 5-HT (ca. 40%) but did not change DA concentration. Locally infused, clozapine (10(-5) M) significantly increased DA (75%) and reduced 5-HT extracellular concentration (50%). The reduction of 5-HT cannot be explained by a clozapine-induced blockade of DA receptors, because the local infusion (10(-5) M) of the DA D2-like antagonist raclopride and the DA D1-like antagonist SCH 23390 significantly increased DA (ca. 300% and 200%, respectively) but did not modify 5-HT extracellular concentration. Conversely, the DA D2-like agonist quinpirole and the DA D1-like agonist SKF-38393 significantly decreased (ca. 60% in both cases) DA extracellular concentration without affecting that of 5-HT. The present results indicate that clozapine displays a powerful anti-serotoninergic effect by inhibiting 5-HT release in the nucleus accumbens, an effect probably derived from the reduction of firing activity at the dorsal raphe and by local mechanisms that may involve some 5-HT receptor subtype(s).

Protais P, Chagraoui A, Arbaoui J, Mocaer EDopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodents. Eur J Pharmacol 271:167-177

Article

Dec 1994
EUR J PHARMACOL

S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piper azine hydrochloride), 8-OH-DPAT ((+/-)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and raclopride were compared in some behavioural models able to characterize dopamine antagonist properties. In mice treated with apomorphine (0.75 mg/kg, s.c.), stereotyped climbing and sniffing were dose dependently antagonized by S 14506, by clozapine and by raclopride, but were virtually not modified by 8-OH-DPAT. Stereotyped climbing and sniffing induced by (+)-amphetamine (1.25 mg/kg, s.c.) in mice treated with L-DOPA (L-3,4-dihydroxyphenylalanine 75 mg/kg, associated with benserazide, i.p.) were also dose dependently antagonized by S 14506 and by raclopride, but were only partially antagonized by clozapine and unaffected by 8-OH-DPAT. Grooming behaviour induced by SK&F 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, 1.87 mg/kg, s.c.) in mice was inhibited by low doses of S 14506 and of clozapine, and by relatively high doses of 8-OH-DPAT and of raclopride. The decreased grooming behaviour observed in apomorphine-treated mice was partly antagonized by high dose of raclopride but was significantly potentiated by S 14506, 8-OH-DPAT and clozapine. Raclopride produced the same effect in mice treated with (+)-amphetamine and L-DOPA. In rats treated with apomorphine (0.6 mg/kg, s.c.), sniffing was dose dependently antagonized by S 14506, by raclopride and by clozapine, but not by 8-OH-DPAT. Again, whereas increasing doses of raclopride allowed grooming to reappear in apomorphine (0.6 mg/kg)-treated rats, S 14506, 8-OH-DPAT and clozapine did not. Raclopride induced catalepsy in rats, whereas like clozapine, S 14506 was virtually ineffective. All the tested compounds inhibited in vitro [3H]raclopride binding in rat striatum (raclopride > S 14506 > clozapine > 8-OH-DPAT), whereas only clozapine inhibited [3H]SCH 23390 binding. Finally, S 14506 inhibited the in vivo binding of [3H]raclopride in striatum and olfactory bulbs, but did not affect the striatal in vivo binding of [3H]SCH 23390. From these data, it appears that like raclopride, S 14506 displays dopamine antagonist properties by blocking dopamine D2 receptors. However, the psychopharmacological profile of S 14506 is closer to that of clozapine than to that of raclopride, probably as a result of its actions at 5-HT receptors.

Plasma Clozapine Levels and the Treatment of L-DOPA-Induced Psychosis in Parkinson's Disease A High Potency Effect of Clozapine

Article

Mar 1995

The purpose of this study was to determine the plasma level of clozapine and its metabolite, N-desmethylclozapine, in Parkinson's disease patients with L-DOPA-induced psychosis responsive to clozapine. The psychotic symptoms of the three patients studied responded to low doses of clozapine with plasma levels of clozapine between 4.5 and 16.1 ng/ml and N-desmethylclozapine between 2.6 and 6.1 ng/ml, much below the plasma clozapine levels usually found in clozapine-treated refractory schizophrenia or affective disorders (range 100 to 687 ng/ml). Possible mechanisms that may account for clozapine's antipsychotic action in dopaminomimetic-induced psychosis in Parkinson's disease, including serotonin2A (5-HT2A) and dopamine D4 receptor blockade, at plasma levels that would be ineffective in refractory schizophrenia, are discussed. It is suggested that 5-HT2A receptor blockade is the most likely basis for the effectiveness of clozapine in L-DOPA psychosis.

The role of 5-HT2A receptors in antipsychotic activity

Article

Feb 1995
LIFE SCI

The correlation between the clinical activity of antipsychotic agents and their affinity for the D2 dopamine receptor has been the mainstay of the hypothesis that schizophrenia is due to excessive dopaminergic function. More recently, the unique clinical profile of the atypical antipsychotic clozapine has been proposed to involve actions on additional receptor systems. In particular, the high affinity of clozapine for the 5HT2A receptor subtype has been suggested to contribute to its reduced side-effect liability, greater efficacy and its activity in therapy-resistant schizophrenia. We have used the highly selective 5-HT2A antagonist MDL 100,907 to explore the contribution of 5-HT2A receptor blockade to antipsychotic activity. Biochemical, electrophysiological and behavioral studies reveal that selective 5HT2A receptor antagonists have the preclinical profile of an atypical antipsychotic. The limited clinical evidence available also suggests that compounds producing 5-HT2A receptor blockade are effective, in particular, against the negative symptoms of schizophrenia.

The Physiological Relevance of Glucocorticoid Endangerment of the Hippocampusa

Article

Dec 1994

Robert Sapolsky

Serotonergic and dopaminergic aspects ofneurok-p-tic-induced extrapyramidal syndromes in nonhuman primates

Article

Feb 1993

Daniel E. Casey

Neuroleptic drug-induced acute extra-pyramidal syndromes are one of the major reasons why patients discontinue their antipsychotic medicines. The typical (e.g., haloperidol) neuroleptic drug produces acute extrapyramidal symptoms in the majority of patients, whereas the atypical (clozapine) neuroleptic produces only minimal motor system side effects. Serotonin S2 antagonists often reduce or prevent catalepsy in rodents, but the limited number of studies in nonhuman primates have produced conflicting results. The hypothesis of a high serotonin S2/dopamine D2 antagonism ratio as a mechanism underlying atypical neuroleptic effects in preventing acute extrapyramidal syndromes deserves further evaluation in nonhuman primate models because extrapyramidal symptoms in monkeys closely resemble those in patients. Cebus monkeys (22-28 years old) were tested with compounds that ranged from low to high S2/D2 antagonism ratios. These were haloperidol, fluphenazine, clopenthixol, melperone, tefludazine, setoperone, risperidone, and clozapine. A saline control was included with a wide dose range of each of these drugs that was tested in a once-weekly, blindly-scored random drug administration schedule. Dystonia was scored on four different symptoms by an experienced rater who was blind to drug dosage. All the compounds, with the exception of clozapine, produced clinically indistinguishable dose-related dystonia. The only difference was the dose at which dystonia appeared. In contrast to rodent studies, these nonhuman primate investigations with drugs, spanning a wide range of S2/D2 antagonism ratios, produced clinically similar extrapyramidal symptoms. Thus, adding an S2 antagonism component to neuroleptics does not appear to provide an explanation for the motor side effect profile of atypical neuroleptics, or a method for designing neuroleptic drugs that will be free of extrapyramidal symptoms.

Reduction of Suicidality during Clozapine Treatment of Neuroleptic-Resistant Schizophrenia: Impact on Risk-Benefit Assessment

Article

Mar 1995

Suicide has been reported to occur in 9%-13% of schizophrenic patients. It has been suggested that neuroleptic-resistant or neuroleptic-intolerant schizophrenic patients are at higher risk for suicide than neuroleptic-responsive patients. Clozapine is the treatment of choice for neuroleptic-resistant patients, but its use has been greatly limited because of its ability to cause potentially fatal agranulocytosis. The purpose of this study was to compare the suicidality of neuroleptic-resistant and neuroleptic-responsive patients and to determine if clozapine treatment decreased suicidality in the former group. Prior episodes of suicidality were assessed in a total of 237 neuroleptic-responsive and 184 neuroleptic-resistant patients with schizophrenia or schizoaffective disorder. Eighty-eight of the neuroleptic-resistant patients were treated with clozapine and prospectively evaluated for suicidality for periods of 6 months to 7 years. There was no significant difference in prior suicidal episodes between neuroleptic-responsive and neuroleptic-resistant patients. Clozapine treatment of the neuroleptic-resistant patients during the follow-up period resulted in markedly less suicidality. The number of suicide attempts with a high-probability of success decreased from five to zero. This decrease in suicidality was associated with improvement in depression and hopelessness. These results suggest a basis for reevaluation of the risk-benefit assessment of clozapine, i.e., that the overall morbidity and mortality of patients with neuroleptic-resistant schizophrenia are less with clozapine treatment than with typical neuroleptic drugs because of less suicidality. This conclusion also has implications for increasing the use of clozapine with neuroleptic-responsive patients.

Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine 6 (5-HT6) and 5-hydroxytryptamine 7 (5-HT7) receptors

Article

Mar 1994

The authors examined the affinities of 36 typical and atypical antipsychotic agents for the cloned rat 5-hydroxytryptamine-6 (5-HT6) and rat 5-hydroxytryptamine-7 (5-HT7) receptors in transiently expressed COS-7 cells (5-HT7) or stably transfected HEK-293 cells (5-HT6 receptors). Clozapine and several related atypical antipsychotic agents (rilapine, olanzepine, tiospirone, fluperlapine, clorotepine and zotepine) had high affinities for the newly discovered 5-HT6 receptor (Kis < 20 nM). The 5-HT7 receptor bound clozapine, rilapine, fluperlapine, clorotepine, zotepine and risperidone but not tiospirone and olanzepine, with affinities less than 15 nM. In addition, several typical antipsychotic agents (chloroprothixene, chlorpromazine, clothiapine and fluphenazine) had high affinities for both the 5-HT6 and 5-HT7 receptors. Pimozide, a diphenylbutylpiperidine, had the highest affinity of all the typical antipsychotic agents tested for the 5-HT7 receptor (Ki = 0.5 nM). Three putative atypical antipsychotic agents melperone, amperozide and MDL 100907 did not bind with high affinities to either the 5-HT6 or 5-HT7 receptors (Kis > 50 nM). Several dopamine-selective antipsychotic agents (raclopride, rimcazole and penfluridol) had essentially no affinity for either the 5-HT6 or 5-HT7 receptors (Ki values > 5000 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Clozapine in treatment-refractory mood disorders

Article

Oct 1994

Lithium remains the mainstay of treatment for patients with bipolar affective disorder; however, nearly half of patients with bipolar disorder fail to respond to lithium. Recently, there have been an increasing number of preliminary clinical reports that clozapine, an atypical antipsychotic agent, has potential efficacy in patients with mood disorders. We review the available clinical data supporting the potential use of clozapine in these psychiatric disorders and report our preliminary data from a study that used clozapine in the acute treatment of mania in treatment-refractory patients. Twenty-five patients meeting the DSM-III-R criteria for the manic phase of either bipolar or schizoaffective disorder entered a 13-week open prospective trial of clozapine. These patients either had failed to respond to or had been intolerant to treatment with lithium, an anticonvulsant, and at least two typical neuroleptics. Eighteen of 25 patients demonstrated a greater than 50% decrease in the Young Mania Rating Scale score. These preliminary data as well as the clinical reports reviewed indicate that the efficacy of clozapine in treatment-resistant patients is not limited to patients with schizophrenia.

Robertson GS, Matsumura H, Fibiger HC. Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity. J Pharmacol Exp Ther 271: 1058-1066

Article

Dec 1994

Clozapine and haloperidol produce different induction patterns of c-fos expression in the forebrain, with haloperidol increasing Fos-like immunoreactivity (FLI) in the striatum, nucleus accumbens, lateral septal nucleus and clozapine producing such effects in the nucleus accumbens, prefrontal cortex and lateral septal nucleus. Accordingly, it was deemed possible that this approach may be useful in characterizing compounds with known or suggested antipsychotic actions. We therefore examined the effects of 17 compounds considered to be either typical, or atypical, antipsychotics on FLI in the prefrontal cortex, medial and dorsolateral striatum, nucleus accumbens and the lateral septal nucleus. Consistent with the hypothesis that the prefrontal cortex may be a target for some antipsychotic actions, FLI was elevated in this structure by clozapine, ICI 204,636, fluperlapine, RMI-81,582, remoxipride, molindone, melperone and tiospirone. Likewise, the ability of all of the compounds, except for risperidone, to enhance FLI in the lateral septal nucleus suggests that this limbic region also may be an important locus of antipsychotic action. All of the compounds examined elevated FLI in the nucleus accumbens and medial striatum, indicating that potential antipsychotic activity is predicted most consistently on this basis. Neuroleptics with a clearly documented liability for producing extrapyramidal side effects (EPS) such as chlorpromazine, fluphenazine, haloperidol, loxapine, metoclopramide and molindone elevated FLI in the dorsolateral striatum. In contrast, compounds unlikely to produce EPS such as clozapine, thioridazine, risperidone, remoxipride, fluperlapine, sulpiride, melperone and RMI-81,582 either failed to increase or produced minor elevations in FLI in the dorsolateral striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin2/1C receptor activation causes a localized expression of the immediate-early gene c-fos in rat brain: evidence for involvement of dorsal raphe nucleus projection fibres

Article

Apr 1993
NEUROSCIENCE

Immunocytochemistry has been used to monitor the expression of the immediate-early gene c-fos in rat brain following administration of the serotonin2/1C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. At parenteral doses of 2 or 8 mg/kg the drug caused a highly localized expression of the Fos protein in frontal, parietal, cingulate and piriform cortex as well as in claustrum, mamillary bodies, globus pallidus, amygdala, nucleus accumbens and dorsomedial striatum. In particular, the location of heavy Fos immunoreactivity in the primary somatosensory cortex corresponds precisely to that region (layer Va) shown in other reports to receive a dense input of fine, non-varicose fibres which may arise from the dorsal raphe nucleus. All of the Fos-positive brain regions in the present study have been previously demonstrated to contain serotonin2 receptor ligand binding sites. Interestingly, no Fos-positive cells were found in the hippocampus, another brain region known to contain serotonin2 receptors. Pretreatment of animals with the serotonin2/1C receptor antagonist ritanserin (0.4 mg/kg) markedly attenuated Fos expression in all reactive areas of the brain. Counts of reactive cells indicated that this antagonism of the Fos response was statistically significant in these brain regions. Spiperone (1 mg/kg), a mixed serotonin2 and dopamine D2 antagonist, also attenuated the Fos response in the same regions, but had the effect of inducing Fos expression on its own in other extrapyramidal brain regions. Double labelling of reactive cells with different antisera recognizing Fos and neuron-specific enolase, and lack of double labelling with a glial fibrillary acidic protein antiserum, indicated that the Fos expression was in neurons within the brain nuclei examined.(ABSTRACT TRUNCATED AT 250 WORDS)

The interactions of typical and atypical antipsychotics with the (−)2,5,-dimethoxy-4-methamphetamine (DOM) discriminative stimulus

Article

Nov 1995
NEUROPHARMACOLOGY

The present study was designed to test the hypothesis that atypical, but not typical, antipsychotics produce a functional in vivo blockade of 5-HT2A receptors. The magnitude of functional in vivo 5-HT2A receptor blockade elicited by representative compounds from each of the six major structural classes of typical antipsychotics, and the representative atypical antipsychotics clozapine and risperidone, was indicated by their respective abilities to block the stimulus effects of the phenylalkylamine hallucinogen (-)DOM in the rat. Chlorpromazine, thioridazine, fluphenazine, thiothixene and haloperidol did not produce a significant antagonism of the (-)DOM stimulus. The benzoxapine, loxapine (60%), and the atypical dibenzodiazepine, clozapine (62%), partially blocked and risperidone fully blocked (100%) the (-)DOM stimulus. None of these agents elicited significant levels of (-)DOM-appropriate responding when administered alone. These results indicate that the typical antipsychotics, with the exception of lozapine, fail to produce effective in vivo antagonism of 5-HT2A receptors at doses compatible with the preservation of operant behavior. In contrast, the atypical antipsychotics clozapine and risperidone elicit effective in vivo antagonism of 5-HT2A receptors without severe behavioral disruption. Thus, these data are supportive of the hypothesis that the mechanism of action of atypical, but not typical, antipsychotics involves the antagonism of 5-HT2A receptors in vivo.

Pindolol pretreatment blocks stimulation by meta-chlorophenylpiperazine of prolactin but not cortisol secretion in normal men

Article

Oct 1995
PSYCHIAT RES

Previous reports from this laboratory have shown that pindolol, a partial serotonin1A receptor agonist, inhibited prolactin, but not cortisol secretion induced by administration of the serotonin (5-HT) precursor L-5-hydroxytryptophan or the direct-acting 5-HT2A/5HT2C receptor agonist MK-212. The findings suggest additive or interactive effects of 5-HT1A and 5-HT2A/5-HT2C receptors in modulating 5-HT-related prolactin, but not cortisol, responsivity. To examine further the role of 5-HT1A and 5-HT2A/5-HT2C receptors in prolactin and cortisol secretion in healthy men, the effects of meta-chlorophenylpiperazine (mCPP), a potent 5-HT receptor agonist, on the above hormones were studied in eight healthy men with and without pindolol pretreatment. It has previously been demonstrated that ketanserin, a 5-HT2A antagonist, and ritanserin, a 5-HT2A/5-HT2C antagonist, block the prolactin and attenuate the hypothalamic-pituitary-adrenal axis responses to mCPP in man or rodents. Administration of mCPP induced a significant increase in plasma concentrations of prolactin and cortisol. The mCPP-induced prolactin concentrations were significantly blocked by pretreatment with pindolol, whereas mCPP-stimulated cortisol levels were not diminished by pindolol pretreatment. Thus, mCPP-induced prolactin secretion appears to require the availability of both 5-HT2C and 5-HT1A receptor activation, since blockade of either of these receptors may diminish the mCPP-induced prolactin response. Cortisol secretion stimulated by mCPP may occur following 5-HT2C receptor stimulation in the presence of 5-HT1A receptor blockade.

Serotonin-Dopamine interaction and its relevance to schizophrenia

Article

May 1996

The therapeutic success of clozapine and risperidone has focused attention on the interaction between serotonin and dopamine systems as an avenue for superior therapeutics in schizophrenia. The authors review the neurobiological basis for this interaction and its clinical relevance. The authors synthesized information from more than 100 published articles obtained through electronic and bibliography-directed searches. The serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain. Serotonergic antagonists release the dopamine system from this inhibition. This disinhibition of the dopamine system in the striatum may alleviate neuroleptic-induced extrapyramidal symptoms, and a similar disinhibition in the prefrontal cortex may ameliorate negative symptoms. However, the benefits of combined serotonergic-dopaminergic blockade may be observed in only a narrow dose range and may be lost with doses that produce suprathreshold dopaminergic blockade. Serotonergic modulation of dopaminergic function provides a viable mechanism for enhancing therapeutics in schizophrenia, but much remains unclear. Future research will have to establish the existence of this interaction in humans in vivo, specify the conditions under which it leads to optimal therapeutic benefits, and explore the possibility of using specific serotonergic treatments as flexible adjuncts to typical neuroleptics, rather than the present trend toward using single drugs with combined actions.

Clozapine for treatment-refractory mania

Article

Jul 1996

The efficacy of clozapine for treatment-resistant mania was examined in a prospective trial for patients with bipolar or schizoaffective disorder. The subjects were 25 acutely manic patients with either bipolar disorder (N = 10) or schizoaffective disorder-bipolar subtype (N = 15) for whom lithium, anticonvulsants, and neuroleptics had been ineffective, had produced intolerable side effects, or both. After a 7-day washout, the patients were treated with clozapine monotherapy. They were evaluated over 13 weeks with the Young Mania Rating Scale and the Brief Psychiatric Rating Scale (BPRS). Of the 25 patients, 18 (72%) exhibited marked improvement on the Young Mania Rating Scale, and eight (32%) exhibited marked improvement on the BPRS. The bipolar patients as compared to schizo-affective patients, and the nonrapid as compared to rapid cyclers, had significantly greater improvement in total BPRS score. These results suggest that clozapine is an effective therapy for treatment-resistant bipolar and schizoaffective mania.

Reversal of dizocilpine-induced disruption of prepulse inhibition of an acoustic startle response by the 5-HT2 receptor antagonist ketanserin

Article

Jan 1996
EUR J PHARMACOL

Prepulse inhibition can be reliably disrupted by non-competitive NMDA receptor antagonists such as dizocilpine. In recent study, we found that the potent D2/5-HT2 receptor antagonist, risperidone, but not the selective dopamine D2 receptor antagonist, raclopride, could reverse this disruption. The present study was therefore designed to examine the effect of the 5-HT2 receptor antagonist, ketanserin, against a dizocilpine-induced disruption of prepulse inhibition, as well as the behavioural stereotypy produced by this drug. Ketanserin (2 mg/kg) reversed the prepulse inhibition disruption produced by dizocilpine (0.15 mg/kg), as did the non-selective 5-HT1/5-HT2 receptor antagonist metergoline (1 mg/kg). Both drugs also attenuated some components of the behavioural stereotypy syndrome produced by dizocilpine (0.15 mg/kg). The present studies therefore suggest an interaction between 5-HT2 receptors and glutamatergic systems. This may be important for the antipsychotic profile of drugs having antagonist activity at 5-HT2 receptors.

The effects of antipsychotic drugs on Fos protein expression in the prefrontal cortex: Cellular localization and pharmacological characterization

Article

Feb 1996
NEUROSCIENCE

The assessment of immediate-early gene induction has proven to be a useful method for delineating the neural systems that subserve antipsychotic drug actions. In order to differentiate the sites and mechanisms of action of typical and atypical antipsychotic drugs, we examined the effects of antipsychotic drugs on Fos protein expression in the medial prefrontal cortex. The atypical antipsychotic drug clozapine selectively increased the number of neurons that expressed Fos-like immunoreactivity in the prefrontal cortex, targeting the deep layers of the infralimbic and prelimbic cortices. Pyramidal cells were the major cell type in which Fos was expressed. A small number of calbindin-like immunoreactive, but not parvalbumin- or reduced nicotinamide adenine dinucleotide phosphate diaphorase-containing, interneurons also expressed Fos after clozapine challenge.

Melperone in the treatment of iatrogenic psychosis in Parkinson’s disease

Article

Nov 1999
FUNCT NEUROL

The pharmacological management of Parkinson's disease (PD) can be complicated by psychiatric disorders induced by antiparkinsonian drugs. The reduction or withdrawal of levodopa (l-dopa) and other drugs commonly used in the treatment of PD may attenuate the psychosis but exacerbate motor impairment and disability. Melperone is an atypical antipsychotic drug showing in vivo a greater relative affinity for the 5-HT2 than the D2 receptors. A two-year study to assess the clinical efficacy and the safety of melperone in the management of iatrogenic psychosis in 30 parkinsonian patients was carried out. Neurological evaluation was performed with patients in the "off" and in the "on" state using the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). Time spent in "on" state was evaluated using the self-evaluation diary of daily life. To assess psychiatric disturbances the modified version of the Brief Psychiatric Rating Scale (BPRS) was used. The mean BPRS score was significantly reduced when comparing baseline with individual examinations; no statistically significant differences were found between subsequent examinations. UPDRS motor score and time spent in "on" state during daily life showed no statistically significant differences when comparing baseline with subsequent examinations. Two patients dropped out because of excessive sedation problems but in the remaining 28 patients melperone proved to be optimally tolerated.

The Role of Serotonin in Antipsychotic Drug Action

Abstract

No full-text available

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