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Journal of Psychopharmacology (Oxford,... Jun 2024The highly selective 5-HT serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD)...
The 5-HT1A receptor biased agonists, NLX-204 and NLX-101, like ketamine, elicit rapid-acting antidepressant activity in the rat chronic mild stress model via cortical mechanisms.
BACKGROUND
The highly selective 5-HT serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM).
AIMS
Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT receptor activation in the RAAD activity of NLX compounds.
RESULTS/OUTCOMES
In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT receptors.
CONCLUSIONS/INTERPRETATION
These data indicate that 5-HT receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine's primary mechanism of action) but also by activating 5-HT receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine's troublesome side effects.
PubMed: 38825869
DOI: 10.1177/02698811241254832 -
Psychiatry Research Aug 2024The aim of the study was to evaluate interaction effect of various augmentation strategies with clozapine in patients with Treatment-resistant schizophrenia.
Evaluation of the pharmacodynamic interaction effect of augmentation agents with clozapine in patients with treatment-resistant schizophrenia: A simulation study of clinical data.
INTRODUCTION
The aim of the study was to evaluate interaction effect of various augmentation strategies with clozapine in patients with Treatment-resistant schizophrenia.
METHODS
Data was extracted for change in positive and negative syndrome scale (PANSS) or brief psychiatric rating scale (BPRS) scores for monotherapy with various antipsychotic agents alone and their combination with clozapine. Individual patient data was generated using simulation of data (factorial trial framework) from published clinical trials for sample sizes from eight to 400 to evaluate interaction effect through linear modeling. Dose equivalents were calculated, and best fit models were determined for simulated data.
RESULTS
The polynomial model was found to be the best fit for the simulated data to determine interaction effect of combination. The clozapine augmentation with risperidone and ziprasidone was found to be antagonistic, whereas it was additive for haloperidol, aripiprazole, and quetiapine. A synergistic effect was observed for ECT combined with clozapine (Interaction effect: -7.62; p <0.001). A sample size of 250-300 may be sufficient to demonstrate a clinically significant interaction in future trials.
CONCLUSION
Clozapine may be augmented with electroconvulsive therapy, leading to the enhancement of antipsychotic effect. Though some antipsychotics like aripiprazole demonstrate additive effects, they may also add to the adverse effects.
Topics: Humans; Clozapine; Antipsychotic Agents; Drug Therapy, Combination; Schizophrenia, Treatment-Resistant; Adult; Male; Female; Computer Simulation; Drug Interactions; Drug Synergism; Middle Aged; Schizophrenia; Risperidone; Piperazines; Thiazoles
PubMed: 38824710
DOI: 10.1016/j.psychres.2024.115989 -
CNS Drugs Jul 2024Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology... (Review)
Review
Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology and the impacts of this on therapeutic developments, there remains a need for treatment options for patients underserved by currently available therapies. The first specific drugs developed to treat migraine acutely, the serotonin-5-hydroxytryptamine [5-HT] receptor agonists (triptans), seem to require headache onset in order to have an effect, while early treatment during mild pain before headache escalation improves short-term and long-term outcomes. Some patients find treating in the early window once headache has started but not escalated difficult, and migraine can arise from sleep or in the early hours of the morning, making prompt treatment after pain onset challenging. Triptans may be deemed unsuitable for use in patients with vascular disease and in those of older age and may not be effective in a proportion of patients. Headache is also increasingly recognised as being just one of the many facets of the migraine attack, and for some patients it is not the most disabling symptom. In many patients, painless symptoms can start prior to headache onset and can reliably warn of impending headache. There is, therefore, a need to identify therapeutic targets and agents that may be used as early as possible in the course of the attack, to prevent headache onset before it starts, and to reduce both headache and non-headache related attack burden. Early small studies using domperidone, naratriptan and dihydroergotamine have suggested that this approach could be useful; these studies were methodologically less rigorous than modern day treatment studies, of small sample size, and have not since been replicated. The emergence of novel targeted migraine treatments more recently, specifically calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), has reignited interest in this strategy, with encouraging results. This review summarises historical and emerging data in this area, supporting use of the premonitory phase as an opportunity to intervene as early as possible in migraine to prevent attack-related morbidity.
Topics: Migraine Disorders; Humans; Tryptamines; Serotonin Receptor Agonists
PubMed: 38822165
DOI: 10.1007/s40263-024-01091-2 -
Scientific Reports May 2024Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by...
Association between voriconazole-induced visual hallucination and dopamine in an analysis of the food and drug administration (FDA) adverse event reporting system database.
Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587-42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421-7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.
Topics: Humans; Voriconazole; Hallucinations; United States; United States Food and Drug Administration; Male; Female; Aged; Middle Aged; Dopamine; Levodopa; Adult; Antifungal Agents; Adverse Drug Reaction Reporting Systems; Chlorpromazine; Risperidone; Dopamine Antagonists; Parkinson Disease; Young Adult; Adolescent; Databases, Factual
PubMed: 38822123
DOI: 10.1038/s41598-024-63504-y -
Nature Communications May 2024Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the...
Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.
Topics: Magnetic Resonance Imaging; Male; Animals; Prefrontal Cortex; Amygdala; Neural Pathways; Frontal Lobe; Limbic System; Brain Mapping; Rest; Macaca mulatta; Designer Drugs; Clozapine; Nerve Net
PubMed: 38821963
DOI: 10.1038/s41467-024-49140-0 -
Molecular Pharmacology May 2024Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical...
Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin (5-HT) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT receptors and VGSCs. Towards this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT receptors and blocks sodium current. The new compound, -(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, G-mediated, calcium flux at 5-HT receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT, 5-HT, and 5-HT receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. We synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT receptors and voltage-gated sodium channels (VGSCs), in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.
PubMed: 38821630
DOI: 10.1124/molpharm.123.000837 -
Biomedicine & Pharmacotherapy =... Jul 2024Diabetes and derived complications, especially diabetic nephropathy and neuropathy annually cause great morbimortality worldwide. 5-hydroxytryptamine (5-HT) acts as a...
Diabetes and derived complications, especially diabetic nephropathy and neuropathy annually cause great morbimortality worldwide. 5-hydroxytryptamine (5-HT) acts as a modulator of renal sympathetic input and vascular tone. In this line, 5-HT receptor blockade has been linked with reduced incidence and progression of diabetic microvascular alterations. In this work, we aimed to determine, in diabetic rats, whether 5-HT blockade ameliorates renal function and to characterize the serotonergic modulatory action on renal sympathetic neurotransmission. Diabetes was induced in male Wistar rats by alloxan administration (150 mg/kg, s.c.), and sarpogrelate (30 mg/kg·day, p.o.; 5-HT antagonist) was administered for 14 days (DM-S). Normoglycemic and diabetic (DM) animals were maintained as aged-matched controls. At 28th day, DM-S animals were anesthetized and prepared for the in situ autoperfusion of the kidney. Renal vasoconstrictor responses were induced electrically or by i.a. noradrenaline (NA) administration. The role of 5-HT and selective 5-HT agonist/antagonist were studied on these renal vasopressor responses. Sarpogrelate treatment decreased renal sympathetic-induced vasopressor responses, reduced renal hypertrophy and kidney damage markers increased in DM. Intraarterial 5-HT inhibited the sympathetic-induced renal vasoconstrictions, effect reproduced by 5-CT, AS-19, L-694,247 and LY 344864 (5-HT, 5-HT, 5-HT and 5-HT receptor agonists, respectively). Blocking 5-HT receptors completely abolished the 5-CT sympatho-inhibition. NA vasoconstrictions were not altered by any of the 5-HT agonists tested. Thus, in experimental diabetes, chronic sarpogrelate treatment reduces renal damage markers, kidney hypertrophy and renal sympathetic hyperactivity and modifies serotonergic modulation of renal sympathetic neurotransmission, causing a sympatho-inhibition by prejunctional 5-HT and 5-HT activation.
Topics: Animals; Succinates; Male; Diabetes Mellitus, Experimental; Rats, Wistar; Kidney; Sympathetic Nervous System; Rats; Serotonin 5-HT2 Receptor Antagonists; Serotonin; Diabetic Nephropathies; Vasoconstriction
PubMed: 38820974
DOI: 10.1016/j.biopha.2024.116814 -
Journal of Clinical Psychopharmacology
Topics: Humans; Antipsychotic Agents; Lurasidone Hydrochloride; Asthma; Piperazines; Female; Male; Schizophrenia; Adult
PubMed: 38820328
DOI: 10.1097/JCP.0000000000001871 -
Journal of Psychiatric Practice May 2024Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence...
OBJECTIVE
Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence that prescribers consider before using these agents is lacking. While empirical literature on the long-term safety and efficacy of these medications is available, the literature concerning their use in these younger age groups is relatively sparse. In this study, we examined the current prescribing patterns of medical professionals employed by a public health service in Australia.
METHODS
A survey examining their current practice when prescribing atypical antipsychotics to children and adolescents was completed by 103 physicians. Questions were asked about commonly prescribed atypical antipsychotics, indications, dose ranges, target symptoms, duration of treatment, and the evidence base(s) used when making treatment decisions.
RESULTS
Physicians prescribed atypical antipsychotics for a wide range of indications in this age group, with the most common agents being risperidone, quetiapine, and olanzapine. Adverse effects were reported as the main reason for treatment discontinuation. More than half of the respondents indicated that the most common source of guidance/evidence they referred to when initiating prescriptions were peers or expert opinion.
CONCLUSIONS
Children and adolescents were prescribed a number of atypical antipsychotics for a variety of indications, with variable perceived confidence and a relatively heavy reliance on "own or peer experience" as opposed to good quality evidence. Challenges exist for both prescribers and policymakers, and further "head-to-head" studies are needed in this age group to ensure that a balance is maintained between therapeutic benefit and safety.
Topics: Humans; Antipsychotic Agents; Adolescent; Practice Patterns, Physicians'; Australia; Child; Male; Female; Drug Prescriptions; Risperidone; Surveys and Questionnaires; Olanzapine
PubMed: 38819247
DOI: 10.1097/PRA.0000000000000785 -
Annals of General Psychiatry May 2024Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to... (Review)
Review
Personality disorders (PD) are described as enduring patterns of markedly deviant and pervasive inner experiences and behaviors, with onset in adolescence, which lead to severe distress or impairment. Patients suffering from major depressive disorder (MDD) display higher rates of comorbidity with personality disorders, often complicating the treatment, and worsening the outcomes. Borderline personality disorder (BPD) is the most common of PD and is frequently associated with MDD, with which shares several features. The most part of research agrees on the fact that comorbid BPD in MDD patients quite doubles the poor response to treatments. Moreover, no treatment strategy stands out currently to emerge as more effective in these cases, thus urging the call for the need of new approaches. Herein, we revise the current literature on BPD, its neurobiology and comorbidity with MDD, as well as the more recent treatment strategies used. Then, based on its pharmacology, we propose a possible role of trazodone as a valuable tool to approach comorbid BPD-MDD.
PubMed: 38816843
DOI: 10.1186/s12991-024-00507-z