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1.
Biol Pharm Bull ; 47(2): 478-485, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38382927

RESUMO

The medial prefrontal cortex (mPFC) is associated with various behavioral controls via diverse projections to cortical and subcortical areas of the brain. Dysfunctions and modulations of this circuitry are related to the pathophysiology of schizophrenia and its pharmacotherapy, respectively. Clozapine is an atypical antipsychotic drug used for treatment-resistant schizophrenia and is known to modulate neuronal activity in the mPFC. However, it remains unclear which prefrontal cortical projections are activated by clozapine among the various projection targets. To identify the anatomical characteristics of neurons activated by clozapine at the mesoscale level, we investigated the brain-wide projection patterns of neurons with clozapine-induced c-Fos expression in the mPFC. Using a whole-brain imaging and virus-mediated genetic tagging of activated neurons, we found that clozapine-responsive neurons in the mPFC had a wide range of projections to the mesolimbic, amygdala and thalamic areas, especially the mediodorsal thalamus. These results may provide key insights into the neuronal basis of the therapeutic action of clozapine.


Assuntos
Antipsicóticos , Clozapina , Ratos , Animais , Clozapina/farmacologia , Ratos Sprague-Dawley , Antipsicóticos/farmacologia , Córtex Pré-Frontal , Neurônios
2.
J Neurochem ; 168(3): 238-250, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38332572

RESUMO

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain.


Assuntos
Antipsicóticos , Clozapina , Animais , Humanos , Clozapina/farmacologia , Haloperidol/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Maleato de Dizocilpina/farmacologia , Proteoma/metabolismo , N-Metilaspartato , Ácido Glutâmico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteômica , Antipsicóticos/farmacologia , Encéfalo/metabolismo
3.
Free Radic Biol Med ; 212: 384-402, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38182072

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet treatment options are limited. Clozapine (CLZ), an antipsychotic used for schizophrenia, has potential as a PD treatment. CLZ and its metabolite, Clozapine-N-Oxide (CNO), show neuroprotective effects on dopaminergic neurons, with mechanisms needing further investigation. This study aimed to confirm the neuroprotective effects of CLZ and CNO in a rotenone-induced mouse model and further explore the underlying mechanisms of CNO-afforded protection. Gait pattern and rotarod activity evaluations showed motor impairments in rotenone-exposed mice, with CLZ or CNO administration ameliorating behavioral deficits. Cell counts and biochemical analysis demonstrated CLZ and CNO's effectiveness in reducing rotenone-induced neurodegeneration of dopaminergic neurons in the nigrostriatal system in mice. Mechanistic investigations revealed that CNO suppressed rotenone-induced ferroptosis of dopaminergic neurons by rectifying iron imbalances, curtailing lipid peroxidation, and mitigating mitochondrial morphological changes. CNO also reversed autolysosome and ferritinophagic activation in rotenone-exposed mice. SH-SY5Y cell cultures validated these findings, indicating ferritinophage involvement, where CNO-afforded protection was diminished by ferritinophagy enhancers. Furthermore, knockdown of NCOA4, a crucial cargo receptor for ferritin degradation in ferritinophagy, hampered rotenone-induced ferroptosis and NCOA4 overexpression countered the anti-ferroptotic effects of CNO. Whereas, iron-chelating agents and ferroptosis enhancers had no effect on the anti-ferritinophagic effects of CNO in rotenone-treated cells. In summary, CNO shielded dopaminergic neurons in the rotenone-induced PD model by modulating NCOA4-mediated ferritinophagy, highlighting a potential therapeutic pathway for PD treatment. This research provided insights into the role of NCOA4 in ferroptosis and suggested new approaches for PD therapy.


Assuntos
Clozapina , Ferroptose , Neuroblastoma , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Doença de Parkinson , Camundongos , Humanos , Animais , Rotenona/toxicidade , Neurônios Dopaminérgicos/metabolismo , Clozapina/farmacologia , Clozapina/metabolismo , Fármacos Neuroprotetores/farmacologia , Neuroblastoma/metabolismo , Síndromes Neurotóxicas/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Ferro/metabolismo , Óxidos/metabolismo , Óxidos/farmacologia
4.
Brain Behav Immun ; 115: 223-228, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37832895

RESUMO

BACKGROUND AND HYPOTHESIS: Use of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis that reductions in immunoglobulin levels would occur over the first 6 months following initiation of clozapine treatment. Relationships between immunoglobulin levels and symptom severity over the course of clozapine treatment were also explored. DESIGN: This prospective observational study measured immunoglobulin (Ig) levels (A, M and G) in 56 patients with treatment-resistant schizophrenia at 6-, 12- and 24-weeks following initiation with clozapine. Clinical symptoms were also measured at 12 weeks using the positive and negative syndrome scale (PANSS). RESULTS: IgA, IgG and IgM all decreased during clozapine treatment. For IgA and IgG the reduction was significant at 24 weeks (IgA: ß = -32.66, 95% CI = -62.38, -2.93, p = 0.03; IgG: ß = -63.96, 95% CI = -118.00, -9.31, p = 0.02). For IgM the reduction was significant at 12 and 24 weeks (12 weeks: ß = -23.48, 95% CI = -39.56, -7.42, p = 0.004; 24 weeks: ß = -33.12, 95 %CI = -50.30, -15.94, p = <0.001). Reductions in IgA and IgG during clozapine treatment were correlated with reductions in PANSS-total over 12 weeks (n = 32, IgA r = 0.59, p = 0.005; IgG r = 0.48, p = 0.03). CONCLUSIONS: The observed reductions in immunoglobulin levels over six months of clozapine treatment add further evidence linking clozapine to secondary antibody deficiency. Associations between Ig reduction and symptom improvement may however indicate that immune mechanisms contribute to both desirable and undesirable effects of clozapine.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Clozapina/uso terapêutico , Clozapina/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/complicações , Antipsicóticos/efeitos adversos , Estudos Transversais , Imunoglobulina A , Imunoglobulina G , Imunoglobulina M
5.
J Clin Psychopharmacol ; 44(1): 16-24, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38100777

RESUMO

BACKGROUND: Preclinical and clinical investigations have revealed deficits in cortical inhibition in individuals with schizophrenia. Transcranial magnetic stimulation, a commonly used noninvasive measurement technique, is used for assessing these deficits. Limited research has been conducted on the effects of antipsychotic medications on cortical inhibition. This study aimed to evaluate the effects of clozapine on cortical inhibition with transcranial magnetic stimulation longitudinally and compare it with unaffected controls. METHODS: Ten patients who started clozapine were assessed at baseline, with 8 reassessed after 4 months. Eight age- and sex-matched unaffected controls were included. Psychopathology, neurocognitive performance, formal thought disorder, and disability were assessed, and the cortical excitability parameters (resting motor threshold, cortical silent period, short-interval intracortical inhibition, intracortical facilitation, and short-latency afferent inhibition [SAI]) were measured at baseline and four months after clozapine treatment. RESULTS: Resting motor threshold, ICF, and SAI were significantly different between patients and controls at baseline, whereas resting motor threshold, SAI, and ICF became similar to controls after clozapine with only ICF having a trend for significance. Clozapine prolonged cortical silent period significantly in the patients. CONCLUSIONS: This is the first study to investigate the effect of clozapine on SAI, a potential cholinergic biomarker, and the first follow-up study to investigate the relationship between the effects of clozapine on cortical inhibition and cognition. Clozapine seems to cause an increase in cortical inhibition through GABAergic and possibly cholinergic mechanisms. However, additional follow-up studies with larger sample sizes are required to reach more robust conclusions.


Assuntos
Clozapina , Esquizofrenia , Humanos , Estimulação Magnética Transcraniana/métodos , Seguimentos , Clozapina/farmacologia , Esquizofrenia/tratamento farmacológico , Colinérgicos
6.
Psiquiatr. biol. (Internet) ; 30(3): 100415, sep.-dic. 2023.
Artigo em Espanhol | IBECS | ID: ibc-228301

RESUMO

Esta guía internacional propone mejorar los prospectos de la clozapina en todo el mundo mediante la inclusion de información sobre la titulación del fármaco en función de la ascendencia del paciente. Las bases de datos de reacciones adversas a medicamentos (RAM) sugieren que la clozapina es el tercer fármaco más tóxico en los Estados Unidos de América (EE. UU.) y que produce una mortalidad por neumonía en todo el mundo 4 veces mayor que la correspondiente a la agranulocitosis o la miocarditis. El rango terapéutico de referencia para las concentraciones séricas estables de clozapina es estrecho, de 350 a 600 ng/ml, con potencial de toxicidad y reacciones adversas más fecuentes a medida que aumentan las concentraciones. La clozapina se metaboliza principalmente por CYP1A2 (las mujeres no fumadoras requieren la dosis más baja y los hombres fumadores la dosis más alta). A través de la conversión fenotípica, la prescripción conjunta de inhibidores del metabolismo de la clozapina (incluidos los anticonceptivos orales y el valproato), la obesidad o la inflamación con elevaciones de la proteína C reactiva (PCR), pueden convertir al paciente en un metabolizador lento/pobre (MP). Las personas de ascendencia asiática (de Pakistán a Japón) o los habitantes originarios de las Américas tienen menor actividad de CYP1A2 y requieren dosis más bajas de clozapina para alcanzar concentraciones de 350 ng/ml. En los EE. UU. se recomiendan dosis diarias de 300-600 mg/día. La dosificación personalizada lenta puede prevenir RAM tempranas (incluidos el síncope, la miocarditis y la neumonía). La esencia de esta guía se fundamenta en 6 esquemas de titulaciones personalizadas para pacientes hospitalizados...(AU)


This is the Spanish translation of an international guideline which proposes improving clozapine package inserts worldwide by using ancestry-based: 1) dosing and 2) titration. Adverse drug reaction (ADR) databases suggest clozapine: 1) is the third most toxic drug in the United States (US), and 2) produces worldwide pneumonia mortality four times greater than that of agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers require the lowest dose and male smokers the highest dose). Poor metabolizer (PM) status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity or inflammation with C-reactive protein (CRP) elevations. People with ancestry from Asia (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/ml. Daily doses of 300-600 mg/day are recommended in the US. Slow personalized titration may prevent early ADRs (including syncope, myocarditis and pneumonia). The core of this guideline consists of six personalized titration schedules for inpatients...(AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Clozapina/administração & dosagem , Titulometria , Etnicidade , Proteína C-Reativa , Clozapina/metabolismo , Clozapina/farmacologia , Clozapina/uso terapêutico , Titulometria/classificação , Titulometria/métodos , Titulometria/estatística & dados numéricos , Proteína C-Reativa/administração & dosagem , Proteína C-Reativa/efeitos adversos , Proteína C-Reativa/efeitos dos fármacos , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Proteína C-Reativa/uso terapêutico
7.
Redox Biol ; 67: 102915, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37866162

RESUMO

Long-term treatment of schizophrenia with clozapine (CLZ), an atypical antipsychotic drug, is associated with an increased incidence of metabolic disorders mediated by poorly understood mechanisms. We herein report that CLZ, while slowing down the morphological changes and lipid accumulation occurring during SW872 cell adipogenesis, also causes an early (day 3) inhibition of the expression/nuclear translocation of CAAT/enhancer-binding protein ß and peroxisome proliferator-activated receptor γ. Under the same conditions, CLZ blunts NADPH oxidase-derived reactive oxygen species (ROS) by a dual mechanism involving enzyme inhibition and ROS scavenging. These effects were accompanied by hampered activation of the nuclear factor (erythroid-derived2)-like 2 (Nrf2)-dependent antioxidant responses compared to controls, and by an aggravated formation of mitochondrial superoxide. CLZ failed to exert ROS scavenging activities in the mitochondrial compartment but appeared to actively scavenge cytosolic H2O2 derived from mitochondrial superoxide. The early formation of mitochondrial ROS promoted by CLZ was also associated with signs of mitochondrial dysfunction. Some of the above findings were recapitulated using mouse embryonic fibroblasts. We conclude that the NADPH oxidase inhibitory and cytosolic ROS scavenging activities of CLZ slow down SW872 cell adipogenesis and suppress their Nrf2 activation, an event apparently connected with increased mitochondrial ROS formation, which is associated with insulin resistance and metabolic syndrome. Thus, the cellular events characterised herein may help to shed light on the more detailed molecular mechanisms explaining some of the adverse metabolic effects of CLZ.


Assuntos
Clozapina , Lipossarcoma , Humanos , Animais , Camundongos , NADPH Oxidases/metabolismo , Adipogenia , Espécies Reativas de Oxigênio/metabolismo , Clozapina/farmacologia , Clozapina/metabolismo , Peróxido de Hidrogênio/metabolismo , Superóxidos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fibroblastos/metabolismo , Mitocôndrias/metabolismo , Lipossarcoma/metabolismo
8.
Psychopharmacology (Berl) ; 240(12): 2545-2560, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37594501

RESUMO

RATIONALE: Repeated chemogenetic stimulation is often employed to study circuit function and behavior. Chronic or repeated agonist administration can result in homeostatic changes, but this has not been extensively studied with designer receptors exclusively activated by designer drugs (DREADDs). OBJECTIVES: We sought to evaluate the impact of repeated DREADD activation of dopaminergic (DA) neurons on basal behavior, amphetamine response, and spike firing. We hypothesized that repeated DREADD activation would mimic compensatory effects that we observed with genetic manipulations of DA neurons. METHODS: Excitatory hM3D(Gq) DREADDs were virally expressed in adult TH-Cre and WT mice. In a longitudinal design, clozapine N-oxide (CNO, 1.0 mg/kg) was administered repeatedly. We evaluated basal and CNO- or amphetamine (AMPH)-induced locomotion and stereotypy. DA neuronal activity was assessed using in vivo single-unit recordings. RESULTS: Acute CNO administration increased locomotion, but basal locomotion decreased after repeated CNO exposure in TH-CrehM3Dq mice relative to littermate controls. Further, after repeated CNO administration, AMPH-induced hyperlocomotion and stereotypy were diminished in TH-CrehM3Dq mice relative to controls. Repeated CNO administration reduced DA neuronal firing in TH-CrehM3Dq mice relative to controls. A two-month CNO washout period rescued the decreases in basal locomotion and AMPH response. CONCLUSIONS: We found that repeated DREADD activation of DA neurons evokes homeostatic changes that should be factored into the interpretation of chronic DREADD applications and their impact on circuit function and behavior. These effects are likely to also be seen in other neuronal systems and underscore the importance of studying neuroadaptive changes with chronic or repeated DREADD activation.


Assuntos
Anfetamina , Clozapina , Camundongos , Animais , Anfetamina/farmacologia , Neurônios Dopaminérgicos , Clozapina/farmacologia
9.
Psychopharmacology (Berl) ; 240(10): 2101-2110, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37530882

RESUMO

RATIONALE: Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. OBJECTIVES: Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. METHODS: Male and female TH:Cre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of TH:Cre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order. RESULTS: All three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre + rats were correlated and were present in both sexes. CONCLUSIONS: Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.


Assuntos
Clozapina , Drogas Desenhadas , Ratos , Masculino , Feminino , Animais , Área Tegmentar Ventral , Neurônios Dopaminérgicos/metabolismo , Clozapina/farmacologia
10.
Eur J Pharmacol ; 953: 175802, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37295763

RESUMO

Antipsychotic drugs of different chemical/pharmacological families show preferential dopamine (DA) D2 receptor (D2-R) vs. D1 receptor (D1-R) affinity, with the exception of clozapine, the gold standard of schizophrenia treatment, which shows a comparable affinity for both DA receptors. Here, we examined the ability of Lu AF35700 (preferential D1-R>D2-R antagonist), to reverse the alterations in thalamo-cortical activity induced by phencyclidine (PCP), used as a pharmacological model of schizophrenia. Lu AF35700 reversed the PCP-induced alteration of neuronal discharge and low frequency oscillation (LFO, 0.15-4 Hz) in thalamo-cortical networks. Likewise, Lu AF35700 prevented the increased c-fos mRNA expression induced by PCP in thalamo-cortical regions of awake rats. We next examined the contribution of D1-R and D2-R to the antipsychotic reversal of PCP effects. The D2-R antagonist haloperidol reversed PCP effects on thalamic discharge rate and LFO. Remarkably, the combination of sub-effective doses of haloperidol and SCH-23390 (DA D1-R antagonist) fully reversed the PCP-induced fall in thalamo-cortical LFO. However, unlike with haloperidol, SCH-23390 elicited different degrees of potentiation of the effects of low clozapine and Lu AF35700 doses. Overall, the present data support a synergistic interaction between both DA receptors to reverse the PCP-induced alterations of oscillatory activity in thalamo-cortical networks, possibly due to their simultaneous blockade in direct and indirect pathways of basal ganglia. The mild potentiation induced by SCH-23390 in the case of clozapine and Lu AF35700 suggests that, at effective doses, these agents reverse PCP effects through the simultaneous blockade of both DA receptors.


Assuntos
Antipsicóticos , Clozapina , Ratos , Animais , Fenciclidina/farmacologia , Clozapina/farmacologia , Haloperidol/farmacologia , Dopamina , Antipsicóticos/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D1
11.
Brain Res ; 1814: 148446, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37301424

RESUMO

Hippocampal phase precession, wherein there is a systematic shift in the phase of neural firing against the underlying theta activity, is proposed to play an important role in the sequencing of information in memory. Previous research shows that the starting phase of precession is more variable in rats following maternal immune activation (MIA), a known risk factor for schizophrenia. Since starting phase variability has the potential to disorganize the construction of sequences of information, we tested whether the atypical antipsychotic clozapine, which ameliorates some cognitive deficits in schizophrenia, alters this aspect of phase precession. Either saline or clozapine (5 mg/kg) was administered to rats and then CA1 place cell activity was recorded from the CA1 region of the hippocampus as the animals ran around a rectangular track for food reward. When compared to saline trials, acute administration of clozapine did not affect any place cell properties, including those related to phase precession, in either control or MIA animals. Clozapine did, however, produce a reduction in locomotion speed, indicating that its presence had some effect on behaviour. These results help to constrain explanations of phase precession mechanisms and their potential role in sequence learning deficits.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Ratos , Animais , Clozapina/farmacologia , Potenciais de Ação/fisiologia , Hipocampo , Antipsicóticos/farmacologia , Esquizofrenia/tratamento farmacológico , Ritmo Teta/fisiologia
12.
Psychopharmacology (Berl) ; 240(8): 1667-1676, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37318540

RESUMO

RATIONALE: Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown. OBJECTIVE: To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this. METHOD: Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport. RESULTS: There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone. CONCLUSIONS: There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed.


Assuntos
Antipsicóticos , Transtorno Bipolar , Clozapina , Transtornos Psicóticos , Humanos , Transtorno Bipolar/tratamento farmacológico , Clozapina/farmacologia , Clozapina/uso terapêutico , Lítio , Transtornos Psicóticos/tratamento farmacológico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico
13.
J Psychopharmacol ; 37(10): 1023-1029, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37377097

RESUMO

BACKGROUND: Between 25% and 50% of patients suffering from treatment-resistant schizophrenia fail to achieve a clinical response with clozapine. The rapid identification and treatment of this subgroup of patients represents a challenge for healthcare practice. AIMS: To evaluate the relationship between metabolic alterations and the clinical response to clozapine. METHODS: A multicenter, observational, case-control study was performed. Patients diagnosed with schizophrenia treated with clozapine were eligible (minimum dose 400 mg/d for at least 8 weeks and/or clozapine plasma levels ⩾ 350 µg/mL). According to the Positive and Negative Syndrome Scale (PANSS) total score, patients were classified as clozapine-responsive (CR) (<80 points) or clozapine non-responsive (CNR) (⩾80 points). Groups were compared based on demographic and treatment-related characteristics, together with body mass index (BMI), waist circumference, insulin, leptin, and C-reactive protein plasma levels. Plasma levels of clozapine and its main metabolite, nor-clozapine, were measured in all the participants. In addition, the potential relationship between PANSS scores and leptin or insulin plasma levels was assessed. RESULTS: A total of 46 patients were included: 25 CR and 21 CNR. BMI and waist circumference, fasting insulin and leptin plasma levels were lower in the CNR group, while C-reactive protein was not different. Moreover, significant negative correlations were observed between PANSS positive and general psychopathology subscores, on one hand, and insulin and leptin plasma levels, on the other hand, as well as between PANSS negative subscores and leptin plasma levels. CONCLUSIONS: Our results suggest that the lack of metabolic effect induced by clozapine is associated with the lack of clinical response.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Clozapina/farmacologia , Esquizofrenia/metabolismo , Índice de Massa Corporal , Insulina , Antipsicóticos/uso terapêutico , Antipsicóticos/farmacologia , Leptina , Circunferência da Cintura , Estudos de Casos e Controles
14.
Behav Brain Res ; 452: 114553, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37352979

RESUMO

Designer receptors exclusively activated by designer drugs (DREADDs) are a promising tool for analyzing neural circuitry, and improved DREADD-selective ligands continue to be developed. Relative to clozapine-N-oxide (CNO), JHU37160 is a selective DREADD agonist recently shown to exhibit higher blood brain barrier penetrance and DREADD selectivity in vivo; however, relatively few studies have characterized the behavioral effects of systemic JHU37160 administration in animals. Here, we report a dose-dependent anxiogenic effect of systemic JHU37160 in male Wistar and Long-Evans rats, regardless of DREADD expression, with no impact on locomotor behavior. These results suggest that high dose (1 mg/kg) JHU37160 should be avoided when performing chemogenetic experiments designed to evaluate circuit manipulation on anxiety-like behavior in rats.


Assuntos
Barreira Hematoencefálica , Clozapina , Ratos , Masculino , Animais , Ratos Wistar , Ratos Long-Evans , Barreira Hematoencefálica/metabolismo , Clozapina/farmacologia
15.
Neuroimage ; 275: 120161, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37172662

RESUMO

The hierarchical characteristics of the brain are prominent in the pharmacological treatment of psychiatric diseases, primarily targeting cellular receptors that extend upward to intrinsic connectivity within a region, interregional connectivity, and, consequently, clinical observations such as an electroencephalogram (EEG). To understand the long-term effects of neuropharmacological intervention on neurobiological properties at different hierarchical levels, we explored long-term changes in neurobiological parameters of an N-methyl-D-aspartate canonical microcircuit model (CMM-NMDA) in the default mode network (DMN) and auditory hallucination network (AHN) using dynamic causal modeling of longitudinal EEG in clozapine-treated patients with schizophrenia. The neurobiological properties of the CMM-NMDA model associated with symptom improvement in schizophrenia were found across hierarchical levels, from a reduced membrane capacity of the deep pyramidal cell and intrinsic connectivity with the inhibitory population in DMN and intrinsic and extrinsic connectivity in AHN. The medication duration mainly affects the intrinsic connectivity and NMDA time constant in DMN. Virtual perturbation analysis specified the contribution of each parameter to the cross-spectral density (CSD) of the EEG, particularly intrinsic connectivity and membrane capacitances for CSD frequency shifts and progression. It further reveals that excitatory and inhibitory connectivity complements frequency-specific CSD changes, notably the alpha frequency band in DMN. Positive and negative synergistic interactions exist between neurobiological properties primarily within the same region in patients treated with clozapine. The current study shows how computational neuropharmacology helps explore the multiscale link between neurobiological properties and clinical observations and understand the long-term mechanism of neuropharmacological intervention reflected in clinical EEG.


Assuntos
Clozapina , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Clozapina/farmacologia , Clozapina/uso terapêutico , N-Metilaspartato , Neurofarmacologia , Encéfalo/diagnóstico por imagem , Eletroencefalografia , Alucinações , Mapeamento Encefálico , Imageamento por Ressonância Magnética , Rede Nervosa
16.
Int J Mol Sci ; 24(10)2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37240267

RESUMO

Packed with hemoglobin, an essential protein for oxygen transport, human erythrocytes are a suitable model system for testing the pleiotropic effects of lipophilic drugs. Our study investigated the interaction between antipsychotic drugs clozapine, ziprasidone, sertindole, and human hemoglobin under simulated physiological conditions. Analysis of protein fluorescence quenching at different temperatures and data obtained from the van't Hoff diagram and molecular docking indicate that the interactions are static and that the tetrameric human hemoglobin has one binding site for all drugs in the central cavity near αß interfaces and is dominantly mediated through hydrophobic forces. The association constants were lower-moderate strength (~104 M-1), the highest observed for clozapine (2.2 × 104 M-1 at 25 °C). The clozapine binding showed "friendly" effects: increased α-helical content, a higher melting point, and protein protection from free radical-mediated oxidation. On the other hand, bound ziprasidone and sertindole had a slightly pro-oxidative effect, increasing ferrihemoglobin content, a possible "foe". Since the interaction of proteins with drugs plays a vital role in their pharmacokinetic and pharmacodynamic properties, the physiological significance of the obtained findings is briefly discussed.


Assuntos
Antipsicóticos , Clozapina , Humanos , Antipsicóticos/farmacologia , Clozapina/farmacologia , Simulação de Acoplamento Molecular , Olanzapina , Benzodiazepinas
17.
Psychiatry Res ; 325: 115217, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37146461

RESUMO

Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR <0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.


Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia Resistente ao Tratamento , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Clozapina/farmacologia , Clozapina/uso terapêutico , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico
19.
Elife ; 122023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36892930

RESUMO

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remote control of targeted cell populations using chemical actuators that bind to modified receptors. Despite the popularity of DREADDs in neuroscience and sleep research, potential effects of the DREADD actuator clozapine-N-oxide (CNO) on sleep have never been systematically tested. Here, we show that intraperitoneal injections of commonly used CNO doses (1, 5, and 10 mg/kg) alter sleep in wild-type male laboratory mice. Using electroencephalography (EEG) and electromyography (EMG) to analyse sleep, we found a dose-dependent suppression of rapid eye movement (REM) sleep, changes in EEG spectral power during non-REM (NREM) sleep, and altered sleep architecture in a pattern previously reported for clozapine. Effects of CNO on sleep could arise from back-metabolism to clozapine or binding to endogenous neurotransmitter receptors. Interestingly, we found that the novel DREADD actuator, compound 21 (C21, 3 mg/kg), similarly modulates sleep despite a lack of back-metabolism to clozapine. Our results demonstrate that both CNO and C21 can modulate sleep of mice not expressing DREADD receptors. This implies that back-metabolism to clozapine is not the sole mechanism underlying side effects of chemogenetic actuators. Therefore, any chemogenetic experiment should include a DREADD-free control group injected with the same CNO, C21, or newly developed actuator. We suggest that electrophysiological sleep assessment could serve as a sensitive tool to test the biological inertness of novel chemogenetic actuators.


Scientists have developed ways to remotely turn on and off populations of neurons in the brain to test the role they play in behaviour. One technique that is frequently used is chemogenetics. In this approach, specific neurons are genetically modified to contain a special 'designer receptor' which switches cells on or off when its corresponding 'designer drug' is present. Recent studies have shown that the drug most commonly used in these experiments, clozapine-N-oxide (CNO), is broken down into small amounts of clozapine, an antipsychotic drug that binds to many natural receptors in the brain and modulates sleep. Nevertheless, CNO is still widely believed to not affect animals' sleep-wake patterns which in turn could influence a range of other brain activities and behaviours. However, there have been reports of animals lacking designer receptors still displaying unusual behaviours when administered CNO. This suggests that the breakdown of CNO to clozapine may cause off-target effects which could be skewing the results of chemogenetic studies. To investigate this possibility, Traut, Mengual et al. treated laboratory mice that do not have a designer receptor with three doses of CNO, and one dose of a new designer drug called compound-21 (C21) that is not broken down to clozapine. They found that high and medium doses of CNO, but also C21 altered the sleep-wake patterns of the mice and their brain activity during sleep. These findings show that CNO and C21 both have sleep-modulating effects on the brain and suggest that these effects are not only due to the production of clozapine, but the drugs binding to off-target natural receptors. To counteract this, Traut, Mengual et al. recommend optimizing the dose of drugs given to mice, and repeating the experiment on a control group which do not have the designer receptor. This will allow researchers to determine which behavioural changes are the result of turning on or off the neuron population of interest, and which are artefacts caused by the drug itself. They also suggest testing how newly developed designer drugs impact sleep before using them in behavioural experiments. Refining chemogenetic studies in these ways may yield more reliable insights about the role specific groups of cells have in the brain.


Assuntos
Clozapina , Camundongos , Masculino , Animais , Clozapina/farmacologia , Imidazóis , Sono , Óxidos
20.
Biomed Pharmacother ; 160: 114327, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36736280

RESUMO

The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A2AR-D2R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.


Assuntos
Antipsicóticos , Clozapina , Animais , Humanos , Dopamina , Clozapina/farmacologia , Antipsicóticos/farmacologia , Receptores de Dopamina D2/metabolismo , Aripiprazol , Adenosina/farmacologia , Mamíferos
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