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1.
J Clin Psychopharmacol ; 37(3): 310-314, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28353490

RESUMEN

PURPOSE: The present study aimed to assess the level of agreement between clinicians' routine assessments of medication status and plasma levels of commonly prescribed antipsychotic medications in patients presenting to an emergency room with an exacerbation of psychosis. METHODS: We studied 105 patients presenting to an emergency room and admitted to an inpatient psychiatric unit with a diagnosis of schizophrenia, schizoaffective disorder, bipolar I disorder, or psychotic disorder not otherwise specified and a prior outpatient medication regimen including risperidone, olanzapine, quetiapine, aripiprazole, or paliperidone. Plasma levels of antipsychotics were drawn and sent to a specialty laboratory for testing. FINDINGS: Of the 97 patients with usable samples, 33 (34%) were found to have therapeutic antipsychotic levels. Of these, 22 were judged by emergency room staff to be taking their medications at the appropriately prescribed doses, whereas 11 were judged not to be taking medication at all. Sixty-four patients were found to have subtherapeutic antipsychotic levels, 31 of whom had been assessed to be taking medication as prescribed. Emergency assessment of medication status predicted therapeutic and nontherapeutic antipsychotic levels at rates of 41.5% and 75%, respectively. Emergency staff assessment was statistically independent from the likelihood of having a therapeutic antipsychotic level. IMPLICATIONS: In patients presenting to emergency rooms with exacerbations of psychosis who are subsequently admitted to an inpatient facility, common assessments of medication status are frequently misleading. Readily available methods for rapidly measuring antipsychotic plasma levels in clinical settings are needed for clinicians to make reliable assessments.


Asunto(s)
Antipsicóticos/sangre , Trastorno Bipolar/tratamiento farmacológico , Monitoreo de Drogas/normas , Servicio de Urgencia en Hospital , Cumplimiento de la Medicación , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Anciano , Servicio de Urgencia en Hospital/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Admisión del Paciente , Servicio de Psiquiatría en Hospital , Trastornos Psicóticos/sangre , Esquizofrenia/sangre , Adulto Joven
2.
Neurochem Res ; 41(1-2): 398-408, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26857796

RESUMEN

Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol(®)) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor NaB (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be determined, overall it supports continued glutamatergic drug development.


Asunto(s)
D-Aminoácido Oxidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Modelos Animales , Fenciclidina/administración & dosificación , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Cuerpo Estriado/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Serina/sangre , Serina/metabolismo , Serina/farmacología
3.
Int J Neuropsychopharmacol ; 14(5): 691-6, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20875221

RESUMEN

This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high distress.


Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Animales , Antidepresivos/administración & dosificación , Antidepresivos/uso terapéutico , Encéfalo/efectos de los fármacos , Desipramina/administración & dosificación , Desipramina/farmacología , Desipramina/uso terapéutico , Inyecciones , Inyecciones Intraventriculares , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Natación , Factores de Tiempo
4.
J Pharmacol Exp Ther ; 332(1): 266-73, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19828877

RESUMEN

Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2'-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity.


Asunto(s)
Antidepresivos de Segunda Generación , Encéfalo/efectos de los fármacos , Fluoxetina , Plasticidad Neuronal/efectos de los fármacos , Caracteres Sexuales , Animales , Antidepresivos de Segunda Generación/administración & dosificación , Antidepresivos de Segunda Generación/farmacocinética , Antidepresivos de Segunda Generación/farmacología , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Fluoxetina/administración & dosificación , Fluoxetina/farmacocinética , Fluoxetina/farmacología , Masculino , Ratones , Ratones Endogámicos , Factores de Tiempo
5.
J Psychiatr Res ; 120: 103-112, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31654971

RESUMEN

Major depressive disorder (MDD) is common, often under-treated and a leading cause of disability and mortality worldwide. The causes of MDD remain unclear, including the role of the endocannabinoid system. Intriguingly, the prevalence of depression is significantly greater in women than men. In this study we examined the role of endocannabinoids in depressive behavior. The levels of endocannabinoids, N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured along with brain derived neurotrophic factor (BDNF) in postmortem ventral striata of female patients with MDD and non-psychiatric controls, and in Wistar Kyoto (WKY) rat, a selectively inbred strain of rat widely used for testing the depressive behavior. The effect of pharmacological elevation of endocannabinoids through inhibition of their catabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacyl glycerol lipase [MAGL]) on depressive-like phenotype was also assessed in WKY rat. The findings showed lower levels of endocannabinoids and BDNF in the ventral striata of MDD patients and WKY rats. A dual inhibitor of FAAH and MAGL, JZL195, elevated the endocannabinoids and BDNF levels in ventral striatum, and reduced the depressive-like phenotype in female WKY rats. Collectively, our study suggests a blunted ventral striatal endocannabinoid and BDNF signaling in depressive behavior and concludes that endocannabinoid enhancing agents may have an antidepressant effect.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Estriado Ventral/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Carbamatos/farmacología , Modelos Animales de Enfermedad , Femenino , Piperazinas/farmacología , Ratas , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos
6.
Psychopharmacology (Berl) ; 237(2): 519-527, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31773210

RESUMEN

RATIONALE: F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917-1924, 2019). OBJECTIVE: This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [11C]-(+)-PHNO. METHODS: PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC50) calculated. RESULTS: Both doses of F17464 robustly blocked [11C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h post-administration, which increased at 6-9 h (89-98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%). F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC50 was 19 ng ml-1 (~ 40 nM). CONCLUSION: Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.


Asunto(s)
Antipsicóticos/metabolismo , Encéfalo/metabolismo , Radioisótopos de Carbono/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Adulto , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Encéfalo/efectos de los fármacos , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Receptores de Dopamina D3/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo
7.
JAMA Netw Open ; 3(8): e2013211, 2020 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-32785636

RESUMEN

Importance: A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective: To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants: This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention: Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures: Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results: A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only (t5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. Conclusions and Relevance: In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. Trial Registration: ClinicalTrials.gov Identifier: NCT01558063.


Asunto(s)
Antidepresivos/administración & dosificación , Trastorno Depresivo Mayor , Ácido Glutámico/metabolismo , Ketamina/administración & dosificación , Ácido gamma-Aminobutírico/metabolismo , Adulto , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/diagnóstico por imagen , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Femenino , Humanos , Ketamina/efectos adversos , Ketamina/farmacocinética , Ketamina/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/metabolismo
8.
Neurology ; 95(19): e2658-e2665, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-32913021

RESUMEN

OBJECTIVE: To determine whether treatment with escitalopram compared with placebo would lower CSF ß-amyloid 42 (Aß42) levels. RATIONALE: Serotonin signaling suppresses Aß42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram. METHODS: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aß42 was used as the primary outcome in subsequent analyses. RESULTS: An overall 9.4% greater reduction in CSF Aß42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aß status (CSF Aß42 levels <250 pg/mL) was associated with smaller Aß42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aß42 levels >250 pg/mL). CONCLUSIONS: Short-term longitudinal doses of escitalopram decreased CSF Aß42 in cognitively normal older adults, the target group for AD prevention. CLINICALTRIALSGOV IDENTIFIER: NCT02161458. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aß42.


Asunto(s)
Péptidos beta-Amiloides/líquido cefalorraquídeo , Citalopram/administración & dosificación , Duración de la Terapia , Fragmentos de Péptidos/líquido cefalorraquídeo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/efectos de los fármacos , Citalopram/farmacología , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/efectos de los fármacos , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología
9.
Neuropsychopharmacology ; 45(9): 1545-1556, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32417852

RESUMEN

Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice.


Asunto(s)
Ketamina , Animales , Fenómenos Electrofisiológicos , Femenino , Hipocampo/metabolismo , Ketamina/análogos & derivados , Ketamina/farmacología , Masculino , Ratones , Receptores de N-Metil-D-Aspartato/metabolismo
10.
J Psychiatr Res ; 117: 129-134, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31415914

RESUMEN

Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but side effects and abuse potential limit its use. Understanding its mechanism of action could help develop analogous but safer drugs. This post hoc study explored relationships of ketamine and metabolites, including hydroxynorketamine enantiomers, (2S,6S)- and (2R,6R)-HNK, to clinical response in a subgroup from a published trial in suicidal depression. Depressed adults with clinically significant suicidal ideation were randomized to double-blind infusion of sub-anesthetic ketamine or midazolam. Ketamine and metabolites were measured after infusion (N = 53). Plasma (2R,6R)-HNK was associated with change (higher levels correlated with less clinical improvement) from baseline to 24 h post-infusion of depression (HDRS-24: Spearman r = 0.37, p = 0.009) and suicidal thoughts (SSI: Spearman r = 0.29, p = 0.041). There were similar correlations with weekly follow-up clinical rating scores for both HNK enantiomers and dehydronorketamine (DHNK). Ketamine and norketamine were not associated with change in depression or suicidal ideation (unadjusted p > 0.28).


Asunto(s)
Antidepresivos/sangre , Trastorno Depresivo Mayor/tratamiento farmacológico , Ketamina/sangre , Evaluación de Resultado en la Atención de Salud , Ideación Suicida , Adulto , Ansiolíticos/farmacología , Antidepresivos/administración & dosificación , Método Doble Ciego , Humanos , Infusiones Parenterales , Ketamina/administración & dosificación , Ketamina/análogos & derivados , Midazolam/farmacología , Proyectos Piloto , Índice de Severidad de la Enfermedad
11.
Biol Psychiatry ; 86(7): 523-535, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31279534

RESUMEN

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.


Asunto(s)
Trastornos Psicóticos Afectivos/genética , Glicinérgicos/farmacología , Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina/farmacología , Trastornos Psicóticos/genética , Psicotrópicos/farmacología , Receptores de N-Metil-D-Aspartato , Adulto , Variaciones en el Número de Copia de ADN , Método Doble Ciego , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Glicina/administración & dosificación , Glicinérgicos/administración & dosificación , Humanos , Masculino , Prueba de Estudio Conceptual , Psicotrópicos/administración & dosificación , Distribución Aleatoria , Estudios de Casos Únicos como Asunto
12.
Neuropharmacology ; 131: 200-208, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29109060

RESUMEN

Binge alcohol (ethanol) drinking is associated with profound adverse effects on our health and society. Rimonabant (SR141716A), a CB1 receptor inverse agonist, was previously shown to be effective for nicotine cessation and obesity. However, studies using rimonabant were discontinued as it was associated with an increased risk of depression and anxiety. In the present study, we examined the pharmacokinetics and effects of AM4113, a novel CB1 receptor neutral antagonist on binge-like ethanol drinking in C57BL/6J mice using a two-bottle choice drinking-in-dark (DID) paradigm. The results indicated a slower elimination of AM4113 in the brain than in plasma. AM4113 suppressed ethanol consumption and preference without having significant effects on body weight, ambulatory activity, preference for tastants (saccharin and quinine) and ethanol metabolism. AM4113 pretreatment reduced ethanol-induced increase in dopamine release in nucleus accumbens. Collectively, these data suggest an important role of CB1 receptor-mediated regulation of binge-like ethanol consumption and mesolimbic dopaminergic signaling, and further points to the potential utility of CB1 neutral antagonists for the treatment of binge ethanol drinking.


Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Antagonistas de Receptores de Cannabinoides/uso terapéutico , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/efectos de los fármacos , Consumo de Bebidas Alcohólicas/metabolismo , Análisis de Varianza , Animales , Antagonistas de Receptores de Cannabinoides/farmacología , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Etanol/sangre , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microdiálisis , Núcleo Accumbens/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/uso terapéutico
13.
Behav Brain Res ; 332: 172-179, 2017 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-28587819

RESUMEN

Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/- and alpha2-/- mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8mg/kg fluoxetine or 53mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/- mice. Surprisingly, 4mg/kg fluoxetine had anxiogenic-like effects in alpha2+/- mice increasing latency to bite and to eat while 8mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/- mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2-/- mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2-/- mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2-containing GABAA-Rs in the response to serotonin-selective antidepressants.


Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Antidepresivos/farmacología , Desipramina/farmacología , Fluoxetina/farmacología , Receptores de GABA-A/deficiencia , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores de Captación Adrenérgica/sangre , Animales , Antidepresivos/sangre , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Desipramina/sangre , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Fluoxetina/análogos & derivados , Fluoxetina/sangre , Masculino , Ratones de la Cepa 129 , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fenotipo , Receptores de GABA-A/genética , Inhibidores Selectivos de la Recaptación de Serotonina/sangre
14.
Neuropsychopharmacology ; 31(9): 1864-8, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16319911

RESUMEN

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.


Asunto(s)
Antipsicóticos/administración & dosificación , Antipsicóticos/toxicidad , Discinesia Inducida por Medicamentos/psicología , Risperidona/administración & dosificación , Risperidona/toxicidad , Animales , Antipsicóticos/sangre , Relación Dosis-Respuesta a Droga , Haloperidol/administración & dosificación , Haloperidol/sangre , Haloperidol/toxicidad , Masculino , Ratas , Ratas Sprague-Dawley , Risperidona/sangre , Conducta Estereotipada/efectos de los fármacos
15.
Am J Psychiatry ; 162(6): 1165-70, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15932816

RESUMEN

OBJECTIVE: In a platelet/endothelial biomarker substudy of the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART), the authors sought to determine whether plasma levels of sertraline and its primary metabolite N-desmethylsertraline affect the release of platelet/endothelial biomarkers. METHOD: Fifty-five acute coronary syndrome patients with depression were randomly assigned to receive sertraline (N=23) or placebo (N=32). Twenty-six serial plasma samples collected at week 6 (N=12) and week 16 (N=14) were analyzed. Platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), platelet/endothelial cell adhesion molecule 1 (PECAM-1), P-selectin, thromboxane B(2) (TxB(2)), prostacyclin (6-keto-PGF1alpha), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin were measured by enzyme-linked immunosorbent assay. Concentrations of sertraline and N-desmethylsertraline were determined by liquid chromatography with fluorescence detection in autologous samples. RESULTS: Strong, mostly time-dependent negative correlations were found for the plasma levels of sertraline and N-desmethylsertraline with PF4 (week 6: r=-0.69 and -0.33, respectively; week 16: r=-0.63 for both), beta-TG (week 6: r=-0.43 and -0.29; week 16: r=-0.66 and -0.57), PECAM-1 (week 6: r=-0.82 and -0.49; week 16: r=-0.60 for both), P-selectin (week 6: r=-0.82 and -0.49; week 16: r=-0.73 and -0.43), and TxB(2) (week 6: r=-0.66 and -0.59; and week 16: r=-0.64 and -0.41). Regression analysis revealed some borderline correlations for endothelial markers such as 6-keto- PGF1alpha and E-selectin and a positive correlation for VCAM-1. CONCLUSIONS: This is the first documented evidence that plasma release of platelet/endothelial biomarkers is directly related to the levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. The clinical significance of these findings should be assessed in the setting of a randomized clinical trial.


Asunto(s)
Biomarcadores/sangre , Plaquetas/efectos de los fármacos , Enfermedad Coronaria/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sertralina/análogos & derivados , Sertralina/sangre , Sertralina/uso terapéutico , Biomarcadores/metabolismo , Plaquetas/metabolismo , Enfermedad Coronaria/metabolismo , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sertralina/farmacología
16.
Biol Psychiatry ; 53(6): 543-53, 2003 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-12644360

RESUMEN

BACKGROUND: Reports relating phenylalanine kinetics and metabolism to psychiatric disorders led us to undertake the comprehensive screening of the phenylalanine hydroxylase (PAH) coding region and functional testing of discovered mutations in a sample of psychiatric patients and healthy control subjects. METHODS: Genomic DNA from psychiatric patients and control subjects was assayed for sequence variants in all PAH coding regions and splice junctions. In vivo functional analysis of mutations was conducted by assessing the kinetics and conversion to tyrosine of a standardized phenylalanine dose and by measuring fasting pterin levels. RESULTS: A known missense mutation was observed in a schizoaffective subject, and a novel missense mutation was discovered in four subjects with schizophrenia and one normal subject. The schizoaffective patient heterozygous for the known A403V mutation showed the lowest rate of phenylalanine kinetics and lowest conversion to tyrosine in the patient sample. The four schizophrenic patients heterozygous for the novel K274E mutation showed significantly decreased phenylalanine kinetics, reduced conversion to tyrosine, and increased synthesis of the PAH cofactor tetrahydrobiopterin compared with schizophrenic subjects without the mutation. CONCLUSIONS: The study findings suggest that larger scale studies are warranted to test the relationship of the PAH genotype with a psychiatric phenotype.


Asunto(s)
Expresión Génica/genética , Tamizaje Masivo , Mutación Missense/genética , Fenilalanina Hidroxilasa/genética , Trastornos Psicóticos , Esquizofrenia , Adulto , Análisis Mutacional de ADN , Femenino , Variación Genética , Genotipo , Humanos , Masculino , Fenotipo , Reacción en Cadena de la Polimerasa , Polimorfismo Genético/genética , Trastornos Psicóticos/enzimología , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/genética , Pterinas/sangre , Esquizofrenia/enzimología , Esquizofrenia/epidemiología , Esquizofrenia/genética
17.
Am J Psychiatry ; 160(6): 1117-24, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12777270

RESUMEN

OBJECTIVE: The efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men with psychiatric disorders was tested. METHOD: Public-sector psychiatric patients with long histories of antipsychotic treatment and presumably long-standing tardive dyskinesia were randomly assigned to receive branched-chain amino acids or placebo. Treatment frequency was three times a day, 7 days a week for 3 weeks. The efficacy measure was a frequency count of videotaped tardive dyskinesia movements. RESULTS: A robust and highly significant difference was observed between patients who received high-dose branched-chain amino acids (222 mg/kg of body weight t.i.d.) (N=18) and those who received placebo (N=18) in the percent change in tardive dyskinesia symptoms from baseline to the end of the 3-week trial. Significant and marked differences were seen between the two groups at the >/=30% and >/=60% levels of decrease in tardive dyskinesia symptoms. No clinically significant differences were seen between the pre- and posttrial results of physical examinations and laboratory screening tests. Minimal gastrointestinal symptoms occurred during the trial. The reduction in tardive dyskinesia symptoms in the amino acids group was not related to changes in antipsychotic and glucose plasma levels. A mechanism of response related to decreased amine neurotransmitter synthesis was suggested by the significant positive correlations observed between decreases in tardive dyskinesia symptoms and decreases in aromatic amino acid plasma concentrations over the course of the trial. CONCLUSIONS: Branched-chain amino acids constitute a novel, safe treatment for tardive dyskinesia, with a strong potential for providing significant improvement in the diseased physiognomy of the afflicted person.


Asunto(s)
Aminoácidos de Cadena Ramificada/uso terapéutico , Antipsicóticos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Adulto , Aminoácidos Aromáticos/sangre , Aminoácidos de Cadena Ramificada/administración & dosificación , Aminoácidos de Cadena Ramificada/sangre , Antipsicóticos/sangre , Antipsicóticos/uso terapéutico , Glucemia/análisis , Esquema de Medicación , Discinesia Inducida por Medicamentos/sangre , Discinesia Inducida por Medicamentos/diagnóstico , Humanos , Masculino , Trastornos Mentales/sangre , Persona de Mediana Edad , Examen Físico , Placebos , Factores Sexuales , Resultado del Tratamiento , Grabación de Cinta de Video
18.
Neuromolecular Med ; 3(2): 95-104, 2003.
Artículo en Inglés | MEDLINE | ID: mdl-12728192

RESUMEN

N-acetyl-L-aspartate (NAA) is present in the vertebrate brain, where its concentration is one of the highest of all free amino acids. Although NAA is synthesized and stored primarily in neurons, it is not hydrolyzed in these cells. However, after its regulated release into extracellular fluid, neuronal NAA is hydrolyzed by amidohydrolase II that is present in oligodendrocytes. About 30% of neurons do not contain appreciable amounts of NAA, but its prominence in 1H nuclear magnetic resonance spectroscopic (MRS) studies has led to its wide use as a neuronal marker in diagnostic human medicine as both an indicator of brain pathology, and of disease progression in a variety of central nervous system (CNS) diseases. Loss of NAA has been interpreted as indicating either loss of neurons, or loss of neuron viability. In this investigation, the upregulation of NAA in early stages of construction of the CNS, and its downregulation in experimentally induced damage models of the CNS is reported. The results of this study indicate that the buildup of NAA is not required for viability of neurons in monocellular cultures, and that NAA is lost from multicellular cultured brain slice explants that contain viable neurons. Thus, loss of NAA does not necessarily indicate either loss of neurons or their function. The NAA system, when present in the brain, appears to reflect a high degree of cellular integration, and therefore may be a unique metabolic construct of the intact vertebrate brain.


Asunto(s)
Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encefalopatías/metabolismo , Encéfalo/metabolismo , Regulación hacia Abajo/fisiología , Neuronas/metabolismo , Equilibrio Hidroelectrolítico/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Biomarcadores , Encéfalo/fisiopatología , Encefalopatías/fisiopatología , Supervivencia Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Feto , Ratones , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Neuroglía/metabolismo , Técnicas de Cultivo de Órganos , Ratas , Sinaptofisina/metabolismo
19.
Artículo en Inglés | MEDLINE | ID: mdl-14670738

RESUMEN

A liquid chromatographic procedure was developed for the determination of a new antipsychotic agent ziprasidone in plasma using fluorescence detection. A one-step liquid-liquid extraction from 1 ml of alkalinized plasma containing an internal standard alpha-ergocryptine using methyl-t-butyl ether afforded a greater than 84% recovery of ziprasidone. Chromatography was performed using a reversed-phase trimethylsilyl bonded silica column with a mobile phase of 72:28 phosphate buffer:acetonitrile at a flow rate of 1.5 ml/min. Detection of the eluted peaks was observed using excitation and emission wavelengths of 320 and 410 nm, respectively. Chromatographic run time did not exceed 14 min with no interference from endogenous material. The calibration curve was linear over the concentration range of 0.5 to 200 ng/ml and the inter- and intra-assay imprecision (CV) was less than 10%. The lower limit of quantitation was assessed at 0.5 ng/ml. Specificity of the method is demonstrated by the lack of interference from a large number of commonly used drugs and their metabolites in clinical use. The utility of the method is exemplified with the presentation of clinical data from patients receiving ziprasidone.


Asunto(s)
Antipsicóticos/sangre , Cromatografía Liquida/métodos , Piperazinas/sangre , Espectrometría de Fluorescencia/métodos , Tiazoles/sangre , Calibración , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
20.
Artículo en Inglés | MEDLINE | ID: mdl-12031840

RESUMEN

A rapid gas chromatography-mass spectrometric method for the determination of nalmefene in human plasma is described. The procedure involves protein precipitation, extraction with ethanol-chloroform mixture and derivatization with pentafluropropionic anhydride. The deuterated analog of nalmefene, 6beta-naltrexol-d(7), was used as the internal standard. Quantitation was achieved on a HP-1 column (12 mx0.2 mm I.D.) with negative chemical ionization (NCI) using methane:ammonia (95:5) as the reagent gas. The standard curves were fitted using a quadratic equation with the curve encompassing a range of 0.5 to 200 ng/ml, and the intra- and inter-assay variations for three different nalmefene levels were less than 10% throughout. The limit of quantitation was found to be 0.5 ng/ml. The method described is highly specific and reproducible, and could also be applied for the determination of naltrexone and 6beta-naltrexol. Application of the method to actual human plasma samples is demonstrated.


Asunto(s)
Cromatografía de Gases y Espectrometría de Masas/métodos , Naltrexona/análogos & derivados , Naltrexona/sangre , Antagonistas de Narcóticos/sangre , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
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