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1.
BMJ Case Rep ; 12(8)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31383672

RESUMO

Sexual side-effects are common among those using antipsychotic medication and may result in poor compliance and reduced quality of life. Retrograde ejaculation (RE) has been described occurring with a number of antipsychotic medications (thioridazine, risperidone, iloperidone and clozapine) but there are no guidelines regarding management of antipsychotic-associated RE. Imipramine has been suggested as a treatment for antipsychotic-associated RE in one small study of patients prescribed thioridazine and a case series of patients prescribed iloperidone. Quetiapine is a commonly used antipsychotic and is thought to be associated with less sexual side-effects relative to other antipsychotic medications. This case report describes a 25-year-old man with first episode psychosis who developed RE during treatment with quetiapine which improved with low-dose imipramine. This is the first description of RE occurring with quetiapine and successful treatment of quetiapine-associated RE with imipramine.


Assuntos
Antipsicóticos/efeitos adversos , Imipramina/administração & dosagem , Ejaculação Precoce/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Fumarato de Quetiapina/efeitos adversos , Adulto , Ejaculação/efeitos dos fármacos , Humanos , Masculino , Ejaculação Precoce/induzido quimicamente , Resultado do Tratamento
2.
Iran J Kidney Dis ; 13(4): 257-261, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31422392

RESUMO

INTRODUCTION: Nocturnal enuresis is a condition, which can affectthe quality of life in children. The present study was designed toinvestigate the efficacy of low-dose imipramine combined withdesmopressin on treatment of patients with primary nocturnalenuresis who were defined as desmopressin non-responders. METHODS: A randomized clinical trial was carried out on patientswith primary nocturnal enuresis. Forty children with enuresisranging from 5 to 12 years old were randomly divided into theintervention (n = 20) and control groups (n = 20). The subjects inthe intervention group were treated with desmopressin combinedwith 5 mg imipramine at bedtime, and those in the control groupwere given desmopressin alone. The patients were followed upweekly for one month. The number of wet nights was recorded. RESULTS: Two individuals in the intervention and three individualsin the control group were excluded from the study. Our findingsindicated that the age and gender showed no significant difference.Furthermore, a significant better recovery in the enuresis wasobserved in 18 of 20 patients who were treated with combinationtherapy after 1 month (P < .05). In addition, the frequency ofrecovery was significantly higher (83.3%) in the intervention group,compared with the control group (29.4%). CONCLUSION: The analysis showed that low-dose imipramine is welltolerated in clinical practice and may represent a good short-termtreatment option in combination therapy where desmopressinalone is not efficient enough.


Assuntos
Antidiuréticos/administração & dosagem , Desamino Arginina Vasopressina/administração & dosagem , Imipramina/administração & dosagem , Enurese Noturna/tratamento farmacológico , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Masculino , Resultado do Tratamento
3.
Zebrafish ; 16(5): 443-450, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31436486

RESUMO

The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear reduction; as such, drugs that reduce or increase fear or anxiety states should alter inhibitory avoidance (IA) acquisition. The present experiment used white spaces as aversive unconditioned stimuli in IA in zebrafish. Adult zebrafishes were tested in three experiments: validation of white compartment as aversive in IA; open field test; and effect of antidepressant (fluoxetine, imipramine) and anxiolytic (diazepam, clonazepam). The data show the effectiveness of the white compartment as an aversive stimulus in IA. Antidepressant fluoxetine did not alter and imipramine impairs avoidance acquisition in higher doses. Imipramine also produced a sedative effect in lower doses. Anxiolytic and stimulant drugs facilitated learning at doses which did not impair locomotion, suggesting that pharmacological manipulation of other factors in addition to fear/anxiety can impact aversive learning in zebrafish.


Assuntos
Antidepressivos Tricíclicos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Fluoxetina/farmacologia , Imipramina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Antidepressivos Tricíclicos/administração & dosagem , Feminino , Fluoxetina/administração & dosagem , Imipramina/administração & dosagem , Masculino , Aprendizagem em Labirinto , Inibidores de Captação de Serotonina/administração & dosagem , Peixe-Zebra/fisiologia
4.
Acta Neuropsychiatr ; 31(5): 258-265, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230597

RESUMO

OBJECTIVES: Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with Adrenocorticotropic hormone (ACTH) appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate receptor in ACTH-treated animals. METHODS: Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 µg/0.1 ml/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out. RESULTS: We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment. CONCLUSION: The present data confirm development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment-resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Imipramina/uso terapêutico , Ketamina/uso terapêutico , Oligopeptídeos/uso terapêutico , Hormônio Adrenocorticotrópico/sangue , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Transtorno Depressivo Resistente a Tratamento/sangue , Modelos Animais de Doenças , Imipramina/administração & dosagem , Ketamina/administração & dosagem , Masculino , Oligopeptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Natação , Resultado do Tratamento
5.
Psychopharmacology (Berl) ; 236(11): 3125-3133, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31069424

RESUMO

RATIONALE: Some antidepressants have been previously found to produce anti-parkinsonian effect; nicotine was known to mitigate experimental neurotoxic lesions. The anticataleptic efficacy of antidepressant-nicotine co-administration is unstudied. OBJECTIVES: This work aimed to evaluate anticataleptic action of imipramine-nicotine combination in rotenone model. METHODS: Catalepsy was measured by the bar test. Concentrations of tyrosine hydroxylase, dopamine, and DOPAC were determined in the substantia nigra and dorsal striatum using ELISA and HPLC techniques; additionally, dopamine/DOPAC ratio was calculated for both areas. RESULTS: Imipramine and nicotine alone were ineffective; however, co-administration of the drugs significantly (p < 0.01) inhibited rotenone-induced catalepsy and mitigated neurochemical changes in the nigrostriatal system. Anticataleptic effect of the combination exceeded that of levodopa, a standard drug for anti-parkinsonian treatment. CONCLUSION: The combined use of imipramine and nicotine at relatively low doses inhibits neurotoxin-induced catalepsy and nigrostriatal neurochemical changes. The co-administration of these drugs might be a new approach to the treatment of extrapyramidal dysfunctions.


Assuntos
Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Imipramina/administração & dosagem , Nicotina/administração & dosagem , Rotenona/toxicidade , Inibidores da Captação Adrenérgica/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Relação Dose-Resposta a Droga , Inseticidas/toxicidade , Masculino , Agonistas Nicotínicos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/fisiologia
6.
J Clin Psychopharmacol ; 39(3): 254-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30925498

RESUMO

PURPOSE/BACKGROUND: According to available international clinical guides, tricyclic antidepressants are our first- or second-line treatment of choice for severe unipolar major depression. However, the therapeutic option after an unsuccessful response to a tricyclic antidepressant drug in unipolar major depression is still unclear. METHODS/PROCEDURES: This 10-week randomized open-label study assessed the effectiveness of add-on lithium (adjusted to plasma levels) compared with add-on citalopram (30 mg/d) in 104 severe unipolar major depressive patients after a 10-week unsuccessful imipramine (adjusted to plasma level). Efficacy analyses examined changes in the severity of depression symptoms from baseline visit to endpoint and the comparative remission rate between treatment subgroups. FINDINGS/RESULTS: The randomized sample consisted of 104 imipramine-resistant severe unipolar major depressed patients. Both, the percentage of remitters (40.4% vs 21.1%, P = 0.034) and the mean reduction of the Hamilton Depression Rating Scale score (58.8% vs 42.5%, P = 0.005) were significantly greater in the add-on citalopram subgroup at endpoint visit. IMPLICATIONS/CONCLUSIONS: Although we should be cautious about generalizing these results to patients with a less severe unipolar major episode, results from the present study suggest that add-on citalopram is a very effective treatment option in unipolar major depressive episodes after an unsuccessful imipramine regimen.


Assuntos
Citalopram/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Imipramina/administração & dosagem , Compostos de Lítio/administração & dosagem , Adulto , Idoso , Antidepressivos/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Transtorno Depressivo Maior/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
7.
Nutrients ; 11(3)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866491

RESUMO

Maternal hypercaloric exposure during pregnancy and lactation is a risk factor for developing diseases associated with inflammation such as obesity, diabetes and, neurological diseases in the offspring. Neuroinflammation might modulate neuronal activation and flavonoids are dietary compounds that have been proven to exert anti-inflammatory properties. Thus, the aim of the present study is to evaluate the effect of maternal supplementation with flavonoids (kaempferol-3-O-glucoside and narirutin) on the prevention of depression-like behaviour in the female offspring of dams fed with an obesogenic diet during the perinatal period. Maternal programming was induced by high fat (HFD), high sugar (HSD), or cafeteria diets exposure and depressive like-behaviour, referred to as swimming, climbing, and immobility events, was evaluated around postnatal day 56⁻60 before and after 30 mg/kg i.p. imipramine administration in the female offspring groups. Central inflammation was analyzed by measuring the TANK binding kinase 1 (TBK1) expression. We found that the offspring of mothers exposed to HSD programming failed to show the expected antidepressant effect of imipramine. Also, imipramine injection, to the offspring of mothers exposed to cafeteria diet, displayed a pro-depressive like-behaviour phenotype. However, dietary supplementation with flavonoids reverted the depression-like behaviour in the female offspring. Finally, we found that HSD programming increases the TBK1 inflammatory protein marker in the hippocampus. Our data suggest that maternal HSD programming disrupts the antidepressant effect of imipramine whereas cafeteria diet exposure leads to depressive-like behaviour in female offspring, which is reverted by maternal flavonoid supplementation.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/metabolismo , Flavonoides/farmacologia , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Antidepressivos/administração & dosagem , Dieta , Dissacarídeos/administração & dosagem , Dissacarídeos/farmacologia , Interações de Medicamentos , Feminino , Flavanonas/administração & dosagem , Flavanonas/farmacologia , Flavonoides/administração & dosagem , Imipramina/administração & dosagem , Imipramina/farmacologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Quempferóis/administração & dosagem , Quempferóis/farmacologia , Masculino , Monossacarídeos/administração & dosagem , Monossacarídeos/farmacologia , Gravidez , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Wistar
8.
Lancet Gastroenterol Hepatol ; 3(12): 837-844, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30361080

RESUMO

BACKGROUND: Guidelines recommend the use of neuromodulators in patients with functional dyspepsia not responding to proton pump inhibitors (PPIs) and prokinetics; however, there is a lack of data from randomised controlled trials supporting their use. We aimed to assess the safety and efficacy of imipramine, a tricyclic antidepressant (TCA), in treatment-refractory functional dyspepsia. METHODS: In this single-centre, double-blind, randomised controlled trial, we enrolled consecutive patients with Rome II functional dyspepsia aged 18-80 years. Eligible patients were Helicobacter pylori-negative, had a normal upper gastrointestinal endoscopy and abdominal ultrasound, and remained symptomatic after open-label treatment with 8 weeks of esomeprazole and 4 weeks of domperidone. Patients completed questionnaires assessing dyspepsia symptoms, mood, and insomnia, and were then randomly assigned (1:1) via a computer-generated list of random numbers to receive imipramine (at a dose of 25 mg once nightly for the first 2 weeks, and then 50 mg thereafter) or placebo for 12 weeks. The primary endpoint was overall satisfactory relief of global dyspepsia symptoms at 12 weeks, via patient-reported assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00164775, and is completed. FINDINGS: Between Sept 11, 2005, and Aug 20, 2010, 107 patients with treatment-refractory functional dyspepsia were randomly assigned to receive imipramine (n=55) or placebo (n=52). Relief of global dyspepsia symptoms at 12 weeks occurred in 35 (63·6%, 95% CI 50·4-75·1) of 55 patients on imipramine compared with 19 (36·5%, 95% CI 24·8-50·1) of 52 on placebo (p=0·0051). Ten (18%) patients on imipramine discontinued the study due to adverse events (three dry mouth, two constipation, two drowsiness, and one each insomnia, palpitations, and blurred vision), compared with four (8%) on placebo (one dry mouth and constipation, and one each palpitations, worsening of gastro-oesophageal reflux, and limb paraesthesia). There were no serious adverse events. INTERPRETATION: Low-dose imipramine should be considered as a possible therapy for patients with functional dyspepsia refractory to both PPIs and prokinetics, although patients should be cautioned about the adverse event profile. FUNDING: None.


Assuntos
Dispepsia/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Imipramina/administração & dosagem , Adulto , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/efeitos adversos , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Imipramina/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/tratamento farmacológico , Uso Off-Label , Resultado do Tratamento
9.
J Psychopharmacol ; 32(10): 1133-1140, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30182787

RESUMO

BACKGROUND: A significant proportion of depressed patients fail to respond to treatment with antidepressant drugs. Such patients might nonetheless respond to deep brain stimulation of the prefrontal cortex. Deep brain stimulation has also been shown to normalize behaviour in the chronic mild stress (CMS) model of depression. However, these studies have involved animals that are in general treatment responsive. Thus, this is not the ideal situation in which to investigate how deep brain stimulation is effective where antidepressant drugs are not. AIMS: Here, we studied the behavioural effects of deep brain stimulation in treatment-resistant animals. METHODS: Wistar rats were exposed to chronic mild stress and concurrent treatment with saline or one of three antidepressant drugs, imipramine, citalopram and venlafaxine. Individuals were selected from the CMS-exposed drug-treated groups that had failed to increase their sucrose intake by week 5 of drug treatment. All animals were then implanted with deep brain stimulation electrodes in the ventro-medial prefrontal cortex, and tested for sucrose intake and in the elevated plus maze and novel object recognition test, following 2 × 2 h of deep brain stimulation. RESULTS: The selected drug-treated animals were found to be antidepressant-resistant in all three tests. With a single exception (sucrose intake in imipramine-treated animals), deep brain stimulation reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all four conditions, with no significant differences between saline- and drug-treated animals. CONCLUSIONS: These data provide a proof of principle that deep brain stimulation of the prefrontal cortex can be effective in a rat model of resistance to chronic antidepressant treatment, replicating the clinical effect of deep brain stimulation in treatment-resistant depression.


Assuntos
Comportamento Animal/fisiologia , Estimulação Encefálica Profunda/métodos , Transtorno Depressivo Resistente a Tratamento/terapia , Estresse Psicológico/terapia , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Citalopram/administração & dosagem , Citalopram/farmacologia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Modelos Animais de Doenças , Imipramina/administração & dosagem , Imipramina/farmacologia , Masculino , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Estresse Psicológico/fisiopatologia , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/farmacologia
10.
Eur J Pain ; 22(5): 973-988, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29363217

RESUMO

BACKGROUND: Drugs are prescribed for chronic low back pain without knowing in advance whether a patient will respond to them or not. Quantitative sensory tests (QST) can discriminate patients according to sensory phenotype, possibly reflecting underlying mechanisms of pain processing. QST may therefore be a screening tool to identify potential responders to a certain drug. The aim of this study was to investigate whether QST can predict analgesic effects of oxycodone, imipramine and clobazam in chronic low back pain. METHODS: Oxycodone 15 mg (n = 50), imipramine 75 mg (n = 50) and clobazam 20 mg (n = 49) were compared to active placebo tolterodine 1 mg in a randomized, double-blinded, crossover fashion. Electrical, pressure and thermal QST were performed at baseline and after 1 and 2 h. Pain intensity was assessed on a 0-10 numeric rating scale every 30 min for up to 2 h. The ability of baseline QST to predict pain reduction after 2 h was analysed using linear mixed models. Genetic variants of drug-metabolizing enzymes and genes affecting pain sensitivity were examined as covariables. RESULTS: No predictor of analgesic effect was found for oxycodone and clobazam. Thermal QST was associated with analgesic effect of imipramine: patients more sensitive to heat or cold were more likely to experience an effect of imipramine. Pharmacogenetic variants and pain-related candidate genes were not associated with drug efficacy. CONCLUSIONS: Thermal QST have the potential to predict imipramine effect in chronic low back pain. Oxycodone and clobazam effects could not be predicted by any of the selected QST or genetic variants. SIGNIFICANCE: Predicting drug efficacy in chronic low back pain remains difficult. There is some evidence that patients more sensitive to heat and cold pain respond better to imipramine.


Assuntos
Analgésicos/uso terapêutico , Clobazam/uso terapêutico , Imipramina/uso terapêutico , Dor Lombar/tratamento farmacológico , Oxicodona/uso terapêutico , Limiar da Dor/efeitos dos fármacos , Adulto , Idoso , Analgésicos/administração & dosagem , Clobazam/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Estimulação Elétrica , Feminino , Humanos , Imipramina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Oxicodona/administração & dosagem , Medição da Dor , Pressão
11.
Int J Biol Macromol ; 111: 534-541, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29289668

RESUMO

This study aimed at evaluating the antidepressant-like action of the marine alga Solieria filiformis lectin (SfL) and to investigate the participation of the monoaminergic system in this action. For this, male Swiss mice (n=10) were pretreated with intravenous injections (i.v.) of SfL (1, 3 or 9mg/kg) and submitted to open field (OFT), tail suspension (TST), forced swimming (FST), elevated plus-maze (EPMT) and hole-board tests (HBT). As controls, mice received sterile saline (i.v.), imipramine (10 or 30mg/kg; intraperitoneally - i.p.) or diazepam (1 mk/kg; i.p.). To assess the involvement of the monoaminergic system in SfL effects, the FST was conducted in mice pretreated with PCPA, an inhibitor of serotonin synthesis, or noradrenergic and dopaminergic receptors specific antagonists. The results showed that SfL has an antidepressant-like effect, with no psychostimulant and anxiolytic-like effects. When denatured or combined with mannan, SfL lost the ability to reduce the immobility time in the FST. In addition, SfL antidepressant-like effect was inhibited by the pretreatment of mice with SCH 23390, a dopamine D1 receptor antagonist, and by sulpiride, a dopamine D2 receptor antagonist. Thus, SfL produced an antidepressant-like effect, which is probably dependent on its interaction with the dopaminergic system.


Assuntos
Depressão/tratamento farmacológico , Neurônios Dopaminérgicos/efeitos dos fármacos , Lectinas/administração & dosagem , Rodófitas/química , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Comportamento Animal/efeitos dos fármacos , Depressão/fisiopatologia , Dopamina/metabolismo , Dopaminérgicos/administração & dosagem , Dopaminérgicos/química , Elevação dos Membros Posteriores , Humanos , Imipramina/administração & dosagem , Lectinas/química , Lectinas/isolamento & purificação , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismo , Natação
12.
Neurochem Int ; 113: 85-91, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29196145

RESUMO

Time dependent sensitization (TDS) - phenomenon described originally by Chiodo and Antelman (1980) in context of dopamine receptors, refers to cascade of events that continue to develop in the organism, after the initiating stimulus is no longer available. Treatment could be recognized as such a initiating stimulus (in case of depression, example of electroconvulsive therapy would be obvious, but some aspects of pharmacotherapy too). The process leads to improvement, but, on the other hand, phenomena of kindling in recurrent depression is well known (more relapses and therapies make heavier and longer lasting subsequent episodes). Hence our interest in delayed effects of treatment. Here we report alterations in rat immune system after Imipramine (IMI) treatment cessation. Wistar male rats were treated with IMI (10 mg/kg i.p. in 2 ml/kg of saline) repeatedly for 21 days or once - on the last day of drug administration period. Then the 3 weeks discontinuation phase begun, during which, at certain time points (3 h, 72 h, 7days, 21days) the trunk blood was collected. Tissue concentrations of IMI and its metabolite desipramine (DMI), as well as ACTH and various cytokines were measured. The IMI and DMI was detectable only 3 h after the last i.p. injection of the drug. Ever since the second time point (72 h of discontinuation) the levels of either compound were below detection threshold.There was no significant changes in ACTH levels between rat groups, although IMI seemed to attenuate alterations of the hormone level comparing to control groups. We observed differences between groups regarding certain cytokines at certain time points. Namely: at 72 h of discontinuation IL-2 and IL-4 were elevated in sera of rats treated with IMI acutely; at 7d of discontinuation levels of IL-1α, IL-5, IL-10 and IL-12 were affected in both acutely and chronically treated animals. Presented data support, regarding some cytokines in serum, the TDS theory. Furthermore they refer to important aspect of antidepressants (ADs) action - antidepressant discontinuation syndrome (ADS). The most frequently, ADS has been described in context of ADs-disrupted monoamine homeostasis. Here, the other principle (i.e. immunomodulation) of the syndrome is proposed.


Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Citocinas/sangue , Imipramina/administração & dosagem , Animais , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Suspensão de Tratamento
14.
Drug Dev Res ; 78(8): 381-389, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28921671

RESUMO

Preclinical Research The effects of methyl jasmonate (MJ; 5, 10, 20 mg/kg, i.p), a natural product widely used for the relief of stress, depression, and exhaustion on unpredictable chronic mild stress (UCMS)-induced depression-like behaviors in mice was assessed and compared to those of imipramine (IMP; 10 mg/kg, i.p). MJ and IMP were given 30 min before exposure to UCMS with the procedure repeated daily for 2 weeks; 24 h after the stress session, the tail suspension test (TST) and sucrose preference test were assessed. MJ decreased immobility time in the TST and reversed impaired intake of sucrose relative to the stressed control suggesting antidepressant-like activity. MJ also reduced UCMS-induced increases in corticosterone and MDA (malondialdehyde) levels and attenuated UCMS-induced decreases in GSH and TNF-α levels and SOD activity. These findings suggest that MJ attenuated UCMS-induced depressive-like behaviors through decreased levels of corticosterone and decreasing oxidative stress and neuroinflammation in mouse brain.Drug Dev Res 78 : 381-389, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Acetatos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Ciclopentanos/administração & dosagem , Imipramina/administração & dosagem , Oxilipinas/administração & dosagem , Estresse Psicológico/tratamento farmacológico , Acetatos/farmacologia , Animais , Encéfalo/metabolismo , Corticosterona/metabolismo , Ciclopentanos/farmacologia , Modelos Animais de Doenças , Glutationa/metabolismo , Imipramina/farmacologia , Masculino , Malondialdeído/metabolismo , Camundongos , Oxilipinas/farmacologia , Estresse Psicológico/patologia , Superóxido Dismutase/metabolismo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
15.
Drug Dev Res ; 78(5): 196-202, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28736839

RESUMO

Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS1 receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS1 receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Receptores de Neurotensina/agonistas , Animais , Antidepressivos/farmacologia , Depressão/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Imipramina/administração & dosagem , Imipramina/uso terapêutico , Camundongos , Oligopeptídeos/farmacologia , Resultado do Tratamento
16.
J Toxicol Sci ; 42(4): 427-436, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28717101

RESUMO

Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.


Assuntos
Clorpromazina/administração & dosagem , Clorpromazina/toxicidade , Colestase/induzido quimicamente , Ciclosporina/administração & dosagem , Ciclosporina/toxicidade , Diclofenaco/administração & dosagem , Diclofenaco/toxicidade , Medição de Risco/métodos , Toxicogenética/métodos , Administração Oral , Animais , Colesterol/biossíntese , Relação Dose-Resposta a Droga , Flutamida/administração & dosagem , Flutamida/toxicidade , Expressão Gênica , Humanos , Imipramina/administração & dosagem , Imipramina/toxicidade , Inflamação/genética , Cetoconazol/administração & dosagem , Cetoconazol/toxicidade , Fígado , Metiltestosterona/administração & dosagem , Metiltestosterona/toxicidade , Estresse Oxidativo/genética , Ratos , Sulindaco/administração & dosagem , Sulindaco/toxicidade , Tamoxifeno/administração & dosagem , Tamoxifeno/toxicidade
17.
Acta Psychiatr Scand ; 136(1): 118-128, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28478653

RESUMO

OBJECTIVE: To compare the efficacy of two antidepressant treatment strategies in severely depressed in-patients, that is, imipramine vs. venlafaxine, both with subsequent lithium addition in non-responders. METHOD: In-patients (n = 88) with major depressive disorder were randomized to 7-week treatment with imipramine or venlafaxine (phase I). All non-responders (n = 44) received 4-week plasma level-targeted dose lithium addition (phase II). Efficacy was evaluated after 11 weeks of treatment. RESULTS: Analyzing phases I and II combined, non-inferiority was established and the difference in the proportion of responders (HAM-D score reduction ≥50%) by the end of phase II demonstrated the venlafaxine-lithium treatment strategy to be significantly superior to the imipramine-lithium treatment strategy (77% vs. 52%) (χ2 (1) = 6.03; P = 0.01). Regarding remission (HAM-D score ≤ 7), 15 of 44 (34%) patients in the imipramine-lithium treatment group were remitters compared to 22 of 44 (50%) patients in the venlafaxine-lithium treatment group, a non-significant difference. Patients in the venlafaxine-lithium treatment group had a non-significant larger mean HAM-D score reduction compared with patients in the imipramine-lithium treatment group (16.1 vs. 13.5 points, respectively; Cohen's d = 0.30). CONCLUSION: The venlafaxine-lithium treatment strategy can be considered a valuable alternative for the imipramine-lithium treatment strategy in the treatment of severely depressed in-patients.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Imipramina/farmacologia , Compostos de Lítio/farmacologia , Cloridrato de Venlafaxina/farmacologia , Adulto , Antidepressivos/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Imipramina/administração & dosagem , Compostos de Lítio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Cloridrato de Venlafaxina/administração & dosagem
18.
Sci Rep ; 7: 46523, 2017 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-28425449

RESUMO

Evidence is growing that vulnerability to depression may be characterized by strong negative feedback loops between mental states. It is unknown whether such dynamics between mental states can be altered by treatment. This study examined whether treatment with imipramine or treatment with Mindfulness-Based Cognitive Therapy (MBCT) reduces the connectivity within dynamic networks of mental states in individuals with depressive symptoms. In the Imipramine trial, individuals diagnosed with major depression were randomized to imipramine treatment or placebo-pill treatment (n = 50). In the Mind-Maastricht trial, individuals with residual depressive symptoms were randomized to Mindfulness-Based Cognitive Therapy (MBCT) or to a waiting-list control condition (n = 119). Lagged associations among mental states, as assessed with the Experience Sampling Method (ESM), were estimated at baseline and post-intervention. The results show that few of the dynamic network connections changed significantly over time and few of the changes after MBCT and imipramine treatment differed significantly from the control groups. The decrease in average node connectivity after MBCT did not differ from the decrease observed in the waiting-list control group. Our findings suggest that imipramine treatment and MBCT do not greatly change the dynamic network structure of mental states, even though they do reduce depressive symptomatology.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Transtorno Depressivo Maior/tratamento farmacológico , Imipramina/uso terapêutico , Mentalização/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Adolescente , Adulto , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Imipramina/administração & dosagem , Masculino , Mentalização/fisiologia , Pessoa de Meia-Idade , Atenção Plena/métodos , Rede Nervosa/fisiopatologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
19.
Lancet Psychiatry ; 4(5): 378-388, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28408193

RESUMO

BACKGROUND: Functional somatic syndromes, including chronic fatigue syndrome or irritable bowel syndrome, often co-exist. Treatment guidelines supported by high quality evidence exist for most functional somatic syndromes, but are lacking for multiple comorbid functional somatic syndromes. We aimed to assess the effect of the tricyclic antidepressant, imipramine, in patients with multiple functional somatic syndromes defined by the criteria for multiorgan bodily distress syndrome, a unifying diagnosis that encompasses most functional somatic syndromes and somatoform disorders. METHODS: In this single-centre, double-blind, randomised trial done in a Danish university hospital setting, participants were patients consecutively referred (age 20-50 years) fulfilling criteria for multiorgan bodily distress syndrome with no concurrent comorbid depression or anxiety disorder. Participants were randomly assigned (1:1) to receive either 10 weeks of low-dose imipramine or placebo (oral daily doses of 25-75 mg). The hospital pharmacy handled randomisation (computer-generated) and masking, providing sequentially numbered packs of study drug that were given serially to the participants. All others involved were masked to allocation. Primary outcome was patient-rated overall health improvement on a 5-point clinical global improvement scale. Improvement was defined as patients responding "better" or "much better" as opposed to "unchanged" and "worse" or "much worse" when rating their overall health status after 10 weeks of minimum 25 mg study drug. Analyses included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01518634. FINDINGS: Between Jan 30, 2012, and Nov 24, 2014, 138 patients were randomly assigned; 70 to receive imipramine and 68 to receive placebo. The study was completed on May 1, 2015. 125 patients received at least one dose of study drug: 65 received imipramine and 60 received placebo. Treatment was terminated prematurely for eight (12%) patients receiving imipramine and seven (12%) patients receiving placebo. Data were missing for two (3%) patients receiving imipramine and three (5%) patients receiving placebo. Of the 120 patients (96%) who provided primary outcome data, 33 (53%) receiving imipramine reported their overall health status as "better" or "much better" compared with 14 patients (25%) receiving placebo. The improvement after imipramine was significantly greater than after placebo (odds ratio 3·3 [95% CI 1·6-6·8]; p=0·001). Number needed to treat was 3·6 (95% CI 2·3-8·9). Analysis of the worst-case scenario for patients with missing outcome did not change the interpretation of the results. 32 patients (49%) receiving imipramine and 10 patients (17%) receiving placebo had at least one adverse event of moderate intensity (p=0·0001); eight patients (12%) receiving imipramine and three patients (5%) receiving placebo had at least one adverse event of severe intensity (p=0·1496). One patient (1%) receiving placebo experienced a serious adverse event (a subdural haematoma sustained after an accident). Adverse events caused dropout in four patients (6%) receiving imipramine and three patients (5%) receiving placebo. INTERPRETATION: Imipramine treatment compared with placebo significantly improved overall health in patients with multiple functional somatic syndromes when both treatments were supported by regular contacts with clinicians. Adverse events were more common in the imipramine group, but only rarely led to discontinuation of treatment. FUNDING: The Danish Foundation, Trygfonden.


Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Imipramina/administração & dosagem , Transtornos Somatoformes/tratamento farmacológico , Adulto , Dinamarca , Método Duplo-Cego , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
Drug Alcohol Depend ; 175: 133-139, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28414989

RESUMO

INTRODUCTION: Although a role for alpha-2 adrenoceptors (alpha-2 ARs) in alcohol use disorder (AUD) and depression is suggested, very little information on a direct interaction between alcohol and these receptors is available. METHODS: In this study adult female Wistar and Wistar-Kyoto (WKY) rats, a putative animal model of depression, were exposed to alcohol vapor 3h daily for 10days (blood alcohol concentration ∼150mg%) followed by daily injection of 10mg/kg of imipramine (IMP, a selective norepinephrine NE/serotonin reuptake inhibitor) or nomifensine (NOMI, a selective NE/dopamine reuptake inhibitor). On day 11 animals were tested for open field locomotor activity (OFLA) and forced swim test (FST) and were sacrificed 2h later for measurement of alpha-2 ARs densities in the frontal cortex and hippocampus using [3H]RX 821002 as the specific ligand. RESULTS: Chronic alcohol treatment increased the immobility in the FST, without affecting OFLA in both Wistar and WKY rats, suggesting induction of depressive-like behavior in Wistar rats and an exacerbation of this behavior in WKY rats. Alcohol treatment also resulted in an increase in cortical but not hippocampal alpha-2 ARs densities in both Wistar and WKY rats. The behavioral effects of alcohol were completely blocked by IMP and NOMI and the neurochemical effects (increases in alpha-2 ARs) were significantly attenuated by both drugs in both strains. CONCLUSIONS: The results suggest a role for cortical alpha-2 ARs in alcohol withdrawal-induced depression and that selective subtype antagonists of these receptors may be of adjunct therapeutic potential in AUD-depression co-morbidity.


Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Depressão/tratamento farmacológico , Imipramina/administração & dosagem , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Concentração Alcoólica no Sangue , Depressão/sangue , Depressão/induzido quimicamente , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Ratos , Ratos Endogâmicos WKY , Ratos Wistar , Síndrome de Abstinência a Substâncias/sangue , Síndrome de Abstinência a Substâncias/psicologia , Natação/psicologia
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