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Psychiatric drugs are among the leading medications prescribed for humans, with their presence in aquatic environments raising concerns relating to potentially harmful effects on non-target organisms. Nortriptyline (NTP) is a selective serotonin-norepinephrine reuptake inhibitor antidepressant, widely used in clinics and found in environmental water matrices. In this study, we evaluated the toxic effects of NTP on zebrafish (Danio rerio) embryos and early larval stages. Developmental and mortality analyses were performed on zebrafish exposed to NTP for 168 h at concentrations ranging from 500 to 46,900 µg/L. Locomotor behaviour and acetylcholinesterase (AChE) activity were evaluated by exposing embryos/larvae to lower NTP concentrations (0.006-500 µg/L). The median lethal NTP concentration after 168 h exposure was 2190 µg/L. Although we did not identify significant developmental changes in the treated groups, lack of equilibrium was already visible in surviving larvae exposed to ≥ 500 µg/L NTP. The behavioural analyses showed that NTP was capable of modifying zebrafish larvae swimming behaviour, even at extremely low (0.006 and 0.088 µg/L) environmentally relevant concentrations. We consistently observed a significant reduction in AChE activity in the animals exposed to 500 µg/L NTP. Our results highlight acute toxic effects of NTP on the early-life stages of zebrafish. Most importantly, exposure to environmentally relevant NTP concentrations may affect zebrafish larvae locomotor behaviour, which in turn could reduce the fitness of the species. More studies involving chronic exposure and sensitive endpoints are warranted to better understand the effect of NTP in a more realistic exposure scenario.

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Los antidepresivos son agentes que causan una importante morbilidad y mortalidadcon presentación de un espectro de toxicidad único, principalmente cardiovasculary neurológico, el cual se basa principalmente en su farmacología y que determina sutratamiento específico. Por desgracia, los niños son una población vulnerable, y con elaumento de patologías psiquiátricas que son tratadas con este tipo de medicamentos,cada vez es más probable encontrar toxicidad en esta población. El propósito de estapublicación es revisar la farmacocinética, la presentación clínica y el tratamiento de laintoxicación aguda por antidepresivos tricíclicos...

Antidepressants are agents that cause significant morbidity and mortality with importanttoxicity particularly on cardiovascular and neurological systems, which is mainly basedon their pharmacology and is that determines specific treatment. Unfortunately, childrenare vulnerable population because the increase in psychiatric disorders which are treatedwith these drugs. The purpose of this article is to review the pharmacokinetics, clinicalpresentation and treatment of acute poisoning with tricyclic antidepressants...

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Introdução: A intoxicação aguda por antidepressivos tricíclicos é comum nas salas de emergência. Anormalidades no eletrocardiograma de 12 derivações (ECG) são associadas a este tipo de intoxicação, com implicações diagnósticas e prognósticas. O ECG pode ter valor incremental principalmente em situações de alteração de consciência, convulsões ou distúrbios do ritmo cardíaco associado. Objetivo: Revisar as principais alterações eletrocardiográficas descritas na intoxicação por antidepressivos tricíclicos e estabelecer suas implicações prognósticas no manejo desta condição clínica. Metodologia: Pesquisa bibliográfica no MEDLINE (PubMEd) limitada aos artigos publicados entre 1980 e 2010 em língua inglesa, utilizando-se unitermos (tricyclic antidepressant overdose OR tricyclic antidepressant intoxication OR tricyclic antidepressant poisoning OR tricyclic antidepressant ingestionAND electrocardiography). Dos 133 artigos identificados, foram selecionados 44 para a revisão...

Introduction: The acute poisoning by tricyclic antidepressants is common in emergency rooms. Abnormalities in 12-lead electrocardiogram (ECG) are associated with this type of poisoning, with diagnostic and prognostic implications. The ECG may have incremental value especially in situations of altered consciousness, seizures or heart rhythm disturbances associated. Objective: To review the electrocardiographic changes described in tricyclic antidepressant poisoning and to establish their prognostic implications in the management of this condition. Methods: Bibliographic search in MEDLINE (PubMed) limited to articles published between 1980 and 2010 in English, using key words (tricyclic antidepressant overdose OR tricyclic antidepressant intoxicationOR tricyclic antidepressant poisoning OR tricyclic antidepressant ingestion AND electrocardiography). Of the 133 articles identified, 44 were selected for review...

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Imipramine (IMI) and desipramine (DES) are two drugs widely used for the treatment of depression as well as for other diseases. In the present study, we determined their capacity to induce chromosomal aberrations in mouse bone marrow cells. Three doses of each compound were tested and their results were compared with the frequency of chromosomal aberrations obtained in a control group as well as with a group treated with cyclophosphamide. Our results showed a significant increase in chromosome damage with the doses tested for each compound: 7, 20, and 60 mg/kg in the case of IMI, and 2, 20, and 60 mg/kg as regards DES. This last drug induced stronger chromosomal damage than IMI. Our results agree with previous studies regarding the induction of micronuclei and sister chromatid exchanges by the drugs in mouse and suggest caution with respect to their use in long-term treatments.

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Depression is a common disease that may cause severe damage to human health. Imipramine (IMI) and desipramine (DES) are medicaments used for treatment, yet studies on their genotoxic potential have given controversial results. Therefore, we designed the present assay to determine their effect as inducers of micronucleated polychromatic erythrocytes (MNPE) and micronucleated normochromatic erythrocytes (MNNE) in mice. The study was carried out in animals administered daily with the compounds for 4 weeks, and the determination of micronuclei was done each week. We also evaluated the bone marrow cytotoxicity induced by the chemicals. Besides, the same determinations were carried out in the following 4 consecutive weeks, but in this period the animals were not treated with the tested compounds. Our results showed a significant increase in both MNPE and MNNE induced by both compounds from the first week of administration. At the fourth week, IMI increased three times the control level, while the effect of DES was about seven times such level. In the second, 4-week phase, we observed a reduction in the rate of micronuclei approaching the control level. We also detected a bone marrow-mitotic division decrease by the evaluated chemicals. Our results point to the need for cautiousness in the clinical use of the compounds as well as for testing the effect in patients under treatment.

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Os antidepressivos tricíclicos (ADT) constituem uma classe de drogas de alta importância toxicológica,porque o uso abusivo dessa substância acarreta alguma sintomatologia ou mesmo risco de vida, pelo fácil acesso, em razão do baixo custo, da distribuição pelo sistema público de saúde e pela prescrição indiscriminada.Este trabalho teve por objetivos avaliar o impacto das intoxicações por ADT atendidos em um hospital terciário comparando com as intoxicações ocasionadas por outras drogas depressoras do “sistema nervoso central”. Para a realização deste trabalho foram avaliados os atendimentos realizados pelo Centro de Assistência Toxicológica (CEATOX) de São José do Rio Preto, entre o período de 01 de janeiro de 2001 até 31 de dezembrode 2003, através da Ficha de Notificação do CEATOX. Nesse estudo, de um total de 2950 atendimentos, 123 eram casos de intoxicação por antidepressivos tricíclicos (ADT) e 275 de outras drogas depressoras do“sistema nervoso central” (DSNC) atendidos neste hospital. O ADT mais utilizado foi a Amitriptilina; já entre os DSNC temos os Benzodiazepínicos (BZD). Houve uma maior internação por parte dos ADT, com maior tempo de internação em relação aos DSNC. Com isso, observamos o significativo impacto que as intoxicações pelos ADT causam em termos de atendimento e internação para o nosso hospital. Concluímos que os benefícios e os riscos da prescrição de ADT, hoje largamente utilizados em várias patologias, precisam ser bem avaliados, e sempre que possível, a opção por outros medicamentos com potencial toxicológico menos intenso deve ser feita.

A considerably important toxicological class of drugs is the Tryciclic antidepressants (TCA) because thedrug abuse can trigger some complex combined symptoms of a disease or even risk of death; it is easilyattainable; owing to his low cost; it is available at the health public system; and it is widely prescribed. Thisstudy directly aimed at to estimate the poisoning impact by TCA of patients treated at a tertiary hospitalcompared to poisoning caused by other central nervous system depressant drugs. To the completion of thisessay the exams performed by the Center for Toxicological Assistance (CEATOX) of São José do Rio Preto,from January 1st 2001 to December 31st 2003, were estimated by the Center for Toxicological Assistance(CEATOX) Notification Form. In this study, from a total of 2,950 treated in-hospital patients, 123 werepoisoning cases caused by tryciclic antidepressants (TCA), and 275 from other central nervous systemdepressant drugs. Amytriptiline was the most used Tryciclic antidepressant while among the central nervoussystem depressant drugs the benzodiazepine compounds were the mostly used ones. There was a higherhospitalization rate with tryciclic antidepressants but a higher length of hospitalization related to the centralnervous system depressant drugs. The hospitalization costs to the Unified Health System (SUS) werefurther analyzed indicating that the poisoning costs by tryciclic antidepressants were the same when comparedto central nervous system depressant drugs. And therewith we could see the significant impact that thepoisonings by tryciclic antidepressants caused in relation to medical attendance and hospitalization to ourhospital. It was inferred that the benefits and risks of tryciclic antidepressant prescription, nowadaysextensively used in several pathologies, need to be estimated and whenever is possible, the choice for amedication with a much less intense toxicological potential should be made.

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Although the effects of antidepressants in brain neurochemistry have been extensively studied, there are scarce and inconsistent data on the effect of these drugs in learning and memory. The authors studied the effect of daily administration of a single dose of either clomipramine or desipramine, two monoamine-reuptake-inhibitors with preferential serotonergic and noradrenergic profiles, respectively, during 15 days, on the visuo-spatial memory of adults rats measured through their performance in an eight-arm radial maze. Rats receiving 10 mg/kg i.p. daily of clomipramine or desipramine, 30 min before testing, committed a significantly greater number of errors than saline-treated control rats throughout the duration of the test (5 sessions, 15 days), excepting for session one (after 3 days of testing) where there were no differences between the 3 groups of rats. Results indicated that both serotonergic and noradrenergic antidepressants could impair long-term visuo-spatial memory in the rat, whereas inducing no changes in working memory, effects that are likely related to changes in brain monoamine metabolism induced by the antidepressant drugs.

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O monitoramento terapêutico é fundamental no acompanhamento de diversos tratamentos, pois permite avaliar se os níveis plasmáticos dos fármacos estão dentro do intervalo terapêutico possibilitando a melhora da resposta clínica e a diminuição da morbidez dos pacientes. Os antidepressivos tricíclicos (ADT) são exemplo de fármacos que necessitam monitoramento terapêutico, pois apresentam estreita faixa terapêutica, risco de toxicidade, metabólitos ativos e baixa correlação entre a dose administrada e níveis plasmáticos. Além disso, fatores como idade, outras patologias associadas e interações medicamentosas podem interferir nos níveis plasmáticos dos ADT. O objetivo deste trabalho foi revisar algumas características farmacológicas dos ADT assim como demonstrar a importância do monitoramento terapêutico para essa classe de fármacos

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Wild running (WR) behavior of rats seen in response to intense acoustic stimulation of audiogenic seizure-paradigm is very similar to the panic flight and can be facilitated by subconvulsive doses of strychnine. The present work aimed to test whether antipanic procedures, such as dorsal periaqueductal gray (dPAG) lesion and imipramine treatments, affect the strychnine-facilitated WR. In study 1, six Wistar male adult rats with electrolytic lesion of dPAG had their WR completely blocked, whereas it was facilitated in 50% of sham-lesioned control rats by a dose of 0.5 mg/kg of strychnine administered intraperitoneal. This effect was not reproduced with a higher strychnine dose (1.0 mg/kg). In study 2, the effects of imipramine were investigated by testing 36 rats under a dose of strychnine that induces WR in 50% of subjects. They were assigned into three experimental groups: imipramine treatments of 5.0 and 10.0 mg/kg, and infusions of saline. All these treatments were subchronical with three intraperitoneal injections within 24 h. Imipramine (10.0 mg/kg) reduced the incidence of WR in comparison to the saline results. It is concluded that strychnine-facilitated WR is reduced by antipanic procedures and, therefore, can be viewed as a manifestation closely related to panic.

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Imipramine and desipramine are two widely used tricyclic antidepressants which have shown conflicting results in regard to their in vitro genotoxic evaluation. The aim of this investigation was to determine the capacity of these compounds to induce in vivo sister-chromatid exchanges (SCEs) in mouse bone marrow cells. For each compound, the animals were organized in five groups constituted by five individuals. They were intraperitoneally (ip) administered with the test substances as follows: a negative control group treated with 0.4 ml of distilled water, a positive control group administered with cyclophosphamide (70 mg/kg), three groups treated with imipramine (7, 20 and 60 mg/kg), and three other groups treated with desipramine (2, 20 and 60 mg/kg). The general procedure included the subcutaneous implantation to each mouse of a 5-bromodesoxyuridine tablet (45 mg), and 1 h later, the administration of the chemicals involved. Twenty-one hours after the tablet implantation, the mice received colchicine, and 3 h later their femoral bone marrow was obtained in KCL, fixed, and stained with the Hoechst-Giemsa method. The results showed that both compounds were SCE inducers, starting from the second tested dose. The response of these compounds was dose-dependent, and showed that the highest tested dose increased about four times the SCE control level. The cellular proliferation kinetics was not affected by the chemicals, and the mitotic indexes were slightly diminished with the highest dose. These results indicate an in vivo genotoxic potential for both chemicals, and suggest that it is pertinent to follow their evaluation in other models.

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Day-night differences in locomotor and anxiety-related behavior and brain serotonin metabolism were examined in adult Syrian hamsters that received clomipramine (15 mg/kg) or vehicle from day 8 to day 21 of life. Locomotor activity was significantly greater at the beginning of scotophase (20.00 h) than at noon (12.00 h) and it was highest in hamsters treated with clomipramine at both examined times. Significant day-night differences in anxiety-related behavior, as measured in a plus-maze paradigm, were found in saline-treated hamsters only, with higher values at night. Clomipramine-treated hamsters exhibited augmented 5-hydroxyindoleacetic acid/serotonin ratio in hypothalamus and midbrain raphe, while serotonin content decreased in frontal cortex and hypothalamic areas. The results indicate that neonatal clomipramine treatment produces a long-lasting change in locomotion and anxiety-related behavior, as well as reduces brain serotonin content in hamsters.

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