The elevated gradient of aversion: a new apparatus to study the rat behavior dimensions of anxiety, fear, and impulsivity

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.

Reacciones adversas de los antidepresivos: consideraciones actuales / Adverse reactions to antidepressants: current considerations

RESUMEN Las reacciones adversas a los medicamentos, son una reacción nociva o no intencionada. Ocurre con las dosis habituales empleadas en el ser humano para la profilaxis, diagnóstico o tratamiento de enfermedades y también para modificar las funciones fisiológicas. Con esta revisión se pretendió proporcionar una actualización de las reacciones de los fármacos antidepresivos. Se tuvo en cuenta cuestiones importantes, tales como: la selección, forma de uso, duración de la terapia y consideraciones relacionadas con situaciones patológicas particulares (AU).

ABSTRACT Adverse reactions to drugs are a noxious and non-intended reaction. It occurs with the doses usually used for prophylaxis, diagnosis and disease treatment in the human being, and also for modifying the physiologic functions. The aim of this review was giving an update of the reactions to anti-depressant drugs. Important questions were taken into account like drug choose, form of use, therapy lasting and considerations related to particular pathologic situations (AU).

Chronic dosing with mirtazapine does not produce sedation in rats

Objective: Sedation/somnolence are major side effects of pharmacotherapies for depression, and negatively affect long-term treatment compliance in depressed patients. Use of mirtazapine (MIR), an atypical antidepressant approved for the treatment of moderate to severe depression with comorbid anxiety disorders, is associated with significant sedation/somnolence, especially in short-term therapy. Nonetheless, studies with human subjects suggest that MIR-induced sedation is transient, especially when high and repeated doses are used. The purpose of this study was to explore the effects of acute and chronic administration of different doses of MIR on sedation in the rat. Methods: Assessment of sedation was carried out behaviorally using the rotarod, spontaneous locomotor activity, and fixed-bar tests. Results: A 15-mg/kg dose of MIR induced sedative effects for up to 60 minutes, whereas 30 mg/kg or more produced sedation within minutes and only in the first few days of administration. Conclusion: These results suggest that 30 mg/kg is a safe, well-tolerated dose of MIR which generates only temporary sedative effects.

Effects of chronic corticosterone and imipramine administration on panic and anxiety-related responses

It is known that chronic high levels of corticosterone (CORT) enhance aversive responses such as avoidance and contextual freezing. In contrast, chronic CORT does not alter defensive behavior induced by the exposure to a predator odor. Since different defense-related responses have been associated with specific anxiety disorders found in clinical settings, the observation that chronic CORT alters some defensive behaviors but not others might be relevant to the understanding of the neurobiology of anxiety. In the present study, we investigated the effects of chronic CORT administration (through surgical implantation of a 21-day release 200 mg pellet) on avoidance acquisition and escape expression by male Wistar rats (200 g in weight at the beginning of the experiments, N = 6-10/group) tested in the elevated T-maze (ETM). These defensive behaviors have been associated with generalized anxiety and panic disorder, respectively. Since the tricyclic antidepressant imipramine is successfully used to treat both conditions, the effects of combined treatment with chronic imipramine (15 mg, ip) and CORT were also investigated. Results showed that chronic CORT facilitated avoidance performance, an anxiogenic-like effect (P < 0.05), without changing escape responses. Imipramine significantly reversed the anxiogenic effect of CORT (P < 0.05), although the drug did not exhibit anxiolytic effects by itself. Confirming previous observations, imipramine inhibited escape responses, a panicolytic-like effect. Unlike chronic CORT, imipramine also decreased locomotor activity in an open field. These data suggest that chronic CORT specifically altered ETM avoidance, a fact that should be relevant to a better understanding of the physiopathology of generalized anxiety and panic disorder.

Ventajas y desventajas de brindar a los pacientes información detallada sobre potenciales efectos adversos a los ISRS / Advantages and disdvantages of providing patients with detailed information on the potential adverse effects of SSRis

La introducción de los inhibidores selectivos de la recaptación de serotonina (ISRS) significó un gran avance en el tratamiento de los trastornos del humor y los trastornos de ansiedad. No es infrecuente escuchar entre los profesionales de la salud que brindar información detallada sobre potenciales efectos adversos puede generar un mayor reporte de estos. ¿Con qué evidencia científica contamos para decidir sobre brindar más o menos información sobre potenciales efectos adversos de los antidepresivos del grupo de los ISRS? ¿Cuál es el impacto de esta información en términos de reporte de efectos adversos y adherencia al tratamiento con estos fármacos? En este trabajo se revisaron los métodos para la evaluación de efectos adversos farmacológicos, el concepto de adherencia y las modalidades para su medición y los fundamentos de la jerarquía de la evidencia científica con que se clasifican los resultados de las investigaciones. Para ello se realizó una revisión exhaustiva de la literatura médica utilizando las bases de datos de MEDLINE (1966-2008), Cochrane (2008, número 4) y LILACS (1982-2008). No hemos encontrado estudios que hayan tenido como objetivo primario el reporte de efectos adversos de los ISRS al brindar información detallada, aunque sí existe alguna información no concluyente con otras clases de antidepresivos y psicofármacos. No hay trabajos específicos para los ISRS pero sí para los antidepresivos tricíclicos: los resultados de estos trabajos permiten señalar que la adherencia a los tratamientos presentan una mejoría significativa cuando se registran intervenciones consistentes en brindar a los pacientes información sobre los medicamentos que reciben. Sobre la base de los datos disponibles en la actualidad, puede sostenerse que, a mayor información se registra también una adherencia al tratamiento con antidepresivos; sin embargo, no se sabe a ciencia cierta si existe un mayor reporte de efectos adversos.

The introduction of selective serotonin reuptake inhibitors (SSRIs) has meant a significant progress for the treatment of mood and anxiety disorders. It is not unusual for health care professionals to state that providing patients with detailed information on the potential adverse events of SSRIs may result in a higher amount of reports on such events. On what scientific evidence do we base our decision of providing more or less informations about the potential adverse effects of SSRIs antidepressants? What impact does this piece of information has in terms of the reporting of adverse events and adherence to treatment with these pharmacological drugs? This article offers a review of the methods for evaluating pharmacological adverse events, the concept of adherence and the modalities for assessing it, as well as the foundtions of the scientific evidence hierarchy by which the outcomes and the modalities for assessing it, as well as the pundations of the scientific evidence hierarchy by which the outcomes of investigations are classed into. For that purpose, an extensive review of medical literature was conducted using MEDLINE (1966-2008), Cochrane (2008, number 4) and LILACS (1982-2008) databases. We did not find any study whose primary goal was the report of SSRIs adverse effects when providing detailed informations, and there is non conclusive information as regards other types of antidepressants and psychopharmacological drugs. There are no specific studies on SSRIs, although there are for tricyclic antidepressants: the latter demonstrated a significant improvement in terms of adherence when information on the medications administered to the patients is offered. We may therefore conclude that, based upon current evidence, the more informations is offered, the higher the adherence to antidepressants, although it is not know for certain whether the number of reports on adverse events increases or not.

Imipramine induced elevation of prolactin levels in patients with HIV/AIDS improved their immune status / La elevación de niveles de prolactina mediante inducción con imipramina mejoró el estatus inmune de pacientes con VIH/SIDA

Prolactin is known to have significant immunomodulatory properties. Imipramine, a monoamine oxidase inhibitor, stimulates prolactin production because it decreases dopamine which inhibits secretion of prolactin. The study objective was to determine if use of imipramine can result in immunological benefits for HIV-positive patients by restoration and preservation of immunological function. A cohort of 19 retroviral positive patients was identified for the prospective study which continued for a 28-week period. Three patients dropped out before the study began. Inclusion criteria accepted only patients on the same highly active antiretroviral therapy (HAART) regimen for a nine-month period and who had reached a plateau with respect to the CD4 cell count and also had no prior history of antidepressant use for a 12-month period. This study had a "before and after" design, patients serving as their own control. The study drug imipramine was prescribed for a 12-week period up to visit 4, and then discontinued for 4-weeks (washout period) at which time blood investigations were done at visit 5. Finally, patients were prescribed the study drug for a further 12-week period to the end of the trial (visit 7). At the 95 per cent probability level, significant differences in average prolactin and CD4 levels from visit 4 to the end of the trial period were recorded. Results showed a trend of prolactin levels decreasing after washout (p = 0.015) and increasing by the end of the trial period once imipramine dispensation had recommenced (p = 0.006). With respect to the CD4 cell count, there was a significant increase after wash-out (p = 0.022). These results indicate a trend to immune boosting in HIV-positive patients who had obtained the maximum response from HAART.

Se sabe que la prolactina posee importantes propiedades inmunomudolatorias. La imipramina, un inhibidor de la monoamino oxidasa, estimula la producción de la prolactina porque disminuye la dopamina, que a su vez inhibe la secreción de prolactina. El objetivo de este estudio fue determinar si el uso de la imipramina puede traer beneficios inmunológicos a los pacientes VIH positivos mediante la restauración y preservación de la función inmunológica. Se identificó una cohorte de 19 pacientes retrovirales positivos, a fin de realizar este estudio prospectivo que continuó por un período de 28 semanas Tres pacientes se retiraron antes de que el estudio comenzara. Los criterios de inclusión aceptaban sólo pacientes que tuvieran el mismo régimen de terapia antiretroviral altamente activa (HAART) por un período de nueve meses, que hubieran alcanzado un nivel de estabilización con respecto al conteo de células CD4, y que no hubieran además tenido con anterioridad una historia de uso de anti-depresantes por espacio de 12 meses. Este estudio tuvo un diseño "antes y después", sirviendo los pacientes como su propio control. La imipramina para el estudio fue prescrita por un período de 12 semanas hasta la visita 4, y luego descontinuada por 4 semanas para un reposo farmacológico (período de lavado), realizándose entonces pruebas de sangre en la visita 5. Finalmente se prescribió el medicamento de estudio a los pacientes por un nuevo período de 12 semanas hasta el final del ensayo (visita 7). En el nivel de probabilidad del 95 por ciento, se registraron diferencias significativas en los niveles promedio de prolactina y CD4 desde la visita 4 hasta el final del período de ensayo. Los resultados mostraron una tendencia de los niveles de prolactina a descender tras el lavado (p = 0.015) y a aumentar hacia el final del período de ensayo, una vez que la dispensación de imipramina hubiese recomenzado (p = 0.006). Con respecto al conteo de células de CD4, hubo un aumento significativo luego del lavado (p = 0.022).

Terapia medicamentosa na depressão pós-acidente vascular encefálico / Drug treatment of poststroke depression

OBJETIVO: Este estudo visa realizar uma revisão de literatura sobre a terapia farmacológica na depressão pós-AVE. MÉTODO: Foi feita uma revisão nos bancos de dados MedLine e SciELO, utilizando-se como descritores primários "stroke", "depression" e "treatment", incluindo artigos publicados entre 1996 e 2008. RESULTADOS: Treze artigos foram selecionados. Foram encontrados dez artigos que apresentaram terapias farmacológicas eficazes no tratamento da depressão pós-AVE e três em que as terapias farmacológicas utilizadas não trouxeram benefício para a depressão dos grupos em estudo. CONCLUSÃO: O manejo farmacológico da DPAVE pode ser realizado de maneira profilática ou terapêutica. Em ambas as modalidades, os inibidores de recaptação seletiva são as medicações mais adequadas, destacando-se a fluoxetina e, em pacientes adequadamente selecionados, a reboxetina e o citalopram. A nortriptilina, antidepressivo tricíclico, é uma alternativa com relativa eficácia na conduta da DPAVE.

INTRODUCTION: Poststroke depression (PSD) is one of the most frequent psychiatric sequelae in populations affected by stroke. Effective drug therapy is essential in the proper management of patients. OBJECTIVE: This study aims to conduct a review of the literature on pharmacological therapy in PSD. METHOD: A review was made in databases MedLine and SciELO using as primary descriptors "stroke", "depression" and "treatment", including articles published between 1996 to 2006. RESULTS: Thirteen articles were selected. Ten trials were found that described effective pharmacological therapies in the treatment of the PSD. CONCLUSION: The pharmacological management of PSD can be done prophylactic or therapeutically. In both methods, selective reuptake inhibitors, particularly fluoxetine, and in some instances, citalopram and reboxetine, seem to be the most appropriate medications to be used in PSD. Alternatively, nortriptyline, a tricyclic antidepressant, may be employed in some cases of PSD.

Pyridoxine effect on the antidepressant action of imipramine in albino mice

To evaluate the behavioral effect of pyridoxine on the antidepressant action of imipramine. Male Wistar albino mice of weights 25-35gms were used. Two experiments were carried out; the first on the acute effect of pyridoxine on the duration of immobility, and the second on the sub-chronic effects of pyridoxine alone and in combination with imipramine. In the first experiment, 4 groups of animals received saline, 65, 125, and 250mg/kg pyridoxine. Forced swimming test [FST] was performed 30 minutes after drug administration. In the second experiment, 6 groups of mice were used. The first group received saline, the second group received imipramine 10 mg/kg, the third group received pyridoxine 65mg/kg, the fourth group received pyridoxine 250mg/kg, the fifth group received combined treatment of imipramine and pyridoxine 65 mg/kg, while the sixth group received a combined treatment of imipramine and pyridoxine 250 mg/kg. Administration of drugs was at 24, 5, and one hour before the test. This work was carried out in the Biotechnology Research Center, Twisha, Libya, in June 2007. Acute administration of pyridoxine did not change the duration of immobility compared to the control group. Sub-chronic administration showed that pyridoxine [65mg/kg] did not change the immobility time, while a higher dose of pyridoxine [250mg/kg] decreased the immobility time. Imipramine at 10mg/kg reduces the immobility time significantly. Pyridoxine did not change imipramine action. Pyridoxine alone may produce an antidepressant effect. Pyridoxine in combination with imipramine did not change the imipramine action

Imipramine in persistent vomiting.

A 21-year-old female presented with persistent vomiting for last 3 years. She had all the investigations done including gastroscopy but there was no abnormality detected. She was tried earlier with medicines prescribed in a medical college or a private nursing home. The cause of vomiting was thought of psychogenic. She was advised imipramine 25 mg thrice daily and responded to the treatment favourably.

Effect of Withania somnifera on forced swimming test induced immobility in mice and its interaction with various drugs.

The objective of the present study was to evaluate the antidepressant action of Withania somnifera (WS) as well as its interaction with the conventional antidepressant drugs and to delineate the possible mechanism of its antidepressant action using forced swimming model in mice. Effect of different doses of WS, fluoxetine and imipramine were studied on forced swimming test induced mean immobility time (MIT). Moreover effect of WS 100 mg/kg, i.p. was observed at different time intervals. Effect produced by combination of sub therapeutic doses of WS with imipramine (2.5 mg/kg, i.p.) as well as fluoxetine (2.5 mg/kg, i.p.) were also observed. Effect of WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) were observed in mice pretreated with reserpine (2 mg/kg, i.p.) and clonidine (0.15 mg/kg, i.p.). Effects of prazosin (3 mg/kg, i.p.) or haloperidol (0.1 mg/kg, i.p.) pre-treatment were also observed on WS induced decrease in MIT. WS produced dose dependent decrease in MIT. Maximum effect in MIT was observed after 30 min of treatment with WS 100 mg/kg, i.p. Combination of WS (37.5 mg/kg, i.p.) with imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) also produced significant decrease in the MIT. Clonidine and reserpine induced increase in MIT, was significantly reversed by treatment with WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.). Pre-treatment with prazosin but not haloperidol, significantly antagonized the WS (100 mg/kg, i.p.) induced decrease in MIT. It is concluded that, WS produced significant decrease in MIT in mice which could be mediated partly through a adrenoceptor as well as alteration in the level of central biogenic amines.

Fármacos antidepresivos / Antidepressant drugs

En el presente artículo se describen las diferentes drogas utilizadas para el tratamiento de la depresión, sus modos de acción, sus efectos adversos y las diversas precauciones y advertencias

Thyroid function in depression.

Studies on thyroid functions were performed on patients suffering from depression. Thirty four cases of depression were studied for their thyroid function and showed a diminished level of T3 and T4 with concomitant rise in TSH (Thyroid Stimulating Hormone) level. This work showed that depressive patients had been suffering from sub-hypothyroidism.

Role of emotionality on inter and intrastrain variations in imipramine response. a comparative study in Balb/c and Swiss mice.

Association between emotionality and effect of imipramine on immobility time in forced swimming test was investigated in Swiss and Balb/c mice. Mice of both the strains were segregated into normal emotional (mean +/- 1SD), low emotional (> mean + 1SD) and high emotional (< mean - 1SD) based on their performance with respect to each indices of emotionality in novel arena and elevated plus maze. Baseline immobility and effect of imipramine (20 mg/kg, po) on immobility time was evaluated in these emotionally different groups of mice using forced swimming test model. Baseline immobility time of low emotional mice was found to be significantly less (P<0.01) and that of high emotional mice was found to be significantly more (P<0.01) when compared to normal emotional mice of both the strains. Immobility time after imipramine administration was found to be significantly less (P<0.05) with low emotional mice and significantly more (P<0.01) with high emotional mice when compared to normal emotional mice of both the strains.

Fenotipagem de enzimas metabolizadoras polimórficas e monitoramento terapêutico como uma ferramenta na farmacologia clínica dos antidepressivos tricíclicos, uma revisão / Phenotyping of polymorpghic metabolizing enzymes and therapeutic drug monitoring as a tool in the clinical pharmacology of tryicyclic antidepressants, a review

Polymorphism in drug metabolizing enzymes is related with interindividual variability in drug therapy effectiveness. The polymorphisms of oxidative enzymes of the P450 cytochrome system have been characterized, and their impacts in enzyme activity are already known. Considering their substrate specificity, CY2D6 and CYP2c19 are the most important enzymes in the tricyclic antidepressant metabolism. Several methods are avaiable in order to classify an individual regarding metabolic activity of these enzymes. Although genotyping is a fast growing approach, phenotyping seems to be more feasible as a "moment picture" of CYPs activity. Phenotyping of CYp2D6 and CYP2c19 is usually done by the use of probe drugs, with some degree of specificity for the tested enzymes. The simultaneous administration of probe drugs specific for samples of blood or urine are taken at standarized time intervals. After parent drug and metabolite quantitative analysis, usually by high-performance liquid chromatography, a pharmacokinetic parameter is used to classify the individuals as poor, extensive or ultra-fast metbolizers. One of the most promising possibilities of the individual metabolic characterization is costomizing drug therapy, wich has not been fully exploited until now...

Bipolaridad tipo III en niños: una situación no diagnosticada / Type III bipolar disorder in children: an infrequent diagnosis

Introducción: Los antidepresivos se han asociado a viraje desde depresión a hipomanía o manía. Objetivo: Dar a conocer el viraje farmacológico y su implicancia en el diagnóstico de la bipolaridad tipo III. Metodología: Se revisa la literatura, presentando una actualización sobre la manía e hipomanía farmacógena y sus implicancias para la clínica. Resultados: El viraje por antidepresivos es mayor en depresión bipolar, con el uso de tricíclicos y depende directamente del tiempo de la terapia antidepresiva. Conclusión: Los unipolares que viran con antidepresivos serían más bien bipolares que no han desarrollado aún la otra fase de modo espontáneo. El viraje farmacológico es el mejor predictor para el desarrollo de enfermedad bipolar con una especificidad del 100 por ciento, por lo que se les denomina ôpseudounipolaresõ, englobándolos dentro del espectro bipolar como ôbipolares tipo IIIõ.

Crises de pânico na clínica médica / panic disorder in general practice

Sabe-se, de ha muito, que as crises de pânico estão entre os diagnósticos mais freqüentes que levam os pacientes a procurar servicos de emergência; assim sendo, seu conhecimento e manejo não se devem restringirmos psiquiatras, mas interessar aos médicos em geral. Cerca de 43 por cento dos pacientes com crises de Pânico são atendidos, Pela primeira vez, em unidades de pronto-socorro, sendo que 15 por cento desses pacientes chegam ao local de atendimento em ambulâncias, pela intensidade do quadro.

Eficácia dos antidepressivos para dor crônica / Effectiveness of antidepressants for chronic pain

Há evidências de que os antidepressivos tricíclicos säo eficazes para dor neuropática. Entretanto,os efeitos colaterais limitam seu uso. Os inibidores seletivos da recaptaçäo de serotonina e os atípicos causam menos efeitos colaterais. Para avaliar o efeito analgésico dessas medicaçöes foi feita pesquisa (Medline, Cinhah, ,PsycLIT and Cochrane Library) de estudos em lingua inglesa de 1966 a 2000. As medicaçöes avaliadas foram : trazodona, nefazodona, paroxetina, citalopram, sertralina, fluoxetina e venlafaxina. Os estudos säo insuficientes para estabeleceer eficácia dos antidepressivos ISRS e atípicos para alívio da dor.(au)

Padronização de método utilizando a cromatografia a gás para determinação quantitativa de imipramina e desipramina em amostras de soro para fins de monitorização terapêutica / Standardization of method using gas chromatography for the quantification of imipramine and desipramine in sample of serum for therapeutic drug monitoring

Antidepressivos tricíclicos são eficazes e de custo acessível e, não obstante seus efeitos colaterais, são ainda usados no tratamento da depressão. Devido ao fato de apresentarem variações consideráveis de cinética e faixa terapêutica estreita, a monitorização terapêutica se faz necessária, para evitar efeitos sub-terapêuticos ou tóxicos. Neste trabalho foi desenvolvido um método para quantificação de imipramina e desipramina em amostras de soro utilizando a cromatografia gasosa com coluna capilar e detetor de nitrogênio e fósforo com finalidade de monitorização terapêutica. Nas condições padronizadas imipramina, desipramina e padrão interno (clomipramina) eluiram com tempos de retenção de...

Antidepressivo tricíclico e erupçäo liquenóide / Tricyclic antidepressive and liquenoid eruption

Os autores apresentam um caso de erupçäo liquenóide desencadeada sete dias após o início do uso de nortriptilina e realizam uma revisäo de literatura, na qual näo foram encontrados relatos desta associaçäo. É ressaltada a necessidade dos médicos, em particular, dos dermatologistas manterem atençäo permanente para possíveis novas associaçöes causais entre uma fármaco e determinado quadro clínico cutâneo.