Atualmente, a quantidade de pacientes que são diagnosticados com alguma forma de depressão, entre elas, o transtorno depressivo maior, aumenta consideravelmente, quer seja em razão de diagnósticos mais precisos ou pela própria epidemiologia da doença. Acresça-se o fato de que muitos pacientes, apesar da quantidade de tipos de antidepressivos atualmente disponíveis para a terapêutica, são refratários ao tratamento prescrito, em razão dos efeitos adversos apresentados, ou de seus efeitos tóxicos, ou ainda por simplesmente não se observar melhora com a prescrição seguida. Portanto, novos tratamentos farmacológicos são disponibilizados, e entre eles, a duloxetina, um duplo inibidor de recaptação de serotonina e norepinefrina. Para auxiliar na máxima eficácia em sua utilização, esse trabalho apresenta metodologia em HPLC para determinação simultânea de sete antidepressivos, tricíclicos e não tricíclicos, moclobemida, venlafaxina, citalopram, agomelatina, duloxetina, amitriptilina e sertralina, em plasma humano, para posteriormente ser aplicada na monitorização de pacientes depressivos. O simples e preciso método de preparo da amostra consiste na extração líquido-líquido, com recuperação entre 73% a 86% (exceto para moclobemida, de 55%), e para a duloxetina, de aproximadamente 73%. A separação foi obtida usando uma coluna em fase reversa Lichrospher® 60 RP-select B em LichroCART 250mm x 4mm, 5?m de diâmetro interno, Merck, sob condições isocráticas, com detecção em UV em 230nm, com fase móvel composta por 35% de uma mistura de acetonitrila:metanol 55/5 (v/v) e 65% de tampão acetato 0,25M, pH 4,4. As curvas padrões foram lineares em uma faixa de trabalho de 2,5-1000ng/mL para moclobemida, 5-2000ng/mL para venlafaxina, citalopram, agomelatina, duloxetina e amitriptilina, e 10-2000ng/mL para sertralina. As precisões intra e interensaios foram efetuadas em três concentrações (50, 200 e 500ng/mL). Os coeficientes de variação para a precisão intraensaio foram menores que 8,6% para todos os compostos e os coeficientes de variação para a precisão interensaio foram menores que 8,5%. Os limites de quantificação foram de 2,5ng/mL para a moclobemida, 5ng/mL para venlafaxina, citalopram, duloxetina, agomelatina, amitriptilina e 10ng/mL para sertralina. Não se observou qualquer interferência das drogas normalmente associadas aos antidepressivos. / Currently, the number of patients who are diagnosed with some form of depression, among them, major depressive disorder, increases considerably, either because of more accurate diagnosis or by the epidemiology of the disease. One should add the fact that many patients, despite the amount of types of antidepressants currently available for therapy are refractory to the treatment prescribed, because of the adverse effects appear, or their toxic effects, or by simply not observed improvement then the prescription. Therefore, new pharmacological treatments are available, and among them, duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. To assist in maximum effectiveness in its use, this paper presents a methodology on HPLC for simultaneous determination of seven antidepressants, tricyclic and non-tricyclic, moclobemide, venlafaxine, citalopram, agomelatine, duloxetine, amitriptyline and sertraline in human plasma, later to be applied in monitoring depressed patients. The simple and accurate method of sample preparation consists of the liquid-liquid extraction with recovery between 73% to 86% (except for moclobemide, 55%), and duloxetine, of approximately 73%. Separation was achieved using a reverse phase column Lichrospher® 60 RP-select B LiChroCART 4mm x 250mm, 5?m internal diameter, Merck, under isocratic conditions, with UV detection at 230nm, with a mobile phase consisting of a mixture of 35% acetonitrile:methanol 55/5 (v/v) and 65% 0.25M acetate buffer, pH 4.4. The standard curves were linear in the working range of 2,5-1000ng/mL for moclobemide, 5-2000ng/mL to venlafaxine, citalopram, agomelatine, duloxetine and amitriptyline and 10-2000ng/mL to sertraline. The intra and interassay precisions were performed at three concentrations (50, 200 and 500ng/mL). The coefficients of variation for intra-assay precision were less than 8.6% for all compounds and the coefficients of variation for interassay precision were lower than 8.5%. The limits of quantification were 2.5ng/mL for moclobemide, 5ng/mL for venlafaxine, citalopram, duloxetine, agomelatine, amitriptyline and 10ng/mL for sertraline. No interference of drugs normally associated with antidepressants was observed.

Atualmente, a quantidade de pacientes que são diagnosticados com alguma forma de depressão, entre elas, o transtorno depressivo maior, aumenta consideravelmente, quer seja em razão de diagnósticos mais precisos ou pela própria epidemiologia da doença. Acresça-se o fato de que muitos pacientes, apesar da quantidade de tipos de antidepressivos atualmente disponíveis para a terapêutica, são refratários ao tratamento prescrito, em razão dos efeitos adversos apresentados, ou de seus efeitos tóxicos, ou ainda por simplesmente não se observar melhora com a prescrição seguida. Portanto, novos tratamentos farmacológicos são disponibilizados, e entre eles, a duloxetina, um duplo inibidor de recaptação de serotonina e norepinefrina. Para auxiliar na máxima eficácia em sua utilização, esse trabalho apresenta metodologia em HPLC para determinação simultânea de sete antidepressivos, tricíclicos e não tricíclicos, moclobemida, venlafaxina, citalopram, agomelatina, duloxetina, amitriptilina e sertralina, em plasma humano, para posteriormente ser aplicada na monitorização de pacientes depressivos. O simples e preciso método de preparo da amostra consiste na extração líquido-líquido, com recuperação entre 73% a 86% (exceto para moclobemida, de 55%), e para a duloxetina, de aproximadamente 73%. A separação foi obtida usando uma coluna em fase reversa Lichrospher® 60 RP-select B em LichroCART 250mm x 4mm, 5?m de diâmetro interno, Merck, sob condições isocráticas, com detecção em UV em 230nm, com fase móvel composta por 35% de uma mistura de acetonitrila:metanol 55/5 (v/v) e 65% de tampão acetato 0,25M, pH 4,4. As curvas padrões foram lineares em uma faixa de trabalho de 2,5-1000ng/mL para moclobemida, 5-2000ng/mL para venlafaxina, citalopram, agomelatina, duloxetina e amitriptilina, e 10-2000ng/mL para sertralina. As precisões intra e interensaios foram efetuadas em três concentrações (50, 200 e 500ng/mL). Os coeficientes de variação para a precisão intraensaio foram menores que 8,6% para todos os compostos e os coeficientes de variação para a precisão interensaio foram menores que 8,5%. Os limites de quantificação foram de 2,5ng/mL para a moclobemida, 5ng/mL para venlafaxina, citalopram, duloxetina, agomelatina, amitriptilina e 10ng/mL para sertralina. Não se observou qualquer interferência das drogas normalmente associadas aos antidepressivos. / Currently, the number of patients who are diagnosed with some form of depression, among them, major depressive disorder, increases considerably, either because of more accurate diagnosis or by the epidemiology of the disease. One should add the fact that many patients, despite the amount of types of antidepressants currently available for therapy are refractory to the treatment prescribed, because of the adverse effects appear, or their toxic effects, or by simply not observed improvement then the prescription. Therefore, new pharmacological treatments are available, and among them, duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine. To assist in maximum effectiveness in its use, this paper presents a methodology on HPLC for simultaneous determination of seven antidepressants, tricyclic and non-tricyclic, moclobemide, venlafaxine, citalopram, agomelatine, duloxetine, amitriptyline and sertraline in human plasma, later to be applied in monitoring depressed patients. The simple and accurate method of sample preparation consists of the liquid-liquid extraction with recovery between 73% to 86% (except for moclobemide, 55%), and duloxetine, of approximately 73%. Separation was achieved using a reverse phase column Lichrospher® 60 RP-select B LiChroCART 4mm x 250mm, 5?m internal diameter, Merck, under isocratic conditions, with UV detection at 230nm, with a mobile phase consisting of a mixture of 35% acetonitrile:methanol 55/5 (v/v) and 65% 0.25M acetate buffer, pH 4.4. The standard curves were linear in the working range of 2,5-1000ng/mL for moclobemide, 5-2000ng/mL to venlafaxine, citalopram, agomelatine, duloxetine and amitriptyline and 10-2000ng/mL to sertraline. The intra and interassay precisions were performed at three concentrations (50, 200 and 500ng/mL). The coefficients of variation for intra-assay precision were less than 8.6% for all compounds and the coefficients of variation for interassay precision were lower than 8.5%. The limits of quantification were 2.5ng/mL for moclobemide, 5ng/mL for venlafaxine, citalopram, duloxetine, agomelatine, amitriptyline and 10ng/mL for sertraline. No interference of drugs normally associated with antidepressants was observed.

No description available.

Following decades of research on stress and its impact on behaviour, it is now widely accepted that selective psycho-pathologies, in particular clinical depression are more prevalent in humans with prior history of life-stress events. Interest in stress has led to questions about how it might affect the physiology and behaviour of animals exposed indirectly during gestational development. Not unexpectedly gestational stress has been shown to affect the offspring in several ways: endocrine responses to stress are elevated, fear, arousal and affective disturbances are all subject to vary if the pregnant animal is subjected to periods of aversive stimulation. Beginning in 1997, Michael Meaney of McGill University produced a series of publications suggesting that peri-natal events influence offspring and infant development, not via physical discomfort or physiological disturbance, but does so through modifications of maternal behaviour. Highly nurturant mothers (those who engage in active arched-back nursing (ABN), and spend more time licking and grooming (L/G) their pups), programme their offspring with improved cognitive abilities, decreased anxiety and fear, and reduced HPA axis hormone secretion. Low-nurturant mothers, who engage in less ABN and less L/G, tend to programme the opposite responses in their offspring. Our initial foray into this field was to investigate if gestational stress might also produce responses in the offspring via changes in maternal behaviour, and indeed ABN and L/G were reduced in dams which were subjected to gestational stress. We queried why stressed Dams would be less maternal towards their infants, and tested gestationally-stressed Dams in the Porsolt test for depressive-like behaviour. Our results suggested that these stressed Dams were actually depressed and this resulted in less maternal behaviour. Human mothers with depression are also less maternal and have been shown to divest themselves of infant care much like our prenatally-stressed Dams. On this basis we have proposed that gestational stress induced decrements in maternal behaviour represent a novel rat model for postnatal depression with face and construct validities. In the present work we have attempted to replicate the findings of Smythe's group (Smith et al., 2004), and have investigated the potential for antidepressants to alter the influence of gestational stress on maternal behaviours and depressive-like response, and whether or not the offspring are modified by maternal treatment with ant-depressants. Approximately 140 time-mated, lister hooded rats were generated in house, and subjected to gestational stress on days 10-20 (1hr restraint/day) or remained undisturbed in their home cages. Following birth, cohorts of control and stressed Dams were administered vehicle or an antidepressant (imipramine 15mg/kg; or sertraline 10mg/kg) once daily until postnatal day 10. We assessed maternal Porsolt activity, nurturance (ABN, L/G, nest building) and anxiety-like behaviour in the elevated plus maze (EPM). Representative offspring of each Dam's treatment conditions were maintained post weaning and assessed in the Porsolt and EPM to determine if any changes in maternal behaviour elicited by the antidepressants altered their behavioural programming. Our findings confirm that Dams show depressive-like symptoms following gestational stress, and that administration of antidepressants to the Dams reduces depressive-like behaviour and increased maternal care. We propose that rat gestational stress is a putative model for human postnatal depression. Prenatal stress effects on maternal behaviour in the rat Dam represent a novel, and innovative model for human postnatal depression.

Patients with both depression and anxiety show an increased tendency to deploy attention towards negative information. Cognitive models of the illnesses predict that these negative attentional biases are causally related to the symptoms of the disorders. Consistent with this, modifying attentional bias using either antidepressant medication or simple, computer based training tasks has previously been associated with altered symptomatology in both non-clinical and clinical populations. The current thesis aimed to investigate the mechanisms by which attentional bias training tasks alter attention. The investigations were conducted within an experimental neuroscience framework which has previously been successfully deployed in studies of antidepressant medication. The thesis then sought to use these initial results to improve the basic understanding of attentional control processes and, ultimately, guide the development of novel treatment strategies. The initial studies of the thesis characterised the behavioural and neural effects of attentional bias training. Behaviourally, a high degree of generalisation of the training effect was found across a range of emotional stimuli. Neurally, training was found to alter activity in a network of prefrontal regions known to be involved in the control of attention. Further analysis, utilising a computational learning model, suggested that the attentional control systems identified in this study could be understood in terms of expectation based processes. These studies therefore indicated that, in contrast to the predominately limbic effects of antidepressant medication, training initially altered the response of frontal control circuitry. The later studies of the thesis investigated possible strategies for extending the use of attentional bias training. Firstly, combining training with antidepressant medication was found to produce an interference effect on emotional memory suggesting that administering both interventions concurrently is likely to erode their cognitive impact. Lastly, attentional bias training was found not to alter attention in patients with bipolar disorder, with the results of the study indicating that standard assessments of attentional bias in this clinical population are likely to be unreliable. Overall, these studies indicate that attentional bias training may be used to alter the top-down control of attention to emotional information and suggest that such effects may interfere with the bottom-up effects of antidepressant drugs. More generally the work demonstrates the utility of using a cognitive-neuroscientific framework to explore the mechanisms and impact of novel therapeutic strategies.

Although extensive evidence suggests antidepressants are a non-effective treatment for the majority of depressive cases where they are prescribed and despite other developed countries taking steps to provide alternative treatments, Canada's prescription rates continue rising and no state action is being taken. The primary purpose of this study is to explore whether the media in English-speaking Canada, represented by its "newspaper of record," The Globe and Mail, has been performing its essential role in informing Canadians about the controversy surrounding antidepressants and the pharmaceutical system that that has made them central to treating depression. Data was collected in the form of newspaper articles from between 2000 and 2015 in order to analyze media coverage to ensure the essential facts were reported and to qualify to what degree a patient advocacy role challenging the norms of contemporary treatment has been adopted. / February 2017

Depression in adolescence is a major health problem, associated with poor psychological function and key risk factors both for later illness and suicidal behaviours. The antidepressant fluoxetine is commonly used in this population and it is shown to have a favourable benefit-to-risk profile. However, controversy still exists about the use of antidepressants in young people and there is little research focusing on underlying mechanisms of wanted and unwanted actions in this group. This doctoral thesis aims to investigate, for the first time, the acute effects of fluoxetine on emotional processing, using a combination of behavioural and neuroimaging techniques. The aim is to achieve a greater understanding of the mechanisms underlying fluoxetine use in depressed adolescents, in light of differences seen in their clinical presentation and response to antidepressant drugs. In the first study (Chapter Two), a single dose of fluoxetine was shown to decrease the recognition of anger in a sample of young adult volunteers, an effect not previously seen in acute studies of older participants. This effect may be particularly relevant for the treatment of adolescent depression, in which symptoms of anger and irritability are often prominent. Beyond this, fluoxetine was shown to increase the recognition of positive vs. negative facial information, and also exerted an anxiolytic-like influence, eliminating the emotion-potentiated startle effect. However, no influence was seen in measures of attentional vigilance to threat. In an attempt to overcome methodological limitations of this study, a paradigm was developed that is particularly sensitive to the detection of automatic biases towards threatening information (Chapter Three). Chapter Four describes a neuroimaging study with depressed adolescents, in which a single dose of fluoxetine was found to reduce amygdala activity in response to anger. Early changes in amygdala activity to fear correlated with decreased symptoms of anxiety and depression in the first 7-10 days of treatment. Chapter Five explores the effects of acute fluoxetine in a sample of high trait anger males. This study replicated the finding that fluoxetine acts to increase the recognition of positive information, whilst showing preliminary evidence for a reduction in attentional vigilance to angry faces. Overall, fluoxetine was found to decrease the processing of anger across studies. This effect was seen alongside a broader influence on positive vs. negative information and anxiolytic-like properties. Together, these results indicate that fluoxetine has direct effects on processes that are especially relevant to adolescent depression and suggest a potential cognitive mechanism for the efficacy of this particular antidepressant in adolescent patients.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Psychiatry Melbourne, 2005 / Sexual dysfunction is a common side effect of treatment with antidepressants, particularly those with a serotonergic action. The problem has significant implications for a patient’s quality of life and their compliance with medication. Given the often longterm nature of depressive disorders and their treatment this side effect poses a potential management challenge and may have serious prognostic implications. There are currently few evidence-based treatment strategies for the management of antidepressant induced sexual dysfunction. This study was conducted to evaluate the usefulness of granisetron, a serotonin type-3 receptor antagonist, in the treatment of women experiencing sexual dysfunction due to serotonergic antidepressants. Twelve women with antidepressant induced sexual dysfunction were assigned to receive either granisetron (N=5) or placebo (N=7) in a 14-day randomised, double blind, placebo controlled drug trial. Two subjects in the granisetron group did not complete the study. Each subject’s sexual functioning was assessed at baseline, day 7 and day 14 using both the Arizona Sexual Experience Scale and the Feiger Sexual Function and Satisfaction Questionnaire. No statistical differences were measured either at baseline or at endpoint between the granisetron and placebo groups. The study did not produce evidence supporting the usefulness of granisetron as an adjunctive medication in women with antidepressant induced sexual dysfunction. Furthermore, this finding does not suggest a primary role for the serotonin type-3 receptor in the pathogenesis of this side effect.

As recentes técnicas miniaturizadas de preparo de amostra, microextração em fase sólida (SPME) e in tube SPME, apresentam uma série de vantagens em relação aos métodos clássicos de extração (extração líquido-líquido e extração em fase sólida), tais como: não requer instrumentação analítica sofisticada, utilização de pequenas quantidades de solventes orgânicos, rápido processo operacional, permite automação das análises, a reutilização das fases extratoras, e integra em um único sistema a extração, concentração e introdução da amostra no cromatográfico. Esta dissertação tem como objetivo a padronização, validação e comparação dos métodos SPME/LC-UV com dessorção off line e in tube SPME/LC-UV, para a análise dos antidepressivos da nova geração (mirtazapina, citalopram, paroxetina, duloxetina, fluoxetina e sertralina) em amostras de plasma para fins de monitorização terapêutica. As variáveis: fase extratora, pH da matriz, tempo e temperatura de extração e de dessorção e força iônica apresentaram grande influência na eficiência do processo SPME. O método SPME/LC-UV padronizado, apresentou limite de quantificação (LQ) de 25 a 50 ng mL-1, ampla faixa de linearidade (LQ ? 500 ng mL-1, r2 > 0,9970) e precisão inter ensaios com coeficientes de variação menor que 15% para todos os analitos. Apesar das baixas taxas de recuperação obtidas, de 8,1% (citalopram) a 17,1% (mirtazapina), o método SPME/LC-UV apresentou seletividade e sensibilidade analítica adequada. As variáveis: pH da matriz, fluxo e número de ciclos aspirar/dispensar e volume de amostra apresentaram grande influência na eficiência do processo in tube SPME. A etapa de precipitação de proteínas do plasma, anterior ao processo de extração, foi necessária para a eliminação dos compostos endógenos. O método in tube SPME/LC-UV padronizado apresentou seletividade adequada, precisão inter ensaios com coeficiente de variação menor que 10%, LQ de 20 a 50 ng mL-1, linearidade na faixa de concentração do LQ a 500 ng mL-1, com r2 > 0,9983 para todos os analitos e recuperação absoluta de 5,32% (mirtazapina) a 43,5% (sertralina). A técnica in tube SPME, quando comparada à SPME, permitiu a automação das análises, menor exposição do analista às amostras biológicas e solventes orgânicos, menor tempo de análise e menor volume de amostra de plasma. A eficácia dos métodos, SPME/LC-UV e in tube SPME/LC-UV, foi comprovada através das análises de amostras de plasma de pacientes em terapia com os antidepressivos, para fins de monitorização terapêutica. / The recent miniaturized sample techniques preparation, solid phase microextraction (SPME) and in tube SPME, present several advantages when compared with classic extraction methods (liquid-liquid extraction and solid phase extraction), such as: it does not require sophisticated analytical instrumentation, use small organic solvent amounts, fast operational process, automation of the analyses, reuse extraction phases, and incorporates, into a single procedure, sample extraction, concentration and sample introduction. The aim of this work is development, validation and comparison of methods SPME/LC-UV with off line desorption and in tube SPME/LC-UV, for analyses of antidepressants of the new generation (mirtazapine, citalopram, paroxetine, duloxetine, fluoxetine and sertraline) in plasma samples for therapeutic drug monitoring. Variables: extraction phase, matrix pH, time and temperature of extraction and desorption and ionic strength showed great influence in SPME process efficiency. The method SPME/LC-UV presented limit of quantification (LOQ) variety from 25 to 50 ng mL-1, wide range the of linearity (LOQ 500 ng mL-1, r2 > 0.9970) and interassays precision with coefficient of variation lower than 15% for all analytes. Although the low recovery, from 8.1% (citalopram) to 17.1% (mirtazapine), the method SPME/LC-UV presented adequate selectivity and analytical sensitivity. Variables: matrix pH, flow and number of aspirate/dispense cycles and sample volume showed great influence in the in tube SPME process efficiency. The protein precipitation of the plasma steps, previous to the extraction process, was necessary for the endogenous compounds elimination. The method in tube SPME/LC showed adequate selectivity, interassays precision with coefficient of variation lower than 10%, LOQ variety from 20 to 50 ng mL-1, linearity in range concentration from LOQ to 500 ng mL-1, with r2 > 0.9983 for all analytes and recovery from 5.32% (mirtazapine) to 43.5% (sertraline). The technique in tube SPME, compared with the SPME, permitted the automation of the analyses, minor exposition of the analyst to the biological samples and organic solvent, shorter analyses time and minor plasma sample volume. The effectiveness methods, SPME/LC-UV and in tube SPME/LC-UV, was proven through the analyses of plasma samples of patients in therapy with antidepressants, for therapeutic drug monitoring.

O objetivo deste estudo foi realizar uma analises econômica dos fármacos antidepressivos aplicáveis no tratamento da distimia, objetivando o uso racional de fármacos. O debate a cerca da competição alegada aos novos fármacos antidepressivos (SSRI e atípicos) e os antigos, menos dispendiosos como TCAs e IMAOs têm implicações para a prática clínica e prescrições. Distimia é uma depressão de natureza crônica mas de menor severidade que a depressão maior. Vários tratamentos com diferentes fármacos têm sido propostos, mas em decorrência de muitas variáveis, não é possível até o presente momento determinar qual o tratamento de escolha . A conclusão foi que a escolha do fármaco deve ser realizada levando-se em conta características individuais, efeitos colaterais e custos. / The objective of this study was to do the economic analyses of antidepressant drugs support for the treatment of dysthymia for the rational use perspective of antidepressants d rugs. The debate over the competing claims newer antidepressants drugs (SSRIs and atypical) and the older, cheaper TCAs and IMAOs has implications for clinical practive and prescribing expenditure. Dysthymia is a depressive disorder of chronic nature but of less severity than major depression. Many d rug treatments have been proposed for the treatment of dysthymia, but with so many potencial comparisons it is not possible at the present time to determine which is the treatment of choice. The conclusion was that the choice of drug must be made maching patient individual characteristics, side-effects and costs.