Generation Antidepressants Research Articles

Entropía aproximada del efecto placebo en ensayos clínicos con antidepresivos de nueva generación

Recent research concluded that antidepressant drugs are ineffective in treating moderate or severe depression. Statistically, there are no differences between the results with active drugs or placebo. Some authors have attributed this fail to variability or irregularity of the placebo effect in depressed patients or artifacts induced by meta-analysis.This fact highlights the difficulties faced by the research of psychoactive drugs in depression and revives the debate about the usefulness of the employ of placebo in these studies. This study aimed to determine the variability of the placebo effect in antidepressant clinical trials in simple linear and nonlinear complex models. We performed a secondary analysis of data from 35 trials presented as evidence to the Food and Drug Administration (FDA) for approval of new generation antidepressants, all double-blind controlled with placebo in patients with unipolar mild or moderate depressive disorder, according to the criteria of "Diagnostic and Statistical Manual of Mental Disorders (DSM).Articles reviewed included 5133 patients . We have calculated the coefficient of variability, autocorrelation and approximate entropy of the placebo and treatment effects to determine whether the variability or regularity between different studies should be attributed to meta-analytical methods, placebo effect or ineffective treatment itself. The coefficient of variability in the placebo group was 26.49% and 18.81% in the treatment group. The placebo effect autocorrelation was within the confidential limits while the treatment group was outside showed cyclical variation. The approximate entropy value (ApEn N=35,m=2,R=2) in the placebo group was 0.5579 and 0.5744 in treatment group, leading to the conclusion that placebo effect is highly consistent and regular in complex non-linear models. The apparent variability of the placebo effect in depressed patients slould be due to artifacts induced by simple linear models analysis.

Dépression : concepts actuels

Since the eighties, the discovery of second generation antidepressants has led to an improvement of knowledge and practices in the field of major depressive disorders. From a short term perspective focusing on the major depressive episode, a long term approach of major depressive disorders has emerged with definitions of relapses and recurrences. The outcome of major depressive disorders under treatment has also been focused on, with the description of partial or complete remission, recovery or residual symptoms. Nowdays, these definitions are used in daily practice. They are also used as phenotypic descriptions of physiopathologic studies of major depressive disorders, which will certainly enable new therapeutic improvements in this area.

Efficacy of Second Generation Antidepressants in Late-Life Depression: A Meta-Analysis of the Evidence

Objective:Second-generation antidepressants are commonly used to treat major depression in late-life. This systematic review and meta-analysis was undertaken to assess the evidence for efficacy of second-generation antidepressants in late-life major depression. Methods:The Cochrane Library (2006 (3)), MEDLINE (1966 to August 2006), and meeting presentations were searched for trials of second-generation antidepressants (nontricyclics) marketed in the United States. Published and unpublished placebo-controlled randomized clinical trials in outpatients 60 years and older, with nonpsychotic, unipolar major depression were selected. Clinical characteristics and outcomes were extracted. Outcomes were expressed as odds ratios (OR), risk differences, and weighted mean differences. Results:Ten unique trials (four unpublished) with 13 contrasts met selection criteria. Trials were 6–12 weeks duration, and included 2,377 patients who received active drug and 1,788 received placebo. The ORs by meta-analysis for respon...

Prescribing practices in psychiatric hospitals in Eastern Europe

Background There has been no evidence about the prescribing practices in psychiatric care in Eastern Europe. Aims To examine the patterns of psychotropic prescribing in five countries of Eastern Europe. Method We conducted a one-day census of psychiatric treatments used in eight psychiatric hospitals in Albania, Croatia, Macedonia, Serbia and Romania. We examined clinical records and medication charts of 1304 patients. Results The use of polypharmacy was frequent across all diagnostic groups. Only 6.8% of patients were on monotherapy. The mean number of prescribed drugs was 2.8 (SD 0.97) with 26.5% receiving two drugs, 42.1% receiving three drugs and 22.1% being prescribed four or more psychotropic drugs. Typical antipsychotics were prescribed to 63% and atypical antipsychotics to 40% of patients with psychosis. Older generations of antidepressants were prescribed to 29% of patients with depression. Anxiolitic drugs were prescribed to 20.4% and benzodiazepines to 68.5% of patients. One third of patients received an anticholinergic drug on a regular basis. Conclusions Older generation antipsychotics and antidepressants were used more frequently than in the countries of Western Europe. Psychotropic polypharmacy is a common practice. There is a need for adopting more evidence-based practice in psychiatric care in these countries.

The concept of depression as a dysfunction of the immune system.

Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids, as occurs in chronically stressful situations and in depression, contribute to the behavioural changes associated with depression.A defect in serotonergic function is associated with hypercortisolaemia and the increase in proinflammatory cytokines that accompany depression. Glucocorticoids and proinflammatory cytokines enhance the conversion of tryptophan to kynurenine. In addition to the resulting decrease in the synthesis of brain serotonin, this leads to the formation of neurotoxins such as the glutamate agonist quinolinic acid and contributes to the increase in apoptosis of astrocytes, oligodendroglia and neurons.The importance of the inflammation hypothesis of depression lies in raising the possibility that psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants.

Microextraction in packed sorbent for analysis of antidepressants in human plasma by liquid chromatography and spectrophotometric detection

A sensitive and reproducible method by microextraction packed sorbent and liquid chromatography with UV detection (MEPS/LC–UV) is described for the determination of new generation antidepressants (sertraline, mirtazapine, fluoxetine, citalopram and paroxetine) in human plasma samples. The MEPS variables, such as sample volume, pH, number of extraction cycles (draw–eject), and desorption conditions (solvent and solvent volume of elution) influenced the MEPS/LC efficiency significantly. Important factors in the optimization of MEPS efficiency, as well as washing steps and carryover effect are discussed. The analyses were carried out using small sample volumes (400 μL), and in a short time period (3 min for the entire sample preparation step). The MEPS/LC–UV method was shown to be linear at concentrations ranging from the limit of quantification (LOQ) to 1000 ng mL −1. The LOQ values ranged from 10 to 25 ng mL −1. The inter-day precision of the method presented coefficient of the variation ranging from 1.3% to 8.7%. On the basis of analytical validation, it is shown that the MEPS/LC–UV methodology is adequate for antidepressant analysis, from therapeutic to toxic levels. In order to evaluate the proposed method for clinical use, the MEPS/LC–UV method was applied to analysis of plasma samples from elderly depressed patients.

Milnacipran: a unique antidepressant?

Tricyclic antidepressants (TCAs) are among the most effective antidepressants available, although their poor tolerance at usual recommended doses and toxicity in overdose make them difficult to use. While selective serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs, they have their own specific problems, such as the aggravation of sexual dysfunction, interaction with coadministered drugs, and for many, a discontinuation syndrome. In addition, some of them appear to be less effective than TCAs in more severely depressed patients. Increasing evidence of the importance of norepinephrine in the etiology of depression has led to the development of a new generation of antidepressants, the serotonin and norepinephrine reuptake inhibitors (SNRIs). Milnacipran, one of the pioneer SNRIs, was designed from theoretic considerations to be more effective than SSRIs and better tolerated than TCAs, and with a simple pharmacokinetic profile. Milnacipran has the most balanced potency ratio for reuptake inhibition of the two neurotransmitters compared with other SNRIs (1:1.6 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine), and in some studies milnacipran has been shown to inhibit norepinephrine uptake with greater potency than serotonin (2.2:1). Clinical studies have shown that milnacipran has efficacy comparable with the TCAs and is superior to SSRIs in severe depression. In addition, milnacipran is well tolerated, with a low potential for pharmacokinetic drug–drug interactions. Milnacipran is a first-line therapy suitable for most depressed patients. It is frequently successful when other treatments fail for reasons of efficacy or tolerability.

Antidepressants and the placebo response

To evaluate new generation antidepressants in relation to the placebo response. I review meta-analyses in which response to antidepressant medication and response to placebo were calculated. All but one of these meta-analyses included unpublished as well as published trials. Most trials failed to show a significant advantage of SSRIs over inert placebo, and the differences between drug and placebo are not clinically significant for most depressed patients. Documents obtained from the U.S. Food and Drug Administration (FDA) revealed an explicit decision to keep this information from the public and from prescribing physicians. Because they do not incur drug risks, exercise and psychotherapy, which show at benefits at least equal to those of antidepressants, may be a better treatment choice for depressed individuals.

Wishing Away Inflammation? New Links between Serotonin and TNF Signaling

Wishing Away Inflammation? New Links between Serotonin and TNF Signaling

Efficacité de l’escitalopram et sévérité de la dépression : nouvelles données

According to recent data in the literature, severe forms of depression represent almost half of all characterised episodes of depression; in view of this their treatment is a real public health challenge. According to the recommendations of various health authorities, treatment first relies on antidepressant medication. A recent meta-analysis of 12 new generation antidepressants has shown that these products are not all equivalent in the treatment of major depression, and that differences exist in terms not only of efficacy but also of acceptability. These differences in efficacy also appear true in the treatment of severe depression. Very recent publications, with a meta-analysis carried out on large cohorts of patients included in clinical trials, have shown the superior efficacy of escitalopram (which is the most active enantiomer of the racemic component, citalopram) in severe depression (defined by a total score on the MADRS scale > or =30). A pooled analysis by Kilts et al. assessed the response to treatment according to the baseline severity of the depression, under escitalopram and under six comparable products: citalopram, duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine. It showed that the rate of responders to the different treatments decreased when baseline severity increased, which agrees with the data in the literature, except for escitalopram, with which the rate of responders remained stable. The pooled analysis of Kennedy et al., that partly referred to the same studies, showed that for all the patients exhibiting severe depression, escitalopram was significantly superior to the other same six comparable products (mean estimated difference of 1.8 on the total MADRS score [p<0.0001]; a rate of 64.4 responders vs 55.8% [odds ratio=1.60, p<0.0001]; rate of remission of 47.7 vs 41.6% [odds ratio=1.39, p<0.0007]). In parallel with the statistical significance of the results, the criterion of clinical pertinence of the differences revealed between the medicinal products is highly significant. Regarding antidepressants, the criteria of clinical pertinence most frequently applied are the difference in rate of responders, the number needed to treat (NNT) and, to a lesser extent, the difference between the rates of patients in remission and the difference in the effect of treatment. According to these criteria, Montgomery and Möller (2009) assessed the clinical pertinence of the results showing the superior efficacy of escitalopram on three products: citalopram, paroxetine and duloxetine. Hence, they established this clinical pertinence for all of the depressed patients, but also in the particular case of severe depression. All these new data confirm the interest of escitalopram in the treatment of characterised depression and notably in the severe forms, with a particularly favourable efficacy/acceptability ratio.

S.27.05 From gene to brain: neurotransmitter pathways to depression in humans

This review summarises the evidence that chronic low grade inflammation plays an important role in the pathology of depression. Evidence is provided that pro-inflammatory cytokines, together with dysfunctional endocrine and neurotransmitter systems, provide a network of changes that underlie depression and may ultimately contribute to the neurodegenerative changes that characterise depression in the elderly.Antidepressants attenuate the inflammatory changes and hypercortisolaemia by reducing the release of the pro-inflammatory cytokines from activated microglia, and by sensitizing the glucocorticoids receptors in the HPA axis. These effects correlate with an improvement in monoamine neurotransmitter function. The possible mechanisms whereby this cascade of changes occurs are outlined.In conclusion, the mechanisms whereby antidepressants act should now consider the involvement of the immune and endocrine systems in addition to the central neurotransmitters. This may open up possibilities for a new generation of antidepressants in the future.

P.l.c.058 Evaluation of an inpatient therapeutic interchange protocol for second generation antidepressants and clinical follow-up

P.l.c.058 Evaluation of an inpatient therapeutic interchange protocol for second generation antidepressants and clinical follow-up

Modern Bioanalytical Methods for the Rapid Detection of Antidepressants: SNRIs and SSRIs in Human Biological Samples

Serotonin-norepinephrine-reuptake inhibitors (SNRIs) and selective serotonin-reuptake inhibitors (SSRIs) belong to a new generation of antidepressants used in the treatment of depression and other mood disorders. SSRIs act as reuptake inhibitors primarily via the inhibition of the neuronal reuptake of serotonin (5-HT) in the CNS. SNRIs have additional inhibitory activity at noradrenaline-reuptake sites. Different analytical methods for the routine monitoring and toxicological screening of SNRIs and SSRIs have been developed. Rapid quantification is a necessity for clinical use, allowing the possibility of diagnostics. This review focuses on recent advances of the methods that concern the determination of SSRIs and SNRIs in human biological samples. Sample preparation methodologies are discussed, because sample pretreatment is the most limiting and crucial step in analysis of biological matrices. Furthermore, information concerning the mechanism of action, side effects and toxicity are also given.

Antidepressants, suicidality and rebound effect: evidence of similitude?

Samuel Hahnemann noticed that palliative treatments for the symptoms of chronic diseases, after an initial improvement, provoked symptoms similar but stronger symptoms to those initially suppressed. He regarded this as a consequence of the vital reaction of the organism: an automatic and instinctive capacity to return to the initial health condition altered by medicines. Using this homeostatic conception of the organism as a treatment rationale, Hahnemann proposed the therapy of similarity, administering to the patients medicines capable of causing, in healthy individuals, similar symptoms to the natural disease. Based on experimental observations, he proposed that the primary action of the drug was followed by the secondary and opposite action of the organism, inaugurating homeopathic pharmacology, and alerting to the harmful consequences of palliative medicines in susceptible individuals. Such iatrogenic events can be observed in contemporary medicine, after the withdrawal of modern enantiopathic medicines, according to the study of the rebound effect or paradoxical reaction of the organism. This study reviews the recent studies which describe suicidality after the suspension or discontinuation of second generation antidepressants according to the hypothesis of the paradoxical reaction of the organism. Rebound and withdrawal effects, including suicidality occur with antidepressant drugs. They are relatively rare but more intense than the primary action of the drug. The probability of such effects is influenced by patient factors including age and diagnosis, and drug factors including half-life.

Anxiety does not predict response to antidepressant treatment in late life depression: results of a meta‐analysis

Previous studies of mixed aged and older adult samples with major depressive disorder (MDD) reported reduced depression response in anxious patients, but a systematic review and analysis has not been performed. Our aim was to determine if anxiety predicts antidepressant response in previously identified placebo-controlled trials of second generation antidepressants for late-life depression. From a previous systematic review that identified ten randomized, placebo-controlled trials of community dwelling patients aged 60 or older with major depression, anxious patients were identified by a score >or=7 on the anxiety/somatization factor of the Hamilton Depression Rating Scale (HDRS). Response was defined as 50% or greater improvement on the HDRS or the Montgomery Asberg Depression Rating Scale. A meta-analysis was performed using a random effects model to calculate Odds Ratios (OR). Data were available from eight trials having ten drug-placebo contrasts that included 2322 anxious and 1387 non-anxious patients. The odds ratio for response to drug compared to placebo in anxious patients was 1.57 (95% CI 1.15, 2.14; z = 2.86, n = 10, p < 0.001), in non-anxious patients was 1.44 (95% CI 1.15, 1.80, z = 3.21, n = 10, p < 0.001), and did not differ between groups. Pooled response rates to drug and placebo respectively were 49.4% vs 37.4% in anxious patients and 44.2 vs 35.5% in non-anxious patients. In randomized, placebo-controlled trials, anxiety in late-life depression was not associated with decreased response to second generation antidepressants.

From Descartes to Desipramine: Psychopharmacology and the Self

Despite the remarkably widespread use of the new generation of antidepressants, almost everything we know about their effects comes from animal studies and clinical trials in which the sole parameter of interest is depressive symptomatology. Almost nothing is known about the effects that antidepressants have on cognition, affect, or motivation when used over a period of months or years. Nor do we understand what effects, if any, antidepressants have on what we think of as the self. In this article, we argue that neither psychiatry nor philosophy, in their current state, are well equipped to think about these issues. In order to explore this idea, we consider the neurobiology of romantic love and its relation to antidepressant neurochemistry. This case study, we suggest, supports the view that antidepressants are very likely to have significant effects on personhood as well as the suggestion that we are in need of new ways of thinking about the self and its pathologies.

Anticonvulsants – Antidepressants Pharmacokinetic Drug Interactions: The Role of the CYP450 System in Psychopharmacology

The combined treatment with anticonvulsant and antidepressant drugs is reported in both neurologic and psychiatric practice; it is, therefore, evident that the issue of managing such type of polytherapy is frequently encountered by clinicians. To review current literature on pharmacokinetic interactions between anticonvulsant and antidepressant drugs. A search of MEDLINE and EMBASE was conducted for original papers and review articles published in English between January 1970 and July 2008. Among antidepressants, older compounds, such as tricyclics and monoaminoxidase inhibitors, have higher potential for interactions than newer ones. In almost all cases, drug dosages need to be adjusted when prescribed in combination with inducers such as carbamazepine, barbiturates and phenytoin. Data concerning new antiepileptic drugs are still limited; however, in several cases, new generation compounds are characterized by a favorable pharmacokinetic profile, thus, limiting the risk of interactions. In fact, gabapentin, topiramate, lamotrigine and levetiracetam are expected to be safely used in association with antidepressants, although it should be considered that topiramate may have interactions at doses higher than 200 mg. Although new generation antidepressants are not equivalent in their potential for interactions, their use seems to be safe in combination with anticonvulsant drugs. When prescribed with well-known inducers, the drug dose needs to be adjusted in relationship with the clinical response.

Strategy for a Genetic Assessment of Antipsychotic and Antidepressant- Related Proarrhythmia

Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic. In this field, accurate understanding of genetics, which per se is a non-controllable risk factor, may help clinicians to prevent life-threatening side effects. So far, a number of genes have been associated with arrhythmia: SCN5A, SCN4B, CACNL1AC, KCNH2, KCNQ1, KCNE1, ANK2, ALG10, KCNJ2, KCNE2, RYR2, KCND3, KCND2, ACE, NOS1AP, CASQ2 and Rad. These genes represent good candidates for the definition of a genetic pro-arrhythmic profile. A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed. Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics. A list of relevant rare mutations within the selected genes is presented, together with a complete list of Tag SNPs covering the whole genetic sequence. The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics. The selected variants, both mutations and polymorphisms, may help in defining a next-to-come genetic assessment to be performed before drug prescription in order to improve drug safety.

Pharmacotherapy of Schizophrenic Patients: Preponderance of Off-Label Drug Use

Multiple drug class combinations are often prescribed for the treatment of schizophrenia, although antipsychotic monotherapy reflects FDA labeling and scientific justification for combinations is highly variable. This study was performed to gain current data regarding drug treatment of schizophrenia as practiced in the community and to assess the frequencies of off-label drug class combinations. 200 DSM IV-diagnosed schizophrenic patients recruited from community treatment sources participated in this cross-sectional study of community based schizophrenic patients. Drug class categories include First and Second Generation Antipsychotic drugs (FGA and SGA, respectively), mood stabilizers, antidepressants and anti-anxiety drugs. 25.5% of patients received antipsychotic monotherapy; 70% of patients received an antipsychotic and another drug class. A total of 42.5% of patients received more than one antipsychotic drug. The most common drug class combination was antipsychotic and a mood stabilizer. Stepwise linear discriminant function analysis identified the diagnosis of schizoaffective schizophrenia, history of having physically hurt someone and high scores on the General Portion of the PANSS rating scale predicted the combined use of an antipsychotic drug and a mood stabilizer. “Real world” pharmacotherapy of schizophrenia has developed its own established practice that is predominantly off-label and may have outstripped current data support. The economic implications for public sector payers are substantial as well as for the revenue of the pharmaceutical industry, whose promotion of off-label drug use is an increasingly problematic. These data are consistent with the recognition of the therapeutic limitations of both first and second generation antipsychotic drugs.

Cochrane review: Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents

AbstractBackgroundDepressive disorders are common in young people and are associated with significant negative impacts. Selective serotonin reuptake inhibitors (SSRIs) are often used, however, evidence of their effectiveness in children and adolescents is not clear. Furthermore, there have been warnings against their use in this population due to concerns about increased risk of suicidal ideation and behaviour.ObjectivesTo determine the efficacy and adverse outcomes, including definitive suicidal behaviour and suicidal ideation, of SSRIs compared to placebo in the treatment of depressive disorders in children and adolescents.Search strategyWe searched the CCDAN Trials Register, MEDLINE, PSYCHINFO and CENTRAL. Reference lists were checked, letters were sent to key researchers and internet databases searched.Selection criteriaWe included published and unpublished randomised controlled trials.Data collection and analysisTwo or three review authors selected the trials, assessed the quality and extracted trial and outcome data. We used a fixed‐effect meta‐analysis. The relative risk was used to summarise dichotomous outcomes and the mean difference to summarise continuous measures.Main resultsTwelve trials were eligible for inclusion, with ten providing usable data. At 8‐12 weeks, there was evidence that children and adolescents 'responded' to treatment with SSRIs (RR 1.28, 95% CI 1.17 to 1.41). There was also evidence of an increased risk of suicidal ideation and behaviour for those prescribed SSRIs (RR 1.80, 95% CI 1.19 to 2.72). Fluoxetine was the only SSRI where there was consistent evidence from three trials that it was effective in reducing depression symptoms in both children and adolescents (CDRS‐R treatment effect ‐5.63, 95% CI ‐7.38 to ‐3.88), and 'response' to treatment (RR 1.86, 95% CI 1.49 to 2.32). Where rates of adverse events were reported, this was higher for those prescribed SSRIs.Authors' conclusionsCaution is required to interpret the results. First, there were methodological issues, including high attrition, issues regarding measurement instruments and clinical usefulness of outcomes, often variously defined across trials. Second, patients seen in clinical practice are likely to be more unwell, and at greater risk of suicide, compared to those in the trials, and it is unclear how this group would respond to SSRIs. This needs to be considered, along with the evidence of an increased risk of suicide related outcomes in those treated with SSRIs. It is unclear what the effect of SSRIs is on suicide completion. While untreated depression is associated with the risk of completed suicide and impacts on functioning, it is unclear whether SSRIs would modify this risk in a clinically meaningful way.Plain language summarySelective serotonin reuptake inhibitors (new generation antidepressants) for depressive disorders in children and adolescentsDepressive disorders are common in young people and have significant negative impacts. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of depressive disorder in children and adolescents. The review of 12 trials highlighted limitations with the data, making it difficult to answer questions about the effectiveness and safety of SSRIs in clinical practice. Overall, there was evidence of greater reduction in depressive symptoms to a predetermined level deemed a "response" on SSRI compared to placebo. However, response was variously defined across trials making interpretation of this outcome difficult. Fluoxetine was the only SSRI where there was consistent evidence from three trials showing that it was effective in reducing symptoms of depressive disorder in both children and adolescents. Those receiving fluoxetine had a greater improvement, scoring on average 5.63 lower on the Children's Depression Rating Scale‐Revised (CDRS‐R) scale (range 17‐113) than those on placebo. It is unclear whether this small difference is a meaningful outcome for children and adolescents with depressive disorders. Nor is it apparent how children and adolescents with co‐morbid conditions and at risk of suicide would respond to SSRIs, given this group were largely excluded from the trials.There is evidence that those prescribed SSRIs are at an increased risk of suicidal ideation and attempts (RR 1.80, 95% CI 1.19 to 2.72) consistent with a number of similar reviews in the area. Additionally, there was an increased risk of other adverse events. It is unclear how this relates to the risk of suicide completion. The trials were not designed to measure any of the suicide related outcomes adequately. At the same time, untreated depression is associated with the risk of completed suicide and impacts on academic and social functioning, however, it is not clear whether treatment with an SSRI will modify this risk in a clinically meaningful way for children and young people.Clinicians need to provide accurate information to children and adolescents and their families about the uncertainties regarding the benefits and risks of SSRI medication for depressive disorders.