Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio

There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.     

Remission, dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials

OBJECTIVE: To summarize remission rates and dropouts due to adverse drug reactions (ADRs) or lack of efficacy (LoE) of serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs) in treating major depressive disorder. METHODS: We searched MEDLINE, EMBASE, IPA, and the Cochrane International Library from 1980-2005. Meta-analysis summarized outcomes from head-to-head randomized clinical trials comparing >or= 2 drugs from three antidepressants classes (SNRIs, and/or SSRIs, and/or TCAs) followed by >or= 6 weeks of treatment. Remission was a final Hamilton Depression Rating Scale (HAMD) score 0.05 for SNRIs versus TCAs; p < 0.001 for TCAs versus SSRIs and SNRIs versus SSRIs). When categorized as inpatients (n = 582) and outpatients (n = 1613), SNRIs had the highest remission rates (52.0% for 144 inpatients and 49.3% for 559 outpatients). SNRIs had lowest overall dropouts (26.1%), followed by SSRIs (28.4%), and TCAs (35.7%). Dropouts due to ADRs and LoE were 10.3% and 6.2% for SNRIs, 8.3% and 7.2% for SSRIs, and 19.8% and 9.9% for TCAs, respectively (p > 0.05 for ADR dropouts only). One limitation was the inclusion of only venlafaxine-XR; results may not be the same for immediate release forms. In addition, few studies reported remission rates. CONCLUSIONS: SNRIs had the highest efficacy remission rates (statistically significant for inpatients and outpatients), and the lowest overall dropout rates, suggesting clinical superiority in treating major depression.     

Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10.

Serotonin (5-HT) is a neurotransmitter and an immune modulator. In vitro, antidepressants with a serotonergic mode of action have, at concentrations within the therapeutical range, negative immunoregulatory effects, i.e., they increase the production rate of interleukin-10 (IL-10), a negative immunoregulatory cytokine. We have hypothesized that part of these effects may be explained by the serotonergic activities of antidepressants on immunocytes. This study was carried out to examine the effects of 5-HT, p-chlorophenylalanine (PCPA), a 5-HT depleting agent, flesinoxan (a 5-HT1A agonist), m-chlorophenylpiperazine (mCPP; a 5-HT2A/2C agonist), and ritanserin (a 5-HT2A/2C antagonist) on the production rate of interferon-gamma (IFNgamma), a proinflammatory cytokine, and IL-10 by whole blood stimulated with polyclonal activators. The IFNgamma/IL-10 production ratio was computed, since this ratio reflects the pro- versus anti-inflammatory capacity of cultured whole blood. We found that: 1) 5-HT, 150 ng/mL, 1.5 microg/mL, and 15 microg/mL significantly decreased the IFNgamma/IL-10 ratio; 2) PCPA (5 microM) significantly suppressed the production of IFNgamma and IL-10; 3) flesinoxan (15 ng/mL; 1.5 microg/mL) had no significant effects on the production of the above cytokines; and 4) mCPP (2.7 microg/mL) and ritanserin (5.0 microg/mL) suppressed the IFNgamma/IL-10 ratio. It is concluded that intracellular 5-HT may be necessary for an optimal synthesis of IFNgamma and IL-10, and that extracellular 5-HT concentrations at or above serum values may suppress the production of the proinflammatory cytokine IFNgamma. The negative immunoregulatory effects of antidepressive drugs are probably not related to their serotonergic activities.     

Remission,dropouts, and adverse drug reaction rates in major depressive disorder: a meta-analysis of head-to-head trials

ABSTRACT

Objective: To summarize remission rates and dropouts due to adverse drug reactions (ADRs) or lack of efficacy (LoE) of serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin-reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs) in treating major depressive disorder.

Methods: We searched MEDLINE, EMBASE, IPA, and the Cochrane International Library from 1980–2005. Meta-analysis summarized outcomes from head-to-head randomized clinical trials comparing ≥ 2 drugs from three antidepressants classes (SNRIs, and/or SSRIs, and/or TCAs) followed by ≥ 6 weeks of treatment. Remission was a final Hamilton Depression Rating Scale (HAMD) score ≤ 7 or Montgomery-Åsberg Depression Rating Scale (MADRS) ≤ 12. Intent-to-treat data were combined across study arms using random effects models, producing point estimates with 95% confidence intervals.

Results: We obtained data from 30 arms of 15 head-to-head trials with 2458 patients. SNRIs had the highest ITT remission rate (49.0%), then TCAs (44.1%), and SSRIs (37.7%) (?p > 0.05 for SNRIs versus TCAs; p < 0.001 for TCAs versus SSRIs and SNRIs versus SSRIs). When categorized as inpatients (?n = 582) and outpatients (?n = 1613), SNRIs had the highest remission rates (52.0% for 144 inpatients and 49.3% for 559 outpatients). SNRIs had lowest overall dropouts (26.1%), followed by SSRIs (28.4%), and TCAs (35.7%). Dropouts due to ADRs and LoE were 10.3% and 6.2% for SNRIs, 8.3% and 7.2% for SSRIs, and 19.8% and 9.9% for TCAs, respectively (?p > 0.05 for ADR dropouts only). One limitation was the inclusion of only venlafaxine‐XR; results may not be the same for immediate release forms. In addition, few studies reported remission rates.

Conclusions: SNRIs had the highest efficacy remission rates (statistically significant for inpatients and outpatients), and the lowest overall dropout rates, suggesting clinical superiority in treating major depression.     

Neuronal and immunological basis of action of antidepressants in chronic pain – clinical and experimental studies

The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain.We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However, evidence from basic science is needed to improve our understanding of the mechanisms of action and their possible pharmacodynamic interactions.     

The economic impact of introducing serotonin-noradrenaline reuptake inhibitors into the Brazilian national drug formulary: cost-effectiveness and budget-impact analyses

OBJECTIVE: To determine the cost effectiveness, from the Brazilian Ministry of Health viewpoint, of three antidepressant classes for major depressive disorder (MDD), and the budget impact of introducing serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) into the current Brazilian national drug formulary, assuming a 6-month treatment duration. METHODS: An existing decision-tree model was adapted to Brazil, based on local guidelines. Clinical data were obtained from published meta-analyses. Patients included adults aged > or =18 years with MDD, diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, third and fourth editions (DSM-III/IV), with moderate-to-severe disease (Hamilton Depression Rating Scale [HAMD] > or =15 or Montgomery-Asberg Depression Rating Scale [MADRS] > or =18), without co-morbidities or co-medications, receiving > or =6 weeks of treatment with SNRIs, selective serotonin reuptake inhibitors (SSRIs) and/or tricyclic antidepressants (TCAs). Clinical outcome was remission (HAMD < or =7 or MADRS < or =12). Direct costs (drugs, physician visits, hospitalisations) were included. Drug costs were obtained from the 2006 Brazilian National Drug Price List, and hospitalisation and physician costs from the 2006 Healthcare System database. Costs were valued in Brazilian Reais ($Brz), year 2006 values ($Brz1 = $US0.47). Univariate and Monte Carlo sensitivity analyses tested model robustness. RESULTS: Expected costs per patient treated were SNRIs $Brz4848; SSRIs $Brz5466; and TCAs $Brz5046, and overall success rates (primary plus secondary treatment across all decision tree branches) were SNRIs 78.1%; SSRIs 74.0%; and TCAs 76.4%. Average costs/success were SNRIs $Brz6209; SSRIs $Brz7385; and TCAs $Brz6602. SNRIs dominated in incremental cost-effectiveness analyses. Monte Carlo analysis confirmed drug classes' relative positions; however, there was considerable uncertainty. Introducing SNRIs into the formulary could generate average savings of 1% of the total budget, with a 52% probability of savings. CONCLUSIONS: SNRIs appear to be cost effective against SSRIs and TCAs when prescribed to patients with MDD in Brazil. However, their inclusion into the national drug list would generate minor savings compared with the current formulary of SSRIs and TCAs. Thus, we considered such inclusion as 'cost-neutral', since no major probability of savings or increased expenditures were observed.     

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.     

Specific serotonin and noradrenaline reuptake inhibitors (SNRIs). A review of their pharmacology,clinical efficacy and tolerability

Considerable progress has been made in improving the tolerability of antidepressant drugs. The classical tricyclic antidepressants (TCA) are still, however, the standard for efficacy. The selective serotonin reuptake inhibitors are better tolerated that the tricyclics, but their efficacy in major depression is, at best, equivalent to the earlier compounds and probably inferior in certain cases. Recently a new class of antidepressants has been developed that inhibit selectively the reuptake of both serotonin and noradrenaline with no affinity for the receptors responsible for the adverse effects of the TCAs. These compounds are referred to as the specific serotonin and noradrenaline reuptake inhibitors or SNRIs. This article reviews the pharmacological and clinical characteristics of the two principal compounds of this class, milnacipran (Ixel®) and venlafaxine (Effexor®). This new class of antidepressants, as represented by these two compounds, presents an efficacy comparable to TCAs with a more benign side-effect profile. Certain trials suggest that they may have efficacy superior to SSRIs, especially in more severe depression, with a tolerability which is globally similar. This class therefore appears to offer a potential useful addition to the therapeutic arsenal of antidepressant drugs. © 1998 John Wiley & Sons, Ltd.     

我院2005～2007年抗抑郁药利用分析

目的：评价我院门诊患者抗抑郁药的应用现状及趋势，为临床合理用药提供参考。方法：对我院2005～2007年门诊患者使用抗抑郁药的种类、销售金额、用药频度（DDDs）等进行统计、分析。结果：抗抑郁药的处方数、购药金额及DDDs等逐年增长，5-羟色胺再摄取抑制剂（SSRI）是临床治疗抑郁症的首选药物，3年处方数比例都在80％以上。帕罗西汀、西酞普兰、氟西汀、舍曲林等SSRI在3年中都是应用最多的药物。结论：本院的抗抑郁药应用基本合理。SSRI类抗抑郁药的应用3年中占主导地位．三环类抗抑郁药（TCAs）应用较少。     

Cost effectiveness of representatives of three classes of antidepressants used in major depression in the UK

OBJECTIVE: To estimate the cost effectiveness of representatives of three different classes of antidepressants used in major depression in the UK NHS. DESIGN, PATIENTS AND INTERVENTIONS: A decision-tree model for the treatment of major depression was constructed by interviewing UK GPs and psychiatrists (as part of a Delphi panel). An important part of the tree was that patients in primary care were treated until remission (pre-morbid state). Three classes of antidepressants (serotonin and noradrenaline reuptake inhibitors [SNRIs; venlafaxine], selective serotonin reuptake inhibitors [SSRIs; fluoxetine, paroxetine and fluvoxamine] and tricyclic antidepressants [TCAs; amitriptyline]) were compared by populating the tree with clinical success rates determined by a meta-analysis and a clinical trial. Where there were insufficient data from clinical trials a Delphi panel was used. Costs within the tree were taken from UK data sources. Six-monthly costs and cost effectiveness were then calculated. MAIN OUTCOME MEASURES AND RESULTS: Treatment costs for 6 months were pound 1285 for venlafaxine, pound 1348 for SSRIs and pound 1385 for amitriptyline. Cost effectiveness as measured by cost per symptom-free day was pound 21 for venlafaxine, pound 26 for SSRIs and pound 32 for TCAs (2001 values). Incremental cost-effectiveness analyses showed a treatment strategy of using venlafaxine and switching if necessary to an SSRI was dominant over all other strategies considered. Sensitivity testing demonstrated that the cost of an SSRI could be reduced to 4 pence daily and amitriptyline to zero before the expected 6-monthly cost of venlafaxine ceased to be the lowest. CONCLUSION: The SNRI, venlafaxine, may be a cost-effective option compared with the SSRIs and TCAs when used as a first-line drug for depression in primary care in the UK. As this is a model, cost effectiveness can be suggested but not proven.     

Treatment of childhood anxiety disorders: what is the place for antidepressants?

INTRODUCTION: Anxiety disorders represent one of the most prevalent forms of psychopathology among children and adolescents. As these problems tend to persist and have a negative impact on young people's development, there is a need for evidence-based interventions. Cognitive-behavioral therapy (CBT) is at present the treatment of first choice, but pharmacotherapy and in particular antidepressant medication may be a viable alternative or adjunct to CBT. AREAS COVERED: This paper provides a detailed overview of controlled treatment outcome studies on the efficacy of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) in children and adolescents with anxiety disorders. Further, a discussion is provided on how clinically anxious youths should be preferably treated, with special focus on the position of pharmacotherapy in the treatment process. EXPERT OPINION: The short-term efficacy of antidepressants in anxious youths is good, and this is particularly true for SSRIs. Therefore, this type of medication should be viewed as a viable treatment option, in particular for youths with obsessive-compulsive disorder (OCD) or other severe and pervasive anxiety disorders. More research is needed on the long-term effects, the consequences of prolonged use of this type of medication for children's developing brains and the efficacy of an intervention in which CBT and SSRIs are combined.     

Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder

The aim of the present clinical positron emission tomography study was to examine if the 5-HTT is a common target, both for tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Serotonin transporter (5-HTT) occupancy was estimated during treatment with TCA, SSRI and mirtazapine in 20 patients in remission from depression. The patients were recruited from out-patient units and deemed as responders to antidepressive treatment. The radioligand [11C]MADAM was used to determine the 5-HTT binding potential. The mean 5-HTT occupancy was 67% (range 28-86%). There was no significant difference in 5-HTT occupancy between TCA (n=5) and SSRI (n=14). 5-HTT affinity correlated with the recommended clinical dose. Mirtazapine did not occupy the serotonin transporter. The results support that TCAs and SSRIs have a shared mechanism of action by inhibition of 5-HTT.     

Severe depression: is there a best approach?

A major depressive episode can be categorised as severe based on depressive symptoms, scores on depression rating scales, the need for hospitalisation, depressive subtypes, functional capacity, level of suicidality and the impact that the depression has on the patient. Several biological, psychological and social factors, and the presence of comorbid psychiatric or medical illnesses, impact on depression severity. A number of factors are reported to influence outcome in severe depression, including duration of illness before treatment, severity of the index episode, treatment modality used, and dosage and duration of and compliance with treatment. Potential complications of untreated severe depression include suicide, self-mutilation and refusal to eat, and treatment resistance. Several antidepressants have been studied in the treatment of severe depression. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin 5-HT(2) receptor antagonists, monoamine oxidase inhibitors, and amfebutamone (bupropion). More recently, atypical antipsychotics have shown some utility in the management of severe and resistant depression. Data on the differential efficacy of TCAs versus SSRIs and the newer antidepressants in severe depression are mixed. Some studies have reported that TCAs are more efficacious than SSRIs; however, more recent studies have shown that TCAs and SSRIs have equivalent efficacy. There are reports that some of the newer antidepressants may be more effective than SSRIs in the treatment of severe depression, although the sample sizes in some of these studies were small. Combination therapy has been reported to be effective. The use of an SSRI-TCA combination, while somewhat controversial, may rapidly reduce depressive symptoms in some patients with severe depression. The combination of an antidepressant and an antipsychotic drug is promising and may be considered for severe depression with psychotic features. Although the role of cognitive behaviour therapy (CBT) in severe depression has not been adequately studied, a trial of CBT may be considered in severely depressed patients whose symptoms respond poorly to an adequate antidepressant trial, who are intolerant of antidepressants, have contraindications to pharmacotherapy, and who refuse medication or other somatic therapy. A combination of CBT and antidepressants may also be beneficial in some patients. Electroconvulsive therapy (ECT) may be indicated in severe psychotic depression, severe melancholic depression, resistant depression, and in patients intolerant of antidepressant medications and those with medical illnesses which contraindicate the use of antidepressants (e.g. renal, cardiac or hepatic disease).     

IL-6 levels decrease with SSRI treatment in patients with major depression

OBJECTIVE: Some evidence indicates that an immune response with an increased production of proinflammatory cytokines often accompanies major depression. The objective of this study was to examine the serum levels of IL-6 in patients with major depression and the changes occurring in IL-6 levels during treatment with selective serotonin reuptake inhibitors (SSRI). METHOD: Twenty-three patients with a DSM-IV diagnosis of major depressive disorder and 23 healthy matched controls were included in the study. The severity of depression was measured with the Hamilton rating scale for depression. Blood samples for IL-6 levels were obtained at baseline and at week 6 of treatment and IL-6 concentrations were evaluated using a solid phase sandwich enzyme immunoassay. All patients were treated with an SSRI. RESULTS: The IL-6 levels showed no statistically significant difference between the patients and the controls at baseline. However, IL-6 levels after treatment with SSRIs were significantly lower compared with the baseline IL-6 levels of both the patients and the controls. CONCLUSION: The results of this study suggest that proinflammatory cytokines show some changes during the course of treatment of major depression. These findings might also be considered as supporting the hypothesis of a modulatory role of antidepressants on the immune system.     

Differential effects of fluvoxamine, paroxetine and milnacipran for depression, especially with regard to age

INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) and dual serotonin and noradrenaline reuptake inhibitors (SNRIs) are the most commonly prescribed classes of antidepressants, yet it is not known whether one is superior to the other. It seems that an investigation of the characteristics of patients being treated with SSRIs and SNRIs would be useful in determining which patients would be most likely to benefit from these antidepressant medications. AIMS: The purpose of this retrospective study was to compare the response to fluvoxamine, paroxetine and milnacipran treatment for depression with regard to patient age. METHODS: A retrospective cohort analysis was carried out among depression outpatients treated in the Department of Psychiatry, Kawasaki Medical School Hospital, Kurashiki, Japan, in 2001. A total of 159 patients who met the criteria and who were receiving fluvoxamine, paroxetine and milnacipran were identified. To examine the influence of antidepressants with regard to patient age, the response rate of patients aged 50 years or older was compared with that of those aged 49 years or younger. RESULTS: In patients aged 49 years or younger, the clinical effect of fluvoxamine was greater than that of the other antidepressants. Conversely, in those aged 50 years or older, milnacipran had a tendency to be more effective than the others. CONCLUSIONS: The differential response of SSRIs and SNRIs with regard to age should help to guide clinicians in determining the selection of antidepressants for depression.     

Selective serotonin reuptake inhibitors: a review of efficacy and tolerability in depression

Selective serotonin reuptake inhibitors (SSRIs) are now generally regarded as effective and better tolerated alternatives to tricyclic antidepressants (TCAs) for the treatment of depression. SSRIs also seem to be as well tolerated as moclobemide, mirtazapine, venlafaxine, reboxetine and nefazodone and show comparable efficacy. Minor differences have been observed between some SSRIs and some of the newer antidepressants but these findings are far from conclusive. Widespread use of the SSRIs has highlighted some unforseen adverse effects associated with SSRIs, namely hyponatraemia, EPSE and sexual dysfunction. Overall, differences in efficacy and tolerability between individual SSRIs are small and clinically insignificant.     

In vitro immunoregulatory effects of antidepressants in healthy volunteers

Major depression is accompanied by an activation of the inflammatory response system (IRS) and antidepressants may have immunoregulatory activities. This study was carried out to compare the effect of imipramine, mianserin and lithium on the in vitro production of Th1-like cytokines, such as IL-2, IFN-gamma, lymphotoxin and Th2-like cytokines such as IL-4, IL-10 as well as IL-12 and TGF-beta. Peripheral blood mononuclear cells (PBMC) of 16 healthy volunteers were stimulated with polyclonal activators (phytohemagglutinin with lipopolysaccharide PHA + LPS) with or without incubation with imipramine, mianserin (1 microM) or lithium (1 mM). Imipramine and mianserin exhibited similar activities enhancing unstimulated IFN-gamma and IL-10 production. In PHA + LPS-stimulated PBMC both antidepressants inhibited IFN-gamma, IL-2 and lymphotoxin production (Th1-like cytokines) as well as IL-12 and IL-4 production. Under the same in vitro conditions, both antidepressants stimulated production of negative immunoregulatory cytokines such as IL-10 and TGF-beta. Lithium differed significantly from imipramine and mianserin, as it enhanced IL-2, IFN-gamma, IL-10 and TGF-beta production and inhibited only IL-4. All three examined antidepressants reduced IFN-gamma/IL-10 ratio. None of the antidepressants at the used concentrations induced apoptosis in PBMC so those changes in cytokine production were not the result of selective killing of certain cell subpopulations. Imipramine and mianserin at high concentrations negatively influenced reactive oxygen species (ROS) production in neutrophils, however, at concentrations in the therapeutical range none of the antidepressants used influenced "oxidative burst" in neutrophils. The results indicate that antidepressants exert immunoregulatory effects on human leukocyte functions, especially on cytokine production.     

Current trends in the development of new antidepressants

Early antidepressant medications e.g. tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are effective because they enhance either noradrenergic or serotonergic mechanisms, or both. Unfortunately, these compounds block cholinergic, histaminergic and alpha-1-adrenergic receptor sites, interact with a number of other medications and bring about numerous undesirable side effects. Several chemically unrelated agents have been developed and introduced in the past decade to supplement the early antidepressants. These include selective inhibitors of the reuptake of serotonin (the selective serotonin reuptake inhibitors (SSRIs)) or noradrenaline (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. All these newer compounds are the results of rational developmental strategies to find drugs that were as effective as the TCAs but of higher safety and tolerability profile. In spite of the remarkable structural diversity, most currently introduced antidepressants are monoamin based and modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research. It must be emphasised, however, that these newer antidepressants are far from the ideal ones, also resulting in undesirable side effects and requiring 2-6 weeks of treatment to produce therapeutic effect. Furthermore, approximately 30% of the population do not respond to current therapies. An important new development has been the emergence of potential novel mechanisms of action beyond the monoaminergic synapse. The results of recent novel developmental approaches have suggested that modulation of N-methyl-D-aspartate (NMDA), neuropeptide (substance P and corticotrophin-releasing factor) receptors and the intracellular messenger system may provide an entirely new set of potential therapeutic targets. This paper discusses the advances from monoamine-based treatment strategies and looks at the future developments in the treatment of depression.     

Changes in the prescribing pattern of antidepressant drugs in elderly patients: an Italian,nationwide, population-based study

Background

Despite the high use of antidepressants (ADs) among the elderly, there is limited information about the prescribing pattern of these drugs in the Italian elderly population. The aim of this study was to analyze the trend in the use of ADs in the Italian elderly patients in the years 2003-2009, and specifically, to evaluate rates and predictors of AD treatment discontinuation in depressed older patients.

Methods

The nationwide general practice Health Search Database (HSD) was used to identify AD users aged 65 years old and over from 2003 to 2009. ADs were categorized as (1) selective serotonin reuptake inhibitors (SSRIs); (2) serotonin-norepinephrine reuptake inhibitors (SNRIs); (3) tricyclic antidepressants (TCAs); (4) noradrenergic and specific serotonergic antidepressants (NaSSAs); and (5) other ADs. Incidence and prevalence of AD use per 1,000 inhabitants was calculated by drug class and single compound. We also measured rates and predictors of AD discontinuation (i.e., treatment gap?≥?60 days) during the first year of therapy.

Results

Overall, 39,557 AD users ≥65 years (17 % of the total HSD elderly population) were included in the study. SSRIs were increasingly and most frequently prescribed ADs (102.7-195.3 per 1,000 over seven years). The most common indications for AD use were depression and anxiety. Overall, 14 % of AD users continued their AD medication without treatment gaps, 27 % were intermittent AD users and 58 % discontinued their ADs during the first year of follow-up. Specific AD classes such as TCAs and ‘other ADs were found to be predictors of discontinuation. In depressed patients, the use of NaSSas, TCAs and ‘other ADs as well the concomitant use of >5 drugs (other than ADs) and living in Southern Italy were more likely to predict discontinuation.

Conclusion

ADs, especially SSRIs, are widely and increasingly prescribed in elderly Italian patients in recent years. The observed high AD discontinuation rates are likely to impact the achievement of a therapeutic endpoint in depressed patients. Patients who are at high risk of AD discontinuation such as those receiving multi-drug therapy or living in Southern Italy should be monitored more closely to improve benefits of AD treatments.     

Triple uptake inhibitors: therapeutic potential in depression and beyond

Drugs that interfere with the uptake and/or metabolism of biogenic amines have been used to treat depression for > 4 decades. Early medications such as tricyclic antidepressants and monoamine oxidase inhibitors are effective but possess many side effects that limit their usefulness. Selective serotonin reuptake inhibitors (SSRIs) or selective noradrenaline reuptake inhibitors (SNRIs) are the results of rational design to find drugs that are as effective as the tricyclic antidepressants, but with more selectivity towards a single monoamine transporter. The SSRI class of drugs, which includes fluoxetine, paroxetine and sertraline, were previously viewed as the agents of choice for treating major depression. Recently, inhibitors of both serotonin and noradrenaline uptake ('dual uptake inhibitors'; SSRI/SNRI such as venlafaxine, duloxetine and milnacipran) have gained acceptance in the market. However, neither the SSRIs nor the SSRI/SNRI are fully satisfactory due to a delayed onset of action, low rate of response and side effect that can affect compliance. An important recent development has been the emergence of the triple uptake inhibitors (SSRI/SNRI/selective dopamine reuptake inhibitor), which inhibit the uptake of all three neurotransmitters that are most closely linked to depression: serotonin, noradrenaline and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the uptake of all three of these neurotransmitters could produce a more rapid onset of action and possess greater efficacy than traditional antidepressants. This review discusses the evolution of biogenic amine-based therapies, the emerging strategies involved in the design and synthesis of novel triple uptake inhibitors as antidepressants and the therapeutic potential of triple uptake inhibitors.