Prescribing selective serotonin reuptake inhibitors in older age

Apart from commercial reasons, two motivations have led to the introduction of SSRIs to replace the first and second generation antidepressants already available. One was the search for a more rational treatment, based on specific mechanisms, the other the development of effective treatments with fewer side effects, particularly for older patients, who have a greater sensitivity to cardio-vascular and central nervous system effects. The first has been frustrated up to a point, in that SSRIs and other single mechanism drugs do not appear to be more effective than the earliest relatively non-specific antidepressants. The second has been fulfilled, in that SSRIs generally are better tolerated in older patients and in overdose. However, there is a spectrum of other side effects that are particularly relevant in older age and that need attention when treating depression in this particular patient group.     

Salivary cortisol in women with major depressive disorder under selective serotonin reuptake inhibitors therapy

Depression is one of the widespread diseases whose etiology is still unclear. Dysregulation of the hypothalamic–pituitary–adrenal axis can be the cause of this illness which is concomitant with a high level of cortisol. For this reason, the purpose of the study was to estimate the influence of the selective serotonin reuptake inhibitors (SSRIs) therapy used in monotherapy and polypragmasy on cortisol level in saliva of depressed women. Cortisol was determined in saliva collected from 40 depressed patients treated with SSRIs. HPLC with UV detection was used for quantification of cortisol after its extraction with dichloromethane. For statistical evaluation of the data, the cluster analysis and principal components analysis were used. Results of the study have shown that the SSRIs treatment reduces the cortisol level in saliva. The therapy with sertraline and polypragmasy had a strong influence on suppressing the cortisol secretion. Besides, the amplitude of changes of the cortisol level during the treatment had an impact on the duration of hospitalization. In conclusion, it can be stet that the process of reduction of the cortisol level is multiphasic and that the combination treatment had a stronger influence on suppressing the cortisol secretion than did antidepressants used in monotherapy.     

The pharmacogenetics of the selective serotonin reuptake inhibitors

Summary Citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are selective serotonin reuptake inhibitors (SSRIs), which are thought to act as antidepressants through their ability to inhibit presynaptic serotonin reuptake in the brain. The elimination of the SSRIs proceeds predominantly via oxidation catalyzed by cytochrome P450 in the liver. Paroxetine and fluoxetine are potent inhibitors of cytochrome P4502D6 and hence may cause serious interactions with drugs metabolized by this isozyme, notably tricyclic antidepressants, some neuroleptics, and some antiarrhythmics. Citalopram, fluvoxamine and sertraline do not share this property. Fluvoxamine is the only SSRI that is a potent inhibitor of cytochrome P4501A2 and hence causes serious pharmacokinetic interactions with amitriptyline, clomipramine, imipramine, theophylline, and presumably caffeine and other drugs which are metabolized by the isozyme. Citalopram and fluoxetine are administered as racemates, but practically nothing is known about the stereoselective metabolism of the two drugs. Citalopram is partially metabolized via the mephenytoin oxidation polymorphism, and paroxetine is partially metabolized via the sparteine/debrisoquine oxidation polymorphism. The pharmacogenetic differences in the oxidation of the SSRIs themselves are probably of no clinical relevance.Abbreviations CYP cytochrome P450 - EM extensive metabolizer - PM poor metabolizer - SSRI selective serotonin reuptake inhibitor     

Progressive resistance to a selective serotonin reuptake inhibitor but not to cognitive therapy in the treatment of major depression

Recent research suggests that there may be a reduction in therapeutic response after multiple administrations of antidepressant drug (AD) therapy in patients with major depressive disorder. This study assessed the response to AD therapy and cognitive therapy (CT) of patients with a history of prior AD exposures. A sample of 240 patients with moderate-to-severe major depressive disorder entered a randomized controlled trial comparing pharmacotherapy with paroxetine to CT. Treatment was administered for 16 weeks. History of prior AD exposure was assessed with structured interviews, self-report, and medical records. Analyses were conducted using hierarchical linear models on the intent-to-treat sample. After controlling for various demographic and clinical factors, more prior AD exposures predicted poor response to paroxetine therapy but not to CT, as measured by the Hamilton Rating Scale for Depression (Hamilton, 1960; Williams, 1988). Whereas CT outcome was not significantly related to the number of prior AD exposures, a higher number of prior AD exposures was significantly associated with a lower response to paroxetine. If these findings are replicated in methodologically rigorous studies of paroxetine and other antidepressants, CT should be recommended, in preference to AD, for patients with multiple prior AD exposures.     

The safety of selective serotonin reuptake inhibitors: hemostasis

The literature data of the reaction of haemostatic system to antidepressants from the group of selective inhibitors of serotonin reuptake are summarized. The development of haemorrhagic complications is analyzed. The risk/benefit ratio is estimated for the treatment of depression in patients with acute myocardial infarction and stroke. A differential approach to indication of antidepressants is substantiated for the treatment of comorbid depressive disorders in different types of somatic pathology.     

Treatment with selective serotonin reuptake inhibitors for enhancing wound healing

Selective serotonin reuptake inhibitors (SSRIs) are well-established medications for the treatment of mood disorders including major depression. These agents are also known to exhibit potent antiplatelet and endothelium protective effects effects. Additionally, SSRIs can exacerbate the development of inflammation, and modulate the interleukin and interferon production. All of the above suggest that SSRIs therapy could be considered as a potential strategy for the wound healing treatment. We summarized some body of the available data on the history of serotonin metabolism, mechanism of action of ketanserin, and hypothesize why SSRIs may be beneficial in the wound repair natural history. Different pathophysiological considerations are also reflected in this review. Finally, we suggest that the topical use of SSRIs may represent a promising avenue for future strategies affecting wound repair in high-risk patients, especially those with diabetes mellitus, venous insufficiency, obesity, and other vascular disorders.     

Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability

Background: A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against tricyclic antidepressants (TCAs) in depressed patients was carried out. Methods: Efficacy data from 102 randomised controlled trials (10706 patients) were pooled to provide a summary variance-weighted effect size. Tolerability data from 95 studies (10553 patients) were combined to give variance-weighted relative risk of drop out for all reasons and for adverse effects from each study. The effect of age, treatment setting, severity and TCA dose were examined as well as the performance of individual SSRIs and TCAs where there were sufficient studies. Results: There is no overall difference in efficacy between SSRIs and TCAs (effect size -0.03, 95% confidence interval -0.09 to 0.03). TCAs do appear more effective in in-patients (-0.23, -0.40 to -0.05) and amitriptyline is more effective than SSRI comparators (-0.14, -0.25 to -0.03) but publication bias cannot be excluded. The SSRIs are better tolerated, with significantly lower rates of treatment discontinuations overall (relative risk 0.88, 0.83 to 0.93; number needed to treat 26) and due to side effects (0.73, 0.67 to 0.80; number needed to treat 33). Individual SSRIs show a similar advantage except for fluvoxamine which does not differ from the TCAs. Individual TCAs show a similar disadvantage in tolerability compared to SSRIs except for dothiepin against which SSRI treatment results in more side-effect related drop outs (2.64, 1.50 to 4.63; number needed to harm 12). Limitations: The evidence is from short-term studies and subgroup analyses may result in chance results. Conclusions: Overall efficacy between the two classes is comparable but SSRIs are not proven to be as effective as TCAs in in-patients and against amitriptyline. SSRIs have a modest advantage in terms of tolerability against most TCAs.     

Selective serotonin reuptake inhibitors and tricyclic antidepressants in the acute treatment of chronic depression and dysthymia: A systematic review and meta-analysis

IntroductionChronic depression represents a substantial portion of depressive disorders and is associated with severe consequences. This review examined the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in the treatment of chronic depression. Additionally, the comparative effectiveness of the two types of antidepressants has been examined.MethodsA systematic search was conducted in the following databases: CENTRAL, MEDLINE, EMBASE, ISI Web of Science, BIOSIS, PsycINFO, and CINAHL. Primary efficacy outcome was a response to treatment; primary acceptance outcome was dropping out of the study. Only randomized controlled trials were considered.ResultsWe identified 20 studies with 22 relevant comparisons. 19 studies focused on samples with a majority of dysthymic patients. Both SSRIs and TCAs are efficacious in terms of response rates when compared to placebo (Benefit Ratio [BR]=1.49; p<0.001 for SSRIs and BR=1.74; p<0.001 for TCAs) and no statistically significant differences between the active drugs and placebo in terms of dropout rates could be found. No differences in effectiveness were found between SSRIs and TCAs in terms of response rates (BR=1.01; p=0.91), yet, SSRIs showed statistically better acceptability in terms of dropout rates than TCAs (Odds Ratio [OR]=0.41; p=0.02).LimitationsThe methodological quality of the primary studies was evaluated as unclear in many cases and more evidence is needed to assess the efficacy of SSRIs and TCAs in patients suffering from chronic forms of depression other than dysthymia.ConclusionsThis systematic review provides evidence for the efficacy of both SSRIs and TCAs in the treatment of chronic depression and showed a better acceptability of SSRIs.     

Economic evaluation of duloxetine versus serotonin selective reuptake inhibitors and venlafaxine XR in treating major depressive disorder in Scotland

BackgroundMajor depressive disorders (MDD) are responsible for substantial direct and indirect health care costs. Despite the availability of numerous treatments, the need for effective pharmacotherapy remains. Duloxetine is a relatively balanced serotonin norepinephrine reuptake inhibitor (SNRI) with favourable clinical and tolerability profile. The cost-effectiveness of duloxetine versus established SSRIs, venlafaxine XR and mirtazapine was estimated in the UK.MethodsA decision analysis simulating clinical management of MDD was developed to estimate health and economic impacts of alternative treatments over one year. Patients on treatment experience remission, response without remission, no response, relapse or discontinue the initial regimen. Model outcomes were total treatment costs and quality-adjusted life years. Resource utilization data were derived from literature and practising UK psychiatrists and GPs. The robustness of findings with respect to modelling assumptions was assessed in extensive sensitivity analyses.ResultsWith similar efficacy to venlafaxine XR but lower drug costs, duloxetine is less costly and marginally more effective than venlafaxine XR both in the overall MDD population and in a more severe subgroup. Duloxetine has a low cost-effectiveness ratio in primary care against SSRIs and mirtazapine, and was found cost-saving against mirtazapine in more severe patients.LimitationsCost-effectiveness results are sensitive to changes in efficacy parameters and resource use data were collected from physician panel.ConclusionsDuloxetine represents an important option in the treatment of MDD in the UK that can be recommended on economic grounds. With similar efficacy and different side-effect profile to venlafaxine XR it represents a valuable choice to MDD patients.     

High-performance liquid chromatographic method to screen and quantitate seven selective serotonin reuptake inhibitors in human serum

A high-performance liquid chromatographic screening method (HPLC) is described for the determination of seven selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, milnacipran, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine) and for three pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram and norfluoxetine). A tricyclic antidepressant, clomipramine, was used as an internal standard. The method consists of liquid extraction of serum after alcalinisation at pH 9.50, followed by chromatography on a Beckman C18 reversed-phase column. Compounds were detected at 200.4 nm. The standard curves were linear over a working range of 50-1,000 ng/ml for fluvoxamine, 15-1,000 ng/ml for fluoxetine, 25-500 ng/ml for norfluoxetine, 50-500 ng/ml for sertraline, 20-500 ng/ml for paroxetine, 25-550 ng/ml for citalopram, 25-750 ng/ml for desmethylcitalopram, 25-800 ng/ml for didesmethylcitalopram, 25-650 ng/ml for milnacipran, and 25-500 ng/ml for venlafaxine. The quantitation limits of the method were 15 ng/ml for fluoxetine, 20 ng/ml for paroxetine, 25 ng/ml for venlafaxine, norfluoxetine and citalopram, and its metabolites, 40 ng/ml for sertraline and 50 ng/ml for fluvoxamine. No interferences were noted with this sensitive and specific method which can be used for therapeutic drug monitoring.     

The future of selective serotonin reuptake inhibitors (SSRIs) in psychiatric treatment

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed and widely regarded as a first-line treatment for depression. Yet, a growing body of evidence indicates that these agents are only moderately more effective than placebo in treating major depressive disorder. In recent years, it has been debated whether SSRIs offer any clinically meaningful advantage over placebos. As part of this debate, it has been argued that these agents are first-line treatments for some forms of depression but not necessarily for others. The present paper examines two hypotheses that are central to these issues. The first hypothesis is that SSRIs are more effective than placebo for some types of depression but not for others. The second is that SSRIs are more effective than psychotherapies for some types of depression than others. A review of the empirical literature reveals three main classifications of depression that are relevant to the first hypothesis: (a) more vs. less severe depression, (b) melancholic vs. non-melancholic depression, and (c) depression defined according to associated genetic factors (particularly the long vs. short allele of the serotonin transporter gene promoter). There is no strong or consistent support for (a) or (b). There is, however, emerging and consistent evidence for (c), and so the first hypothesis is tentatively supported, but only for (c). Most of the empirical evidence does not support the second hypothesis. Psychotherapies (cognitive-behavioral and interpersonal therapies) and SSRIs generally have equivalent efficacy, regardless of the severity of depression. The research literature also suggests a third hypothesis that remains to be evaluated: that SSRIs are more effective for treating anxiety disorders (and possibly other disorders) than they are for treating depression. If that hypothesis is supported by subsequent research, then the future of SSRIs may lie largely in the treatment of anxiety disorders, and in the management of particular subtypes of depression.     

抑郁患者选择性5-羟色胺再摄取抑制剂治疗与周期性肢体运动综合征

目的:考察选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitor,SSRI)与抑郁患者的周期性肢体运动综合征(periodic limb movement syndrome,PLMS)的关系。方法:本研究是病例回顾性分析,来自广东省精神卫生研究所的多导睡眠图(polysomnography,PSG)数据库(2006年11月-2009年11月)。选择了31例接受SSRI治疗的抑郁患者组(治疗组),并设定了2个对照组:27例未接受药物治疗抑郁患者组(未治疗组)和31例正常对照组。根据2007版美国睡眠研究会标准,判定了睡眠分期、睡眠相关事件和PLMS。结果:SSRI治疗组(13.7±2.6)比未治疗组(5.3±1.4)和正常对照组(4.1±1.1)的周期性肢体运动指数(periodic limb movement index,PLMI)更高(F=10.373,P0.001),而且治疗组的PLMS发生率(41.9%)明显高于其他两组(未治疗组:11.1%,正常对照组:6.5%,χ2=10.227,P0.001)。logistic回归显示的SSRI剂量越高(OR=1.107,1.036～1.184)、REM潜伏期越长(OR=1.289,1.176～1.413)和微觉醒越多(OR=1.483,1.219～1.748),接受SSRI的被治疗者就越容易出现PLMS。结论:选择性5-羟色胺再摄取抑制剂可能增加了抑郁患者出现周期性肢体运动综合征的风险,是一个值得临床学家重视的药源性副反应。     

Inhibitory effect of selective serotonin reuptake inhibitors on the vesicular monoamine transporter 2

The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [³H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [³H]dopamine uptake in vitro. The rank order of potency was reserpine ? fluoxetine, paroxetine > fluvoxamine, methamphetamine > MDMA. Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine. Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine. These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.     

Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors

BACKGROUND: There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. METHODS: Starting from the clinical studies that gave rise to this issue, this paper reviews an unselected cohort of randomized clinical trials (RCTs), a series of meta-analyses undertaken to investigate aspects of the problem, studies in recurrent brief depressive disorders, epidemiological studies and healthy volunteer studies using SSRIs to shed light on this issue. RESULTS: The original clinical studies produced evidence of a dose-dependent link, present on a challenge, dechallenge and rechallenge basis, between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted around this time indicate that SSRIs may reduce suicidal ideation in some patients. These same RCTs, however, yield an excess of suicides and suicide attempts on active treatments compared with placebos. This excess also appears in the best-controlled epidemiological studies. Finally, healthy volunteer studies give indications that SSRIs may induce agitation and suicidality in some individuals. CONCLUSIONS: The data reviewed here, which indicate a possible doubling of the relative risk of both suicides and suicide attempts on SSRIs compared with older antidepressants or non-treatment, make it difficult to sustain a null hypothesis, i.e. that SSRIs do not cause problems in some individuals to whom they are given. Further studies or further access to data are indicated to establish the magnitude of any risk and the characteristics of patients who may be most at risk.     

Functional recovery in cerebral palsy may be potentiated by administration of selective serotonin reuptake inhibitors

Cerebral palsy is a disorder of movement and posture caused by a non-progressive lesion to the brain. The incidence of cerebral palsy is over 2 per 1000 live births in Europe. Management of cerebral palsy is primarily supportive - none of the current treatments offered attempt to correct the primary problem of a brain lesion.Neurological problems may be treated by upregulating cerebral plasticity. Evidence suggests that this is the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Encouraging evidence of motor improvements in stroke patients treated with SSRIs suggest the possibility of similar improvements in cerebral palsy. Patients with less severe cerebral palsy show more evidence of plasticity than patients with more severe forms.Evidence should initially come from animal models, and thereafter case reports and case series in selected cases, before progression to large scale trials. SSRIs would have to be used in conjunction with cooling, which prevents secondary damage. Due consideration is needed to prevent harmful side-effects.     

Review of evidence for genetic testing for CYP450 polymorphisms in management of patients with nonpsychotic depression with selective serotonin reuptake inhibitors

PurposeCytochrome P450 (CYP450) enzymes metabolize selective serotonin reuptake inhibitor (SSRI) drugs used in treatment of depression. Variants in these genes may impact treatment efficacy and tolerability. The purpose of this study was 2-fold: to systematically review the literature for evidence supporting CYP450 genotyping to guide SSRI treatment for major depression, and, where evidence is inadequate, to suggest future research.MethodsWe searched MEDLINE® and other databases for studies addressing five key questions suggested by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Eligibility criteria were defined, and studies were reviewed independently by paired researchers. A conceptual model was developed to guide future research.ResultsReview of 1200 abstracts led to the final inclusion of 37 articles. The evidence indicates relatively high analytic sensitivity and specificity of tests detecting a subset of polymorphisms of CYP2D6, 2C19, 2C8, 2C9, and 1A1. We found marginal evidence regarding a clinical association between CYP450 variants and SSRI metabolism, efficacy, and tolerability in the treatment of depression.ConclusionsCurrent evidence does not support the use of CYP450 genotyping to guide SSRI treatment of patients with depression. Studies are proposed that will effectively guide decision-making in the area of CYP450 testing in depression, and genetic testing more generally.