Neuropsychological functioning in major depression and responsiveness to selective serotonin reuptake inhibitors antidepressants

BACKGROUND: Only two thirds of patients with major depression (MD) respond to antidepressants. Thus, far applicable predictors of responsiveness to selective serotonergic reuptake inhibitors (SSRIs) have not been found. Cumulative evidence linking serotonergic depletion and cognition led us to hypothesize that the neuropsychological functioning of major depression patients may predict their responsiveness to SSRI antidepressants. METHODS: Fifty-five patients meeting DSM-IV criteria for major depression and strict inclusion and exclusion criteria underwent an extensive clinical and neuropsychological assessment prior to the initiation of selective serotonergic treatment. Following 6 weeks of treatment, severity of depression was reassessed, yielding a responsiveness score by which classification of each subject as a responder or nonresponder was made. The study was double blind. RESULTS: Logistic regression yielded neuropsychological indices, which significantly predicted the probability of depressed patients to respond favorably to SSRIs. Responders were characterized by better functioning in "simple" tasks and by worse functioning in "complex" tasks compared to nonresponders. No differences were found for more lateralized right or left hemisphere functions between responders and nonresponders. LIMITATIONS: Drug treatment comprised of SSRIs but was not standardized. Responsiveness was assessed following 6 weeks of treatment providing for initial amelioration rather than full remission. Placebo response was not controlled for. These limitations may influence the interpretation of the findings. CONCLUSIONS: The present findings suggest that responders and nonresponders to SSRIs might be distinguished by their neuropsychological functioning before treatment. If our findings are replicated, more efficient treatment might be practiced.     

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。     

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.     

Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients

OBJECTIVES: To determine the impact of depression on highly active antiretroviral therapy (HAART) adherence and clinical measures and investigate if selective serotonin reuptake inhibitors (SSRIs) improve these measures. DESIGN: Retrospective cohort study. METHODS: In 2 large health maintenance organizations, we measured the effects of depression (with and without SSRI use) on adherence and changes in viral and immunologic control among HIV-infected patients starting a new HAART regimen. HAART adherence, HIV RNA levels, and changes in CD4 T-cell counts through 12 months were measured. RESULTS: A total of 3359 patients were evaluated; 42% had a depression diagnosis, and 15% used SSRIs during HAART. Depression without SSRI use was associated with significantly decreased odds of achieving > or =90% adherence to HAART (odds ratio [OR] = 0.81, 95% confidence interval [CI]: 0.70 to 0.98; P = 0.03). Depression was associated with significantly lower odds of an HIV RNA level <500 copies/mL (OR = 0.77, 95% CI: 0.62 to 0.95; P = 0.02). Depressed patients compliant with SSRI medication (>80% adherence to SSRI) had HAART adherence and viral control statistically similar to nondepressed HIV-infected patients taking HAART. Comparing depressed with nondepressed HIV-infected patients, CD4 T-cell responses were statistically similar; among depressed patients, those compliant with SSRI had statistically greater increases in CD4 cell responses. CONCLUSIONS: Depression significantly worsens HAART adherence and HIV viral control. Compliant SSRI use is associated with improved HIV adherence and laboratory parameters.     

A selective serotonin reuptake inhibitor reduces REM sleep in the homing pigeon

Avian and mammalian 'rapid eye movement' sleep (REM sleep) resemble each other in several aspects. However, the question of whether REM sleep has a shared evolutionary ancestry in birds and mammals has yet to be thoroughly explored. The brain regions and neurotransmitter systems involved in the generation of mammalian REM sleep are phylogenetically ancient, and are also found in extant birds and reptiles. Several pharmacological experiments in birds indicate that similar neural substrates are involved in the regulation of avian and mammalian sleep. However, because the drugs used in these studies generally resulted in non-specific sleep loss, the neurochemical regulation of avian REM sleep in particular remains uncertain. The selective serotonin reuptake inhibitor (SSRI) zimelidine is known to reduce REM sleep in mammals. If avian REM sleep is similarly regulated by serotonin, it would be expected that an acute dose of a SSRI should also reduce avian REM sleep. To investigate a putative role of serotonin in the regulation of avian REM sleep, changes in sleep electroencephalogram (EEG) and behavior were recorded in five pigeons (Columba livia) after the administration of an acute dose of zimelidine. Our results demonstrate that the effects of zimelidine on avian REM sleep are comparable to those observed in mammals, indicating that serotonin may serve a similar function in the control of avian and mammalian REM sleep.     

Selective serotonin reuptake inhibitor effects on neural biomarkers of perinatal depression

Archives of Women's Mental Health - The effect of perinatal selective serotonin reuptake inhibitors (SSRIs) on brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B...     

Depression impairs learning,whereas the selective serotonin reuptake inhibitor,paroxetine, impairs generalization in patients with major depressive disorder

To better understand how medication status and task demands affect cognition in major depressive disorder (MDD), we evaluated medication-naïve patients with MDD, medicated patients with MDD receiving the selective serotonin reuptake inhibitors (SSRI) paroxetine, and healthy controls. All three groups were administered a computer-based cognitive task with two phases, an initial phase in which a sequence is learned through reward-based feedback (which our prior studies suggest is striatal-dependent), followed by a generalization phase that involves a change in the context where learned rules are to be applied (which our prior studies suggest is hippocampal-region dependent). Medication-naïve MDD patients were slow to learn the initial sequence but were normal on subsequent generalization of that learning. In contrast, medicated patients learned the initial sequence normally, but were impaired at the generalization phase. We argue that these data suggest (i) an MDD-related impairment in striatal-dependent sequence learning which can be remediated by SSRIs and (ii) an SSRI-induced impairment in hippocampal-dependent generalization of past learning to novel contexts, not otherwise seen in the medication-naïve MDD group. Thus, SSRIs might have a beneficial effect on striatal function required for sequence learning, but a detrimental effect on the hippocampus and other medial temporal lobe structures is critical for generalization.     

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     

Prevention of the serotonin reuptake inhibitor discontinuation syndrome

Prevention of the serotonin reuptake inhibitor discontinuation syndrome (SRIDS) is an important issue. The author suggests: (1) serotonin reuptake inhibitors (SRIs) should be used only when they are necessary. Sometimes tablets should be replaced with other treatment modalities; (2) patients should be given the lowest dosage of SRIs possible; (3) patients who have a history of medication noncompliance, who have experienced the discontinuation symptoms in the past, or who have treatment-emergent anxiety are at highest risk for experiencing the SRIDS and need closer monitoring; (4) SRIs should be tapered prior to stoppage; (5) generic drugs are allowed up to a 20% difference in bioequivalence from the brand original. Patients should receive continuity of supply from the dispenser, with no intermanufacturer switching; (6) patients and healthcare professionals should be educated to ensure that SRIs are not stopped abruptly; (7) neonatal SRIDS can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and physician should take this into consideration when making treatment decision.     

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.     

CB-1 receptors modulate the effect of the selective serotonin reuptake inhibitor, citalopram on extracellular serotonin levels in the rat prefrontal cortex

A large percentage of depressed individuals use drugs of abuse, like cannabis. This study investigates the impact of cannabis on the pharmacological effects of the antidepressant citalopram. Using microdialysis in the prefrontal cortex of rats we monitored serotonin levels before and after cannabinoid (WIN55,212-2 or rimonabant) and citalopram administration. Stimulating CB-1 decreased the effect of citalopram on increasing serotonin levels in the prefrontal cortex. Blocking CB-1 augmented this effect of citalopram. Although repeating these experiments in a chronical setting is recommended the present results might have implication for the clinical effects of citalopram.     

Randomized comparison of selective serotonin reuptake inhibitor (escitalopram) monotherapy and antidepressant combination pharmacotherapy for major depressive disorder with melancholic features: a CO-MED report

Background

The clinical effects of antidepressant combinations vs. monotherapy as initial treatment for major depression with melancholic features (MDD-MF) are unknown.

Methods

Outpatients with chronic or recurrent major depression (MDD) were randomized to initial treatment with escitalopram + placebo (the MONO condition), bupropion-sustained release + escitalopram, or venlafaxine-extended release + mirtazapine (the COMB conditions) in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. Secondary data analyses were conducted to compare demographic and clinical characteristics, and contrast clinical responses according to drug treatment, in patients with MDD-MF (n = 124) and non-melancholic MDD (n = 481).

Results

While numerically lower, remission rates in MDD-MF did not differ significantly from those with non-melancholic MDD either at 12 (33.1% vs. 41.0%, aOR 1.16, p = 0.58) or 28 (39.5% vs. 46.8%, aOR = 1.02, p = 0.93) weeks of treatment. Remission rates did not differ significantly between combination and monotherapy groups in either MDD-MF or non-melancholic MDD patients at either time point. Similar conclusions were reached for response rates, premature study discontinuation, and self-rated depression symptom severity.

Limitations

This is a secondary analysis of data from the CO-MED trial, which was not designed to address differential treatment response in melancholic and non-melancholic MDD.

Conclusions

We found no evidence of differential remission or response rates to antidepressant combination or monotherapy between melancholic/non-melancholic MDD patients, or according to antidepressant treatment group, after 12 and 28 weeks. Melancholic features may not be a valid predictor of more favorable response to antidepressant combination therapy as initial treatment.     

Shifts in affective balance during cognitive therapy of major depression.

Thirty-two outpatient depressives were treated by experienced therapists during a 16- to 20-week, 20- to 24-session cognitive-behavioral therapy (CBT) protocol. Patients were classified as CBT responders (n = 22) or nonresponders (n = 10) on the basis of independent clinical ratings of Hamilton (1960) depression severity. Point and confidence interval estimation procedures yielded results consistent with hypotheses derived from the states-of-mind (SOM; Schwartz & Garamoni, 1986) model. At posttreatment, CBT responders shifted the balance of positivity and negativity to the optimal range, whereas nonresponders remained in a predominantly negative SOM. Response status was related more strongly to change in positivity than in negativity. Findings support the view that clinical response to CBT depends on reducing negativity and increasing positivity until an optimal balance is achieved.     

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.     

Selective serotonin reuptake inhibitor treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction

Prenatal stress has long-lasting effects on cognitive function and on the hypothalamic-pituitary-adrenal response to stress. We previously reported that the serotonin concentration and synaptic density in the hippocampus were reduced following prenatal stress [Int J Dev Neurosci 16 (1998) 209]. Since serotonin plays a role in the formation and maintenance of synapses, we hypothesized that a neonatal reduction in hippocampal serotonin levels may lead to learning disabilities in prenatally stressed mice. To test this hypothesis, we treated prenatally stressed mice with a selective serotonin reuptake inhibitor in order to normalize their postnatal serotonin turnover levels. What we found was that the oral administration of a selective serotonin reuptake inhibitor to prenatally stressed mice during postnatal weeks 1-3 but not 6-8 normalized their corticosterone response to stress, serotonin turnover in the hippocampus, and density of dendritic spines and synapses in the hippocampal CA3 region. Concomitantly, such treatment partially restored their ability to learn spatial information.     

Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy

This study evaluated mindfulness-based cognitive therapy (MBCT), a group intervention designed to train recovered recurrently depressed patients to disengage from dysphoria-activated depressogenic thinking that may mediate relapse/recurrence. Recovered recurrently depressed patients (n = 145) were randomized to continue with treatment as usual or, in addition, to receive MBCT. Relapse/recurrence to major depression was assessed over a 60-week study period. For patients with 3 or more previous episodes of depression (77% of the sample), MBCT significantly reduced risk of relapse/recurrence. For patients with only 2 previous episodes, MBCT did not reduce relapse/recurrence. MBCT offers a promising cost-efficient psychological approach to preventing relapse/recurrence in recovered recurrently depressed patients.