The aim of this study was to examine the degree in which measurements of trait experiential avoidance (EA) are affected by current emotional disorder and whether EA is a causal factor in the course of emotional disorders (anxiety and depressive disorders) and the development of comorbidity among emotional disorders. In a sample of 2,316 adults aged 18 to 65, consisting of healthy controls, persons with a prior history of emotional disorders, and persons with a current emotional disorder, DSM-IV-based emotional disorders (CIDI: Composite Interview Diagnostic Instrument) were assessed at T2 and 2 (T4) and 4years later (T6) and experiential avoidance (AAQ: Acceptance and Action Questionnaire) at T2 and T4. Results showed that EA scores were stable over a 2-year period notwithstanding state fluctuations because of current emotional disorder. Moreover, EA scores at T2 predicted changes in distress (major depressive disorder, dysthymia, generalized anxiety disorder) and in fear disorders (social anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without panic) at T4. Finally, EA at T4 mediated the longitudinal association of fear disorders at T2 with distress disorders at T6 as well as of distress disorders at T2 with fear disorders at T6. These findings suggest that EA scores are more than epiphenomena of emotional disorders and that EA may be conceptualized as a relevant transdiagnostic factor affecting the course and development of comorbidity of emotional disorders.
OBJECTIVES:Recent data showing possible increased risk for suicidal behavior among children and adolescents treated with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants have created significant concern among patients, families, and providers, including concerns about the risk of individual antidepressants. This study was designed to compare the risk for medically treated suicide attempts among new users of sertraline, paroxetine, citalopram, escitalopram, and venlafaxine to risk for new users of fluoxetine.METHODS:A retrospective cohort study included 36 842 children aged 6 to 18 years enrolled in Tennessee Medicaid between 1995 and 2006 who were new users of 1 of the antidepressant medications of interest (defined as filling no prescriptions for antidepressants in the preceding 365 days). Medically treated suicide attempts were identified from Medicaid files and vital records and confirmed with medical record review.RESULTS:Four hundred nineteen cohort members had a medically treated suicide attempt with explicit or inferred attempt to die confirmed through medical record review, including 4 who completed suicide. The rate of confirmed suicide attempts for the study drugs ranged from 24.0 per 1000 person-years to 29.1 per 1000 person-years. The adjusted rate of suicide attempts did not differ significantly among current users of SSRI and SNRI antidepressants compared with current users of fluoxetine. Users of multiple antidepressants concomitantly had increased risk for suicide attempt.CONCLUSIONS:In this population-based study of children recently initiating an antidepressant, there was no evidence that risk of suicide attempts differed for commonly prescribed SSRI and SNRI antidepressants.
Most adults with Major Depressive Disorder (MDD) will not experience a remission with the first antidepressant trial. No practical biomarkers presently exist to predict responsiveness to antidepressants. Herein we report pilot data for a rest-activity biomarker of antidepressant response. Fifty-eight medication-free adults with MDD underwent a week-long collection of actigraphic data before beginning a 9 week open label trial of fluoxetine, coupled with blinded randomized assignment to eszopiclone/placebo. Depression severity was repeatedly measured with the Hamilton Rating Scale for Depression (HRSD). Baseline actigraphic data was analyzed with functional data analysis to create smoothed 24-h curves of activity. The time of the lowest point of activity (the bathyphase) was calculated for each patient, as well the mean difference between bedtime and the bathyphase (BBD). At the end of treatment, patients were characterized as treatment responders (50% reduction in HRSD) or non-responders, and receiver operating curves were calculated to find the optimal cut point of the BBD for prediction of treatment response. The best cut point for BBD was at 260.2 min, resulting in an effect size of 1.45, and with a positive predictive value of 0.75 and a negative predictive value of 0.88. We conclude that actigraphically-determined measures of rest-activity patterns show promise as potential biomarker predictors of antidepressant response. However, this conclusion is based upon a small number of patients who received only one choice of antidepressant, for a single trial. Replication with a larger sample is needed.
It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these drugs act either as anti- or pro-inflammatory. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21 days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.
One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject’s relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky’s (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not “normal” when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs.
Agomelatine is an antidepressant with a unique mechanism of action. Since its marketing in 2009, concerns have been raised regarding its potential to induce liver injury. The authors therefore address the need to comprehensively evaluate the potential risk posed by agomelatine of inducing liver injury by reviewing data from published and unpublished clinical trials in both the pre- and postmarketing settings, as well as data from non-interventional studies, pharmacovigilance database reviews and one case report. Recommendations for clinicians are also provided. In this review, agomelatine was found to be associated with higher rates of liver injury than both placebo and the four active comparator antidepressants used in the clinical trials for agomelatine, with rates as high as 4.6% for agomelatine compared to 2.1% for placebo, 1.4% for escitalopram, 0.6% for paroxetine, 0.4% for fluoxetine, and 0% for sertraline. The review also provides evidence for the existence of a positive relationship between agomelatine dose and liver injury. Furthermore, rates of liver injury were found to be lower in non-interventional studies. Findings from pharmacovigilance database reviews and one case report also highlight the risk of agomelatine-induced liver injury. As agomelatine does pose a risk of liver injury, clinicians must carefully monitor liver function throughout treatment. However, agomelatine’s unique mechanism of action and favourable safety profile render it a valuable treatment option. A quantitative analysis of agomelatine-induced liver injury is lacking in the literature and would be welcomed.
Selective Serotonin Reuptake Inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org). This article is protected by copyright. All rights reserved.
A retrospective cohort study was conducted including 3688 patients age 60 years or older without dementia enrolled in a depression screening study in primary care clinics. Information on antidepressant use and incident dementia during follow-up was retrieved from electronic medical records. The Cox proportional hazard models were used to compare the risk for incident dementia among 5 participant groups: selective serotonin re-uptake inhibitors (SSRI) only, non-SSRI only (non-SSRI), mixed group of SSRI and non-SSRI, not on antidepressants but depressed, and not on antidepressants and not depressed. SSRI and non-SSRI users had significantly higher dementia risk than the nondepressed nonusers (hazard ratio [HR]=1.83, P=0.0025 for SSRI users and HR=1.50, P=0.004 for non-SSRI users). In addition, SSRIs users had significantly higher dementia risk than non-users with severe depression (HR=2.26, P=0.0005). Future research is needed to confirm our results in other populations and to explore potential mechanism underlying the observed association.
Background: Recent meta-analyses of the efficacy of second-generation antidepressants for youth have concluded that such drugs possess a statistically significant advantage over placebo in terms of clinician-rated depressive symptoms. However, no meta-analysis has included measures of quality of life, global mental health, self-esteem, or autonomy. Further, prior meta-analyses have not included self-reports of depressive symptoms. Methods: Studies were selected through searching Medline, PsycINFO, and the Cochrane Central Register for Controlled Trials databases as well as GlaxoSmithKline’s online trial registry. We included self-reports of depressive symptoms and pooled measures of quality of life, global mental health, self-esteem, and autonomous functioning as a proxy for overall well-being. Results: We found a nonsignificant difference between second-generation antidepressants and placebo in terms of self-reported depressive symptoms (k = 6 trials, g = 0.06, p = 0.36). Further, pooled across measures of quality of life, global mental health, self-esteem, and autonomy, antidepressants yielded no significant advantage over placebo (k = 3 trials, g = 0.11, p = 0.13). Discussion: Though limited by a small number of trials, our analyses suggest that antidepressants offer little to no benefit in improving overall well-being among depressed children and adolescents. © 2014 S. Karger AG, Basel.
OBJECTIVE The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of l-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). METHOD In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive l-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by l-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the l-methylfolate dosage was 15 mg/day during both 30-day periods. RESULTS In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive l-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive l-methylfolate at 15 mg/day. l-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. CONCLUSIONS Adjunctive l-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.