Selective serotonin reuptake inhibitors in pediatric depression: is the balance between benefits and risks favorable?

Recent controversies surrounding the use of selective serotonin reuptake inhibitors (SSRIs) have highlighted the need to reassess potential benefits, as well as potential risks of this class of medications in the treatment of pediatric depression. The recent availability of data from meta-analyses of published and unpublished antidepressant trials, epidemiological studies, and the Treatment for Adolescents with Depression Study (TADS) has facilitated a reanalysis of this risk/benefit relationship. Despite reviewing similar data, various regulatory agencies have arrived at rather disparate conclusions regarding the data, resulting in continued controversy. Although all groups appear to agree that careful assessment, education regarding risks, and closer monitoring are essential for SSRIs, only the U.S. Food and Drug Administration (FDA) and the U.K. Medicine and Health Care Products Regulatory Agency maintain that an acceptable risk/benefit relationship exists for fluoxetine. The European Medicines Agency concluded that the SSRIs should not be used in the treatment of depression in children and adolescents. The authors of this review have taken into consideration many of these same data and offer a critical discussion of the pros and cons of SSRIs in pediatric depression. The authors have concluded that SSRIs -- in particular, fluoxetine -- do have a role in the treatment of pediatric depression.     

Suicidality with selective serotonin reuptake inhibitors: Valid claim?

The red flags raised by the 1990 clinical reports of increased suicidality associated with treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine were followed by anecdotal reports of similar symptoms with other antidepressants of the same class. Recent discussions by Healy have argued in favour of a suicidogenic potential of the SSRIs. This paper reviews the relevant literature addressing the epidemiological data of Western populations and the data accumulated from clinical trial databases in several countries. The evidence currently available does not support the hypothesis that antidepressants or, more specifically, SSRIs cause increased suicidality in patients with depression, nor do they appear to do so in patients treated with these drugs for other reasons.     

Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized,double-blind,placebo-controlled,dose-finding studies in major depressive disorder

The purpose of this meta-analysis is to examine the relationship between selective serotonin reuptake inhibitor (SSRI) starting dose and treatment outcome in major depressive disorder (MDD). Medline/Pubmed, EMBASE, the Cochrane database, as well as a number of online clinical trial registries were searched for double-blind, placebo-controlled, fixed-dose trials comparing different starting doses of SSRIs for MDD. Data from nine trials (n=2340) were combined using a random-effects model. Patients randomized to receive the usual starting dose (10 mg escitalopram; 20 mg fluoxetine, paroxetine, citalopram; 50 mg sertraline and fluvoxamine) were less likely to respond than patients who received higher starting doses (RR=0.9; P=0.04; response rate 50.8 vs. 54.8%). The rate of discontinuation due to adverse events was lower among the usual starting dose group (9.8%) compared to the higher starting dose group (16.5%).Initiating treatment with SSRIs at doses higher than those typically used in clinical trials/settings is associated with higher response rates but also higher rates of discontinuation due to intolerance. Developing treatment strategies allowing clinicians to deliver higher initial SSRI doses while enhancing the tolerability of treatment may represent an alternative approach to improving the efficacy of treatment of MDD.     

What is the effect of selective serotonin reuptake inhibitors on temperament and character in patients with fibromyalgia?

Objective

The purpose of the present study was to assess a group of patients with fibromyalgia (FM) and control subjects using the personality questionnaire proposed by Cloninger and to determine possible changes in the Italian version of the Temperament and Character Inventory—Revised patterns of patients with FM after therapy with serotoninergic antidepressants (selective serotonin reuptake inhibitors [SSRIs]).

Methods

Sixty patients with FM filled out the Temperament and Character Inventory—Revised and Beck Depression Inventory before and after 6-month therapy with SSRIs (escitalopram 10 mg, fluoxetine 20 mg, or paroxetine 20 mg). A total of 80 age-, sex-, and education level-matched healthy subjects were selected as a control group.

Results

Both in the pretreatment and posttreatment period, patients were found to have higher harm avoidance and lower self-directedness scores than healthy controls. In addition, harm avoidance and self-directedness were state and trait dependent.

Conclusions

Depressive symptoms in patients with FM can be significantly decreased by treatment with SSRIs. A careful clinical assessment and study of personality profile is needed to identify patients with FM who may benefit from antidepressant pharmacologic therapy and specific psychotherapeutic interventions.     

Treating children and adolescents with selective serotonin reuptake inhibitors: how long is appropriate?

This article addresses a key question on the use of selective serotonin reuptake inhibitors (SSRIs) among children and adolescents. As briefly reviewed, recent randomized controlled trials have established the safety and efficacy of SSRIs in the acute treatment of major depression and anxiety disorders among children and adolescents. Major questions emerge in light of these data concerning the potential risks and benefits of long-term SSRI use among children and adolescents who receive significant short-term benefits from SSRI treatment. The current review summarizes research on longitudinal outcomes, neuroscience, and psychopharmacology to formulate a set of preliminary recommendations on long-term SSRI use. A review of data in these areas supports three conclusions. First, for children who achieve marked reduction in anxiety or depressive symptoms on an SSRI, clinicians should consider recommending a medication-free trial. Second, when indicated, this medication-free trial should coincide with the first low-stress period occurring after 1 year of continual SSRI treatment. Third, SSRI treatment should be reinitiated in children who exhibit signs of relapse during this medication-free trial.     

What happens with adverse events during 6 months of treatment with selective serotonin reuptake inhibitors?

OBJECTIVE: Although adverse events are a key factor in compliance, their evolution during treatment with antidepressants is poorly documented. Therefore, the time course of adverse events during 6 months of antidepressant treatment was investigated. METHOD: 85 psychiatric outpatients with a DSM-IV diagnosis of major depressive disorder (with the exclusion of other DSM-IV Axis I disorders) were enrolled between September 2002 and March 2003 in a multicenter, randomized, double-blind trial with selective serotonin reup-take inhibitors (fluoxetine [N = 42] and paroxetine [N = 43]). At each visit, the presence and severity of treatment-emergent adverse events were assessed systematically using the UKU Side Effect Rating Scale (UKU). General linear mixed modeling was used to investigate the predictors of the time course of adverse events. RESULTS: Overall, the number of at least moderately severe adverse events decreased with time. More severely depressed patients reported overall more (at least moderately severe) adverse events than less severely depressed patients (p = .0002), but the decrease in reported adverse events was comparable over time. Men (N = 30) and women (N = 55) reported initially the same number of at least moderately severe adverse events, but the habituation was more rapid in men (p < .0001). Completers (N = 58) and dropouts (N = 27) did not differ initially, but completers' habituation was more rapid (p = .014). The habituation of adverse events was also more rapid in recurrent than in first-episode patients but only in men (p = .0025). CONCLUSION: The time course of adverse events varies with the severity of depression, sex, completer or dropout status, and recurrent versus first-episode depression.     

Drug repurposing of selective serotonin reuptake inhibitors: Could these drugs help fight COVID-19 and save lives?

The current 2019 novel coronavirus disease (COVID-19), an emerging infectious disease, is undoubtedly the most challenging pandemic in the 21st century. A total of 92,977,768 confirmed cases of COVID-19 and 1,991,289 deaths were reported globally up to January 14, 2021. COVID-19 also affects people’s mental health and quality of life. At present, there is no effective therapeutic strategy for the management of this disease. Therefore, in the absence of a specific vaccine or curative treatment, it is an urgent need to identify safe, effective and globally available drugs for reducing COVID-19 morbidity and fatalities. In this review, we focus on selective serotonin reuptake inhibitors (SSRIs: a class of antidepressant drugs with widespread availability and an optimal tolerability profile) that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials. We also summarize the existing literature on what is known about the link between serotonin (5-HT) and the immune system. From the evidence reviewed here, we propose fluoxetine as an adjuvant therapeutic agent for COVID-19 based on its known immunomodulatory, anti-inflammatory and antiviral properties. Fluoxetine may potentially reduce pro-inflammatory chemokine/cytokines levels (such as CCL-2, IL-6, and TNF-α) in COVID-19 patients. Furthermore, fluoxetine may help to attenuate neurological complications of COVID-19.     

Do selective serotonin re-uptake inhibitors enhance the efficacy of very brief cognitive behavioral therapy for panic disorder? A pilot study

Selective serotonin re-uptake inhibitors (SSRIs) and cognitive behavioral therapies (CBTs) are both considered as first-line treatments for panic disorder, but the advantages of a combined therapy have yet to be definitively demonstrated. We evaluated in this pilot study the effects of combining SSRIs (vs. a placebo) with a very brief form of cognitive-behavioral therapy provided to all participants. Thirty-three subjects with DSM-IV panic disorder, with or without agoraphobia, were randomized to receive either paroxetine or a placebo with flexible dosing (10-50 mg/day). Medication visits were brief (15 min), infrequent (6 in total) and non-directive. An expert cognitive-behavior therapist administered one initial 45-min session and one subsequent 30-min session of very brief CBT (vbCBT) at weeks 5 and 7, respectively. Sessions were supplemented with educational and directive reading materials. Patients in both groups (i.e. vbCBT+paroxetine; vbCBT+placebo) improved similarly and substantially on most measures during the 10 weeks of acute treatment. At week 10, the proportion of panic-free patients was significantly higher in the paroxetine-treated group than in the placebo group (80 vs. 25%; P<0.007), as was the proportion of subjects who rated themselves as 'very much improved' at week 10 (60 vs. 13%; P<0.017). These findings point to the need for additional studies to confirm the effectiveness of very brief forms of CBT, and to document the circumstances in which combined treatment with an SSRI would be warranted.     

Is meat consumption associated with depression? A meta-analysis of observational studies

Background

A number of epidemiological studies have examined the effect of meat consumption on depression. However, no conclusion has been reached. The aim of this study was to examine the relationship between meat consumption and depression.

Methods

The electronic databases of PUBMED and EMBASE were searched up to March 2017, for observational studies that examined the relationship between meat consumption and depression. The pooled odds ratio (OR) for the prevalence of depression and the relative risk (RR) for the incidence of depression, as well as their corresponding 95% confidence interval (CI), were calculated respectively (the highest versus the lowest category of meat consumption).

Results

A total of eight observational studies (three cross-sectional, three cohort and two case-control studies) were included in this meta-analysis. Specifically, six studies were related to the prevalence of depression, and the overall multi-variable adjusted OR suggested no significant association between meat consumption and the prevalence of depression (OR?=?0.89, 95% CI: 0.65 to 1.22; P?=?0.469). In contrast, for the three studies related to the incidence of depression, the overall multi-variable adjusted RR evidenced an association between meat consumption and a moderately higher incidence of depression (RR?=?1.13, 95% CI: 1.03 to 1.24; P?=?0.013).

Conclusions

Meat consumption may be associated with a moderately higher risk of depression. However, it still warrants further studies to confirm such findings due to the limited number of prospective studies.

     

Should antidepressant drugs of the selective serotonin reuptake inhibitor family be tested as antiepileptic drugs?

For a long time, there has been a misconception that all antidepressant drugs have proconvulsant effects. Yet, antidepressants of the selective serotonin reuptake inhibitor (SSRI) family not only have been shown to be safe when used in patients with epilepsy (PWE) but also have been found to possess antiepileptic properties in animal models of epilepsy. In humans randomized to SSRIs vs. placebo for the treatment of major depressive episodes, the incidence of epileptic seizures was significantly lower among those treated with the antidepressants. These data raise the question of whether there is enough evidence that would support a randomized placebo-controlled trial to test antiepileptic effect of SSRIs in PWE. This article reviews the preclinical and clinical data to address this question.This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.     

‘Accepting what is’: an approach for managing the long-term sexual side effects of selective serotonin reuptake inhibitors (SSRIs) in women

Sexual difficulties may not be a pressing issue for women on antidepressants during the early phase of selective serotonin reuptake inhibitor (SSRI) treatment; however, this can emerge as a substantial problem once women are stabilised on medication. Little is known about how women cope with the adverse sexual effects of SSRIs. This qualitative study used Interpretative Phenomenological Analysis to explore the experiences of Australian women currently coping with the sexual side effects of this antidepressant. Interviews were conducted with 10 heterosexual women, aged 45 years and younger. Four major coping strategies were identified “searching”, “suffering in silence”, “trying to resolve” and “accepting what is”. This paper explores one particular response “accepting what is”, which includes a number of strategies commonly employed by women on long-term medication. Findings from the study have particular relevance for sex and relationship therapists and may assist women in managing sexual side effects that are perceived to be beyond their control. This paper adds to the current literature by increasing understanding of how “accepting what is” can be a step forward, particularly for women who have chosen to remain on long-term medication. In theoretical terms, a deeper understanding of how women cope could inform debate about the appropriate management of long-term sexual side effects in the absence of effective pharmacological interventions.     

Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder

OBJECTIVE: The authors conducted a meta-analysis of published randomized, controlled medication trials in children and adolescents with obsessive-compulsive disorder (OCD) to assess evidence for differential efficacy based on type of drug, study design, and outcome measure. METHOD: A systematic literature search was performed for articles pertaining to the pharmacological treatment of pediatric and/or adolescent OCD. All baseline, posttreatment, and change scores with standard deviations reported in each study were included in the analyses. Effect sizes for dependent measures were expressed as standardized mean differences. The analysis included data on efficacy for four selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, fluvoxamine, and sertraline) and clomipramine, four study designs, four dependent outcome measures, and two types of outcome scores (change and posttreatment scores). Multivariate regression was performed to assess the degree to which the effect sizes varied with the methodological features of each study. RESULTS: Twelve studies with a total of 1,044 participants met all inclusion criteria for the analysis. The pooled standardized mean difference for the results of all studies was 0.46 and showed a highly significant difference between drug and placebo treatment. Only one of the four outcome measures evaluated was not sensitive to change with treatment. A multivariate regression analysis of drug effect with other variables controlled showed that clomipramine was significantly superior to each of the SSRIs but that the SSRIs were comparably effective. CONCLUSIONS: Although highly significant, the overall effect sizes for medication were modest. Similarities and differences between the variables studied that emerged in the meta-analysis may have implications for both clinical care and future research.