The Use of Selective Serotonin Reuptake Inhibitors in Children and Adolescents with Major Depression

TOPIC: Recent warnings about suicidal thoughts and self-injurious behavior in youth treated with selective serotonin reuptake inhibitors raise fundamental questions about the risk-benefit ratio of this class of medications. METHODS: Data from placebo-controlled trials are used to elucidate the potential risks and benefits of the selective serotonin reuptake inhibitors (SSRIs) in children and adolescent with major depression. This analysis forms the basis of clinical recommendations. SOURCES: The review includes the six large-scale, placebo-controlled trials that have been published over the past decade. These data were augmented by information from regulatory hearings in 2003-2004 and selected open-label reports. CONCLUSIONS: Emerging data from several clinical trials show that the SSRIs have modest effects on childhood depression. In addition, SSRI treatment may be associated with behavioral activation, self-harm, and suicidal ideation. Appropriate use of SSRIs in children and adolescents requires careful diagnostic assessment, evaluation of co-occurring conditions, and diligent monitoring, especially within the first weeks of treatment.     

Selective Serotonin Reuptake Inhibitors Versus Tricyclic Antidepressants in Young Patients: A Meta-analysis of Efficacy and Acceptability

Purpose

A meta-analysis comparing the efficacy and acceptability of selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) in depressed children, adolescents, and young adults was performed.

Methods

A comprehensive literature search of the PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to December 2013. Only clinical trials that randomly assigned one SSRI or TCA to patients aged 7 to 25 years who met the diagnostic criteria for unipolar depressive disorder were included. Primary efficacy was determined by the pooling of standardized mean differences (SMDs) calculated from the difference in the reduction in mean depression rating scale scores for the 2 antidepressants. Acceptability was determined by pooling the risk ratios (RRs) of dropouts for all reasons and for adverse effects as well as the suicide-risk outcome.

Findings

Five trials with a total of 422 patients were considered to be eligible for inclusion. SSRIs were significantly more effective than TCAs in primary efficacy (SMD = −0.52; 95% CI, −0.81 to −0.24; P = 0.0003). Patients taking SSRIs had a significantly greater response to depressive symptoms than patients taking TCAs (RR = 1.55; 95% CI, 1.04 to 2.29; P = 0.03). On an individual SSRI basis, fluoxetine had a significantly greater efficacy than TCAs (SMD = −0.82; 95% CI, −1.34 to −0.29; P = 0.003). On an individual TCA basis, only imipramine was not significantly worse than SSRIs (SMD = −0.27; 95% CI, −0.56 to 0.02; P = 0.06). Significantly more patients taking TCAs discontinued treatment than patients taking SSRIs (35.8% vs 25.1%; RR = 0.70; 95% CI, 0.52 to 0.93; P = 0.02).

Implications

SSRI therapy has a superior efficacy and is better tolerated compared with TCA therapy in young patients.     

The effects of Selective Serotonin Reuptake Inhibitors on newborn adaptation and withdrawal symptoms: A scoping review

BackgroundSince becoming the most frequently prescribed antidepressants in pregnancy, the effects of Selective Serotonin Reuptake Inhibitors on newborns is hotly debated. The aims of this review were to examine terminology and adaptation, withdrawal, and toxicity risks for newborns.MethodScoping review methodology guided the search of electronic databases EBSCOhost, PubMed Central and Springer Online Journals.ResultsOut of 90 articles screened, 23 were eligible for inclusion in the synthesis. Terminology is used interchangeably with poor delineation. Poor Neonatal Abstinence Syndrome is usually mild and transient with newborns experiencing neuro-behaviour and/or respiratory symptoms, initial lowered Apgar score, inhibited respiratory regulation, and hypoglycaemia. Limited studies examined Serotonin toxicity.ConclusionsNewborns exposed to Selective Serotonin Reuptake Inhibitors in-utero are affected, however the evidence is limited due to a lack of high-quality, robust studies to accurately make generalisations regarding Poor Neonatal Adaptation Syndrome or to support the diagnosis over withdrawals. Further research is needed to adequately differentiate between the conditions.     

Case Report: The Effects of Selective Serotonergic Reuptake Inhibitors Combined with Behavioral Treatment on Self-Injury Associated with Lesch-Nyhan Syndrome

A 6-year-old African-American male child with Lesch-Nyhan syndrome participated. Because of the occurrence of unmanageable self-injurious behavior (SIB) in a group home, James at the age of 3.5 years was admitted to a large residential facility for persons with mental retardation. A behavior treatment program was implemented soon after admission and produced a large decrease in SIB; however, rates of SIB remained clinically unacceptable and a danger to him. The program consisted of differential reinforcement, extinction, and noncontingent protective restraint. Because SIB may be caused by decreased serotonergic activity, open trials of serotonergic drugs in combination with a serotonergic diet were conducted. The use of a serotonergic diet alone resulted in no change in SIB. Dose-dependent reductions in SIB occurred during paroxetine and sertraline phases, suggesting some benefit in the use of serotonergic drugs.     

Selective Serotonin Reuptake Inhibitor Use and Risk of Arrhythmia: A Nationwide,Population-Based Cohort Study

PurposeThis study compares the risks of arrhythmia among patients with depression receiving selective serotonin reuptake inhibitors (SSRIs) and those receiving other classes of antidepressants and among patients with depression receiving citalopram-escitalopram and those receiving other SSRIs.MethodsThis retrospective cohort study used data from the 2000–2011 National Health Insurance Research Database in Taiwan. Patients with depression who were new antidepressant users were included in the study sample. Propensity score matching was used to balance the covariates between the comparison groups. Crude incidence rates were generated by Poisson regressions, and Cox proportional hazards regression models were used to assess the rates of arrhythmia among SSRI users and nonusers of SSRI antidepressants as well as between citalopram-escitalopram users and users of other SSRIs.FindingsNeither SSRI (hazard ratio [HR] = 0.95; 95% CI, 0.83–1.08) nor citalopram-escitalopram (HR = 1.20; 95% CI, 0.95–1.51) exposure was associated with a risk of arrhythmia compared with other, newer non-SSRI antidepressants or noncitalopram SSRIs. An increase in mortality was, however, observed among citalopram-escitalopram users (HR = 1.21; 95% CI, 1.08–1.31).ImplicationsCitalopram, escitalopram, and other SSRIs were not associated with an elevated risk of arrhythmia compared with each other or with non-SSRI antidepressants. Nevertheless, citalopram and escitalopram were associated with an increase in mortality risk compared with other SSRIs and deserve further investigation.     

Selective Serotonin Reuptake Inhibitors and Poststroke Epilepsy: A Population-Based Nationwide Study

Objective

To investigate the effects of selective serotonin reuptake inhibitors (SSRIs) on poststroke epilepsy in a population-based nationwide study.

Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome

Objective.— The present study was designed to discern the prevalence of concomitant use of a 5‐hydroxytryptamine receptor agonist (triptan), and a selective serotonin reuptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) after the US Food and Drug Administration issued an alert regarding serotonin syndrome in 2006 and to contrast findings with data published prior to the federal warning. Background.— In July 2006, the US Food and Drug Administration warned patients and health‐care professionals to be aware that use of a triptan in combination with an SSRI or SNRI may result in a potentially life‐threatening problem known as serotonin syndrome. In 2010, the American Headache Society published a position paper noting that there existed conflicting and insufficient information to discern the risk of serotonin syndrome with the use of triptan, and SSRI or SNRI, and that said Class IV data were not to be used as the basis for limiting the prescribing of triptan with SSRI or SNRI (Level U). Clinicians were cautioned as to the seriousness of serotonin toxicity and that monitoring was warranted. Methods.— We used weighted data from the US National Ambulatory Medical Care Survey for years 2007 and 2008 to derive national estimates of the number of office‐based physician–patient encounters (visits), documenting the concomitant use of triptan, and SSRI or SNRI. Results are compared with previously published findings for the years 2003 and 2004. Results.— During the time‐frame 2007‐2008, an annualized mean of 5,256,958 patients were prescribed a triptan (vs 3,874,367 in 2003‐2004, a 35.7% increase), and 68,603,600 patients were prescribed an SSRI or SNRI (vs 50,402,149 in 2003‐2004, a 36.1% increase). An annualized mean of 1,319,763 patients were simultaneously prescribed or continued use of triptan, along with SSRI or SNRI (vs 694,276 in 2003‐2004, a 90.1% increase). Conclusion.— Our study documents that 1.8% (1,319,763/73,860,558) of patients in 2007‐2008 were prescribed triptan, and SSRI or SNRI (vs 1.3% in 2003‐04, an increase of 38.5%). While this is a small fraction overall, the actual number of patients on a nationwide basis is substantial. What remains missing from the literature is documentation as to the number of cases of serotonin syndrome and resulting consequences (clinical and economic) because of the concomitant use of triptan, and SSRI or SNRI in the time‐frame 2007‐2008. Absent in these data, it remains difficult to assess the risk benefit associated with the use of triptan, and SSRI or SNRI.     

Ontogeny and regulation of the serotonin transporter: providing insights into human disorders

Serotonin (5-hydroxytryptamine, 5-HT) was one of the first neurotransmitters for which a role in development was identified. Pharmacological and gene knockout studies have revealed a critical role for 5-HT in numerous processes, including cell division, neuronal migration, differentiation and synaptogenesis. An excess in brain 5-HT appears to be mechanistically linked to abnormal brain development, which in turn is associated with neurological disorders. Ambient levels of 5-HT are controlled by a vast orchestra of proteins, including a multiplicity of pre- and post-synaptic 5-HT receptors, heteroreceptors, enzymes and transporters. The 5-HT transporter (SERT, 5-HTT) is arguably the most powerful regulator of ambient extracellular 5-HT. SERT is the high-affinity uptake mechanism for 5-HT and exerts tight control over the strength and duration of serotonergic neurotransmission. Perturbation of its expression level or function has been implicated in many diseases, prominent among them are psychiatric disorders. This review synthesizes existing information on the ontogeny of SERT during embryonic and early postnatal development though adolescence, along with factors that influence its expression and function during these critical developmental windows. We integrate this knowledge to emphasize how inappropriate SERT expression or its dysregulation may be linked to the pathophysiology of psychiatric, cardiovascular and gastrointestinal diseases.