Antidepressant-Induced Activation in Children and Adolescents: Risk, Recognition and Management

Abstract

The tolerability of antidepressants is poorly characterized in children and adolescents with depressive and anxiety disorders. Among adverse events that affect the tolerability of antidepressants in youth is activation, a cluster of symptoms that represent a hyperarousal event characterized by impulsivity, restlessness, and/or insomnia. This cluster of symptoms was first identified as a side effect of selective serotonin and selective serotonin norepinephrine inhibitors (SSRIs and SSNRIs) in the early 1990s; however, activation remains poorly characterized in terms of prevalence, risk factors, and pathophysiology. This article describes the pathophysiology of antidepressant-related activation, predictors of activation and its clinical management in youth with depressive and anxiety disorders who are treated with antidepressant medications.

Optimal doses of antidepressants in dependence on age: Combined covariate actions in Bayesian network meta-analysis

“…S2), which ultimately limits the clinical interferences to be made on both ends of the age spectrum. The nonlinearity of the observed age effects however supports earlier reports that the risk-benefit ratio is most favorable for adults between 25 and 65 years, while both younger adults > 25 years, due to an increased risk of suicidality [23] and hyperarousal events [24], as well as elderly patients > 65 years, due to more side effects [11À16], pharmacodynamic tolerance [19], and suicidality [20À22], may not respond as well to antidepressants. Considering the presented balanced dosing recommendations may thus not necessarily lead to better response rates, but may keep tolerability at endurable levels, which is important for treatment compliance and adherence.…”

“…Indeed, antidepressant prescribing in older adults has recently been reported to be pharmacokinetically inappropriate in 77% (underuse) and 42% (overuse) [18], with a subset of patients experiencing pharmacodynamic tolerance after long-term treatment [19]. Antidepressant use is also associated with higher suicidality [20], particularly in elderly men (completed suicides) [21,22] but also in patients < 25 years (not completed suicides) [23]; with the latter also having a higher risk of hyperarousal events in response to antidepressants [24]. Together, age is an important consideration for whether, when, and how to treat a patient with antidepressants throughout the life cycle, and with what potential risk versus benefit.…”

The development of monoaminergic neurotransmitter systems in childhood and adolescence

“…Serotonergic psychopharmaceuticals, such as selective serotonin uptake inhibitors (SSRI), show similar effects in children and youth as in adults for the treatment of depression and anxiety disorders (Bridge et al, 2007; Luft et al, 2018). However, particularly in children there are unwanted effects such as restlessness, agitation, increased motor activity, and nausea / vomiting that occur more often than in adults.…”

“…However, particularly in children there are unwanted effects such as restlessness, agitation, increased motor activity, and nausea / vomiting that occur more often than in adults. As a possible explanation, a development‐related increased sensitivity of the serotonergic system has been discussed (Safer and Zito, 2006; Luft et al, 2018). Activation of the 5‐HT2A receptor which shows a developmental peak in childhood has been associated with impulsivity.…”

Choosing the appropriate pharmacotherapy for obsessive-compulsive disorder in adult patients with comorbid anxiety disorders: clinical and nosological considerations

“…Tolerability considerations would likewise do. For example, comorbid PD or GAD would be expected to require a lower dose of serotonergic modulators in order to avoid excessive neurovegetative activation or to reduce the chance of 'jittering syndrome' with the serotonergic antidepressants [8][9][10]; on the converse, comorbid OCD associated with SAD may require increased doses to achieve a clinically meaningful response (please refer to Table 1).…”