The results of this study suggest that AC-AEs are a relatively common side effect of fluvoxamine in this sample of children with an anxiety disorder. The frequency of SSRI-related activation side effects in this study (48%) is consistent with the 50% reported in a small prospective study (Riddle et al. 1991
). One third of AC-AEs occurred in the first month of treatment. Other investigators also have noted that activation occurs early in the course of treatment or after dose changes (Walkup and Labellarte 2001
). In addition, 75% of children in the current study who developed AC-AEs before week 8 also experienced symptoms at week 8 of the study once the medication dose had been retitrated. This suggests that AC-AEs either recurred or persisted with subsequent dose increases.
The relatively lower fluvoxamine doses and significantly higher mean blood levels among children who developed AC-AEs raise the question of a correlation between metabolism and SSRI tolerance. Fluvoxamine is metabolized mainly via the CYP 2D6 isoenzyme and inhibits several other cytochrome P450 enzymes. Genetic polymorphism could influence the variability of these metabolic enzymes and affect SSRI metabolism. Individual metabolic differences or younger age may potentially influence fluvoxamine blood levels (Labellarte et al. 2004
). A recent study reported that activation was two- to three-fold more prevalent in children than adolescents (Safer and Zito 2006
), suggesting a possible underlying biological vulnerability for developing activation with SSRIs. A pharmacokinetic study suggests that younger children may have a higher exposure to fluvoxamine than adolescents or adults (Labellarte et al. 2004
). In this study, although females and younger children had higher blood levels than males and older children respectively, these differences did not reach statistical significance (p
The comparatively low rate of AC-AEs in the placebo group of our study, and the resolution of symptoms following dose maintenance or lowering, suggest that AC-AEs are most likely related to fluvoxamine as a pharmacological agent rather than a placebo effect. These findings highlight the importance of remaining vigilant to this side effect, even after initial acute dosing changes, and the need for continued close monitoring. Future studies are needed to assess the influence of cytochrome P450 and individual polymorphisms as this might inform more thoughtful dosing and lessen the likelihood of developing AC-AEs.
AC-AEs often subsided with a dose reduction, which mirrors previously reported findings (King et al. 1991
; Riddle et al. 1991
). This activation symptom resolution may parallel the agent's pharmacokinetic profile (Walkup and Labellarte 2001
), such that AC-AEs would resolve more quickly with agents that have a shorter half-life compared to those with a longer half-life. Fluvoxamine may exhibit nonlinear kinetics, and children 11 years old and younger may show higher mean peak plasma concentration compared with adolescents (Labellarte et al. 2004
). These age-related influences on fluvoxamine metabolism might have influenced our findings, with regard to AC-AEs and blood levels, because the average age in this study was 10 years of age.
Our findings are consistent with earlier research showing that AC-AEs are distinct from typical DSM-IV–defined manic symptoms. For one, AC-AE symptoms are discrete from the symptoms of bipolar disorder except for the increased motor activity (Walkup and Labellarte 2001
). The lack of euphoria and absence of decreased need for sleep associated with AC-AEs in this study were distinguishable from symptoms of typical mania; this paralleled features previously reported by other investigators (Riddle et al. 1991
). Second, 20% of participants (n
2) with AC-AEs experienced insomnia but not concurrently with AC-AE, nor a decreased need for sleep. Although this is lower than previous findings that suggested up to 46% of youths had sleep disturbance as a behavioral side effect when treated with fluoxetine (Riddle et al. 1991
), the small number of participants limits our ability to draw any definitive conclusions regarding this association. Third, 30% of children developed AC-AEs within the first 4 weeks of treatment; however, it is possible that some children may develop these symptoms much later in the course of treatment. This is in contrast to the onset of manic symptoms whereby decreased need for sleep, euphoria, or grandiosity generally present earlier in the course of treatment (Walkup and Labellarte 2001
). Last, the presence of a family history of bipolar disorder did not appear to predispose children to develop AC-AEs, which corroborates observations suggesting that AC-AEs are different from manic symptoms (Walkup and Labellarte 2001
). Neither age, gender, nor a family history of psychiatric disorders was associated with the development of AC-AEs.
This study defined AC-AEs beyond just increased motor activity, which makes comparison to other studies difficult. Findings from the RUPP multicenter study (Research Units for Pediatric Psychopharmacology Anxiety Study Group 2001
) showed across all sites a nonsignificant trend toward increased motor activity in 20% of children who received active treatment (p
0.06). However, this only describes motor activity, not the other behavioral components of AC-AEs, and therefore may be an underestimate this side effect. In addition, the frequency of AC-AEs reported in the current study is higher than that found with adult patients treated with fluoxetine (10–25%) (Lipinski et al. 1989
). It is not clear what factor is responsible for this difference, but perhaps age, neurodevelopmental differences, or specific SSRI-related metabolic differences could influence the prevalence of AC-AEs in the younger participants in our study.
Although not much is known about the pathophysiology of AC-AEs, several possible mechanisms for the activation syndrome have been proposed. An increase in energy or a movement disorder, similar to akathisia (Gerber and Lynd 1998
), may lead to an increased expression of aggressive, impulsive, or self-injurious behavior, particularly if mood has not yet improved synchronously with improved energy level. It is also possible that patients actually switched to a variant of a manic or mixed state (Walkup and Labellarte 2001
). It is unclear if AC-AEs are related to akathisia, which may have a similar clinical presentation. Moreover, it is hypothesized in one case report that activation is related to self-injurious behavior via serotonergic-mediated effects that could compromise a patient's ability to self-regulate their behavior (King et al. 1991
). The disinhibition related to activation also could lead to impulse control problems (Wilens et al. 1998
; Wilens et al. 2003
SSRIs may increase the serotonin-related inhibition of dopaminergic cells in the ventral tegmental area of the midbrain, which may lead to activation (Lipinski et al. 1989
). The role of the frontal lobe in SSRI-induced behavioral activation, disinhibition, and SSRI-induced amotivational syndrome or apathy is not known, although the frontal lobe may mediate different adverse events (Hoehn-Saric et al. 1991
; Garland and Baerg 2001
; Reinblatt and Riddle 2006
). A better understanding of the mechanisms of activation could potentially improve monitoring and the clinical management of children treated with SSRIs.
These findings should be interpreted with an appreciation for several methodological limitations. First, the study was a retrospective review of existing data and does not allow for long-term follow up to determine the persistence or recurrence of AC-AEs. This approach does not provide definitive answers to primary research questions; however, the authors thought this was an important first step in the field, given the significance of the subject matter and the limited information available. Because the AC-AE ratings were subjective measures, there is the potential for under- or over-reporting AC-AEs. In an attempt to minimize this potential bias, the first author examined the research charts to verify the severity of the event; however, this potentially might have inadvertently introduced misclassification error. Without systematic inquiry for adverse events, AC-AEs may have been underreported; the method of eliciting AC-AEs spontaneously by clinicians after open-ended questions and using COSTART terms was the standard in clinical trials at that time.
The dose titration schedule used in this clinical trial reflected a rapid dose escalation to minimize placebo exposure. As is common in many other pediatric psychopharmacology studies, the dose escalation is not typical of titration schedules used in clinical practice; this would impact the generalizability of these results to clinical practice because it possibly may overestimate the frequency of AC-AEs resulting from rapid dose increases. These data describe only moderate-to-severe activation effects that were sufficient to cause clinicians to reduce dosage in the context of a research study; thus, they may not represent the full prevalence of all activation adverse events. The lower mean dose of fluvoxamine among those who developed AC-AEs relative to those who did not may have been related to protocol guidelines, such as dose reduction in the “activated” children over the course of the study. Unfortunately, data were not available to permit examination of the effect of very large body mass differences independent of age. The study included younger children, which may have limited the ability to detect an association between the development of AC-AEs and age.
The sample in this study may not be generalizable to some patients because the child sample was predominantly Caucasian and did not have psychiatric co-morbidities. Data were not collected on the P450
genotype of the participants; because genotype variants may affect fluvoxamine metabolism, plasma blood level differences may have been related to genotype variation in metabolism. Although parents did not report any other co-prescribed psychotropic medications, which may have affected fluvoxamine blood levels, it is possible that they did not recall such information accurately. The results also are limited by a small sample size. Examining only one site might be a potential source of bias because there might be site-specific differences; thus, not replicating findings at the other RUPP sites limits the power of this report. Even though most of the blood level samples were obtained at the JHU site, the study protocol was strictly enforced across all sites to reduce site-specific variation, and so it is unlikely that this compromised the integrity of the data. However, because there are no other data that have examined this phenomenon, this exploratory work is important for future research in this field.
Several potentially important clinical findings emerged from this investigation. First, AC-AEs are relatively common side effects of fluvoxamine in children and may appear at any point within the first 8 weeks of treatment, suggesting the need for close monitoring in the first month after initiating treatment because this is when many adverse events occur. There also is a risk of recurrence of AC-AEs that highlights the utility for careful SSRI dose titration and continued monitoring for AC-AEs reoccurrence. AC-AEs may not only impact daily functioning, but they may also compromise medication compliance. It appears that these adverse effects resolve with dose reduction. This work provides some preliminary evidence of increased fluvoxamine blood levels associated with increased AC-AEs. These preliminary data require further study to determine whether the AC-AEs associated with increased blood levels are related to metabolic variability and to help identify clinical strategies that would minimize this relatively frequent adverse event among children treated with SSRIs.