Medication-Induced Activation in Children and Adolescents

Doctors treating children who appear to become agitated, irritable or activated on medication want to know how to manage these reactions and whether these types of medication responses are a harbinger of future bipolar disorder (BD) (e.g., Ghaemi et al., 2003). Unfortunately, we cannot answer these questions for a number of reasons (for a review, see Carlson and Mick [2003]).

For starters, there are few data and no agreed-upon term or terms that address the behavior, emotional or cognitive problems that may occur as unwanted effects of drugs that act on the central nervous system. The terms behavioral toxicity, disinhibition or drug-induced disinhibition, psychiatric adverse events, and paradoxical reaction (the inconsolable crying, rage, disorientation, dysphoria and restlessness that occur in children after sedative administration) have all been used, but inconsistently. Although there is some overlap, terms used to describe selective serotonin reuptake inhibitor-related activation events are not synonymous and include irritability, anger outbursts, excitability, manic symptoms, hyperkinesis, hyperactivity, agitation, nervousness, lability, hostility and motor activity.

Second, in the published literature, anecdotal reports far outnumber systematic studies. The shortcomings of this approach are evident in the controversy over SSRIs and suicidal behavior in young people, which as yet is unresolved because events have been inconsistently elicited and operationalized. The same limitation is true for activation-like effects. Even if asking about symptoms produces clinically insignificant responses (Beasley et al., 1991), that would be easier to interpret than the inconsistency and heterogeneity that appear to emerge when relying on spontaneously reported and recorded events. Obtaining consistency and reliability has been the justification for using structured measures such as interviews and rating scales.

Third, it is always difficult to tease apart medication effects from pre-existing psychopathology. Irritable, disinhibited children are usually the ones being treated. This is why placebo-controlled trials and baseline rates of the problem in question are needed. The time course for when adverse events occur is also essential. Implications are likely to differ for symptoms that occur soon after the medication is started versus those that occur after the patient has taken the medication for a while. Wilens et al. (2003) noted two patterns to SSRI activation events, i.e., those that occurred shortly after the drug was started and those that occurred some months later. The former was not associated with diagnosis; however, the authors speculated the latter might be.

Also, we are just beginning to learn about factors related to individual differences in drug metabolism. Developmental factors are crucial and include immaturity of neuroendocrine systems, changes in blood-brain barriers, levels of detoxifying enzymes and ongoing development of neural circuitry (Vitiello and Jensen, 1995). Behavioral toxicity to different drugs may look similar but does not necessarily reflect the same mechanisms.

For instance, no one describes acute alcohol-induced disinhibition (intoxication) or benzodiazepine/barbiturate-induced paradoxical reactions in children as examples of secondary mania, yet behaviorally they are quite similar.

The U.S. Food and Drug Administration has only recently required additional safety data in medications that are likely to be used in children, in addition to drugs specifically approved for children. Already, there are a surprising number of medications known to cause psychiatric adverse events in some children.

For example, aggression, excitement, irritability or hallucinations are known to occur with alcohol, antihistamines, barbiturates, tricyclic antidepressants, acetazolamide (Dazamide, Diamox), benzodiazepines, steroids, bromides, primidone (Mysoline), sulthiamine and stimulants (Rie and Rie, 1980). Regrettably, there has been no systematic reporting of pre- or postmarketing behavioral adverse events in children who have been given nonapproved medications, so frequency and severity are unknown.

Finally, there are really two issues embedded in the question of behavioral toxicity to medications, which I will address. The first is whether activation events occur under different circumstances in young people versus adults, and the second is whether there is any future diagnostic predictive validity to the activation if it occurs. I will specifically cover activation-like events predominantly in stimulants (stimulant rebound, stimulant response in children/teens with bipolar spectrum conditions, stimulant psychosis) and in antidepressants, including SSRI activation.

Stimulants

Rebound (increased hyperactivity, irritability, dysphoria occurring as stimulant medication wears off) is often described by parents and can be mistaken for mania, but is rarely examined in stimulant trials (Sarampote et al., 2002). When it is specifically examined, it is either difficult to document (e.g., Nolan et al., 1999), or the irritability that is usually measured generally improves with treatment (e.g., Greenhill et al., 2001). In one of the few systematic studies of rebound, Carlson and Kelly (2003) reported that some children (11%) behaved worse at night even without medication, while others (21%) had transient rebound. Only 9% of their sample of hospitalized children had clear, persistent, stimulation-related dysphoria, i.e., rebound severe enough to stop the medication. Within this sample, there were no indications that this response occurred more often in children with manic symptoms.

Intravenous and abused stimulants can produce euphoria, mania, hallucinations and paranoia in adults. For this reason, there is some concern that stimulants, even at prescribed doses, will induce/perpetuate mania or psychosis in children. There is surprisingly little systematic data, let alone controlled studies, on this subject in adults or children. In a post hoc analysis of the Multimodal Treatment of Attention Deficit Hyperactivity Disorder study data, stimulant response was compared in 579 children with attention-deficit/hyperactivity disorder and with and without a mania proxy based upon a Child Behavior Checklist (CBCL) (Galanter et al., 2003). Stimulants worked equally well in both groups and no one became manic. Similarly, in an inpatient study of children with ADHD, those who also had manic symptoms did no worse on stimulants than children without manic symptoms (Carlson and Kelly, 1998). Thus, direct and systematic studies of children with parent-described manic symptoms do not suggest inevitable worsening on stimulants, though, like rebound, some children could not tolerate the medication. Important to note, however, is that these children did not meet criteria for classic mania as defined by DSM-IV and Leibenluft et al. (2003).

How common and which adults become psychotic on stimulants and why remains unclear. Nontherapeutic use is usually studied. Apparently, people with mild psychotic symptoms or schizotypal traits and/or those who begin methamphetamine abuse at an early age are more vulnerable to psychosis; also, a large enough dose will produce at least a transient psychosis in almost anyone (Chen et al., 2003; Curran et al., 2004). Stimulant-induced psychosis on ostensibly therapeutic doses of medication is rarely reported in children (Cherland and Fitzpatrick, 1999; Young, 1981), so little is known of the risk factors.

I have had child patients develop paranoia on what was a previously therapeutic dose of stimulant taken after a drug holiday. (The paranoia subsequently resolved at a lower dose.) I have also seen children develop hallucinations at a younger age but not when retried on stimulants a few years later. Interestingly, in two small case series, children with psychosis or schizophrenia with ADHD symptoms were successfully treated with stimulants, provided they took antipsychotic medication concurrently (Pine et al., 1993; Tossell et al., 2004).

Children with developmental disabilities, including autism and mental retardation, may be especially vulnerable to behavioral toxicity (Aman, 2004; Aman et al., 2003; Handen et al., 2000; Stigler et al., 2004), though children with ADHD and these conditions may improve, too. Children with epilepsy often have ADHD and are treated with stimulants. However, seizure induction/exacerbation, rather than behavioral toxicity, has been the focus of study (Tan and Appleton, 2005). Positive response to stimulants appears variable in preschool children more so than older children (Connor, 2002), and comparative rates of behavioral toxicity to older children await further study.

Antidepressants

While there is no consensus on the inevitability of patients with bipolar depression destabilizing on antidepressants (Ghaemi et al., 2003; Gijsman et al., 2004), the extant assumptions are that older antidepressants (e.g., TCAs) cause more switching than newer antidepressants (e.g., SSRIs) and that adults who are depressed who become activated on an antidepressant are truly bipolar.

Although TCA use may sometimes cause activation in children (Geller et al., 1993), it was not a predictor of subsequent bipolarity in children who were depressed (Geller et al., 2001), thus suggesting there may be no prognostic implication to the activation when it occurs. In a meta-analysis of over 500 children treated in placebo-controlled trials with a TCA, no activation symptoms were reported (Hazell et al., 2002). While recent investigations may be more sensitive to activating events, it is hard to believe prior TCA studies would have ignored mania conversion.

Short-term SSRI use for depression and anxiety in young people appears to produce differing rates of irritability, anger outbursts, agitation and activation depending on the term and the study (6% to 28% on SSRIs versus 0% to 13% on placebo, and mania induction 0.9% to 6.25%) (Carlson and Mick, 2003). Rates in the recently published Treatment of Adolescent Depression Study found rates of 8% in teens treated with placebo, 18.3% in those treated with fluoxetine (Prozac), and 11.2% in those treated with fluoxetine and cognitive behavioral therapy (March et al., 2004). No consistency exists across drugs or diagnoses.

Rates in adults are difficult to compare because adverse event ascertainment varies. Studies using fluoxetine initially reported high rates of systematically obtained activation symptoms compared to placebo and occasionally to imipramine (Tofranil), but they were not clinically significant rates (i.e., patients did not drop out of studies) (Beasley and Potvin, 1993; Beasley et al., 1991). In later trials, for example, those comparing paroxetine (Paxil), imipramine and placebo, psychiatric events (suicidal behavior, agitation, irritability, manic/hypomanic switches) were never mentioned at all, either as present or specifically absent. Adverse events were elicited by asking nonleading questions rather than systematically.

Only two published studies in which an SSRI and TCA were compared in randomized studies of teen-agers are available (Braconnier et al., 2003; Keller et al., 2001). These studies used either imipramine or clomipramine (Anafranil) and paroxetine. Keller and colleagues specifically excluded teens with bipolar depression and included a placebo control. Side effects were actively solicited at each visit. Activation-like events in these two reports did not use identical terms, but it did appear possible to group suicidal behaviors, manic symptoms, psychosis and other agitated states. Rates were generally low, but always higher in the paroxetine group, but not the TCA group. Overall rates were 1.1% in 87 teen-agers treated with placebo, 9.3% in 153 treated with TCAs and 16.6% in 156 treated with paroxetine.

I found only one study that compared imipramine, paroxetine and placebo (patients were all on at least one mood stabilizer at the time) in adults with bipolar depression (Nemeroff et al., 2001). In this case, since manic conversion was a concern, symptoms were carefully elicited. Interestingly, no mania or hostility was reported in 35 patients treated with paroxetine. Three of the patients treated with imipramine (7.7%) and one patient on placebo (2.3%) experienced treatment-emergent mania.

Given method differences, sample sizes and the question of which trials are even published, it is difficult to draw conclusions about activation/mania by drug, age or diagnosis. There is some suggestion that young people become activated more frequently and while taking certain medications.

We examined drug-induced behavioral disinhibition (DIBD) in a well-characterized sample of 267 children hospitalized for psychiatric reasons (Carlson and Mick, 2003). We operationalized DIBD as a dramatic increase in irritability identified by increased children's "time-outs" for impulsive/aggressive behavior while on medication. The children's reactions were carefully measured and recorded weekly during unmedicated and medicated weeks by two shifts of nurses. Age, gender, diagnosis and medication were covariates. Using this definition, we found only 20 (7.5%) children with DIBD. Severe ADHD and pervasive developmental disorder (but not mania or depression) appeared to increase the risk for DIBD, while older age and stimulant use decreased the likelihood. A trend suggested an increase in DIBD with SSRIs. However, it was often difficult to distinguish true DIBD from the behavioral fluctuations of these disturbed children. Fifteen percent of children subsequently improved on the same regimen; 40% improved when the offending drug was stopped and another treatment started; and the remainder had adverse responses to many medications.

The most robust data on the vulnerability of young people to antidepressant-induced switching come from a large pharmacoepidemiologic study of 87,920 mental health users ages 5 to 29. Martin et al. (2004) defined a "manic" conversion by the presence of a mood stabilizer prescription three or more months after antidepressant prescription. (The three-month time period was chosen to eliminate activation that subsides on drug discontinuation.) A new diagnosis of BD was also present in the claims. An overall rate of 5.4% of this phenomenon was found. However, prepubertal children were found to be at highest risk for this occurrence with a "number needed to harm" rate of 10 (95% CI=9-12). In 15- to 19-year-olds, this rate dropped to 16; in 20- to 24-year-olds, to 31; and in 25- to 29-year-olds, to 29.

The question here is not so much whether the event took place, but whether children prescribed antidepressants at a younger age have a greater vulnerability to behavioral toxicity, whether this vulnerability will persist as they develop, and whether it means they even have BD. In nonresearch settings, the diagnostic accuracy of a BD diagnosis is poor (e.g., Pogge et al., 2001). As noted in the inpatient study described, a variety of disorders were found to be present when drug-induced disinhibition occurred.

Conclusion

Activation-like events should be defined, anchored and obtained systematically in future drug trials and subsequently in postmarketing surveillance efforts. In clinical settings, baseline measures of aggression, agitation, irritability and mood should be obtained before starting treatment. Ideally, these should be obtained prospectively for several weeks in order to determine whether an event is part of the natural history of the condition or due to the medication.

Activation events may occur more frequently in children and adolescents, especially those with developmental disabilities, than they do in adults. It is premature to conclude what the clinical or pharmacological significance of these events is because the data are so limited. Switching children from the frying pan of antidepressants to the fire of mood stabilizers and atypical antipsychotics on the basis of behavioral toxicity alone seems ill-advised.

How specifically to handle behavioral toxicity will depend on what the symptoms are, how severe they are and the effectiveness of the medication. Choices obviously range from stopping the drug, lowering the dose and/or changing the dosing schedule to adding another medication that mitigates the unwanted symptoms.

Prior to starting any medication, families should always be warned about the potential for psychiatric adverse events, with specific caution taken in young children, those with developmental disabilities and those with pre-existing problems with severe emotion regulation (e.g., severe ADHD and BD). Data are not sufficient yet, however, to draw unequivocal conclusions that children who develop medication-related activation symptoms will develop BD in the future.

Disclosures:

Dr. Carlson is professor and director of child and adolescent psychiatry at Stony Brook University School of Medicine. She is best known for her research and teaching on mood disorders, especially BD and its comorbidities, in young people.

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