Gabrielle A. Carlson, MD

For those of us who treat seriously emotionally disturbed children, We’ve Got Issues is a welcome change from the invectives of those who believe that the use psychotropic medication is virtually criminal. Ms Warner began with that supposition-and when she dug deeper into the matter, she found that most parents and doctors do the best they can for children whose psychological problems are anything but trivial.

“Issues” is a clever word. I had first heard the term from the mother of a boy with high-functioning autism. She called his explosive meltdowns “issues.” I thought, “What kind of euphemism is that?” It is a nice disguise, though, for the many behavioral difficulties parents face with their children when they don’t want to use a more stigmatizing label.

Ms Warner turns out to have other “issues” too. Her first was finding that much of the ambient information that depicts doctors as “drugging and pathologizing kids,” “profit-mad scientists” and parents who are looking for a quick fix comes from uninformed and oversimplified “public opinion and most media treatment.”

Hunkering down with well-referenced research, she fills her chapters with “observation, scores of interviews with mental health experts, critical thinking and, above all, the compassion gained from talking to dozens and dozens of the parents who stare at the whole ‘issue’ of children’s mental health.” Ms Warner then returns to a discussion of how public understanding of children’s mental health treatment has gone wrong.

Among other things, the author recognizes that “kids with serious problems are no longer routinely institutionalized . . . they’re kept functioning with medication,” and there are real risks in not being properly treated. She debunks what she calls the MedScare-the “now common conviction that psychiatric drugs are being used to control and denature normal and healthy children and adults who don’t conform to society’s expectations.”

Ms Warner says “Industry/BigPharma” has corrupted medicine and psychiatry. However, her understanding of how drugs are studied is naive, and her notion of “conflicts of interest” is limited only to financial ones. Like many in the public sector, she doesn’t recognize that more is broken than overzealous marketing. She fails to realize that if there were no connection between academic clinicians and pharmaceutical companies, drug development would be seriously compromised.

Any practicing child psychiatrist can get behind the book’s most serious concern that “science has outpaced our capacity to use it well. Progress has been betrayed by commercial interests, political complaisance, and a lack of policy directed at making sure that new scientific advances are safely . . . made available to . . . the public.” While Ms Warner tends to be redundant and oversimplifies matters-and diehard opponents of the practice of mental health medicalization will not be persuaded-worried parents and caring doctors have an articulate champion in their corner.

Articles

 For those of us who treat seriously emotionally disturbed children, We’ve Got Issues is a welcome change from the invectives of those who believe that the use psychotropic medication is virtually criminal.  

We’ve Got Issues: Children and Parents in the Age of Medication

Temper outbursts, sometimes called rages, are a major reason for outpatient and inpatient referral. These behaviors have also been a focus of assessment in child psychology and psychiatry since 

 were developed. In fact, items consistently loading on the same factors in frequently used behavior rating scales for children reflect negative mood (mood changes quickly/explosive, easily angered/ stubborn, sullen, irritable), oppositionality (being demanding, unco­operative and disobedient) and aggression (argumentativeness, having tem­per tantrums).

Rages have been associated with extreme irritability or mania, 

 and conduct disorder, autism/Asperger disorder, and other conditions.

, which is defined by markedly increased and frequent reactivity to negative emotional stimuli (eg, response to frustration with extended temper tantrums, verbal rage, and/or aggression toward persons or property) that occurs at least 3 times a week in the context of 

 This co-occurs with other symptoms, such as those related to 

attention-deficit/hyperactivity disorder (ADHD)

 or anxiety (ie, hyperarousal, distracti­bility, rapid speech/racing thoughts, 

Jordan, 8 years old, has been referred for psychiatric evaluation because of his restless, distractible, impulsive, unpredictable, oppositional, and defiant behavior. He has difficulty in following directions; sometimes he refuses to do a task, other times he doesn’t seem to understand what is needed. His frequent frustration often results in prolonged outbursts at home. In school, he has to be removed from class because his behavior becomes dangerous. When he is restrained by his parents or a classroom aide, he becomes even more agitated, and rages violently.

The term “rage” implies that these outbursts consist solely of high-intensity anger, but we actually know little about their content or structure. It has been suggested that outburst content and/or structure might vary with psychiatric conditions, such as oppositional defiant disorder, depression, and mania.

Our team at Stony Brook has studied rages by direct observation (rather than parent interview), measuring the duration of outbursts, the kinds of behaviors that occur in them, and their diagnostic specificity.

 We examined rages in inpatients at a pediatric psychiatric service, which cares for children aged 4 through 12 years-rage outbursts precipitated admission in over half the children. The median length of stay of about a month gave us ample opportunity to observe behavior. Because of our long-standing interest in bipolar disorder and because rages have become synonymous with bipolar disorder, we were interested in whether these rages reflect a manic rapid cycle and/or occur disproportionately in children with mania.


 To understand rages better, we collected diagnostic and observational data for more than 18 months. The study involved 130 children aged 9.7 ± 2.1 years (one-fifth female), for 151 hospitalizations.

 Examining first admissions, we found that 71 (54.6%) were admitted for rages, but only 37 (52.1%) had an outburst of rage while hospitalized. (Seven other children also had rages but had been hospitalized for different reasons.)

Of the 44 children with rages observed in the hospital, 23 had just 1 episode; the remaining 21 had 2 to 9 outbursts. No significant gender differences were found. Half of the children with serious dysregulation at home or in school were able to maintain self-control on a structured inpatient unit that had clear expectations, positive support, and a less stressful environment than at home or in school.

A rage was defined as having started when the child became loudly verbally defiant and out of control when asked to do or stop doing something by the staff. The outburst was observed at 5, 15, 30, 45, 60, 90, and 120 minutes after onset by the nursing staff. Behaviors coded during each rage included verbal acts (whining, verbal threats, cursing, yelling, screaming), discrete physical acts (stamping, pushing, pulling, throwing things, biting, scratching, punching the wall, hitting, kicking), and expressive psychomotor behaviors (tearful/sad, anxious/fearful, withdrawn/unresponsive). Notably, manic symptoms were never seen.

During more than 18 months of data collection, 117 outbursts were recorded for 49 patients. Of the coded behaviors observed, angry behaviors (eg, yelling, screaming, cursing, violent threats, stamping, kicking, hitting, throwing objects) were the most common and occurred in 93% of the episodes; tearful/sad or anxious/fearful behaviors occurred in fewer than half (46%) the rages. An episode of rage generally lasted over 45 minutes, but length varied wide­ly, with 19% of outbursts lasting less than 30 minutes and 19% lasting longer than 60 minutes.

Rage outbursts usually occurred early in the course of hospitalization. For instance, 44% of children with outbursts had their first/only episode within 2 days of admission. The remainder occurred 2 days after admission through discharge. Half of the children had an episode of rage immediately after admission; then, after “testing the waters,” they quickly desisted.

In addition to the question of whether outburst content and/or structure might vary depending on psychiatric conditions, we were mindful of frequent parental comments to the effect that their rage-prone child had “never outgrown the terrible twos.” This raised the hypothesis that rages might resemble childhood temper tantrums. A set of factor analyses of coded behaviors identified 5 groups: 3 were interpretable as progressive levels of anger intensity, 2 others as levels of distress (ie, sadness/anxiety).

This model of outburst organization accounted for 54% of total variance. An independent cluster analysis of behavior slope revealed that anger behaviors peaked early and declined relatively rapidly; distress behaviors were more evenly distributed. Thus, rages closely resembled the observed tantrums of typically developing preschoolers with respect to behavior types and time course (early peaking anger, more evenly distributed distress).

 However, in terms of severity and duration, they were similar to parent-reported tantrums of pre­schoolers with depression and disruptive behavior disorders whose rages lasted more than 20 minutes.12 Inpatient rages lasted at least twice as long as temper trantrums of typically developing preschoolers, and because the patients were bigger, they were more destructive.


 In determining how children with observed rage outbursts during hospitalization differed from their hospitalized peers, we found that younger children were marginally more likely to have rages (r = –0.155). Their IQ, history of abuse, and living status (with or without a parent) had no significant effect. Best-estimate diagnoses encompassing parental and school history, child mental status, and hospital course were made after discharge.

Considering single psychiatric diagnoses, 

 were almost 5 times more likely to have a best-estimate diagnosis of ADHD than children without rages. They were over 5 times more likely to have a learning or language disorder but 3 times less likely to have an anxiety disorder. However, children with rages were almost 3 times more likely than those without rages to have 3 or more concurrent diagnoses. The most common combination was ADHD, oppositional defiant disorder, and learning/language disorder. This was seen in 70% of children who had rages compared with 34% of those who did not. The association between language disorder and outbursts is consistent with the more general connection between language and behavior

; however, it is almost never studied in research based solely on structured interviews.

Given the current interest in rages as a symptom of mania and severe mood dysregulation,

 we examined the frequency of those conditions based on referral information and subsequent best-estimate diagnoses for all hospitalizations (N = 151) because a child might have been admitted for mania on 1 admission but not another. In fact, hospitalized children with rages had been referred with a diagnosis of mania more often than those without rages (34.7% vs 15.7%, odds ratio [OR], 2.8; confidence interval [CI], 1.3, 6.3). However, of the 33 admissions where a referral diagnosis of mania had been given, mania was observed and confirmed in only 5 children. Of 44 children with rages, we observed only 9% with mania or manic symptoms (ie, bipolar not otherwise specified), compared with 4.7% of 86 children without mania, and always comorbid with other disorders. Mania, as defined by DSM-IV, did not account for most children whose rages occurred while hospitalized, nor were their outbursts examples of rapid cycles.

We also tried to determine how many children might have met criteria for severe mood dysregulation. Two-thirds of children with rages (65.9%) were defined as having this condition based on behavior at home, compared with only one-quarter of children without rages in the hospital (25.6%)  (OR, 5.6; CI, 2.55, 12.39). Once hospitalized, 1 child had rage episodes 3 times a week. He was given a diagnosis of childhood-onset schizophrenia.


 The evidence-based treatment algorithm for ADHD and aggression consists of medication and behavior modification.

 is added, and then lithium or divalproex. While treatment makes some positive impact, the reality is that complete remission is rare in children with ADHD who have outbursts of rage. For example, in the Multimodal Treatment of ADHD study, rigorous treatment with stimulant medications with or without behavior modification significantly improved behavior in children with comorbid ADHD and in children with the Child Behavior Checklist bipolar phenotype (T scores greater than 67 on the ADHD, aggression, anxiety/depression scales).16 At the end of 14 months, however, these children were still considerably more impaired than those with uncomplicated ADHD.

Another study of outpatient children with ADHD in a ummer treatment program revealed that the combination of stimulant medications and rigorous behavior modification reduced symptoms on the Young Mania Rating Scale (YMRS) from 23.7 ± 3.5 to 15.4 ± 6.1.17,18 Aggression and irritability were shown to be decreased by almost 45% with treatment; ADHD symptoms improved as well, but to a lesser extent. The data specifically address comorbidity and suggest that the combination of  ADHD and irritability/mood symptoms improves with treatment but does not completely remit with strategies directed at ADHD alone. Four “manic” symptoms (elevated mood, sexual interest, sleep disorder, and thought disorder) decreased from mild to even less impairing. There is no evidence that children with severe mood dysregulation respond to lithium alone.

In our sample, children with rages had had a range of treatments as outpatients, including ADHD medications, atypical antipsychotics, and mood stabilizers. In addition, 88% of children with rage outbursts had been in special education, and almost half had been hospitalized previously.

The number of rages correlated positively with length of stay in the hospital (r = 0.32; P < .001): rage episodes added at least 2 weeks to the duration of hospitalization (median, 36 days for children with rages compared with 22 days for children without). Most children improved with a combination of behavior modification, family treatment, appropriate academic intervention, and medication.

Our inpatient behavior-modification approach focuses on teaching children self-control and helps parents learn suitable responses to their child’s behavior.

 Hospitalized children who behave appropriately earn points toward fun activities and increased time for home visits. It is especially important for children with a history of rages to learn to take a Time Out. By sitting quietly in a chair for 10 minutes and then talking with a therapist or staff member, the child learns to identify the triggers that lead to a rage outburst and alternative behaviors for mitigating an episode of rage.

Many children respond favorably to the unit structure and Time Outs from the time of admission. Staff members who observe children starting to lose control will also teach them to “chill out” before a full-blown raging episode occurs. This technique places self-control in the child’s hands.

Children who are unable to take a Time Out are escorted to the quiet room where the door remains open (as long as they stay in the room and don’t try to hurt themselves). A nurse unobtrusively observes until the child has remained quiet for 10 minutes and can subsequently talk about alternatives. This option has cut the use of closed seclusion and physical restraint dramatically.

Some children simply cannot calm themselves down and require immediate medication intervention over and above whatever medication they are taking. An oral alternative (eg, liquid risperidone or a rapidly dissolving oral atypical antipsychotic) is offered first.

 When oral medication is unsuccessful, an injection of diphenhydramine is used.

A few children become so unreachable when they are angry or distressed that no corrective intervention has been successful. Alternative strategies (such as collaborative problem solving) may be an option, but most have not been studied systematically.

 This group of children is the most difficult to manage and requires the longest duration of hospitalization. Some children may require out-of-home placement, depending on psychosocial circumstances.


 To maintain the gains made by children, work with parents begins immediately on admission. To ensure cooperation and reduce defensiveness, the therapist helps parents understand that while they didn’t create the child’s problems, these problems nevertheless require a particular approach. For parents who feel sorry for the child and think any form of consequence is unfair, the social learning paradigm (which underlies behavior modification) is reframed so that behavior that causes failure has a negative consequence and behavior that ensures success earns a positive consequence.

 Most parents want their children to succeed.

Parents are taught how to use the Time Out procedure when the child is not following directions, or when he or she exhibits verbal or physical  aggression.

 In optimum circumstances, parents learn this procedure and are able to get their child to take a successful Time Out before the child has a pass for a home visit and certainly before discharge. Like children themselves, parents have different learning curves in understanding and responding consistently and appropriately to their children.

Time on therapeutic passes provides plenty of opportunity for parents to practice skills with the option of bringing the child back from home pass if the child is unable to take successful Time Outs. This step is vital to support the parents’ effort to gain the child’s cooperation. A confident, reasonable, and well-trained parent helps the child after discharge. Some children need a readmission before they understand that coercing caregivers into capitulating is not an option.

Discharge planning included smaller, special education class placements (for 75%); 90% of children with rages received an ADHD medication and/or an atypical antipsychotic/mood stabilizer and were 4 times more likely to receive both than children without rages.


 Rage behaviors may represent a disease modifier (such as psychosis) that complicates a number of disorders. A precise and accurate diagnostic label is needed to be able to undertake further studies. To date, successful treatment has required a combination of psychopharmacology and nonmedical interventions. Although most children stopped having rages once hospitalized, or perhaps had only 1 episode, children who had continued outbursts remained difficult to treat. Conceptualizing children with rages as having mania or bipolar disorder was not consistent with our observations. Few hospitalized children were observed in an episode of mania; however, we did see children with severe language-processing problems.

Multidisciplinary treatment was partially successful for most children, but children continued to need many services and polypharmacy. Successful parenting was necessary but rarely sufficient in and of itself to manage children with rage behaviors. Some children required readmission and a very small percentage needed residential placement after discharge. For a condition that is as common and disabling to children as rage outbursts, a more consistently successful series of options is sorely needed.

Drugs Mentioned in This Article
Diphenhydramine HCl (Benadryl, others)
Divalproex (Epival, Depakote)
Lithium (Eskalith, Lithane, Lithobid)
Risperidone (Risperdal)

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3. Budman C, Bruun RD, Park KS, et al. Explosive outbursts in children with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry. 2000;39:1270-1276.
4. Campbell M, Gonzalez NM, Silva RR. The pharmacologic treatment of conduct disorders and rage outbursts. Psychiatr Clin North Am. 1992;15:69-85. 
5. Connor D, McLaughlin TJ. Aggression and diagnosis in psychiatrically referred children. Child Psychiatry Hum Dev. 2006;37:1-14.
6. Smith-Myles B, Southwick J. Asperger Syndrome and Difficult Moments: Practical Solutions for Tantrums, Rage, and Meltdowns. Shawnee Mission, KS: Autism Asperger Publishing; 2005.
7. Leibenluft E, Charney DS, Towbin KE, et al. Defining clinical phenotypes of juvenile mania. Am J Psychiatry. 2003;160:430-437.
8. Carlson G, Potegal M, Margulies D, et al. Rages: What are they? Who has them? J Child Adolesc Psychopharmacol. In press.
9. Potegal M, Carlson GA, Margulies D, et al. The behavioral organization, temporal characteristics, and diagnostic concomitants of rage outbursts in child psychiatry inpatients. Curr Psychiatry Rep. 2009;11: 127-133.
10. Potegal M, Davidson RJ. Temper tantrums in young children, 1: behavioral composition. J Dev Behav Pediatr. 2003;24:140-147.
11. Potegal M, Kosorok MR, Davidson RJ. Temper tantrums in young children, 2: tantrum duration and temporal organization. J Dev Behav Pediatr. 2003;24: 148-154.
12. Belden AC, Thomson NR, Luby JL. Temper tanÂ­trums in healthy versus depressed and disruptive preschoolers: defining tantrum behaviors associated with clinical problems. J Pediatr. 2008;152:117-122.
13. Cohen N. Unsuspected language impairments in psychiatrically disturbed children: developmental issues and associated conditions. In: Beitchman JH, Cohen NJ, Konstantareas MM, Tannock R, eds. Language, Learning, and Behavior Disorders: Developmental, Biological, and Clinical Perspectives. New York: Cambridge University Press; 1996:105-127. 
14. Carlson GA. Who are the children with severe mood dysregulation, a.k.a. “rages”? Am J Psychiatry. 2007;164:1140-1142.
15. Pliszka SR, Crismon ML, Hughes CW, et al; Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention Deficit Hyperactivity Disorder. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child Adolesc Psychiatry. 2006;45:642-657.
16. Galanter CA, Pagar DL, Davies M, et al. ADHD and manic symptoms: diagnostic and treatment implications. Clin Neurosci Res. 2005;5:283-294.
17. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.
18. Waxmonsky J, Pelham WE, Gnagy E, et al. The efficacy and tolerability of methylphenidate and behavior modification in children with attention-deficit/hyperactivity disorder and severe mood dysregulation. J Child Adolesc Psychopharmacol. 2008;18:573-588.
19. Dickstein DP, Towbin KE, Van Der Veen JW, et al. Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation. 
J Child Adolesc Psychopharmacol. 2009;19:61-73. 
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21. Patterson GR. Families. Champaign, IL: Research Press; 1971.
22. Carlson G, Potegal M, Margulies D, et al. Liquid risperidone in the treatment of rages in psychiatrically hospitalized children with possible bipolar disorder. Bipolar Disord. In press.
23. Greene RW, Ablon JS. Treating Explosive Kids: The Collaborative Problem-Solving Approach. New York: Guilford Press; 2006.
Evidence-Based References
Dickstein DP, Towbin KE, Van Der Veen JW, et al. Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation. J Child Adolesc Psychopharmacol. 2009;19:61-73.
Waxmonsky J, Pelham WE, Gnagy E, et al. The efficacy and tolerability of methylphenidate and behavior modification in children with attention-deficit/hyperactivity disorder and severe mood dysregulation. 
J Child Adolesc Psychopharmacol. 2008;18:573-
588.  â


Rages are part of a syndrome of severe mood dysregulation, which is defined by markedly increased and frequent reactivity to negative emotional stimuli.

Helping Children Hospitalized for Rages

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,

 (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.

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 

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.

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.

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.

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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Treating bipolar disorder in young patients can often result in aggravation, irritability or even reactivation depending on the type of medication used. What are typical examples of medication-induced rebound and what are the implications of these types of responses in children?

Author | Gabrielle A. Carlson, MD

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