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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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.