The results show that DMI produced antidepressant-like activity in peripubertal rats. On the basis of the predictive validity of the FST, this outcome suggests that DMI should have antidepressant activity in peripubertal humans; however, the clinical data show that DMI is not efficacious in this age group. The reason for the discrepancy between the preclinical and clinical data is not known. Although the predictive validity of the FST has been rigorously evaluated in adult animals, few studies have been carried out in young rodents. Abel (1993)
found that the immobility response emerges at 21 days of age and stabilizes beginning at 26 days. Therefore, the immobility response is present in young rats. Nakamura and Tanaka (2001)
found that 63-day-old rats showed reduced immobility in the FST in response to tricyclic antidepressants, and repeated treatment with DMI in this same age group causes downregulation of β-adrenergic receptors (Deupree et al., 2007
). This age corresponds to young adulthood in humans, around 20 years of age (Spear, 2000
). To our knowledge the predictive validity of the FST has not been characterized in peripubertal rats. It is possible that the test does not have predictive validity in immature animals.
In humans, the reasons for differential efficacy of tricyclic antidepressants in childhood and adult depression are not clear. It has been suggested that the etiology of depression might be different in adolescents and adults (Kaufman et al., 2001
). Another possibility is that neural substrates on which antidepressants act are not mature during adolescence. The immaturity of these systems might not allow an adult-type response to occur. Preclinical data do show that there are developmentally related differences in the adaptive responses to repeated antidepressant administration (McCracken and Poland, 1995
; Carrey et al., 2002
). Furthermore, Moll and colleagues (2000)
found that the density of serotonergic and noradrenergic transporters display different developmental patterns. It is interesting to note that in this study the pattern of behavioral activity was not the same in the saline-treated peripubertal and adults rats. The peripubertal rats showed significantly more climbing and less swimming behavior. Thus, the fundamental neurobehavioral mechanisms underlying these behaviors might differ across age groups.
Apart from the well-known side effects profile of tricyclic antidepressants, in adolescent patients they can produce activational effects (i.e. activation syndrome), such as anxiety, hostility, agitation and irritability. It is possible that tricyclic antidepressants do have antidepressant activity in adolescents, but only at higher doses. A similar DMI dosing procedure has been found to produce comparable brain levels of DMI in juvenile and adults rats (Kozisek et al., 2007
); however, because in this study only a single dose of antidepressant was tested, it is not possible to determine whether there was a difference in sensitivity to DMI between the peripubertal and adult rats. In adolescent patients, the tricyclic antidepressant imipramine produced a far greater incidence of adverse effects compared with the selective serotonin reuptake inhibitor paroxetine (Keller et al., 2001
). If adolescents can respond but are less sensitive to DMI, the adverse effect profile might preclude the ability to administer the drug at therapeutic doses.
In conclusion, although tricyclic antidepressants have no or limited efficacy in treating depression in adolescents, the results of this study demonstrate that the tricyclic antidepressant DMI has antidepressant-like activity in peripubertal rats in the FST. A limitation of this study is that the experimental design did not include a positive control, that is, a drug that produces some type of behavioral response, but does not have antidepressant activity. Moreover, there might be some assay conditions (e.g. water depth or tank size) under which tricyclic antidepressants do not produce antidepressant activity in the FST. The discrepancy between the results of this study and the clinical data, however, indicates that the predictive validity of the FST needs to be reevaluated across different age groups.